preparation & evaluation of tablets from ma &...

Preparation & Evaluation of Tablets

from MA & Optimized

Agglomerates.

Chapter 11: Preparation and evaluation of tablets from MA and optimized

agglomerates.

Direct tabletting and BA improvement of MA by spherical crystallization tech. 303

11. Preparation and evaluation of Tablet dosage form by direct compression

method:

Compactibility is the process of volume reduction and bond formation in a powder bed

during compression, which produces compacts of a certain mechanical strength. When

pressure is applied to a powder bed, particle rearrangement occurs first, followed by

particle fragmentation and deformation (plastic and elastic deformation), and bond

formation on the contact surfaces (1). Plastic deformation is an irreversible process of

particle shape changing that contributes to stronger tablets, while elastic deformation is

reversible and leads to elastic recovery of compacts in the decompression phase and the

breakage of some previously formed bonds, which results in lower tablet strength and

capping problems. In the case of plastically flowing material, the particle shape changes

during compression, but the surface area remains nearly unchanged.

On the other hand, primary particles of materials that fragment (break) into smaller parts

during compression, lead to an increased surface area and increased number of contact

points suitable for bond formation. In both cases plastic deformation occurs at later stages

of compression and adequate tablet strength can be obtained. Typical examples of

materials with mainly plastic flow include microcrystalline cellulose (MCC), typical

materials that mainly fragment include dicalcium phosphate dihydrate, crystal lactose,

etc. (2-3).

The main bonding mechanisms involved in compact formation are:

1. Solid bridges, which represent the strongest bonds between particles.

2. Intermolecular or long distance forces (van der Waals forces, electrostatic forces,

hydrogen bonding), representing weaker attraction forces.

3. Mechanical interlocking, denoting hooking and twisting of irregularly shaped

particles.

The most common dominant bonding mechanisms for pharmaceutical materials are long

distance forces, especially van der Waals forces and hydrogen bonds in some cases. The

fundamentals for solid bridges are a relatively simple molecular structure and plastic

deformation. In order to form a coherent tablet, bonds between the particle contact

surfaces must be strong enough to withstand the elastic component of the material. The

final compact strength is dependent on many materials and process attributes. The tensile

strength of tablets is generally higher if the particle size is smaller (4). If the material

undergoes fragmentation during volume reduction, the particle size and shape will have a

minor effect on tablet strength.

Poor compactibility of powders, weak bonds between particles, or extensive elastic

relaxation of materials can decrease tablet strength and increase the capping tendency.

Capping is a phenomenon whereby extensive elastic relaxation breaks bonds that were

formed during compression, leading to laminar breakage of the upper part of the tablet.

Capping increases with increasing compression pressure, tableting speed, and tablet

thickness, as well as low powder humidity (5). Using precompression before the main

compression during tableting can lead to lower capping incidence (6).

The solid-state material properties, surface free energy, and structural changes have

important influence on powder compression behavior. The existence of polymorphism

and the degree of material crystallinity can have a significant impact on the tablet

properties. During compaction, mechanical energy can cause surfaces to become

disordered and activated, which can cause more intensive bonding (7).


agglomerates.


11.1. Direct compression:

In early days, most of the tablets require granulation of the powdered Active

Pharmaceutical Ingredient (API) and Excipients. The availability of new excipients or

modified form of old excipients and the invention of new tablet machinery or

modification of old tablet machinery provides an ease in manufacturing of tablets by

simple procedure of direct compression.

Amongst the techniques used to prepare tablets, direct compression is the most advanced

technology. It involves only blending and compression. Thus offering advantage

particularly in terms of speedy production. Because it requires fewer unit operations, less

machinery, reduced number of personnel and considerably less processing time along

with increased product stability.

Tablet manufacturing by direct compression has increased steadily over the years. It

offers advantages over the other manufacturing processes for tablets, such as wet

granulation and provides high efficiency (7).As direct compression is more economic,

reducing the cycle time and straight forward in terms of good manufacturing practice

requirements. On the other hand wet granulation not only increases the cycle time, but

also has certain limits imposed by thermolability and moisture sensitivity of the active

drug substances. Therefore pharmaceutical industry is now focusing increasingly on the

direct compression process (8-9). Tablets produced by direct compression method give

lower microbial levels than those prepared by the wet granulation method. The

compaction process exerts lethal effect on the survival of microorganisms (10). The

tablets prepared by direct compression disintegrate into API particles instead of granules

that directly come into contact with the dissolution fluid and exhibit a comparatively

faster dissolution (11). The direct compression is a process of applying pressure (via an

upper and a lower punch) to materials held in a die cavity. The events that occur in the

process of compression are (12)

1. Transitional repacking.

2. Deformation at point of contact.

3. Fragmentation and/or deformation.

4. Bonding.

5. Deformation of the solid body.

6. Decompression.

7. Ejection.

The term ―direct compression‖ is defined as the process by which tablets are compressed

directly from powder mixture of API and suitable excipients. No pretreatment of the

powder blend by wet or dry granulation procedure is required. The events that motivate

the industry people to use direct compression technique is commercial availability of the

directly compressible excipients possessing both good compressibility and good

flowability. Terashita and Imamura in 2002 suggested that direct compression is able to

produce tablets at a lower cost than wet granulation and tableting method, due to a fewer

items of process validation. (13)

11.1.1. Merits of direct compression:

1. Direct compression is more efficient and economical process as compared to other

processes, because it involves only dry blending and compaction of API and

necessary excipients.


agglomerates.


2. The most important advantage of direct compression is cost effectiveness. It is due to

reduced processing times, reduced labor costs, fewer manufacturing steps, and less

number of equipments are required, less process validation and reduced consumption

of power.

3. Elimination of heat and moisture, thus increasing not only the stability but also the

suitability of the process for thermolabile and moisture sensitive API’s.

4. Particle size uniformity.

5. Prime particle dissolution. In case of directly compressed tablets after disintegration,

each primary drug particle is liberated. While in the case of tablets prepared by

compression of granules, small drug particles with a larger surface area adhere

together into larger agglomerates; thus decreasing the surface area available for

dissolution.

6. The chances of batch-to-batch variation are negligible, because the unit operations

required for manufacturing processes is fewer.

7. Chemical stability problems for API and excipient would be avoided.

8. Provides stability against the effect of aging which affects the dissolution rates.

11.1.2. Merits of direct compression over wet granulation process:

The variables used in the processing of the granules can lead to significant tableting

problems. Properties of granules formed can be affected by viscosity of granulating

solution, the rate of addition of granulating solution, type of mixer used and duration of

mixing, method and rate of dry and wet blending. The above variables can change the

density and the particle size of the resulting granules and may have a major influence on

fill weight and compaction qualities. Drying can lead to unblending as soluble API

migrates to the surface of the drying granules.

11.1.3. Demerits

11.1.3.1. Excipient related demerits 1. Problems in the uniform distribution of low dose drugs.

2. High dose drugs having high bulk volume, poor compressibility and poor flowability

are not suitable for direct compression.

3. The choice of excipients for direct compression is extremely critical. Direct

compression diluents and binders must possess both good compressibility and good

flowability.

4. Many active ingredients are not compressible either in crystalline or amorphous

forms.

5. Direct compression blends may lead to unblending because of difference in particle

size or density of drug and excipients. Similarly the lack of moisture may give rise to

static charges, which may lead to unblending.

6. Non-uniform distribution of colour, especially in tablets of deep colours.

11.1.3.2. Process related demerits 1. Capping, lamination, splitting, or layering of tablets is sometimes related to air

entrapment during direct compression. When air is trapped, the resulting tablets

expand when the pressure of tablet is released, resulting in splits or layers in the

tablet.

2. In some cases require greater sophistication in blending and compression

equipments.

3. Direct compression equipments are expensive.


agglomerates.


11.1.4. Manufacturing steps for direct compression

Direct compression involves comparatively few steps:

1. Milling of drug and excipients.

2. Mixing of drug and excipients.

3. Tablet compression.

Figure: 11.1. Manufacturing Steps for Direct Compression.

11.1.5. Direct compression Excipients:

Direct compression excipients mainly include diluents, binders and disintegrants.

Generally these are common materials that have been modified during the chemical

manufacturing process, in such a way to improve compressibility and flowability of the

material. The physicochemical properties of the ingredients such as particle size,

flowability and moisture are critical in direct compression tableting. The success of direct

compression formulation is highly dependent on functional behavior of excipients.

11.1.5.1. Ideal properties of directly compressible excipients

1. It should have good compressibility.

2. It should possess good hardness after compression, that is material should not

possess any deformational properties; otherwise this may lead to capping and

lamination of tablets.

3. It should have good flowability.

4. It should be physiologically inert.

5. It should be compatible with wide range of API.

6. It should be stable to various environmental conditions (air, moisture, heat, etc.).

7. It should not show any physical or chemical change in its properties on aging.

8. It should have high dilution potential. i.e. able to incorporate high amount of API.

9. It should be colorless, odorless and tasteless.

10. It should accept colorants uniformity.

11. It should possess suitable organoleptic properties according to formulation type, i.e.

in case of chewable tablet diluents should have suitable taste and flavor. For example

mannitol produces cooling sensation in mouth and also sweet taste.

12. It should not interfere with bioavailability and biological activity of active

ingredients.

13. It should be easily available and economical in cost.

11.1.5.2. Ideal Properties of API for direct tabetting:

1. Absence of static charge on surface

2. Good compatibility with excipients

3. Good compressibility

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agglomerates.


4. Good flowability

5. Good organoleptic properties

6. High Purity

7. High stability

8. Optimum and Uniform particle size-particle size distribution

9. Optimum bulk powder properties

10. Optimum moisture content

11. Spherical shape

11.2. Procedure for preparation of directly compressible tablet: The tablets of macrolide antibiotics and optimized recrystallized agglomerates were

prepared by direct compression method. The following steps are involved in preparation

of tablets

Raw material dispensing and sifting: Dispense the raw materials as per mentioned in

individual formula for formulation of tablets.

Sifting: Sift all inactive ingredients through sieve no #30

Mixing: Mix macrolide antibiotics or prepared recrystallized agglomerates as mentioned

in formula with diluents for five minutes in polybag.

Prelubrication: To the above mixed blend added sifted quantity of super disintegrant

Crosscarmelose Sodium (AC-Di-Sol) and talc and continue mixing for 3 minutes.

Lubrication: To the above pre lubricated blend added sifted quantity of magnesium

stearate and mix for few minutes in polybag.

Flow rate determination:

Physical properties such as bulk density, tapped density, compressibility index, Hausnar

ratio and the angle of repose of blend were determined to evaluate the flow of lubricated

blend.

Compression:

The lubricated blend for average weight per unit tablet as mentioned below table:11.1

was Compressed by using KBR Press with flate type punches and die (diameter 13mm)

for azithromycin, clarithromycin and by using 8-station compression machine with

standard concave type punches and die(9.5mm) for roxithromycin and erythromycin

which are lubricated with 0.5% magnesium stearate.

Table: 11.1. Average weights of macrolide antibiotics tablets with their respective

strength. Sr.No. Name of tablet Average weight(mg)

01 Azithromycin 500mg tablet 700-750

02 Clarithromycin 500mg tablet 700-760

03 Roxithromycin 300mg tablet 440-480

04 Erythromycin 250mg tablet 350-381

11.3. Evaluation of tablets:

11.3.1. Assay (drug content):

Single tablet of macrolide antibiotic was weighed and powdered .The powder was

weighed equivalent to 50mg of macrolide antibiotics and diluted to 60ml with 0.1N HCl,

adjusted the pH 6 to 7 by adding 0.4M NaOH solution and made up the volume up to

100ml with distilled water. 1ml form the above solution was diluted to 6 ml with the

distilled water in 10 ml volumetric flask and to it added Eosin Y solution (4 X 10-3

M) (

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agglomerates.


Azithromycin-0.5ml,Clarithromycin-1.2ml,Roxithromycin-0.7ml and Erythromycin-

0.7ml), mixed well and to it added 1 ml 0.4M acetate buffer (pH 3) adjust the volume up

to 10ml with distilled water. The absorbance was measured spectrophotometrically at

544.5nm, 542.5nm, 545nm, 547nm for Erythromycin, Roxithromycin, Clarithromycin

and Azithromycin respectively against an appropriate blank prepared simultaneously.

Content of macrolide antibiotics were determined either the calibration graph by using

the corresponding regression equation.(14)

11.3.2. Content uniformity:

Determine the content of macrolide antibiotics in each of 10 tablets as per above

analytical procedure mentioned in drug content determination. The tablet complies with

the test if each individual content is 85-115% of the average content. The tablet fails to

comply the test if more than one individual content is out side theses limits or if one

individual content is outside the limit of 75-125% of the average content. (15)

11.3.3. Thickness, length and width measurement:

The thickness of a tablet was determined by the amount of fill permitted to enter the die

and the amount of pressure applied during compression (16). Five tablets were taken and

their thickness, length and width were determined individually by vernier caliper. Mean

and standard deviation were calculated.

11.3.4. Crushing strength or hardness determination:

Five tablets were taken randomly and hardness was measured using Hardness Tester

(Pfizer hardness tester).

11.3.5. Friability:

For tablet with an average weight of 650mg or less take a sample of whole tablets

corresponding to about 6.5 gm and for tablet with an average weight of more than 650mg

take sample of 10 whole tablets.

As the average weight of Azithromycin and Clarithromycin tablet was above 650mg take

whole 10 tablets for the study. In case of roxithromycin and erythromycin the average

weight of tablets was below 650mg therefore take 15 and 20 tablets of roxithromycin and

erythromycin for friability study.

Dedust the tablets carefully and weigh accurately the required number of tablets for the

study as per above mentioned number of tablets selection condition. Place the tablets in

the drum of Roche friabilator apparatus and rotate it for 100 times or rotated at 25 rpm

for 4 minutes. Remove the tablets and any loose dust from them and weigh accurately

after revolving the tablets. The percentage friability was measured using the formula,

Where %F = Friability in percentage.

W0 = Initial weight of tablets.

W = Weight of tablet after revolution.

A maximum loss of weight was not greater than 1.0 % which is acceptable for most

tablets. If one or more tablets were cracked, chipped or broken during the test the tablets

fails the friability test as per Indian Pharmacopoeia. If the size and shape of tablets causes

irregular tumbling, adjust the drum base so that it forms an angle of about 100 with the

horizontal and tablets do not binds together when lying next to each other. (17)


agglomerates.


11.3.6. Weight variation:

The variation in weight of individual tablets is a valid indication of the corresponding

variation in the drug content (18). The average tablet weight was determined by weighing

20 units of tablets individually using an analytical balance. Weigh the average weight of

20 tablets and than weigh individually 20 tablets on analytical balance. Not less than two

of the individual weight deviates from the average weight by more than the % shown in

the table: 12.2.

Table: 11.2. Limits of percentage deviation of weight in weight variation study of

tablets. Sr.No. Average weight (mg) % Deviation

1 80 or less 10

2 80-250 7.5

3 250 or more 5

11.3.7. Tablet elastic recovery test: Place the powder blend equivalent to average weight of samples in 13.0 mm die for

azithromycin, clarithromycin and in 9.5 mm die for roxithromycin, erythromycin and

compress by using KBr Press. Measure the thickness of compacted tablet under

maximum pressure (HC) and 24 hrs after tablet ejection (He).The following equation was

used to calculate the elastic recovery ratio(ER) (19)

ER = [(He – Hc) / Hc] X100

11.3.8. Tensile strength:

Plastic deformation of agglomerates having porous structure and lower crystallinity,

during compression might be responsible for increasing the interparticle bonding in a

tablet. (20) The tensile strength of tablet (T) was calculated using the following formula,

T = 2F / π DL.

Where, T = Tablet tensile strength.

D = Tablet diameter (mm).

L = Thickness (mm).

F = Hardness (Kg/cm2).

11.3.9. Porosity of tablet:

Twenty-four hours after ejection of compacted tablet of macrolide antibiotics and their

agglomerated crystals, measured the volume of the compacted tablet by measuring

thickness and diameter (19).

The %Porosity (ε) was calculated from the following equation.

ε = {(v-vo) / v} Χ 100

Where, v = Tablet volume(r Χ h.)

r = Radius of the compacted tablet.

h = thickness of the compacted tablet.

vo = the volume of material at zero porosity (true volume)

11.3.10. Wetting Time and Water Absorption Ratio:

A piece of tissue paper folded twice was kept in a culture dish (internal diameter 5.5 cm)

containing ≈6 mL of purified water. A tablet having a small amount of amaranth powder

on the upper surface was placed on the tissue paper. The time required to develop a red

color on the upper surface of the tablet was recorded as the wetting time. The same

procedure without amaranth was followed for determining the water absorption ratio


agglomerates.


(21). The wetted tablet was weighed and the water absorption ratio, R, was determined

according to the following equation,

Where Wb and Wa were the weights of the tablet before and after study.

11.3.11. Disintegration time:

Disintegration is evaluated to ensure that the drug substance is fully available for

dissolution and absorption from the gastrointestinal tract (22).The test determines

whether tablet disintegrate with in the prescribed time when placed in liquid medium

under the prescribed condition. Disintegration test was carried out as described under

procedure for uncoated tablets in IP.Introduce one tablet into each tube and kept disc

above the tablet in each tube. Suspend the assembly in the beaker containing 900mL

purified water as the immersion fluid at 37 ± 20C for specified time period. Remove the

assembly from the liquid, the time required for complete disintegration was noted for

each tablet. Tablet passes the test if all of them have disintegrated. If one or two tablets

fails to disintegrate, repeat the test on additional 12 tablets, not less than 16 of the total 18

tablets tested disintegrate.

11.3.12. Dissolution study:

The in vitro dissolution studies were carried out using eight station USP type II

dissolution apparatus. The study was carried out in 900 ml of dissolution medium as per

mentioned in below table: 11.3. Dissolution medium was kept in a thermostatically

controlled water bath, maintained at 37±0.50C.The paddle was rotated at 50-100 rpm as

per mentioned in table. At predetermined time intervals, 5ml of samples were withdrawn

and assessed for drug release spectrophotometrically. At each withdrawal, 5ml of fresh

dissolution medium was added to dissolution jar so as to maintain sink condition. 1ml

quantity of withdraw sample was taken into 10ml volumetric flask and diluted to 6ml

with distilled water. Eosin Y solution (4 X 10-3

M) was added (Azithromycin-

0.5ml,Clarithromycin-1.2ml,Roxithromycin-0.7ml and Erythromycin-0.7ml) and mixed

well than to it added 1 ml 0.4M acetate buffer (pH 3) and adjusted the volume up to 10ml

with distilled water. The absorbance was measured spectrophotometrically at 540.5nm,

542.5nm, 540nm, 544nm for Azithromycin, Clarithromycin, Roxithromycin and

Erythromycin respectively against an appropriate blank prepared simultaneously.

In vitro release was demonstrated by comparison of the dissolution profile after fitting

into the mathematical model, similarity factor, f2. The similarity factor, f2 used as the

mathematical model for comparing the dissolution profile.

Where, f2 = Similarity factor; n = Number of time points; R (t) = Mean percent drug

dissolved e.g. a reference product; T (t) = Mean percent drug dissolved of e.g. a test


agglomerates.


product. Not more than one mean value of >85% dissolved for each formulation. An f2

value between 50 and 100 suggests that the two dissolution profiles are similar12.

Table: 11.3. Dissolution conditions of tablets prepared from macrolide antibiotics

and their optimized recrystallized agglomerates. Macrolide

Antibiotics

App: Speed Volume Medium

Azithromycin App-II (Paddle) 75rpm 900ml 0.1M Phosphate buffer pH 6.0

Clarithromycin App-II (Paddle) 50rpm 900ml 0.1M Sodium Acetate buffer pH 5.0

Roxithromycin App-II (Paddle) 100rpm 900ml Acetate buffer pH 5.0

Erythromycin App-II (Paddle) 50rpm 900ml 0.05M pH 6.8 phosphate buffer

Table: 11.4. Marketed tablets of macrolide antibiotics used for comparative study. Macrolide

antibiotics

Marketed tablet Tablet code Strength

(mg)

Weight

(mg)

Description of Tablet.

Azithromycin Zathrin Tablet

(FDC Ltd.)

ATM(m)-Tab 500mg 760mg Pink colored capsule shaped

tablet plain on both side

Clarithromycin Claribid Tablet

(Pfizer Ltd.)

CTM(m)-Tab 500mg 790mg Oval shaped yellow colored

tablet

Roxithromycin Roxid Tablet

(Alembic Ltd.)

RTM(m)-Tab 300mg 870mg Capsule shaped pink colored

tablet having one sided beak line

and plain on other side

Erythromycin Althrocin Tablet

(Alembic Ltd.)

ETM(m)-Tab 250mg 500mg White round shaped tablet having

Althrocin and 250 embossing

with break line which bifurcate

the Althrocin and 250 embossing

on one side and plain on other

side.

Table: 11.5. Evaluation parameters of macrolide antibiotics marketed tablets used for

comparative study. Marketed tablet Shape Diameter(mm) Thickness(mm) Length(mm) Width(mm)

Zathrin Tablet

(FDC Ltd.)

Capsule NA 6.00 19.00 10.00

Claribid Tablet

(Pfizer Ltd.)

Oval NA 7.00 19.00 9.00

Roxid Tablet

(Alembic Ltd.)

Capsule NA 7.00 17.00 8.00

Althrocin Tablet

(Alembic Ltd.)

round 12.00 4.00 NA NA


agglomerates.


Figure: 11.2. Shape and packing of marketed macrolide antibiotics tablets taken for

comparative study.

Table: 11.4, 11.5 represent the evaluation parameters like physical description, weight,

shape, strength, shape and size and figure: 11.2 represent the photographs of marketed

macrolide antibiotics tablets for comparative purpose. For comparative purpose the

marketed strength of 500mg, 500mg, 300mg and 250mg for azithromycin,

clarithromycin, roxithromycin and erythromycin tablets were taken. The respective

weight of the taken marketed strength was given in table: 11.4.


agglomerates.


11.4. Formulation, preparation and evaluation of Azithromycin tablet:

Table: 11.6. Tablet formulations of ATM and their optimized recrystallized

agglomerates.

Sr.

No: Name of ingredients

Quantity(mg)

ATM-

Tab

ATME-

Tab

ATMP-

Tab

ATMS-

Tab

ATMN-

Tab

1 ATM 500 ----- ----- ----- -----

2 ATM- EudS (equiv.) ----- 543 ----- ----- -----

3 ATM-PVP ----- ----- 543 ----- -----

4 ATM-SSG ----- ----- ----- 549 -----

5 ATM-N(HPMC) ----- ----- ----- ----- 543

6 Dibasic Calcium Phosphate 75 75 75 75 75

7 Microcrystalline

cellulose(Avicel pH 102) 100 100 100 100 100

8 Crosscarmelose

Sodium(AC-Di-Sol) 20 20 20 20 20

9 Talc 2.5 2.5 2.5 2.5 2.5

10 Magnesium Stearate 2.5 2.5 2.5 2.5 2.5

Total weight (mg) 700 743 743 749 743

Table: 11.7. Evaluation of lubricated blend of ATM and their optimized

recrystallized agglomerates.

Sr.

No Evaluation parameters

Tablet code

ATM-

Tab

ATME-

Tab

ATMP-

Tab

ATMS-

Tab

ATMN-

Tab

1 Bulk density (gm/mL) 0.667 0.333 0.333 0.313 0.313

2 Tap density (gm/mL) 0.833 0.385 0.400 0.370 0.376

3 Compressibility index (CI) 20 13.33 16.66 15.625 16.88

4 Hausner’s ratio 1.25 1.15 1.20 1.19 1.20

5 Angle of repose (Degree) 28 18 20 21 23

6 Flow rate (gm/sec) 0.25 0.71 0.50 0.62 0.55

Table: 11.8. Weight variation studies of azithromycin tablets.

Tablet no Weight in mg (% deviation)

ATM-Tab ATME-Tab ATMP-

Tab

ATMS-Tab ATMN-Tab

1 685(2.7) 740(0.1) 735(0.8) 750(0.1) 737(0.5)

2 725(3.0) 735(0.6) 737(0.5) 755(0.5) 745(0.5)

3 741(5.2) 732(1.0) 745(0.6) 747(0.5) 742(0.1)

4 725(3.0) 737(0.3) 745(0.6) 753(0.3) 741(0.0)

5 680(3.4) 734(0.7) 738(0.4) 752(0.1) 742(0.0)

6 666(5.4) 729(1.4) 740(0.1) 750(0.1) 742(0.1)

7 722(2.5) 751(1.6) 742(0.2) 749(0.3) 742(0.1)

8 675(4.1) 746(0.9) 743(0.3) 748(0.4) 740(0.1)

9 705(0.1) 742(0.4) 742(0.2) 754(0.4) 739(0.3)

10 709(0.7) 745(0.8) 741(0.0) 751(0.0) 740(0.1)

Avg.weight

(mg) 704.1 739.1 740.8 750.9 741


agglomerates.


Table: 11.9. Content uniformity study of Azithromycin tablet.

Tablet

no.

Concentration (%)

ATM-Tab ATME-Tab ATMP-Tab ATMS-Tab ATMN-Tab

1 95 93 97 98 93

2 90 95 94 92 95

3 88 97 103 95 97

4 115 92 92 96 94

5 107 90 90 97 95

6 108 88 93 94 98

7 112 103 94 95 92

8 94 97 96 95 93

9 87 95 98 96 97

10 83 96 93 98 90

Avg 97.9 94.6 95 95.6 94.4

Min. 83 88 90 92 90

Max. 115 103 103 98 98

SD 11.55 4.20 3.68 1.84 2.50

%SD 11.80 4.43 3.88 1.92 2.65

Table: 11.10. Evaluation of tablets prepared from ATM and their optimized


Sr.No: Evaluation parameters

Tablet Code

ATM-

Tab

ATME-

Tab

ATMP-

Tab

ATMS-

Tab

ATM

N-Tab

ATM(m)

-Tab

1 Description

2 Assay (Drug content) 95 93 94 97 95 95

3 Thickness (mm) 6.0 5.4 5.8 5.4 5.2 8.0

4 Hardness (kg) 4.5 7.0 6.2 8.5 5.8 6.5

5 Friability 1.75 0.72 0.45 0.65 0.61 0.56

6 Tensile strength 0.037 0.064 0.052 0.077 0.055 NA 7 Porosity of tablet 1.67 5.56 6.90 3.70 7.69 NA 8 Elastic recovery 5.00 3.64 3.45 3.70 3.85 NA

9 Wetting Time(Minutes) 9 5 6 4 5 6

10 Water Absorption Ratio ( R ) 34 39 42 46 40 38

11 Disintegration time (min.) 5-6 6-7 5-6 3-4 4-5 3-4

12 Dissolution % Cumulative drug release (%CDR)

Dissolution condition:

Medium:0.1M Phosphate

buffer pH 6.0, 900ml ,

75rpm

USP App-II (Paddle)

5 Min. 48 61 57 62 58 53

15 Min. 57 74 68 70 72 61

30 Min. 64 82 78 81 84 71

45 Min. 74 88 85 89 92 84

60 Min. 82 96 94 97 97 94

F2 values (Ref:ATM-Tab) NA 48.17 54.30 48.83 47.29 61.59

F2 values (Ref:ATM(m)-Tab) 61.59 60.39 72.58 62.86 60.0 NA


agglomerates.


Wetting time and water absorption ratio of Azithromycin tablet

0

10

20

30

40

50

ATM-Tab ATME-Tab ATMP-Tab ATMS-Tab ATMN-Tab ATM(m)-Tab

Wetting Time(min) Water Absorption Ratio ( R )

Figure: 11.3. Wetting time and water absorption ratio of tablets prepared from

ATM and their recrystallized agglomerates.

Dissolution profile of Azithromycin tablet

0

20

40

60

80

100

0 10 20 30 40 50 60

Time(min.)

%C

DR

ATM-Tab ATME-Tab ATMP-Tab

ATMS-Tab ATMN-Tab ATM(m)-Tab

Figure: 11.4. Comparative dissolution studies of prepared azithromycin tablet with

optimized recrystallized agglomerates and marketed tablet.


agglomerates.


11.5. Formulation, preparation and evaluation of Clarithromycin tablet:

Table: 11.11. Tablet formulations of CTM and their optimized recrystallized

agglomerates.

Sr.N

o: Name of ingredients

Quantity(mg)

CTM-Tab CTME –

Tab

CTMP –

Tab

CTMS -

Tab

CTMN-

Tab

1 CTM 500 ----- ----- ----- -----

2 CTM- EudS(equiv.) ----- 556 ----- ----- -----

3 CTM-PVP ----- ----- 538 ----- -----

4 CTM-SSG ----- ----- ----- 556 -----

5 CTM-N(HPMC) ----- ----- ----- ----- 556

6 Microcrystalline

Cellulose(Avicel pH 102) 175 175 175 175 175

8 Crosscarmelose Sodium(AC-

Di-Sol) 20 20 20 20 20

9 Talc 2.5 2.5 2.5 2.5 2.5

10 Magnesium Stearate 2.5 2.5 2.5 2.5 2.5

Total weight (mg) 700 756 738 756 756

Table: 11.12. Evaluation of lubricated blend of CTM and their optimized recrystallized

agglomerates.

Sr.

No:

Evaluation

parameters

Tablet code

CTM-Tab CTME –Tab CTMP –Tab CTMS -Tab CTMN-Tab

1 Bulk density

(gm/mL) 0.455 0.294 0.313 0.303 0.278

2 Tap density

(gm/mL) 0.588 0.345 0.370 0.345 0.333

3 Compressibility

index (CI) 22.72 14.71 15.62 12.12 16.67

4 Hausner’s ratio 1.29 1.17 1.18 1.14 1.20

5 Angle of repose

(Degree) 30 23 24 21 24

6 Flow rate

(gm/sec) 0.06 2.50 1.30 0.63 0.50


agglomerates.


Table: 11.13. Weight variation studies of Clarithromycin tablets.

Tablet no Weight in mg (% deviation)


1 722(2.6) 740(0.0) 747(0.9) 755(0.5) 746(0.6)

2 713(1.3) 742(0.3) 735(0.7) 757(0.8) 750(0.0)

3 695(1.3) 747(1.0) 736(0.6) 753(0.2) 754(0.5)

4 729(3.6) 733(0.9) 738(0.3) 745(0.8) 756(0.8)

5 737(4.7) 735(0.6) 740(0.1) 747(0.6) 758(1.0)

6 740(5.1) 737(0.4) 742(0.2) 748(0.4) 760(1.3)

7 667(5.2) 740(0.0) 743(0.3) 744(1.0) 742(1.1)

8 685(2.7) 740(0.0) 740(0.1) 752(0.1) 741(1.2)

9 675(4.1) 744(0.6) 738(0.3) 755(0.5) 754(0.5)

10 675(4.1) 739(1.0) 746(0.7) 757(0.8) 742(1.1)

Avg.weight

(mg) 703.8 739.7 740.5 751.3 750.3

Table: 11.14. Content uniformity study of Clarithromycin tablet.

Tablet

no.

Concentration (%)


1 98 95 97 94 93

2 92 97 94 97 96

3 95 94 93 95 98

4 86 95 95 96 98

5 82 98 96 97 96

6 97 96 97 97 95

7 99 94 97 97 97

8 85 93 97 93 96

9 105 94 95 94 94

10 107 95 94 95 98

Avg 94.6 95.1 95.5 95.5 96.1

Min. 82 93 93 93 93

Max. 107 98 97 97 98

SD 8.37 1.52 1.51 1.51 1.73

%SD 8.85 1.60 1.58 1.58 1.80


agglomerates.


Table: 11.15. Evaluation of tablets prepared from CTM and their optimized


Sr.No Evaluation parameters

Tablet Code

CTM-

Tab

CTME –

Tab

CTMP

–Tab

CTMS

-Tab

CTMN-

Tab

CTM(m)-

Tab

1 Description


3 Thickness(mm) 5.9 5.5 5.3 5.4 5.7 8.5

4 Hardness(kg) 5 8 7 9 7 9

5 Friability 1.17 0.42 0.41 0.51 0.48 0.58

6 Tensile strength 0.042 0.071 0.065 0.082 0.060 NA

7 Porosity of tablet 3.39 7.27 5.66 5.56 7.02 NA

8 Elastic recovery 8.47 3.64 3.77 3.70 5.26 NA

9 Wetting Time(hrs) 8 4 5 3 4 6

10 Water Absorption Ratio

( R ) 23 38 35 40 37 32

11 Disintegration

time(minutes) 5-6 4-5 5-6 3-4 4-5 3-4


Medium: 0.1M Sodium

Acetate,buffer pH

5.0,900ml, 50rpm,

USP App-II (Paddle)

5 Min. 27 51 47 52 48 40

15 Min. 40 65 63 68 66 59

30 Min. 47 76 78 79 76 67

45 Min. 58 86 83 86 83 80

60 Min. 70 95 93 96 94 87

F2 values (Ref:CTM-Tab) NA 36.52 37.88 35.22 37.48 44.16

F2 values (Ref:CTM(m)-Tab) 44.16 61.46 65.45 57.61 64.54 NA

Wetting time and water absorption ratio of Clarithromycin tablet

0

10

20

30

40

50

CTM-Tab CTME –Tab CTMP –Tab CTMS -Tab CTMN-Tab CTM(m)-Tab



CTM and their recrystallized agglomerates.


agglomerates.


Dissolution profile of Clarithromycin tablet

0

20

40

60

80

100

0 10 20 30 40 50 60

Time(min.)

%C

DR

CTM-Tab CTME-Tab CTMP-Tab

CTMS-Tab CTMN-Tab CTM(m)-Tab

Figure: 11.6. Comparative dissolution studies of prepared clarithromycin tablet

with optimized recrystallized agglomerates and marketed tablet.

11.6. Formulation, preparation and evaluation of Roxithromycin tablet:

Table: 11.16. Tablet formulation of RTM and their optimized recrystallized

agglomerates.

Sr.No: Name of ingredients

Quantity(mg)

RTM-

Tab

RTMH-

Tab

RTMP-

Tab

RTMS-

Tab

RTMN-

Tab

1 RTM 300 ----- ----- ----- -----

2 RTM- HPC(equiv.) ----- 330 ----- ----- -----

3 RTM-PVP ----- ----- 326 ----- -----

4 RTM-SSG ----- ----- ----- 330 -----

5 RTM-N(HPMC) ----- ----- ----- ----- 337

6 Microcrystalline

Cellulose (Avicel) 72 72 72 72 72

7 Lactose 44 44 44 44 44

8 Crosscarmelose


9 Magnesium Stearate 4 4 4 4 4

Total weight (mg) 440 470 466 470 477


agglomerates.


Table: 11.17. Evaluation of lubricated blend of RTM and their optimized


Sr.No.

Evaluation

parameters

Tablet code

RTM-

Tab

RTMH-Tab RTMP-Tab RTMS-Tab RTMN-Tab

1 Bulk density

(gm/mL) 0.667 0.357 0.352 0.333 0.333

2 Tap density

(gm/mL) 0.833 0.417 0.410 0.379 0.397

3 Compressibility

index (CI) 20 14.28 14.08 12.00 16.00

4 Hausner’s ratio 1.25 1.17 1.16 1.14 1.19

5 Angle of repose

(Degree) 27 23 22 24 25

6 Flow rate

(gm/sec) 0.33 0.50 0.63 0.71 0.42

Table: 11.18. Weight variation studies of Roxithromycin tablets. Tablet no Weight in mg (% deviation)

RTM-Tab RTMH-Tab RTMP-Tab RTMS-Tab RTMN-Tab

1 445(1.0) 471(0.0) 465(0.0) 474(0.3) 482(0.6)

2 447(1.4) 470(0.2) 462(0.7) 475(0.5) 483(0.8)

3 446(1.2) 468(0.6) 467(0.4) 473(0.0) 479(0.0)

4 442(0.3) 472(0.2) 465(0.0) 472(0.2) 476(0.6)

5 437(0.8) 472(0.2) 465(0.0) 471(0.4) 477(0.4)

6 434(1.5) 473(0.4) 466(0.2) 470(0.6) 478(0.2)

7 433(1.7) 471(0.0) 464(0.3) 470(0.6) 479(0.0)

8 438(0.6) 468(0.6) 467(0.4) 472(0.2) 482(0.6)

9 440(0.2) 474(0.7) 466(0.2) 475(0.5) 473(1.3)

10 445(1.0) 470(0.2) 465(0.0) 476(0.7) 482(0.6)

Avg.weight

(mg) 440.7 470.9 465.2 472.8 479.1

Table: 11.19. Content uniformity study of Roxithromycin tablet. Tablet

no.

Concentration (%)

RTM-Tab RTMH-Tab RTMP-Tab RTMS-Tab RTMN-Tab

1 93 96 94 95 95

2 96 97 97 96 96

3 95 95 95 92 94

4 91 94 95 94 96

5 94 95 96 95 95

6 97 95 98 98 94

7 96 95 95 95 96

8 92 98 99 96 95

9 98 95 94 95 94

10 93 98 95 95 97

Avg 94.5 95.8 95.8 95.1 95.2

Min. 91 94 94 92 94

Max. 98 98 99 98 97

SD 2.27 1.40 1.69 1.52 1.03

%SD 2.41 1.46 1.76 1.60 1.08


agglomerates.


Table: 11.20.Evaluation of tablets prepared from RTM and their optimized


Sr.No: Evaluation parameters

Tablet Code

RTM-

Tab

RTMH-

Tab

RTMP-

Tab

RTMS-

Tab

RTMN-

Tab

RTM(m)

-Tab

1 Description


3 Thickness(mm) 6 5.7 5.6 5.6 5.7 7.0

4 Hardness(kg) 3 5 6 5 7 8

5 Friability 1.29 0.26 0.62 0.52 0.34 0.48




9 Wetting Time(hrs) 8 5 5 4 6 7

10 Water Absorption Ratio

( R ) 27 37 35 42 37 32

11 Disintegration time

(minutes) 3-4 2-3 2-3 1-2 3-4 2-3


Medium: Acetate

buffer pH 5.0,

900ml, 100rpm,USP

App-II (Paddle)

5 Min. 32 45 47 50 48 43

15 Min. 47 53 56 61 58 58

30 Min. 55 68 71 74 72 70

45 Min. 63 81 84 85 83 79

60 Min. 74 92 94 96 93 90

F2 values (Ref:RTM-Tab) NA 49.66 46.25 43.27 46.06 50.12

F2 values (Ref:RTM(m)-Tab) 50.12 82.31 78.57 70.17 79.85 NA

Wetting time and water absorption ratio of Roxithromycin tablet

0

10

20

30

40

50

RTM-Tab RTMH-Tab RTMP-Tab RTMS-Tab RTMN-Tab RTM(m)-Tab



RTM and their recrystallized agglomerates.


agglomerates.


Dissolution profile of Roxithromycin tablet

0

20

40

60

80

100

0 10 20 30 40 50 60

Time(min.)

%C

DR

RTM-Tab RTMH-Tab RTMP-Tab

RTMS-Tab RTMN-Tab RTM(m)-Tab

Figure: 11.8. Comparative dissolution studies of prepared roxithromycin tablet with

optimized recrystallized agglomerates and marketed tablet.

11.7. Formulation, preparation and evaluation of Erythromycin tablet:

Table: 11.21. Tablet formulations of ETM and their optimized recrystallized

agglomerates.

Sr.No: Name of ingredients

Quantity(mg)

ETM-

Tab

ETME-

Tab

ETMB-

Tab

ETMS-

Tab

ETMN-

Tab

1 ETM 250 ----- ----- ----- -----

2 ETM-EudS(equiv.) ----- 275 ----- ----- -----

3 ETM-BCD ----- ----- 278 ----- -----

4 ETM-SSG ----- ----- ----- 272 -----

5 ETM-N(HPMC) ----- ----- ----- ----- 281

6 Microcrystalline

Cellulose 58 58 58 58 58

7 Lactose 30 30 30 30 30

8 Crosscarmelose


9 Magnesium Stearate 2 2 2 2 2

Total weight (mg) 350 375 378 372 381


agglomerates.


Table: 11.22. Evaluation of lubricated blend of ETM and their optimized


Sr.

No

Evaluation parameters

Tablet code

ETM-

Tab

ETME-

Tab

ETMB-

Tab

ETMS-

Tab

ETMN-

Tab

1 Bulk density

(gm/mL) 0.357 0.238 0.294 0.313 0.303

2 Tap density

(gm/mL) 0.455 0.263 0.345 0.370 0.362

3 Compressibility

index (CI) 21.43 9.52 14.71 15.63 16.36

4 Hausner’s ratio 1.27 1.11 1.17 1.18 1.19

5 Angle of repose

(Degree) 34 26 28 25 27

6 Flow rate

(gm/sec) 0.04 1.67 0.83 0.63 0.55

Table: 11.23.Weight variation studies of Erythromycin tablets. Tablet no Weight in mg (% deviation)

ETM-Tab ETME- Tab ETMB- Tab ETMS- Tab ETMN- Tab

1 335(5.5) 376(0.3) 382(0.9) 370(0.2) 381(0.1)

2 355(0.1) 380(1.4) 375(1.0) 375(1.5) 385(1.1)

3 365(2.9) 370(1.3) 377(0.4) 367(0.6) 376(1.2)

4 345(2.7) 372(0.7) 379(0.1) 368(0.4) 378(0.7)

5 360(1.5) 375(0.1) 380(0.4) 370(0.2) 380(0.2)

6 366(5.8) 376(0.3) 374(1.2) 366(0.9) 384(0.9)

7 347(2.1) 378(0.9) 378(0.2) 368(0.4) 384(0.9)

8 348(1.9) 380(1.4) 379(0.1) 370(0.2) 381(0.1)

9 360(1.5) 368(1.8) 382(0.9) 372(0.7) 378(0.7)

10 365(2.9) 373(0.5) 380(0.4) 368(0.4) 380(0.2)

Avg.weight

(mg) 355.5 374.8 378.6 369.4 380.7

Table: 11.24. Content uniformity study of Erythromycin tablet. Tablet

no.

Concentration (%)

ETM-Tab ETME- Tab ETMB- Tab ETMS- Tab ETMN- Tab

1 92 94 98 95 95

2 96 96 96 96 93

3 105 97 97 94 94

4 95 95 96 97 96

5 97 96 96 96 95

6 108 95 97 95 95

7 88 96 98 98 95

8 93 97 96 96 96

9 95 94 98 95 97

10 102 95 96 96 94

Avg 97.1 95.5 96.8 95.8 95

Min. 88 94 96 94 93

Max. 108 97 98 98 97

SD 6.15 1.08 0.92 1.14 1.15

%SD 6.34 1.13 0.95 1.19 1.22


agglomerates.


Table: 11.25. Evaluation of tablets prepared from ETM and their optimized


Sr.No: Evaluation

parameters

Tablet Code

ETM-

Tab

ETME-

Tab

ETMB

- Tab

ETMS

- Tab

ETMN-

Tab

ETM(m)

- Tab

1 Description


3 Thickness(mm) 5.2 4.8 4.9 4.7 4.8 4.5

4 Hardness(kg) 3 4.2 4.5 5.0 4.4 5.0

5 Friability 1.27 0.41 0.22 0.65 0.55 0.35




9 Wetting Time(min) 7 4 3 3 5 5

10 Water Absorption

Ratio ( R ) 25 34 31 45 38 35

11 Disintegration time 3-4 2-3 2-3 1-2 2-3 3-4


Medium: 0.05M pH

6.8 phosphate

Buffer, 900ml,

50rpm

USP App-II

(Paddle).

5 Min. 28 40 42 48 46 35

15 Min. 40 58 57 62 60 47

30 Min. 52 72 68 71 74 62

45 Min. 60 84 78 82 83 78

60 Min. 74 94 90 95 96 92

F2 values (Ref:ETM-Tab) NA 43.30 46.90 41.54 41.29 51.69

F2 values (Ref:ETM(m)-Tab) 51.69 63.22 67.53 57.31 57.86 NA

Wetting time and water absorption ratio of Erythromycin tablet

0

10

20

30

40

50

ETM-Tab ETME- Tab ETMB- Tab ETMS- Tab ETMN- Tab ETM(m)- Tab



ETM and their recrystallized agglomerates.


agglomerates.


Dissolution profile of Erythromycin tablet

0

20

40

60

80

100

0 10 20 30 40 50 60

Time(min.)

%C

DR

ETM-Tab ETME-Tab ETMB-Tab

ETMS-Tab ETMN-Tab ETM(m)-Tab

Figure: 11.10. Comparative dissolution studies of prepared erythromycin tablet

with optimized recrystallized agglomerates and marketed tablet.

Figure: 11.11.Shape of macrolide antibiotics tablets prepared from



agglomerates.


11.8. Discussion and Conclusion:

In the field of pharmaceutical powder compaction, it is often necessary to improve the

material flow properties in order to obtain a uniform die-filling in a tablet press. The flow

properties can be enhanced by converting fine powders into larger agglomerates. Wet

granulation is traditionally applied because the equipment and knowledge are available. In

wet granulation, a fluid binder is distributed on a powder blend and subsequently the

granules are dried. A more cost efficient alternative is the dry process—roller compaction

where the material is densified between two counter rotating rolls under pressure forming

a compact ribbon, which is milled into granules. This fairly simple technique is especially

applicable for voluminous materials as it enhances the bulk density greatly. The

disadvantages of the roller compaction comprise the formation of a relative large amount

of dust and fines and the decrease in the compaction properties of powders. Differences in

compression of wet and dry granulated material are observed as wet processed granules

often are more voluminous and roller compacted granules more dense than the original

powder mixture.

There has been renewed interest in examining the potential of direct compression tableting

over recent years in comparison to the use of the more traditional granulation process.

Such manufacture of tablets involves simple mixing and compression of powders, which

results in a number of overall benefits including time and cost savings. Direct compression

tableting is a technique which has been successfully applied to numerous drugs on the

industrial scale, although the success of any procedure, and resulting mechanical

properties of tablets, is strongly affected by the quality of the crystals used. When the

mechanical properties of the drug particles are inadequate a primary granulation is

necessary. The use of spherical crystallization as a technique appears to be an efficient

alternative for obtaining suitable particles for direct tableting. Spherical crystallization is a

particle design technique, by which crystallization and agglomeration can be carried out

simultaneously in one step and which has been successfully utilized for improvement of

flowability and compactibility of crystalline drugs. This technique is also improving the

wettability and dissolution rate of different drug substances.

Blend of all formulations of recrystallized agglomerates except raw macrolide antibiotics

were individually compressed, with out any problem, by direct compression method. A

typical tablet formulation consists of the active Pharmaceutical ingredient(s), fillers,

disintegrants, lubricant and other inactive ingredients. When formulating direct

compression tablets, the choice of binder or diluents is extremely critical since a slight

variation in the binder ratio can lead to capping, lamination, chipping and friable tablets

and all of these are common defects experienced with direct compressible formulations.

Here, microcrystalline cellulose (Avicel PH 102) was used as filler or diluent which

showed excellent compressibility with the recrystallized agglomerates of macrolide

antibiotics. It is self-lubricating (23) and adds compactibility and strength into the tablets

considerably (24). Since the macrolide antibiotic does not possess excellent fluidity and

flow so magnesium stearate was selected as lubricant, because of it, a uniform flow from

hopper to die was possible. It prevents the adhesion of tablet material to the machine parts

such as punches and dies, reduce inter particle friction and facilitates the ejection of tablets

from the die cavity (25).It is hydrophobic and may retard the dissolution of a drug from a

solid dosage form; the lowest possible concentration is therefore used in such formulations

(26-28).


agglomerates.


Table: 11.6, 11.11, 11.16 and 11.21 represents the formulation of tablets by using

recrystallized agglomerates of ATM, CTM, RTM and ETM respectively.

11.8.1. Weight variation and content uniformity:

In order to achieve uniformity in tablet weight, the feed crystals must flow and pack

smoothly into the die cavity of the tablet machine. Therefore, it is essential to improve the

flow and packing properties of the lubricated powder blend. Table 11.7, 11.12, 11.17 and

11.22 represented the flowability parameters in terms of the angle of repose and Carr's

index for lubricated blend of macrolide antibiotics and recrystallized agglomerates. The

data reveals that the lubricated blend with recrystallized agglomerates was much improved

compared to those of lubricated blend containing original raw powders of macrolide

antibiotics. This is due to the large and spherical shape of treated samples obtained in this

study. Fine particles having high surface to mass ratios are more cohesive than coarser

particles, hence more influenced by gravitational force. In addition, powders with similar

particle sizes but dissimilar shapes can have markedly different flow properties owing to

differences in interparticle contact areas. It is generally believed that the flowability of

powders decreases as the shapes of particles become more irregular. These are the main

reasons for an improvement in the flowability of the recrystallized agglomerated powders.

During the compressing of the lubricated blend of tablets with raw crystals of macrolide

antibiotics great friction was indicated by a powerful machine sound. The die cavity was

filled unevenly due to the unfavorable habit of the crystals (irregular stone shaped crystals

shown in SEM study) and their electrostatic charges. In consequence of this a high degree

of pressure force variation could be observed, which also influenced the other parameters,

thus, e.g., deviation from the theoretical mass was high and weight variation exceeded

5%.The lubricated blend of tablets with recrystallized agglomerates of macrolide

antibiotics has a greater particle size and partially spherical, exhibited better properties of

compressibility. Table: 11.8, 11.13, 11.18 and 11.23 represent the weight variation study

of azithromycin, clarithromycin, roxithromycin and erythromycin tablet. The machine

sound caused by friction became less intense and the weight variation value of the tablet

was below 5%, which is related to the great cohesivity value of the recrystallized

agglomerates. The latter can be attributed not only to the shape and size parameters of the

crystals but also to their surface properties. The results obtained with tablets compressed

from the lubricated blend of recrystallized agglomerates were in harmony with the values

of flow property, compactibility and cohesivity of the sample. The crystal agglomerates

can be compressed to tablets almost in a frictionless manner. This was confirmed by the

slight variation of the average weight and weight variation value.

Table: 11.09, 11.14, 11.21 and 11.24 represent the data of content uniformity study of

azithromycin, clarithromycin, roxithromycin and erythromycin tablets. From the obtained

data it reveals that the obtained standard deviation from tablets of macrolide antibiotics

were on significantly higher side compared to tablets prepared from recrystallized

agglomerates. The erratic content uniformity of the tablets prepared from macrolide

antibiotics may be due to irregular particle size and poor flow property.

Table: 11.10, 11.15, 11.20 and 11.25 represent the tablet evaluation data of azithromycin,

clarithromycin, roxithromycin and erythromycin tablets.

11.8.2. Disintegration time (DT):

Tablets made from recrystallized agglomerates of macrolide antibiotics in absence of any

disintegrants did not disintegrate even after 5 minutes. Incorporation of sodium starch


agglomerates.


glycolate resulted in a reduction in the disintegration time. The disintegration time

decreased as a function of disintegrant concentration.

Tablets containing agglomerates without sodium starch glycolate were found to have

longer disintegration times than tablets containing recrystallized agglomerates having

intragranular sodium starch glycolate. The sodium starch glycolate swells very quickly

and results in rapid tablet break-up. The mechanism by which this action takes place

involves rapid absorption of water leading to an enormous increase in volume of tablets

result in rapid and uniform disintegration.

11.8.3. Tablet elastic recovery:

The elastic recoveries of the tablets prepared from recrystallized agglomerates were

smaller than that of the tablets prepared from the original drug crystals. Those findings

suggested that the agglomerated crystals were easily fractured, and the new surface of

crystals produced might contribute to promote plastic deformation under compression.

11.8.4. Tensile strength:

The tensile strength of tablets prepared with agglomerated crystals and untreated raw drug

crystals were calculated. The tablet compressed with the agglomerated crystals exhibited

higher tensile strength than that of compressed tablet with raw crystals of macrolide

antibiotics. This was due to greater plastic deformation of the agglomerated crystals

resulting in greater permanent interparticle contact and strong bond force than the tablets

of raw crystals. This could be also due to superior compactibility of recrystallized

agglomerates in comparison with raw crystals. The results showed that the tablets

prepared using the untreated (original) macrolide antibiotics particles were prone to

capping at higher compression pressure. Where as, in contrast any of the agglomerated

crystals were successfully tableted without capping at any of the compression pressures

applied.

Remarkable fragmentation, increased plastic deformation and lowered elastic recovery of

the agglomerated crystals during tabletting process were responsible for improving the

compactibility. Even at higher compression speed with a single punch tabletting machine,

the agglomerated crystals were tableted directly, although the mechanical strength of

resultant tablet tended to decrease, which was within tolerable difference compared with

that of the tablet with granules. The addition of MCC to the formulation enhance the

plastic deformation potential of formulation resulting in a linear compression

force/crushing strength profile without capping tendency leading to tablet with higher

crushing strength value.

The tablets prepared from the untreated raw macrolide antibiotics showed 100% capping

tendency. The data indicate an appreciable improvement in tabletability of the raw

crystalline materials of macrolide antibiotics following the recrystallization and

agglomeration with different polymers and excipients, owing to fragmentation and better

interlocking of the modified drug particles.

11.8.5. Hardness study:

The tablets prepared with the agglomerated crystals were mechanically stronger (higher

hardness) due to the stronger bonding built between the fresh crystals of agglomerates

fractured under the pressure applied.

11.8.6. Friability study:

The friability of the tablets with macrolide antibiotics raw crystals shows on higher side

above one comparative to all tablets prepared from recrystallized agglomerates of


agglomerates.


macrolide antibiotic. The lower friability value of tablets prepared from recrystallized

agglomerates may be due to higher tensile strength and hardness.

11.8.7. Wetting Time (minutes)/Water Absorption Ratio (R):

The wetting times of tablets were measured and values are tabulated in table. Wetting time

was on higher side and Water Absorption Ratio (R) was on lower side for tablet

containing plain macrolide antibiotics crystals comparative to tablet containing

recrystallized agglomerates of macrolide antibiotics. The tablet containing both intra and

extra granular superdisintegrants show significant changes in both parameters comparative

to other tablets. The good disintegrating property of product was closely related to the

excellent wetting nature of ingredients.

11.8.8. Dissolution study: Tables 11.10, 11.15, 11.20, 11.25 and figures 11.4, 11.6, 11.8, 11.10 represent the in vitro

release data of azithromycin, clarithromycin, roxithromycin and erythromycin tablets

respectively.

The in vitro release of macrolide antibiotics from the tablets containing raw crystals of

macrolide antibiotics is on lower side comparative to the tablets containing recrystallized

agglomerates of macrolide and marketed tablet. For azithromycin tablet, the tablet

containing raw crystals of azithromycin shows 82% release within 60 minutes

comparative to tablet containing its recrystallized agglomerates around 94-97% and

marketed tablet 94%.For clarithromycin tablet, the tablet containing raw crystals of

clarithromycin shows 70% release within 60 minutes comparative to tablet containing its

recrystallized agglomerates around 93-96% and marketed tablet 87%.For roxithromycin

tablet, the tablet containing raw crystals of roxithromycin shows 74% release within 60

minutes comparative to tablet containing its recrystallized agglomerates around 92-96%

and marketed tablet 90%.For erythromycin tablet, the tablet containing raw crystals of

erythromycin shows 74% release within 60 minutes comparative to tablet containing

recrystallized agglomerates around 90-96% and marketed tablet 92%.

As far as the dissolution profile is concerned the similarity factor was calculated by

comparing the dissolution profile data of tablets containing the recrystallized agglomerates

with tablets containing the raw crystals of macrolide antibiotics and marketed tablets. The

similarity factor of tablets dissolution profile containing recrystallized agglomerates of

macrolide antibiotics were below 50 compared with the tablet containing raw crystals of

macrolide antibiotic indicating that tablets with recrystallized agglomerates shows

dissimilar dissolution profile due to change in crystal habit and crystalline form of

recrystallized agglomerates in tablet dosage form. The similarity factor of tablets

dissolution profile containing recrystallized agglomerates of macrolide antibiotics were

above 50 compared with the marketed tablet indicating similar dissolution profile with

marketed tablet.

The cost of the recently used macrolide antibiotics like azithromycin and clarithromycin

was around 11250 and 12500 rupees per kilogram. According to the cost of these

macrolide antibiotics, single 500mg tablet of azithromycin and clarithromycin required

API having cost 5.625 and 6.250 rupees respectively. But the marketed tablets of

azithromycin (Zathrin) and clarithromycin (Claribid) taken for the comparative study

study were around cost 20 and 90 rupees per tablet for azithromycin and clarithromycin

respectively. This difference between the costs is due to the higher manufacturing cost of

marketed tablets. By using the spherical crystallization technique bypassing the


agglomerates.


granulation process and reduction in the manufacturing cost is possible by reducing the

number of steps involved in the manufacturing process of tablets. The prepared

recrystallized agglomerates are spherical, free flowing and have good compressibility

suitable for direct compression with small quantity of directly compressible excipients into

tablet dosage form. Finally it may be concluded that the prepared recrystallized

agglomerated crystals of MA can be easily formulated into tablet dosage form with

improvement in DT, hardness, friability, tensile strength, wetting time and dissolution rate

as compared to tablets prepared from raw crystals of MA.

11.9. References:

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electron microscopy of powders mixed with magnesium stearate. Powder Technol.

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mechanism and tensile strength of tablets. J. Pharm. Pharmacol. 34; 347–351.

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243, Tablets.

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solid dosage forms. Int. J. Pharm. 14; 1–28.

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of Commonly Used Direct Compression Binders. AAPS Pharm. Sci. Tech., 4(4); 1-

11.

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Formulations of Atenolol. Pak. J. Pharm Sci., 18(1); 49.

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properties of the polymorphs of Paracetamol. J. Am. Chem. Soc., 123; 5086-5094.

11. Ibrahim and Olurinola (1991) Comperative microbial contamination levels in wet

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compression and its evaluation. Chem. Pharm. Bull. (Tokyo). 50(12); 1542-1549.

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Determination of Four Macrolide Antibiotics in Pharmaceutical Formulations and

Biological Fluids via Binary Complex Formation with Eosin and Spectrophotometry.

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preparation & evaluation of tablets from ma &...

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