Drug Dosage Forms II (PHR 312) Lecture 6 (Continued) Quality control (Q. C.

) tests for tablets Quality of tablets should fulfill certain specifications: 1. The tablet should i nclude the correct dose of the drug (Weight uniformity and content uniformity test). 2. The drug should be released from the tablet in a controlled and reproducible way (Dissolution test). 3. The tablet should show sufficient mechanical strength to withstand fracture and erosion during manufacturing and handling (Hardness a nd friability test). 4. The appearance of the tablet should be elegant and its w eight, size and appearance should be consistent (Visual observation, weight variation, thickness and diameter of the tablet). 5. The tablet should be packed in a safe manner. Quality control tests and speci fications for some of these properties are given in pharmacopoeias. The most imp ortant for these are; - Weight uniformity, - Dose uniformity, - The drug release in terms of tablet disintegration and drug dissolution, - Resistance of tablets to fracture in terms of friability and harness testing, and - The microbial qua lity of the product. These factors must be controlled during production (in-proc ess control) and verified after production. Some test methods are described in t he pharmacopeias; others are not and thus are referred to as "non-compendial" te sts. 1

A part of Good Manufacturing Practice (GMP), the production run is monitored und er control chart. At regular intervals (10-15 min.) during the course of manufac turing, the operator must sample specified number of tablets for testing (in-pro cess control) e.g. weight of tablet, tablet thickness, friability, disintegratio n time, Official Quality control tests for tablets (Compendial tests) British Pharmacopoeia (B.P.) & US Pharmacopoeia (USP) 1- Uniformity of content o f active ingredient (Uniformity of weight & Content uniformity) 2- Disintegratio n test. 3- Dissolution test. 4- Friability test. USP mentions some Q.C. tests be fore the powder is compressed e.g. powder fineness, density, Non-Compandial tests There are many tests are frequently applied to tablets for which there are non-p harmacopoeial requirements but will form a part of manufacture's owner product s pecifications. 1- Tablet thickness. 2- Tablet hardness. I- Non-Compandial tests: 1. Tablet thickness Tablet thickness is important for tablet packaging; very thick tablets affect pa ckaging either in blisters or plastic containers. The tablet thickness is determ ined by the diameter of the die, the amount of fill permitted to enter the die a nd the force or pressure applied during compression. The thickness of the tablet may be measured manually or by automatic equipment. 2

Micrometer (tablet thickness) (Tablet thickness & diameter) Tablet packaging in blisters Tablet packaging in plastic containers 2. Hardness test In general, tablets should be sufficiently hard to resist breaking during normal handling, packaging and shipping, and yet soft enough to disintegrate properly after swallowing. Hardness of the tablet is controlled by (or is affected by) th e degree of the pressure applied during the compression stage.

Hardness is an important criterion, since it can affect disintegration and disso lution. Special hardness testers are used for this purpose (manually or motor dr iven testers). The test measures crushing strength property defined as the compr essional force applied diametrically to a tablet which just fracture (break) it. (The Figure below) (N.B. In manual hardness testers, the strain rate depends on the operator). "Monsanto" Tablet hardness tester A force of about 4 Kg (may be measured in Kg) is considered the minimum requirem ent for a satisfactory tablet. Certain tablets such as lozenges and buccal table ts that are intended to dissolve slowly intentionally are made hard; others such as immediate-release tablets are made soft.

The Electronics Tablet Hardness, Thickness and Diameter Tester II- Official standards (Q. C. tests) for tablets (Compendial tests): British Pharmacopoeia (B.P.) & US Pharmacopoeia (USP) 1- Uniformity of content o f active ingredient (Uniformity of weight & Content uniformity) 2- Disintegratio n test. 3- Dissolution test. 4- Friability test. USP mentions some Q.C. tests be fore the powder is compressed e.g. powder fineness, density, 1- Uniformity of active ingredient: (WHY?) To ensure a constant dose of drug between individual tablets. Traditional ly, dose variation between tablets is tested in two separate tests; 1- Weight un iformity 2- Content uniformity If the drug forms greater part of the tablet, any variation in the tablet weight obviously indicates a variation in the active in gredient. (Weight uniformity test) 5

If the drug is potent (USP specifies 50 mg of the active ingredient or less), th e excipients form the greater part of the tablet weight and the correlation betw een the tablet weight and amount of the active ingredient can be poor, in this c ase another test (Content uniformity) must be performed. A. Weight uniformity B.P. design: - Weigh 20 tablets individually (i.e. determine the weight of each tablet alone; X1, X2, X3 X20) - Calculate the average weight of tablets ( = Total weight of ta blets ) Number of tablets Average weight of tablets (X) = (X1+X2 +X3++ X20)/20 Not more than two of the individual weights (for example, X1 and X7) deviate fro m the average weight (X) by more than the % deviation shown in the table below a nd none deviates by more than twice that %: Pharmaceutical form Average tablet weight (X) 80 mg or less > 80- < 250 mg 250 m g or more Percentage deviation 10 7.5 5 Tablets (IMPORTANT) Example for Weight uniformity test (B.P. design): - Weigh 20 tablets individually (X1, X2, X3 X20) For example; (200, 202, 190, 205, 201, 200, 198, 190, 199, 203, 210, 220, 210, 201, 202, 199, 190, 195, 200, 200 mg) - Calculate the average weight of tablets X = Total weight of tablets Number of tablets Average weight of tablets (X) = (200+202+190+ 205+201+200+198+190+199+ 203+210+2 20+210+ 201+202+ 199+ 190+195+200+200)/20 = 201.75 mg 6

% Error for a tablet= Difference between Actual tablet weight & Average tablet w eight x 100 Average tablet weight % % % % % error error error error error for fo r for for for tablet tablet tablet tablet tablet 1= 2= 3= 4= 5= 201.75 - 200/201 .75 202 - 201.75/201.75 201.75 - 190/201.75 205 - 201.75/201.75 x x x x 100= 100= 10 0= 100= 0.86% 0.12% 5.82% 1.61% Calculate % error for each tablet Tablet no 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 % 0.86 0.12 5.82 1.61 0.37 0.86 1.85 5.82 1.36 0.6 4.08 9.04 4.08 0.37 0.12 1.36 5.82 3.34 0.86 0.86 error Pharmacopoeial requirement: Not more than two of the individual tablet weights deviate from the average weig ht (X) by more than 7.5% according to the following table and none deviate by do uble this %: Pharmaceutical form Average tablet weight (X) 80 mg or less > 80- < 250 mg 250 mg or more Percentage deviation 10 7.5 5 Tablets Test result: Only one tablet (tablet number 12) deviated >7.5%, and this deviati on (%error 9.04 %) is less than 15 %, i.e. tablets passed this test successfully B. Content uniformity USP defines content uniformity test for tablets containin g 50 mg or less of drug substance in case of uncoated tablets and for all sugar coated tablets regardless to the drug content. USP design: Ten tablets are individually assayed for their content (according to the method described in the individual monograph) The requirements for content uniformity are met if the amount of the active ingredient in each tablet lies wi thin the range of 85115 % of the label claim. (If one or more tablet does not meet these criteria, additional tests as prescri bed in the USP are required) 7

If content uniformity test is required, the weight uniformity test is not requir ed I- Match: - Friability test 1- USP quality control test performed for tablets containing 20mg drug to ensure that each include the correct dose 2- Quality control test performed for tablet s to ensure that each shows sufficient mechanical strength 3- Quality control te st performed for tablets to ensure that the drug is released in a controlled and reproducible way - Dissolution test - Hardness test - Weight uniformity - Content uniformity II- Put Write or Wrong: 1- Tablet thickness and hardness test are non-compendial quality control tests 2 - Tablet thickness is important for tablet packaging 3- Hardness does not affect disintegration or dissolution of the tablet 4- If content uniformity test is re quired, the weight uniformity test is not required 5- 1 Kg is a suitable hardnes s value for a satisfactory buccal tablet 6- Disintegration test is a Pharmacopoe ial Requirement for chewable tablets 7- Content uniformity test is essential for all sugar coated tablets regardless to their drug content 8- In weight uniformi ty test, tablets are individually assayed for their content III- What is the only suitable Quality Control Test for Dexamethasone tablet (0. 5 mg/Tab), to ensure a constant dose of drug between individual tablets

IV- During the in-process quality control testing of tablet hardness, many table t samples were found to be very hard (10 Kg) What are the possible reasons? What are your suggestions? What are the expected problems with these hard tablets? Remember No Quizzes will be held next week during lab sessions (16, 18/11/2009) Next Quiz (in lab 23, 25/11/2009) Tablet coating and Quality control tests for t ablets Ux j|{x