Assist.lecturer Qasim Allawi Bader Suppositories Assist.lecturer Qasim Allawi Bader

Displacement value (DV) The number of parts by weight of the drug that displace one part by weight of the base. e.g. Calculate the DV for zinc oxide in the following batch Zinc oxide 40% Theobroma oil q.s. Mitt 4 supp. Mould 1 g If you know that weight of 1 supp. Containing the drug is 1.5 g

Answer You should calculate for 6 supp. Wt. of six unmedicated supp.= 6g Wt of 6 medicated supp.= 9 g amount of Theobroma oil in 6 medicated supp. = 60/100 * 9 =5.4 g Amount of zinc oxide in 6 medicated supp.= 40/100*9 = 3.6 g Theobroma oil displaced by (3.6 g) of drug = 6 – 5.4= 0.6 g T.F. DV for zinc oxide = 3.6/0.6= 6

e.g. If a prescription requires 400 mg of bismuth subgallate per suppository weighing 2 grams, what would be the displacement value if it is known That 6 suppositories with required bismuth subgallate weigh 13.6 g? Answer : Theoretical weight of six cocoa butter suppositories without bismuth subgallate = 12 g Given weight of six cocoa butter suppositories with bismuth subgallate = 13.6 g Amount of bismuth subgallate in the suppositories = 0.4 × 6 = 2.4 g Amount of cocoa butter in the bismuth subgallate suppositories = 13.6 − 2.4 = 11.2 g Cocoa butter displaced by 2.4 g of bismuth subgallate = 12 − 11.2 = 0.8 The displacement value of bismuth subgallate is 2.4/0.8 = X/1, or X = 3

Example 2: If 12 cocoa butter suppositories containing 40% zinc oxide weigh 17.6 grams, what is the displacement value of zinc oxide? Assume that the suppositories are made in a 1-g mold.

Answer Given weight of 12 suppositories with zinc oxide = 17.6 grams Weight of zinc oxide in the suppositories = (40/100) × 17.6 = 7.04 g Weight of cocoa butter in the suppositories = (60/100) × 17.6 = 10.56 g Theoretical weight of 12 suppositories without zinc oxide = 12 g Cocoa butter displaced by 7.04 g of zinc oxide = 12 − 10.56 = 1.44 Displacement value of zinc oxide = (7.04/1.44) = (X/1); X = 4.89

Practice Problems (1) What would be the displacement value of hydrocortisone acetate if it is known that ten suppositories containing 250 mg each of the drug weigh 20.83 g? (2) What would be the displacement value of belladonna extract if it is known that six suppositories containing 60 mg each of the drug weigh 12.08 g? (3) If a prescription requires 360 mg of bismuth subgallate per suppository of two grams, what would be the displacement value if it is known that six suppositories with required bismuth subgallate weigh 13.44 g?

(4) From the information provided below, find the displacement value of phenobarbital sodium: Twelve phenobarbital sodium suppositories containing 60 mg of drug each weigh 24 g. The mold of suppository used was 2 g. (5) From the information provided below, find the displacement value of quinidine hydrochloride: Ten quinidine hydrochloride suppositories containing 600 mg of drug

DETERMINATION OF THE DOSAGE REPLACEMENT FACTOR METHOD

DETERMINATION OF DENSITY FACTOR METHOD 1. Determine the average blank weight, A, per mold using the suppository base of interest. 2. Weigh the quantity of suppository base necessary for 10 suppositories. 3. Weigh 1.0 g of medication. The weight of medication per suppository, B, is equal to 1 g/10 supp = 0.1 g/supp. 4. Melt the suppository base and incorporate the medication, mix, pour into molds, cool, trim, and remove from the molds.

5. Weigh the 10 suppositories and determine the average weight (C). 6. Determine the density factor as follows 7. Take the weight of the medication required for each suppository and divide by the density factor of the medication to find the replacement value of the suppository base. 8. Subtract this quantity from the blank suppository weight. 9. Multiply by the number of suppositories required to obtain the quantity of base required for the prescription. 10. Multiply the weight of drug per suppository by the number of suppositories required to obtain the quantity of active drug required for the prescription

EXAMPLE Prepare 12 acetaminophen 300 mg suppositories using cocoa butter. The average weight of the cocoa butter blank is 2 g and the average weight of the medicated suppository is 1.8 g. From step 7: (0.3 g)/0.6 = 0.5 (the replacement value of the base) From step 8: 2.0 − 0.5 g = 1.5 g From step 9: 12 × 1.5 g = 18 g cocoa butter required From step 10: 12 × 0.3 g = 3.6 g acetaminophen

DETERMINATION OF OCCUPIED VOLUME METHOD 1. Determine the average weight per mold (blank) using the designated base. 2. Weigh out enough base for 10 suppositories. 3. Divide the density of the active drug by the density of the base to obtain a ratio. 4. Divide the total weight of active drug required for the total number of suppositories by the ratio obtained in step 3. This will give the amount of base displaced by the active drug.

5. Subtract the amount obtained in step 4 from the total weight of the prescription (number of suppositories multiplied by the weight of the blanks) to obtain the weight of base required. 6. Multiply the weight of active drug per suppository times the number of suppositories to be prepared to obtain the quantity of active drug required.

EXAMPLE Prepare 10 suppositories, each containing 200 mg of a drug with a density of 3.0. The base has a density of 0.9, and a prepared blank weighs 2.0 g. Using the determination of occupied volume method, prepare the requested suppositories. From step 1: The average weight per mold is 2.0 g. From step 2: The quantity required for 10 suppositories is 2 × 10 g = 20 g. From step 3: The density ratio is 3.0/0.9 = 3.3. From step 4: The amount of suppository base displaced by the active drug is 2.0 g/3.3 = 0.6 g. From step 5: The weight of the base required is 20 − 0.6 g = 19.4 g. From step 6: The quantity of active drug required is 0.2 × 10 g = 2.0 g. The required weight of the base is 19.4 g, and the weight of the active drug is 2 g.

SPECIFIC PROBLEMS IN FORMULATING SUPPOSITORIES : 1- Water in suppositories: Use of water as a solvent for drug should be avoided for the following Reasons: a- Water accelerates oxidation of fats. b- If water evaporates, the dissolved substance crystallizes out. c- Unless H2O is present at level than that requires for dissolving the drug, the water has little value in facilitating drug absorption. Absorption from water containing suppository enhance only if an oil in water emulsion exist with more than 50% of the water in the external phase . d- Reaction between ingredients (in suppository) are more likely to occur in the presence of water. e- The incorporation of water or other substances that might be contaminate with bacteria or fungi necessitates the addition of bacteriostatic agents (as parabens)

2- Hygroscopicity: a- Glycerinated gelatin suppositories lost moisture by evaporation in dry climates and absorbed moisture under conditions of high humidity b- PEG bases are also hygroscopic.

3- Incompatibilities: a- PEG bases are incompatible with silver salt, tannic acid, aminopyrine , quinine , icthammol, asprine , benzoc.aine & sulphonamides . b- Many chemicals have a tendency to crystallize out of PEG, e.g.: sodium sarbital, salicylic acid & camphor. c- Higher concentration of salicylic acid softens PEG to an ointment-like consistency, d- Aspirin complexes with PEG. e- Penicillin G , although stable in cocoa butter and other fatty bases , was found to decompose in PEG bases . f- Fatty bases with significant hydroxyl values may react with acidic ingredients.

4- Viscosity: The viscosity of the melted suppository base is important in the manufacture of the suppository and to its behavior in the rectum after melting. Melted cocoa butter have low viscosity than glycerinated gelatin and PEG type base in low viscosity bases, extra Care must be exercised to avoid sedimentation of suspended particles. To overcome the problems caused by use of low viscosity bases: a- Use base with a more narrow melting rang that is closer to body temperature. b- The inclusion of approximately 2% aluminum monostearate not only increase the viscosity of the fat base but to maintain homogenous suspension of insoluble material. c- Cetyl , stearyl or myristyl alcohols or stearic acid are added to improve the consistency of suppositories .

5- Brittleness : Suppositories made from cocoa butter are elastic and don't fracture readily. Synthetic fat base with high degree of hydrogenation and high stearate content and a higher solids content at room temperature are usually more brittle. To overcome, 1) the temperature difference between the melted base & the mold should be minimal. 2) Addition of small amount of Tween 80, castor oil, glycerin imparts plasticity to a fat

6- Volume contraction: Occurs in many melted suppository base after cooling the mold, result in: a- Good mold release (contraction facilitate the removal of the suppository from the mold , eliminating the need for mold release agents). b- Contraction hole formation at the open end of the mold . The contraction can be eliminated by pouring a mass slightly above its congealing temperature into a mold warmed at about the same temperature or the mold is overfilled so that the excess mass containing the contraction hole can be scraped off.

Lubricant or mold releasing agent: Cocoa butter adhere to suppository molds because of its low volume contraction. A various mold lubricants or release agents must be used to overcome this difficulty (mineral oil , aqueous solution of sodium lauryl sulfate , alcohol , silicones , soap). The release of suppository from damaged mold was improved by coating the cavities with polytetrofluoroethylene (Teflone).

7- Rancidity and Antioxidant: Rancidity results from the autoxidation and subsequent decomposition of unsaturated fats into low & medium molecular weight saturated & unsaturated aldehydes , ketones and acids , which have strong unpleasant odor. Example of effective antioxidant are phenols such as " hydroquinone or B-naphtholquinone.

WEIGHT AND VOLUME CONTROLE: The amount of active ingredient in each suppository depends on: 1 . Its concentration in the mass. 2. The volume of the mold cavity. 3. The specific gravity of the base. 4. The volume variation between molds (within 2% of the desired value). 5. Weight variations between suppositories due to inconsistencies in the manufacturing process. e.g. incomplete closing of molds, uneven scrapings (variations in weight should be within ± 5%)

Quality Control of Suppository Surface appearance and shape: to evaluate: absence of fissuring – absence of migration of active ingredient, absence of pitting, absence of fat blooming (dullness of surface)

2) MELTING RANGE TEST: Macromelting range: measures the time it takes for the entire suppository to melt when immersed in a constant temperature (370C) water bath. Micromelting range: is the melting range measured in capillary tubes for the fat base only. .

3) LIQUIFACTION OR SOFTENING TIME TESTS OF RECTAL SUPPOSITORIES: The "softening test" measures the liquefaction time of rectal suppositories are an apparatus that simulate in-vitro conditions (at 37oC).

4) BREAKING TEST: It is designed as a method for measuring the fragility or brittleness of suppositories.

5) Mechanical strength: It is a force necessary to break a supp 5) Mechanical strength: It is a force necessary to break a supp. And indicate whether supp is brittle or elastic. ( not less than 1.8-2 Kg) by Erweka method 6) Melting & solidification Solidification can be determine by using evacuated flask into which the melt is placed, the temp of cooling is noted to determine the solidification point.

PACKAGING OF SUPPOSITORY Suppository must be placed in a container in such a manner that they do not touch each other. • Staining, breakage or deformation by melting caused by adhesion can result from poorly wrapped packaged suppository. Suppository is foiled in tin or Al paper and plastic. • Over wrapping is done by hand or machine. Many suppositories are not individually, wrapped. In such cases, they are placed into cardboard boxes or plastic containers that have been molded to provide compartment for 6 or 12 suppositories.

IN- PACKAGE MOLDING: A significant advance in suppository manufacturing was the development of automated method for molding suppository, directly in their wrapping materials. This is currently accomplished with either plastic or Al-foil. *ADVANTAGE OF INPACKAGE MOLDING: 1. high production rate. 2. no generation of scraping. 3. no bulk handling. 4. maintenance of strict temperature control

STORAGE Suppository should be protected from heat, preferably stored in the refrigerator. Glycerinated gelatin suppositories should be protected from heat, moisture, and dry air by packaging in well-sealed containers and storing in a cool place.