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Innovative R&D Models for Generic Crop Protection Chemical Companies
Dr. Surendra BhatiaSenior Technical Advisor – Sapec Group
sbhatia@agro.sapec.pt
11th April 2013
Outline
1. Milestone Method- From Concept to Commercial Manufacturing.
2. Technical Grade Manufacturing3. Formulation Development4. Analytics/Registration requirements for
EU/Brazil
Success Stories - India
• India has become the largest producer of Mancozeb.• Synthetic Pyrethroids produced in India are being sold to
Innovative companies for Global sales.• Backward integration of Triazoles has helped companies produce
these fungicides at competitive prices.• Up gradation of manufacturing facility by use of DCS/PLC
systems.• Waste water recycle by use of MEE and RO and many of the
producers have achieved the goal of ZLD(Zero Liquid Discharge).• Air monitoring standards are stringent and use of modern PLC
systems are being followed with full compliance. • Consistency in Quality by implementation of ISO Systems.
Defining Milestones
• A project can be divided in to three phases:
• Concept Phase• Creation Phase• Realization Phase
Division of ProjectConcept Phase Go
/No go
Creation Phase Go/No go
Realization Phase
M0 Idea M8 Scale Up Concepts
M16 Detailed Eng.
M1 Literature M9 Design Req. M17 Project Planning
M2 Lab trials M10 Pilot Trials M18 SOPsM3 Analysis-
5BA , PCPM11 Safety
StudiesM19 Setting up plant facility
M4 Proto type prepared
M12 Pilot Plant Results
M20 Raw Materials
M5 Safety Studies
M13 Documentation M21 Hazop
M6 Cost M14 Cost M22 Plant TrialsM7 Documen-
tationM15 Basic design
Concept
Agrochemicals
Category
Conventional Products Modern Products
Group Application rates(g/Hectare)
Group Application rates(g/Hectare)
Herbicides Phenoxides(Older)TriazinesUreas
500-2500200-3000500-2000
Phenoxides(Newer)ImidazolinesSulfonyl Ureas
100-20050-10010-100
Fungicides DithiocarbamateMorpholines
250-3500750-1000
TriazolesStroliburins
5-25050-200
Insecticides OrganochlorinesOrganophosphates
100-10000200-5000
PyrethroidsNeonicotinoids
5-25050-200
Off Patent Molecules- Fungicides
• Boscalid• Cyflufenamid• Flumorph• Dimethomorph• Orysastrobin• Pyraclostrobin• Trifloxystrobin• Prothiaconazole• Simeconazole
Off Patent Molecules- Herbicides
• Dimethanamid P• S-Metolachlor• Formasulfuron• Monosulfuron• Mesosulfuron• Oxaziclomefone• Pyribenzoxim• Fentrazamide• Benzobicyclon
Off Patent Molecules- Insecticides
• Spirodiclofen• Thiamethoxam• Xiaochonogthion• Flonicamid• Bifenazate• Dinotefuran• Profurite aminium• Pyridalyl
SULFONYL UREAS :
TRIAZOLES
STROLIBURINS
NEONICOTINIDES
FOP Series
X O
R3R2
R1
O
CH3
OR4
O
Sr. No.
Name Substituents X R1 R2 R3 R4
1 Chlorazifop N H Cl Cl H 2 Clodinafop N H Cl F H 3 Diclofop-methyl C H Cl Cl CH3 4 Cyhalofop C H CN F H 5 Fluazifop-P N H CF3 H H 6 Haloxyfop-P N H CF3 Cl H 7 Isoxapyrifop N H Cl Cl
ONH
New Opportunity with Old Knowhow and Old Product
3 CH3OH + PCl3 P (OCH 3)3
Trimethyl Phosphite
OH P
Cl Cl
Cl
+ PH
O O
O
HCl+ +Cl
3 2
diethyl phosphonateMolecular Weight: 138,10
Monocrotophos Intermediate
Fosetyl Aluminium
Old Molecules- New Opportunities
• 2,4- D Choline salts ↓
• Can this knowledge be suitably used for other acids like
Glyphosate FOP family
Important Properties
• Crystal Polymorph Studies• Cyclohexanedione Herbicides• Cyprodinil fungicide• Pyrimethalin• There are new opportunities like A. The development of Cocrystals. N-heterocycles are good candidates. B. Amorphous compounds
Formulations -WDGs
• Spray Fluid Bed Drier: Availability of local equipment at manufacturing scale has made this technology viable and the problem of dust due to wettable powders is reduced.
• Can we extend this know-how to Chlorpyrifos DF?
• Hot Melt Extrusion is another opportunity to be followed in place of extrusion for low melting compounds by incorporating suitable polymers with matching Tg.
Suspension Concentrates
• Mixtures as suspension concentrates are popular in Europe.
• Oil based suspension concentrates are also used in limited way.
• EU task force is looking at Essential oils which are known to have bactericidal/Fungistatic properties.
• Important oils used are: cottonseed oil, cinnamon oil , Neem oil.
Microencapsulation
Syngenta has achieved success with microencapsulated formulation of lambda Cyhalothrin ( Zeon). The process uses simple technique of a. Interfacial polymerization b. We can innovate by the use of Core and Shell method followed in emulsion polymerizationc. These methods are used extensively in India by Coating Industries . d. Why not follow same principles for agchem.
Chemistry requirements for the registration
• Physicochemical Properties• 5-Batch Analysis for Technical• 5- Batch analysis for the formulation.• Spectral Studies.
Physico Chemical Properties
• Appearance• pH Value acidity and alkalinity• Explosive Properties and oxidizing Properties,
where relevant.• Flash Point, Flammability, Autoflammability
where relevant• Relative density where relevant• Storage stability.
5 Batch Analysis
• Phase 1: NON-GLP( During lab scale process development)
a. Synthesis of the compound b. Screening for active impurities by LCMS/GCMS c. Isolation of Active and impurities by Prep HPLC/HPTLC. d. Identification of the impurities.
5 Batch Analysis- Phase 2
• During commercial Production:• Production of 7 batches• Impurities Synthesis• Method development for Active ingredient
and Impurities( if NON-CIPAC).• Quantification of active and impurities.• Analysis • Report.
Challenges – 4 Pillars
1. GLP Labs – NABL accreditation.2. Shift from Batch Process to Continuous
Process3. Shift to Green Chemistry4. Novel Formulations
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