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M/s. R L FineChem Pvt. Ltd.,
- 1 -
CHAPTER 1
EXECUTIVE SUMMARY
1.1 INTRODUCTION
1.1.1 Preamble
Amendment of the Environmental Impact Notification No. S.O. 60(E) dated 27.01.1994, issued by the MoEF, Govt. of India has made mandatory under Schedule-I of EIA notification for 30 different activities to obtain NOC (No Objection Certificate) from the State Pollution Control Board and Environmental Clearance from the Ministry of Environment & Forests, Govt. of India. This amendment to the EIA Notification is effective from 14.09.2006. It is in this context that all such activities need to prepare Rapid Environmental Impact Assessment (REIA) report. The proposed project comes within the interstate boundary of 5 KM due to which this industry falls under category A which necessitate the EC clearance from MOEF as per the above said notification. M/s. R L Finechem Pvt. Ltd., HIG;#2000, Ray House; Near Yelahanka New Town Police Station; Yelahanka; Bangalore-560 064, intends to establish an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. The APIs proposed to be manufactured are provided under section 1.1.2 (Project at Glance)
Sl. No.
APIs Production capacity (kg/month)
Nature/ Type of product
1 Amtriptyline hydrochloride 10,000
All products are API’s
2 Imipramine HCl/Desipramine HCl 1,150
3 Cyproheptadine HCl 700
4 Pitofenone HCl 700
5 Pyrimethamine 600
6 Cyclobenzaprine HCl 1,150
7 Clomipramine HCl 600
8 Chlorpromazine HCl 1,500
9 Doxylamine Succinate 1,400
10 Orphenadrine Citrate/ HCl 4,000
11 Trimipramine Maleate/ Mesylate 500
12 Flupentixol HCl 40
13 Melitracen HCl 300
14 Carbinoxamine Maleate 700
15 Opipramol HCl 400
16 Sulfadoxine 2,400
M/s. R L FineChem Pvt. Ltd.,
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17 Doxepin HCl 280
18 Nitrazepam 240
19 Dothiepin HCl 1,200
20 Bromazepam 60
21 Flunarazine HCl 430
22 Cinnarazine 2,500
23 Clonazepam 130
24 Lorazepam 130
25 Duloxetine HCl 300
26 Dapoxetine HCl 50
27 Desvenlafaxine HCl 400
28 Trihexyphenadyl HCl 300
29 Tramadol HCl 2,500
30 Sulfamethoxy Pyrazine HCl 500
31 Alimemazine Tartarate 200
32 Alprazolam 110
33 Diazepam 120
34 Buclazine HCl 400
35 Meclazine HCl 400
36 Carbamezapine 2,000
TOTAL 38,390
Sl.No. Details
1 Project Establishment of Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity – “M/s. R L Finechem Pvt. Ltd.,”
2 Project developers M/s. R L Finechem Pvt. Ltd., HIG;#2000, Ray House; Near Yelahanka New Town Police Station; Yelahanka; Bangalore-560 064
3 Location of the site
Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka.
4 Constitution of the Organization
Private Limited Company
5 Raw materials Details of the raw materials required by the industry is appended in Section 3.6.1, Chapter 3 of this report.
6 Product/s proposed to be manufactured with production capacities? #
The following APIs are proposed to be manufactured
Sl. No.
APIs Production capacity
(kg/month)
Production capacity
(kg/annum)
1 Amtriptyline 10,000 1,20,000
1.1.2 PROJECT AT GLANCE
M/s. R L FineChem Pvt. Ltd.,
- 3 -
hydrochloride
2 Imipramine HCl/Desipramine HCl
1,150 13,800
3 Cyproheptadine HCl 700 8,400
4 Pitofenone HCl 700 8,400
5 Pyrimethamine 600 7,200
6 Cyclobenzaprine HCl 1,150 13,800
7 Clomipramine HCl 600 7,200
8 Chlorpromazine HCl 1,500 18,000
9 Doxylamine Succinate 1,400 16,800
10 Orphenadrine Citrate/ HCl
4,000 48,000
11 Trimipramine Maleate/ Mesylate
500 6,000
12 Flupentixol HCl 40 480
13 Melitracen HCl 300 3,600
14 Carbinoxamine Maleate 700 8,400
15 Opipramol HCl 400 4,800
16 Sulfadoxine 2,400 28,800
17 Doxepin HCl 280 3,360
18 Nitrazepam 240 2,880
19 Dothiepin HCl 1,200 14,400
20 Bromazepam 60 720
21 Flunarazine HCl 430 5,160
22 Cinnarazine 2,500 30,000
23 Clonazepam 130 1,560
24 Lorazepam 130 1,560
25 Duloxetine HCl 300 3,600
26 Dapoxetine HCl 50 600
27 Desvenlafaxine HCl 400 4,800
28 Trihexyphenadyl HCl 300 3,600
29 Tramadol HCl 2,500 30,000
30 Sulfamethoxy Pyrazine HCl
500 6,000
31 Alimemazine Tartarate 200 2,400
32 Alprazolam 110 1,320
33 Diazepam 120 1,440
34 Buclazine HCl 400 4,800
35 Meclazine HCl 400 4,800
36 Carbamezapine 2,000 24,000
Total 38,390 4,60,680
7 Project cost? Sl. no.
Cost of ` (Crores)
M/s. R L FineChem Pvt. Ltd.,
- 4 -
1 Land 2.5
2 Construction 6.7
3 Proposed investment on Plant and machinery
21
4 Environment Management Budget 3
TOTAL 33.2
Rupees Thirty Three Crores & Two Lakhs Only
8 Total man power requirement during construction
phase occupancy
phase
Construction phase: 50 people during peak construction period. Occupancy/Operational phase: 110 employees.
9 Proposed trees to be planted?
Tress proposed to be planted – 300
10 Species of trees to be planted?
Araka, Silver Oak, Wild Badam, Mango, Neem trees, Michelia champaca, Butea monosperma, Pongamia pinnata, Bauhinia purpurea, Cassia fistula, Alstonia scholaris, and several native species
11 Rain water harvesting tank details?
114 KL capacity
12 Groundwater recharging pits details?
1.2 m dia x 2.5 m deep spaced at 10 m center to center all along the storm water drain.
13 Elevation of the project site with respect to MSL?
686 m above MSL; Latitude: 13°42'23.74"N; Longitude: 77°30'11.96"E
14 Total area of the project?
24,290 SQM (about 6 Acres)
15 Hydrology and hydrogeology?
Gollapuram Lake at a distance of about 3.5 km towards North East direction, Kudumaldkunta Lake at a distance of about 1 km towards South West direction, Yerrahalli Lake at a distance of about 2.5 km towards South direction, Yerrahalli Lake at a distance of about 2.5 km towards South direction, Gaudasandra Lake at a distance of about 4 km towards South East direction, Thumakunta Lake at a distance of about 2 km towards North direction, Penner River at a distance of about 2.5 km towards West direction, Melya Lake at a distance of about 5 km towards East direction.
16 Ground water quality?
Potabilty of water has to be tested.
17 Noise levels? Noise levels are to be tested.
M/s. R L FineChem Pvt. Ltd.,
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18 Facilities provided for the workers during construction phase at site?
1. Adequate potable drinking water supply 2. Septic tank and soak pit facility for treating wastewater generated from the workers.
1.1.3 Summary of water, wastewater, air & solid waste details
Sl. No.
Particulars Details
A Water, wastewater details
1 Water supply sources Bore well water supply
2 Total water requirement 186.050 KLD
3 Total wastewater generated
72.955 KLD
4 Treatment/Disposal details
Effluent Treatment Plant (ETP) with Multiple Effect Evaporator (MEE) followed by RO Filtration.
B Air pollution details
1 Sources of air pollution Process sections, Boiler, DG set
2 Air pollution control units provided
* Packed column scrubbers for process sections with Chimney height of 5 m above RL. * DG set stack height as per the stack height calculation for 500 KVA is 7 m above RL. * For agro based fuel boiler for 3 Tons stack height of 30.5 m above RL and with Mechanical dust collector. * Thermic Fluid Heater (TFH) of stack
Briquette Fired- 1 no with chimney height 30.5 m AGL
Furnace Oil Fired- 1 no with chimney height 13 m AGL
Furnace Oil Fired- 1 no with chimney height 13 m AGL
Furnace Oil Fired- 1 no with chimney height 13 m AGL
C Solid/Hazardous wastes
1 Source of solid waste Domestic sources and Manufacturing process.
2 Total quantity of solid waste generated
Domestic solid waste – 6,600 kg/annum
M/s. R L FineChem Pvt. Ltd.,
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Hazardous solid waste
Sl. no
Hazardous waste Quantity kg/annum
1 Residue from the manufacturing process – (solvent recovery)
55,200
2 Spent Carbon 25,464
3 Waste oil generation from DG set
200 L
4 Inorganic salt from MEE.
85,140
3 Treatment/Disposal of solid wastes
* The domestic wastes are segregated at source and collected in bins. The organic portion of the solid wastes will be composted and recyclable portion will be disposed to the recycler for scientific recycling. * The disposal optioclingns for various types of generated hazardous waste handling and management is detailed in Chapter 3, Section 3.9.5 of this report.
1.1.4 Water requirement and wastewater treatment and discharge details
i) QUANTITY OF WATER REQUIRED AND WASTEWATER GENERATED The total quantity of water requirement for the industry is about 186.050 KLD. The break-up of the consumption of water is as presented in table below.
Water consumption and discharge
Water consumed for Consumption (LPD)
Discharge (LPD)
(a) Domestic (toilet, canteen etc.) 4,950 4,455
(b) Gardening/Landscape development
5,000 -
(c) Industrial purpose 1,76,100 68,500
1 Process
DM plant and its rejects 20,400 or say 20,500+2,000=22,500
22,459 (from process) + 2,000
(DM reject)=24,459 or say 25,500
2 Washing/Cleaning 29,810 or say 30,000 30,000
M/s. R L FineChem Pvt. Ltd.,
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3 Softener/rejects 20,000 2,000 (blow-down) Boiler feed for 3 MT boiler 18,000
4 Cooling tower – 5 nos. 75,600 (make-up water)
1,000 (bleed off)
5 Scrubber – 4 no. 5,000 5,000
6 R&D 5,000 5,000
Total 1,86,050 LPD or say 186.050 KLD
72,955 LPD or say 72.955
KLD Note:
LPD = L/day; KLD = kilo liter/day The excess quantity of process effluent generated is due to the reactions taking
place during the manufacturing process. ii) WASTEWATER TREATMENT AND DISPOSAL DETAILS
The treatment methods and the final disposal of each type of wastewater generated is appended in the table below
Sewage/wastewater treatment and discharge
Sewage/effluent generated from
Treatment provided Final disposal point
(a) Domestic Sewage is mixed and treated along with Low strength Effluent treatment plant
Recycle and on land irrigation
(b) Industrial Full fledged ETP with collection tanks of 10 KL capacity (3 no.s) are proposed to be provided.
Industrial effluent is proposed to be treated in Effluent Treatment Plant (ETP) with Multiple Effective Evaporator (MEE) followed by RO fitration for treatment, reuse and disposal.
The raw materials required for the manufacture of APIs are appended in the table 1 below. Raw materials as listed will be procured as per the production requirement.
Table 1: Raw materials requirement
Sl. No.
Product Raw materials Quantity required Solvents required after recycling
kg/annum kg/batch kg/month kg/annum
1 Amtriptyline THF 40 1360 16320
1.1.5 RAW MATERIALS
M/s. R L FineChem Pvt. Ltd.,
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hydrochloride Dibenzo suberone 208 7072 84864
Toluene 2200 74800 897600 163200
Water 1600 54400 652800
Mg 24 816 9792
Dimethylamino propyl chloride
120 4080 48960
Con Hcl acid 110 3740 44880
N-Butanol 1000 34000 408000 40800
HCl gas 36 1224 14688
Acetone 1800 61200 734400 163200
NaOH 80 2720 32640
H2O2 (20%) 80 2720 32640
Carbon 20 680 8160
2 Imipramine HCl/Desipram
ine HCl
Imino Dibenzyl 195 780 9360
Dimethylamino Propyl Chloride
120 480 5760
Sodamide 39 156 1872
Toluene 1000 4000 48000 4800
Water 600 2400 28800
Methanol Hcl 110 440 5280
Acetone 800 3200 38400 4800
Carbon 10 40 480
3 Cyproheptadine HCl
THF 25 75 900
Dibenzo Suberenone
206 618 7416
N-Methylchloro Piperidine
133 399 4788
Toluene 2600 7800 93600 7200
Water 500 1500 18000
Methanol 600 1800 21600 3600
Con. HCl 110 330 3960
IPA 1500 4500 54000 9000
Carbon 15 45 540
Magnesium 24 72 864
4 Pitofenone HCl
Potassium bicarbonate
100 200 2400
Methyl ester intermediate
256 512 6144
Chloro ethyl piperidine
147 294 3528
Toluene 1000 2000 24000 2400
Water 600 1200 14400
Methanol Hcl 110 220 2640
Acetone 1000 2000 24000 3600
M/s. R L FineChem Pvt. Ltd.,
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Carbon 10 20 240
5 Pyrimethamine
PCBC 150 450 5400
Ester 116 348 4176
Toluene 750 2250 27000 3600
Water 1000 3000 36000
MEG 60 180 2160
Methanol 1200 3600 43200 4500
Guanidine 60 180 2160
Carbon 10 30 360
6 Cyclobenzaprine HCl
Dimethylamino Propyl Chloride
120 360 4320
Dibenzo Suberenone
206 618 7416
Toluene 2500 7500 90000 9000
Water 600 1800 21600
Con. Hcl 110 330 3960
Acetone 1000 3000 36000 6300
Mg 24 72 864
Carbon 10 30 360
7 Clomipramine HCl
3-Chlorolmino Dibenzyl
230 460 5520
Dimethylamino Propyl Chloride
120 240 2880
Sodamide 39 78 936
Toluene 1000 2000 24000 2400
Water 600 1200 14400
Methanol Hcl 110 220 2640
Acetone 800 1600 19200 2400
Carbon 10 20 240
8 Chlorpromazine HCl
KOH 59 295 3540
2-Chloro pheno thiazine
233 1165 13980
Toluene 1000 5000 60000 6000
Water 600 3000 36000
Dimethylamino Propyl Chloride
120 600 7200
Acetone 1000 5000 60000 12000
Methanol Hcl 100 500 6000
Carbon 10 50 600
9 Doxylamine Succinate
2-Acetyl pyridine 120 600 7200
Chloro Benzene 112 560 6720
Diethylamino ethyl chloride
107 535 6420
Water 1200 6000 72000
Toluene 1200 6000 72000 9000
M/s. R L FineChem Pvt. Ltd.,
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THF 30 150 1800
NaOH 40 200 2400
Carbon 15 75 900
Mg 24 120 1440
Succinic acid 110 550 6600
Acetone 1000 5000 60000 10500
10 Orphenadrine Citrate/ HCl
2-methyl Benzo phenone
215 2150 25800
NaOH 40 400 4800
Dimethylamino Ehtanol
90 900 10800
Toluene 1000 10000 120000 12000
Citric acid 180 1800 21600
Water 600 6000 72000
Acetone 1500 15000 180000 30000
Carbon 10 100 1200
11 Trimipramine Maleate/ Mesylate
Sodamide 39 78 936
Imino Dibenzyl 195 390 4680
Toluene 1000 2000 24000 2400
Water 600 1200 14400
Dimethylamino Methylpropyl chloride
135 270 3240
Acetone/EA 800 1600 19200 2400
Maleic acid 110 220 2640
Carbon 10 20 240
12 Flupentixol HCl
THF 10 10 120
Trifluorothioxanthone
28 28 336
Mg 2.5 2.5 30
Toluene 700 700 8400 840
Water 200 200 2400
Acetone 300 300 3600 420
Carbon 5 5 60
Con Hcl acid 21 21 252
Piperizino ehtanol intermediate
20 20 240
13 Melitracen HCl
THF 30 30 360
Dimethyl anthrone
220 220 2640
Dimethylamino propyl chloride
120 120 1440
Toluene 2200 2200 26400 4200
Water 600 600 7200
M/s. R L FineChem Pvt. Ltd.,
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Mg 24 24 288
Acetone 1000 1000 12000 2100
Carbon 15 15 180
Con Hcl acid 100 100 1200
14 Carbinoxamine Maleate
Pyridine Benz Hydrol
220 440 5280
NaOH 40 80 960
Dimethylamino Ethyl chloride
107 214 2568
Toluene 1000 2000 24000 2400
Maleic acid 116 232 2784
Water 600 1200 14400
Acetone 1000 2000 24000 4200
Carbon 10 20 240
15 Opipramol HCl
Imino stilbene 96 96 1152
NaOH 40 40 480
Bromochloro Propane
78 78 936
Toluene 2000 2000 24000 2400
Piperizinoethanol 65 65 780
Water 1200 1200 14400
Acetone 1200 1200 14400 2400
Carbon 10 10 120
HCl 36 36 432
16 Sulfadoxine P-Amino sulfonamide
172 1376 16512
Methoxy dichloro pyrimidine
179 1432 17184
Water 2000 16000 192000
Toluene 1500 12000 144000 24000
NaOH 40 320 3840
Methanol 2000 16000 192000 19200
Sodium methoxide
54 432 5184
Carbon 15 120 1440
17 Doxepin HCl Mg 24 24 288
Dimethylamino propyl chloride
120 120 1440
Toluene 2500 2500 30000 3000
Doxiepinone 210 210 2520
THF 20 20 240
Water 600 600 7200
Con Hcl 110 110 1320
Acetone 1000 1000 12000 2100
Carbon 10 10 120
M/s. R L FineChem Pvt. Ltd.,
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18 Nitrazepam Chloroacetyl chloride
112 112 1344
2-amino 5-nitro benzophenone
242 242 2904
Toluene 1000 1000 12000 1800
Ammonia 51 51 612
Carbon 10 10 120
Methanol 1250 1250 15000 3000
19 Dothiepin HCl Mg 24 96 1152
Dimethylamino propyl chloride
120 480 5760
Toluene 2500 10000 120000 12000
Dothiepinone 226 904 10848
THF 20 80 960
Water 600 2400 28800
Con Hcl 110 440 5280
Acetone 1000 4000 48000 8400
Carbon 10 40 480
20 Bromazepam Chloroacetyl chloride
30 30 360
2-amino 5-bromo benzoyl pyridine
70 70 840
Toluene 600 600 7200 1200
Ammonia 14 14 168
Carbon 5 5 60
Methanol 800 800 9600 2400
21 Flunarazine HCl
Difluro Benzhydrol
220 220 2640
Piperizine 86 86 1032
Toluene 1500 1500 18000 2400
HCl 110 110 1320
NaOH 40 40 480
Water 1425 1425 17100
Cinnamyl alcohol 134 134 1608
Acetone/IPA 2000 2000 24000 4200
Carbon 15 15 180
Methanol 2000 2000 24000 3600
HCl Gas 73 73 876
22 Cinnarazine Benzhydrol 184 1288 15456
Piperizine 86 602 7224
Toluene 1500 10500 126000 16800
HCl 110 770 9240
NaOH 40 280 3360
Water 1425 9975 119700
Cinnamyl alcohol 134 938 11256
M/s. R L FineChem Pvt. Ltd.,
- 13 -
Acetone/IPA 2000 14000 168000 29400
Carbon 15 105 1260
Methanol 2000 14000 168000 25200
23 Clonazepam Chloroacetyl chloride
56 56 672
2-amino 5-nitro chloro benzophenone
138 138 1656
Toluene 600 600 7200 1200
Ammonia 25 25 300
Carbon 5 5 60
Methanol 800 800 9600 2400
24 Lorazepam Chloroacetyl chloride
56 56 672
2-amino dichloro benzophenone
133 133 1596
Water 600 600 7200
Toluene 1200 1200 14400 2400
NaOH 60 60 720
Hydroxyl amine 16 16 192
Carbon 10 10 120
Methanol 1300 1300 15600 3000
Acetic anhydride 45 45 540
25 Duloxetine HCl
Formaldehyde 30 30 360
2-Acetyl thiophene
126 126 1512
Water 1800 1800 21600
Toluene 1800 1800 21600 3600
Dimethyl amine 45 45 540
Acetone 1000 1000 12000 2400
HCl 36 36 432
Carbon 10 10 120
H2 gas
Methanol 1000 1000 12000 2400
Ni cat 2 2 24
DMSO 600 600 7200 600
Fluro naphthalene
145 145 1740
KOH 112 112 1344
26 Dapoxetine HCl
3-Chloro propio phenone
34 34 408
Methanol 300 300 3600 600
Water 900 900 10800
Ni 1 1 12
Toluene 500 500 6000 600
M/s. R L FineChem Pvt. Ltd.,
- 14 -
Alfa Napthol 30 30 360
Methane sulfonic acid
19 19 228
Carbon 10 10 120
Dimethyl amine 9 9 108
HCl 7 7 84
KOH 11 11 132
Acetone 500 500 6000 1800
27 Desvenlafaxine HCl
Venalafaxine hydrochloride
313 313 3756
Toluene 2000 2000 24000 1800
NaOH 40 40 480
Acetone 1000 1000 12000 2400
Succinic acid 112 112 1344
Water 1018 1018 12216
Carbon 15 15 180
28 Trihexyphenadyl HCl
Acetophenone 120 120 1440
Formaldehyde 30 30 360
Piperidine 85 85 1020
Water 1200 1200 14400
Toluene 1100 1100 13200 1200
THF 30 30 360
Cyclohexyl chloride
118 118 1416
Carbon 15 15 180
Mg 24 24 288
HCL 36 36 432
Acetone 1000 1000 12000 2100
29 Tramadol HCl Cyclo hexanone 98 980 11760
Formaldehyde 30 300 3600
Dimethylamine 45 450 5400
Toluene 1100 11000 132000 12000
THF 30 300 3600
Water 1200 12000 144000
Metabromo methoxy anisole
187 1870 22440
Mg 24 240 2880
Carbon 15 150 1800
Acetone 1000 10000 120000 21000
HCl 36 360 4320
30 Sulfamethoxy Pyrazine HCl
P-amino sulfonamide
172 344 4128
DMF 1500 3000 36000 2400
Dichloro pyazine 148 296 3552
KHCO3 100 200 12000
M/s. R L FineChem Pvt. Ltd.,
- 15 -
Potassium methoxide
70 140 1680
Water 1000 2000 24000
Carbon 15 30 360
Methanol 2000 4000 48000 8400
31 Alimemazine Tartarate
Phenothiazine 199 199 2388
Sodium methoxide
54 54 648
THF 800 800 9600 1200
Dimethylamino propyl chloride
135 135 1620
IPA 600 600 7200 1200
Carbon
L-Tartaric acid 50 50 600
Hydrogen peroxide20% solu
100 100 1200
HCl 11 11 132
Acetone 1600 1600 19200 4800
32 Alprazolam Chloroacetyl chloride
56 56 672
2-amino 5-chloro benzophenone
115 115 1380
Toluene 600 600 7200 1200
Ammonia 25 25 300
Carbon 5 5 60
Methanol 800 800 9600 2400
33 Diazepam Chloroacetyl chloride
56 56 672
2-methyklamino 5-chloro benzophenone
123 123 1476
Ammonia 25 25 300
Toluene 600 600 7200 1200
Methanol 800 800 9600 1800
Carbon 5 5 60
34 Buclazine HCl P-Chloro benzhydryl piperizine
286 286 3432
P-Tert butyl benzyl chloride
182 182 2184
Water 600 600 7200
Toluene 1000 1000 12000 1200
NaOH 40 40 480
Acetone 800 800 9600 1500
HCl 70 70 840
M/s. R L FineChem Pvt. Ltd.,
- 16 -
Carbon 10 10 120
35 Meclazine HCl
P-Chloro benzhydryl piperizine
286 286 3432
Meta metyl benzyl chloride
140 140 1680
Water 600 600 7200
Toluene 1000 1000 12000 1200
NaOH 40 40 480
Acetone 800 800 9600 1500
HCl 70 70 840
Carbon 10 10 120
36 Carbamezapine
Ammonia 40 320 3840
IPA 2000 16000 192000 24000
Iminostibene Carconyl chloride
255 2040 24480
Water 700 5600 67200
1.1.6 Solvent recovery and recycling
Various solvents are proposed to be used during the manufacturing process. The solvents proposed to be recovered and recycled during the process of recovering the solvent of such product are detailed in table 1.1 below.
Table: 1.1 Solvent recovery
Sl.No
Product Raw materials Quantity (kg/annum)
Recovered and recycled
Lost
1 Amtriptyline hydrochloride Stage 1
Toluene 775200
122400
Acetone 326400 81600
Stage 2 Toulene 367200 40800
Acetone 244800 81600
N-Butanol 367200 40800
2 Imipramine
HCl/Desipramine HCl
Toluene 43200 4800
Acetone 33600 4800
3 Cyproheptadine HCl Toluene 86400 7200
Methanol 18000 3600
IPA 45000 9000
4 Pitofenone HCl Toluene 21600 2400
Acetone 20400 3600
5 Pyrimethamine Toluene 23400 3600
M/s. R L FineChem Pvt. Ltd.,
- 17 -
Methanol 38700 4500
6 Cyclobenzaprine HCl Toluene 81000 9000
Acetone 29700 6300
7 Clomipramine HCl Toluene 21600 2400
Acetone 16800 2400
8 Chlorpromazine HCl Toluene 54000 6000
Acetone 48000 12000
9 Doxylamine Succinate Toluene 63000 9000
Acetone 49500 10500
10 Orphenadrine Citrate/ HCl
Toluene 108000 12000
Acetone 150000 30000
11 Trimipramine Maleate/ Mesylate
Toluene 21600 2400
Acetone/EA 16800 2400
12 Flupentixol HCl Toluene 7560 840
Acetone 3180 420
13 Melitracen HCl Toluene 22200 4200
Acetone 9900 2100
14 Carbinoxamine Maleate
Toluene 21600 2400
Acetone 19800 4200
15 Opipramol HCl Toluene 21600 2400
Acetone 12000 2400
16 Sulfadoxine Toluene 120000 24000
Methanol 172800 19200
17 Doxepin HCl Toluene 27000 3000
Acetone 9900 2100
18 Nitrazepam Toluene 10200 1800
Methanol 12000 3000
19 Dothiepin HCl Toluene 108000 12000
Acetone 39600 8400
20 Bromazepam Toluene 6000 1200
Methanol 7200 2400
21 Flunarazine HCl Toluene 15600 2400
Acetone/IPA 19800 4200
Methanol 20400 3600
22 Cinnarazine Toluene 109200 16800
Acetone/IPA 138600 29400
Methanol 142800 25200
23 Clonazepam Toluene 6000 1200
Methanol 7200 2400
24 Lorazepam Toluene 12000 2400
Methanol 12600 3000
25 Duloxetine HCl Toluene 18000 3600
Acetone 9600 2400
Methanol 9600 2400
M/s. R L FineChem Pvt. Ltd.,
- 18 -
DMSO 6600 600
26 Dapoxetine HCl Methanol 3000 600
Toluene 5400 600
Acetone 4200 1800
27 Desvenlafaxine HCl Toluene 22200 1800
Acetone 9600 2400
28 Trihexyphenadyl HCl Toluene 12000 1200
Acetone 9900 2100
29 Tramadol HCl Toluene 120000 12000
Acetone 99000 21000
30 Sulfamethoxy Pyrazine HCl
DMF 33600 2400
Methanol 39600 8400
31 Alimemazine Tartarate
THF 8400 1200
IPA 6000 1200
Acetone 14400 4800
32 Alprazolam Toluene 6000 1200
Methanol 7200 2400
33 Diazepam Toluene 6000 1200
Methanol 7800 1800
34 Buclazine HCl Toluene 10800 1200
Acetone 8100 1500
35 Meclazine HCl Toluene 10800 1200
Acetone 8100 1500
36 Carbamezapine IPA 168000 24000
Note: * The solvent lost during the process of solvent distillation is mainly due to organic thermal disintegration and in form of residue left behind from the bottom un-distilled product. Evaporation loss is minimized by the passage of chilled brine solution and chilled water through the double condenser.
1.1.7 Air pollution details
The major air pollution sources from the industry are DG set, boiler and process sections. These sources are provided with stacks of adequate height so as to disperse the emanating flue gases containing SPM, oxides of sulfur and nitrogen without affecting the ground level concentrations and packed column scrubbers are proposed to the process sections with adequate stack height as per the regulatory requirements. The sources of air pollution, type of fuel used, fuel consumption and chimney heights for each of the air pollution sources of the proposed project are indicated in the following table 1.2.
M/s. R L FineChem Pvt. Ltd.,
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Table: 1.2 Air pollution sources, fuel consumption and chimney height details
SI. no.
Stack attached to
Fuel used Fuel consumption
Number of
stacks
Stack height
Air pollution control unit
Predicted emissions
1 Process section
- - 1 5 m ARL
Packed column scrubber – 1 no.
Acid mist/ VOCs
2 R&D - - 1 3 m ARL
Packed column scrubber – 1 no.
-
3 Steam boiler – 3Ton capacity – 2 no.s
Briquette 300 L/hr 1 30.5 m AGL
Stack SO2, NOx, SPM
4 D.G. set – 500 kVA – 1 no.
HSD 117.5 L/hr 1 7 m AGL
Stack SOx, NOx, SPM
5 Thermic Fluid Heater
Briquette Fired- 1 no
75 Kgs/hr 1 30.5 m AGL
Stack SOx, NOx, SPM
Furnace Oil Fired- 1 no
25 L/Hr 1 13 m AGL
Stack SOx, NOx, SPM
Furnace Oil Fired- 1 no
13 L/Hr 1 13 m AGL
Stack SOx, NOx, SPM
Furnace Oil Fired- 1 no
6 L/Hr 13 m AGL
Stack SOx, NOx, SPM
* Stack height calculation for DGs Formula adopted for stack height calculation
H = 14(Q)0.3
Where, H is stack height Above Ground Level Q is sulfur content in exhaust in kg/hr (As per Handbook on Environmental Legislations and Technologies) Fuel consumption = 117.5 L/hr = 0.1175 m3/hr Sulfur content in HSD = 0.25% Density of sulfur = 2046 kg/m3 Therefore, Q = 0.1175 x (0.25/100) x 2046 = 0.0601 kg/hr
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Therefore, height of chimney = 14 (0.0601)0.3 = 6.02 m AGL Or say 7 m AGL Therefore it is proposed to provide 1 stack of height 7 m AGL for one diesel generator of 500 kVA capacity. ** Stack height calculation for boiler Formula adopted for stack height calculation
H = 74(Q)0.27
Where, H is stack height Above Ground Level Q is ash produced in tons/hr Type of fuel used – briquettes, husk, wood Capacity of boiler = 3 MT Fuel consumption = 0.3 tons/hr For agro based fuel ash produced per ton of fuel burnt = 6.5 kg (As per Handbook on Environmental Legislations and Technologies) Therefore, Q = 1.95 kg/hr = 0.00195 tons/hr Therefore, height of chimney = 74 (0.00195)0.27 = 13.72m AGL Or say 30.5 m AGL However it is proposed to install a stack of height 30.5 m AGL with Mechanical dust collector to collect the fly ash.
1.1.8 Noise pollution details
The major source of noise pollution in the industry is the DG set for which acoustic enclosure is proposed. Also ambient noise levels will be ensured within the ambient standards by inbuilt design of mechanical equipment and building apart from vegetation (tree plantations) along the periphery and at various locations within the industry premises.
1.1.9 Solid waste details
The quantity of solid waste generated from the proposed industry is detailed in the following table 1.3.
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Table: 1.3 Solid waste generation during the operation phase
Total no. of employees 110
Assuming per capita solid waste generation rate as 0.25 kg/capita/day
Quantity of solid waste generated 27.5 kg/day
Organic solid waste : 60 % of the total waste 16.5 kg/day
Inorganic solid waste : 40 % of the total waste 11 kg/day
Disposal of domestic solid waste The domestic wastes are segregated at source, collected in bins and composted.
1.1.10 Hazardous raw materials used in the manufacturing process
The following raw materials used during the process of manufacture of APIs are hazardous in nature according to Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II in the table 1.4
Table: 1.4 Hazardous raw materials
Hazardous raw material Sl. No. as per Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II
Hydrochloric acid 313
N- Butanol 412
Sodium Hydroxide 571
Magnesium 350
Potassium hydroxide 522
Methanol 377
Ammonia 31
Toulene 628
Iso Propyl Alcohol 334
Formaldehyde 295
Dimethyl Amine 215
Acetone 4
Chloroacetyl Chloride 124
Acetic anhydride 45
Cyclohexanone 161
Hydrogen peroxide 318
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1.1.11 Hazardous waste generation and its management during the manufacturing process
The hazardous wastes generated during the process of manufacture of different APIs are stored at hazardous waste storage area and sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. The quantities of hazardous waste generated from various processes are shown in the following tables 1.5.
1) Organic process/solvent residue and spent carbon
Table: 1.5 Quantity of process residue generation from solvent recovery and spent carbon generation from manufacturing process
Sl. No.
APIs Quantity of hazardous waste generated, kg/annum
Quantity of spent carbon, kg/annum
1 Amtriptyline hydrochloride 1st stage
9,384 9,792
2nd stage 9,384
2 Imipramine hydrochloride
1,584 576
3 Cyproheptadiene HCl 1,908 720
4 Pitofenone HCl 864 288
5 Pyrimethamine 2,016 432
6 Cyclobenzaprine HCl 936 432
7 Clomipramine HCl 744 288
8 Chlorpromazine HCl 2,280 720
9 Doxylamine Succinate
2,160 1,080
10 Orphenadrine Citrate/ HCl
5,520 1,440
11 Trimipramine Maleate/ Mesylate
840 288
12 Flupentixol HCl 96 72
13 Melitracen HCl 360 216
14 Carbinoxamine Maleate
1,128 288
15 Opipramol HCl 252 144
16 Sulfadoxine 576 1728
17 Doxepin HCl 408 144
18 Nitrazepam 516 144
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19 Dothiepin HCl 1,728 576
20 Bromazepam 264 84
21 Flunarazine HCl 552 216
22 Cinnarizine 3,024 1512
23 Clonazepam 336 84
24 Lorazepam 396 144
25 Duloxetine HCl 396 144
26 Dapoxetine HCl 96 144
27 Desvenlafaxine HCl 168 216
28 Trihexyphenadyl HCl 312 216
29 Tramadol HCl 3,480 2160
30 Sulfamethoxy Pyrazine HCl
744 432
31 Alimemazine Tartarate 1st step A
348 288
2nd step B 132
32 Alprazolam 300 84
33 Diazepam 276 84
34 Buclazine HCl 624 144
35 Meclazine HCl 588 144
36 Carbamezapine 480 -
TOTAL 55,200 25,464
Spent carbon is used during the process of manufacture of different APIs. The spent carbon will be disposed for co-incineration in cement manufacturing.
2) Others : The various hazardous waste generated from the industry is presented in table 1.6
Table: 1.6 Miscellaneous types of hazardous waste generated
Sl. No.
Particulars Quantity of hazardous waste
generated kg/annum
Disposal Options Category
1 Waste oil generation from DG set
200 L Disposed through authorized recyclers
5.1
2 Residue from solvent recovery plant
55,200 Disposed through Cement industries for co incinerations
28.1
3 Used MS drums (either reused if it cannot scrapped)
120 Disposed through authorized recyclers
33.3
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4 Used poly bags 180 Disposed through authorized recyclers
33.3
5 Inorganic salt from MEE
85,140 Disposed to TSDF for scientific landfill.
34.3
6 Spent carbon 25,464 Disposed through Cement industries for co incinerations
28.2
7 Spent organic solvent fraction from MEE stripper
205 KL/Annum Disposed through authorized solvent recyclers
28.5
The project proponents will usually identify certain basic factors while selecting the site for the project. Such factors are usually related to the titles of the property, commercial viability, location of the site, availability of raw materials and resources required etc. In addition to this the environmental setting of the proposed location is also an important factor while deciding the site for a project. All these criteria are favorable for the establishment of M/s. R L Fine Chem Pvt. Ltd., Since the project site is located at KIADB Industrial Area. The project well connected by Hindupur Gouribidanoor road at about 0.5 km SH 9. Therefore the project site is well connected by roadways. Devarapalli Railway Station is at a distance of about 3.5 km towards North direction. Hence the raw materials and the other utilities required by the industry can be easily transported. From the view point of basic infrastructural facilities required for the industry Viz. power supply, water supply and sanitation facilities will not be a problem as the industry is coming up in a designated industrial area. As far as the environmental setting is concerned the proposed project site is located at KIADB industrial area, surroundings have villages, individual residential units, few commercial establishments. The general topographical features of the area reveal that the proposed project site and its surroundings is generally a plain land with slight undulations. This plot is located at an elevation of about 686 m above MSL, the climatic conditions is temperate (semi arid) with moderate annual rainfall varies from 500 mm to 850 mm. Site bearings The proposed project site is surrounded by vacant plots/industrial plot in all directions.
1.1.12 Project setting
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Sl.No. Particulars Direction w.r.t. project site
1 40' road West
2 Site no 26, belong to industry
North
3 Industrial Area second phase South
4 Small scale industrial area East
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1.2. ENVIRONMENTAL IMPACTS AND MANAGEMENT PLAN
Sl. no.
Environmental components
Predicted impacts Probable source of impact Mitigation measures Remarks
1 Ambient air quality
Marginal negative impact inside the construction site premises. No negative impact outside.
Fugitive dust emissions generated during construction in the beginning followed by fabrication, erection of plant and machinery installations during later part of the project.
Carrying out the construction activities in closed manner.
Intermittent spraying of water.
Use of PPE.
Impacts are temporary (only during construction period) in nature. Also the proposed project does not involve extensive construction activities (total built-up area is 8,000 SQM); construction is more of fabrication and erection type except admin, R & D and Watch and ward buildings.
2 Noise Marginal negative impact near noise generation sources inside the premises. No significant impact on the ambient noise levels to the surrounding area.
Noise generation from construction activities and operation of construction equipments and also from the movement of vehicles carrying construction materials to and from the project site.
Use of well maintained construction equipments.
Use of PPE – ear plugs and muffs by the construction workers.
Temporary impact only during construction phase.
3 Water quality No significant impact
Discharge of sewage from housing facilities of construction workers
The sewage generated will be treated in septic tank and soak pit
Impact will be temporary. Local construction workers
will be employed.
4 Land No negative impact
Solid waste generated from housing facilities of construction workers
Wastes will be collected and composted on site. Non-compostable
-
1.2.1 Environmental management plan during construction phase
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waste will be disposed scientifically.
5 Socio-economic
Overall positive impact
Employment opportunities - -
Sl. no.
Environmental components
Predicted impacts
Probable source of impact
Mitigation measures Remarks
1 Ambient air quality
Minor negative impact.
Process of manufacture of APIs
Particulate and gaseous emissions from DG set and boiler
Manufacturing process involves closed operations in various controlled reactors.
The process area will be provided with abundant natural light and ventilation and high roofs to disperse the fumes/gases to the outside atmosphere; preventing the increase of ground level concentrations (GLC’S) as it gets dispersed.
Packed column scrubbers are proposed to neutralize and control dust and fumes from the process section.
The treated waste gases and fumes will be let out through stacks of 5 m height ARL.
The emissions from DG & boiler
DG sets will be used only during power failure.
1.2.2 Environmental management plan during operation phase
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will be let out through stacks of heights 7 m AGL and 30.5 m AGL respectively.
2 Noise Minor negative impact near noise generation sources inside the premises.
Operation of machineries during the manufacturing process.
Handling and conveying of raw materials and semi-finished components to different areas of operations
Operation of DG set.
The conveying system shall be maintained by following routine and periodic maintenance to reduce noise generation in material handling.
DG set with prebuilt acoustic enclosure as per CPCB norms will be installed in dedicated utility area, where the access will be restricted. Also the use of PPE (ear plugs) will be mandatory in this area.
Green belt at the project boundary will further act as noise barrier and help in attenuation of noise.
-
3 Water quality No significant adverse impact
Discharge of domestic sewage and industrial effluent
Domestic sewage will be mixed with industrial effluent at aeration stage and treated.
The industrial effluent is proposed to be treated in a Effluent Treatment Plant (ETP) with Multiple Effect Evaporator (MEE) followed by RO Filtration for treatment, reuse and disposal.
Water conservation measures will be encouraged.
4 Land No negative impact
Discharge of wastewater.
Storage and disposal of solid
Domestic sewage will be mixed with industrial effluent at aeration stage and treated. The industrial effluent is proposed
-
M/s. R L FineChem Pvt. Ltd.,
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wastes. to be treated in Effluent Treatment Plant (ETP) with Multiple Effect Evaporator followed by RO Filtration for treatment, reuse and disposal.
5 Socio-economic
Overall positive impact
Employment opportunities
Locally available man power will be utilized to the maximum possible extent.
-
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CHAPTER 2
INTRODUCTION OF THE PROJECT/ BACKGROUND INFORMATION
2.1 INTRODUCTION OF PROJECT PROPONENT
The M/s. R L Fine Chem Pvt. Ltd., having a registered office at M/s. R L Fine Chem Pvt. Ltd., HIG; #2000, Ray House; Near Yelahanka New Town Police Station; Yelahanka; Bangalore-560 064 proposed to establish an industry at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka.
2.2 BRIEF DESCRIPTION ABOUT THE NATURE OF THE PROJECT
The proposed industry M/s. R L Finechem Pvt. Ltd., is a Private Limited company with Shri Anjan Kumar Roy as the Director. The industry is proposed to be established at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. The main activity of the company is to manufacture Active Pharmaceutical Ingredients (API’s).
An active ingredient (AI) is the substance of a pharmaceutical drug that is biologically active. Terms in similar use include: active pharmaceutical ingredient (API) and bulk active in medicine. Some medications may contain more than one active ingredient. The traditional word for the API is pharmacon or pharmakon which originally denoted a magical substance or drug. A dosage form of a drug is traditionally composed of two things: The API, which is the
drug itself; and an excipient, which is the substance of the tablet, or the liquid the
API is suspended in, or other material that is pharmaceutically inert. Drugs are chosen
primarily for their active ingredients.
Anjan Kumar Roy is the founder of M/s R L Finechem Pvt Ltd., With a M Sc. degree
and a Diploma in Business Management; he has worked in various capacities in
reputed multinational companies for 9 years. Apart from this he is having experience
of running the pharma industry for more than 25 years. Mr. Roy is also been
recognized as an approved expert chemist in the manufacture of basic drugs by the
Drugs Controller of Karnataka. By virtue of his rich experience both technically &
commercially in running the units for more than 25 years & also supported by well
qualified & highly experienced technical force, the group is confident of the success
of the new project.
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The company already has an Active Pharmaceutical Ingredients (API) manufacturing
facility (M/s. R L Finechem I) at No. 15, Yelahanka. Now the company proposes to
obtain Environmental Clearance from SEIAA for the Active Pharmaceutical Ingredients
(API) manufacturing industry at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor,
Karnataka.
The M/s. R L Finechem Pvt. Ltd.HIG; # 2000, Ray house, near Yelahanka New Town
Police Station, Yelahanka, Bangalore – 560 064 proposes to establish an industry at
Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka.
2.3 NEED FOR THE PROJECT AND ITS IMPORTANCE TO THE COUNTRY AND/REGION
Bulk drugs have become a part of our life for sustaining many of our day-to-day activities, preventing and controlling diseases. Bulk drugs manufacturing sector in India is well established and has recorded a steady growth in the overall Indian industrial scenario. The bulk drugs and allied industries have been amongst the fastest growing segments of the Indian industry.
The Indian Pharmaceutical Industry today is in the front rank of India’s science-based industries with wide ranging capabilities in the complex field of drug manufacture and technology. It is expected to reach a level of Rs 3200 billion by 2012. It ranks very high in the third world, in terms of technology, quality and range of medicines manufactured. From simple headache pills to sophisticated antibiotics and complex cardiac compounds, almost every type of medicine is now made indigenously.
Playing a key role in promoting and sustaining development in the vital field of medicines, Indian Pharma Industry boasts of quality producers and many units approved by regulatory authorities in USA and UK. International companies associated with this sector have stimulated, assisted and spearheaded this dynamic development in the past years and helped to put India on the pharmaceutical map of the world.
India's pharmaceutical industry is the third largest in the world in terms of volume. Its rank is 14th in terms of value. India is also one of the top five active pharmaceutical ingredients (API)producers (with a share of about 6.5 per cent).
The pharmaceutical industry in India meets around 70% of the country's demand for bulk drugs, drug intermediates, chemicals, tablets, capsules, orals and injectibles. .Between September 2008 and September 2009, the total turnover of India's pharmaceuticals industry was US $21.04 billion. The domestic market was worth US $12.26 billion. This was reported by the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers. As per a report by IMS Health India, the Indian pharmaceutical market reached US $10.04 billion in size in July 2010. A highly organized sector, the Indian Pharma Industry is estimated to be worth $4.5 billion, growing at about 8 to 9 percent annually.
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The pharmaceutical industry in Karnataka contributes Rs. 350 crore in revenue to the State exchequer and provides employment for 12,000 people. Its growth rate is between 10-12 per cent as against the national pharma growth of 12-14 percent. Pharma products worth Rs. 2,000 crore are produced annually, which is 10 per cent of the national production. The exports sales are Rs.850 crore which is 8 per cent of Indian exports. International pharma majors have preferred many companies from the State. When large companies offer their services on contractual basis to global MNCs, they want to outsource drug production for the domestic market from quality small-medium manufacturers in State. Here the small-medium units ideally fit into slot as third party manufacturers and serve as major hubs for pharmaceutical outsourcing. In fact, two of Indian pharma sectors top five brands, are already outsourced from Karnataka. The units have been recognised for stringent regulatory enforcement and known to manufacture quality products. Another added advantage favoring the State is that it is emerging as an investment destination. Hence the proponents have proposed setting-up of the new pharmaceutical industry - M/s. R L Fine Chem Pvt. Ltd., at Plot no: 27-29, KIADB industrial area, Gouribidanoor, Karnataka.
2.4 DEMAND SUPPLY GAP, IMPORTS vs INDIGENOUS PRODUCTION
Indian pharmaceutical companies supply almost all the country's demand for API and nearly 70 per cent of demand for bulk drugs. The imports of pharmaceuticals are estimated at 10 to 12 percent of the total market. The major suppliers are Switzerland, China, USA, Germany, Italy, Denmark, France, and UK. Imports include raw materials and finished products. Some major pharmaceuticals which are imported include Provitamins and Vitamins, Cortisones, Hydrocortisone, Insulin, Penicillin, Osetrogen, Progesterone and other hormones, Erythromycin and other ANTIBIOTICS, Antisera & other blood fraction, and Glycosides. The imports are from Switzerland, US and Germany primarily consist of finished medicament in dosage forms for retail sales.
2.5 EXPORT POSSIBILITY
The size of the domestic pharmaceutical market is larger than export market. However, owing to the growth of global generics market, stringent price controls in the domestic market, and better margins, the export market is growing much faster than the domestic market.
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India exports pharmaceuticals to numerous countries around the world, including to the U.S., Germany, France, Russia and UK. The Indian pharmaceutical industry ranks 17th with respect to exports value of bulk actives and dosage. Exports constitute nearly 40 per cent of the production, with bulk drugs 45 per cent. According to the Pharmaceutical Export Promotion Council (Pharmexcil), the pharmaceutical exports in 2007-08 stood at US $6.68 billion against US $5.73 billion in 2006-07, recording a growth rate of 16 per cent. The industry has been clocking export growth rate, recording 18 per cent, 23 per cent and 17 per cent growth rates during 2006-07, 2005-06, and 2004-05, respectively. The overall pharmaceutical exports are estimated to increase at a CAGR of 30-32 percent and reach US $ 18.3 billion in 2010 - 11.
2.6 EMPLOYMENT GENERATION DUE TO THE PROJECT
The total direct employment potential of the proposed industry is about 110 people. However, there are indirect employment generation due to the project during the transportations, marketing & distribution etc.
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CHAPTER 3
PROJECT DESCRIPTION
3.1 TYPE OF PROJECT
The main activity of the proposed industry is manufacturing of Active Pharmaceutical Ingredients (APIs). The total production capacity 38,390 kg/month.
3.2 LOCATION OF THE PROPOSED INDUSTRY
The industry is proposed to be established at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. Google map is appended as fig 3.1.
fig 3.1: Google map showing project site Note: Latitude: 13°42'23.74"N; Longitude: 77°30'11.96"E 686 m above MSL;
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GOWRIBIDANOOR DISTRICT
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Fig 3.1: Maps showing project boundary & project site location
3.3 BASIS OF SELECTING THE PROPOSED SITE
The efficient functioning of any industry mainly depends on the availability of its basic requirements viz. raw materials, fuel, power, water, manpower etc. The industry is proposed to be established in KIADB Industrial Area, Gouribidanoor. The choice of the land confers several advantages, which are summarized below.
1. The site is well connected by roadways. 2. Water will be supplied from Borewell. 3. Power will be supplied from BESCOM. 4. Housing colonies, educational facilities, hospitals and other amenities are expected to
be developed due to proposed industrial area development. 5. No incidence of cyclones, earthquake, floods or landslides in the region.
3.3.1 Proposed environmental safeguards
1.Industrial effluent is proposed to be treated in Effluent Treatment Plant with Multiple Effective Evaporator followed by RO Filtration for treatment, reuse and disposal.
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The domestic sewage will be mixed with industrial effluent at aeration stage and treated.
Adequate measures are adopted for collection and storage of effluents generated in the Industry and also to prevent spillages and overflows. Therefore pollution in the surrounding areas is not anticipated.
2.Well-designed stacks of adequate heights are proposed for the boiler and generator for dispersion of gaseous emissions at levels as per the guidelines.
Well designed scrubbers (column – 4 no.s – one each for production and R&D) will be proposed for scrubbing the fumes emanating from the process area so that the neutralized fumes are let out into the atmosphere at a height so as to not affect GLC’s.
3.The proposed APIs manufacturing industry is coming up in a designated industrial area & and it is not an ecologically sensitive area. Therefore no adverse effects on the fragile ecosystem are anticipated.
3.4 SIZE/MAGNITUDE OF OPERATION
The industry “M/s. R L Fine Chem Pvt. Ltd.,” is a large scale industrial unit with a total capital investment of Thirty Three Crores Two Lakhs only. The total production capacity proposed is 38,390 kg/month.
3.5 MANUFACTURING PROCESS DESCRIPTION
3.5.1 Products manufactured
The following APIs are proposed to be manufactured.
Table 3.1: APIs are proposed to be manufactured
Sl. no. APIs Production capacity
kg/month kg/annum
1 Amtriptyline hydrochloride 10,000 1,20,000
2 Imipramine HCl/Desipramine HCl
1,150 13,800
3 Cyproheptadine HCl 700 8,400
4 Pitofenone HCl 700 8,400
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5 Pyrimethamine 600 7,200
6 Cyclobenzaprine HCl 1150 13,800
7 Clomipramine HCl 600 7,200
8 Chlorpromazine HCl 1500 18,000
9 Doxylamine Succinate 1400 16,800
10 Orphenadrine Citrate/ HCl 4000 48,000
11 Trimipramine Maleate/ Mesylate
500 6,000
12 Flupentixol HCl 40 480
13 Melitracen HCl 300 3,600
14 Carbinoxamine Maleate 700 8,400
15 Opipramol HCl 400 4,800
16 Sulfadoxine 2400 28,800
17 Doxepin HCl 280 3,360
18 Nitrazepam 240 2,880
19 Dothiepin HCl 1200 14,400
20 Bromazepam 60 720
21 Flunarazine HCl 430 5,160
22 Cinnarazine 2500 30,000
23 Clonazepam 130 1,560
24 Lorazepam 130 1,560
25 Duloxetine HCl 300 3,600
26 Dapoxetine HCl 50 600
27 Desvenlafaxine HCl 400 4,800
28 Trihexyphenadyl HCl 300 3,600
29 Tramadol HCl 2500 30,000
30 Sulfamethoxy Pyrazine HCl 500 6,000
31 Alimemazine Tartarate 200 2,400
32 Alprazolam 110 1,320
33 Diazepam 120 1,440
34 Buclazine HCl 400 4,800
35 Meclazine HCl 400 4,800
36 Carbamezapine 2,000 24,000
TOTAL 38,390 4,60,680
Note:
The total production capacity is 4,60,680 kg/annum.
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3.5.2 Manufacturing process description
The manufacturing process for each product proposed to be produced is described with stoichiometric and gravimetric balances along with process description and material balance flow charts as under. 3.5.2.1 AMTRIPTYLINE HYDROCHLORIDE
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N
OH
N .HCl
Amitriptyline Grignardbase
Amitriptyline HCl
Acetone
295
36.5
313.5
18
N
OH
Amitriptyline Grignardbase
295
O
Dibenzo suberoneDimethylamino propyl chloride
208121
THF/Toluene
Mg
MgCl
Reaction scheme
Cl N
5924
NH
263
H2O
299.5
HCL
36.5
18
NaOH
Nortrityline base
1st step
2nd step A
2nd step B
CH3OHNa
54NH
Nortrityline (DesAmitriptylne)Hydrochloride
.HCl
N butanol
Acetone
H2O
HCl
NaOH
40
H2O2
80(20%)=16
N
293
AmitriptylineN-oxide
O
NaCl H2O
8258.5
Salt A
Salt C
Salt B
Toluene
40
MANUFACTURING PROCESS (FOR SALTS OF AMITRIPTYLINE) 1st step: Dibenzo suberone is converted to Hydroxy Amitriptyline base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction solvent is removed by distillation in another SS reactor and the product Hydroxy Amitriptyline base is isolated with water. Solid is centrifuged and taken for next step.
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The solvent is recovered and reused. 2nd step ( to make 3-salts/ derivative): 1) The Hydroxy Amitriptyline base (Grignard Base) is dissolved in Toluene by heating at 40-50 * C in SS reactor, charcoaled and filtered. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Amitriptyline hydrochloride crystals (Salt A). These are centrifuged washed with Acetone and the solid is dried. The Mother liquor is sent for recovery. 2) The Amitriptyline hydrochlorideis Heated at temp 90*C in sodium hydroxide solution and cooled to 10*C. The mass is reacted with Hydrogen peroxide solution (20%) which is added slowly maintaining temp< 10*C to get Amitrityline N-Oxide (Salt B). 3) The Hydroxy Amitriptyline base (Grignard Base) is refluxed in N- butanol solvent is in presence of base Sodium hydroxide in SS reactor to get Des Amitriptyline Base (Nortriptyline base). Solvent is removed by Vacuum distillation and quenched with water to get 2 layers. Top organic layer is liquid Nortrityline base which is immediately dissolved in acetone. This solution in Acetone is charcoaled , filtered and clear filtrate is converted to Nortriptyline Hydrochloride (Des Amitrityline) Crystals (Salt C) are obtained by passing Hcl gas in GL reactor at temp <%*C; which is isolated by Centrifuging and the solid is dried . The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.
AMTRIPTYLINE HYDROCHLORIDE (SALT A) MASS BALANCE SL NO PRODUCTION B Size 300kg No of batchs 34/Month
All inclusive
Raw material used
1 THF 40kg
2 Dibenzo suberone 208kg
3 Toluene 2200Lt For salt A)
4 Water 1600Lt(for salt AB &C)
5 Mg 24kg
6 Dimethylamino propyl chloride 120kg
7 Con Hcl acid 110kg
8 N-Butanol 1000L
9 HCl gas 36kg
8 Acetone 1800 Lt( for AB& C salt)
9 NaOH 80kg (for B&C salt)
10 H2O2 (20%) 80kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 42 -
11 Carbon 20Kg(for A& C)
Yield (Amitriptyline HCL (Salt A)) Des methyl Amitriptyline HCl(Salt C)
290kgs/280kg Only 1 batch for every 3 months of salt B is taken (260kg)
Batch size 300kgs --- Amtriptyline HCL (Salt A) given for salt A
Input Reactors Output
THF 40L SSR 3000L(for step 1 Grignard reaction)
Amtriptyline HCL (Salt A) Yield :: 290kg Oveall yield ::92.5%
Dibenzo suberone – 208KG
SSR 3000L (for step 1 reaction workup)
I.Product: stage-1 :96.5% Stage-2A:96%
Toluene -2200Lt SSR 3000L (for step 2 Dissolution)
Toluene: 1900L Loss: 340L Include THF(40L) Acetone: 800L Loss: 200L P. Water: 752 L Contns Mg Cl Cleaning water 1500L goes to CETP Hazardous waste: salt A 20-25kg Spent Carbon: 12kg
Water – 600Lt GLR 1500L(for step 2 reaction)
Mg – 24KG
Dimethylamino propyl chloride – 120KG
SSR 3000L (for solvent recovery)
Con Hcl acid – 110KG
Acetone – 1000Lt
Carbon – 10Kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… 10-14hrs (MLR-1) 10-14hrs (MLR-2) ----- Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 752kgs Batch size 300kgs ---
Nortriptyline HCL (Desmethyl amitriptyline Hcl: Salt C) Input Reactors Output
THF – 40L SSR 3000L(for step 1 Grignard reaction)
Des methylAmtriptyline HCL (Salt C) Yield :: 280kg Oveall yield ::92.5%
Dibenzo suberone – 208KG
SSR 3000L (for step 1 reaction workup)
I.Product: stage-1 :96.5%
3000M/s. R L Fine Chem Pvt. Ltd.,
- 43 -
Toluene -1000Lt SSR 3000L (for step 2 Reaction)
Toluene: 900L Loss: 140L Include THF(40L) Acetone: 800L Loss: 200L N butanol :900L loss 100L P. Water: Stage-1 ;660kg/L (Contns MgCl) stage-2 :672kg/L (Contns NaCl) Cleaning water 1500L goes to CETP Hazardous waste: salt A 16-18kg Spent Carbon: 12kg
Water – 1200Lt GLR 1500L(for step 2 reaction)
Mg – 24KG
Dimethylamino propyl chloride – 120KG
SSR 3000L (for solvent recovery)
Con Hcl acid – 36.5KG
Acetone – 800Lt
Carbon – 10Kg
N-Butanol – 1000L
NaOH- 40kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs -
Solvent recovery…… 10-14 hrs (MLR-3) ------ Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 1332kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 44 -
Process Waste Water-1,23&4 : 1975.5kgCleaning Waste Water : 1500L
FLOW CHART FOR AMTRIPTYLINE HYDRCHLORIDE
Total waste water to CETP is 3475.5L/kg
2nd stepproduct A&C
SS reactor-1cap 3000LToluene layer& MLR
SSreactor -1cap:3000L
Grignard
Toluene/THF1000L/40L
Dibenzo suberone208 kg
Dimethylaminopropyl chloride120kg
Water600L
Centrifuge
RecoveredToluene900L
Amitriptyline base 295kgwet(Conent 285kg)
Water-1includes660 kgs/MgCL
MLR TolueneSolvent Loss:140L
Residue-1haz waste10.0kg
1st step
Toluene 1200L SS reactor-2cap :3000LDissolution
Haz Waste 1,::22-25kgHaz wate -2&3:: 22-25kg
Amitritylinebase 285kgs
GL reactor
Solvent recovery
Toluene MLR-1loss 100.0L
Toluene 1000LLoss :100L
reaction
1500LConc HCL acid 110kgs(36.5+74)
Centrifuge
SSreactor 2noscap:3000/ 1500Lfor recovery Acetone 1600L
Loss :200Lfrom 1&3
Amitriptylinehydrochloride290.0kgs(Salt A)
Acetone wash1000L
Acetone MLR-2Loss ::100L
MLR-1MLR-2MLR-3
Nortriptyline (Salt C)Hydrochloride280Kg(desmethyl Amitriptyline)
Mg 24
SS reactor-2cap :3000LReaction
GL reactor
reaction
1500L
SS reactor-3cap :2000LDissolution
N-Butanol 1000L
NaOH 40 kg
HCl 36.5
Acetone800L
Water-3 672kg
Water-292kg
Water 600L
Amitritylinebase 285kgs
NButanol 900L Loss :100L
MLR-3
Acetone loss 100L
Centrifuge
Water 400L
NaOH 40kg
AMTN HCL290kg
CentrifugeAmtriptyline N-Oxide265kg (Salt B)
Water-4::548.5kg2nd stepProduct B
C- 10kg
C-12 kg
C-10 kg
Spent C -12kg
Spent carbon wet 24 kg
H2O2 80kg20%
12
10
11
10
3000M/s. R L Fine Chem Pvt. Ltd.,
- 45 -
3.5.2.2 IMIPRAMINE HCL/DESIPRAMINE HCL
Dimethylamino propyl chloride
121
Cl N
N
N
N
N
+ HCl
Imipramine Base
280
Hydrochloric acid
36.5
.HCl
Imipramine Hydrochloride
316.5
Acetone
N
N
Imipramine Base
280
NH
Imino dibenzyl
195
Toluene
NaCl NH3NaNH2
39
58 17
Reaction scheme
1st step
2nd step
COOH COOH
OH
HO
388
N
N .pamoate
Imipramine palmoate
668
Ethyl acetate
3000M/s. R L Fine Chem Pvt. Ltd.,
- 46 -
MANUFACTURING PROCESS
It involves 2 steps
1st step
Iminodibenzyl is dissolved in SS reactor in Solvent Toluene and to this was added
Sodamide base under nitrogen and Dimethylamino propyl chloride is added slowly.
The resultant mass is refluxed for 24 hrs to get Imipramine base. The product is
then worked up with water, after the reaction is complete by quenching in water,
and separating the organic layer.
The organic layer is distilled to recover the Toluene and concentrated liquid
Imipramine base is taken for the next step.
Recovered Toluene is recycled.
2nd step
Imipramine base is dissolved in solvent Acetone in SS reactor, charcoaled and
filtered. The clear filtrate is transferred to Glass lined reactor. This clear solution
is cooled < 15*C in Glass lined reactor and treated with methanolic solution of HCL
to get imipramine hydrochloride crude.
The resultant mixture is heated to reflux for 4hrs and cooled to <15* C to get pure
Imipramine hydrochloride in crystals which is centrifuged and dried.
The mother liquor is sent for recovering sovent which is recycled.
Imipramine base is also converted another salt as pamoate by dissolving in Ethyl
acetate and treating with Pamoic acid.
IMIPRAMINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs 4/Month
Raw material used
1 Imino Dibenzyl 195kg
2 Dimethylamino Propyl Chloride 120kg
3 Sodamide 39 kg
4 Toluene 1000Lt
5 Water 600Lt
6 Methanol Hcl 130kg
7 Acetone 800L
3000M/s. R L Fine Chem Pvt. Ltd.,
- 47 -
8 Carbon 10kg
Yield (Imipramine Hydrochloride) 285kgs
Batch size 300kgs --- Imipramine Hydrochloride
Input Reactors Output
Imino Dibenzyl 195kg SSR 3000L(for step 1 Reaction)
Imipramine Hydrochloride Yield ::285kgs Overall yield:90%
Dimethylamino Propyl Chloride 120 kg
SSR 3000L (for step 1 workup)
I.Product: 1st stage::95% 2nd stage:95%
Sodamide 39kg SSR 2000L (for step 2 dissolution)
Toluene: 900L Loss: 100L Acetone: 700L Loss: 200L Methanol loss : 70kg(100L) NH3 :17kg P.Water: 660 L stage-1 (Cont NaCl ) Cleaning water::500L goes to CETP Hazardous waste: 30-35kg Spent carbon: 12Kg
Toluene 1000L GLR 2000L (for step2 reaction)
Water 600 L SSR 2000L (for solvent recovery)
Methanol Hcl 110kg
Acetone 800 L
Carbon 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 22-24hrs 12-14hrs ----
Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs ---
3) Solvent recovery…… 8-10hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 660kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 48 -
Process Waste Water ::660 kgCleaning waste Water :500L
Imipramine base265 kgs
Acetone 800L
SS reactor-22000L
GLreactor2000L
SSreactor 2000Lfor solvent recovery
FLOW CHART FOR IMIPRAMINE HYDROCHLORIDE
MLR Acetonemixfor recycle
acetone
dissolution
Reaction
Total waste water to CETP is 1160kg
centrifuge +
Acetone Pure 700Lloss 100L
Haz Waste kgs 30-35kg
MLRAcetone
Methanol hcl110.0 kgs(120L)
Imipramine hydrochloride285.0kgs
2nd Step
(74kg+35.0kg)
Solvent lossAceton100.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up
IminoDibenzyl 195kg
DimethylaminoPropyl chloride120kg
Sodamide39kg
Toluene1000L
NH3 17kg
Water 600L
Water +NaCl660kg
Recov Toluene900L Loss:100L
Imipramine Base280kg(cont 265kg)
1st step
Imipramine pamoate(Base-56:&P acid-67)gives110kg final
Carbon 10kg Spent C12 kg wet
Spentcarbon 12 kg wet
15
15
100L methanol
3000M/s. R L Fine Chem Pvt. Ltd.,
- 49 -
3.5.2.3 CYPROHEPTADINE HCL
N
OH
N .HCl
+ HCl + H2O
Cyproheptadine Grignardbase
Hydrochloric acid Cyproheptadine HCl Water
Toluene
30536.5 323.5 18
N
OH
Cyproheptadine Grignardbase
305
N
Cl
O
206
Dibenzosuberenone N-methyl chloropiperidine
133.5
Mg
24
Toluene/ THF
MgCl
59.5
Reaction scheme
IPA
MANUFACTURING PROCESS This involves 2 steps 1st step Dibenzosuberenone is converted to Hydroxy cyproheptadiene baseby Grignard reaction in SS reactor with N-methyl chloro piperidine in suitable solvent THF and Toluene mixture using Magnessium filings at temperature 80-85*C for 16 hrs. After the reaction is complete, reaction mass is quenched with water at temperature <35*C to get 2-layers which is separated. Organic layer is concentrated to recover Toluene and solid Grignard baseis obtained by adding Methanol. Solid is centrifuged and taken for 2nd step.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 50 -
Mother liquor is sent for recovery of methanol by distillation. Both recovered solvents are then recycled after purification in SRP. 2nd step The Hydroxy cyproheptadiene base is dissolved in Toluene by heating at 40-50 * C in SS reactor. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get cyproheptadiene hydrochloride crystals. These are centrifuged and the solid is dried. The product is crystallized in IPA BY Heating and cooling. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.
CYPROHEPTADIENE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 300kgs No of batchs:3/month
Raw material used
1 THF 25L
2 Dibenzo Suberenone 206kg
3 N-Methylchloro Piperidine 133 kg
4 Toluene 2600Lt(1st &2nd stage)
5 Water 500Lt (1st stage)
6 Methanol 600Lt (1st stage)
7 Con. HCl 110Kg
8 IPA 1500Lt(2nd stage)
9 Carbon 15kg
10 Magnessium 24kg
Yield (Cyproheptadiene) 270kgs
Input Reactors Output
THF 25L(20kg) SSR 3000L(Griganard Reaction)
Cyproheptadiene::270kg (Theo::323kg)overall yield84%
Dibenzo Suberenone 206kg
SSR 3000L (for workup) Product: 1st stage 95% 2nd stage 88%
N-Methylchloro Piperidine 133kg
SSR 3000L (for Dissolution) Toluene: 2400L Loss: 200L Methanol: 500L Loss: 100L IPA: 1250L Loss:250L P Water-1 : 575L/kg step-1
Toluene 2600L GLR 3000L (for reaction)
Magnessium 24kg SSR 3000L (for dissolution
3000M/s. R L Fine Chem Pvt. Ltd.,
- 51 -
crystallisation) (includes MgCl/THF) P Water-2 :90 L step-2 Total P water 665L Cleaning water::1500L goes to CETP Hazardous waste: 50-55kg Spent Carbon: 20kg
Water 500L SSR 3000L/2000L (for solvent recovery) Methanol 600L
Con. HCl 110Kg
IPA 1500 L
Carbon 15Kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs -
Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
3) Solvent recovery…… 8-10hrs (MLR-1) 10-12hrs(MLR-2) 12-16hrs(MLR-3)
Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 1080kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 52 -
Toluene1800LSS reactor-23000LDissolution
Haz Waste 1, 2 & 3 50-55kgsCarbon :20 kgs
Process Waste Water-1&2: 675kgCleaning Waste Water : 1500LTotal water 2175kg/L
FLOW CHART FOR CYPROHEPTADIENE
Hydroxycyproheptadiene290kgs
GL reactor
2nd step
MLR-1 MethanolMLR-2 TolueneMLR-3 IPA
Tol Solvent loss 75.0L
Toluene recov 1650LLoss Tol :75L
reaction
3000L
Conc HCL acid 110.0kgs(36+74watr)
Centrifuge
Solvent recoverycap3000/2000LMLR SSReactor
Cyproheptadiene320.0 kgs Crude +
TolueneMLR-2
Water-292.0kgs
SS REactor-33000L dissolutionCrystallisation
Pure Cyproheptadiene 270 kgs
Isolation
Iso propyl alcohol 1500L
Carbon 15 kgs
IPA recov 1250LLoss :150L
Centrifuge IPA Loss 100LMLR-3
Carbon 20 kg wet
Toluene/THF: 800/25L
SS reactor-1 cap :3000LGrignard ReactionDibenzo
suberenone 206kg
1st step
Methanol Recov 500L Loss 50L
SS REactor-1cap 3000Lwork /up
Hydroxy CyproheptadieneBase 305kg wet(content::290 kgs)
Water 500L
Methanol600L
Centrifuge
N-methylchloro pipridine133.0kg Aqueous water-1
Layer 575 Kg
Recov Toluene 750 LLoss 50L
Solvent Loss50L MLR-1
Mg 24kg
Solvent recovery
15
37
3000M/s. R L Fine Chem Pvt. Ltd.,
- 53 -
3.5.2.4 PITOFENONE HCL
Reaction scheme
CO2CH3
O
N
O
CO2CH3
O
N
O
.HCl
+ HCl
Pitofenone Base Hydrochloric acid Pitofenone hydrochloride
Acetone
367 36.5 403.5
CO2CH3
O
N
O
Pitofenone Base
367
N
CO2CH3
OH
OCl
Methyl ester intermediate
256
Chloroethyl piperidine
147
toluene
BaseKHCO3
100
KCl CO2
74 44
H2O
18
MANUFACTURING PROCESS
It involves 2 steps
1st step
Ester intermediate is dissolved in solvent toluene and reacted with chloroethyl
piperidine in presence of base (potassium carbonate) and the reaction mass is
3000M/s. R L Fine Chem Pvt. Ltd.,
- 54 -
refluxed and after the reaction the reaction mass is quenched with water and
separated the organic layer which contains Pitophenone base.
The organic layer is having pitofenone base which is isolated by solvent distillation
and the thick organic mass (residue) is taken for the next step.
Solvent is reused after recovery.
2nd step
Pitofenone base is dissolved in Acetone in SS reactor, treated with carbon, filtered
and transferred the clear filtrate to Glass lined reactor.
The above solution is cooled to<10*C and hydrogen chloride gas is passed slowly over a
period of 4 hrs by maintaining temperature below 20* C till Ph 2 is achieved.
The above reaction mixture is stirred at temp <25*C for 4hrs and cooled to temp < 10
*C to get pitofenone hydrochloride crystals which is separated by centrifuging to
isolate the product and dried.
The mother liquor from the above centrifuge is sent for recovery of Acetone solvent
which is recycled.
PITOFENONE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 350kg No of batchs 2/month
Raw material used
1 Potassium bicarbonate 100kg
2 Methyl ester intermediate 256kg
3 Chloro ethyl piperidine 147kg
4 Toluene 1000Lt
5 Water 600Lt
6 Methanol Hcl 110kg
7 Acetone 1000L
8 Carbon 10kg
Yield (Pitofenone Hydrochloride) 365kgs
Batch size 350kg --- Pitofenone Hydrochloride
Input Reactors Output
Potassium bicarbonate – 100kg
SSR 3000L(for step 1 Reaction)
Pitofenone Hydrochloride Yield 365kg Overall yield 90%
3000M/s. R L Fine Chem Pvt. Ltd.,
- 55 -
Methyl ester intermediate – 256kg
SSR 3000L (for step 1 workup) I.Product stage-1 ::95% Stage-2 ::95%
Chloro ethyl piperidine – 147kg
SSR 2000L (for step 2 dissolution)
Toluene: 900L Loss: 100L Acetone: 850L Acetone mix Loss: 250L (conts 70kgMethanol) CO2 ::44kg P. Water: stage-1 :: 695kg/ L Contns NaCl Cleaning water :::500L goes to CETP Hazardous waste: 34-38kg Spent carbon: 12Kg
Toluene – 1000L GLR 2000L (for step2 reaction)
Water – 600L SSR 2000L (for solvent recovery)
Methanol Hcl – 110kg
Acetone – 1000L
Carbon – 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 22-24hrs 12-14hrs ----
Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs ---
3) Solvent recovery…… 8-10hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 695kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 56 -
FLOW CHART FOR PITOFENONE HYDROCHLORIDE
Process Waste Water ::695.0 kgCleaning waste Water :500L
Pitofenone base350 kgs
Acetone 1000L
SS reactor-2cap 2000LDissolution
GLreactor2000L
SSreactorcap 2000Lsolvent recovery
MLR AcetoneLoss :;150L
Reaction
Total waste water to CETP is 1195 L/kg
centrifuge
Acetone Pure 850Lloss ::100L
Haz Waste 34-38kgkgs
MLRAcetone
Methanol hcl110.0 kgs(120L)
Pitofenone hydrochloride365.0kgs
2nd Step
(74kg+36.0kg100L methanol)
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up/Org layer
Chloro ethylPiperidine 147kg
Methyl esterintermediate 256kg
Toluene1000L
Water 600L
Water +NaCl695kg
Recov Toluene900L Loss:100L
Pitofenone BaseLiquid 365 crude(content 350kg)
1st step
Carbon 10kg Spent C12 kg wet
Spentcarbon 12 kg wet
Potassium bi carbonate 100kg
CO2 44kg
Solvent recovery
17
20
3000M/s. R L Fine Chem Pvt. Ltd.,
- 57 -
3.5.2.5 PYRIMETHAMINE
Reaction scheme
Cl
CNOO
+H2N NH2
NH
Cl
NN
NH2
NH2
Cyano Ketal Compound
GuanidinePyremethamine
Methanol
248.559251.5
+ CH2OHCH2OH
Ethylene Glycol
62
Cl
CNOO
Cyano Ketal Compound
251.5
OHHO
Cl
CN
O
Cation resin
Toluene
Keto nitrile
207.5
MEG
62
H2O
18
2nd step
3rd step
Cl
CN
O
Keto nitrile
207.5
Cl
CN
151.5
p-Chloro benzyl cyanide
O
O
IsopropylPropionate
116
OH
Iso propanol
60
base
Toluene
1st Step
3000M/s. R L Fine Chem Pvt. Ltd.,
- 58 -
MANUFACTURING PROCESS
This involves 3 steps
1st step
P-chloro benzyl cyanide is reacted with Iso propyl propionate ester (ester) in SS
reactor by refluxing for 16hrs in Toluene solvent using anion resin to get Keto nitrile.
After the reaction is complete the mass is filtered to remove resin and the filtrate is
worked with water to get 2 layers. The water layer is separated and organic layer is
taken for the next step. Resin is reused.
2nd step
Keto nitrile in toluene media is reacted with Monoethylene glycol to get Cyano ketal
compound by refluxing for 14hrs using cation resin simultaneously removing water
azeotropically.After the reaction is complete the reaction mass is filtered to remove
the resin . The filtered mass is quenched in water and top organic layer is
concentrated by distilling the solvent to get syrupy liquid mass. This is Cyano ketal
compound which is taken for the next step Resin is recycled.
3rd step
Cyano ketal compound is dissolved in SS reactor in Methanol solvent charcoaled with
carbon and filtered to get clear solution. The above solution is treated with guanidine
and the reaction mass is refluxed for 16 hrs at 65-70*C and the the mass is stirred at
temp <25*C for 2-4hrs and cooled to temp < 10 *C to get Pyrimethamine crystals
which is separated by centrifuging to isolate the product and dried.
The mother liquor from the above centrifuge is sent for recovery of Methanol solvent
at 75*C, which is recycled. The ethylene glycol is distilled later at higher temp > 110*
C under vacuum which is used in the chilling brine solution.
PYRIMETHAMINE Gravimtric/MASS BALANCE
SL NO PRODUCTION (B size) No of batchs 3/Month
Raw material used
1 PCBC 150kg
2 Ester 116kg
3 Toluene 750Lt
4 Water 1000Lt
5 MEG 60kg
6 Methanol 1200L
7 Guanidine 60kg
8 Carbon 10Kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 59 -
Yield (Pyrimethamine) 200kgs
Batch size 200 kgs --- Pyrimethamine
Input Reactors Output
PCBC 150kgs SSR 2000L(for step 1 reaction)
Pyrimethamine
Ester 116 kgs SSR 2000L (for step 2 reaction workup)
Product: 200kgs Yeild:81% (Theo::248kg)
Toluene 750L SSR 2000L (for step 3 condensation)
Toluene: 650L Loss: 100L Methanol: 1075L Loss: 125L P Water: 1st step ::560 kg/L 2nd step::520kg/L Total P.Wwater; ::1080 L Cleaning water :500L Totalwaste ::1580 goes to CETP By product: 50kg (Ethylene glycol) Hazardous waste: 55-58 Spent Carbon: 12kg
MEG 60 kg SSR 2500L (for solvent recovery)
Water 1000L
Methanol 1200L
Guanidine 60kg
Carbon 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs 16-18hrs Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs 6-8hrs
3) Solvent recovery… 2hrs 10-12hrs 12-16hrs
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 1080kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 60 -
Cyano ketal intermediate250kgs
Guanidine 60.0 kgs
SS reactor-22000LCondensation
SSreactor 2500Lfor solvent recovery
Solv Loss DistillationMethanol 75.0L
By product ::Ethylene glycol 50.0 kgs
Process Waste Water 1&2:1080kgCleaning waste Water :500 L
FLOW CHART FOR PYRIMETHAMINE
MLR
Total waste water to CETP is 1580L
centrifuge
Solvent loss 50.0 L Methanol
Methanol recovered1075 L recycle
Haz Waste 55-58 kgs
Solvent recoveryMLR
Methanol 1200L
Pyrimethamine200.0kgs
SS Reactor-2
2000L Reaction workup
MLR
Ethylene glycol50.0kgs
Condensation and reaction
3rd step
MEG 60 kg
SSReactor-1cap 2000L
Reaction
Water500L
Cyano ketal Intermediate::280 kgsSS reactor concentratecontains250kg purepd.
Water-2520Kg
Toluene recov:650LLoss:50L
Resin cat
2nd step
PCBC150Kg
Ester116kg
Toluene750 L Water
500L
Organic layerKeto NitrileMass:205Kg/700LToluene
W/up
W/up
Water -1IPA mix :560L
Solv. Toluene loss :: 50L
Transfer
!st step
Carbon 10kg
Spent carbon 12kg
Spent carbon 12kg
48
10
3000M/s. R L Fine Chem Pvt. Ltd.,
- 61 -
3.5.2.6 CYCLOBENZAPRINE HCL
Reaction scheme
N
OH
N .HCl
+ HCl + H2O
Cyclobenzaprine Grignardbase
Hydrochloric acid Cyclobenzaprine HCl Water
Acetone
29336.5 311.5 18
N
OH
Cyclobenzaprine Grignardbase
293
O
Dibenzo suberenone
206
Cl N
Dimethylamino propyl chlooride
121
THF/Toluene
Mg
MgCl
24 59
MANUFACTURING PROCESS 1st step Dibenzo suberonone is converted to Cyclobenzaprine Grignard base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction the mass is quenched in water and layers were separated. Top organic layer is transferred to other SS reactor and 50% Solvent is removed by distillation and the product Cyclobenzaprine Grignard base is isolated by cooling to < 5*C and centrifuging. The solid is taken for next step.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 62 -
The solvent is recovered and reused. 2nd step The Cyclobenzaprine Grignard base is dissolved in Toluene by heating at 40-50 * C in SS reactor Charcoaled and filtered. The clear filtrate is transferred to GL reactor To the clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Cyclbenzaprine hydrochloride crystals. These are centrifuged, washed with acetone and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and both the recovered solvent is recycled. CYCLOBENZAPRIN HYDROCHLORIDE MASS BALANCE
SL NO PRODUCTION B Size 300kg No of batchs 3/Month
Raw material used
1 Dimethylamino Propyl Chloride 120kg
2 Dibenzo Suberenone 206kg
3 Toluene 2500Lt(1st &2nd stage
4 Water 600Lt (1st stage)
5 Con. Hcl 110kg
6 Acetone 1000L(final)
7 Mg 24kg
8 Carbon 10Kg
Yield (Cyclobenzaprin Hydrochloride) 285kgs
Batch size 300kgs --- Cyclobenzaprin Hydrochloride
Input Reactors Output
Dimethylamino Propyl Chloride 120kgs
SSR 3000L(for step 1 Grignard)
Cyclobenzaprin Hydrochloride Yield:285Kg(Theo:311kg) Overall yield:91%
Dibenzo Suberenone 206kgs SSR 3000L (for step 1 Toluene layer)
Stage-1yield 97% Stage -2 yield 94%
Toluene 2500 L SSR 3000L (for step 2 dissolution)
Toluene: 2250 loss ::250L Acetone: 825L Loss: 175L P Water : stage-1 660kg/L (cont MgCl) P water : Stage-2 ::90kg Total P.water ::750kg/L Cleaning water :::500L
Water 600L GLR 3000L (for step2 reaction)
Con. Hcl 110 Kgs SSR 2000L (for solvent recovery)
Acetone 1000L
Mg 24Kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 63 -
Carbon 10Kg goes to CETP Hazardous waste: 25-28kg Spent Carbon: 12kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs ---- Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs ---
3) Solvent recovery… 8-10hrs (MLR-1) 10-12hrs(MLR-2)
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
- 64 -
Toluene1500L SS reactor-2cap 3000L
Haz Waste 1& 2 25-28kg
Process Waste Water-1&2 :750kgCleaning Waste Water : 500L
CyclobenzprineGrignard base290.0 kgswet
Total waste water to CETP is 1250L
dissolution
2nd step
MLR -1MLR-2
MLR-1 TolueneSolvent loss:75L
Recovered Toluene1350L Loss:75L
Conc HCL acid 110.0kgs(36+70)
Centrifuge
Solvent recovery MLRCap:;SSreactor 2000L Recovered Acetone
825L Loss :75L
Cyclobenzaprinehydrochloride285.0 kgs
Water-290.0kgs
MLR -2 AcetoneSolvent Loss :100L
Acetone 1000L(Top wash)
SS reactor-1cap 3000LToluene layer& MLR
GLreactorcap 3000LReaction
SSreactor -1cap:3000L
Grignard
Toluene1000L
Dibenzo suberenone206 kg
Dimethylaminopropyl chloride120kg
Water600L
Centrifuge
RecoveredToluene900L
Cyclo benzaprine Grignard base 290wet(content 285 Kg )
MLR
Water-1includes660 kgs/MgCL
Solvent Loss:100L
Residue-1haz waste8.0kg
1st step Grignard reaction
Mg 24
Carbon 10 kg
Spent carbon 12kg wet
Spentcarbon 12 kg wet
8
17
3000M/s. R L Fine Chem Pvt. Ltd.,
- 65 -
3.5.2.7 CLOMIPRAMINE HCL
Reaction scheme
Dimethylamino propyl chloride
121
Cl N
N
N
N
N
+ HCl
CIomipramine Base
314
Hydrochloric acid
36.5
.HCl
CIomipramine Hydrochloride
350.5
Acetone
N
N
CIomipramine Base
314
NH
3-ChloroImino dibenzyl
229
Toluene
NaCl NH3NaNH2
39
58 17Cl
Cl
Cl Cl
MANUFACTURING PROCESS
It involves 2 steps
1st step
3-Cloro Iminodibenzyl is dissolved in SS reactor in Solvent Toluene and to this was
added Sodamide base under nitrogen and the mass is refluxed for 24 hrs to get
clomipramine base. The product is then worked up, after the reaction is complete
by quenching in water, and separating the organic layer.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 66 -
The organic layer is distilled to recover the Toluene and concentrated liquid
CIomipramine base is taken for the next step.
Recovered Toluene is recycled.
2nd step
Clomipramine base is dissolved in solvent Acetone in SS reactor, charcoaled and
filtered. The clear filtrate is transferred to Glass lined reactor. This CIomipramine
base is dissolved in glass lined reactor is cooled < 15*C and treated with
methanolic solution of HCL to get Clomipramine hydrochloride crude.
The resultant mixture is heated to reflux for 4hrs and cooled to <15* C to get pure
Clomipramine hydrochloride in crystals which is centrifuged and dried.
The mother liquor is sent for recovering solvent which is recycled.
CLOMIPRAMINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs 2/Month
Raw material used
1 3-Chlorolmino Dibenzyl 230kg
2 Dimethylamino Propyl Chloride 120kg
3 Sodamide 39 kg
4 Toluene 1000Lt (1st step)
5 Water 600Lt
6 Methanol Hcl 110kg
7 Acetone 800L(final)
8 Carbon 10kg
Yield (Clomipramine Hydrochloride) 320kgs
Batch size 300kgs --- Clomipramine Hydrochloride
Input Reactors Output
3-Chlorolmino Dibenzyl 230kg
SSR 3000L(for step 1 Reaction)
ClomipramineHydrochloride Yield 320kg (Theo:350kg) Overall yield 91%
Dimethylamino Propyl Chloride 120 kg
SSR 3000L (for step 1 workup)
Product: 1st stage 98% 2nd stage 93%
Sodamide 39kg SSR 2000L (for step 2 dissolution)
Toluene: 900L Loss: 100L Acetone: 700L Loss: 100L Methanol loss : 74kg(100L) NH3 :17kg P.Water: 660 L stage-1 (Cont NaCl )
Toluene 1000L GLR 2000L (for step2 reaction)
Water 600 L SSR 2000L (for solvent recovery)
3000M/s. R L Fine Chem Pvt. Ltd.,
- 67 -
Methanol Hcl 110kg Methanol 74kg Hcl 36kg
Cleaning water :500L goes to CETP Hazardous waste: 28-30kg Spent Carbon: 12kg
Acetone 800 L
Carbon 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 22-24hrs 12-14hrs ---- Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs ---
3) Solvent recovery…… 8-10hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
- 68 -
Clomipramine base310 kgs
Acetone 800L
SS reactor-22000L
GLreactor2000L
SSreactor 2000Lfor solvent recovery
Process Waste Water ::660 kgCleaning waste Water :500L
FLOW CHART FOR CLOMIPRAMINE HYDROCHLORIDE
MLR Acetonemixfor recycle
acetone
dissolution
Reaction
Total waste water to CETP is 1160kg
centrifuge
+
Acetone Pure 700LLoss 100L
Haz Waste 30-32kgs
MLRAcetone
Methanol hcl110.0 kgs(120L)
Clomipramine hydrochloride320.0kgs
2nd Step
(74kg+36.0kg)
Solvent lossAceton100.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up
3--chloroIminoDibenzyl 230kg
DimethylaminoPropyl chloride120kg
Sodamide39kg
Toluene1000L
NH3 17kg
Water 600L
Water +NaCl660kg
Recov Toluene900L Loss:100L
Clomipramine Base320 (content 310kg)
1st step
Carbon10kg Spent carbon12 kg wet
spent caron 12 kg
4
Cont 100L methanol)
25
3000M/s. R L Fine Chem Pvt. Ltd.,
- 69 -
3.5.2.8 CHLORPROMAZINE HCL
Reaction scheme
N
S
Cl
N .HCl
N
S
Cl
N
.HCl+
Chlorpromazine Base Hydrochloric acid
Acetone
Chlorpromazine Hydrochloride
318.5 36.5 355
N
S
Cl
N
Chlorpromazine Base
318.5
NH
S
Cl
233.5
2-Chloro pheno thiazine
N
Cl
Dimethylamino propyl chloride
121
KOH
Toluene
56
KCl
74
H2O
18
MANUFACTURING PROCESS INVOLVES 2- STEPS
1st step
3-chloro phenothiazine is converted to Chlopromazine base by reacting with
Dimethylamino propyl chloride in SS reactor in Solvent Toluene in presence of KOH
base at temperature 85-100*C for 15-17 hrs. After the reaction is complete, the
mass is quenched in water to get 2- layers. Top organic layer containing the
product Chlopromazine base.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 70 -
The Chlopromazine base is isolated as thick mass by concentration of Toluene
layer by distillation.
The recovered Toluene after purification in Solvent recovery plant is recycled.
2nd step
Chlopromazine base is disoolved in solvent Acetone in SS reactor charcoaled with
carbon, filtered to get clear solution. This clear solution is transferred to glass
lined reactor. The solution is then cooled < 15*C in Glass lined reactor and treated
with methanolic solution of HCL to get Chlopromazine hydrochloride crude.
The resultant mixture is heated to reflux for 4hrs and cooled to <15* C to get pure
Chlopromazine hydrochloride in crystals which is centrifuged and dried.
The mother liquor is sent for recovering solvent acetone which is recycled.
CHLORPROMAZINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 300kg No of batchs::5/month
Raw material used
1 KOH 59kg
2 2-Chloro pheno thiazine 233kg
3 Toluene 1000Lt(1st stage)
4 Water 600Lt (1st stage)
5 Dimethylamino Propyl Chloride 120kg
6 Acetone 1000Lt(final)
7 Methanol Hcl 100kg
8 Carbon 10kg
Yield (Chlorpromazine Hydrochloride) 315kgs
Batch size 300kgs --- Chlorpromazine Hydrochloride
Input Reactors Output
KOH – 59kg SSR 3000L(for step 1 reaction)
ChlorpromazineHydrochloride Yield :315.0kg Overall yield : 88.5%
2-Chloro pheno thiazine – 233kg
SSR 3000L (for step 2 reaction workup)
I.Product:stage-1::94% Stage-2::94%
Toluene – 1000L SSR 1000L (for step 2 dissolution)
Toluene: 900L Loss: 100L Acetone 850L Loss:225L (Contns 65kgMeOH) P.Water: stage-1 ::692 kg/L Cleaning water ::500L goes to CETP
Water- 600L GLR 1000Lfor reaction)
Dimethylamino Propyl Chloride – 120kg
GLR 2500L (for solvent recovery)
3000M/s. R L Fine Chem Pvt. Ltd.,
- 71 -
Acetone – 1000L Hazardous waste: 35-40kg Spent Carbon: 12kg Methanol Hcl – 100kg
Carbon – 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 22-24hrs 12-14hrs ---- Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs ---
3) Solvent recovery…… 8-10hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 692kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 72 -
Chlorpromazinebase 300.0 kgs
Acetone 1000LSS reactor-21000L
GLreactor1000L
SS reactor cap 3000LMLR solv recovery
Process Waste Water 692kgCleaning waste Water :500L
FLOW CHART FOR CHLORPROMAZINE HYDROCHLORIDE
MLR Acetonemixfor recycle
dissolution
Reaction
Total waste water 1192kg/L
centrifuge
Acetone 850L Loss mix :100L
Haz Waste 35-40 kgs
Solvent recoveryMLR
Methanol hcl100 kg (110L)35.5kg +75L
Chlorpromazine hydrochloride315.0kgs
1st Step
2nd Step
Solvent Acetone Loss(mix)125.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up
2-chloro phenothiazine 233kg
DimethylaminoPropyl chloride120kg
KOH 59kg
Toluene 1000L
Water 600L
Water + KCl692kg
Recov Toluene900L Loss:100L
Chlorpromazine Base 315kgCrude (content:: 300kg)
Carbon 10kg
Spent carbon 12kgwet
18
Spent carbon 12kg wet
20
3000M/s. R L Fine Chem Pvt. Ltd.,
- 73 -
3.5.2.9 DOXYLAMINE SUCCINATE
NO
NO
OH
O
O
H
Doxylamine succinate
388
NO
N
Doxylamine base
270
HOOH
O
O
+
Succinic acid
118
SOlvent
NO
N
Doxylamine base
270
NCl
107
N
O
121
Cl
112
Mg
24
MgCl
58
NaOH
40
NaCl
58
H2O
18
Raection scheme
2-acetyl pyridine Chloro benzene dimethylamino ethylchloride
1st step
2nd step
Acetone
3000M/s. R L Fine Chem Pvt. Ltd.,
- 74 -
MANUFACTURING PROCESS This involves 2 steps 1st step A 2-Acetyl Pyridine (or 2-Benzoyl pyridine) is converted to Grignard base by reaction with Chloro benzene in solvent Toluene in SS reactor using Magnesium filings under Nitrogen atmosphere. The reaction is carried out at temp ~10-15*C. After the reaction Reaction mass is quenched in water to get the Grignard base in Toluene. (Top layer) This layer is taken for the next step. 1st step B This is immediately reacted with Diethylamino ethylchloride at temp 85*C to get Doxylamino base in solvent in SS reactor. After the reaction is complete, the Reaction mass is basified with sodium hydroxide in water to get 2 layers. The top organic layer is distilled to remove solvent completely to get Doxylamine base liquid. The recovered Toluene is purified in SRP which is recycled. 2nd step Doxylamine base is dissolved in Acetone solvent in SS reactor treated with carbon and filtered. The clear filtrate is treated with Succinic acid at temp 10-15*C to get Doxylamine succinate which is centrifuged to get pure product. Product is later dried. The mother liquor is distilled to recover Acetone which is re used.
DOXYLAMINE SUCCINATE MASS BALANCE SL NO PRODUCTION B size ::350kg No of batchs 5/Month
Raw material used
1 2-Acetyl pyridine 120kg
2 Chloro Benzene 112kg
3 Diethylamino ethyl chloride 107kg
4 Water 1200Lt(1st stage A& B)
5 Toluene 1200Lt(1st stageA)
6 THF 30Lt
7 NaOH 40kg
8 Carbon 15kg
9 Mg 24kg
10 Succinic acid 110kg
11 Acetone 1000Lt
Yield (Doxylamine Succinate) 345kgs
Input Reactors Output
2-Acetyl pyridine – 120kg
SSR 2500L(for step 1 grignard reaction)
Doxylamine Succinate Yield 345kg Overall yield :: 89%
3000M/s. R L Fine Chem Pvt. Ltd.,
- 75 -
Chloro Benzene – 112kg SSR 2500L (for step 2 Toluene layer)
I.Product stage92.5% Stage : 96%
Diethylamino ethyl chloride – 107kg
SSR 3000Lfor dissolution Toluene: 1050L Loss: 150L Acetone: 825L Loss:175L P.Water stage1A::660kg/L (Contns MgCl) Stage 1B::676kg/L (Contns NaCl) Total water :: 1336kg/L Cleaning water ::500L goes to CETP Hazardous waste: 34-38kg Spent Carbon: 18kg
Water – 1200L GLR 3000L (for reaction)
Toluene – 1200L SSR 3000L (for solvent recovery)
THF – 30L/20kg
NaOH – 40kg
Carbon – 15kg
Mg – 24kg
Succinic acid – 110kg
Acetone – 1000L
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 14-16hrs 20-22hrs 6-8hrs Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs 4-6hrs
3) Solvent recovery…… ----- ------ 12-16hrs(MLR-3)
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP
along with process waste water 1336kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 76 -
FLOW CHART FOR DOXYLAMINE SUCCINATE
SS reactor-3cap 3000LDissolution
Haz Waste 34-38kg Process Waste Water-1&2:; 1336kgCleaning Waste Water : 500L
Doxylamine base 250.0 kgs
Total water : 1836L/kg
GL reactorcap 3000Lreaction
2nd Step
Solvent recoveryMLR
Centrifuge
Solvent recovery Cap 3000LSSreactor MLR
Doxylamine succinate345 kgs
MLR-1 AcetoneLoss 75L
SS reactor-2cap 2500LToluene layer
SS reactor-1cap 2500Lgrignard
Toluene/THF1200L/ 30L
2_acetyl pyridine 120kg
Chloro benzene 112kg
Water 600L
Doxylamine baseCrude 270kg(content:250kg)
Water-1includes660 kgs/MgCL
Tol Recovered 1050L Loss:150 L
1st step A Grignard reaction
Mg 24kg
Acetone 1000L
Acetone recov:825Lloss:100L
Carbon -15kgSpent carbon18 kgwet
Spent carbon 18 kg wet
Diethylamino ethylchloride 107kg
Water 600L
NaOH 40kg
Water-2 676kg / NaCl mix
Succinic acid110kg
20
15
1st step B
3000M/s. R L Fine Chem Pvt. Ltd.,
- 77 -
3.5.2.10 ORPHENADRINE CITRATE/ HCL
ONO
N
Orphenadrine Base
+
CO2H
CO2H
HO2C
OH
192
Citric Acid
citrate
269 461
Orphenadrine Citrate
Acetone
ON
Orphenadrine Base
269
NClHO
21689
NaOH
40
Toluene
NaCl H2O
58 18
1st step
2nd step
2-Methyl benzophenone
DimethylaminoEthanol
Reaction scheme
3000M/s. R L Fine Chem Pvt. Ltd.,
- 78 -
MANUFACTURING PROCESS The reaction involves 2 steps 1st step 2 methyl benzhydryl chlorides are reacted with Dimethylamino ethanol in SS reactor using solvent Toluene in presence of base like Sodium hydroxide by refluxing for 15-16hrs. After the reaction is complete the reaction mass is worked up by quenching with water. The organic layer is separated and Toluene is removed by distillation to get the Orphenadrine base. The recovered Toluene is purified in SRP which is reused. 2nd step The orphenadarine base is dissolved in SS reactor at 50-550 C in solvent Acetone; charcoaled and filtered and the clear solution is then transferred to GL reactor. The clear solution is treated with citric acid at slightly elevated temperature of 60-65*C to get orphenadrine citrate, for 14-16hrs, cooled to get solid; which is isolated by centrifuging. The product is then dried. The mother liquor is transferred to SS reactor for recovery. Solvent recovery The mother liquor from the centrifuge is distilled to recover ethyl acetate, which is recycled.
ORPHENADRINE CITRATE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 400kg No of batchs 10/Month
Raw material used
1 2-methyl Benzo phenone 215kg
2 NaOH 40kg
3 Dimethylamino Ehtanol 90 kg
4 Toluene 1000Lt
5 Citric acid 180kg
6 Water 600L
7 Acetone 1500L
8 Carbon 10kg
Yield (Orphenadrine Citrate) 400kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 79 -
Batch size 400kgs --- Orphenadrine Citrate DIHydrochloride
Input Reactors Output
2-methyl Benzo phenone – 215kg
SSR 3000L(for step 1 Reaction)
Orphenadrine Citrate Yield :400 kg Overall yield 86.7%
NaOH – 40kg SSR 3000L (for step 1 workup)
I.Product: 1st stage 92% 2nd stage ::94%
Dimethylamino Ehtanol – 90kg
SSR 3000L (for step 2 dissolution reaction)
Toluene: 900L Loss: 100L Acetone: 1250L Loss: 250L P.Water: 1st stage 676kg/ L Cleaning water ::1000L goes to CETP Hazardous waste: 45-48kg Spent Carbon: 12kgwet
Toluene – 1000L GLR 3000L (for step 2 condensation)
Citric acid – 180kg SSR 2000L (for solvent recovery)
Water – 600L
Acetone – 1500L
Carbon – 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 14-16hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
3) Solvent recovery…… ------ 10-12hrs(MLR-2) -----
Water used for washing/cleaning equipment, cleaning waste water 1000L goes to
CETP along with process waste water 676kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 80 -
Orphenadrine base250 kgs
Acetone 1500LSS reactor-2cap 3000LDissolution
GL reactor cap:3000Lcondensation
SSreactor 2000Lfor solvent recovery
Process Waste Water ::676.0L/ kgCleaning waste Water :1000L/kg
FLOW CHART FOR ORPHENADRINE CITRATE
MLR Acetonefor recovery
acetone
Total waste water to CETP is 1675 L/kg
centrifuge
Acetone Reco: 1250LLoss:100L
Haz Waste 45-48kg
MLRAcetone
Citric acid180kg
Orphenadrine Citrate400.0kgs
2nd Step
Solvent AcetonLoss :150.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up
2-methyl BenzHydrylchloride 215kg
DimethylaminoEthanol 90kg
NaOH 40 kg
Toluene1000L
Water 600L
Water +Nacl676L/kg
Recov Toluene900L Loss:100L
Orphenadrine base270 crude (Cont 250kg)
1st step
Solvent recovery
Carbon 10kg
Spent carbon12kg
Spent carbon 12 kg
19
26
3000M/s. R L Fine Chem Pvt. Ltd.,
- 81 -
3.5.2.11 TRIMIPRAMINE MALEATE/ MESYLATE
Dimethylamino Methyl propyl chloride
135
Cl N
NH
Imino dibenzyl
195
Toluene
NaCl NH3NaNH2
39
58 17
Reaction scheme
N
N
Trimipramine
294 g
N
N
Maliec acid
116 g
OH
OH
OO
. C4H4O4
Trimipramine Maleate
410 g
N
N
Trimipramine
294
Acetone
N
N
.CH3SO3HCH3SO3H
390
96
Ethyl acetate
Methane sulphonic acid
Trimipramine Mesylate
1st step
2nd step
3000M/s. R L Fine Chem Pvt. Ltd.,
- 82 -
MANUFACTURING PROCESS
It involves 2 steps
1st step
Iminodibenzyl is dissolved in SS reactor in Solvent Toluene and to this was added
Sodamide base under nitrogen and then added slowly 2-Methyl Dimethylamino
propyl chloride. The reaction mass is then refluxed for 24 hrs to get Trimipramine
base. The product is then worked up, after the reaction is complete by quenching
in water, and separating the organic layer.
The organic layer is distilled to recover the Toluene and concentrated liquid
Trimipramine base is taken for the next step.
Recovered Toluene is recycled.
2nd step
Trimipramine base is dissolved in solvent Acetone in SS reactor treated with
carbon and filtered. The clear filtrate Is transferred to glass lined reactor. The
clear solution is cooled < 15*C in Glass lined reactor and treated with Maleic acid
solution in acetone to get Trimipramine Maleate crude.
The resultant mixture is heated to reflux for 4hrs and cooled to <15* C to get pure
Trimipramine Maleate in crystals which is centrifuged and dried.
The mother liquor is sent for recovering sovent which is recycled.
Also Trimipramine base in Ethyl acetate is treated with Methane sulphonic acid to
get another salt Trimipramine Mesylate in same condition as above.
TRIMIPRAMINE MALEATE MASS BALANCE
SL NO PRODUCTION B size 350kg No of batchs::2/Month
Raw material used
1 Sodamide 39kg
2 Imino Dibenzyl 195kg
3 Toluene 1000Lt
4 Water 600Lt
5 Dimethylamino Methylpropyl chloride 135kg
6 Acetone/EA 800Lt
7 Maleic acid 114kg
8 Carbon 10kg
Yield (Trimipramine Maleate)and salt 370kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 83 -
Batch size 350kgs --- Trimipramine Maleate
Input Reactors Output
Sodamide – 39kg SSR 3000L(for step 1 reaction)
Trimipramine Maleate / or Mesylate Yield 370kg/350kg 0verall yield :90%
Imino Dibenzyl – 195kg SSR 3000L (for step 2 reaction workup)
I . Product Stage-1: 95% Stage-2:94.5%
Toluene – 1000L SSR 2000L (for step 2 dissolution)
Toluene: 900L Loss: 100L Acetone/EA: 700L Loss:100L NH3 ::17kg P.Water stage-1::: 660 L Cleaning water :::500L goes to CETP Hazardous waste: 32-36kg Spent Carbon: 12kg
Water – 600L GLR 2000Lfor reaction)
Dimethylamino Methylpropyl chloride – 135kg
SSR 1000L (for solvent recovery)
Acetone/EA – 800L
Maleic acid – 110kg or Methane sulfonic acid 92kg
Carbon – 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 22-24hrs 12-14hrs ---- Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs ---
3) Solvent recovery…… 8-10hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 660kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 84 -
Trimipramine base280 kgs
Acetone/ EA800L
SS reactor-22000L
GLreactor2000L
SSreactor2cap 1000Lfor solvent recovery
Solv Loss: 50LAcetone /EA
Process Waste Water ::660 kgCleaning waste Water :500L
FLOW CHART FOR TRIMIPRAMINE MALEATE
MLR Acetonefor recycle(750L)
dissolution
Reaction
Total waste water to CETP is 1160kg
centrifuge +
Acetone/EA Pure700L Recycle
Haz Waste 34-36kgs
MLRAcetone
Maleic acid110kg/
or MSA-92kg
Trimipramine Maleate370.0kgs
2nd Step
Solvent lossAceton/EA50.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up
Imino Dibenzyl 195kg
DimethylaminoMethylPropyl chloride 135kg
Sodamide39kg
Toluene1000L
NH3 17kg
Water 600L
Water + NaCl660kg
Recov Toluene900L Loss:100L
Trimpramine base 295kg crude(content ::280kgs)
1st step
Trimipramine Mesylate:350kg
Carbon 10 kg
Spent carbon 12kg wet
Spent carbon 12kg wet
14
20
3000M/s. R L Fine Chem Pvt. Ltd.,
- 85 -
3.5.2.12 FLUPENTIXOL HCL
Reaction scheme
S
CF3
N
NOH
HO
S
CF3
N
NOH
.2 HCl
Flupentixol Hydrochloride
+ 2 HCl
Acetone
Flupentixol base Hydrochloric acid
452 73507
+ H2O
Water
18
2nd step
S
N
NHO
S
Cl
N
N
OH
+
F3C
F3C
Trifluorothioxanthone
Piperazino intermediate Flupentixol Grignard Base
Toluene,Mg 24
OH
O
207280
452
Mg Cl
59
1st step
Decanoyl chloride
Flupentxol decanoate
C9H19COCl
OH to ester decanoate
588
136
2 Na OH
2-H2O
36
NaCl
108
80
3000M/s. R L Fine Chem Pvt. Ltd.,
- 86 -
MANUFACTURING PROCESS
This involves 2 steps
1st step
The Trifluro Thioxoanthrone is reacted with piperizine ethanol intermediate in SS
reactor in Solvent toluene and THF mixture in presence of Magnesium filings (Grignard
reaction) at <35*C.
After the reaction mass is quenched with water and the layers were separated.
Organic layer is concentrated by distillation to recover Toluene which is purified and
reused. The thick liquid mass is then treated with Methanol to get solid Grignard
product. (Grignard intermediate, flupentixol Grignard base) Solid is isolated by
centrifuging and mother liquor is sent for recovery of methanol which is reused.
2rd step
The Flupentixol Grignard base is dissolved in Toluene by heating at 40-50 * C in SS
reactor charcoaled and filtered. The clear solution is transferred to GLR eactor.
To the clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor (GLR) and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Flupentixol hydrochloride crystals. These are centrifuged and the solid is dried. Also Hydrochloride is converted to another salt Decanoate by treating with Decanoyl chloride in Glreactor in solvent Toluene. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.
FLUPENTIXOL HYDROCHLORIDE MASS BALANCE
SL NO PRODUCTION 50kg
Raw material used
1 THF 10L
2 TRIFLUOROTHIOXANTHONE 28kg
3 Mg 2.5kg
4 Toluene 700Lt(1st and 2nd stage)
5 Water 200L(1st stage)
6 Acetone 300L
7 Carbon 5kg
8 Con Hcl acid 21kg
9 Piperizino ehtanol intermediate 20kg
Yield (Flupentixol Hydrochloride) 40kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 87 -
Batch size 50kgs --- Flupentixol Hydrochloride
Input Reactors Output
THF – 10L(7KG) SSR 600L(for step 1 griganard)
Flupentixol Hydrochloride Yield ::40kg Overall yield80%
Triflurothioxanthone– 28Kg SSR 600L (for step 1 workup)
I.Product: stage-1::88% Stage-2::92%
Mg – 2.5kg SSR 1000L (for step 2 dissolution reaction)
Toluene: 630L Loss: 70L (Incl THF) Acetone: 265L Loss: 35L P.Water: stage-1 ::225 kg/L (Contns MgCl) Cleaning water ::500L/kg goes to CETP Hazardous waste: 6-8kg Spent Carbon: 6kg
Toluene – 700L GLR 1000L (for step 2 reaction)
Water – 200L
Acetone – 300L
Carbon – 5kg
Con Hcl acid – 21kg
Piperizino ehtanol intermediate – 20kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
3) Solvent recovery…… ---- 10-12hrs(MLR-2) 12-16hrs(MLR-3)
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 225kgs Piperizino ehtanol intermediate – 20kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 88 -
Toluene 500LSS reactor-21000L
Haz Waste1 &2 7-10 kgsProcess Waste Water 225 kgsCleaning Waste Water : 500L
FLOW CHART FOR FLUPENTIXOL HYDRCHLORIDE
FlupentixolGrignard base 40.0 kgs
Total waste water to CETP is 725L/kg
dissolution
GL reactor
2nd Step
Solvent recoveryMLR-1&MLR-2
Solvent lossTol: 25.0LSolvent loss Acetone:25L
Toluene Recov 450L Loss:25L
reaction
1000L
Conc HCL acid 21.0kgs(7.3+13.5)
Centrifuge
Solvent recovery MLRSSreactor 1000L
Flupentixolhydrochloride40.0 kgs
MLR-1 TolueneMLR-2 Acetone
Water 15.5kgs
SS reactor-1cap 600LToluene layer& MLR
SS reactor-1cap 600Lgrignard
Toluene/THF200L/10L
Trifluorothioxanthone28 kg Piperizino ethanol
Intermediate20kg
Water200L
Centrifuge
RecoveredToluene170L
Flupentixol Grignard base 45kg wet (cont 40kg)
MLR
Water-1includes206 kgs/MgCL
Solvent Loss:40L
Residue-1haz waste3.0kg
1st step Grignard reaction
Mg 2.5kg
Acetone wash 300L
Acetone recov:265Lloss:30L
Ester(Deconate)2nd Derivtive1:! Yield
Carbon -5kg
Spent carbon6 kgwet
Spent carbon 6 kg wet
2
5
3000M/s. R L Fine Chem Pvt. Ltd.,
- 89 -
3.5.2.13 MELITRACEN HCL
Reaction Scheme
N
.HCl+
Millitracen Grignard Base
Hydrochloric acid
Acetone
Millitracen Hydrochloride
309 36.5 327.5
OH
N
Water
18
.HCl
N
Millitracen Grignard Base
309
OHN
O
222
Cl
121
Dimethyl anthrone Dimethlamino propyl chloride
Toluene/THF
Mg
24
MgCl
59
H2O
MANUFACTURING PROCESS This involves 2 steps 1st step Dimethyl anthrone is reacted with Dimethyl amino propylchloride in Solvent mixture of THF and Toluene under nitrogen atmosphere using Magnessium catalyst (Grignard reaction) at temp <35*C. After the reaction is complete, the reaction mass is quenched with water and cooled < 15*C. Solid Hydroxy millitracene (Grignard intermediate is centrifuged to isolate the solid. Mother liquor from the centrifuge is taken to another SS reactor layers
3000M/s. R L Fine Chem Pvt. Ltd.,
- 90 -
separated and organic layer is sent for recovering the solvent Toluene. Recovered solvent is recycled. 2nd step The Hydroxy millitracene base is dissolved in Toluene by heating at 40-50 * C in SS reactor Char coaled and filtered. To the clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Millitracen hydrochloride crystals. These are centrifuged and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled. MILLITRACEN HYDROCHLORIDE Gravimetric/MASS BALANCE
SL NO PRODUCTION B Size 300kgs No of batchs 1/Month
Raw material used
1 THF 30L
2 Dimethyl anthrone 220kg
3 Dimethylamino propyl chloride 120 kg
4 Toluene 2200Lt (1st and 2nd step)
5 Water 600Lt (1st stage)
6 Mg 24kg
7 Acetone 1000L
8 Carbon 15kg
9 Con Hcl acid 100kg
Yield (Millitracen Hydrochloride) 295kgs
Batch size 300kgs --- Millitracen Hydrochloride
Input Reactors Output
THF – 30L SSR 2500L(for step 1 grignard Reaction)
Millitracen Hydrochloride Yield 295kg Overall yield 90%
Dimethyl anthrone – 220kg
SSR 600L (for step 1 workup)
I.Product:stage-1 ::94% Stage-2::96%:
Dimethylamino propyl chloride – 120kg
SSR 3000L (for step 2 dissolution)
Toluene: 1850L Loss: 380L (incld THF) Acetone: 825L Loss: 175L P.Water: Stage-1 ::660kg/L Conts MgCl Stage-2 :: 80kg Total water ::
Toluene – 2200L GLR 3000L (for step2 reaction)
Water – 600L SSR 3000L (for solvent recovery)
Mg – 24kg
Acetone – 1000L
3000M/s. R L Fine Chem Pvt. Ltd.,
- 91 -
740kg/L Cleaning water ::500L goes to CETP Hazardous waste: 28-32kg Spent carbon: 18Kg
Carbon – 15kg
Con Hcl acid – 100kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 4-6hrs -
3) Solvent recovery…… ------ 10-12hrs(MLR-2) 12-16hrs(MLR-3)
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 740kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 92 -
FLOW CHART FOR MILLITRACEN HYDRCHLORIDE
Toluene 1000LSS reactor-2cap 3000LDissolution
Haz Waste1 &2 28-32kgProcess Waste Water-1&2:; 740kgCleaning Waste Water : 500L
MilitrceneGrignard base 290.0 kgs
Total water ::1240L/kg
GL reactorcap 3000Lreaction
2nd Step
Solvent recoveryMLR-1&MLR-2
Solvent lossTol: 75.0LSolvent loss Acetone:75L
Toluene Recov 850L Loss:75L
Conc HCL acid 100 kg(35.0+65kg)
Centrifuge
Solvent recovery Cap 3000LSSreactor MLR
Militricene hydrochloride295 kgs
MLR-1 TolueneMLR-2 Acetone
Water-2 80kgs
SS reactor-1cap 600LToluene layer& MLR
SS reactor-1cap 2500Lgrignard
Toluene/THF1200L/ 30L
Dimethyl anthrone 220kg
Dimetylamino propyl chloride 120kg
Water 600L
Centrifuge
RecoveredToluene 1000LLoss :100L
Militricin Grignard base 305 crude (content )290kg
Water-1includes660 kgs/MgCL
Tol Solvent Loss:130 L
Residue-1haz waste9.0kg
1st step Grignard reaction
Mg 24kg
Acetone wash 1000L
Acetone recov:825Lloss:100L
Carbon -15kg
Spent carbon18 kgwet
Spent carbon 18 kg wet
MLR 19
11
3000M/s. R L Fine Chem Pvt. Ltd.,
- 93 -
3.5.2.14 CARBINOXAMINE MALEATE
Reaction scheme
NO
Cl
N NO
Cl
N+
CO2H
CO2H
Carbinoxamine Base Maleic acid Carbinoxamine Maleate
Acetone
.C4H4O4
290.5116
406.5
NO
Cl
N
Carbinoxamine Base
290.5
NClN
OH
Cl
219
107.5
Toluene
NaOH
40
NaCl H2O
58 18
Pyridine benz Hydrol
Dimethylamino ethyl chloride
MANUFACTURING PROCESS
This involves 2 steps
1st step
The Carbinoxamine base is obtained by reacting pyridine Benz hydrol with
dimethylamino ethyl chloride in SS reactor in suitable solvent like Toluene in presence
of sodium hydroxide base. After the reaction is complete, mass is quenched with
water and organic layer is separated.
This organic layer is then concentrated to remove Toluene by distillation to get a
syrupy liquid base.
The recovered Solvent toluene is purified in Solvent recovery plant and reused.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 94 -
2nd step
Carbinoxamine base is dissolved in Acetone in SS reactor, charcoaled and filtered. The
clear filtrate is transferred to Glass lined reactor and cooled to<10*C. The above
solution is cooled at temp <10*C treated with Maleic acid which is added slowly by
maintaining temperature below 10* C.
The above reaction mixture is refluxed for 6hrs at 65-70*C and the the mass is stirred
at temp <25*C for 2-4hrs and cooled to temp < 10 *C to get Carbinoxamine maleate
crystals which is separated by centrifuging to isolate the product and dried.
The mother liquor from the above centrifuge is sent for recovery of Acetone solvent
which is recycled.
CARBINOXAMINE MALEATE MASS BALANCE
SL NO PRODUCTION B Size350kg No of batchs 2/Month
Raw material used
1 Pyridine Benz Hydrol 220kg
2 NaOH 40kg
3 Dimethylamino Ethyl chloride 107kg
4 Toluene 1000Lt
5 Maleic acid 116kg
6 Water 600L
7 Acetone 1000L
8 Carbon 10kg
Yield (Carbinoxamine Maleate) 350kgs
Batch size 350kgs --- Carbinoxamine Maleate
Input Reactors Output
Pyridine Benz Hydrol – 220kg
SSR 3000L(for step 1 condensation)
Carbinoxamine Maleate Yield 350kg Overall yield 86%
NaOH – 40kg SSR 3000L (for step 1 workup)
I.Product: 1st stage: 93% 2nd stage :92%
Dimethylamino Ethyl chloride – 107kg
SSR 3000L (for step 2 dissolution reaction)
Toluene: 900L Loss: 100L Acetone: 825L Loss: 175L P. Water: stage-1 ::676kg/ L Incl NaCl Cleaming water 500L goes to CETP
Toluene – 1000L GLR 3000L (for step 2 reaction)
Maleic acid – 116kg SSR 2000L (for solvent recovery)
Water – 600L
3000M/s. R L Fine Chem Pvt. Ltd.,
- 95 -
Acetone – 1000L
Hazardous waste: 45-48kg Spent Carbon: 12kg
Carbon - 10kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 8-10hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
3) Solvent recovery…… ---- 10-12hrs(MLR-) ---
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP
along with process waste water 676kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 96 -
Acetone 1000LSS reactor-2cap 3000L
Haz Waste 46-48kg
Process Waste Water- : 675L/kgCleaning Waste Water : 500L
FLOW CHART FOR CARBINOXAMINE MALEATE
Carbinoxaminebase 270.0 kgs
Total waste water to CETP is 1250L
dissolution
2nd step
Maleic acid108kg
Centrifuge
SS reactorCap 2000LMLR
Recovered Acetone825L Loss :75L
Carbinoxamine Maleate 350kg
MLR AcetoneSolvent Loss :100L
SS reactor-1cap 3000LToluene layer
GLreactorcap 3000LReaction
SSreactor -1cap:3000L
condensation
Toluene 1000L
Pyridine BenzHydrol 220kg
DimethylaminoEthyl chloride 107kg
Water600L
RecoveredToluene900L Loss:100L
Carbinoxamine base290 kgcrude (content 270kg)
Water-1includes676 kgs/NaCL
1st stepNaOH 40kg
MLR
Solvent recovery
Carbon 10 kg
Spent carbon 12 kg
Spent carbon 12 kg
20
28
3000M/s. R L Fine Chem Pvt. Ltd.,
- 97 -
3.5.2.15 OPIPRAMOL HCL
Reaction scheme
N
N
NOH
.2HCl
N
N
NOH
Opipramol Base Opipramol Dihydrochloride
+ 2 HCl
Hydrochloric acid
36373 436
N
N
N
NOH
Opipramol Base
363
HN N
OH
Cl
269130
NaOH
Toluene
40
NaCl
58
H2O
18
Imino stilbene propyl chloride
Piperizino ethanol
N
Cl
269
Imino stilbene propyl chloride
Acetone
NH
ClBr
Imino stilbene Bromo chloro propane
193156
NaOH
Toluene
40
NaBr H2O
102 18
1st step
2nd step
3rd step
3000M/s. R L Fine Chem Pvt. Ltd.,
- 98 -
MANUFACTURING PROCESS
This involves 3 steps
1st step
Imino stilbene is reacted with 3-Bromo chloro propane in SSreactor using Toluene
solvent in presence of base Sodium hydroxide by refluxing for 14 hrs .after the
reaction is completed the mass is cooled and quenched with water. Top organic layer
is separated and Toluene layer is removed by distillation to get imino stilbene propyl
chloride liquid.
The toluene recovered is reused after purification in SRP.
2nd step
Iminostilbene propyl chloride is then converted to Opipramol base by refluxing with
Piperizine ethanol in Toluene solvent in SS reactor using base Sodium hydroxide for 20
hrs. After the reaction mass is quenched with water to get 2 layers which is
separated.
Top organic layer is concentrated by distilling toluene to get syrupy Opipramol liquid.
The recovered solvent from this is reused after purification in SRP.
3rd step
Opipramol base is dissolved in Acetone solvent in SS reactor to get clear solution,
which is charcoaled and filtered. Th clear solution is transferred to GLR Reactor.The
above solution is cooled to<10*C and hydrogen chloride gas is passed slowly over
aperiod of 2 hrs by maintaining temperature below 20* C till Ph 2 is achieved.
The above reaction mixture is stirred at temp <25*C for 4hrs and cooled to temp < 10
*C to get Opipramol Dihydrochloride crystals which is separated by centrifuging to
isolate the product and dried.
The mother liquor from the above centrifuge is sent for recovery of Acetone solvent in
SRP which is recycled.
OPIPRAMOL HYDROCHLORIDE Gravimetric/MASS BALANCE
SL NO PRODUCTION B size 200kg No of batchs 1/month
Raw material used
1 Imino stilbene 96kg
2 NaOH 40kg
3 Bromochloro Propane 78 kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 99 -
4 Toluene 2000Lt(1st stage& 2nd stage)
5 Piperizinoethanol 65kg
6 Water 1200kg(1st &2nd stage)
7 Acetone 1200L
8 Carbon 10kg
9 HCl 36
Yield (Opipramol Hydrochloride) 210kgs
Input Reactors Output
Imino stilbene – 96Kg SSR 3000L(for step 1 Dissolution Reaction)
Opipramol Hydrochloride Yield :195kg Overall yield 89%
NaOH – 40Kg SSR 3000L (for step 1 workup)
I.Product: 1st stage not isolated 2nd stage 95% 3rd stage 94%
Bromochloro Propane 78kg
SSR 3000L (for step 2 dissolution reaction)
Toluene: 1800L Loss: 200L Acetone: 1000L Loss: 200L P.Water: stage-1 :: 660kg/L (Conts NaBr) Stage-2 :: 638kg/L ContsNaCl) Total P Water ::1300kg/ L Cleaning water ::1000L goes to CETP Hazardous waste: 20-22kg Spent Carbon: 12kg
Toluene – 2000L SSR 2000L (for step2 workup)
Piperizinoethanol – 65kg
SSR 3000L (for step 1 dissolution )
Water – 1200kg/L GLR 3000L (for step 1 reaction)
Acetone – 1200L SSR 3000L (for solvent recovery)
Carbon - 10kg
HCl – 36Kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 14-16hrs 20-22hrs 6-8hrs Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs 4-6hrs-16hrs (MLR-3)
Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP along with process waste water 1080kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 100 -
Opipramol base170.0 kgs
HCL 36 kgs
SS reactor cap 3000Lsolvent recovery
Solv Loss DistillationAcetone 100.0L
Process Waste Water 1300kg/LCleaning waste Water :1000L
FLOW CHART FOR OPIPRAMOL HYDROCHLORIDE
MLR
Total waste water 2300L/kg
+Solvent loss 100.0 L Acetone
Acetonefor recycle1000.0L
Haz Waste 20-22 kgs
Solvent recoveryMLR
Acetone 1200L
Opipramol hydrochloride195.0kgs
1st Step
3rd step
SSreactor-2cap3000LDissolution Reaction
Imino stibene propylchloride 135kg
Piperizinoethanol65kg Toluene
1000L
NaOH 20kg
SSreactor-2cap3000L Work Up
SSreactor-1cap3000LDissolution Reaction
SSreactor-1cap3000LWork up
Water 600L
W/U
Water 638kg
Opipramol base170kg Liquid
Recov Toluene900L Loss:100L
Water660kg
Recov Toluene900L Loss:100L
Water600L
W/U
Imino stilbene 96kg kg
Toluene1000L
Bromo chloroPropane 78 kg
NaOH 20kg
Imino stilbenePropylchloride 140 kg liquid(content 135kg)2nd step
SS reactor-2cap 3000Ldissolution
Centrifuge
GLreactorcap 3000LReaction
Spent carbon 12 kgCarbon 10kg
Spent carbon 12kg
11
10
3000M/s. R L Fine Chem Pvt. Ltd.,
- 101 -
3.5.2.16 SULFADOXINE
Reaction scheme
N N
Cl
OCH3
Cl
N N
Cl
OCH3HN
NH2
H2N
O
S
O
NH2
O
S
O
+ NaCl + H2O
Methoxydi-chloro pyrimidine
p-aminosulfonamide
IntermediateSOdiumchloride
Water
179 172
310
58.5 18
+
+ NaOH
SOdium hydroxide 40
315
N N
H3CO
OCH3HN
NH2
O
S
O
NaOCH3Mol WT: 54
Sulfadoxine
SodiumChloride
N N
Cl
OCH3HN
NH2
O
S
O
Intermediate
315
1st stage
2nd stage
NaCl
58
MANUFACTURING PROCEDURE The reaction involves 2 stages 1st stage (production of sulphone intermediate involves 2 steps) 1st step reaction Methoxy dichloro pyrimidine is reacted with p –amino sulfonamide in presence of sodium hydroxide in toluene media at an elevated temperature of 1000 C in SS reactor. Water formed during the reaction is removed azeotropically. After the reaction is complete the reaction mass is cooled < 300 C and centrifuged to remove by-product sodium chloride.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 102 -
2nd step (Isolation of sulphone) The liquid mass from the centrifuge is taken in SS Reactor and treated with water and the reaction mass is cooled < 200 C. During this time sulphone intermediate crystallizes out. The product is separated by centrifuging and dried. The mother liquor is transferred for recovery of solvent. Solvent recovery The mother liquor in SS reactor is allowed to separate into 2 layers. The bottom aqueous layer is water, which goes to CETP. The top organic layer is distilled to recover toluene, which is recycled. 2nd stage (Involves 2-step) 1st step reaction The sulphone intermediate is refluxed in methanol solvent in presence of sodium methoxide. After the reaction is complete, the mass is cooled and centrifuged to remove sodium chloride by-product. The methanolic filtrate is taken back in SS reactor treated with carbon, filtered and the clear filtrate is concentrated by removing methanol, which is recycled. 2nd step (isolation of sulphadoxine) The concentrated mass is treated with water for 2-3 hrs and cooled to get Sulphadoxine, which is separated, by centrifuging and dried. The mother liquor is sent for recovery. Wastewater is sent to CETP. SULFADOXINE MASS BALANCE
SL NO PRODUCTION B Size 300kgs No of batchs 8/Month
Raw material used
1 P-Amino sulfonamide 172kg
2 Methoxy dichloro pyrimidine 179kg
3 Water 2000Lt(stage1&2)
4 Toluene 1500Lt(stage-1)
5 NaOH 40kg
6 Methanol 2000Lt(stage-2)
7 Sodium methoxide 54kg
8 Carbon 15kg
Yield (SULFADOXINE) 300kgs
Batch size 300kgs --- Sulfadoxine
Input Reactors Output
P-Amino sulphonamide – 172kg
SSR 5000L(for step A condensation reaction)
Sulfadoxine Yield :300kg Overall yield ::96.5%
Methoxy dichloro SSR 5000L (for step B) I.Product stage-1 ::98%
3000M/s. R L Fine Chem Pvt. Ltd.,
- 103 -
pyrimidine – 179kg Stage-2::98%
Water – 2000L SSR 3000L(for reaction) Toluene: 1250L Loss: 250L Methanol: 1800L Loss:200L P.Water stage-1 :1018kg/L Stage-2: 1006kg/L Total P Water :::2024kg/L By product NaCl:116kg Cleaning water :::1500L goes to CETP Hazardous waste: 5-8kg Spent Carbon: 18kg
Toluene – 1500L SSR 3000L (for workup)
NaOH – 40kg SSR 2000L (for solvent recovery)
Methanol – 2000L
Sodium methoxide – 54kg
Carbon – 15kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs -
3) Solvent recovery…… 10-14hrs (MLR-1) ----- ------
Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 2020kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 104 -
SS reactor-2cap 3000Lwork up
Haz Waste 5-8kg Process Waste Water-1&2 :2020LCleaning Waste Water-1&2: 1500 L
FLOW CHART FOR SULFADOXINE
Total waste water to CETP is 3520L
2nd step A
MLR Toluene from step1B
Recovered Toluene1250L Loss: 50L
Centrifuge
Solvent recovery MLRCap:;SSreactor 2000L
Recovered Methanol1800L Loss :100 L
Water-1000 kg/L
SS reactor-2cap 3000LReaction
SSreactor -1cap:5000Lcondensation
Toluene1500L
P-amino sulfonamide172kg
Methoxy di chloro pyrimidine 179kg
Centrifuge
Suphone Intermediate310kg
Solvent MethanolLoss:100L
1st step A
SSreactor -1cap:5000L
Centrifuge
Water18kg
Solvent Loss ::100L
Sodium Chloride 58.5kg
Water 1000L
CentrifugeSolvent Loss 100L
Sulphone Intermediate310kg
MLR 2-layers
Water layer 1000L and Tol layer toRecovery
Methanol 2000L
Sodium methoxide 54kg
Sodium chloride58 kg
Water1000L
!st step -B
2nd step B
Sulpha doxine300kg
Solvent recovery
NaOH 40kg
Carbon 15kg Spent carbon 18kg wet
spent carbon 18kg wet
5
5
By product NaCl 116kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 105 -
3.5.2.17 DOXEPIN HCL
Reaction scheme
O
N
OH
Doxiepinone Grignardbase
297
O
O
DoxiepinoneDimethylamino propyl chloride
210 121
THF/Toluene
Mg
MgClCl N
5924
+ HCl
O
N..HCl
31536
Hydrochloric acid Doxiepin HCl
TolueneO
N
OH
Doxiepinone Grignard base
297
H2O
18Acetone
MANUFACTURING PROCESS 1st step Doxiepinone is converted to Doxiepine Grignard base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction the mass is quenched in water and layers were separated. Top organic layer is transferred to other SS reactor and 50% Solvent is removed by distillation and the product Doxiepine Grignard base is isolated by cooling to < 5*C and centrifuging. The solid is taken for next step. The solvent is recovered and reused.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 106 -
2nd step The Doxiepine Grignard base is dissolved in Toluene by heating at 40-50 * C in SS reactor. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Doxiepine Hydrochloride crystals. These are centrifuged and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.
DOXIEPINE HYDROCHLORIDE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs ::1/Month
Raw material used
1 Mg 24kg
2 Dimethylamino propyl chloride 120kg
3 Toluene 2500L
4 Doxiepinone 210kg
5 THF 20Lt
6 Water 600Lt
7 Con Hcl 110kg
8 Acetone 1000Lt
9 Carbon 10kg
Yield (Doxiepine Hydrochloride) 280kgs
Batch size 300kg--- Doxiepine Hydrochloride
Input Reactors Output
Mg – 24kg SSR 3000L(for step 1 Grignard reaction)
Doxiepine Hydrochloride Yield :280kg Overall yield:89%
Dimethylamino propyl chloride – 120kg
SSR 3000L I.Product: stage-1::94% stage-2 ::94%
Toluene – 2500L SSR 3000L( for dissolution) Toluene: 2250L Loss: 250L (Contns 20L THF) Acetone: 825L Loss:175L P.Water: stage-1::660kg stage-2 ::90kg Total P water ::750kg/L Cleaming water ::500L goes to CETP Hazardous waste: 32-36kg
Doxiepinone – 210kg GLR 3000L(for reaction)
THF- 20L SSR 3000L (for solvent recovery)
Water – 600L
Con Hcl – 110kg
Acetone – 1000L
3000M/s. R L Fine Chem Pvt. Ltd.,
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Carbon – 10kg
Spent Carbon: 12kg
Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 20-23hrs 14-16hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) ----- Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 750kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 108 -
Toluene1500L SS reactor-2cap 3000L
Haz Waste 1& 2 32-36kg
Process Waste Water-1&2 :750kgCleaning Waste Water : 500L
FLOW CHART FOR DOXIEPINE HYDRCHLORIDE
Doxiepine Grignard base280.0 kgs
Total waste water to CETP is 1250L
dissolution
2nd step
MLR -1MLR-2
MLR-1 TolueneSolvent loss:75L
Recovered Toluene1350L Loss:75L
Conc HCL acid 110.0kgs(36+70)
Centrifuge
Solvent recovery MLRCap:;SSreactor 2000L Recovered Acetone
825L Loss :75L
Doxiepinehydrochloride280.0 kgs
Water-290.0kgs
MLR -2 AcetoneSolvent Loss :100L
Acetone 1000L(Top wash)
SS reactor-1cap 3000LToluene layer& MLR
GLreactorcap 3000LReaction
SSreactor -1cap:3000L
Grignard
Toluene/THF1000/20L
Doxiepinone210kg
Dimethylaminopropyl chloride120kg
Water600L
Centrifuge
RecoveredToluene900L
Doxiepine Grignard base280 Kg
MLR
Water-1includes660 kgs/MgCL
Solvent Loss:120L(contains THF20L)
Residue-1haz waste13.0kg
1st step
Mg 24
Carbon 10 kg
Spent carbon 12kg wet
Spentcarbon 12 kg wet
17
17
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.18 NITRAZEPAM
Reaction sheme
N
HN
O2N
O
+ 2NH4Cl
+ Ammonia3
51
281
Nitrazepam
Ammonium chloride
106
O
NH2
O2NCl
O
318.5
O
HN
O2N
Cl
O
Nitro chloro intermediate
5-nitro 2amino benzophenone
Cl
chloro ethyl acetyl chloride
112
+
H2O
18
+
242
Toluene
Methanol
MANUFACTURING PROCESS 5-Nitro 2-Amino Benzophenone ( Nitro amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Nitro chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is cooled and centrifuged .Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake is dissolved in Methanol and the clear solution is Nitro chloro intermediate which is taken in SS reactor.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 110 -
The Nitro Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in solvent methanol for 8 hrs at temp 65* C and cooled to isolate by product Ammonium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Nitrazepam which separates as crystals. These crystals are centifuged and the pure Nitrazepam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.
NITRAZEPAM MASS BALANCE SL NO PRODUCTION 250kg
Raw material used
1 Chloroacetyl chloride 112kg
2 2-amino 5-nitro benzophenone 242kg
3 Toluene 1000L
4 Ammonia 51kg
5 Carbon 10kg
6 Methanol 1250Lt
Yield (Nitrazepam) 250kgs
Batch size 250kgs --- Nitrazepam
Input Reactors Output
Chloroacetyl chloride – 112kg
GLR 2000L(for step 1 reaction)
Nitrazepam Yield ::240kg Overall yield :85%
2-amino 5-nitro chloro benzophenone – 242kg
SSR 2000L (for reaction) Product: stage-1:94% wet stage-2 ::91%
Toluene – 1000L SSR 2000L( for methanol solution)
Toluene: 850L Loss: 150L Methanol: 1000L Loss:250L P.Water: nil Am Chloride:125kg incl water and scrubbed HCL Cleaning water ::1000L goes to CETP Hazardous waste: 40-45kg Spent Carbon: 12kg
Ammonia – 51kg SSR 2000L (for solvent recovery)
Carbon – 10kg
Methanol – 1250L
3000M/s. R L Fine Chem Pvt. Ltd.,
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Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 12-16hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) ----- Water along with cleaning water sent to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
- 112 -
Process Waste Water :: NilCleaning waste Water :1000LTotal water ::1000L/kg
SS reactor-2 cap 2000LMethanol solution
SSreactor 2000Lfor solvent recoveryMLR
FLOW CHART FOR NITRAZEPAM
Methanol 1000LSolv loss 100L
Haz Waste1&2 ::40-45kg
MLR-1 TolueneMLR-2 Methanol
GL reactor-1 cap:2000LRection
Chloroacetylchloride 112kg
2-amino 5-Nitro benzophenone 242kg
Toluene 1000L
1st step
Spentcarbon 12 kg wet
Centrifuge Solv loss75L MLR-1
Nitrochloro intermediatewet 315kg(actual 300kg)
Methanol1250L
HCl 36 kg scrubber
Ammonia 51kg
Filter-Nutch Wet Am.Cl 125kg inclu 18kg water
Solv methanolloss 75L
Centrifuge
2nd step
Am.Choride 125kg wet
Tolu recov 850Lloss 75L
Nitrochloro intermediate 300kg
SS reactor-1 cap 2000L reaction
Carbon10kg
Spent C12kg
Solution Reaction mass Taken back
Solv loss 75LMLR-2
Nitrazepam240kg 23
18
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.19 DOTHIEPIN HCL
Reaction scheme S
N
OH
Dothiepinone Grignardbase
313
S
O
DothiepinoneDimethylamino propyl chloride
226 121
THF/Toluene
Mg
MgClCl N
5924
+ HCl
S
N..HCl
331.536.5
Hydrochloric acid Dothiepin HCl
TolueneS
N
OH
Dothiepinone Grignard base
313
H2O
18Acetone
Manufacturing process 1st step Dothiepinone is converted to Dothiepinone Grignard base by reacting with dimethylamino propylchloride in solvent THF and Toluene (Grignard reaction) at <35*C.in SS reactor over a period of 20 hrs. After the reaction the mass is quenched in water and layers were separated. Top organic layer is transferred to other SS reactor and 50% Solvent is removed by distillation and the product Dothiepine Grignard base is isolated by cooling to < 5*C and centrifuging. The solid is taken for next step.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 114 -
The solvent is recovered and reused. 2nd step The Dothiepine Grignard base is dissolved in Toluene by heating at 40-50 * C in SS reactor. The clear solution from above is added slowly to conc Hydrchloric acid in glass lined reactor and then refluxed for 12-14 hrs with simultaneous removal of water Azetrope. After the removal of water reaction is complete, cooled gradually over a period of 2-4 hrs to temp < 15*C to get Dothiepine hydrochloride crystals. These are centrifuged and the solid is dried. The mother liquor from the centrifuge is sent for solvent recovery and the recovered solvent is recycled.
DOTHIEPINE HYDROCHLORIDE Gravimetric/MASS BALANCE SL NO PRODUCTION B size 300kg No of batchs : 4/Month
Raw material used
1 Mg 24kg
2 Dimethylamino propyl chloride 120kg
3 Toluene 1000L
4 Dothiepinone 226kg
5 THF 20Lt
6 Water 600Lt
7 Con Hcl 110kg
8 Acetone 1000Lt
9 Carbon 10kg
Yield (Dothiepine Hydrochloride) 295kgs
Batch size 300kgs --- Dothiepine Hydrochloride
Input Reactors Output
Mg – 24kg SSR 3000L(for step 1 Grignard reaction)
Dothiepine Hydrochloride Yield :295kg Oveall yield :89%
Dimethylamino propyl chloride – 120kg
SSR 3000L Product: stage -1 :94% Stage-2 :: 94.5%
Toluene – 2500L SSR 3000L( for dissolution) Toluene: 2250L Loss: 250L Acetone: 825L Loss:175L P.Water: stage-1:660kg/L (Contns Mg Cl ) Stage-2 :: 90kg/L Total P water ::750kg/L Cleaning water :500L goes to CETP Hazardous waste: 35 -
Dothiepinone – 226kg GLR 3000L(for reaction)
THF- 20L SSR 3000L (for solvent recovery)
Water – 600L
Con Hcl – 110kg
Acetone – 1000L
3000M/s. R L Fine Chem Pvt. Ltd.,
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Carbon – 10kg
40kg Spent Carbon: 12kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 20-23hrs 14-16hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 750kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 116 -
Toluene1500L SS reactor-2cap 3000L
Haz Waste 1& 2 35-38kg
Process Waste Water-1&2 :750kgCleaning Waste Water : 500L
FLOW CHART FOR DOTHIEPINE HYDRCHLORIDE
Dothiepine Grignard base295.0 kgs
Total waste water to CETP is 1250L
dissolution
2nd step
MLR -1MLR-2
MLR-1 TolueneSolvent loss:75L
Recovered Toluene1350L Loss:75L
Conc HCL acid 110.0kgs(36+70)
Centrifuge
Solvent recovery MLRCap:;SSreactor 2000L Recovered Acetone
825L Loss :75L
Dothiepinehydrochloride295.0 kgs
Water-290.0kgs
MLR -2 AcetoneSolvent Loss :100L
Acetone 1000L(Top wash)
SS reactor-1cap 3000LToluene layer& MLR
GLreactorcap 3000LReaction
SSreactor -1cap:3000L
Grignard
Toluene/THF1000/20L
Dothiepinone226kg
Dimethylaminopropyl chloride120kg
Water600L
Centrifuge
RecoveredToluene900L
Dothiepine Grignard base295 Kg
MLR
Water-1includes660 kgs/MgCL
Solvent Loss:120L(contains THF20L)
Residue-1haz waste13.0kg
1st step
Mg 24
Carbon 10 kg
Spent carbon 12kg wet
Spentcarbon 12 kg wet
17
18
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.20 BROMAZEPAM
N
HN
Br
N
O
2NH4Cl
+
Ammonia3
51
353.5
316
Bromazepam
Ammonium chloride
106
+ Water (18)
O
HN
Br
N
Cl
O
bromo chloro intermediate
O
NH2
Br
N
Cl
O
Cl
277112
Chloro acetyl chloride2-amino 5-bromo benzoyl pyridine
Reaction scheme
Toluene
Methanol
MANUFACTURING PROCESS 5-Bromo2-Amino Benzoyl pyridine ( Bromo amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Bromo chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is cooled and centrifuged .Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake isdissolved in Methanol and the clear solution is Bromo chloro intermediate which is taken in SS reactor.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 118 -
The Bromo Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in sovent methanol for 10hrs at temp 65* C and cooled to isolate by product Ammonium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Bromazepam which separates as crystals. These crystals are centifuged and the pure Bromazepam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.
BROMAZEPAM MASS BALANCE SL NO PRODUCTION B Size 60 kg No of batchs ::1/Month
Raw material used
1 Chloroacetyl chloride 30kg
2 2-amino 5-bromo benzoyl pyridine 70kg
3 Toluene 600L
4 Ammonia 14kg
5 Carbon 5kg
6 Methanol 800Lt
Yield (Bromazepam) 60kgs
Batch size 100kgs --- Bromazepam
Input Reactors Output
Chloroacetyl chloride – 30kg
GLR 2000L(for step 1 reaction)
Bromazepam Yield ::60kg Overall yield :75%
2-amino 5-bromo benzoyl pyridine – 70kg
SSR 2000L (for reaction) Product: stage-1:90% wet stage-2 :: 83%
Toluene – 600L SSR 2000L( for methanol solution)
Toluene: 500L Loss: 100L Methanol: 600L Loss:200L P.Water: nil Am Chloride: 30kg incl water and scrubbed HCL Cleaning water ::1000L goes to CETP Hazardous waste: 20-25kg Spent Carbon: 7kg
Ammonia – 14kg SSR 2000L (for solvent recovery)
Carbon – 5kg
Methanol – 800L
3000M/s. R L Fine Chem Pvt. Ltd.,
- 119 -
Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 12-16hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1,) 10-14hrs (MLR-2) ----- Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
- 120 -
Process Waste Water :: NilCleaning waste Water :1000LTotal water ::1000L/kg
SS reactor-2 cap 2000LMethanol solution
SSreactor 2000Lfor solvent recoveryMLR
FLOW CHART FOR BROMAZEPAM
Methanol 600LSolv loss 75L
Haz Waste1&2 ::20-23kg
MLR-1 TolueneMLR-2 Methanol
GL reactor-1 cap:2000LRection
Chloroacetylchloride 30kg
2-amino 5-bromo benzoyl pyridine 70kg
Toluene 600L
1st step
Spentcarbon 7 kg wet
Centrifuge Solv loss50L MLR-1
Bromochloro intermediate88kg wet (actual 80kg)
Methanol800L
HCl 9 kg scrubber
Ammonia 14kg
Filter-Nutch Wet Am.Cl 30kg inclu 4kg water
Solv methanolloss 75L
Centrifuge
2nd step
Am.Choride 30kg wet
Tolu recov 500Lloss 50L
Bromo chloro intermediate 80kg
SS reactor-1 cap 2000L reaction
Carbon5kg
Spent C7kg
Solution Reaction mass Taken back
Solv loss 50LMLR-2
Bromazepam60kg 12
8
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.21 FLUNARAZINE HCL
HN
NH
F
F
HO
N
NF
F
+
Cinnamyl alcohol
Flunarazine Base
N
NF
F
Flunarazine Base
N
NF
F
Flunarazine Dihydrochloride
.2HCl
OH
4,4'-difulorobenzhydrol
HCl
Piperizine
86
134
36
NaOH
40
NaCl 3 H2O
58 54
404220
404 477
2 HCl
Acetone
Methanol
2nd step
1st step
Reaction scheme
73
MANUFACTURING PROCESS The process involves 2 steps 1st step A 4, 4’DifluoroBenzhydrol is reacted with HCl in Glass reactor to get corresponding Benzhydryl chloride at temp ~60-70*C which, after10hrs, the reaction is checked for completion and the reaction is worked up by extraction with Toluene solvent. The resultant mass is having 2 layers which is separated .Top toluene layer contains Chloro fluro Benzhydryl intermediate which is taken in SS reactor for conversion to Chloro FluroBenzhydryl piperizine .
3000M/s. R L Fine Chem Pvt. Ltd.,
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1st step B Chloro Fluro Benzhydryl intermediate in Toluene is condensed with Piperizine in presence of NaOH base and water is removed azeotropicaly to get Di FluroBenzhydryl piprizine and refluxed for 6hrs more. After the reaction the toluene layer is washed with water and Top organic layer containing Piperizine derivative is taken in another SS reactor in next step. 1st stepC The above Di FluroBenzhdryl piperizine in toluene solvent treated with Cinnamyl alcohol which is slowly added over a period of 5-6 hrs. The resultant reaction mixture is then refluxed for 10-12 hr with slow removal of water by azeatropic distillation. After complete removal of water, the reaction is checked for completion .The solvent is totally removed to get Flunarizine base crude. Recovered toluene is reused. 2nd step The crude Flunarizine base is dissolved in Acetone solvent to get clear solution which is reacted with HCl to get Flunarizine DiHydrochloride which is centrifuged. This Flunarizine Dihydrochloride is purified by dissolving in Methanol and clear solution is chrcoaled and filtered.The clear solution is 50% concentrated and mass is cooled to <10*C during which period crystals of Flunarizine separates out. The product is centrifuged, and dried. The mother liquor from the centrifuge is sent for recovering acetone and Methanol which is recycled. FLUNARIZINE MASS BALANCE SL NO PRODUCTION 400kg
Raw material used
1 Difluro Benzhydrol 220kg
2 Piperizine 86kg
3 Toluene 1500L
4 HCl 36kg
5 NaOH 40kg
6 Water 1425Lt
7 Cinnamyl alcohol 134kg
8 Acetone/IPA 2000Lt
9 Carbon 15kg
10 Methanol 2000L
11
Yield (Flunarizine) 430kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
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Batch size 400kgs --- Flunarizine Input Reactors Output
Difluro Benzhydrol – 220kg GLR 4000L(for step 1 reaction)
Flunarizine Yield ::430kg Oveall yield :90%
Piperizine – 86kg SSR 4000L (for condensation) I.Product: stage-1 ::(not isolated wet) is taken for next step Stage-2 :: 90%
Toluene – 1500L SSR 4000L( for condensation) Toluene: 1300L Loss: 200L Methanol: 1700L Loss:300L Acetone+IPA: 1650L Loss:350L P.Water: stage-1 ::300L/kg Stage1B ::695kg/L (Contns NaCl) Stage-1C :620kg/L Total P water :: 1615kg/L Cleaning water ::1500L goes to CETP Hazardous waste: 45-48kg Spent Carbon: 18kg
HCl – 110kg(36kg+74kg) GLR 4000L(for step 2 reaction)
NaOH – 40kg SSR 4000L (for crystalisation)
Water – 1425L SSR 3000L (for solvent recovery)
Cinnamyl alcohol – 134kg
Acetone/IPA – 2000L
Carbon – 15kg
Methanol – 2000L
HCl Gas::73kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 30-36hrs 14-16hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) -----
Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 1615kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
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Process Waste Water-1,2&3 :1615kg/LCleaning Waste Water-1&2 :1500 LTotal water ::3115kg/L
FLOW CHART FOR FLUNARIZINE
2nd step A
Centrifuge
Solvent recovery Cap:;3000LSSreactor MLR-1&2
GLR reactor-1cap 4000LReaction
GLRreactor -1cap:4000Lreaction
Toluene 1500L
DifluroBenzhydrol220kg
HCl acid110kg( 36 + 74kgwater)
Centrifuge
Flunarizine crude405kg wet
1st step A
SSreactor -1cap:4000LCondensation-1
Piperizine 86kg
Acetone/IPA2000L
1st step -B
2nd step B
Spent carbon 18kg wet
Water-2695L/Kgcont NaCl
Water-1300L
Water 225L
SS REactor-2cap 4000Lcondensation -2Tolu layer
NaOH 40kg
Water 600L
Cinnamyl alcohol134 kg
Water 600L
Recov Toluene1300L
Water-3620kg
Flunarizine crude405kg wet
1st step C
Solv Acetoneloss 200L MLR-1
Flunarizine hydrochloride 455kg wet
MLR-1 acetoneMLR-2 methanol
Recov Acetone1650L loss:150L
Haz waste 45-48kgSpent Carbon 18kg wet
HCl 73kg
SS reactor-3cap 4000LCrystallisation
Methanol2000L
Carbon 15 kg
Flunarizine hydrochloride430kg
Centrifuge Solv methanolloss:: 200L MLR-2
20
25
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.22 CINNARAZINE
HN
NH
Benzhydrol
+
HO
Cinnamyl Alcohol
N
N
CinnarizineCrude
N
N
CinnarizineCrude
N
NAcetoneCharcoalcrystalize
Cinnarizine pure
OH
134
Piperizine
86
184
HCl
NaOH
40
36
Toluene
368
3 H2O
54
1st step
2nd step
NaCl
58
Reaction scheme
MANUFACTURING PROCESS The process involves 2 steps 1st stepA Benzhydrol is reacted with HCl acid in Glass reactor to get Benzhydryl chloride at tem ~60-70*C which , after10hrs , the reaction is checked for completion and the reaction is worked up by extraction with Toluene .The resultant mass is having 2 layers which is separated .Top toluene layer contains Chloro Benzhydryl intermediate which is taken in SS reactor for conversion to Benzhydryl piprizine .
3000M/s. R L Fine Chem Pvt. Ltd.,
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1st step B Chloro Benzhydryl intermediate in Toluene is condensed with Piperizine in presence of NaOH base and water is removed azeotropicaly to get Benzhydryl piprizine and refluxed for further 6hrs. After the reaction the toluene layer is washed with water and Top organic layer containing Piperizine derivative is taken in another SS reactor in next step. 1st stepC The above Benzhydryl piperizine in toluene solvent is then treated with Cinnamyl alcohol which is slowly added over a period of 5-6 hrs. The resultant reaction mixture is then refluxed for 10-12 hr with slow removal of water by azeatropic distillation. After complete removal of water, the reaction is checked for completion .The solvent is totally removed and quenched with water to get Cinnarizine crude which is centrifuged. Recovered toluene is reused. 2nd step The crude Cinnarizine is dissolved in Acetone or IPA solvent to get clear solution which is charcoaled and filtered. The clear solution is 50% concentrated and mass is cooled to <10*C during which period crystals of Cinnarizine separates out. The product is centrifuged, and dried. The mother liquor from the centrifuge is sent for recovering acetone which is recycled. CINNERIZINE MASS BALANCE SL NO PRODUCTION B size 400kg No of batchs ::7/Month
Raw material used
1 Benzhydrol 184kg
2 Piperizine 86kg
3 Toluene 1500L
4 HCl 36kg
5 NaOH 40kg
6 Water 1425Lt
7 Cinnamyl alcohol 134kg
8 Acetone/IPA 2000Lt
9 Carbon 15kg
10 Methanol 2000L
Yield (Cinnerizine) 330kgs
Batch size 400kgs --- Cinnerizine Input Reactors Output
Benzhydrol – 184kg GLR 4000L(for step 1 reaction)
Cinnerizine Yield :330kg Overall yield ::90%
Piperizine – 86kg SSR 4000L (for condensation) I.Product: stage1A,B C not
3000M/s. R L Fine Chem Pvt. Ltd.,
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isolated Stage-2:90%
Toluene – 1500L SSR 4000L( for condensation) Toluene: 1300L Loss: 200L Methanol: 1700L Loss:300L Acetone+IPA: 1650L Loss:350L P.Water: stage-1A::300kg/L Stage -1B :::695kg/L (Contns NaCl) Stage -1C ::620kg Total P water ::: 1615kg/L Cleaning water 1500L goes to CETP Hazardous waste: 34-38kg Spent Carbon: 18kg
HCl – 110kg(36kg+74kg) GLR 4000L(for step 2 reaction)
NaOH – 40kg SSR 4000L (for crystalisation)
Water – 1425L SSR 3000L (for solvent recovery)
Cinnamyl alcohol – 134kg
Acetone/IPA – 2000L
Carbon – 15kg
Methanol – 2000L
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 30-36hrs 14-16hrs - Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1,2) 10-14hrs (MLR-3) -----
Water used for washing/cleaning equipment, cleaning waste water 1500L goes to CETP along with process waste water 1615kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
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Process Waste Water-1,2&3 :1615kg/LCleaning Waste Water-1&2 :1500 LTotal water ::3115kg/L
FLOW CHART FOR CINNERIZINE
2nd stepCrystallisation
Centrifuge
Solvent recovery MLRCap:;SSreactor 2000L
SS reactor-3cap 4000LReaction
GLRreactor -1cap:4000Lreaction
Toluene 1500L
Benzhydrol 184kg
HCl acid110kg( 36 + 74kgwater)
Centrifuge
Cinnarizine crude 370kg
1st step A
SSreactor -1cap:4000LCondensation-1
Piperizine 86kg
Acetone/IPA2000L
1st step -B
Carbon 15kg
Spent carbon 18kg wet
Water-2695L/Kgcont NaCl
Water-1300L
Water 225L
SS REactor-2cap 4000Lcondensation -2Tolu layer
NaOH 40kg
Water 600L
Cinnamyl alcohol134 kg
Water 600L
Recov Toluene1300L
Water-3620kg
Cinnarizine crude370kg wet
1st step C
Solv loss 200LMLR
Cinnarizine Pure330kg
MLR
Recov Acetone1650L loss:150L
Haz waste 34-38kgSpent Carbon 18kg wet
38
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.23 CLONAZEPAM
Reaction scheme
N
HN
O2N
O
+ 2NH4Cl
+ Ammonia3
51
315.5
Clonazepam
Ammonium chloride
106
O
NH2
O2NCl
OCl
Cl
353
O
HN
O2N
Cl
O
Nitro Dichloro intermediate
Cl
5-nitro 2amino 2'chlorobenzophenone
276
Cl
chloro ethyl acetyl chloride
112
+
H2O
18
+
Toluene
Methanol
MANUFACTURING PROCESS 5-Nitro 2-Amino 2’Chloro Benzophenone ( Nitro chloro amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Nitro Di chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is cooled and centrifuged .Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake isdissolved in Methanol and the clear solution is Nitro dichloro intermediate which is taken in SS reactor. The Nitro Di Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in sovent methanol for 10 hrs at temp 65* C and cooled to isolate by product Ammonium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled).
3000M/s. R L Fine Chem Pvt. Ltd.,
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The concentrated mass is further cooled to 15* C to get Clonazepam which separates as crystals. These crystals are centifuged and the pure Clonazepam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.
CLONAZEPAM MASS BALANCE SL NO PRODUCTION B size 100kg No of batchs 1/Month
Raw material used
1 Chloroacetyl chloride 56kg
2 2-amino 5-nitro chloro benzophenone 138kg
3 Toluene 600L
4 Ammonia 25kg
5 Carbon 5kg
6 Methanol 800Lt
Yield (Clonazepam) 135kgs
Batch size 100kgs --- Clonazepam
Input Reactors Out put
Chloroacetyl chloride – 56kg
GLR 2000L(for step 1 reaction)
Clonazepam Yield ::130kg Overall yield :83%
2-amino 5-nitro chloro benzophenone – 138kg
SSR 2000L (for reaction) Product: stage-1:91% wet stage-2 ::91%
Toluene – 600L SSR 2000L( for methanol solution)
Toluene: 500L Loss: 100L Methanol: 600L Loss:200L P.Water: nil Am Chloride: 60kg incl water and scrubbed HCL Cleaning water ::1000L goes to CETP Hazardous waste: 26-30kg Spent Carbon: 7kg
Ammonia – 25kg SSR 2000L (for solvent recovery)
Carbon – 5kg
Methanol – 800L
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 12-16hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1,) 10-14hrs (MLR-2) -----
Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
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Process Waste Water :: NilCleaning waste Water :1000LTotal water ::1000L/kg
SS reactor-2 cap 2000LMethanol solution
SSreactor 2000Lfor solvent recoveryMLR
FLOW CHART FOR CLONAZEPAM
Methanol 600LSolv loss 75L
Haz Waste1&2 ::26-30kg
MLR-1 TolueneMLR-2 Methanol
GL reactor-1 cap:2000LRection
Chloroacetylchloride 56kg
2-amino 5-Nitro Chloro benzophenone 138kg
Toluene 600L
1st step
Spentcarbon 7 kg wet
Centrifuge Solv loss50L MLR-1
Dichloro nitrointermediate160kg
Methanol800L
HCl 18 kg scrubber
Ammonia 25kg
Filter-Nutch Wet Am.Cl 60kg inclu 9kg water
Solv methanolloss 75L
Centrifuge
2nd step
Am.Choride 60kg wet
Tolu recov 500Lloss 50L
Dichloro Nitro intermediate160kg
SS reactor-1 cap 2000L reaction
Carbon5kg
Spent C7kg
Solution Reaction mass Taken back
Solv loss 50LMLR-2
Clonazepam130kg 13
16
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.24 LORAZEPAM
N
N
Cl
H O
Cl
O+ (CH3CO)2O
N-Oxide intermediate
320
Acetic anhydride
102
+ 2 NaOH
Sodium Hydroxide
80
N
N
Cl
HO
Cl
OH
Lorazepam
320
+ 2 CH3CO2Na
Sodium acetate
164
O
NH2
Cl
+
266
+
Cl
ClO
112
2-amino-2'5 Dichloro benzophenone
Chloroacetyl chloride
2 Water
Methanol
NH2OH
Hydroxylamine
33
Cl
N
N
Cl
H O
Cl
O
N-Oxide intermediate
320
2nd stage
1st stage
Reaction scheme
NaCl
NaOH
40
58 36
H2O
18
O
NH
Cl
Cl
ClO
341.5
Trichloro intermediate
HCl
36.5
O
NH
Cl
Cl
ClO
341.5
Trichloro intermediate
Toluene
3000M/s. R L Fine Chem Pvt. Ltd.,
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MANUFACTURING PROCESS 1st step 2-Amino 2’5 DiChloro Benzophenone ( Di chloro amino Ketone) is reacted with chloro acetyl chloride in solvent toluene in presence of Sodium hydroxide by refluxing for 10-12 hrs ;to get Tri chloro intermediate in GLreactor , After the reaction the mass is cooled and centrifuged. Wet cake is taken for next step .Toluene layer is distilled to recover solvent. Wet cake isdissolved in Methanol and the clear solution is Trichloro intermediate which is taken in SS reactor. The Tri Chloro intermediate in SS reactor is then reacted with Hydroxylamine by refluxing in solvent methanol for 12hrs at temp 65* C in presence of Sodium hydroxide After the reaction is complete the mass is cooled to isolate by product sodium chloride which is removed by filtration.The resultant filtrate is concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Lorazepam N-oxide intermediate which separates as crystals. These crystals are centrifuged and the pure N-oxide intermediate is dried. 2nd step The N-oxide intermediate is taken in toluene solvent in GL reactor and refluxed for 6hrs with Acetic anhydride and the resultant reaction mass is quenched with Sodium hydroxide solution.The layers separated and top organic layer is charcoaled with carbon and filtered The filtrate is transferred to ss reactor back and concentrated to recover solvent which is reused after purification in Solvent recovery plant The aqueous layer contains sodium acetate. The concentrated mass is treated with methanol solvent to get slurry of Lorazepam. This slurry is further chilled to 15*C and centrifuged to get Lorazepam which is dried The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. Both recovered solvents are purified in Solvent recovery plant and reused. The residual mass remaining as undistilled is taken as Haz waste.
LORAZEPAM MASS BALANCE SL NO PRODUCTION B size 100kg No of batchs :1/Month
Raw material used
1 Chloroacetyl chloride 56kg
2 2-amino dichloro benzophenone 133kg
3 Water 600Lt
4 Toluene 1200Lt
5 NaOH 60kg
3000M/s. R L Fine Chem Pvt. Ltd.,
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6 Hydroxyl amine 16kg
7 Carbon 10kg
8 Methanol 1300L
9 Acetic anhydride 45kg
Yield (Lorazepam) 130kgs
Batch size 100kgs --- Lorazepam
Input Reactors Output
Chloroacetyl chloride – 56kg
GLR 2000L(for step 1 reaction)
Lorazepam Yield ::130kg Overall yield ::81%
2-amino dichloro benzophenone – 133kg
SSR 2000L (for reaction) I.Product: stage-1 :87.5% Stage-2 :93%
Water – 600L SSR 2000L(for methanol solution)
Toluene: 1000L Loss: 200L Methanol: 1050L Loss:250L P.Water: stage-2 690kg/ L By product : Hcl : 18kg sent for scrubbing Na Cl ::48kg (contns 9kg water) Cleaning water 1000L goes to CETP Hazardous waste: 24-28kg Spent Carbon: 12kg
Toluene – 1200L GLR1000L (for reaction)
NaOH – 60kg SSR 2000L (for workup)
Hydroxyl amine – 16kg SSR 2000L (for concentration & isolation)
Carbon – 10kg SSR 2000L (for solvent recovery)
Methanol – 1300L
Acetic anhydride – 45kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) -----
P Water used 690kg and for washing/cleaning equipment, cleaning waste water 1000Lalong with process water goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
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Process Waste Water ::690 kgCleaning waste Water :1000LTotal water ::1690L/kg
SS reactor-2 cap 2000LMethanol solution
GLreactor cap1000LReaction
SSreactor 2000Lfor solvent recoveryMLR
FLOW CHART FOR LORAZEPAM
Methanol 1050LSolv loss 125L
Haz Waste1A 1B&2 ::31-35kg
MLR-1 TolueneMLR-2&3 Methanol
2nd Step
GL reactor-1 cap:2000LRection
SS Reactor-1cap:2000L reaction
Chloroacetylchloride 56kg
2-amino dichlorobenzophenone 133kg
Toluene 600L
1st step A
Spentcarbon 12 kg wet
Centrifuge Solv loss50L MLR-1
Trichlorointermediate160kg
11
Methanol800L
HCl 18 kg scrubber
Hydroxylamine 16kg
NaOH 20kg
Filter-Nutch Wet NaCl48kg
Solv methanolloss 75L
CentrifugeSolv methanolloss 75LMLR-2
N-Oxide intermediate140Kg
10
N-oxide intermediate140kg
Acetic anhydride45kg
SS Reactor-3cap2000Lw/up
NaOH 40kg
Water 600L
SS Reactor-3cap2000LConc & isolatn
Water layer690kg(sod acet)
Recov Toluene550L loss::50L
Toluene 600L
Methanol500L
CentrifugeSol methanolloss:50L MLR-3Lorazepam
130kg
10
1st step1B
Carbon 10kg
Spent Carbon 12kg
Sod chloride 48kg wet
Tolu recov 500Lloss 50L
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.25 DULOXETINE HCL
SO S
O
N
SOH
N
SO
N
F
Duloxetine base
2-Acetyl thiophene
CH2O
S O
N
183
Keto intermediate
NH
Hydroxy Intermedite
SOH
N
297
311
S O
NH
SO
N
Reaction scheme
1st step
2nd step
Keto intermediate
183
Methanol
Toluene
185
Hydroxy intermediate
185Fluro naphthaleene
146 Ether intermediate
Ether intermediate
311
KOH
56
DMSO
KF H2O
58 18
H2
2
Cat
3rd step
4th step
KOH
56
Toluene
S O
NH
.HCl
Duloxetine Hydrochloride
333
HCl 36
Acetone
126
3045
H2O
18
KOCH3
70
3000M/s. R L Fine Chem Pvt. Ltd.,
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Manufacturing process This involves 4 steps 1st step 2- Acetyl thiophene is mixed with Formaldehyde and Dimethylamine in SS reactor in Solvent Toluene. The reaction is carried at reflux temp ~105*C for 18hrs and after the reaction is complete the mass is quenched with water, to get Keto intermediate as fine crystalline solid. This is isolated by centrifuging and solid is dried and taken for next step. The Mother liquor is separated off 2 layers and Top toluene layer is sent for recovery of solvent toluene which is reused. 2nd step The keto intermediate is dissolved in Methanol and reduced by hydrogen using Ni catalyst to get Hydroxy intermediate in SS reactor at 50*C . After 10hrs the reaction will be completed and the mass is filtered to remove catalyst. The clear filtrate is concentrated to get thick mass which is dissolved in DMSO and taken for 3rd step. The solvent is sent for recovery and reuse. The catlalyst is used in next step. 3rd step The hydroxy intermediate solution in DMSO is heated in SS reactor is condensed with Fluoro naphthalene using base KOH by refluxing for 12hrs, to get Ether intermediate which is obtained after work up with water and extraction with Toluene This solution is taken for next step. 4th step The Ether intermediate from above in toluene is reacted with KOH in SS reactor by refluxing at temp ~105*C for 16hrs The mass is worked up with water and organic layer is concentrated by distillation under vacuum as thick liquid which is Duloxetine base. The recovered toluene is purified and reused. Benzoic acid is recovered and sold The Duloxetine base (thick liquid mass) is dissolved in Acetone, charcoaled and filtered. The clear filtrate is treated with HCl to get Duloxetine Hydrochloride as fine crystals which separate out after cooling to < 5*C .The solid is centrifuged, and dried. The mother liquor is sent for recovery of solvent Acetone which is recycled. DULOXETINE HYDROCHLORIDE MASS BALANCE
SL NO PRODUCTION B Size 60kg No of batchs :1/Month
Raw material used
1 Formaldehyde 30kg
2 2-Acetyl thiophene 126kg
3 Water 1800Lt
3000M/s. R L Fine Chem Pvt. Ltd.,
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4 Toluene 1800Lt
5 Dimethyl amine 45kg
6 Acetone 1000Lt
7 HCl 36kg
8 Carbon 10kg
9 H2 gas
10 Methanol 1000Lt
11 Ni cat 2kg
12 DMSO 600kg
13 Fluro naphthalene 145kg
14 KOH 112kg
Yield (Duloxetine Hydrochloride) 300kgs
Input Reactors Output
Formaldehyde – 30kg SSR 3000L(for step 1 reaction) Duloxetine Hydrochloride Yield 300 kg Overall yield 90%
2-Acetyl thiophene – 126kg
SSR 3000L (for workup) I.Product:stage-1,2&3 not isolated . Stage-4::90%
Water – 1800L SSR 2000L(for dissolution) Toluene: 1500L Loss: 300L Acetone: 800L Loss:200L Methanol: 800L loss: 200L DMSO ::550L loss 50L P.Water: stage-1::620kg/L Stage-2 ::675kg/L contns KF Stage-3 ::670kg/L Contns KOCH3 Total P water ::: 1965kg/L Cleaning water :: 1500L goes to CETP Hazardous waste: 32-35kg Spent Carbon: 12kg
Toluene – 1800L GLR2000L (for reaction)
Dimethyl amine – 45kg SSR 2000L (for solvent recovery)
Acetone – 1000L
HCl – 36kg
Carbon – 10kg
H2 gas
Methanol – 1000L
Ni cat – 2kg
DMSO – 600kg
Fluro naphthalene – 145kg
KOH – 112kg
Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 12-14hrs 12-14hrs 14-16hrs Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… ---- ---- 10-14hrs (MLR-1)
3000M/s. R L Fine Chem Pvt. Ltd.,
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Water 1940kg along with cleaning water is sent for CETP FLOW CHART FOR DULOXETINE HYDROCHLORIDE
Process Waste Water-1,2&3 ::1965kg/LCleaning waste Water : 1500L
SS reactor-3cap 3000LToluene/EtherIntermediate
GLreactor2000L
SSreactor MLR-1&2cap 2000Lsolvent recovery
AcetoneLoss :;100LMLR-2Reaction
Total waste water to CETP is 3465 L/kg
centrifuge
Acetone Pure800LLoss 100L(MLR-2)
Haz waste 30-35kg
Duloxetine Hydrochloride300kg
2nd Step
SS reactor-2 cap:2000LReduction
SS Reactor-3cap:3000Lcondensationwork up
Ni cat 2.0kg
Keto intermediate180kg
Methanol 1000L
Methanol 800Lloss ::200L
1st step
Toluene 1000L
Spentcarbon 12 kg wet
Centrifuge
Solvent recovery
SS reactor-1 cap: 1000LReaction andisolation
2-Acetyl thiophene126kg Toluene 800L
Dimethyl amine45kg
Water 600kg
Water-1(618kg/L)
Keto intermediate180kg
3rd step
Water-2 (675kg/L)
SS reactor-4cap 2000LReaction/w/up
Recovered Toluene 850LLoss 150L
Acetone 1000L
HCl 36kg
4th step
Formadehyde 30kg
Toluene MLR-1Loss:: 75L
H2 gas
FiterSpent cat :2.2kgrecycle
Methanol solutionHydroxy intermediate
DMSO 600kg
Fluro naphthalene145kg
Water 600L
Recov DMSO550L loss 50L
KOH 56kg
Toluene layerEther intermediate
SS reactor-3cap 2000LIsolation Conc.base
KOH 56kg
Water 600L
Water-3670kg/L
Recov Toluene 650Lloss 75L(MLR-1)
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.26 DAPOXETINE HCL
Cl
O
Cl
OH
O
NCH3H3C
3-chloro-1-phenylpropan-1-one
3-chloro-1-phenylpropan-1-ol
305
OH
144
O
OH
Hydroxy NaphthylEther
278
Dapoxetine base
CH3SO3H
96
Methane sufonic acid
45
Dimethylamine
NH
Toluene
O
NCH3H3C
Dapoxetine Hydrochloride
.HCl
341
HCl
36
Acetone
H2SO4CH4
9816
H2
Cl
OH
3-chloro-1-phenylpropan-1-ol
KOH
170
170
168
Alfa naphthol
O
OH
Hydroxy NaphthylEther
278
KCl
74
H2O
18
56
Toluene
Methanol
Reaction scheme
1st step
2nd step
3rd step
3000M/s. R L Fine Chem Pvt. Ltd.,
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Manufacturing process This involves 3 steps 1st step 3-Chloro propiophenone is reduced with Hydrogen in SS reactor in presence of Catalyst in Methanol solvent to get hydroxy intermediate (3-chloro 1- phenyl propanol). After 10hrs reaction will be completed and the reaction mass is filtered to remove catalyst (which is reused), and the clear filtrate is concentrated to recover solvent. The recovered Methanol is purified in SRP and reused. After the concentration is complete mass is quenched with water and solid Hydroxy compound is isolated by cooling the slurry to < 5*C, and centrifuging. The wet product is taken for next step. 2nd step The Hydroxy intermediate is dissolved in Toluene in SS reactor and to this was added Alfa naphthol solid. Again the mass is heated to dissolve the contents and cooled. Added KOH and slowly raised the temp to reflux. Reaction is completed by refluxing for 10hrs to get Hydroxy Naphthyl Ether intermediate and after the reaction; the mass is cooled to RT and quenched with water. Layers were separated and top organic layer containing the Ether intermediate which is taken for the next step. 3rd step The ether intermediate solution in Toluene is dried and then treated with Methane sulfonic acid in SS reactor at temp < 30 *C and then stirred with Dimethyl amine which is added over a period of 2 hrs. The resultant reaction is slowly heated to 60 *C and maintain for 8 hrs during this time Dapoxetine base is formed. The mass is quenched with water and top toluene Organic layer is separated. This layer is concentrated by distillation under vacuum, to get viscous liquid Dapoxetine base Recovered solvent toluene is reused. This base is dissolved in acetone In SS reactor and transferred to GLReactor and treated with HCl gas at temp, <5*C, to get Dapoxetine Hydrochloride. Sirred at RT for 6hrs during which product is pptd which is isolated by centrifuging and drying. The mother liquor is sent for recovering Solvent acetone which is reused. DAPOXETINE HYDROCHLORIDE MASS BALANCE
SL NO PRODUCTION B Size 60kg No of batchs ::1/month
Raw material used
1 3-Chloro propio phenone 34kg
2 Methanol 300Lt
3 Water 900Lt
4 Ni 1kg
5 Toluene 500Lt
3000M/s. R L Fine Chem Pvt. Ltd.,
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6 Alfa Napthol 30kg
7 Methane sulfonic acid 19kg
8 Carbon 10kg
9 Dimethyl amine 9kg
10 HCl 7kg
11 KOH 11kg
12 Acetone 500L
Yield (Dapoxetine Hydrochloride) 60kgs
Input Reactors Output
3-Chloro propio phenone – 34kg
SSR 1000L(for step 1 reaction)
Dapoxetine Hydrochloride Yield 60 kg Overall yield 88%
Methanol – 300L SSR 2000L (for reaction)
I.Product: stage-1,2&3 not isolated . Stage-4::88%
Water – 900L SSR 3000L(for workup) Toluene: 450L Loss: 50L Acetone: 350L Loss:150L Methanol: 250L loss: 50L P.Water: stage-1::300kg/L Stage-2 ::320kg/L contns KCl Stage-3 ::320kg/L CH4 : 3.0kg, Ni 1.0kg(reuse) Total P water ::: 940kg/L Cleaning water :: 1000L goes to CETP Hazardous waste: 7-9kg Spent Carbon: 12kg
Ni – 1kg SSR3000L (for condensation)
Toluene – 500L SSR 2000L (for solvent isolation)
Alfa Napthol –30kg GLR 2000L (for reaction)
Methane sulfonic acid – 19kg
SSR 2000L (for solvent recovery)
Carbon - 10
Dimethyl amine – 9kg
HCl – 7kg
KOH – 11kg
Acetone – 500L
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 12-14hrs 12-14hrs 14-16hrs Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… ---- ------ 10-14hrs (MLR-1)
Water 940kg along with cleaning water is sent for CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
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FLOW CHART FOR DAPOXETINE HYDROCHLORIDE
Process Waste Water :: 940kg/LCleaning waste Water : 1000L
SS reactor-2cap 3000Lcondensation
GLreactor1000L
SSreactor MLRcap 2000Lsolvent recovery
AcetoneLoss :;50LMLRReaction
Total waste water to CETP is 1940 L/kg
centrifuge
Acetone Pure350L RecycleLoss 100L
Haz Waste 7-9kgs
Dapoxetine Hydrochloride60kg
2nd Step
SS reactor-2 cap:2000LRection
SS Reactor-2cap:2000LWork-up/Org layerEther compound
Alfa Naphthol30kg
Hydroxy compund34.0 kg
Toluene500L
Water 300 kg/L
Water-2 + KCl320kg
1st step
Dimethyl amine 9 kg
Spentcarbon 12 kg wet
Centrifuge
Solvent recovery
SS reactor-1 cap: 1000LReaction
3-chloro propiophenone 34kg
Methanol 300L
Ni 1kgRecovered cat 1.1 kg wet recycle
Recov Methanol 250L loss :50L
Water 300kg
Water-1 300kg/L
Hydroxy compound 34.0kg(wet)
KOH 11kg
3rd step
Methane sufonic acid 19.2kg
Water 300L/kg
Water-3 320kg/L
SS reactor-3cap 1000LIsolation Concbase
Carbon 10kg Spent carbon 12kg
Recovered Toluene 450LLoss 50L
Acetone 500L
HCl 7kg
4th step
7
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.27 DESVENLAFAXINE HCL
N
CH3
H3CO
CH3
HCl
N
CH3
HO
CH3
COOH
COOHN
CH3
HO
CH3COOH
COOH
H2O
Venlafaxine Hydrochloride
Succinic acid
OH OH
OH
313 263
118
NaOH
399
40
CH3OH
32
NaCl
58
N
CH3
HO
CH3OH
263
Acetone
H2O
18
Des venlafaxine base
Des venlafaxine base
Deavenlafaxine succinate
Reaction scheme
1st step
2nd step
Toluene
Manufacturing process This involves 2 steps 1st step Venlafaxine hydrochloride is treated with sodium hydroxide solution (50%) at temp 110*C in SS reactor. After the reaction is complete, the mass is diluted with water and extracted with toluene. Layers are separated and Top organic layer is concentrated to get Desvenlafaxine base. Recovered solvent toluene is recycled.
3000M/s. R L Fine Chem Pvt. Ltd.,
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2nd step Des velafaxine base is dissolved in Acetone, in SS reactor, charcoaled and filtered. The clear filtrate is treated with Succinic acid and small qty of water and the mass is heated to reflux for 14 hrs. After the reaction is complete, the reaction mass is cooled to< 10*C and centrifuged. The mother liquor from centrifuge is taken for solvent recovery. The crude Des evnlafaxine succinate is purified by crystallization by re dissolving in acetone, by heating and chilling to get pure product which is centrifuged and dried. The solvent is recovered from the mother liquor.
DESVENALAFAXINE SUCCINATE Gravimetric/MASS BALANCE SL NO PRODUCTION B Size 400kg No of batchs 1/Month
Raw material used
1 Venalafaxine hydrochloride 313kg
2 Toluene 2000kg
3 NaOH 40kg
4 Acetone 1000Lt
5 Succinic acid 112kg
6 Water 1018Lt(1st & 2nd stage)
7 Carbon 15kg
Yield (Venalafaxine Succinate) 380kgs
Batch size 400kgs --- Venalafaxine Succinate
Input Reactors Output
Venalafaxine hydrochloride – 313kg
SSR 4000L(for step 1 reaction)
Venalafaxine Succinate Yield ::380kg Overall yield ::;95%
Toluene – 2000L SSR 4000L (for concentration & dissolution)
I.Product:stage-1 not isolated stage-2 95%
NaOH – 40kg SSR 3000L Toluene: 1850L Loss: 150L Acetone: 800L Loss:200L P.Water 1st stage :1090kg/L Cleaning water ::500L goes to CETP Hazardous waste: 13-15kg Spent Carbon: 18kg
Acetone – 1000L SSR 3000L (for solvent recovery)
Succinic acid – 112kg
Water – 1018L
Carbon – 15kg
3000M/s. R L Fine Chem Pvt. Ltd.,
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Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 22-24hrs 12-14hrs ---- Drying
2) Isolation , cooling
& Centrifuge … 4-6hrs 2-4hrs ---
3) Solvent recovery…… --- 8-10hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 1090kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 147 -
Toluene 2000LSS reactor-1 cap4000LReaction
Haz Waste 13-15 kgProcess Waste Water :1090kg/LCleaning Waste Water : 500L
FLOW CHART FOR DES VENALAFAXINE SUCCINATE
Venalafaxinehydrochloride 313kg
MLR
Solvent recovery MLRSSreactor 3000L
SS REactor-2
3000L
Water 18kg/L
NaOH 40 kg
Solvent recovery
Recovered Toluene 1850Lloss 150L residue ~255kg
CentrifugeSolvent loss :100 L
MLR
Des venlafaxine Hydrochloride 380kg
Recovered Acetone:800LLoss :100L
Water 1000L
Water 1090kg/L
SS reactor-1 cap4000LConcentration& Dissolution
Acetone 1000L
Carbon 15kg Spent carbon 18kg
Succinic acid112 kg
8+5
Total water :: 1590kg/L
1st step
2nd step
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.28 TRIHEXYPHENADYL HCL
N
O Cl
N
OH+
Trihexphenadyl Base3-Piperidino propiophenone
Cyclohexyl chloride
N
OHHCl, acetone
Trihexphenadyl Hydrochloride
.HCl
N
OH
N
O
3-Piperidino propiophenone
217
217118
Mg
24
THF/toluene
301
Trihexaphenayl base
301 337
HN
O
CH2O
120
30Acetophenone
FormaldehydePiperidine
Water
85
Reaction scheme
H20
18
MgCl
59
36
1st step
2nd step
3rd step
3000M/s. R L Fine Chem Pvt. Ltd.,
- 149 -
Manufacturing process This involves 3 steps 1st step Acetophenone is reacted with Formaldehyde and Piperidine in water in SS reactor at reflux at 90-95*C to get Pipridino propiophenone solid which is cooled , centrifuged and isolated. 2nd step Pipridino propiophenone is then taken for Grignard reaction with Cyclohexyl chloride in Toluene/ THF solvent media under Nitrogen atmosphere, at temp < 15*C .After the reaction the mass is quenched in water and top organic layer is separated .Toluene is totally removed by distillation and concentrated mass is Trihexaphenadyl base which is Dissolved in acetone and taken for next step. Toluene is recovered, purified in column distillation and reused. 3rd step The Trihexaphenadyl base in Acetone solvent is charcoaled in SS reactor, filtered and the clear filtrate is taken in GLreactor and is converted to Trihexaphenadyl hydrochloride by passing HCl gas to pH 2 at temp < 10*C.The crystals of Trihexaphenadyl hydrochloride solid is isolated by centrifuging. The product is then dried. The mother liquor is sent for recovery of solvent acetone which is reused.
TRIHEXAPHENADYL HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION No of batchs:1/Month
Raw material used
1 Acetophenone 120kg
2 Formaldehyde 30kg
3 Piperidine 85kg
4 Water 1200Lt (1st & 2nd stage)
5 Toluene 1100Lt (2nd stage)
6 THF 30Lt
7 Cyclohexyl chloride 118kg
8 Carbon 15kg
9 Mg 24kg
10 HCL 36kg
11 Acetone 1000Lt(final)
Yield (Trihexaphenadyl Hydrochloride) 300kgs
Input Reactors Output
Acetophenone – 120kg SSR 2500L(for step 1 condensation reaction)
Trihexaphenadyl Hydrochloride Yield
3000M/s. R L Fine Chem Pvt. Ltd.,
- 150 -
300kg Overall yield 89%
Formaldehyde – 30kg SSR 2500L (for step 2 grignard reaction)
I.roduct:stage-1 ::96.5% Stage-2 ::96% Stage-3::95.5%
Piperidine – 85kg SSR 600L (for step 2 Toluene layer)
Toluene: 1000L Loss: 100L Acetone: 825L Loss:175L P.Water: stage-1::625kg/L stage-2:: 680kg/L (contnsMgCl/THF) Total water ::: 1305kg/L Cleaning water :: 500L goes to CETP Hazardous waste: 25-28kg Spent Carbon: 18kg
Water – 1200L SSR 3000Lfor dissolution
Toluene – 1100L GLR 3000L (for reaction)
THF – 30L(20kg) SSR 3000L (for solvent recovery)
Cyclohexyl chloride – 118kg
Carbon – 15kg
Mg – 24kg
HCL – 36kg
Acetone – 1000L
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 14-16hrs 20-22hrs 6-8hrs Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs 4-6hrs
3) Solvent recovery…… ----- ------ 12-16hrs(MLR-3)
Water used for washing/cleaning equipment, cleaning waste water 500L goes
to CETP along with process waste water 1315kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 151 -
FLOW CHART FOR TRIHEXAPHENADYLHYDRCHLORIDE
SS reactor-2cap 3000LDissolution
Haz Waste 25-28kg
Process Waste Water-1&2:; 1305kgCleaning Waste Water : 500L
TrihexaphenadylGrignrd base 280.0 kgs
Total water ::1805L/kg
GL reactorcap 3000Lreaction
2nd Step
Solvent recoveryMLR
AcetoneLoss:75L HCl 36 kg
Centrifuge
Solvent recovery Cap 3000LSSreactor MLR
Trihexaphenadylhydrochloride300 kgs
SS reactor-1cap 600LToluene layer
SS reactor-1cap 2500Lgrignard
Toluene/THF1100/30L
3-Piperidinopropiophenone 210kg
Cyclohexyl chloride118kg
Water 600L
RecoveredToluene 1000LLoss :100L
Tri hexa phenadyl Grignard base 280kg
Water-1 680 kgsincludes(/MgCL/THF)
1st step
Grignard reaction Mg 24kg
Acetone 1000L
Acetone recov:825Lloss:100L
Carbon -15kg
Spent carbon18 kgwet
Spent carbon 18 kg wet
SS reactor-1cap 2500LCondensation
Acetophenone 120kg
Formadehyde 30kg
Piperidine 85kg
Centrifuge Water-1 625.L(incldes p phenone 7kg)
Water 600L
3-Pipridino Propiophenone 210kg
11
13
3000M/s. R L Fine Chem Pvt. Ltd.,
- 152 -
3.5.2.29 TRAMADOL HCL
N
O
+
Br
OCH3 N
OH
OCH3
N
OH
OCH3
.HCl
Tramadol BaseMeta -Bromo
methoxyanisole2-methyldimethylamino
cyclohexanone
Tramadol Hydrochloride
N
O
2-methyldimethylaminocyclohexanone
O
CH2O NH
45
30
98155
Toluene
H2O
18
1st step
Reaction scheme
2nd step
N
OH
OCH3
Tramadol Base
HCl
Acetone
263
299.5
36.5
263
Mg
THF/Toluene
24
Mg Br
103
155 187
3rd step
Cclohexanone Dimethylamine
Formaldehyde
Manufacturing process This involves 3 steps 1st step Cyclohexanone is reacted in SS reactor with Formaldehyde and Dimethylamine in Solvent Toluene by refluxing the reaction mass at 105*C for 12hrs. After the reaction is complete the mass is quenched with water and cooled to get 2-
3000M/s. R L Fine Chem Pvt. Ltd.,
- 153 -
Dimethylaminomethyl cyclohexanone crystals .This is isolated by centrifuging and dried. The Mother liquor is separated and top organic layer is distilled to get pure Toluene which is recycled. 2nd step 2-Dimethylaminomethyl cyclohexanone is dissolved in Toluene solvent in SS reactor and stirred with Magnessium filings and treated with solution of Meta bromo anisole in THF solvent under Nitrogen atmosphere (Grignard reaction ) at temp < 15*C . After the addition the reaction is carried out at 65*Cfor 10hrs to complete the reaction. Reaction mass is then quenched with water. Layers were separated and top organic layer is then distilled to recover Toluene .The concentrated mass is intermediate Tramadol Base which is immediately dissolved in Acetone and taken for next step. Both recovered solvents are purified and reused. 3rd step The Tramadol Base in acetone is charcoaled and the clear filtrate after filtration is taken in GL reactor and cooled to < 10 *C. HCl gas is passed and after the reaction stirred for 10-12 hrs extra during which complete rection takes place and Tramadol hydrochloride separates out as crystalline solid . This is isolated by centrifuging and dried. The mother liquor is sent for recovery of solvent Acetone which is reused.
TRAMADOL HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 250kg No of batchs 10/Month
Raw material used
1 Cyclo hexanone 98kg
2 Formaldehyde 30kg
3 Dimethylamine 45kg
4 Toluene 1100Lt
5 THF 30Lt
6 Water 1200Lt
7 Metabromo methoxy anisole 187kg
8 Mg 24kg
9 Carbon 15kg
10 Acetone 1000Lt
11 HCl 36kg
Yield (Tramadol Hydrochloride) 270kgs
Input Reactors Output
3000M/s. R L Fine Chem Pvt. Ltd.,
- 154 -
Cyclo hexanone – 98kg SSR 4000L(for step 1 reaction)
Tramadol Hydrochloride Yield :270kg Overall yield ::90%
Formaldehyde – 30kg SSR 4000L (for concentration & dissolution)
I.Product: stage-1 :98% wet Stage-2:95% Stage-3 ::94.5%
Dimethylamine – 45kg SSR 3000L Toluene: 1000L Loss: 100L Acetone: 825L Loss:175L P.Water: stage-1 :: 625kg/L Incl 7kg cycl hexanone Stage-2 ::723kg/L (Contns Mg Br Total P water ::; 1347kg/L Cleaning water :: 1000L goes to CETP Hazardous waste: 25-30 kg Spent Carbon: 18kg
Toluene -1100L SSR 3000L (for solvent recovery)
THF – 30L/20kg
Water – 1200L
Metabromo methoxy anisole -187kg
Mg – 24kg
Carbon – 15kg
Acetone – 1000L
HCl – 36kg
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
3) Solvent recovery…… 8-10hrs (MLR-1) 10-12hrs(MLR-2) 12-16hrs(MLR-3)
Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP along with process waste water 1350kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 155 -
FLOW CHART FOR TRAMADOL HYDRCHLORIDE
SS reactor-3cap 3000LDissolution
Haz Waste 28-30kg
Process Waste Water-1&2:; 1350kgCleaning Waste Water : 1000L
Tramadol Grignrd base 250.0 kgs
Total water ::2350L/kg
GL reactorcap 3000Lreaction
2nd Step
Solvent recoveryMLR
AcetoneLoss:75L HCl 36 kg
Centrifuge
Solvent recovery Cap 3000LSSreactor MLR
Tramadolhydrochloride270 kgs
SS reactor-2cap 4000LToluene layer
SS reactor-1cap 2500Lgrignard
Toluene/THF1100/30L
2-dimethylamino methylcyclohexanone 155kg
Metabromo methoxyanisole 187kg
Water 600L
Rec.toluene 1000LLoss :100L for recycle
Tramadol base crude265kg(pure content 250kg)
Water-2:: 725 kgsincludes(MgBr/THF)
1st step
Grignard reaction Mg 24kg
Acetone 1000L
Acetone recov:825Lloss:100L
Carbon -15kg
Spent carbon18 kgwet
Spent carbon 18 kg wet
SS reactor-1cap 2500LCondensation
Cyclo hexanone 98kg
Formadehyde 30kg
Dimethylamine 45kg
Centrifuge Water-1 625Lincludes 5kg c hexanone
Water 600L
2-dimethylaminomethylcyclohexanone 155kg(wet)
13+15
3000M/s. R L Fine Chem Pvt. Ltd.,
- 156 -
3.5.2.30 SULFAMETHOXY PYRAZINE HCL
N
N Cl
Cl N
NHN
Cl
NH2
NH2OS
O
NH2
O
S
O
+
Dichloropyrazine Sulfanilamide Intermediate
N
NHN
Cl
NH2
O
S
O
N
NHN
OCH3
NH2
O
S
OKOCH3
Intermediate Sulfamethoxypyrazine
148 172284
284 280
KHCO3
100
DMF
70
Methanol
Reaction scheme
1st step
2nd step
KCl H2O CO2
18 4474
KCl
74
MANUFACTURING PROCESS
This involves 2 steps 1st step Dichloropyrazine is reacted with Sulfanilamide in SSreactor by heating for 14hrs to temp 85-90*C in DMF solvent media in presence of base Potassium bicarbonate During the reaction Evolution of gas CO2 is observed.. After the reaction is complete the solution is filtered to remove Pot.chloride and the clear filtrate is distilled under vacuum to recover the solvent DMF .The concentrated mass is quenched with water to get Sulfa-Intermediate as solid which is isolated by centrifuging. This is dried and taken for the next step. The recovered DMF is reused.
2nd step This Sulfa-intermediate is dissolved in solvent methanol in another SS reactor and treated with Potassium methoxide under nitrogen.The reaction mass is then refluxed
3000M/s. R L Fine Chem Pvt. Ltd.,
- 157 -
for 16 hrs to get Sulamethoxy pyrazine. After the reaction is complete the mass is filtered to remove Potassium chloride.
The clear filtrate is concentrated to 25% volume by distilling Methanol .Added carbon and filtered. The clear filtrateis transferred to another SS reactor and the resultant mass is cooled to <15 *C to get solid Sulamethoxy pyazine which separates out as crystals.This is centrifuged to get pure product which is dried.
The mother liquor is sent for recovery of solvent Methanol which is reused.
SULFAMETHOXY PYRAZINE MASS BALANCE SL NO PRODUCTION B size 250 kg No of batchs 2/month
Raw material used
1 P-amino sulfonamide 172kg
2 DMF 1500L
3 Dichloro pyazine 148kg
4 KHCO3 100kg
5 Potassium methoxide 70kg
6 Water 1000Lt
7 Carbon 15kg
8 Methanol 2000Lt
9
10
11
Yield (Sulfamethoxy Pyrazine) 250kgs
Batch size 250kgs --- Sulfamethoxy Pyrazine
Input Reactors Output
P-amino sulphonamide- 172kg
SSR 4000L(for step 1 reaction)
Sulfamethoxy Pyrazine Yield ::250kg Overall yield ::89%
DMF – 1500L SSR 4000L (for concentration & dissolution)
I.Product:stage-1 :95% Stage-2 :93.5%
Dichloro pyazine – 148kg SSR 3000L DMF: 1400L Loss: 100L Methanol: 1650L Loss:350L CO2 :: 44kg KCl::::148kg P.Water: stage-1::1018kg/L Cleaning water ::1000L goes to CETP Hazardous waste: 30-32kg Spent Carbon: 18kg
KHCO3 – 100kg SSR 3000L (for solvent recovery)
Potassium methoxide – 70kg
Water – 1000L
Carbon – 15kg
Methanol – 2000L
3000M/s. R L Fine Chem Pvt. Ltd.,
- 158 -
Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
3) Solvent recovery…… ----- 10-12hrs(MLR-2) -----
Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP along with process waste water 1020kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 159 -
SS reactor-2cap 3000Lwork up
Haz Waste 1& 2:: 30-32kg Process Waste Water-1:1020kgCleaning Waste Water-1&2:1000 L
FLOW CHART FOR SULFAMETHOXY PYRAZINE
Total waste water to CETP is 2020L
2nd step A
Recov. Methanol1650L Loss:150L
Centrifuge
Solvent recovery MLRCap:;SSreactor 2000L
MLR Methanol loss 100L
SS reactor-1cap 4000LReaction
SSreactor -1cap:4000Lcondensation
DMF1500L
P-amino sulfonamide172kg
Dichloro pyazine148kg
Centrifuge
Suphone Intermediate270kg
Solvent MethanolLoss:100L
1st step A
SSreactor -2cap:4000Lisolation
CentrifugeSolvent DMFLoss ::50L
Potassium Chloride 74kg
Water 1000L
CentrifugeSulphone Intermediate270kg
Water 1018kg
Methanol 2000L
Potassium methoxide 70 kg
Potassium chloride74 kg
1st step -B
2nd step B
Sulpha Methoxy pyrazine 250kgSolvent recovery
MLR
KHCO3 100kg
Carbon 15kgSpent carbon 18kg wet
spent carbon 18kg wet
CO244kg
DMF Recov1400LLoss 50L
14
16
3000M/s. R L Fine Chem Pvt. Ltd.,
- 160 -
3.5.2.31 ALIMEMAZINE TARTARATE
N Cl N
NPhenothiazine
Sodium methoxide2-methyl-3-Dimethyl
amino propylchloride54g
135
Alimemazine Base
298
+ CH3OH + NaCl
32 58
L Tartaric acid
150
Alimemazine Tartarate
747
Isopropyl alcohol
+
S
N
N
S
NH
S
199
2
.Tartarate
N
N
S
OO
Oxomemazine Base
N
N
S
OO
Oxomemazine Hydrochloride
.HCl
N
N
Alimemazine Base
298
S
2
366.5330
HCl
Acetone
36.5
NaOCH3
THF
Reaction scheme
1st step
2nd step A
2nd step B
2-H2O2
68
2-H2O
36
3000M/s. R L Fine Chem Pvt. Ltd.,
- 161 -
Manufacturing process This involves 2 steps 1st step Phenothiazine is dissolved in THF in SS Reactor and to this solution 2-Methyl-N, N-dimethyl amino propyl chloride in THF is added slowly at temp <35*C. To this solution was added sodium methoxide and the reaction mass was refluxed for 8-10 hrs .After the reaction is complete, the mass is cooled to< 10*C and filtered to remove Sod chloride. The filtrate is concentrated by distillation to remove solvent THF which is later reused. The concentrated mass is viscous liquid of Almimazine base 2nd step A The Almimazine base is dissolved in Iso propyl alcohol, in SS reactor, charcoaled with carbon and filtered. The clear filtrate is converted to the Almimazine tartarate with L-tartaric acid by refluxing for 4 hrs and cooling the mass below <10*C when crystals of Almimazine tartarate. This is centrifuged to isolate the crude product. This product is further purified by crystallization in acetone and dried. The Solvent mother liquor IPA and Acetone is recovered, purified and reused. 2nd step B The Almimazine base is treated with molar quantity of Hydrogen peroxide 20% at < 10 *C in SS reactor in 3 hrs time; to get Oxomemezine base which is isolated as solid and separated by centrifuging . The Oxomemezine base thus obtained is dissolved in acetone in SS reactor treated with carbon and filtered. The clear filtrate is converted to hydrochloride salt by passing HCL gas. After the reaction the mass refluxed for 5hrs, and is cooled to 0*C and centrifuged to get pure Oxomemezine Hydrchloride. The mother liquor is sent for recovery of acetone which is reused. ALMEMAZINE TARTARATE AND OXOMEMAZINE
SL NO PRODUCTION 250kg
Raw material used
1 Phenothiazine 199kg
2 Sodium methoxide 54kg
3 THF 800L
4 Dimethylamino propyl chloride 135kg
5 IPA 600L
6 Carbon 20kg
7 L-Tartaric acid 50kg
8 Hydrogen peroxide20% solu 100kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 162 -
9 HCl 11kg
10 Acetone 1600L(for 1A & 1B)
Yield (Almemazine tartarate)/Oxomemazine HCl
230kgs/100kg
Batch size 250kgs --Almemazine tartarate)/Oxomemazine HCl -
Input Reactors Output
Pheno thiazine 199kg SSR 4000L(for step 1 reaction)
Almemazine tartarate/ Oxomemazine HCl Yield 230/100kg Oveall yield 90%
Sodium methoxide 54kg
SSR 4000L (for concentration & dissolution)
I.Product:stge1 :: not isolated Stage1A ::92% Stage-1B::91%
Dimethylamino propyl chloride 135kg
SSR 3000L THF :700L loss100L Acetone: 1200L Loss:400L IPA 500L loss 100L P.Water: 80 L NaCl ::58kg Methanol ::32kg Cleaning water 1000L Goes toto CETP Hazard waste:1A :28-30kg Stage 1B::12-16kg Spent Carbon: 24kg
IPA 600L SSR 3000L (for solvent recovery)
THF – 800L
L-Tartaric acid 50kg
Hydrogen peroxide20% solu 100kg
Carbon
HCl 11kg
Acetone – 1600L
Time cycle 1st stage 2nd stage (A) 2rd stage (B) final
1) Reaction ………… 12-14hrs 6-8hrs 8-10hrs Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… ---- 10-14hrs (MLR-1) 12-14hrs -----
Water 80kg along with cleaning water 1000L goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
- 163 -
Almemazine base200 kgs
IPA 600LSS reactor-22000L
SS reactor-3cap 2000Lreaction
SSreactor2Noscap 1000Lfor solvent recovery
IPA recov500Lloss 50L(from 1)
Process Waste Water ::80 kgCleaning waste Water :1000L
FLOW CHART FOR ALMEMAZINE and OXOMEMAZINE
dissolution
Total waste water to CETP is 1080kg
centrifuge +
Acetone pure1200L(from 2&3)Loss 200L
Haz Waste 1A 28-30kgHaz waste 1B 10-12kgSpent C 24kg wetSod chloride 58kg
MLR-1,2& 3 IPA &Acetone
L-tartaric acid50kg
2nd Step-1A
Solvent IPALoss 50.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000Lorganic layer
Pheno thiazine 199kg
DimethylaminoMethylPropyl chloride 135kg
Sodium methoxide54 kg
THF 800L
Recov THF 700L Loss:130L(mix THF/CH3OH)
Almemazine base300kg (cont:290kg)
1st step
Carbon 10 kg
Spent carbon12kg wet
Centrifuge NaCl 58kg
AlmemazineTartarate
MLR-1IPA
SS reactor-3 cap 2000L crystallistion
Acetone 800L
Centrifuge Solv Acetone loss 100L
Almemazine Tatarate pure230kg
MLR-2Acetone
SS reactor -2cap 2000LReaction
Almemazine base 90kg
Centrifuge Water80kg
Oxamomezine155kg
SS reactor -3cap 2000LDissolution
C 10kg
Acetone800L
GLreactorcap 2000Lreaction
HCl 11kg
Spent C12kg wet
Centrifuge Sol loss100L
OxomemezineHCl 100 kg
MLR-3
2nd step-1B
8
H2O2100kg(20+80)
11
20
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.32 ALPRAZOLAM
O
NH2
Cl
O
HN
Cl
Cl
O
+N
HN
Cl
O
231
308
+
Cl
ClO
112
2-amino-5-chloro benzophenone
Chloroacetyl chloride
1st stage intermediate
Ammonia3
51
270
Alprazolam
+ Water
Reaction scheme
2NH4Cl
106 18Methanol
Toluene
MANUFACTURING PROCESS 2-Amino 5-Chloro Benzophenone ( chloro amino Ketone) is reacted with chloro acetyl chloride in toluene by refluxing for 12 hrs to get Di chloro intermediate in GLreactor , During the reaction Hcl generated is treated / scubbed with ammonia to get by product Ammonium chloride. After the reaction the mass is centrifuged, and solid is dried. The Di Chloro intermediate in SS reactor is dissolved in Methanol and then reacted with ammonia by refluxing in solvent methanol for 14 hrs at temp 65* C and cooled to
3000M/s. R L Fine Chem Pvt. Ltd.,
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isolate by product Ammonium chloride which is removed by filtration. The resultant filtrate is charcoaled, filtered and concentrated 50% to recover solvent (which is recycled). The concentrated mass is further cooled to 15* C to get Alprazolam which separates as crystals. These crystals are centifuged and the pure Alprazolam is dried. The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to recover methanol. The last portion of solvent distilling bet 85*C and 95*C is methanolic water which is sent as effluent. The residual mass remaining as undistilled is taken as Haz waste.
ALPRAZOLAM MASS BALANCE SL NO PRODUCTION B size 100kg No of batchs :1/month
Raw material used
1 Chloroacetyl chloride 56kg
2 2-amino 5-chloro benzophenone 115kg
3 Toluene 600L
4 Ammonia 25kg
5 Carbon 5kg
6 Methanol 800Lt
Yield (Alprazolam) 110kgs
Batch size 100kgs --- Alprazolam
Input Reactors Output
Chloroacetyl chloride – 56kg
GLR 2000L(for step 1 reaction)
Alprazolam Yield :: 110kg Oveall yield ::82%
2-amino 5-chloro benzophenone – 115kg
SSR 2000L (for reaction) I.Product: stage-1 :91% Stage-2 :90%
Toluene – 600L SSR 2000L( for methanol solution)
Toluene: 500L Loss: 100L Methanol: 600L Loss:200L P.Water: nil By product NH4Cl ::60kg (Contns water HCL scrub) Cleaning water :1000L goes to CETP Hazardous waste: 24-26kg Spent Carbon: 7kg
Ammonia – 25kg SSR 2000L (for solvent recovery)
Carbon – 5kg
Methanol – 800L
3000M/s. R L Fine Chem Pvt. Ltd.,
- 166 -
Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 12-16hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery……10-12 hrs (MLR-1, 2) 10-14hrs (MLR-3) -----
Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
- 167 -
Process Waste Water :: NilCleaning waste Water :1000LTotal water ::1000L/kg
SS reactor-2 cap 2000LMethanol solution
SSreactor 2000Lfor solvent recoveryMLR
FLOW CHART FOR ALPRAZOLAM
Methanol 600LSolv loss 75L
Haz Waste1&2 ::24-26kg
MLR-1 TolueneMLR-2 Methanol
GL reactor-1 cap:2000LRection
Chloroacetylchloride 56kg
2-amino 5-chlorobenzophenone 115kg
Toluene 600L
1st step A
Spentcarbon 7 kg wet
Centrifuge Solv loss50L MLR-1
Dichloro intermediate150kgwet(actual 140kg)
Methanol800L
HCl 18 kg scrubber
Ammonia 25kg
Filter-Nutch Wet Am.Cl 60kg inclu 9kg water
Solv methanolloss 75L
Centrifuge
2nd step
Am.Choride 60kg wet
Tolu recov 500Lloss 50L
Dichloro intermediate140kg
SS reactor-1 cap 2000L reaction
Carbon5kg
Spent C7kg
Solution Reaction mass Taken back
Solv loss 50LMLR-2
Alprazolam110kg 12
14
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.33 DIAZEPAM
O
NH
Cl
O
N
Cl
Cl
O
+N
N
Cl
O
245.5
322
+
Cl
ClO
112
2-Methylamino-5-chloro benzophenone
Chloroacetyl chloride
1st stage intermediate
Ammonia3
51
284.5
Diazepam
+ Water
Reaction scheme
2NH4Cl
106 18Methanol
Toluene
MANUFACTURING PROCESS
2-MethylAmino 5-Chloro Benzophenone (chloro Methylamino Ketone) is reacted by
refluxing for 14hrs with chloro acetyl chloride in toluene to get Di chloro intermediate
in GLreactor. During the reaction Hcl generated is treated / scrubbed with ammonia
to get by product Ammonium chloride. After the reaction the mass is cooled
centrifuged and product is dried.MLR is sent for recovery of solvent toluene.
The Di Chloro intermediate in SS reactor is then reacted with ammonia by refluxing in
solvent methanol at temp 65* Cfor 12 hrs and cooled to isolate by product Ammonium
3000M/s. R L Fine Chem Pvt. Ltd.,
- 169 -
chloride which is removed by filtration. The resultant filtrate is concentrated 50% to
recover solvent (which is recycled).
The concentrated mass is further cooled to 15* C to get Diazepam which separates as
crystals. These crystals are centrifuged and the pure Diazepam is dried.
The mother liquor from the centrifuge is sent for recovery of solvent at 65*C to
recover methanol. The last portion of solvent distilling bet 85*C and 95*C is
methanolic water which is sent as effluent.
The residual mass remaining as undistilled is taken as Haz waste.
SL NO PRODUCTION B size 120kg No of batchs 1/Month
Raw material used
1 Chloroacetyl chloride 56kg
2 2-methyklamino 5-chloro benzophenone 123kg
3 Ammonia 25kg
4 Toluene 600Lt
5 Methanol 800Lt
6 Carbon 5kg
Yield (Diazepam) 120kgs
Batch size 100kgs --- Diazepam
Input Reactors Output
Chloroacetyl chloride – 56kg
GLR 2000L(for step 1 reaction)
Diazepam Yield ::120kg Overall yield 84%
2-methyklamino 5-chloro benzophenone – 123kg
SSR 2000L (for reaction) I.Product: ::stage-1::93% Stage-2::91%
Ammonia – 25kg SSR 2000L(for methanol solution)
Toluene: 500L Loss: 100L Methanol: 650L Loss:150L P.Water: stage-2 ::Nil By product NH4Cl:: 60kg (Contns water 9kg) Cleaning water ::1000 L goes to CETP Hazardous waste: 22-25kgkg Spent Carbon: 7kg
Toluene – 600L SSR 2000L (for solvent recovery)
Methanol – 800L
Carbon – 5kg
3000M/s. R L Fine Chem Pvt. Ltd.,
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Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… 10-12 hrs (MLR-1) 10-14hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 1000L goes to CETP
3000M/s. R L Fine Chem Pvt. Ltd.,
- 171 -
Process Waste Water :: NilCleaning waste Water :1000LTotal water ::1000L/kg
SS reactor-2 cap 2000LMethanol solution
SSreactor 2000Lfor solvent recoveryMLR
FLOW CHART FOR DIAZEPAM
Methanol 600LSolv loss 75L
Haz Waste1&2 ::21-25kg
MLR-1 TolueneMLR-2 Methanol
GL reactor-1 cap:2000LRection
Chloroacetylchloride 56kg
2-Methylamino 5-chlorobenzophenone 123kg
Toluene 600L
1st step A
Spentcarbon 7 kg wet
Centrifuge Solv loss50L MLR-1
Dichlorointermediate150kg
Methanol800L
Ammonia 25kg
Filter-Nutch Wet Am.Cl 60kg inclu 9kg water
Solv methanolloss 75L
Centrifuge
2nd step
Am.Choride 60kg wet
Tolu recov 500Lloss 50L
Dichloro intermediate150kg
SS reactor-1 cap 2000L reaction
Carbon5kg
Spent C7kg
Solution Reaction mass Taken back
Solv loss 50LMLR-2
Diazepam120kg 12
11
3000M/s. R L Fine Chem Pvt. Ltd.,
- 172 -
3.5.2.34 BUCLAZINE HCL
N
NHCl
286
p-Chloro benzhydryl piperazine
182
P-t butyl benzyl chloride
+ N
NCl
Buclizine Base
N
NCl
. 2HCl
Buclizine dihydrochloride
Cl
NaOH
40
Toluene
N
NCl
Buclazine base
2 HCl
Acetone
73
505432
NaCl
H2O
18
58
432
Reaction scheme
1st step
2nd step
Manufacturing Process- This involves 2 steps 1st step Para chloro benzhydryl piperazine is dissolved in solvent Toluene and then reacted with p-Tertiary buthyl benzyl chloride in SS Reactor in presence of base Sodium hydroxide is refluxed for 14 hrs at temp ~105*C . After the reaction is complete, the mass is cooled to< 15*C and the solid sodium chloride is removed by filtration. The clear filtrate is then concentrated to remove solvent Toluene, to get Buclazine base as thick liquid.
3000M/s. R L Fine Chem Pvt. Ltd.,
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The recovered solvent is purified and reused. 2nd step The Buclazine base is dissolved in Acetone in SS reactor, charcoalised and filtered. The clear filtrate is transferred to GLreactor and treated with HCl gas and the resultant reaction mass is refluxed for 12 hrs and cooled <10*during this period, DiHydrochloride salt of Buclazine base separates out. This Buclazine dihydrochloride is isolated by centrifuging and dried. The mother liquor is sent for recovery of solvent which is re used.
BUCLAZINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B Size 450kg No of batchs 1/month
Raw material used
1 P-Chloro benzhydryl piperizine 286kg
2 P-Tert butyl benzyl chloride 182kg
3 Water 600Lt(1st stage)
4 Toluene 1000Lt
5 NaOH 40kg
6 Acetone 800Lt
7 HCl 73kg
8 Carbon 10kg
Yield (Buclazine Hydrochloride) 460kgs
Batch size 450kgs --- Buclazine Hydrochloride
Input Reactors Output
P-Chloro benzhydryl piperizine – 286kg
SSR 3000L(for step 1 reaction)
Buclazine Hydrochloride Yield ::450kg Overall yield:90%
P-Tert butyl benzyl chloride – 182kg
SSR 3000L (for workup) I.Product: stage-1::95% Stage-2::94%
Water – 600L SSR 2000L(for dissolution) Toluene: 900L Loss: 100L Acetone: 675L Loss:125L P.Water stage-1 :676kg/L Cleaning water ::500L goes to CETP Hazardous waste: 52-55kg Spent Carbon: 12kg
Toluene – 1000L GLR2000L (for reaction)
NaOH – 40kg SSR 2000L (for solvent recovery)
Acetone – 800L
HCl -70kg
Carbon – 10kg
3000M/s. R L Fine Chem Pvt. Ltd.,
- 174 -
Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… ---- 10-14hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 676kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 175 -
Process Waste Water :: 676 kgCleaning waste Water :500L
Buclazine base 410kgs
Acetone 800L
SS reactor-22000L
GLreactor2000L
SSreactor 2000Lfor solvent recovery
FLOW CHART FOR BUCLAZINE HYDROCHLORIDE
acetone
dissolution
Reaction
Total waste water to CETP is 1176kg
centrifuge +
Acetone 675Lloss 75L
Haz Waste 50-54 kgs
MLRAcetone
HCl 70kg
Buclazine dihydrochloride450.0kgs
2nd Step
Solvent lossAceton50.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up
P-chloro benzhydrylpiperizine 286kg
P-tert butylbenzyl chloride 182kg
NaOH 40kg
Toluene1000L
Water 600L
Water +NaCl676kg
Recov Toluene900L Loss:100L
Buclazine Base 235kg(contains 410kg pure)
1st step
Carbon 10kg Spent C12 kg wet
Spentcarbon 12 kg wet
22
MLR
30
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.5.2.35 MECLAZINE HCL
N
Cl
NH
+
Cl
N
Cl
N
N
Cl
N
Meclizine Base
Meclizine dihydrochloride
p-Chloro benzhydryl piperazine
meta methylbenzylchloride
286 140
NaOH
Toluene
390
N
Cl
N
Meclizine Base
390
HCl
Acetone
NaCl H2O
58 18
.2HCl
463
Reaction scheme
1st step
2nd step
40
73
Manufacturing Process- This involves 2 steps 1st step Para chloro benzhydryl piperazine is dissolved in solvent Toluene and then reacted with m-Methyl benyl chloride in SS Reactor in presence of base Sodium hydroxide is refluxed for 14 hrs at temp ~105*C . After the reaction is complete, the mass is cooled to< 15*C and the solid sodium chloride is removed by filtration.
3000M/s. R L Fine Chem Pvt. Ltd.,
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The clear filtrate is then concentrated to remove solvent Toluene, to get Meclazine base as thick liquid. The recovered solvent is purified and reused. 2nd step The Meclazine base is dissolved in Acetone in SS reactor, added carbon and filtered. The clear filtrate is transferred to GLreactor and treated with HCl and the reaction mass is refluxed for 12 hrs and cooled <10*during this period, DiHydrochloride salt of Meclazine base separates out. This Buclazine dihydrochloride is isolated by centrifuging and dried. The mother liquor is sent for recovery of solvent which is re used.
MECLAZINE HYDROCHLORIDE MASS BALANCE SL NO PRODUCTION B size 400kg No of batchs::1/Month
Raw material used
1 P-Chloro benzhydryl piperizine 286kg
2 Meta metyl benzyl chloride 140kg
3 Water 600Lt(stage-1)
4 Toluene 1000Lt
5 NaOH 40kg
6 Acetone 800Lt
7 HCl 70kg
8 Carbon 10kg
Yield (Meclazine Hydrochloride) 410kgs
Batch size 400kgs --- Meclazine Hydrochloride
Input Reactors Output
P-Chloro benzhydryl piperizine – 286kg
SSR 3000L(for step 1 reaction)
Meclazine Hydrochloride Yield ::410kg Overall yield:: 88.5%
Meta metyl benzyl chloride – 140kg
SSR 3000L (for workup) I.Product stage-1:93.5% Stage-2: 95%
Water – 600L SSR 2000L(for dissolution) Toluene: 900L Loss: 100L Acetone: 675L Loss:125L P. Water: stage-1:676kg/L Cleaning water ::500L goes to CETP Hazardous waste: 48-50kg Spent Carbon: 12kg
Toluene – 1000L GLR2000L (for reaction)
NaOH – 40kg SSR 2000L (for solvent recovery)
Acetone – 800L
HCl -70kg
Carbon – 10kg
3000M/s. R L Fine Chem Pvt. Ltd.,
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Time cycle 1st stage 2nd stage 3rd stage final 1) Reaction ………… 16-18hrs 12-14hrs - Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs 2-4hrs -
Solvent recovery…… ---- 10-14hrs (MLR-1) -----
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 676kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
- 179 -
Process Waste Water :: 676 kgCleaning waste Water :500L
Meclazine base 365kgs
Acetone 800L
SS reactor-22000L
GLreactor2000L
SSreactor 2000Lfor solvent recovery
FLOW CHART FOR MECLAZINE HYDROCHLORIDE
acetone
dissolution
Reaction
Total waste water to CETP is 1176kg
centrifuge +
Acetone 675Lloss 75L
Haz Waste 48-50 kgs
MLRAcetone
HCl 70kg
Meclazine dihydrochloride410.0kgs
2nd Step
Solvent lossAceton50.0L
SS reactor-1 cap:3000LRection
SS Reactor-1cap:3000LWork-up
P-chloro benzhydrylpiperizine 286kg
Meta methylbenzyl chloride 140kg
NaOH 40kg
Toluene 1000L
Water 600L
Water +NaCl676kg
Recov Toluene900L Loss:100L
Meclazine Base 390kg(contains 365kg pure)
1st step
Carbon 10kg Spent C12 kg wet
Spentcarbon 12 kg wet
MLR
25
23
3000M/s. R L Fine Chem Pvt. Ltd.,
- 180 -
3.5.2.36 CARBAMEZAPINE
Reaction scheme
N
Cl O
+ 2 NH3
N
H2N O
236
CarbamazepineIminostilbine carbonylchloride
255
Ammonia
2 x 17
AmmoniumChloride
NH4Cl
54
Manufacturing Procedure The process involves 2 steps and solvent recovery. 1st step reaction Iminostilbene carbonyl chloride is reacted with ammonia in SS reactor by refluxing for 20hrs in isopropyl alcohol (IPA) solvent. 2nd step isolation After the reaction is complete the reaction mass is cooled to <300C and centrifuged to remove the by-product ammonium chloride. The clear liquid is transferred to SS reactor and treated with water for isolation purpose and further cooled to 200C, during which carbamazepine crystallizes out. This will be centrifuged to separate the product from the IPA and water and then the product is dried. Solvent recovery The mother liquor from the centrifuge is sent for solvent recovery in SS reactor to recover isopropyl alcohol. The mother liquor i.e. IPA & water will be separated based on their boiling point in the solvent recovery unit.
3000M/s. R L Fine Chem Pvt. Ltd.,
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CARBAMEZAPINE MASS BALANCE SL NO PRODUCTION B size 220kg No of batchs 5/Month
Raw material used
1 Ammonia 40kg
2 IPA 2000L
3 Iminostibene Carconyl chloride 255kg
4 Water 700Lt
Yield (Carbamezapine) 225kgs
Batch size 200kgs --- Carbamezapine
Input Reactors Output
Ammonia – 40Kg SSR 4000L(for step 1 reaction)
Carbamezapine Yield ::225kg Oveall yield:97%
IPA – 2000L SSR 3000L (for step 1 workup)
I.Product: Nil Am chloride :54kg
Iminostibene Carconyl chloride – 255Kg
SSR 3000L (for solvent recovery)
IPA: 1750L Loss: 250L P.Water: 705kg/ L NH3 :7kg Cleaning water :500L goes to CETP Hazardous waste: 5kg
Water – 700L
Time cycle 1st stage 2nd stage 3rd stage final
1) Reaction ………… 20-22hrs ---------- -------- Drying
2) Isolation , cooling
& Centrifuge… 4-6hrs --------- ---------
3) Solvent recovery……… 12-16hrs ----------
Water used for washing/cleaning equipment, cleaning waste water 500L goes to CETP along with process waste water 705kgs
3000M/s. R L Fine Chem Pvt. Ltd.,
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Isopropyl alcohol 2000L
SS reactor-1
4000L
Haz Waste 5 kg
Process Waste Water :710LCleaning Waste Water : 500L
FLOW CHART FOR CARBAMEZAPINE
Iminostilbene Carconyl chloride 255kg
Reaction
MLR
Solvent recovery MLRSSreactor 3000L
Total water 1210L
SS REactor-2
3000L
Water 700L
Centrifuge
Ammonia 40 kg
Solvent recovery
AmmoniaLoss 7kg
Sovent loss100L
Ammoniumchloride 53 kg
CentrifugeSolvent loss :50 L
MLR
Carbamezapine225kg
Recovered IPA::1750LLoss :100L
Undistilled water,solv mix710kg
3000M/s. R L Fine Chem Pvt. Ltd.,
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3.6 RAW MATERIALS
3.6.1 Quantity requirement
The raw materials required for the manufacture of APIs are appended in the table 3.2 below. Raw materials as listed will be procured as per the production requirement.
Table 3.2: Raw materials requirement
Sl. No.
Product Raw materials Quantity required Solvents required after recycling
kg/annum kg/batch kg/month kg/annum
1 Amtriptyline hydrochloride
THF 40 1360 16320
Dibenzo suberone 208 7072 84864
Toluene 2200 74800 897600 163200
Water 1600 54400 652800
Mg 24 816 9792
Dimethylamino propyl chloride
120 4080 48960
Con Hcl acid 110 3740 44880
N-Butanol 1000 34000 408000 40800
HCl gas 36 1224 14688
Acetone 1800 61200 734400 163200
NaOH 80 2720 32640
H2O2 (20%) 80 2720 32640
Carbon 20 680 8160
2 Imipramine HCl/Desipram
ine HCl
Imino Dibenzyl 195 780 9360
Dimethylamino Propyl Chloride
120 480 5760
Sodamide 39 156 1872
Toluene 1000 4000 48000 4800
Water 600 2400 28800
Methanol Hcl 110 440 5280
Acetone 800 3200 38400 4800
Carbon 10 40 480
3 Cyproheptadine HCl
THF 25 75 900
Dibenzo Suberenone
206 618 7416
N-Methylchloro Piperidine
133 399 4788
Toluene 2600 7800 93600 7200
Water 500 1500 18000
Methanol 600 1800 21600 3600
Con. HCl 110 330 3960
IPA 1500 4500 54000 9000
3000M/s. R L Fine Chem Pvt. Ltd.,
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Carbon 15 45 540
Magnesium 24 72 864
4 Pitofenone HCl
Potassium bicarbonate
100 200 2400
Methyl ester intermediate
256 512 6144
Chloro ethyl piperidine
147 294 3528
Toluene 1000 2000 24000 2400
Water 600 1200 14400
Methanol Hcl 110 220 2640
Acetone 1000 2000 24000 3600
Carbon 10 20 240
5 Pyrimethamine
PCBC 150 450 5400
Ester 116 348 4176
Toluene 750 2250 27000 3600
Water 1000 3000 36000
MEG 60 180 2160
Methanol 1200 3600 43200 4500
Guanidine 60 180 2160
Carbon 10 30 360
6 Cyclobenzaprine HCl
Dimethylamino Propyl Chloride
120 360 4320
Dibenzo Suberenone
206 618 7416
Toluene 2500 7500 90000 9000
Water 600 1800 21600
Con. Hcl 110 330 3960
Acetone 1000 3000 36000 6300
Mg 24 72 864
Carbon 10 30 360
7 Clomipramine HCl
3-Chlorolmino Dibenzyl
230 460 5520
Dimethylamino Propyl Chloride
120 240 2880
Sodamide 39 78 936
Toluene 1000 2000 24000 2400
Water 600 1200 14400
Methanol Hcl 110 220 2640
Acetone 800 1600 19200 2400
Carbon 10 20 240
8 Chlorpromazine HCl
KOH 59 295 3540
2-Chloro pheno thiazine
233 1165 13980
3000M/s. R L Fine Chem Pvt. Ltd.,
- 185 -
Toluene 1000 5000 60000 6000
Water 600 3000 36000
Dimethylamino Propyl Chloride
120 600 7200
Acetone 1000 5000 60000 12000
Methanol Hcl 100 500 6000
Carbon 10 50 600
9 Doxylamine Succinate
2-Acetyl pyridine 120 600 7200
Chloro Benzene 112 560 6720
Diethylamino ethyl chloride
107 535 6420
Water 1200 6000 72000
Toluene 1200 6000 72000 9000
THF 30 150 1800
NaOH 40 200 2400
Carbon 15 75 900
Mg 24 120 1440
Succinic acid 110 550 6600
Acetone 1000 5000 60000 10500
10 Orphenadrine Citrate/ HCl
2-methyl Benzo phenone
215 2150 25800
NaOH 40 400 4800
Dimethylamino Ehtanol
90 900 10800
Toluene 1000 10000 120000 12000
Citric acid 180 1800 21600
Water 600 6000 72000
Acetone 1500 15000 180000 30000
Carbon 10 100 1200
11 Trimipramine Maleate/ Mesylate
Sodamide 39 78 936
Imino Dibenzyl 195 390 4680
Toluene 1000 2000 24000 2400
Water 600 1200 14400
Dimethylamino Methylpropyl chloride
135 270 3240
Acetone/EA 800 1600 19200 2400
Maleic acid 110 220 2640
Carbon 10 20 240
12 Flupentixol HCl
THF 10 10 120
Trifluorothioxanthone
28 28 336
Mg 2.5 2.5 30
Toluene 700 700 8400 840
Water 200 200 2400
3000M/s. R L Fine Chem Pvt. Ltd.,
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Acetone 300 300 3600 420
Carbon 5 5 60
Con Hcl acid 21 21 252
Piperizino ehtanol intermediate
20 20 240
13 Melitracen HCl
THF 30 30 360
Dimethyl anthrone
220 220 2640
Dimethylamino propyl chloride
120 120 1440
Toluene 2200 2200 26400 4200
Water 600 600 7200
Mg 24 24 288
Acetone 1000 1000 12000 2100
Carbon 15 15 180
Con Hcl acid 100 100 1200
14 Carbinoxamine Maleate
Pyridine Benz Hydrol
220 440 5280
NaOH 40 80 960
Dimethylamino Ethyl chloride
107 214 2568
Toluene 1000 2000 24000 2400
Maleic acid 116 232 2784
Water 600 1200 14400
Acetone 1000 2000 24000 4200
Carbon 10 20 240
15 Opipramol HCl
Imino stilbene 96 96 1152
NaOH 40 40 480
Bromochloro Propane
78 78 936
Toluene 2000 2000 24000 2400
Piperizinoethanol 65 65 780
Water 1200 1200 14400
Acetone 1200 1200 14400 2400
Carbon 10 10 120
HCl 36 36 432
16 Sulfadoxine P-Amino sulfonamide
172 1376 16512
Methoxy dichloro pyrimidine
179 1432 17184
Water 2000 16000 192000
Toluene 1500 12000 144000 24000
NaOH 40 320 3840
Methanol 2000 16000 192000 19200
3000M/s. R L Fine Chem Pvt. Ltd.,
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Sodium methoxide
54 432 5184
Carbon 15 120 1440
17 Doxepin HCl Mg 24 24 288
Dimethylamino propyl chloride
120 120 1440
Toluene 2500 2500 30000 3000
Doxiepinone 210 210 2520
THF 20 20 240
Water 600 600 7200
Con Hcl 110 110 1320
Acetone 1000 1000 12000 2100
Carbon 10 10 120
18 Nitrazepam Chloroacetyl chloride
112 112 1344
2-amino 5-nitro benzophenone
242 242 2904
Toluene 1000 1000 12000 1800
Ammonia 51 51 612
Carbon 10 10 120
Methanol 1250 1250 15000 3000
19 Dothiepin HCl Mg 24 96 1152
Dimethylamino propyl chloride
120 480 5760
Toluene 2500 10000 120000 12000
Dothiepinone 226 904 10848
THF 20 80 960
Water 600 2400 28800
Con Hcl 110 440 5280
Acetone 1000 4000 48000 8400
Carbon 10 40 480
20 Bromazepam Chloroacetyl chloride
30 30 360
2-amino 5-bromo benzoyl pyridine
70 70 840
Toluene 600 600 7200 1200
Ammonia 14 14 168
Carbon 5 5 60
Methanol 800 800 9600 2400
21 Flunarazine HCl
Difluro Benzhydrol
220 220 2640
Piperizine 86 86 1032
Toluene 1500 1500 18000 2400
HCl 110 110 1320
NaOH 40 40 480
3000M/s. R L Fine Chem Pvt. Ltd.,
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Water 1425 1425 17100
Cinnamyl alcohol 134 134 1608
Acetone/IPA 2000 2000 24000 4200
Carbon 15 15 180
Methanol 2000 2000 24000 3600
HCl Gas 73 73 876
22 Cinnarazine Benzhydrol 184 1288 15456
Piperizine 86 602 7224
Toluene 1500 10500 126000 16800
HCl 110 770 9240
NaOH 40 280 3360
Water 1425 9975 119700
Cinnamyl alcohol 134 938 11256
Acetone/IPA 2000 14000 168000 29400
Carbon 15 105 1260
Methanol 2000 14000 168000 25200
23 Clonazepam Chloroacetyl chloride
56 56 672
2-amino 5-nitro chloro benzophenone
138 138 1656
Toluene 600 600 7200 1200
Ammonia 25 25 300
Carbon 5 5 60
Methanol 800 800 9600 2400
24 Lorazepam Chloroacetyl chloride
56 56 672
2-amino dichloro benzophenone
133 133 1596
Water 600 600 7200
Toluene 1200 1200 14400 2400
NaOH 60 60 720
Hydroxyl amine 16 16 192
Carbon 10 10 120
Methanol 1300 1300 15600 3000
Acetic anhydride 45 45 540
25 Duloxetine HCl
Formaldehyde 30 30 360
2-Acetyl thiophene
126 126 1512
Water 1800 1800 21600
Toluene 1800 1800 21600 3600
Dimethyl amine 45 45 540
Acetone 1000 1000 12000 2400
HCl 36 36 432
Carbon 10 10 120
3000M/s. R L Fine Chem Pvt. Ltd.,
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H2 gas
Methanol 1000 1000 12000 2400
Ni cat 2 2 24
DMSO 600 600 7200 600
Fluro naphthalene
145 145 1740
KOH 112 112 1344
26 Dapoxetine HCl
3-Chloro propio phenone
34 34 408
Methanol 300 300 3600 600
Water 900 900 10800
Ni 1 1 12
Toluene 500 500 6000 600
Alfa Napthol 30 30 360
Methane sulfonic acid
19 19 228
Carbon 10 10 120
Dimethyl amine 9 9 108
HCl 7 7 84
KOH 11 11 132
Acetone 500 500 6000 1800
27 Desvenlafaxine HCl
Venalafaxine hydrochloride
313 313 3756
Toluene 2000 2000 24000 1800
NaOH 40 40 480
Acetone 1000 1000 12000 2400
Succinic acid 112 112 1344
Water 1018 1018 12216
Carbon 15 15 180
28 Trihexyphenadyl HCl
Acetophenone 120 120 1440
Formaldehyde 30 30 360
Piperidine 85 85 1020
Water 1200 1200 14400
Toluene 1100 1100 13200 1200
THF 30 30 360
Cyclohexyl chloride
118 118 1416
Carbon 15 15 180
Mg 24 24 288
HCL 36 36 432
Acetone 1000 1000 12000 2100
29 Tramadol HCl Cyclo hexanone 98 980 11760
Formaldehyde 30 300 3600
Dimethylamine 45 450 5400
Toluene 1100 11000 132000 12000
3000M/s. R L Fine Chem Pvt. Ltd.,
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THF 30 300 3600
Water 1200 12000 144000
Metabromo methoxy anisole
187 1870 22440
Mg 24 240 2880
Carbon 15 150 1800
Acetone 1000 10000 120000 21000
HCl 36 360 4320
30 Sulfamethoxy Pyrazine HCl
P-amino sulfonamide
172 344 4128
DMF 1500 3000 36000 2400
Dichloro pyazine 148 296 3552
KHCO3 100 200 12000
Potassium methoxide
70 140 1680
Water 1000 2000 24000
Carbon 15 30 360
Methanol 2000 4000 48000 8400
31 Alimemazine Tartarate
Phenothiazine 199 199 2388
Sodium methoxide
54 54 648
THF 800 800 9600 1200
Dimethylamino propyl chloride
135 135 1620
IPA 600 600 7200 1200
Carbon
L-Tartaric acid 50 50 600
Hydrogen peroxide20% solu
100 100 1200
HCl 11 11 132
Acetone 1600 1600 19200 4800
32 Alprazolam Chloroacetyl chloride
56 56 672
2-amino 5-chloro benzophenone
115 115 1380
Toluene 600 600 7200 1200
Ammonia 25 25 300
Carbon 5 5 60
Methanol 800 800 9600 2400
33 Diazepam Chloroacetyl chloride
56 56 672
2-methyklamino 5-chloro benzophenone
123 123 1476
Ammonia 25 25 300
3000M/s. R L Fine Chem Pvt. Ltd.,
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Toluene 600 600 7200 1200
Methanol 800 800 9600 1800
Carbon 5 5 60
34 Buclazine HCl P-Chloro benzhydryl piperizine
286 286 3432
P-Tert butyl benzyl chloride
182 182 2184
Water 600 600 7200
Toluene 1000 1000 12000 1200
NaOH 40 40 480
Acetone 800 800 9600 1500
HCl 70 70 840
Carbon 10 10 120
35 Meclazine HCl
P-Chloro benzhydryl piperizine
286 286 3432
Meta metyl benzyl chloride
140 140 1680
Water 600 600 7200
Toluene 1000 1000 12000 1200
NaOH 40 40 480
Acetone 800 800 9600 1500
HCl 70 70 840
Carbon 10 10 120
36 Carbamezapine
Ammonia 40 320 3840
IPA 2000 16000 192000 24000
Iminostibene Carconyl chloride
255 2040 24480
Water 700 5600 67200
3.6.2 Source of supply of raw materials
The raw materials are either obtained from local suppliers (Gujarat, Maharashtra, Karnataka, and Andhra Pradesh) or imported (China) & transportation mode is by air, road & sea.
Table 3.2 A: Raw materials suppliers
Sl. no.
Raw material Supplier
1 THF NAN YA PLASTICS CORPORATION
2 Dibenzosuberone LUNA CHEMICALS CO LTD
3 Toluene BPCL
4 Methanol Hcl CHEMIELIVA PHARMACEUTICALS LTD
5 Magnesium NANGTONG CHEM-TECH CO LTD
3000M/s. R L Fine Chem Pvt. Ltd.,
- 192 -
6 Con Hcl acid NANJING FINE TECH CHEMICALS CO LTD
7 N-Butanol WENZHOU CHEMICAL MATERIAL FACTORY
8 HCl gas BHURUKA GASES LIMITED
9 Acetone HOCL /RONDER CORPORATION
10 NaOH BEIJING CERAMETEK MATERIALS CO LTD
11 Carbon POLYCHEIMIE SA
12 IminoDibenzyl ZHEJIANG JIUZHOU PHARMACEUTICAL CO LTD
13 Sodamide TILLEY CHEMICALS
14 Methanol DAIREN CHEMICAL CORPORATION
15 N-MethylchloroPiperidine ANHUI RUISAI BIOCHEMICAL TECHNOLOGY CO LTD
16 IPA DEEPAK FERTILISERS PVT LTD
17 Potassium bicarbonate CHANGZHOU SINOWA CHEMICAL CO LTD
18 Methyl ester intermediate HAIHANG INDUSTRY CO.LTD.
19 Chloro ethyl piperidine HUEI-HO INTERNATIONAL CO., LTD.
20 PCBC HEBEI CHENGXIN CO., LTD
21 Ester SUZHOU WUGAN PHARMACEUTICAL CO., LTD.
22 MEG SHAOXING XINGXIN CHEMICAL CO LTD
23 Guanidine PERI NITRATES PVT.LTD.
24 3-Chlorolmino Dibenzyl ZHEJIANG CHEMSYN PHARMA CO., LTD.
25 KOH TAIZHOU BEST PHARM CO LTD
26 2-Chloro pheno thiazine CHANGZHOU SINOWA CHEMICALS CO LTD
27 2-Acetyl pyridine QINGDAO FREE TRADE ZONE UNITED INTERNATIONAL CO LTD
28 Chloro Benzene JIANGXI SYNERGY PHARMACEUTICAL CO., LTD.
29 Succinic acid XUZHOU NHWA PHARMACHEM ENTERPRISE CO LTD
30 2-methyl Benzophenone SINO-HIGH (CHINA) CO., LTD
31 Dimethylamino Ethanol AKI SHOKAI CO., LTD.
32 Citric acid CHANGZHOU UNITED CHEMICAL CO LTD
33 Dimethylamino Methylpropyl chloride
HAIHANG INDUSTRY CO.LTD.
34 Maleic acid JIANGSU GUO TAI INTERNATIONAL GROUP
35 Trifluorothioxanthone SHANGHAI DOMEN INTERNATIONAL CO LTD
36 Piperizino ethanol intermediate
ZHEJIANG MEDICINES AND HEALTH PRODUCTS IMP. AND EXP. CO., LTD
37 Dimethyl anthrone SHANGHAI PINEWOOD INTERNATIONAL TRADE CO., LTD.
38 Pyridine Benz Hydrol SUZHOU WUGAN PHARMACEUTICAL CO., LTD.
39 Dimethylamino Ethyl chloride
TAIZHOU BEST PHARM CO LTD
40 Iminostilbene ZHEJIANG ZONEBANNER JIUZHOU IMP & EXP CO LTD
41 Bromochloro Propane SHAOXING XINGXIN CHEMICAL CO LTD
3000M/s. R L Fine Chem Pvt. Ltd.,
- 193 -
42 P-Amino sulfonamide SHANGHAI DOMEN INTERNATIONAL CO LTD
43 Methoxydichloro pyrimidine
XUZHOU NHWA PHARMACHEM ENTERPRISE CO LTD
44 Sodium methoxide QINGDAO FREE TRADE ZONE UNITED INTERNATIONAL CO LTD
45 Doxiepinone SHOUGUANG FUKANG PHARMACEUTICAL CO. LTD.
46 Chloroacetyl chloride JIANGXI SYNERGY PHARMACEUTICALS IMP & EXP CO LTD
47 Ammonia CHANGSHU WANXING CHEMICAL CO LTD
48 Dothiepinone ANHUI RUISAI BIOCHEMICAL TECHNOLOGY CO LTD
49 2-amino 5-bromo benzoyl pyridine
SYNCHEM INTERNATIONAL CO. LTD.
50 DifluroBenzhydrol LEVA CHEM
51 Piperizine SHAOXING XINGXIN CHEMICAL CO LTD
52 Cinnamyl alcohol XINCHANG GUOBANG IMPORT & EXPORT CO LTD
53 Benzhydrol SHANGHAI DOMEN INTERNATIONAL CO LTD
54 2-amino 5-nitro chlorobenzophenone
ZHEJIANG MEDICINES AND HEALTH PRODUCTS IMP. AND EXP. CO., LTD
55 Hydroxyl amine HANGZHOU PROSERRE CHEMICAL CO. LTD.
56 Acetic anhydride JIANGSU GUO TAI INTERNATIONAL GROUP
57 Formaldehyde QINGDAO FREE TRADE ZONE UNITED INTERNATIONAL CO LTD
58 2-Acetyl thiophene SUZHOU WUGAN PHARMACEUTICAL CO., LTD.
59 Dimethyl amine ZHEJIANG HUAZHOU PHARMACEUTICAL CO.,LTD
60 H2 gas BHURUKA GASES LIMITED
61 Ni cat JINTAN DEPEI CHEMICAL CO. LTD.
62 DMSO XINGJIANG BLUE RIDGE TUNHE POLYESTER CO., LTD.
63 Fluro naphthalene ZHEJIANG JIUZHOU PHARMACEUTICAL CO LTD
64 3-Chloro propiophenone ZHEJIANG TONGXIANG FOREIGN TRADE (GROUP) CO., LTD.
65 Ni HANGZHOU VIWA CO LTD
66 Alfa Napthol CHANGZHOU UNITED CHEMICAL CO LTD
67 Methane sulfonic acid XUZHOU NHWA PHARMACHEM ENTERPRISE CO LTD
68 Dimethyl amine ZHEJIANG XIANJU JUNYE PHARMACEUTICAL CO LTD
69 Venalafaxine hydrochloride ZHEJIANG XIANJU JUNYE PHARMACEUTICAL CO LTD
70 Acetophenone ZHEJIANG TONGXIANG FOREIGN TRADE (GROUP) CO., LTD.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 194 -
71 Cyclohexyl chloride GUJARAT HALOGEN PETROCHEM CORPN.
72 Cyclohexanone SHAOXING XINGXIN CHEMICAL CO LTD
73 Metabromomethoxyanisole TAIZHOU BEST PHARM CO LTD
74 P-amino sulfonamide JINTAN DEPEI CHEMICAL CO. LTD.
75 DMF HANGZHOU QICHUANG CHEMICAL CO.LTD.
76 Dichloropyazine ANHUI RUISAI BIOCHEMICAL TECHNOLOGY CO LTD
77 KHCO3 CHANGSHU WANXING CHEMICAL CO LTD
78 Potassium methoxide SHAOXING XINGXIN CHEMICAL CO LTD
79 Phenothiazine ZHEJIANG TONGXIANG FOREIGN TRADE (GROUP) CO., LTD.
80 Sodium methoxide HANGZHOU PROSERRE CHEMICAL CO. LTD.
81 Dimethylamino propyl chloride
HUEI-HO INTERNATIONAL CO., LTD.
82 L-Tartaric acid SYNCHEM INTERNATIONAL CO. LTD.
83 Hydrogen peroxide20% solu HANGZHOU VIWA CO LTD
84 P-Chlorobenzhydrylpiperizine
CHANGZHOU HUASHAN CHEMICAL CO LTD
85 P-Tert butyl benzyl chloride
SHANGHAI DOMEN INTERNATIONAL CO LTD
86 P-Chlorobenzhydrylpiperizine
SUZHOU WUGAN PHARMACEUTICAL CO., LTD.
87 Meta metyl benzyl chloride ZHEJIANG CHEMSYN PHARMA CO., LTD.
3.6.3 STORAGE FACILITY FOR RAW MATERIALS AND PRODUCTS Adequate storage facilities are proposed to be provided for the raw materials, products etc.
Table 3.3:- Details of Storage Facilities
Sl. No. Storage Facility for Facility
1 Raw Materials Warehouse
2 Products Bonded finished good store
3 Industrial Effluent Effluent treatment Plant with Multiple Effective Evaporator (MEE) followed by RO filtration with adequate storage tanks
4 Hazardous Waste Process residue is sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. Spent carbon will be disposed for coincineration during the manufacture of cement.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 195 -
The inorganic residue from the process and as well from the MEE will be stored scientifically and will be sent to TSDF for scientific treatment and disposal.
3.6.4 MACHINERY & EQUIPMENT DETAILS The detailed list of machinery & equipments in the industry are appended in the tables below
Table 3.4: List of the machinery & equipments
Block – A Equipments
SL.NO Description of Main Machineries / Plant Capacity Nos
1 GLR 1 KL 1
2 GLR 2 KL 1
3 GLR 2 KL 1
4 GLR 3 KL 1
5 GLR 2 KL 1
6 GLR 2 KL 1
7 GLR 3 KL 1
8 SS 0.75 KL 1
9 SS 1 KL 1
10 SS 2 KL 1
11 SS 2 KL 1
12 SS 2 KL 1
13 SS 2 KL 1
14 SS 2 KL 1
15 SS 3 KL 1
16 SS 3 KL 1
17 SS 3 KL 1
18 SS 5 KL 1
19 SS 7.5 KL 1
20 SS 3 KL 1
3000M/s. R L Fine Chem Pvt. Ltd.,
- 196 -
Block – B Equipments
SL.NO Description of Main Machineries / Plant Capacity Nos
1 SS 1.5 KL 1
2 SS 3 KL 1
3 GLR 3 KL 1
4 GLR 5 KL 1
5 GLR 5 KL 1
6 GLR 3 KL 1
7 GLR 3 KL 1
8 GLR 5 KL 1
9 SS 2 KL 1
10 SS 2 KL 1
11 SS 2 KL 1
12 SS 2 KL 1
13 SS 2 KL 1
14 SS 2 KL 1
15 SS 2 KL 1
16 SS 3 KL 1
17 SS 3 KL 1
18 SS 3 KL 1
19 SS 3 KL 1
20 SS 5 KL 1
21 SS 5 KL 1
22 SS 7.5 KL 1
23 SS 3 KL 1
3.7.1 SOLVENT RECOVERY & RE-USE Various solvents are proposed to be used during the process of manufacture of APIs. The solvents proposed to be recovered and recycled during the process of manufacture of each product are detailed in table 3.5.
3.7 RESOURCE OPTIMIZATION/RECYCLING AND RE-USE ENVISAGED IN THE PROJECT
3000M/s. R L Fine Chem Pvt. Ltd.,
- 197 -
Table 3.5: Solvent recovery
Sl.No Product Raw materials Quantity (kg/annum)
Recovered and recycled
Lost
1 Amtriptyline hydrochloride Stage 1
Toluene 775200
122400
Acetone 326400 81600
Stage 2 Toulene 367200 40800
Acetone 244800 81600
N-Butanol 367200 40800
2 Imipramine
HCl/Desipramine HCl
Toluene 43200 4800
Acetone 33600 4800
3 Cyproheptadine HCl Toluene 86400 7200
Methanol 18000 3600
IPA 45000 9000
4 Pitofenone HCl Toluene 21600 2400
Acetone 20400 3600
5 Pyrimethamine Toluene 23400 3600
Methanol 38700 4500
6 Cyclobenzaprine HCl Toluene 81000 9000
Acetone 29700 6300
7 Clomipramine HCl Toluene 21600 2400
Acetone 16800 2400
8 Chlorpromazine HCl Toluene 54000 6000
Acetone 48000 12000
9 Doxylamine Succinate Toluene 63000 9000
Acetone 49500 10500
10 Orphenadrine Citrate/ HCl
Toluene 108000 12000
Acetone 150000 30000
11 Trimipramine Maleate/ Mesylate
Toluene 21600 2400
Acetone/EA 16800 2400
12 Flupentixol HCl Toluene 7560 840
Acetone 3180 420
13 Melitracen HCl Toluene 22200 4200
Acetone 9900 2100
14 Carbinoxamine Maleate
Toluene 21600 2400
Acetone 19800 4200
15 Opipramol HCl Toluene 21600 2400
Acetone 12000 2400
16 Sulfadoxine Toluene 120000 24000
Methanol 172800 19200
17 Doxepin HCl Toluene 27000 3000
Acetone 9900 2100
3000M/s. R L Fine Chem Pvt. Ltd.,
- 198 -
18 Nitrazepam Toluene 10200 1800
Methanol 12000 3000
19 Dothiepin HCl Toluene 108000 12000
Acetone 39600 8400
20 Bromazepam Toluene 6000 1200
Methanol 7200 2400
21 Flunarazine HCl Toluene 15600 2400
Acetone/IPA 19800 4200
Methanol 20400 3600
22 Cinnarazine Toluene 109200 16800
Acetone/IPA 138600 29400
Methanol 142800 25200
23 Clonazepam Toluene 6000 1200
Methanol 7200 2400
24 Lorazepam Toluene 12000 2400
Methanol 12600 3000
25 Duloxetine HCl Toluene 18000 3600
Acetone 9600 2400
Methanol 9600 2400
DMSO 6600 600
26 Dapoxetine HCl Methanol 3000 600
Toluene 5400 600
Acetone 4200 1800
27 Desvenlafaxine HCl Toluene 22200 1800
Acetone 9600 2400
28 Trihexyphenadyl HCl Toluene 12000 1200
Acetone 9900 2100
29 Tramadol HCl Toluene 120000 12000
Acetone 99000 21000
30 Sulfamethoxy Pyrazine HCl
DMF 33600 2400
Methanol 39600 8400
31 Alimemazine Tartarate
THF 8400 1200
IPA 6000 1200
Acetone 14400 4800
32 Alprazolam Toluene 6000 1200
Methanol 7200 2400
33 Diazepam Toluene 6000 1200
Methanol 7800 1800
34 Buclazine HCl Toluene 10800 1200
Acetone 8100 1500
35 Meclazine HCl Toluene 10800 1200
Acetone 8100 1500
36 Carbamezapine IPA 168000 24000
3000M/s. R L Fine Chem Pvt. Ltd.,
- 199 -
Note: * The solvent lost during the process of solvent distillation is mainly due to organic thermal disintegration and in form of residue left behind from the bottom un-distilled product. Evaporation loss is minimized by the passage of chilled water through the condenser. SOLVENT RECOVERY SYSTEM
After the reaction is complete the solvents are recovered in a distillation unit. The distillation unit has two condensers in series (shell and tube type). The first condenser is passed with chilled cooling tower water at 7-12 oC, while
the second condenser will be passed with chilled brine solution at -10 - 200 C as coolants.
After the vapors are condensed, the condensate along with un-condensed vapors is passed through a trap which is cooled externally with chilled water.
The vents of condenser and receiver are connected to scrubber system. All the reaction vessels and centrifuges are connected to a common line. These
fumes and exhausts are sucked by ID fan and scrubbed by alkali solution. The air after scrubbing is let out into the atmosphere and the scrubbed water is
sent to ETP for further treatment. This wet scrubber absorbs acidic vapors, traces of solvents etc. and purified gas
stream is let out into the atmosphere.
Fig 3.2: Typical solvent recovery system
Condenser 2
Condenser 1
Chilled water
Cooling tower water
Distillation
column
Receiver
To scrubber
Recovered solvent
Residue to storage
3000M/s. R L Fine Chem Pvt. Ltd.,
- 200 -
3.7.2 SPENT CARBON Spent carbon is used during the process of manufacture of different APIs. The spent carbon will be dispoed to co-incinerator as axilaury fuel during manufacture of cement. The detailed list of the quantities is appended in table 3.6 below
Table 3.6: Spent carbon recovery and disposal
Sl. No. APIs Quantity of spent carbon generated, kg/annum
1 Amtriptyline hydrochloride 9,792
2 Imipramine hydrochloride 576
3 Cyproheptadiene HCl 720
4 Pitofenone HCl 288
5 Pyrimethamine 432
6 Cyclobenzaprine HCl 432
7 Clomipramine HCl 288
8 Chlorpromazine HCl 720
9 Doxylamine Succinate 1,080
10 Orphenadrine Citrate/ HCl 1,440
11 Trimipramine Maleate/ Mesylate
288
12 Flupentixol HCl 72
13 Melitracen HCl 216
14 Carbinoxamine Maleate 288
15 Opipramol HCl 144
16 Sulfadoxine 1,728
17 Doxepin HCl 144
18 Nitrazepam 144
19 Dothiepin HCl 576
20 Bromazepam 84
21 Flunarazine HCl 216
22 Cinnarizine 1,512
23 Clonazepam 84
24 Lorazepam 144
25 Duloxetine HCl 144
26 Dapoxetine HCl 144
27 Desvenlafaxine HCl 216
28 Trihexyphenadyl HCl 216
29 Tramadol HCl 2,160
30 Sulfamethoxy Pyrazine HCl 432
31 Alimemazine Tartarate 288
32 Alprazolam 84
33 Diazepam 84
34 Buclazine HCl 144
3000M/s. R L Fine Chem Pvt. Ltd.,
- 201 -
35 Meclazine HCl 144
36 Carbamezapine -
TOTAL 25,464
3.7.3 DOMESTIC SOLID WASTE RE-USE The total quantity of domestic wastes generated is about 22 kg/day which will be segregated at source, collected in bins and composted. The composted waste will be used as manure for landscape development.
3.8 WATER, ENERGY/POWER REQUIREMENT & SOURCE
3.8.1 Water
The water demand is met from Bore well water supply. The requirement of water for the unit is for domestic, industrial purposes. Details are appended in section 3.9.1 later in the report.
3.8.2 Power
The total power requirement of the industry is 750 kVA. Further one diesel generator of 500 kVA capacity is proposed to be installed to serve as an alternative source of power supply to this unit.
3.9 WASTES GENERATED & SCHEME FOR THEIR MANAGEMENT/DISPOSAL
3.9.1 Water demand and wastewater/effluent discharge
Source of water supply: Borewell Total number of employees: 110 people Per capita water demand: 45 LPCD
The total quantity of water required for the industry is about 186.050 KLD. The break-up of the consumption of water is as presented below.
Table 3.7: Water consumption and discharge
Water consumed for Consumption (LPD)
Discharge (LPD)
(a) Domestic (toilet, canteen etc.) 4,950 4,455
(b) Gardening/Landscape development
5,000 -
(c) Industrial purpose 1,76,100 68,500
1 Process
DM plant and its rejects 20,400 or say 20,500+2,000=22,500
22,459 (from process) + 2,000 (DM
3000M/s. R L Fine Chem Pvt. Ltd.,
- 202 -
reject)= 24,459 or say 25,500
2 Washing/Cleaning 29,810 or say 30,000 30,000
3 Softener rejects 20,000 2,000 (blow-down) Boiler feed for 3 MT boiler 18,000
4 Cooling tower – 5 nos. 75,600 (make-up water)
1,000 (bleed off)
5 Scrubber – 4 no. 5,000 5,000
6 R&D 5,000 5,000
Total 1,86,050 LPD or say 186.050 KLD
72,955 LPD or say 72.955
KLD Note: LPD – liter per day; KLD – kilo liter per day The treatment methods and the final disposal of each type of wastewater generated is appended in the table 3.6 below
Table 3.8: Sewage/effluent treatment and discharge
Sewage/effluent generated from
Treatment units provided Final disposal point
(a) Domestic Sewage is mixed and treated along with Low strength Effluent treatment plant
Recycle and on land irigation
(b) Industrial Collection tanks of 10 KL capacity (3 no.s) are proposed to be provided.
Industrial effluent is proposed to be treated in Effluent Treatment Plant with Multiple Effect Evaporator (MEE) followed by RO fitration for treatment, reuse and disposal.
3000M/s. R L Fine Chem Pvt. Ltd.,
- 203 -
LANDSCAPING 5,000 LPD
BOREWELL WATER SUPPLY
Cooling Tower bleed off 1,000 LPD
Mixed with low strength wastewater
stream
WATER CONSUMPTION 1,86,050 LPD
DOMESTIC WATER DEMAND 4,950 LPD
Scrubber
5,000 LPD
39.455 KLD (low strength stream) – equalization, aeration & reverse osmosis (RO) & 33.500 KLD (high strength stream) –Effluent Treatment Plant with Multiple Effect Evaporator followed by
RO filtration
* Process effluent & DM
rejects 25,500 LPD
Washing effluent
30,000 LPD
Boiler blow down
2,000 LPD
Boiler consumption 18,000 LPD
Cooling tower Make - up water 75,534.8 or say 75,535 LPD
(75,600-65.314)
Washing/ Cleaning
30,000 LPD
Scrubber effluent
5,000 LPD
INDUSTRIAL WATER DEMAND 1,76,100 LPD- Start up requirement Daily requirement after recycling:
1,76,100-65.314=1,76,034.6 or say 1,76,035 LPD
Fig 3.2: Water balance chart
DM water plant
22,500 LPD
Process consumption 20,500 LPD
Domestic wastewater
4,455 LPD
R&D
5,000 LPD
R&D effluent
5,000 LPD
Softener 20,000 LPD
M/s. R L Fine Chem Pvt. Ltd.,
- 204 -
*Excess quantity is because of inert water content in the chemnicals used in the process 3.9.1.1 PRODUCT-WISE WATER CONSUMPTION AND DISCHARGE Table 3.7: Product-wise water consumption and effluent discharge Table:9 PRODUCT-WISE WATER CONSUMPTION, DISCHARGE, BYPRODUCTS & INORGANIC SALTS GENERATIO
S N
Product Batch-wise water consumption, discharge, Byproduct & Inorganic salt generation
No. of batches /month
Total water
consumption
(L/month)
Total effluent
discharge (L/month)
Total inorganic
salt (kg/month)
Total byproduct (kg/month) Utility
of water Water
consumption (L/batch)
Effluent discharge (L/batch)
Inorganic salt (kg/batch)
By produ
ct (kg/batch)
1 Amtriptyline hydrochloride
Process 4,800 5,200 60 - 34 1,63,200 1,76,800 2040 -
Cleaning 8,250 8,250 2,80,500 2,80,500
Total 13,050 13,450 4,43,700 4,57,300
2 Imipramine hydrochloride
Process 2,400 2,640 60 17 Ammo
nia
4
9600 10560 240 68
Cleaning 2,750 2,750 11000 11000
Total 5,150 5,390 20600 21560
3 Cyproheptadiene HCl
Process 2000 2700 60 - 3 6000 8100 180 -
Cleaning 8250 8250 24750 24750
Total 10250 10950 30750 32850
4 Pitofenone HCl
Process 2400 2780 75 - 2 4800 5560 150 -
Cleaning 2750 2750 5500 5500
Total 5150 5530 10300 11060
5 Pyrimethamine
Process 4000 4320 - 50 MEG
3 12000 12960 - -
Cleaning 2750 2750 8250 8250
M/s. R L Fine Chem Pvt. Ltd.,
- 205 -
Total 6750 7070 20250 21210
6 Cyclobenzaprine HCl
Process 2400 3000 60 - 3 7200 9000 180 -
Cleaning 2750 2750 8250 8250
Total 5150 5750 15450 17250
7 Clomipramine HCl
Process 2400 2640 60 17 Ammo
nia
2 4800 5280 120 -
Cleaning 2750 2750 5500 5500
Total 5150 5390 10300 10780
8 Chlorpromazine HCl
Process 2400 2780 75 - 5 12000 13900 375 -
Cleaning 2750 2750 13750 13750
Total 5150 5530 25750 27650
9 Doxylamine Succinate
Process 4800 5340 120 - 5 24000 26700 600 -
Cleaning 2750 2750 13750 13750
Total 7550 8090 37750 40450
10 Orphenadrine Citrate/ HCl
Process 2400 2700 60 - 10 24000 27000 600 -
Cleaning 5500 5500 55000 55000
Total 7900 8200 79000 82000
11 Trimipramine Maleate/ Mesylate
Process 2400 2640 60 17 Ammo
nia
2 4800 5280 120 34
Cleaning 2750 2750 5500 5500
Total 5150 5390 10300 10780
12 Flupentixol HCl
Process 800 900 6 - 1 800 900 6 -
Cleaning 2750 2750 2750 2750
Total 3550 3650 3550 3550
13 Melitracen HCl
Process 2400 2960 60 - 1 2400 2960 60 -
Cleaning 2750 2750 2750 2750
M/s. R L Fine Chem Pvt. Ltd.,
- 206 -
Total 5150 5710 5150 5710
14 Carbinoxamine Maleate
Process 2400 2700 60 - 2 4800 5400 120 -
Cleaning 2750 2750 5500 5500
Total 5150 5450 10300 10900
15 Opipramol HCl Process 4800 5200 80 - 1
4800 5200 80 -
Cleaning 5500 5500 5500 5500
Total 10300 10700 10300 10700
16 Sulfadoxine Process 8000 8080 - 115 Sodiu
m Chlori
de
8 64000 64640 - -
Cleaning 8250 8250 66000 66000
Total 16250 16330 13000 130640
17 Doxepin HCl Process 2400 3000 60 - 1 2400 3000 60 -
Cleaning 2750 2750 2750 2750
Total 5150 5750 5150 5750
18 Nitrazepam Process - 80 - 106 Ammonium chlori
de
1 - 80 - 106
Cleaning 5500 5500 5500 5500
Total 5500 5580 5500 5580
19 Dothiepin HCl Process 2400 3000 60 - 4 9600 12000 240 -
Cleaning 2750 2750 11000 11000
Total 5150 5750 20600 23000
20 Bromazepam Process - - - 26 ammo
1 - - - 26
Cleaning 5500 5500 5500 5500
M/s. R L Fine Chem Pvt. Ltd.,
- 207 -
Total 5500 5500 nium bromi
de
5500 5500
21 Flunarazine HCl
Process 5700 6460 58 - 1 5700 6460 58 -
Cleaning 8250 8250 8250 8250
Total 13950 14710 13950 14710
22 Cinnarizine Process 5700 6460 58 - 7 39900 45220 406 -
Cleaning 8250 8250 57750 57750
Total 13950 14710 97650 102970
23 Clonazepam Process - - - 54 Ammonium chlori
de
1 - - - 54
Cleaning 5500 5500 5500 5500
Total 5500 5500 5500 5500
24 Lorazepam Process 2400 2760 60 30 Sodiu
m chlori
de
1 2400 2760 60 30
Cleaning 5500 5500 5500 5500
Total 7900 8260 7900 8260
25 Duloxetine HCl
Process 7200 7860 130 - 1 7200 7860 130 -
Cleaning 8250 8250 8250 8250
Total 15450 16110 15450 16110
26 Dapoxetine HCl
Process 3600 3760 - 75 Potass
1 3600 3760 - 75
Cleaning 5500 5500 5500 5500
M/s. R L Fine Chem Pvt. Ltd.,
- 208 -
Total 9100 9260 ium chlori
de
9100 9260
27 Desvenlafaxine HCl
Process 4072 4360 60 - 1 4072 4360 60 -
Cleaning 2750 2750 2750 2750
Total 6822 7110 6822 7110
28 Trihexyphenadyl HCl
Process 4800 5120 60 - 1 4800 5120 60 -
Cleaning 2750 2750 2750 2750
Total 7550 7870 7550 7870
29 Tramadol HCl Process 4800 5400 103 - 10 48000 54000 1030 -
Cleaning 5500 5500 55000 55000
Total 10300 10900 103000 109000
30 Sulfamethoxy Pyrazine HCl
Process 4000 4080 - 150 Potassium
chloride
2 8000 8160 - 300
Cleaning 5500 5500 11000 11000
Total 9500 9580 19000 19160
31 Alimemazine Tartarate
Process 320 320 - 60 SodimChlori
de
1 320 320 - 60
Cleaning 5500 5500 5500 5500
Total 5820 5820 5820 5820
32 Alprazolam Process - - - 54 Ammonium chlori
de
1 - - - 54
Cleaning 5500 5500 5500 5500
Total 5500 5500 5500 5500
M/s. R L Fine Chem Pvt. Ltd.,
- 209 -
33 Diazepam Process - - - 55 Amm onium chlori
de
1 - - - 55
Cleaning 5500 5500 5500 5500
Total 5500 5500 5500 5500
34 Buclazine HCl Process 2400 2700 60 - 1 2400 2700 60 -
Cleaning 2750 2750 2750 2750
Total 5150 5450 5150 5450
35 Meclazine HCl Process 2400 2700 60 - 1 2400 2700 60 -
Cleaning 2750 2750 2750 2750
Total 5150 5450 5150 5450
36 Carbamezapine
Process 2800 2840 - 54 Ammonium chlori
de
8 22400 22720 - 432
Cleaning 2750 2750 22000 22000
Total 5550 5590 44400 44750
GRAND TOTAL 2,70,792 2,82,480 1,665 880 11,40,642
13,06,640
7,095 1,294
Note: Considering no. of working days/month = 25
1. Daily water consumption from process and washings/cleaning = 1140642/25 = 45625.6 or say 45626 LPD 2. Daily effluent discharge from the process and washings = 1306640/25 = 52265.6 or say 52266 LPD 3. Process water demand = 5,09,992/25 = 20399.68 or say 20400 LPD 4. Process effluent discharge = 561460/25 = 22458.4 or say 22459 LPD 5. Cleaning/washing water demand = 745250/25 = 29810 or say 30000 LPD 6. Cleaning/washing effluent discharge = 745250/25 = 29810 or say 30000 LPD
M/s. R L Fine Chem Pvt. Ltd.,
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3.9.1.2 RAINWATER HARVESTING & GROUNDWATER RECHARGING
The total amount/quantity of water i.e., received in the form of rainfall over an
area is called the rain water endowment of that area, out of which the amount of
water that can be effectively harvested is called the rain water harvesting
potential.
Rain water harvesting potential = Intensity of rainfall (m) x Roof area x
Impermeability factor
The collection efficiency accounts for the fact that all the rain water falling over an area can not be effectively harvested due to losses on account of evaporation, spillage or run off etc., According to the data available from the Indian Meteorological Department, the Average annual rainfall around month of September = 194.80 mm. Assuming that about 90 % Rainfall can be effectively harvested.
Number of Rainy Days = 9.3
Therefore the I.R = 194.80/9.3= 20.94 mm/day or 0.02094 m/Day or 0.021 m/day
Quantity of roof top rain water harvested from the project:
The Ground Coverage area of the proposed project is about 8,016 sq m.
For rain water harvesting consider 75% of this total area = 6012 sq m.
Quantity of Rain Water that can be harvested from the proposed project is calculated as below.
Water Harvested per Year = Mean Annual Rainfall x Area x Collection Efficiency
= 0.021 x 6,012 x 0.9
= 113.6 or say 114 m3/day
However, it proposed to initially utilize the entire quantity of the rainfall potential
by providing adequate storage facilities (RCC tank of 100 m3 capacity).
The amount of storm water that the landscaped/open area will produce can be
determined by considering the impermeability factor to be 0.3.
Q = 0.021 x 10000 x 0.3
= 63 m3/day
The amount of storm water that the paved area will produce can be determined
by considering the impermeability factor to be 0.3.
Q = 0.021 x 6274 x 0.9
= 118.5 m3/day or say 119 m3/day
M/s. R L Fine Chem Pvt. Ltd.,
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The total amount of storm water = landscaped area + paved area
= 63 + 119 m3/day
= 182 m3/day
The project Proponents will also provide recharging pits along the inner periphery
of the boundary wall. Each recharging pit will be of size 1.2 m dia x 2.5 m deep
spaced at 20 m center to center. These recharging pits are filled with graded
media comprising of boulder at bottom and with coarse aggregates to facilitate
percolation of harvested rainwater to recharge ground water table. The recharge
pits are interconnected in such a way that the rain led to the first recharge pit is
also led to the next pit.
3.9.1.3 PROCESS EFFLUENT CHARACTERISTICS The characteristics of the effluent generated during the manufacturing process is indicated in the tables below
Table 3.10: High strength wastewater characteristics
Parameter Results
pH 5 – 6
Biological Oxygen Demand, mg/L 10,000 – 15,000
Total dissolved solids, mg/L 25,000 – 30,000
Chemical Oxygen Demand, mg/L 25,000 – 50,000
Table 3.11: Low strength wastewater characteristics
Parameter Results
pH 5 – 6
Biological Oxygen Demand, mg/L 2,000 – 5,000
Total dissolved solids, mg/L 10,000 – 15,000
Chemical Oxygen Demand, mg/L 5,000 – 8,000
3.9.1.4 STORAGE FACILITIES PROVIDED FOR INDUSTRIAL EFFLUENTS The industrial effluent is proposed to be treated in Effluent Treatment Plant with Multiple Effect Evaporator followed by RO Filtration for treatment, reuse and disposal. The industry proposes to provide adequate storage facilities for the industrial effluents. The details of which are appended below.
M/s. R L Fine Chem Pvt. Ltd.,
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Storage facilities at the project site
The industrial effluent is transferred to collection tanks (3 no.s) through ceramic pipes with secondary containment. The collection tanks will be of HDPE and of 10KL capacity (each).
3.9.1.5 TREATMENT SCHEME FOR WASTEWATER The wastewater from the industry is bifurcated into low strength & high strength wastewater streams & subjected to differential treatment as shown below.
Table 3.12: Source, quantity & treatment of industrial wastewater
Type of wastewater
Source Quantity, KLD
Treatment Re-use of treated wastewater
Low strength
Washings, R&D, domestic sewage
39.455 Equalization, aeration & reverse osmosis (RO). The reject from RO goes to MEE
Landscape development, cooling tower make-up water etc.
High strength
Process wastewater (DM rejects), boiler blow-down (softener rejects), scrubber, cooling tower bleed-off
33.500 Multiple Effect Evaporator (MEE).
M/s. R L Fine Chem Pvt. Ltd.,
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3.9.1.6 Treatment scheme for high strength wastewater and low strength wastewater
Figure 3.3: Treatment scheme for high strength wastewater and low strength wastewater
Oil Trap/Seperator
Screening
Neutralization/
Equalization tank
ATFD
Stripper column
Organic fraction
1.675 KLD Condensate 33.75 KLD
33.500 KLD (high strength)
Sent to TSDF
Feed tank
MEE
Loss 3.17
kKkkKLD
Residue (MEE salts) 283.8 kg or say
300 kg + 200 kg= 500 kg
Sent to spent
solvent recycler
Raw sewage pump
RO
Rejects 7.891 KLD
Permeate 31.564 KLD
Permeate + Condensate=65.314 KLD
. KLD
39.455 KLD (Low)
Equalization cum neutralization tank
SBR Tank
Decant Tank
Decant Valve
Filter feed pump
Domestic sewage 5 KLD
Filter back wash
ETP sludge 40 kg/day
TSDF/Cement industries
Pressure sand filter
Activated Carbon filter
Floor washings & other non
process effluents 30 KLD
M/s. R L Fine Chem Pvt. Ltd.,
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The major air pollution sources from the industry are DG set and boiler apart from the process sections. These sources are provided with stacks of adequate height so as to disperse the emanating flue gases containing SPM, oxides of sulfur and nitrogen without affecting the ground level concentrations and packed column scrubbers (2 no.s) are proposed to the process section & R&D facility with adequate stack height as per the regulatory requirements.
The sources of air pollution, type of fuel used, fuel consumption and chimney heights for each of the air pollution sources of the proposed project are indicated in the table 3.10 below.
Table 3.13: Air pollution sources, fuel consumption and chimney height details
SI. no.
Stack attached to
Fuel used Fuel consumption
Number of
stacks
Stack/s height
Air pollution control unit
Predicted emissions
1 Process section
- - 1 5 m ARL
Packed column scrubber – 1 no.
Acid mist/ VOCs
2 R&D - - 1 3 m ARL
Packed column scrubber – 1 no.
-
3 Steam boiler – 3Ton capacity – 2 no.s
Briquette 300 L/hr 1 30.5 m AGL
Stack SO2, NOx, SPM
4 D.G. set – 500 kVA – 1 no.
HSD 117.5 L/hr 1 7 m AGL
Stack SOx, NOx, SPM
5 Thermic Fluid Heater
Briquette Fired- 1 no
75 Kgs/hr 1 30.5 m AGL
Stack SOx, NOx, SPM
Furnace Oil Fired- 1 no
25 L/Hr 1 13 m AGL
Stack SOx, NOx, SPM
Furnace Oil Fired- 1 no
13 L/Hr 1 13 m AGL
Stack SOx, NOx, SPM
Furnace Oil Fired- 1 no
6 L/Hr 13 m AGL
Stack SOx, NOx, SPM
* Stack height calculation for DGs
3.9.2 Air pollution sources
M/s. R L Fine Chem Pvt. Ltd.,
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Formula adopted for stack height calculation
H = 14(Q)0.3
Where, H is stack height Above Ground Level Q is sulfur content in exhaust in kg/hr (As per Handbook on Environmental Legislations and Technologies) Fuel consumption = 117.5 L/hr = 0.1175 m3/hr Sulfur content in HSD = 0.25% Density of sulfur = 2046 kg/m3 Therefore, Q = 0.1175 x (0.25/100) x 2046 = 0.0601 kg/hr Therefore, height of chimney = 14 (0.0601)0.3 = 6.02 m AGL Or say 7 m AGL Therefore it is proposed to provide 1 stack of height 7 m AGL for one diesel generator of 500 kVA capacity. ** Stack height calculation for boiler Formula adopted for stack height calculation
H = 74(Q)0.27
Where, H is stack height Above Ground Level Q is ash produced in tons/hr Type of fuel used – briquittes, husk, wood Capacity of boiler = 3 MT 1) For 3 MT boiler single use Fuel consumption = 0.3 tons/hr For agro based fuel ash produced per ton of fuel burnt = 6.5 kg (As per Handbook on Environmental Legislations and Technologies) Therefore, Q = 1.95 kg/hr = 0.00195 tons/hr Therefore, height of chimney = 74 (0.00195)0.27 = 13.72m AGL Or say 30.5 m AGL However it is proposed to install a stack of height 30.5 m AGL with Mechanical dust collector to collect the fly ash. The exhaust temperature will be nearly ambient and adequate port holes with access platform will be provided as per KSPCB guidelines as under
M/s. R L Fine Chem Pvt. Ltd.,
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1. Location of port holes and approach platform The sampling porthole will be provided at a distance equal to at least eight times the stack diameters downstream and two diameters upstream from source of low disturbance such as bend, expansion, and construction valve fitting or visible flame for rectangular stacks. The equivalent diameter is calculated from the following equation Equivalent diameter = 2 (Length x Width) (Length x Width) 2. The diameter of the sampling port will be minimum 3”. Arrangement will be made to close the port hole firmly during the period when it is not used for sampling. 3. An easily accessible platform will be provided to accommodate 3 to 4 persons to conveniently sample stack emissions from the portholes. Ambient air quality and stack emission monitoring Ambient air quality monitoring will be conducted once in a month as per the guidelines of KSPCB for SPM, RSPM, SOx, NOx, HC and CO and the record of monitoring reports will be maintained and made available to authorities. Similarly stack monitoring will also be conducted for SOx. Scrubber details Scrubber systems are a diverse group of air pollution control devices that can be used to remove particulates and/or gases from industrial exhaust streams. Traditionally, the term "scrubber" has reference to pollution control devices that used liquid to "scrub" unwanted pollutants from a gas stream. Recently, the term is also used to describe systems that inject a dry reagent or slurry into a dirty exhaust stream to "scrub out" acid gases. Scrubbers are one of the primary devices that control gaseous emissions, especially acid gases.
Wet scrubber is a form of pollution control technology in which the polluted gas stream is brought into contact with the scrubbing liquid by spraying it with the liquid, by forcing it through a pool of liquid, or by some other contact method, so as to remove the pollutants.
The design of wet scrubbers or any air pollution control device depends on the industrial process conditions and the nature of the air pollutants involved. Inlet gas characteristics and dust properties (if particles are present) are of primary importance. Scrubbers can be designed to collect particulate matter and/or gaseous pollutants. Wet scrubbers remove dust particles by capturing them in liquid droplets; remove pollutant gases by dissolving or absorbing them into the liquid. Any droplets that are in the scrubber inlet gas must be separated from the outlet gas stream by means of another device referred to as a mist eliminator or entrainment separator (these terms are interchangeable). Also, the resultant
M/s. R L Fine Chem Pvt. Ltd.,
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scrubbing liquid must be treated prior to any ultimate discharge or before being reused in the plant. There are numerous configurations of scrubbers and scrubbing systems, all designed to provide good contact between the liquid and polluted gas stream. The process and solvent recovery sections are provided with scrubber to scrub the fumes and vapors generated in order to remove such emissions before it is let out into the atmosphere. Packed column scrubber specifications Air volume – 6000 CMH Velocity through duct – 8 m/s Scrubbing pad height – 1 m Velocity through scrubbing pads – 1.5 m/s Nozzle type – Full cone type Nozzle spray area – 0.07 m2 Spray chamber height – 350
Fig 3.5: Column scrubber
M/s. R L Fine Chem Pvt. Ltd.,
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DUST COLLECTOR Designed to handle heavy dust loads, a dust collector system consists of a blower, dust filter, a filter-cleaning system, and a dust receptacle or dust removal system. It is distinguished from air cleaners which use disposable filters to remove dust. Specifications FILTER BAGS Size & height of filter bags : 195 mm dia x 900 mm length Material : Non-woven polyster Quantity of bags : 8 no.s Air permeability : 183 L/Dm2/min at 20 mm WG Filteration efficiency : 90% down to 10 microns Temperature of the filter media : 1400 C CENTRIFUGAL BLOWER Capacity : 950 m3/hr Static pressure : 7” (170 mm) WG Fan speed : 2800 RPM Motor : 2 HP/2P
M/s. R L Fine Chem Pvt. Ltd.,
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Fig 6: Dust collector
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The major source of noise pollution in the industry is the DG set for which acoustic enclosure is proposed. Also ambient noise levels will be ensured within the ambient standards by inbuilt design of mechanical equipment and building apart from vegetation (tree plantations) along the periphery and at various locations within the industry premises.
The quantity of solid waste generated from the industry is calculated as follows
Table 3.14: Solid waste generation
Total no. of employees 110
Assuming per capita solid waste generation rate as 0.25 kg/capita/day
Quantity of solid waste generated 27.5 kg/day
Organic solid waste : 60 % of the total waste
16.5 kg/day
Inorganic solid waste : 40 % of the total waste
11 kg/day
Disposal of domestic solid waste The domestic wastes are segregated at source, collected in bins and composted.
3.9.5.1 HAZARDOUS RAW MATERIALS The following raw materials used during the process of manufacture of APIs are hazardous in nature according to Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II
Table 3.15: Hazardous raw materials
Hazardous raw material
Sl. No. as per Manufacture, Storage and Import of Hazardous Chemical (Amendment) Rules, 19th January 2000, Schedule I, Part II
Hydrochloric acid 313
N- Butanol 412
Sodium Hydroxide 571
Magnesium 350
Potassium hydroxide
522
3.9.3 Noise generation and its management
3.9.4 Solid waste generation and management
3.9.5 Hazardous raw materials used in the manufacturing process and hazardous waste generation and management
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Methanol 377
Ammonia 31
Toulene 628
Iso Propyl Alcohol 334
Formaldehyde 295
Dimethyl Amine 215
Acetone 4
Chloroacetyl Chloride
124
Acetic anhydride 45
Cyclohexanone 161
Hydrogen peroxide
318
3.9.5.2 HAZARDOUS WASTE GENERATION AND MANAGEMENT
The hazardous wastes generated during the process of manufacture of different APIs are stored at hazardous waste storage area and sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. The quantities of hazardous waste generated from various processes are shown in the following tables. Organic process/solvent residue and spent carbon
Table: 3.16 Quantity of process residue generation from solvent recovery and
spent carbon generation from manufacturing process
Sl. No.
APIs Quantity of hazardous waste generated,
kg/annum
Quantity of spent carbon generated, kg/annum
1 Amtriptyline hydrochloride 1st stage
9,384 9,792
2nd stage 9,384
2 Imipramine hydrochloride
1,584 576
3 Cyproheptadiene HCl 1,908 720
4 Pitofenone HCl 864 288
5 Pyrimethamine 2,016 432
6 Cyclobenzaprine HCl 936 432
7 Clomipramine HCl 744 288
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8 Chlorpromazine HCl 2,280 720
9 Doxylamine Succinate
2,160 1,080
10 Orphenadrine Citrate/ HCl
5,520 1,440
11 Trimipramine Maleate/ Mesylate
840 288
12 Flupentixol HCl 96 72
13 Melitracen HCl 360 216
14 Carbinoxamine Maleate
1,128 288
15 Opipramol HCl 252 144
16 Sulfadoxine 576 1728
17 Doxepin HCl 408 144
18 Nitrazepam 516 144
19 Dothiepin HCl 1,728 576
20 Bromazepam 264 84
37 Flunarazine HCl 552 216
38 Cinnarizine 3,024 1512
39 Clonazepam 336 84
40 Lorazepam 396 144
41 Duloxetine HCl 396 144
42 Dapoxetine HCl 96 144
43 Desvenlafaxine HCl 168 216
44 Trihexyphenadyl HCl 312 216
45 Tramadol HCl 3,480 2160
46 Sulfamethoxy Pyrazine HCl
744 432
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47 Alimemazine Tartarate 1st step A
348 288
2nd step B 132
48 Alprazolam 300 84
49 Diazepam 276 84
50 Buclazine HCl 624 144
51 Meclazine HCl 588 144
52 Carbamezapine 480 -
TOTAL 55,200 25,464
Spent carbon is used during the process of manufacture of different APIs. The spent carbon will be disposed for co-incineration in cement manufacturing. Others
Table 3.17 : Miscellaneous types of hazardous waste generated
Sl. No.
Particulars Quantity of hazardous waste
generated kg/annum
Disposal Options Category
1 Waste oil generation from DG set
200 L Disposed through authorized recyclers
5.1
2 Residue from solvent recovery plant
55,200 Disposed through Cement industries for co incinerations
28.1
3 Used MS drums (either reused if it cannot scrapped)
120 Disposed through authorized recyclers
33.3
4 Used poly bags 180 Disposed through authorized recyclers
33.3
5 Inorganic salt from MEE
85,140 Dispoded to TSDF for scientific landfill.
34.3
6 Spent carbon 25,464 Disposed through Cement industries for co incinerations
28.2
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7 Spent organic solvent fraction from MEE stripper
205 KL/Annum Disposed through authorized solvent recyclers
28.5
Byproducts
Sl.No Product By product Kg/batch
Kg/month Kg/annum Application/ Uses of Byproducts
1 Imipramine hydrochloride
Ammonia 17 68 816 For neutralization captive use
2 Pyrimethamine
Ethylene glycol
50 150 1800 For chilling plant
3 Nitrazepam Ammonium Chloride
106 106 1272 Can be used as fertiliser
4 Bromazepam
Ammonium Chloride
26 26 312 Can be used as fertiliser
5 Clomipramine Hcl
Ammonia 17 34 408 For neutralization captive use
6 Trimipramine Hcl
Ammonia 17 34 408 For neutralization captive use
7 Clonazepam
Ammonium chloride
54 54 648 Can be used as fertiliser
8 Lorazepam Sodium chloride
30 30 360 For captive , used in soft water for boiler.
(Sodium acetate goes in Haz waste MEE)
9 Sulfadoxine Sodium Chloride
115 920 11040 For captive , used in soft water for boiler
10 Dapoxetine HCl-
Potassium Chloride
75 75 900 Sold to Ray pharma hindupur
11 Sulfamethoxy Pyrazine HCl
Potassium Chloride
150 300 3600 Sold to Ray pharma, hindupur
12 Alimemazine Tartarate
Sodium Chloride
60 60 720 For captive , used in soft water for boiler
13 Alprazolam Ammonium chloride
54 54 648 Can be used as fertiliser
14 Diazepam Ammonium chloride
55 55 660 Can be used as fertiliser
15 Carbamezapine-
Ammonium chloride
54 432 5184 Can be used as fertiliser
Total 880 2398 28776
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Table 3.20: Characteristics of hazardous waste
Sl. No
Parameter Unit Method Observation / Result
CPCB Std. and WLT/TCLP Limit for Direct Landfill
1 Physical state - Visual observation Solid -
2 Color - Visual observation Light grey -
3 Texture - Visual observation Powder & lump
-
4 Bulk density gm/cc ASTM Std: D 5057 -1990 (Reapproved 2001)
1.25 -
5 Paint Filter Liquid Test
- SW-846:9095 A Pass Pass
6 pH (at 29.60 C) - SW-846:9040B, 9045 C 9.51 4.0 - 12.0
7 Calorific Value kcal/kg IS:1350 (Part II)-1970 (Reaffirmed 1983)
2400 <2500.0
8 Flash Point 0C SW-846:1020A 62 >60.0
9 Loss on drying at 103-1050 C
% (w/w) Std.Methods:2540 B 10% -
10 Loss on ignition at 5500 C (dry basis)
% (w/w) Std. Methods:2540 E <10.0 Non-Bio degradable <3.0 Bio degradable
< 20.0 (non-biodegradable) <5.0 (biodegradable)
11 Reactive cyanide
mg/kg SW-846: Ch.7 (7.3.3), 9014 <MDL -
12 Reactive sulfide mg/kg SW-846: Ch.7 (7.3.4), 9034 <10 -
13 Water soluble compounds except salts – in WLT extract
% (w/w) DIN:38414 Part 4 (S4) Std. Methods:2540 B,E
2.0 0.5
<10.0
14 Oil and grease (As n-hexane extractable)
% (w/w) SW-846:3540C, 9071A Nil <4.0
15 Cyanide-total mg/kg SW-846:9010B, 9014 1<MDL -
15 a
Cyanide-WLT mg/L DIN:38414 Part 4 (S4) Std. Methods:4500-CN-C SW-846:9014
<MDL <2.0
16 Fluoride-Total mg/kg Std.Methods:4500-F-B,D <0.1 -
16 a
Fluoride-WLT mg/L DIN:38414 Part 4 (S4) Std.Methods:4500F-B,D
<1.0 <50.0
17 Nitrate-WLT mg/L DIN:38414 Part4 (S4) Std.Methods:4500-NO3
- E <5 <30.0
18 Ammonia -WLT mg/L DIN:38414 Part4 (S4) <10 <1000.0
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Std.Methods:4500-NH3 B,C
19 Arsenic-Total mg/kg SW-846:3050B Std.Methods:3500-As B
<10 -
19 a
Arsenic- WLT mg/L DIN:38414 Part 4(S4) SW-846:3010A Std.Methods:3500-As B
<0.02 <1.0
20 Cadmium –Total mg/kg SW-846:3050B,7130 <0.5 -
20 a
Cadmium - WLT mg/L DIN:38414 Part4(S4) SW-846:3010A,7130
<0.01 <0.20
21 Chromium – Total
mg/kg SW-846 :3050 B, 7190 3<MDL -
21 a
Chromium (VI)-WLT
mg/L DIN:38414 Part4(S4) Std.Methods:3500-Cr B
<MDL <0.50
21 b
Chromium-TCLP mg/L SW-846:1311 SW-846:3010A, 7190
<0.05 <5.0
22 Copper-Total mg/kg SW-846:3050B, 7210 <MDL -
22 a
Copper-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7210
<0.05 <10.0
23 Lead-Total mg/kg SW-846:3050B, 7420 <MDL -
23 a
Lead-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7420
<0.05 <2.0
25 Nickel-Total mg/kg SW-846:3050B, 7520 <MDL -
25 a
Nickel-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7520
<MDL <3.0
27 Zinc-Total mg/kg SW-846:3050B, 7950 <0.5 -
27 a
Zinc-WLT mg/L DIN:38414 Part4(S4) SW-846:3010A, 7950
<MDL <10.0
28 Phenol-Total mg/kg SW-846:9065 <MDL -
28 a
Phenol-WLT mg/L DIN:38414 Part4(S4) SW-846:9065
<0.1 <100.0
3.9.5.3 STORAGE FACILITIES FOR HAZARDOUS WASTE
The industry proposes to provide adequate storage facilities for the hazardous wastes. The details are appended below.
Storage facilities at the project site
A designated impervious structure (sealed drums under cover roof) is proposed at the project site for collection and storage of hazardous waste.
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Hazardous waste disposal Process residue is sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement. The spent carbon will be disposed for co-incineration in cement manufacturing. The inorganic residue from the process and as well from the MEE will be stored scientifically and will be sent to TSDF for scientific treatment and disposal.
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A schematic representation of the overall feasibility and environmental assessment process is shown in Figure 3.6.
Fig 3.6: Feasibility & environmental assessment process
CHAPTER 4
SITE ANALYSIS
4.1 CONNECTIVITY
3.10 SCHEMATIC REPRESENTATIONS OF THE FEASIBILITY DRAWING
Significant
Not
economic
Feasibility study conducted for newly proposed industry
Statement of intent by proponent
Guidelines for EIA by SEAC/MoEF
Abandon project
Determine the coverage of the EIA - scoping
Describe the environment – baseline study
Describe the project
Identify the impacts
Evaluate the impacts
Mitigation
Preventive measures
Prepare draft EIS
FINAL EIS REPORT
CONSIDER ALL PHASES OF PROJECT –
CONSTRUCTION, DEVELOPMENT, INSTALLATION &
FINAL OPERATION/ PRODUCTION
SO
CIO
-ECO
NO
MIC
ISSU
ES
MO
NIT
OR R
EVIE
W
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Fig 4.1: Google map showing connectivity Table 4.1: Connectivity from the project site
Sl. No.
Road Distance from the
project site (km)
Direction w.r.t.
project site
1 SH 9 0.5 West
2 Narasimha Devarbetta Reserve Forest
15 South East
3 Gollapuram Lake 3.5 North East
4 Kudumaldkunta Lake 1 South West
5 Yerrahalli Lake 2.5 South
6 Gaudasandra Lake 4 South East
7 Thumakunta Lake 2 North
8 Penner River 2.5 West
9 Melya Lake 5 East
10 Devarapalli railway station 3.5 North
11 Kempegowda International Airport
59 South
Note: All distances mentioned are aerial.
PROJECT SITE
NARASIMHA DEVARABETTA
RESERVE FOREST
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4.2 LAND FORM, LAND USE & OWNERSHIP
M/s. R L Finechem Pvt. Ltd., is an Active Pharmaceutical Ingredients (APIs), manufacturing industry is proposed to be established at Plot No. 27-29, KIADB Industrial Area, Gouribidanoor, Karnataka. The plot where the industry is being set-up is a designated KIADB industrial area. “M/s. R L Fine Chem Pvt. Ltd.,” has entered into a lease agreement with KIADB & a copy of the lease deed is attached as Annexure C.
4.3 TOPOGRAPHY
M/s. R L Finechem Pvt. Ltd., is located at latitude of 13°42'23.74"N & longitude 77°30'11.96"E at an elevation of 686 m above MSL. The topo map showing the location of the project site is appended as fig 4.2.
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Fig 4.2: Topo map
Source: Survey of India; Scale: 1:50000
PROPOSED SITE
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4.4 EXISTING LAND USE PATTERN
Table 4.2: Existing land-use pattern
Sl. No.
Particulars Details Distance from the project
site (km)
Direction w.r.t.
project site
1 Agriculture Minor activities - scattered Beyond industrial
area
-
2 National park, forest
Narasimha Devarbetta Reserve Forest
15 South East
3 Water bodies Gollapuram Lake 3.5 North East
Kudumaldkunta Lake 1 South West
Yerrahalli Lake 2.5 South
Gaudasandra Lake 4 South East
Thumakunta Lake 2 North
Penner River 2.5 West
Melya Lake 5 East
Note: a) All distances mentioned are aerial. b) The project is a notified by KIADB, Karnataka Govt. industrial area. A copy of
the Allotment/Possession Certificate is enclosed as Annexure -B
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Fig 4.3: Google map showing surrounding environmental features
4.5 EXISTING INFRASTRUCTURE
The list of existing infrastructure at the project site is 1. Water supply from Bore well 2. Power supply will be from BESCOM 3. Storm water drainage system is proposed 4. Domestic sewage & domestic garbage treatment is proposed in-house 5. Industrial wastewater & hazardous waste generated from the industry is
proposed to be out-sourced to CETP & co-incinerated in cement industries respectively.
PROJECT SITE
GOLLAPURAM LAKE
MELYA LAKE
KUDUMALDKUNTA LAKE
DEVARAPALLI RAILWAY STATION
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4.6 METEOROLOGICAL DATA
Assessment of the micro and macro meteorology is important from the standpoint of understanding the nature and extent of air pollution in the study area. Climate has an important role in the build-up of pollution levels in Bangalore. The climatic condition of the area may be classified as moderately or seasonally dry, tropical or temperate savanna climate with four seasons in a year. Winter is critical for air pollution build-up because of frequent calm conditions with temperature inversions resulting in poor atmospheric mixing, natural ventilation and high emission loads during evening traffic peaks. The classification of months according to the seasons is given in the following table
Season Period
Summer March to May
Monsoon June to September
Post monsoon October to November
Winter December to February
The metrological data reflecting minimum, maximum temperature in 0C, relative humidity in %, rainfall in mm/hr, wind speed in m/s, mixing height in m, cloud cover in tenths and atmospheric pressure in mb for the year 2011 obtained from modeling studies carried out using U.S. EPA AERMOD dispersion model, 1996 – 2011 Lakes Environmental Software, Version 7.1.0 has been appended as table 4.3.
Table 4.3: Meteorological data of Bangalore for the year 2014
Month Temperature 0C
Relative humidity %
Precipitation rate (mm)
Atmospheric Pr. (mb)
Wind speed (m/s)
Inversion / mixing height
(m)
Cloud cover
(tenths)
Min Max Max Min Min Max Min Max Min Max Day Night Min Max
Jan 17 25 84.8 58.3 0 0 909 919 0 6.7 2303 2477 2 10
Feb 13 20 76.9 44.8 0 12 908 915 0 5.1 2517 1786 2 5
Mar 15 25 69 38.8 0 90 907 917 0 6.2 2798 2057 2 6
Apr 12 27 76.7 50.7 0 0 908 914 0 5.1 2910 1799 2 5
May 19 27 82.7 61.0 0 48 905 913 0 6.2 3319 2317 2 5
June 15 21 88.6 71.7 0 21 904 913 0 10.3 2828 4000 2 10
July 18 21 89 75.5 0 18 904 912 0 8.7 2691 3638 2 10
Aug 17 28 88.9 74.5 0 81 904 912 0 7.2 2678 2779 3 10
Sept 17 18 91.4 75.3 0 192 905 912 0 7.2 2802 2801 2 10
Oct 22 24 88.5 73.5 0 75 904 913 0 5.7 2575 2046 3 10
Nov 20 21 93.5 78.1 0 93 905 915 0 6.2 2177 2247 2 10
Dec 17 22 87.6 66.8 0 0 906 914 0 6.7 1756 2522 2 10
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4.6.1 Temperature
The mean maximum temperature is observed at (32°C) in the month of May and the mean minimum temperature at (11.8°C) is observed in the month of December. In the summer season the mean minimum temperature is observed during the month of March (16.4°C). During the monsoon the mean maximum temperature is observed to be 30.9°C in the month of June with the mean minimum temperature at 17°C during August. By the end of September with the onset of post monsoon season (October - November), day temperatures drop slightly with the mean maximum temperature at 28.8°C in October and mean minimum temperature is observed at 16.8°C for both October & November. The values are presented in table 4.3.
4.6.2 Relative humidity
Minimum and maximum values of relative humidity have been recorded. The minimum humidity is observed to be at 38.8% in the month of March and the maximum is 91.4% in the month of September. The mean minimum values of humidity during summer, monsoon, post-monsoon and rainy seasons are 38.8%, 71.7%, 73.5% & 44.8% during the months of March, June, October and February respectively. Similarly the maximum values are 82.7%, 91.4%, 93.5%, 87.6% in the months of May, September, November & December during the summer, monsoon, post monsoon & winter seasons. The values are presented in table 4.3.
4.6.3 Rainfall
The monsoon in this region usually occurs twice in a year i.e. from June to September and from October to November. The maximum annual rate of precipitation over this region ranges between 1.02 to 4.83 mm/hr.
4.6.4 Atmospheric pressure
The maximum and the minimum atmospheric pressures are recorded during all seasons. In the summer season, the mean maximum and minimum pressure values are observed to be 917 mb in the month of March and 905 mb in the month of May respectively. During monsoon season, the maximum pressure is 913 mb and minimum 904 mb. The maximum pressure during the post-monsoon season is observed to be 915 mb in November and minimum pressure is 904 mb in the month of October. During the winter season the minimum atmospheric pressure is 906 mb in December and the maximum is 919 mb in the month of January. The values are presented in table 4.3.
4.6.5 Wind
The data on wind patterns are pictorially represented by means of wind rose diagrams for the entire year as figure 4.5 (for different seasons).
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1. March to May (summer season)
WRPLOT View - Lakes Environmental Software
WIND ROSE PLOT:
Wind rose diagram - summer season
COMMENTS:
MODELER:
M/s. Aquatech Enviro Engineers
DATE:
1/18/2012
PROJECT NO.:
NORTH
SOUTH
WEST EAST
4%
8%
12%
16%
20%
WIND SPEED
(m/s)
>= 11.1
8.8 - 11.1
5.7 - 8.8
3.6 - 5.7
2.1 - 3.6
0.5 - 2.1
Calms: 9.19%
TOTAL COUNT:
2208 hrs.
CALM WINDS:
9.19%
DATA PERIOD:
Start Date: 3/1/2010 - 00:00End Date: 5/31/2010 - 23:00
AVG. WIND SPEED:
2.73 m/s
DISPLAY:
Wind SpeedFlow Vector (blowing to)
3/1/2011
5/31/2011
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2. June to September (monsoon season)
WRPLOT View - Lakes Environmental Software
WIND ROSE PLOT:
Wind rose diagram - monsoon season
COMMENTS:
MODELER:
M/s. Aquatech Enviro Engineers
DATE:
1/18/2012
PROJECT NO.:
NORTH
SOUTH
WEST EAST
7%
14%
21%
28%
35%
WIND SPEED
(m/s)
>= 11.1
8.8 - 11.1
5.7 - 8.8
3.6 - 5.7
2.1 - 3.6
0.5 - 2.1
Calms: 1.91%
TOTAL COUNT:
2928 hrs.
CALM WINDS:
1.91%
DATA PERIOD:
Start Date: 6/1/2010 - 00:00End Date: 9/30/2010 - 23:00
AVG. WIND SPEED:
4.09 m/s
DISPLAY:
Wind SpeedFlow Vector (blowing to)
6/1/2011
9/30/2011
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3. October to November (post monsoon season)
WRPLOT View - Lakes Environmental Software
WIND ROSE PLOT:
Wind rose diagram - post monsoon season
COMMENTS:
MODELER:
M/s. Aquatech Enviro Engineers
DATE:
1/18/2012
PROJECT NO.:
NORTH
SOUTH
WEST EAST
4%
8%
12%
16%
20%
WIND SPEED
(m/s)
>= 11.1
8.8 - 11.1
5.7 - 8.8
3.6 - 5.7
2.1 - 3.6
0.5 - 2.1
Calms: 3.76%
TOTAL COUNT:
1464 hrs.
CALM WINDS:
3.76%
DATA PERIOD:
Start Date: 10/1/2010 - 00:00End Date: 11/30/2010 - 23:00
AVG. WIND SPEED:
3.26 m/s
DISPLAY:
Wind SpeedFlow Vector (blowing to)
10/1/2011
11/30/2011
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4. December to February (winter season)
WRPLOT View - Lakes Environmental Software
WIND ROSE PLOT:
Wind rose diagram - winter season
COMMENTS:
MODELER:
M/s. Aquatech Enviro Engineers
DATE:
1/18/2012
PROJECT NO.:
NORTH
SOUTH
WEST EAST
5%
10%
15%
20%
25%
WIND SPEED
(m/s)
>= 11.1
8.8 - 11.1
5.7 - 8.8
3.6 - 5.7
2.1 - 3.6
0.5 - 2.1
Calms: 2.73%
TOTAL COUNT:
2160 hrs.
CALM WINDS:
2.73%
DATA PERIOD:
Start Date: 1/1/2010 - 00:00End Date: 12/31/2010 - 23:00
AVG. WIND SPEED:
3.21 m/s
DISPLAY:
Wind SpeedFlow Vector (blowing to)
Fig 4.4: Wind rose diagrams
1/1/2011
12/31/2011 -
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4.6.6 Inversion height
The maximum inversion heights at the project site during the day time & night time for all the months of the year is as given in the table 4.3. The maximum mixing height of 4000 m is observed during the month of June during the night time and 3319 m during the month of May during the day time. The minimum inversion heights are 1756 m in the month of December during the day and 1786 m during the night in the month of February.
4.6.7 Cloud cover
The minimum cover measured in the unit of tenths is 2 during most of the months. The maximum observed cloud cover is 10 during the months of January, June to December.
4.7 SOCIAL INFRASTRUCTURE AVAILABLE
Infrastructure is the basic physical and organizational structures needed for the operation of a society or enterprise or the services and facilities necessary for an economy to function. The term typically refers to the technical structures that support a society, such as roads, water supply, sewers, electrical grids, telecommunications and so forth and can be defined as "the physical components of interrelated systems providing commodities and services essential to enable, sustain, or enhance societal living conditions. Viewed functionally, infrastructure facilitates the production of goods and services, and also the distribution of finished products to markets, as well as basic social services such as schools and hospitals; for example, roads enable the transport of raw materials to a factory.
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The list of hospitals & other infrastructural facilities available in the vicinity of the proposed industry is tabulated below
Table 4.4: List of health-care facilities in the surroundings
Hospital Distance
Direction w.r.t. the industry
1 DR Colony Ward Hospital, Hindupur
12.24 km North
2 Shri Shirdi Sai Hospital, Gouribidanoor
10.95 km South
3 Prasad Hospital, Gouribidanoor
10.47 km South
4 Primary Govt Hospital, Kirikera
7.17 km North
5 PSC, Chikaballapur 11.93 km South West
Note: All distances mentioned are aerial.
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CHAPTER 5
PLANNING BRIEF
5.1 PLANNING CONCEPT
M/s. R L Finechem Pvt. Ltd., is an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity.
5.2 POPULATION PROJECTION
Maximum workforce employed during peak construction period: 50 people Total no. of people proposed to be employed during operation phase: 110 people
5.3 LAND-USE PLANNING
The industry is designed envisaging adequate area for landscape, process section and utilities, storage areas for raw materials, finished products and internal movement of vehicles as shown in the table below.
Table 5.1: Land-use pattern
Sl. No.
Particulars Area (SQM)
1 Total plot area 24,290 (100 %)
2 Hard paved area 6,274 (25.83 %)
3 Landscape/Green-belt area
10,000 (41.17 %)
4 Ground coverage area 8,016 (33 %)
5 Built-up area 8,000
The site area details are shown in the plot area drawing appended.
5.4 ASSESSMENT OF INFRASTRUCTURE DEMAND
“M/s. R L Finechem Pvt. Ltd.,” is basically an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity. The infrastructure demand for the project is detailed in the following sections
5.4.1 Roadways
Roadways are required for
transportation of materials & workers during construction phase &
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transportation of employees to & from the industry during the operation phase.
The major roadways in the vicinity of the project site are shown in section 4.1, Chapter 4
5.4.2 Water supply & sewerage infrastructure
Water demand for the industry will be met by Bore well. The domestic sewage generated will be mixed with industrial effluent at aeration stage and treated. The industrial wastewater will be treated in Effluent treatment Plant (ETP) with MEE followed by RO filtration for treatment, reuse and disposal.
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CHAPTER 6
PROPOSED INFRASTRUCTURE
6.1 INDUSTRIAL AREA (PROCESSING AREA)
M/s. R L Finechem Pvt. Ltd., is an Active Pharmaceutical Ingredients (APIs) manufacturing industry with R & D activity.
6.2 GREEN-BELT
An area of 10,000 SQM (i.e. 41.17 % of the total plot area) is reserved exclusively for green-belt/landscape development. About 300 trees of various native/indigenous variety are proposed to be planted.
6.3 SOCIAL INFRASTRUCTURE
Detailed in Chapter 4, Section 4.8.
6.4 CONNECTIVITY
Detailed in Chapter 4, Section 4.1.
6.5 DRINKING WATER MANAGEMENT
The source of water supply for the industry is Bore well. The total water requirement is about 186.050 KLD.
6.6 SEWERAGE SYSTEM
At present the industry does not have the common Underground drainage system (UGD) facility. The domestic sewage generated from the project is proposed to be conveyed through closed conduits and mixed with industrial effluent at aeration stage and treated.
6.7 INDUSTRIAL WASTE MANAGEMENT
The industrial wastewater is proposed to be treated in Effluent Treatment Plant with Multiple Effect Evaporator followed by RO filtration for treatment, reuse and disposal.
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The domestic garbage is proposed to be composted within the industry premises & the product will be used as manure for green-belt/landscape development. The hazardous solid wastes generated will be stored at hazardous waste storage area and sent to cement industries for co-incineration (as an auxiliary fuel) during the manufacture of cement or returned to the vendors for recharge & re-use.
6.9 POWER REQUIREMENT & SUPPLY SOURCE
The total power requirement of the industry is 750 kVA which will be sourced from BESCOM. Further one diesel generator of 500 kVA capacity is proposed to be installed to serve as an alternative source of power supply to this unit.
6.8 SOLID WASTE MANAGEMENT
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CHAPTER 7
REHABILITATION & RESETTLEMENT PLAN
M/s. R L Finechem Pvt. Ltd., is coming up in a designated industrial area. No home outstees/land outstees are expected & hence no rehabilitation plan is envisaged.
CHAPTER 8
PROJECT SCHEDULE & COST ESTIMATES
8.1 TIME SCHEDULE
The time schedule for completion of the proposed project is given in the following table
Particulars Time schedule
Start of construction activity Existing plant
Completion July, 2015
8.2 ESTIMATED PROJECT COST
Total capital investment on the proposed Project is detailed as under
Sl. no.
Cost of ` (Crores)
1 Land 2.5
2 Construction 6.7
3 Proposed investment on Plant and machinery
21
4 Environment Management Budget 3
TOTAL 33.2
Rupees Thirty Three Crores & Two Lakhs Only
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CHAPTER – 9
ANALYSIS OF PROPOSAL
Observing the demographic pattern of the study area it can be inferred that occupational pattern is a mixture more of agriculture rather industrial. The proposed project will increase the employment potential by creating direct and in-direct employment opportunities and thus be beneficial for the local and near by populace The management of the industry proposes to give preference to local people with both direct and indirect employment.
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MATERIAL SAFETY DATA SHEETS (MSDS)
The MSDS of the below listed chemicals are enclosed 1. Acetone 2. Acetic anhydride 3. Ammonia 4. Chloroacetyl chloride 5. Cyclohexanone 6. Dimethylamine 7. Formaldehyde 8. Hydrochloric acid 9. Hydrogen peroxide 10. Iso propyl alcohol 11. Magnesium 12. Methanol 13. N- butanol 14. Potassium hydroxide 15. Sodium hydroxide 16. Toluene
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