Drug Dosage Forms II (PHR 312) Lecture 7

Quality control (Q. C.) tests for tablets

II- Official standards (Q. C. tests) for tablets (Compendial tests):
British Pharmacopoeia (B.P.) & US Pharmacopoeia (USP) 1- Uniformity of content of active ingredient (Uniformity of weight & Content uniformity) 2- Disintegration test. 3- Dissolution test. 4- Friability test.

1- Uniformity of content of active ingredient (Uniformity of weight & Content uniformity) . Discussed before 2- Disintegration test: For the drug to be fully available for absorption, the tablet must first disintegrate and discharge the drug to the body fluid for dissolution.
(It is important also for drugs acting locally in the GIT, without absorption; to detect the onset of action and its availability in the form of small particles)

All tablets must pass a test for disintegration except Chewable tablets and some Extended release tablets Problem: A tablet may be excreted from the body without disintegration (as an intact tablet), give reasons. - Excess binder. - Low or no disintegrant. - Very high pressure applied during the compression stage.
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The disintegration instrument consists of six chambers, i.e. tubes are opened at the upper end and closed by a screen at the lower end. - Before disintegration testing, one tablet is placed in each tube and normally a plastic disc is placed over the tablet (to prevent tablet floating during the test). - The tubes are placed in a water bath and Raised and Lowered at a constant rate in the water in such a way that at the highest position of the tube, the screen (and thus the tablet held down by the plastic disc) remains below the surface of water. The end point of the test (i.e. complete disintegration) is achieved when no tablet fragments remain on the screen (fragments of coating may remain). Tablets must disintegrate in the time set in the individual monograph, usually 30 min., but varying from 2 min for nitroglycerin sublingual tablets to up to 4 hrs for buccal tablets.
If one or more tablets failed to disintegrate, additional tests described by USP must be performed.

Disintegration instruments

Six tubes opened at the upper end and closed by a screen at the lower end

Disintegration test for enteric coated tablets: Enteric coated tablets are similarly tested except that the tablets are tested first in the simulated gastric fluid (0.1N HCl) for specific time (2hr in B.P.) for a positive test, after which no signs of disintegration, cracking or softening must be seen, followed by immersion in simulated intestinal fluid (Phosphate buffer pH 6.8) for the time stated in the individual monograph, during which time the tablets disintegrate completely. Disintegration test for effervescent tablets: Place one tablet in a beaker containing 200 ml of water (15-25 C) when the evolution of gas around the tablet stops, the tablet has disintegrated. The same procedures are performed for other 5 tablets. The tablets comply with the test if each of the six tablets used disintegrated within 5 min or as justified.

Disintegration beaker

Effervescent tablet

3- Dissolution test:
For drugs of limited water solubility, dissolution may be more meaningful quality attribute than disintegration testing. Why dissolution test is performed? 1. To differentiate between formulations and to evaluate the potential effect of the formulation and other processes variables on drug bioavailability. 2. To ensure bioequivalence from batch to batch. 3. To ensure that the preparation comply with product specification, as it is a requirement for regulatory approval of marketing for the registered product. 4. To indicate the performance of the preparation under the in vivo conditions. (It is possible to correlate dissolution rate of a drug with its bioavailability) Factors affecting dissolution of a tablet: 1. Disintegration is the important first step to drug dissolution in a tablet. 2. Particle size of drug substance. 3. Solubility and hydrophobicity of the formulation; type and amount of disintegrant, binder and lubricant. 4. Manufacturing method (compactness of the granulation and compression force used in tableting) These factors could be monitored, according to the dissolution test results, in order to obtain a successful formulation. Dissolution test is performed in-process and on the final product. Dissolution test is a standard requirement for tablets and capsules. USP gives standards for tablet dissolution; there are many apparatus for drug release and drug dissolution for immediate release, extended release and enteric-coated tablets.

Dissolution test apparatus

Stirrer shaft Glass vessel (1000 ml volume)

Paddle Thermostated Water Bath

(USP apparatus II)

Stirrer shaft
Cylindrical Stainless steal Basket formed from a screen (USP apparatus I) Paddle (USP apparatus II)

Glass vessel (1000 ml volume)

Dissolution test procedure: - In each test, a volume of the dissolution medium (as stated in the individual monograph) is placed in a vessel at 37C 0.5C. - The tablet is placed into the basket (USP apparatus I) or in the vessel (USP apparatus II). - The stirrer is rotated at the speed specified. - At stated time intervals, samples of the medium are withdrawn for chemical analysis of the drug dissolved. - Tablets must meet the stated monograph requirement for the dissolution rate. For example, "not less than 85% of the labeled amount is dissolved in 30 minutes". Media used in dissolution test: - Purified water. - Simulated gastric fluid. - Simulated intestinal fluid. - Solvents mixture may be used if the drug solubility is very low.

N.B. When dissolution test is prescribed, disintegration test may not be required

4- Friability test
Friability is the tendency of the tablet to crumble. It is important for the tablet to resist attrition (WHY?). During manufacturing and handling, tablets are subjected to stresses from collision and tablet sliding towards one another and other solid surfaces, which can result in the removal of small fragments and particles from the tablet surface. The result will be progressive reduction in weight and change in appearance.

Tablet collisions and sliding during manufacturing process

Another application of the friability test is to detect incipient test capping or laminate when stressed by attrition inside the rotating cylinder present in the friability tester.

Capping

Lamination

Good tablet

To examine this, tablets are subjected to uniform tumbling motion for specified time and weight los is measured. A maximum loss of loss
not more than 1% generally is considered acceptable for most products.

Friability tester 9

Tablet processing problems

1- Capping and lamination 2- Picking and sticking 3- Tablet mottling 1- Capping is the partial or complete separation of the top or the bottom crown from the main body of the tablet. Lamination is separation of the tablet into two or more distinct layers. These problems are usually caused by: - Air entrapment during compression, the resulting tablet expand when the pressure of the tableting is released, resulting in splits or layers in the tablet - Excess amount of lubricant which may decrease the tablet strength due to their interference with the bonding between the particles during compression

Capping

Lamination

Good tablet

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2- Picking is the removal of the surface material of the tablet by the punch Sticking is the adhesion of the tablet punch. material to the die wall. These problems are caused by . excessive moisture or the inclusion of materials with l low melting point (PEG & stearic acid) in the formulation. This problem could be managed by addition of suitable antiadherent.

3- Tablet mottling is unequal color distribution, with light or dark areas. This problem occurs when a drug has . different color than the tablet excipients or when a drug has colored degradation products. This problem may be also caused by intragranular migration of the soluble dye during the drying stage which may give rise to dry granules with a highly colored outer zone and a colorless interior. During compaction granules are fractured and the colorless interior is exposed resulting in mottled tablet.

4- Weight variation (WHY?) Wide range of particle size of the granulation Poor flow of particles Improper adjustment of the die cavity
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QUESTIONS
I- Mention whether this batch of tablets pass weight uniformity test (B.P.) or not giving reasons; given that: 1- After weighing 20 tablets individually, the following results were obtained: (250, 255, 270, 270, 256, 255, 255, 255, 245, 255, 250, 255, 245, 255, 260, 245, 250, 255, 248, 250) mg 2- Average weight for tablets (X) = 253.9 mg

Tab. no

3 6

4 6

10

11

12

13 14

15

16

17

18

19

20

% error 1.84 0.12

0.51 0.12 0.12 0.12 3.8 0.12 1.85 0.12 3.8 2.08 3.8 1.85 0.12 2.63

Complete the above table and revise the Pharmacopoeial requirement according to the following table, then give your judge

Pharmaceutical form

Tablets

Average tablet weight (X) 80 mg or less > 80- < 250 mg 250 mg or more

Percentage deviation 10 7.5 5

II- Give reasons for the following statements: 1- Dissolution test is an important quality control test for tablets (2
reasons)

2- Friability test is an important quality control test for tablets 3- Tablet mottling (2 reasons) III- Put Write or Wrong:
1. Disintegration is the important first step to drug dissolution in a tablet () 2. Solubility and hydrophobicity of the formulation do not affect drug dissolution in a tablet formulation () 3. When dissolution test is prescribed, disintegration test may not be required () 4. Weight variation in tablets may be caused by improper adjustment of the die cavity ()

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IV- Complete the following

1. This apparatus is used for

.. ..

2. This apparatus is used for

..

3. The problems appear in the opposite photo are

and .. These problems could be managed by using oblems ..

V- What are the processing problems appeared in the photo

below? What are the possible reasons for these problems? How these defects could be detected through the in-process quality control test? Mention the name of the test.

Next week (23, 25/11/2008), ISA, a quiz in lectures 5-7 will be held during lab /11/2008), sessions.

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