PREPARATION OF SUPPOSITORIES : PREPARATION OF SUPPOSITORIES By Dr. Ramanjireddy Tatiparthi JIMMA UNIVERSITY PREPARATION OF SUPPOSITORIES : PREPARATION OF SUPPOSITORIES Suppositories are prepared by mainly three methods By molding Compression Hand rolling and shaping Preparation by molding : Preparation by molding The steps involved in molding are Melting of the base Incorporation of any required medicament Pouring the melt in the moulds Allowing the melt to cool and congeal to suppositories Removing the formed suppositories from the mold The molds may be made up of stainless steel, aluminum, brass, plastic The molds generally opened in longitudinal section for cleaning Compression molding: Compression molding The cold mass of the base containing the drug is compressed into suppositories by using compression into the desired shape . It avoids the possibility of sedimentation of the insoluble solids in the suppository base. Advantages: 1.It is a simple method. 2.It gives suppositories that are more elegant than hand moulded suppositories. 3. In this method sedimentation of solids in the base is prevented. 4. Suitable for heat labile medicaments. Disadvantages: 1.Air entrapment may take place. 2.This air may cause weight variation. 3.The drug and/or the base may be oxidized by this air. Hand rolling and shaping : Hand rolling and shaping It is the oldest and simplest method, by rolling the suppository into the desired shape. The mass is then rolled into a cylindrical rod of desire length and diameter It has the advantage of avoiding the necessity of heating the cocoa butt All the operations in pour moulding are done by automatic machines. Using this machine, up to about 10,000 suppositories per hour can be produced Automatic Moulding machine Lubricants for use with suppository bases: Lubricants for use with suppository bases Lubricating the cavities of the mould is helpful in producing elegant suppositories and free from surface depression. The lubricant must be different in nature from the suppository base, otherwise it will be become absorbed and will fail to provide a buffer film between the mass & the metal. The water soluble lubricant is useful for fatty bases while the oily lubricant is useful for water soluble bases. The lubricant should be applied on a pledge of gauze or with fairly stiff brush. Lubricants for use with suppository bases (conti……..): Lubricants for use with suppository bases ( conti ……..) Base Lubricant Theobroma oil Soap spirit Glycero -gelatin base Liquid paraffin Synthetic fats No lubricants required Macrogols No lubricants required Calibration of moulds : Calibration of moulds Different bases have different densities Adding of a medicament results in the altering of weight of the suppository The following steps to calculate the volume of moulds 1. Empty suppositories are prepared from base material alone 2. The suppositories are weighed and their volume is determining by melting 3. Thus, the density is computed for particular base 4. In extemporaneous preparations, the amount of base required is determined by subtracting the volume of medicaments from the total volume of mold The density of the material is used to calculate the volume of base required Determination of displacement value : Determination of displacement value the volume occupied by the active drug is not significant if its quantity is less than 100 mg (on 2 g suppository weight), should consider the active ingredient volume more than 100mg. If the density factor of a base is not known, it can be calculated as the ratio of the blank weight of the base and cocoa butter. Three methods are used to calculate the quantities of base that the replace by active medication METHOD 1: DOSAGE REPLACEMENT FACTOR METHOD: METHOD 1: DOSAGE REPLACEMENT FACTOR METHOD where f is the dosage replacement factor , W is the weight of the pure base suppositories , and A is the weight of suppositories with Y% of the active ingredient . Cocoa butter is arbitrarily assigned a value of 1 as the standard base. If the dosage replacement factor, f, of the incorporated drug is known, the weight of a suppository with Y% of the active ingredient, A, can be calculated by the above equation. METHOD 2: DENSITY FACTOR METHOD: METHOD 2: 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 then equal to 1 g/10 suppositories = 0.1 g/suppository. 4. Melt the suppository base, incorporate the medication, mix, pour into mold, cool, trim, and remove from the mold. 5. Weigh the 10 suppositories and determine the average weight ( C). where A is the average weight of the blank suppository, B is the weight of medication per suppository, and C is the average weight of the medicated suppository. METHOD 2: DENSITY FACTOR METHOD conti……: METHOD 2: DENSITY FACTOR METHOD conti …… 7. Take the weight of the medication required for each suppository and divide it by the density factor of the medication to find the replacement value of the suppository base. Replacement value = medication weight ------------------------- density factor 8. Subtract this quantity from the blank suppository weight. Multiply by the number of suppositories required to obtain the quantity of suppository base required for the prescription. Multiply the weight of drug per suppository by the number of suppositories required to obtain the quantity of active drug required for the prescription. METHOD 3: OCCUPIED VOLUME METHOD: METHOD 3: OCCUPIED VOLUME METHOD 1. Determine the average weight per mold (blank) using the suppository base of interest. 2. Weigh the quantity of suppository base necessary for 10 suppositories. 3. Divide the density of the active drug by the density of the suppository 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 suppository 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 suppository base required. 6. Multiply the weight of active drug per suppository by the number of suppositories to be prepared to obtain the quantity of active drug required. Packaging and storage: Packaging and storage Suppositories are usually packed in tin or aluminum, 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. Storage Suppositories should maintain their shape throughout their shelf-life when stored at the temperature indicated on the label. Labeling: Labeling Every pharmaceutical preparation must comply with the labelling requirements established by Good Manufacturing Practices. The label should include: The name of the pharmaceutical product The name(s) of the active ingredient(s); International Nonproprietary Names (INN) should be used wherever possible The amount of the active ingredient(s) in each suppository and the number of suppositories in the container The batch (lot) number assigned by the manufacturer The expiry date and the date of manufacture Any special storage conditions or handling precautions that may be necessary Directions for use, warnings and precautions that may be necessary The name and address of the manufacturer or the person responsible for placing the product on the market If applicable, the names and concentrations of the antimicrobial agents and/or antioxidants incorporated in the preparation. SPECIFIC PROBLESM IN FORMULATING SUPPOSITORIES : SPECIFIC PROBLESM IN FORMULATING SUPPOSITORIES 1. Water in suppositories: Water is used as a solvent to incorporate a water-soluble substance in the suppository base. Incorporating water should be avoided for the following reasons. (a) Water accelerates the oxidation of fats. (b) If the water evaporates the dissolved substances crystallize out. (c) In presence of water reactions between various ingredients of suppositories may occur. (d) The water may be contaminated with bacteria or fungus. 2. Hygroscopicity : Glycerinated gelatin suppositories lose moisture in dry climates and absorbs moisture in high humidity. Polyethylene glycol bases are also hygroscopic. 3. Incompatibilities: Poyethylene glycol bases are incompatible with silver salts, tannic acid, aminopyrine , quinine, ichthammol , aspirin, benzocaine , iodochlorohydroxyquin , and sulfonamides. Many chemicals have a tendency to crystallize out of PEG e.g. sodium barbital, salicylic acid and camphor. SPECIFIC PROBLESM IN FORMULATING SUPPOSITORIES conti….: SPECIFIC PROBLESM IN FORMULATING SUPPOSITORIES conti …. 4. Viscosity: Viscosity of melted base is low in cocoa butter and high in PEG and glycerinated gelatin. Low viscosity base when melted the suspended particles may sediment very quickly producing nonuniform distribution of drugs. Remedies: (a) The base should be melted at the minimum temperature required to maintain the fluidity of the base. (b) The base is constantly stirred in such a way that the particles cannot settle and no air is entrapped in the suppository.. (c) A base with a narrow melting range closer to rectal temperature is used. (d) Inclusion of approximately 2% aluminium monostearate increase the viscosity of the fatty base and also helps in homogeneous suspension of particles. (e) Cetyl , stearyl , myristyl alcohol or stearic acid are added to improve the consistency of suppositories. 5. Brittleness: Synthetic fat bases with high degree of hydrogenetation and high stearate containing bases are brittle. Brittle suppositories produce trouble during manufacture, handling, packaging and during use. Causes: Rapid chilling (shock cooling) of the melted bases in an extremely cold mold. Remedies: The temperature difference between the melted base and mold should be as small as possible. Addition of small amount of Tween80, castor oil, glycerin or propylene glycol imparts plasticity to a fat and make it less brittle. SPECIFIC PROBLESM IN FORMULATING SUPPOSITORIES conti…..: SPECIFIC PROBLESM IN FORMULATING SUPPOSITORIES conti ….. 6. Volume contraction When the bases are cooled in the mould volume of some bases may contract. Volume contraction produces (a) good mold release facilitating the ejecting from mold. (b) contraction hole formation at the top: This imperfection can be solved by adding slight excess base over the suppositories and after cooled the excess is scrapped off. 7. Lubricants Cocoa butter adheres to suppository molds because of very low volume of contraction. Aqueous lubricant may be used to remove the suppositories easily from the molds. They are applied by wiping, brushing or spraying. The mold surfaces may be coated with teflon to reduce the adhesion of base to mold wall. 8. Rancidity & oxidation Due to auto oxidation of unsaturated fatty acids present in the base, saturated and unsaturated aldehydes , ketones and acids may formed, which have very strong unpleasant odor – this phenomenon is called rancidification . To prevent this suitable antioxidants like hydroquinione , b- naphthoquinone , a- and b- tocopherols , gossypol (present in cotton seed oil), sesamol (present in sesame oil) propyl gallate , gallic acid, tannins and tannic acids, ascorbic acid ( Vit C.), butylated hydroxyanisole (BHA) and butylated hydroxyanisole (BHA).