1. Quality control of suppositories
Lecture 6

2. Suppositories Definition: Suppositories are solid dosage forms intended for insertion into body orifices (rectum, vagina, urethra) where they melt, soften, or dissolve and exert a local or systemic effect. Local action: Rectal suppositories intended for localized action are most frequently used to relieve constipation or pain, irritation, itching, and inflammation associated with hemorrhoids. Systemic action: (e.g. Antiasthmatic, antirheumatic & analgesic drugs).

3.  Finished suppositories are routinely inspected for appearance and after being sliced lengthwise, for uniformity of the mix. They are assayed for active ingredients to ensure that they individually conform to labeled content.  Melting range tests are performed to check the physical and absorption characteristics of each manufactured batch.  Fragility tests are carried out to ascertain that the suppositories can be packaged and shipped with minimal breakage.

4. Quality control tests of suppositories
1. Appearance:
This includes odour, colour, surface condition and shape.
a. Visual examination
● Colour and surface characteristics of the suppository are relatively easy to assess. It is important to check for the absence of fissuring, pitting, fat blooming, exudation, sedimentation and the migration of the active ingredients.
● Suppositories can be observed as an intact unit and also by splitting them longtudinally.

5. b. Shape It is advisable to check the shape of the suppository to see if it is consistent, irrespective of whether the suppository is ogive or bullet or torpedo shaped.
Bullet
Torpedo
c. Surface condition
The following can be checked, brilliance, dullness, mottling, cracks, dark regions, axial cavities, air bubbles, holes, etc.
d. Color
The intensity, nature and homogeneity of the color should be verified.

6. e. Odor ● A change in the odor may also be indicative of a degradation process. This can be occurred as a result of problem in formulation rancidity, that the unsaturated fatty acids in the suppository bases undergo auto-oxidation and decompose to aldehydes, ketones and acids. These products have strong, unpleasant odours. ● The lower the content of unsaturated fatty acids in a base, the higher is its resistance to rancidity.

7. 2. Weight: Suppositories can be weighed on an automatic balance, obtaining the weight of 20 suppositories. ● If the weight is found to be too small, it is advisable to check whether the mold is being well filled and whether there are axial cavities or air bubbles caused by badly adjusted mechanical stirring or the presence of an undesirable surfactant. ● It is important to check that the batch of suppositories is homogenous. ● If the weight is found to be too high, check that scraping has been carried out correctly, and also that the mixture is homogenous. ● Lastly, the weight may decrease during aging when the suppositories contain volatile substances, especially if the packaging is not airtight.

8.  Among the formulation’ problems is the volume contraction
 Among the formulation’ problems is the volume contraction. On solidification of the volume of the suppository decreases. The mass of the suppository pulls away from the sides of the mould. This contraction helps the suppository to easily slip away from the mould, preventing the need for lubricating agent.  Sometimes when the suppository mass is contracting a hole forms at the open end. This gives an inelegant appearance to the suppository.  Weight variation among suppositories is also likely to occur. This contraction can be minimized by: 1. pouring the suppository mass slightly above its congealing temperature into a mould warmed to about the same temperature. 2. Overfill the molds and scrap off the excess mass which contains the contraction hole.

9. a. Weight variation: - Weigh 20 suppositories individually. w1, w2, w3….w20 - Weigh all the suppositories together = W. - Calculate the average weight = W/20. Limit: Not more than 2 suppositories differ from the average weight by more than 5%, and no suppository differs from the average weight by more than 10%.

10. b. Content uniformity testing: ● In order to ensure content uniformity, individual suppository must be analyzed to provide information on dose-to-dose uniformity. ● Preparations with an active ingredient content of less than 2 mg or less than 2 % of the total mass, comply with the test. ● Testing is based on the assay of the individual content of drug substance(s) in a number of individual dosage units to determine whether the individual content is within the limits set. ● Assay 10 units individually as directed in the assay in the individual monograph, unless otherwise specified in the procedure for content uniformity.

11. ● The requirements for dosage uniformity are met if the amount of the drug substance in each of the 10 dosage units as determined from the content uniformity method lies within the range of 85% to 115% of the label claim. The preparation fails to comply with the test if more than one individual content is outside these limits or if one individual content is outside the limits of 75% to 125% of the average content. ● If one individual content is outside the limits of 85% to 115% but within the limits of 75% to 125%, determine the individual contents of another 20 dosage units taken at random. The preparation complies with the test if not more than one of the individual contents of 30 units is outside 85% to 115% of the average content and none is outside the limits of 75% to 125% of the average content. ● Content uniformity is important not only between suppositories, but also within suppositories in the event that a suppository is halved for administration. To determine the uniform distribution of the drug throughout the suppository.

12. 3- Melting range test: - Determines the time taken by an entire suppository to melt when it is immersed in a constant temperature bath at 37°C. -The experiment done by using the USP Tablet Disintegration Apparatus. Procedure: 1-The suppository is completely immersed in the constant temperature water bath, and the time for the entire suppository to melt or disperse in the surrounding water is measured. - The suppository is considered disintegrated when: A- It is completely dissolved or B- Dispersed into its component part. C- Become soft “change in shape” with formation of core which is not resistant to pressure with glass rod.

13. ● The test requires three suppositories and the procedure is applied to each of the suppositories. ● Record the time required for the disintegration of the suppositories. ● Unless otherwise stated in the individual monograph, for each of the three suppositories, examine the state of the sample after 30 minutes for fat-based suppositories, and after 60 minutes for water-soluble suppositories.

14. 4- Liquefaction Time or Softening Time Test:
 Liquefaction testing provides information on the behavior of a suppository when subjected to a maximum temp. of 37°C.
 This test measures the time required for a suppository to liquefy under pressures similar to those found in the rectum (approximately 30 g) in the presence of water at 37°C.
 In general, liquefaction should take no longer about 30 minutes.
 In this test a U tube is partially immersed in a constant temperature bath and is maintained at a temperature between 35 to 37°C.
 There is a constriction in the tube in which the suppository is kept and above the suppository, a glass rod is kept.
 The time taken for the glass rod to go through the suppository and reach the constriction is known as the liquefaction time or softening time.

15.  Another apparatus is there for finding softening time which mimics in vivo conditions.  It uses a cellophane tube is tied to both ends of a condenser with each end of the tube open, and the temperature is maintained by water circulation.  Time taken for the suppository to melt is noted. This apparatus can also be used to determine the melting point of suppositories made with both water-soluble and water insoluble bases. This can be accomplished by increasing the temperature of the water at a set rate, for example one degree every 10 minutes until the suppository melts.

16. 5- Breaking Test (Hardness):
 The breaking test is designed as a method for measuring the fragility or brittleness of suppository.
1. The suppository is placed in the instrument.
● Double wall chamber in which the test suppository is placed.
● Water at 37ºC is pumped through the double wall.
● The suppository, contained in the dry inner chamber, supports a disc to which rod is attached.
● The other end of the rod consist of another disc to which weights are applied.
2. Add 600 g, leave it for one min. (use a stop watch).
3. If not broken, add 200 g every one min. until the suppository is broken.
4. The weight at which the suppository collapses is the breaking point.

17. Calculations:  The hardness of the suppository is calculated by adding the weights together  But if the suppository is broken before the end of the last min. the last weight is canceled.  When the breaking point reached in the first 20 sec, the added weight was not calculated  When the breaking point reached in the second 20 sec, half the added weight was calculated  When the breaking point reached in the third 20 sec, all the added weight was calculated

18.  Suppositories can be classified as brittle or elastic by evaluating the mechanical force required to break them. Tests are used that measure the mass (in kilograms) that a suppository can bear without breaking. A good result is at least 1.8–2 kg pressure.  The purpose of the test is to verify that the suppository can be transported under normal conditions, and administered to the patient.

19. 6- Dissolution test:
 By using different types of apparatus such as wire mesh basket, or dialysis tubing is used to test for in vitro release from suppositories.
 Dissolution testing methods include the paddle method, basket method, membrane diffusion method/dialysis method, and the continuous flow/bead method.

20. 7- Stability testing: -Cocoa butter suppositories on storage, “bloom”; i.e., they form a white powdery deposit on the surface. This can be avoided by storing the suppositories at uniform cool temperatures and by wrapping them in foils. - Fat based suppositories harden on storage, i.e., there is an upward shift in melting range due to slow crystallization to the more stable polymorphic forms of the base. - The suppository overwrap foil also can cause problems in time. For example, if the suppository contains an acid, the foil wrapping may be attacked and develop pinholes. - The softening time test and differential scanning calorimetry can be used as stability indicating test methods. - If we store the suppositories at an elevated temperature, just below its melting range, immediately after manufacture, the aging process is speeded up.

21. Packaging and storage: - Suppositories are usually packed in tin or aluminium, paper or plastic. - Poorly packed suppositories may give rise to staining, breakage or deformation by melting. - Both cocoa butter and glycerinated gelatin suppositories stored preferably in a refrigerator. - Polyethylene glycol suppositories stored at usual room temperature without the requirement of refrigeration.

22. Thank you