RationaleAn Enteric coated stable tablet formulation of

Aspirin will

Reduce harm to stomach

Increase bioavailability

Reduce risk of hospitalization for heart failure, coronary thrombosis deliver

Initial Patent search Inventor: Mahesh K. Patell

Original Assignee: Bristol-Myers CompanyCurrent U.S. Classification: 424/471; 424/480; 424/482; 427/2.19International Classification: A61K 924

Patent number: 4775536Filing date: Feb 24, 1986Issue date: Oct 4, 1988

Current status: Off Patent, Not in Orange Book

Preformulation Studies Name: Aspirin IUPAC name: 2-acetyloxybenzoic acid Formula: CH3COOC6H4COOH Molecular weight: 180.157 g/mol

Bayer’s 300 mg Enteric coated Aspirin DIACETYLATED

MONOGLYCERIDES ANHYDROUS LACTOSE CARNAUBA WAX SILICON DIOXIDE STARCH, CORN CROSCARMELLOSE SODIUM D&C YELLOW NO. 10 HYPROMELLOSES HYPROMELLOSE PHTHALATE

(24% PHTHALATE, 55 CST) FERRIC OXIDE YELLOW METHACRYLIC ACID - METHYL

METHACRYLATE COPOLYMER (1:1)

MCC MINERAL OIL

•PEG 400•POLYSORBATE 80•POVIDONES•STARCH, CORN•PROPYLENE GLYCOL•DIMETHICONE•SILICON DIOXIDE•SODIUM BICARBONATE•SODIUM HYDROXIDE•SODIUM LAURYL SULFATE•STARCH, CORN•STEARIC ACID•TALC•TITANIUM DIOXIDE•TRIACETIN•TRIETHYL CITRATE•FD&C YELLOW NO. 6

Bulk Characteristics Odorless, colorless to white, crystal-line

powder

Bulk density, Tap density, Hausner’s Ratio, Angle of Repose, Compressiblity index of Aspirin Powder were measured.

Particle size distribution was studied and appropriate particle size to be used was determined

Loss on Drying of Aspirin Powder was determined

Bulk Characteristics Assay, Related substances of Aspirin were

studied

Stress testing of Aspirin was performed. The various degradation routes were determined and analytical methods of the by products (if harmful) was determined.

The stability of aspirin to Light, Moisture, Oxygen was determined

Chemical PropertiesBasic Properties Melting point: 136 °C Boiling point: 140 °C Density: 1.39 g/cm3

Vapor pressure: 3×10-5 mmHg Refractive index: 1.5623

Solubility: Slightly soluble in water; freely soluble in alcohol; soluble in chloroform and ether; sparingly soluble in absolute ether. Solubility in water: 1g/100g water at 37°C

Chemical PropertiesHydrophobicity and permeability studies Experimental LogP hydrophobicity:1.4 Predicted LogP hydrophobicity:1.43 Predicted LogS: -2.09 Experimental Caco-2 permeability: -5.06

pKa: 3.5

Chemical Properties specific heat of vaporization: 0.59059 kJ/g specific heat of combustion: 21.8 kJ/g specific heat of fusion: 0.1071 kJ/g (at STP)

Polymorphism: It has no polymorphs

Hygroscopicity: It is weakly hygroscopic

Reactivity Profile Aspirin is Incompatible with oxidizers and

strong acids. Also incompatible with strong bases. May react with water or nucleophiles (e.g.

amines and hydroxy groups). Stable in dry air (hydrolyzes in moist air,

decomposes in hot water). Due to this, It needs to be prepared by direct compression

Incompatibility studies The formulation should be close to Innovators

formula so as to obtain F2 values above 50% Drug excipients compatibility study performed

at 40°C /75% RH of 15 days.

• In case of aspirin , direct compression technique has been employed to compress the tablet, because the powder is highly moisture sensitive.

• Aspirin (80mg) DR tablet is to provide a controlled and predictable release of aspirin and which is used in the treatment of Coronary Thrombosis (heart disease) for Once in Day administration.

Formulation

Aspirin Microcrystalline Cellulose, Maize Starch, Colloidal Silicon Dioxide, Talc, Stearic Acid, Croscarmellose sodium, HPMC 15cps, PEG – 6000, Talcum, Titanium dioxide, Kollicoat, MAE-30 DP, Triacetin

Materials and methods

Preparation of Core Aspirin Tablets

The enteric coating tablet was prepared by direct compression method.

The weighed quantity of aspirin, micro crystalline cellulose, maize starch were sieved through 40# size.

The above shifted materials were mixed using planetary mixer for 10min.

The shifted materials were lubricated with colloidal silicon dioxide, talc and stearic acid for 5 min.

These blended materials were ready for compression.

S.No IngredientsAmount (mg/

per tablet)

Amount (for 1 lac tablet)

1 Aspirin 80.0 8 kg

2 Microcrystalline Cellulose 8.0 0.8 kg

3 Maize Starch 7.0 0.7 kg

4 Colloidal Silicon Dioxide 2.0 0.2 kg

5 Talc 2.0 0.2 kg

6 Stearic Acid 1.0 0.1 kg

7 Croscarmellose sodium 2.0 0.2 kg

10 Average weight of tablet 102 mg -

FORMULA

S. No. Parameters

1 Initial Weight of beads 102 gm 2 Kollicoat MAE 30 DP 50 % 3 Triacetin 2.25 % 4 Talcum 4 % 5 Titanium Dioxide 0.5 % 6 Purified Water 43.25% 7 % w/w Enteric coating

Solution21.75%

8 Theoretical weight of tablets

112.5gm 9 Final weight of tablets

(Enteric Coated)112 gm

10 % Build up 6.4 % 11 pH of coating solution 3.8

Procedure for preparation of Enteric coating solution :

First take 150ml purified water, disperse the talc and titanium dioxide with continues stirring to form sol-A.

Triacetin was dissolved in remaining quantity of water to form a (sol-B). Then weighed quantity of Kollicoat MAE 30 DP was added in sol-B with continuous stirring for 5-10min.

Finally sol-A was added in sol-B with continuous stirring (250 rpm) and filtered.

Evaluation of Precompressional Characteristics of tablets

1. Particle Size & Shape Determination.

2. Surface area.

3. Density

i. Bulk density

ii. True density

iii. Granular density

4. Granule strength & friability.

5. Flow properties.

i. Angle of repose

ii. Percentage Compressibility Index

iii. Hausner’s ratio

6. Moisture content.

7. Percentage fines(% fines).

CHARACTERIZATION OF GRANULES

1) Particle Size & Shape Determination

Size affects the average weight of tablet, Disintegration

Time, weight variation, friability, flowability & drying rate. The size & shape depends upon processing requirements &

during granulation. The method for determining size & shape is

1. Sieving

Parameter Limit

Machine speed 900 tablets/min

Wt. of 20 tabs 2.24g +.2 (2.14-2.34g)

Theoretical weight/tab 112mg

Hardness 3.75Kg/cm2 (3-5 Kg/cm2 )

Thickness (av. of 10 tabs)

3.24mm +0.15mm (3.09 – 3.39mm)

Length 7mm + 0.1 mm (6.9 – 7.1 mm)

Width 5 mm + 0.1mm (4.9 – 5.1 mm)

Disintegration time >2 hours(in stomach pH 1.3) 10-15 min(in intestine 6.8 pH)

Wt. variation + 5% of Av. Wt.

Friability (10 tabs) NMT 1.0% w/w

Compression Parameters

2. Surface area

Most method used is gas absorption & air permeability.

In gas absorption, gas is absorbed as monolayer on particles this

is in term of calculated & converted to surface area.

In air permeability method the rate of air permeates a bed of

powder ,is used to calculate surface area of powder sample.

3. Density

Density may influence compressibility, tablet porosity & dissolution.

i. Bulk Density –

Bulk density is given by equation,

ρb = M / Vb

Where, ρb- bulk density of granules,

M is mass of granules in gm,

Vb – volume of granules in measuring cylinder in ml.

More compressible bed of particulate - less flowable powder or granules.

If less dense/compressible - more flowable powder or granules.

Pycnometer

Bulk density apparatus

4. Flow properties:

It is an ability of the granule to flow from hopper to die cavity for tablet uniformity.

Flow property of material results from many forces

1.Frictional force

2.Surface tension force

3.Mechanical force caused by interlocking of irregular shape particles

4.Electrostatic forces

5.Cohesive/ vander Waals forces

Tilting angleRotating cylinder

Methods of determination of angle of repose

i. Angle of repose – It is measured by using the Equation

tan θ = h/r.

Where, θ - angle of repose, h – height of pile, r – radius of pile.

Flow properties of granules are determined by

measuring three parameters

Sr no. Angle of repose (o) Type of flow

1 < 25 Excellent

2 25-30 Good

3 30-40 passable

4 > 40 Poor

ii. Percentage compressibility Index

It is directly related to the relative flow rate cohesiveness & particle size.

% Compressibility index = 8 %

SR.NO. % Compressibility index

Type of flow

1 5-15 Excellent

2 12-16 Very good

3 18-21 Good

4 23-25 Passable

5 33-38 Poor

6 > 40 Very poor

iii. Hausner's Ratio Hausner’s eatio was related to interparticulate friction and as

such could be used to predict powder flow characteristics.

FORMULA:

Hausner’s ratio = 1.3

5. Moisture content The amount of moisture present in the granule is called moisture content. the granules contain 2% moisture. It is required for the binding of the powder or

granules during compression in die cavity.

Moisture analyzer

IR moisture balance

Sarotorious MA-100

6. Percentage Fines (% Fines)

% fines means amount of powder remain in the granule. Generally the amount is 15% of fines. % fines = 13 %

Official and unofficial tests for evaluation of tablets

Official Tests: 1. Weight variation2. Disintegration 3. Dissolution 4. Drug content Non-Official Tests: 1. Hardness2. friability

Evaluation of

Tablet

Different Hardness Tester

ErwekaPfizer

Schleuniger

Hardness : Tablet requires a certain amount of strength or hardness and resistance to friability to withstand mechanical shocks of handling in manufacture, packaging and shipping. Hardness (crushing strength): It is the load required to crush the tablet when placed on its edge.Limits: 5 kilograms minimum and 8 kilograms maximum.

6.Friability: Friability of a tablet can determine in laboratory by Roche

friabilator. This consist of a plastic chamber that revolves at 25

rpm, dropping the tablets through a Distance of six inches in the

friabilator, which is then operate for 100 revolutions. The tablets

are reweighed. Compress tablet that lose less than 0.5 to 1.0 % of

the Tablet weigh are consider acceptable. Friability (% loss) = W1 - W2/100

It must be less than or equal to1 % .

7. Thickness test

Thickness is an unofficial test .

Thickness of the tablet is inversely proportional to hardness i.e.

increase in hardness decrease the thickness & vice versa.

Thickness of tablet is measured by Vernier caliper/screw gauge.

It is determined for 10tablets.

Vernier caliper

Pilot scale-up, Mfg. Tooling and requirements

Define product economics based on projected market size and competitive selling and provide guidance for allowable manufacturing costs

Steps in scale up

Conduct laboratory studies and scale-up planning at the same time

Define key rate-controlling steps in the proposed process

Conduct preliminary larger-than-laboratory studies with equipment to be used in rate-controlling step to aid in plant design

Design and construct a pilot plant including provisions for process and environmental controls, cleaning and sanitizing systems, packaging and waste handling systems, and meeting regulatory agency requirements

Evaluate pilot plant results (product and process) including process Economics to make any corrections and a decision on whether or not to proceed with a full scale plant development

Personal Requirement Space Requirement Administration Room Physical Testing Area Storage Area Review Formula Production Rate Process Evaluation

GMP Requirements

Circular flow

Name of area Pressure maintainedIn pascals

Warehouse 10

Weighing area 20

Tableting area 15

Central corridor 30

MIXING, GRANULATION & DRYING AREA

Powder mixer

Planetary mixer

Sifter

Chilsonator

FBD

List of equipments

COMPRESSION AREA

Tablet compression machine

Tablet deduster

Tablet inspection unit or belt.

Dissolution testing apparatus

IPQC instruments

COATING AREA

Jacketed kettle (steam, gas, Electrically heated)

Coating pans

Polishing pans

Exhaust system

Air conditioning & Dehumidification equipment

Materials For Construction

Punches- OHNS (Oil Hardened Nitride steel)

Dies- HCHC (High carbon High chromium steel )

Compression machine specifications Flat faced punch Rotary 55 station machine Wilher fette,GMBH Humburg. W. GermanyPunch size :- Length:-19.7mm

Width:-7.3mmEmbossed punch

55 station rotary tablet press

Produce 900 tablet per minute

Takes 111 minutes for 100000 tablet

Batch size:-100000 tablet

Quality Checks During Manufacturing

IPQC Parameters to be measured

I. Physical Parameters: a. temp

b. timec. particle size & textured. pressure mmH2Oe. weightf. hardnessg. thickness & diameterh. disintegrationi. dissolution ( % release)j. friabilityk. moisture content %relative humidity

II. Attributive Features:

a. visible impuritiesb. colorc. eleganced. completeness of productf. Defects like…

• Excessive powder• Pieces of tab• Abrasions• Cracks, chips, swelling,

mottling, fusion of tab..etc….• Appearance of crystals on tab

or container.g. Engraving/Embossing logoh. Labeling & packaging

Parameter Limit Observation

Machine speed 900 tablets/min

Wt. of 20 tabs 2.24g +.2 (2.14-2.34g)

Theoretical weight/tab 112mg

Hardness 3.75Kg/cm2 (3-5 Kg/cm2 )

Thickness (av. of 10 tabs)

3.24mm +0.15mm (3.09 – 3.39mm)

Length 7mm + 0.1 mm (6.9 – 7.1 mm)

Width 5 mm + 0.1mm (4.9 – 5.1 mm)

Disintegration time >2 hours(in stomach pH 1.3) 10-15 min(in intestine 6.8 pH)

Wt. variation + 5% of Av. Wt.

Friability (10 tabs) NMT 1.0% w/w

Compression Parameters

SPECIFICATION

IDENTITY Complies

ASSAY 99.5 to 100.5 %

FREE SALICYLIC ACID 0.1 % max

SULPHATED ASH 0.1 % max

HEAVY METALS (as Pb) 20 ppm max

RELATED SUBSTANCES 0.25% max

Disintegration Test for Apirin Enteric Coated tablets:

1. To remove or dissolve the coat, immerse 6 tablets in distilled water for 5min.

Put the tablet in the apparatus in water or HCL for 30min at 37oC (according to the U.S.P). If not disintegrated, put in intestinal fluid.

>If one or two tablets fail to disintegrate, repeat on 12 tablets. So 16 tablets from the 18 must completely disintegrate within the time >>if two or more not disintegrated the batch is rejected.

U.S.P. Method for Enteric coated tablets: 1. Put in distilled water for five minutes to

dissolve the coat. 2. Then put in simulated gastric fluid (0.1M HCL)

for one hour. 3. Then put in simulated intestinal fluid for two

hours. If one or two tablets fail to disintegrate, repeat

this test on another 12 tablets. So 16 tablets from 18 should completely disintegrate. If more than two fail to disintegrate the patch must be rejected.

B.P. method for Enteric coated tablets: 1. Put in distilled water for five minutes to

dissolve the coat. 2. Put in simulated gastric fluid for two hours

(emptying time). 3. Put in phosphate buffer (PH 6.8) for one

hour. 4. If one or two tablets fail to disintegrate

repeat on 12 tablets. So 16 tablets should disintegrate. If more than two tables fail to disintegrate reject the batch.

8.Weight variation test (uniformity of weight)

Weigh 20 tablet selected at random, each one individually . X1, X2, X3… Xz

Determine the average weight. X= (X1+X2 +X3+…+ Xz)/20

Limit: Upper limit = average weight + (average weight * %

error) Lower limit = average weight - (average weight * % error) The individual weights are compared with the upper and

lower limits. Not more than two of the tablets differ from the average

weight by more than the % error listed, and no tablet differs by more than double that percentage.

Sr. No

Average wt. of tablet(mg) Max. % difference allowed

1 130 or Less 10%

2 130-324 7.5%

3 More than 324 5%

WEIGHT VARIATION TOLERANCES FOR UNCOATED TABLETS

USP XX-NF standards

IP standards

Sr. No

Average wt. of tablet(mg) Max. % difference allowed

1 84 or Less 10%

2 84- 250 7.5%

3 More than 250 5%

DISSOLUTION TESTI.P. 1996, B.P. 2007, U.S.P. XXX

58

1. Use apparatus 1 unless otherwise specified in directed. All parts of the apparatus that may come in contact with the preparation being examined.

2. All metal parts of apparatus that may come into contact with the preparation or the dissolution medium must be made from stainless steel, type 316 or equivalent or coated with a suitable material to ensure that such parts do not react or interfere with preparation

59

Precautionary conditions

3. No part of assembly or environment should contribute for vibration.

Dissolution Medium – For acidic pH – 0.1M HCl For basic pH – phosphate buffer 6.8

Test methodology1. As directed in the individual monograph.2. Repeat the test for 5 times for single tablet.3. If 2 or more tablets, place all together in the

apparatus, carry out 6 replicate tests

60

4.For each of the tablet tested , calculate the amount dissolved of the active ingredient in the solution as % of stated amount.

5.Where 2 or more tablets placed together, determine for each test the amount.

6. Calculate the % of the stated amount.7. If the result do not confirm to the

requirement of stage 1 given in the accompanying table and continue further if it still not comply.

61

DELAYED RELEASE TABLETSContinue testing through the 3 levels unless the

results of both acid and buffer stage confirm at an earlier level.

ACID STAGE

LEVEL NUMBER TESTED

ACCEPTANCE CRITERIA

A1 6 No individual value exceeds 10% dissolved

A2 6 The avg. value of the 12 units is NMT 10% dissolved and no individual unit is greater than 25% dissolved.

A3 12 The avg. value of 24 units is NMT 10% dissolved and no individual unit is greater than 25% dissolved.

BUFFER STAGE

Q = is specified total amount of active substance dissolved in both acid and buffer, if not specified then take 75%.

LEVEL NO. TESTED

ACCEPTANCE

B1 6 No unit is less than Q + 5%

B2 6 The avg. value of 12 units is equal to or greater than Q and no unit is less than Q – 15%.

B3 12 The avg. value of the 24 units is equal to or greater than Q . NMT 2 units are less than Q – 25%.

63

Content uniformity The content uniformity test is used to ensure that every tablet contains

the amount of drug substance intended with little variation among tablets within a batch.

Due to increased awareness of physiological availability, the content uniformity test has been included in the monographs of all coated and uncoated tablets and all capsules intended for oral administration where the range of size of the dosage form available include 50 mg or smaller sizes.

Tablet monographs with a content uniformity requirement do not have weight variation requirements .

For content uniformity test, representative samples of 30tablets are selected and 10 are assayed individually. At least 9must assay within ±15% of the declared potency and none may exceed ±25% .

USP design: content uniformity tests According to United States Pharmacopoeia (USP), the procedure for

content uniformity test is: Stage1: Take 10 units randomly and perform the assay. * It passes the test if the relative standard deviation (RSD) is less than

6% and no value is outside 85–115%.* Fails the test if one or more values are outside 75–125%. Stage2: Take 20 more units and perform the assay procedure. * Passes the test if RSD of all the 30 tablets is less than 7.8%, not

more than one value is outside 85–115%, and no value is outside75–125%. Or else the batch fails the test.

Physical stability

Formulation

Likely physical instability problems

Effects

Aspirin Tablets

Change in:a) Disintegration

timeb) Dissolution profilec) Hardness d) Appearance (soft

and ugly or become very hard)

Change in drug release

• Aspirin subject to hydrolysis due to presence of ester functional group.

Chemical Compatibility

Stability studies

• Stress Testing

• Accelerated Testing (6 months)• 40°C ± 2°C/75% RH ± 5% RH

• Long Term Studies (12 months)• 25°C ± 2°C/60% RH ± 5% RH• 30°C ± 2°C/65% RH ± 5% RH

Packaging

Labeling Condition

References1. http

://www.chemicalbook.com/ChemicalProductProperty_EN_CB5114818.htm

2. http://www.google.com/patents/US4857337 3. http://www.wolframalpha.com/ 4. http://dailymed.nlm.nih.gov 5.

http://avogadro.chem.iastate.edu/MSDS/aspirin.htm

6. http://www.chemspider.com/Chemical-Structure.2157.html

7. www.ich.org 8. www.fda.gov