QUALITY CONTROL TESTS FOR PHARMACEUTICAL DOSAGE FORMS

QUALITY CONTROL TESTS FOR TABLETS, SUSPENSIONS AND OINTMENTS: 

QUALITY CONTROL TESTS FOR TABLETS, SUSPENSIONS AND OINTMENTS Presented by V.SUMAN KUNAGU 109A1S0415 DEPARTMENT OF PHARMACEUTICAL ANALYSIS

QUALITY CONTROL (QC) : 

QUALITY CONTROL (QC) It is a small part of QA and it is concerned with sampling, testing and documentation during manufacturing and also after completion of manufacturing . Quality control is the monitoring process through which manufacturer measures actual quality performance, compares it with standards and find out the causes of deviation from standard to ensure quality product not once but every time . Definition: In general terms, Quality control refers to a procedure or a set of steps taken during the manfacturing of a product to ensure that it meets requirements and that the product is reproducible .

QUALITY CONTROL TESTS FOR TABLETS: 

QUALITY CONTROL TESTS FOR TABLETS General Appearance: Size, shape, and thickness: This is important to facilitate packaging and to decide which tablet compressing machine to use. Organoleptic properties: include color and odor of the tablets. Weight uniformity and content uniformity: The tablet should include the correct dose of the drug

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Dissolution test: Drug should be released from tablet in a controlled and reproducible way. Weight variation, thickness & diameter: The appearance of tablet should be elegant & its weight, size & appearance should be consistent. Hardness & friability: The tablet should show sufficient mechanical strength to withstand fracture & erosion during manufacture & handling.

OFFICIAL STANDARDS AS PER B.P. /I.P./ U.S.P.: 

OFFICIAL STANDARDS AS PER B.P. /I.P./ U.S.P. comparision of different pharmacopoeial quality control tests : BRITISH PHARMACOPOEIA: FOR ALL TABLETS: Content of active ingredients Disintegration Uniformity of content Labeling

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Uncoated tablet: - Disintegration test - Uniformity of weight Effervescent tablet: - Disintegration test -Uniformity of weight Coated tablet: - Disintegration test - Uniformity of weight

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Gastro resistant tablet: - Disintegration test Modified release tablet: - Uniformity of weight. Dispersible tablet: -Disintegration test - Uniformity of dispersion - Uniformity of weight

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INDIAN PHARMACOPOEIA : Uncoated tablet: -Uniformity of container content -Content of active ingredient -Uniformity of weight -Uniformity of content -Disintegration test Enteric coated tablet: - Disintegration test

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Dispersible tablet: Uniformity of dispersion Disintegration Soluble tablet: Disintegration test Effervescent tablet: Disintegration/ Dissolution / Dispersion test

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UNITED STATES PHARMACOPOEIA: Physical tests applicable to tablet formulation: -Bulk density /Tapped density of powder -Powder fineness -Loss on drying -Disintegration test -Tablet friability -Dissolution test -Drug release testing -Uniformity of dosage form -Container permeation test -Labeling of inactive ingredients

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OFFICIAL AND UNOFFICIAL TESTS: Official Tests: uniformity of active ingredient, disintegration, dissolution. Non-Official Tests: Hardness, friability.

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I- NON OFFICIAL TESTS: HARDNESS (CRUSHING STRENGTH): It measures crushing strength property defined as compressional force applied diametrically to a tablet which just fracture it. Why do we measure hardness? To determine the need for pressure adjustments on the tableting machine. Hardness can affect the disintegration. So if the tablet is too hard, it may not disintegrate in the required period of time. And if the tablet is too soft, it will not withstand the handling during subsequent processing such as coating or packaging.

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In general, if the tablet hardness is too high, we first check its disintegration before rejecting the patch. And if the disintegration is within limit, we accept the patch. If H. is high + disintegration is within time è accept the batch .

PROCEDURE:: 

PROCEDURE : MONSANTO TESTER: The apparatus consists of 2 jaws facing each other, one of which move towards the other. Measurements is carried out on 10 tablets, taking care to remove all the fragments of the broken tablets before each determination & then take the average hardness. LIMITS: Normal tablet hardness ranges from 4 – 6 Kg (1 Kg = 10 Newton), however, certain tablets as lozenges and buccal tablets that are intended to dissolve slowly show deliberate higher hardness values.

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Factors Affecting the Hardness: Compression of the tablet and compressive force. Amount of binder (More binder à more hardness). Method of granulation in preparing the tablet (wet method gives more hardness than direct method, Slugging method gives the best hardness). Monsanto tester, pifzer tester, stong cobb hardness tester are manually used & Heberlien schleuniger, Eweka, Casburt hardness tester are motor driven testers .

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FRIABILITY: The tablet may well be subjected to a tumbling motion. For e.g: Coating, packaging, transport, which are not severe enough to break the tablet, but may abrade the small particle from tablet surface. To examine this, tablets are subjected to a uniform tumbling motion for specified time and weight loss is measured.

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Friability is a property that is related to the hardness of the tablet & and also add weight variation, content uniformity problems. An instrument called friabilator is used to evaluate the ability of the tablet to withstand abrasion in packaging, handling, and shipping .

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PROCEDURE: 1. Weigh 20 tab altogether = W1 2. Put these tablets in the friabilator and adjust the instrument at 100 rpm (i.e. = 25 rpm for 4 min) 3. Weigh the 20 tablets (only the intact ones) = W2 4. Friability (% loss) = It must be less than or equal to1% but if more we do not reject the tablets as this test is non-official. Perform this test using 20 tablets that were used first in the weight variation test

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II- OFFICIAL TESTS: DISINTEGRATION: It is the time required for the tablet to break into particles, the disintegration test is a measure only of the time required under a given set of conditions for a group of tablets to disintegrate into particles. Liquids used in disintegration: Water, simulated gastric fluid (PH = 1.2 HCl), or Simulated intestinal fluid (PH = 7.5, KH2PO4 (phosphate buffer) pancreatic enzyme +NaOH)

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LIMITS: For Uncoated tablets: Medium Temperature Time limit According to U.S.P. Simulated gastric fluid 37 o C Not exceed 30min According to B.P. water 37 o C Not exceed 15min

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U.S.P. METHODS For uncoated tablets: Start the disintegration test on 6 tablets. If one or two tablets from the 6 tablets fail disintegrate completely within 30min repeat the same test on another 12 tablet. (i.e. the whole test will consume 18 tablets). Not less then 16 tablets disintegrate completely within the time if more then two tablets (from the 18) fail to disintegrate, the batch must be rejected.

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FOR COATED TABLETS: To remove or dissolve the coat, immerse the tablet in distilled water for 5min. Put the tablet in the apparatus in water or HCL for 30min at 37 o C (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.

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FOR ENTERIC COATED TABLETS: Put in distilled water for five minutes to dissolve the coat. Then put in simulated gastric fluid (0.1M HCL) for one hour. 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.

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B.P. METHOD FOR ENTERIC COATED TABLETS: Put in distilled water for five minutes to dissolve the coat. Put in simulated gastric fluid for two hours (emptying time). Put in phosphate buffer (PH 6.8) for one hour. 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.

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UNIFORMITY OF ACTIVE INGREDIENTS: It measured to ensure a constant dose of drug between individual tablets. Traditionally, dose variation between tablets is tested in two separate tests. A) WEIGHT VARIATION: Weigh 20 tablet selected at random, each one individually X1, X2, X3… Xz. Determine the average weight. X= (X1+X2 +X3+…+ Xz)/20 Not more than 2 of the individual weights deviate from the average weight (x) by more than the % deviation given below & none deviates by more than twice that %. LIMITS: Weight of tablet 80 mg or less then %deviation= ±10% Weight of tablet >80- <250 mg then % deviation = ±7.5 Weight of tablet 250 mg or more then % deviation = ±5%

B) CONTENT UNIFORMITY TEST : 

B) CONTENT UNIFORMITY TEST Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must contain not less than 85% and not more than 115% of the labeled drug content and the 10th tablet may not contain less than 75% and more than 125% of the labeled content. If these conditions are not met, remaining 20 tablet assayed individually and none may fall out side of the 85 to 115% range.

DISSOLUTION TEST: 

DISSOLUTION TEST The release of drug from the tablet into solution per unit time under standardize condition is called dissolution test. Media used in dissolution testing may be purified water, simulated gastric fluid, simulated intestinal fluid or others. Organic solvents are not recommended. Seven official dissolution test apparatuses are present in the USP, however, the most commonly used are USP apparatus I (basket) and USP apparatus II (paddle).

PROCEDURE: : 

PROCEDURE: APPARATUS-1 (BASKET TYPE): A single tablet is placed in a small wire mesh basket attached to the bottom of the shaft connected to a variable speed motor. The basket is immersed in a dissolution medium (as specified in monograph) contained in a 1000 ml flask. The flask is cylindrical with a hemispherical bottom. The flask is maintained at 37±0.5 0 C by a constant temperature bath. The motor is adjusted to turn at the specified speed and sample of the fluid are withdrawn at intervals to determine the amount of drug in solutions.

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APPARATUS-2 (PADDLE TYPE): It is same as apparatus-1, except the basket is replaced by a paddle. The dosage form is allowed to sink to the bottom of the flask before stirring. For dissolution test U.S.P. specifies the dissolution test medium and volume, type of apparatus to be used, rpm of the shaft, time limit of the test and assay procedure for. The test tolerance is expressed as a % of the labeled amount of drug dissolved in the time limit .

QUALITY CONTROL TESTS OF SUSPENSIONS : 

QUALITY CONTROL TESTS OF SUSPENSIONS comparison of different pharmacopoeial quality control tests BRITISH PHARMACOPOEIA Uniformity of dosage unit (single dose) Uniformity of content Uniformity of mass (single dose emulsions or solutions) Uniformity of mass of delivered doses from multidose containers (multi dose)

INDIAN PHARMACOPOEIA : 

INDIAN PHARMACOPOEIA 1) Uniformity of content 2) Uniformity of weight/volume EUROPIAN PHARMACOPOEIA 1) Uniformity of content 2) Uniformity of mass (single dose emulsions or solutions) 3) Dose and uniformity of dose of oral drops 4) Deliverable mass or volume 5) Uniformity of mass of delivered doses from multidose containers

IPQC TESTS OF SUSPENSIONS : 

IPQC TESTS OF SUSPENSIONS APPEARANCE OF PHASES: Viscosity Of Phases Particle Size Of Dispersed Phase pH Test Pourability Final Product Assay Zeta Potential Measurement Centrifugation Test

FINAL QUALITY CONTROL OF SUSPENSIONS : 

FINAL QUALITY CONTROL OF SUSPENSIONS Appearance Color, odor and taste Physical characteristics such as particle size determination and microscopic photography for crystal growth Sedimentation rate and Zeta Potential measurement Sedimentation volume Redispersibility and Centrifugation tests Rheological measurement Stress test pH Freeze-Thaw temperature cycling Compatibility with container and cap liner Torque test

UNIFORMITY OF CONTENT: : 

UNIFORMITY OF CONTENT: Suspension that contain less than 10 mg or less than 10 per cent of active ingreient comply with the following test. Empty each container and carry out the test on the active ingredients. Determine the content of active ingredient(s) of each of 10 containers taken at random using the method given in the monograph or by any other suitable analytical method. The preparation complies with the test if the individual values thus obtained are all between 85 to 115 per cent of the average value. The preparation fails to comply with the test if more than one individual value is outside the limits 85 to 115 per cent of the average value or if any one individual value is outside the limits 75 to 125 per cent of the average value.

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If one individual value is outside the limits 85 to 115 per cent but within the limits 75 to 125 per cent of the average value, repeat the determination using another 20 containers taken at random. The preparation complies with the test if in the total sample of 30 containers not more than 3 individual values are outside the limits 85 to 115 per cent and not more than one is outside the limits 75 to 125 per cent of the average value . DOSE AND UNIFORMITY OF DOSE OF ORAL DROPS: Into a graduated cylinder, introduce by means of the dropping device or by means of measuring device the number of drops usually prescribed for one dose.

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The dropping speed does not exceed 2 drops per second. Weigh the liquid, repeat the addition, weigh again and carry on repeating the addition and weighing until a total of 10 masses are obtained. No single mass deviates by more than 10 per cent from the average mass. The total of 10 masses does not differ by more than 15 per cent from the nominal mass of 10 doses. If necessary, measure the total volume of 10 doses. The volume does not differ by more than 15 per cent from the nominal volume of 10 doses. STORAGE: Store Oral Liquids or powders and granules for the preparation of Oral Liquids in well-closed containers at temperatures not exceeding 30ºc. LABELLING: The label should contain the name of any added antimicrobial preservative

QUALITY CONTROL TESTS FOR OINTMENTS : 

QUALITY CONTROL TESTS FOR OINTMENTS (1) PHYSICAL TESTS: Test of rate of absorption Test of non-irritancy Test of rate of penetration Test of rate of drug release Test of rheological properties Test of content uniformity (2) MICROBIOLOGICAL METHODS : Test of microbial content Test of preservative efficacy

TEST OF RATE OF ABSORPTION : 

TEST OF RATE OF ABSORPTION Diadermic ointments are those from which the drug moves into deeper skin tissues and finally into the systemic circulation. Such ointments should be evaluated for the rate of absorption of drugs. The ointment should be applied over a definite area of the skin by rubbing. At regular intervals of time, serum and urine samples should be analysed for the quantity of drug absorbed. The rate of absorption i.e., the amount of drug absorbed per unit time should be more.

TEST OF NON-IRRITANCY : 

TEST OF NON-IRRITANCY The bases used in the formulation of ointments may cause irritation or allergic reactions. Non-irritancy of the preparation is evaluated by patch test. In this test 24 human volunteers are selected. Definite quantity of ointment is applied under occlusion daily on the back or volarforearm for 21 days. Daily the type of pharmacological action observed is noted. No visible reaction or erythema or intense erythema with edema and vesicular erosion should occur. A good ointment base shows no visible reaction.

TEST OF RATE OF DRUG RELEASE: 

TEST OF RATE OF DRUG RELEASE A clean test tube is taken and the internal surface is coated with the preparation as a thin layer. Saline or serum is poured into the test tube. After a certain period of time, the saline is analyzed for the quantity of the drug. The amount of drug when divided by the time period gives the rate of drug release. TEST OF RHEOLOGICAL PROPERTIES: The viscosity of the preparation should be such that the product can be easily removed from the container and easily applied to the skin. Using cone and plate viscometer the viscosity of the preparation is determined.

TEST OF CONTENT UNIFORMITY: 

TEST OF CONTENT UNIFORMITY The net weight of contents of 10 filled ointment containers is determined. The results should match each other & with the labelled quantity. This test is also called minimum fill test. TEST OF MICROBIAL CONTENT: Micro-organisms like pseudomonas aeruginosa & staphylococcus aureus may contaminate the preparation & finally infect the skin. So ointments should be tested for the absence of such micro-organisms. Solutions of different samples of the preparation are made. Each sample is inoculated into separate volumes of 0.5 ml of rabbit's plasma under aseptic conditions and incubated at 37 0 C for 1-4 hours. No formation of the clot in the incubated mass indicates the absence of the micro-organisms.

TEST OF PRESERVATIVE EFFICACY: 

TEST OF PRESERVATIVE EFFICACY Using pour plate technique the number of micro-organisms initially present in the preparation are determined. Solutions of different samples of the preparation are made and mixed with Tryptone Azolectin (TAT) broth separately. All cultures of the micro-organisms are added into each mixture, under aseptic conditions. All mixtures are incubated. The number of micro-organisms in each sample are counted on 7th, 14th, 21st and 28th days of inoculation. MICROBIAL LIMITS: On 14th day, the number of vegetative cells should not be more than 0.1% of initial concentration.

REFERENCES: 

REFERENCES Indian Pharmacopoeia 1996, volume-I, page no-531, 311. Indian Pharmacopoeia 1996, volume-II, page no-735, 736, A9.5, A11.2, A80, A81. British Pharmacopoeia-1988, volume-II, 2010, page no-704, 893, 894, 895, A141, A143, A144. British Pharmacopoeia-2008, volume-IV, 2008, page no-2380, 2384, A283, A286, A423, A424. British Pharmacopoeia-2008, volume-IV, 2008, page no-A303, A XIIC. United States Pharmacopeia, United States Pharmacopeia / National Formulary (USP24/NF19). 2000, United States Pharmacopeia, United States Pharmacopeia / National Formulary (USP25/NF20). 2002. An sels pharmaceutical dosage form, page no-371. Handbook of Pharmaceutical Excepients, 3 rd Edition, 2000, American Pharmaceutical Association & Pharmaceutical Press: Washington, DC & London, UK .

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