Shenyang Pharmaceutical University LAB 6: SUPPOSITORY PHARMACEUTICS I
LABORATORY 6: Preparation of suppositories and determination of displacement value
1. LABORATORY OBJECTIVES
a) To learn the molding method for preparing suppositories.
b) To learn the method for determining the displacement value and its application.
2. INTRODUCTION
Suppository is a solid dosage form intended for insertion into body orifices where they melt, soften, or dissolve and produce local or systemic therapeutic effects. Suppositories are commonly used rectally and vaginally but occasionally urethrally. They are prepared with different shapes and weights. Rectal suppositories are usually 32 mm long, cylindrical in shape, and have one or both ends tapered. Some rectal suppositories are shaped like a bullet, a torpedo, or a little finger. Vaginal suppositories are usually globular, oviform, or cone shaped.
Suppositories are mainly composed of the medication and a base. Suppository bases play an important role in the release of the medication from the product and the resultant bioavailability of the drug. One of the most important properties for a suppository base is that it remains solid at room temperature but softens, melt, or dissolves readily at body temperature so that the drug is available for absorption after insertion of product. According to the physical characteristics, suppository bases are classified into two categories, (a) fatty or oleaginous bases, such as cocoa butter, hydrogenated fatty acids of vegetable oils, semi synthesized fatty acids such as Fattibase (triglycerides from palm, palm kernel, and coconut oils with self-emulsifying glyceryl monostearate and polyoxyl stearate), Wecobee bases (triglycerides derived from coconut oil) and Witepsol bases (triglycerides of saturated fatty acids C12-C18 with varied portions of the corresponding partial glycerides) and (b) water-soluble or water-miscible bases, such as glycerinated gelatin, polyethylene glycols and polyoxyl 40 stearate (S-40). Some surface active agents may be added in the bases to facilitate drug release and absorption.
Suppositories can be produced by three methods: (a) molding from a melt, (b) compression, and (c) hand rolling and shaping. For fatty bases, either one of these methods can be used. For water-soluble or water-miscible bases, molding is the most frequently used method. The steps for the molding method include: (a) melting the base, (b) incorporating the medicaments, (c) pouring the melt into the molds, (d) allowing the melt to cool and congeal into suppositories, and (e) removing the formed suppositories from the mold. The molding method is applicable to cocoa butter, glycerinated gelatin, polyethylene glycol, and most other bases.
Water bath
Figure 1. Scheme for suppository preparation by the molding method.
Unless specified, the medication incorporated should be passed through a 100 mesh sieve. Depending on the type of formulation, suppository molds may require lubrication before the melt is poured to facilitate easy removal of the molded suppositories and cleaning of the mold afterwards. As a general rule, a fatty lubricant such as liquid paraffin is used for water-soluble bases and a water-soluble lubricant such as soft-soap ethanol solution (soft soap: glycerin: 90% ethanol 1:1: 5) is used for fatty bases.
Every mold is capable of holding a specific volume of materials in each of its openings. Because of the difference in the density of the base materials, the weight of a suppository made of a coca butter base will differ from the weight of the suppository prepared in the same mold with a polyethylene glycol base. Similarly, any added medicinal agents will alter the density of the base and the weight of the resulting suppository differs from that prepared with the base material alone. Therefore, the pharmacist should calibrate each suppository mold with a common base so that a medicated suppository will contain the proper amount of a medicament. Displacement value (DV, also called density factor, f), which is defined as the ratio between the weight of a medicament and the weight of the base of the same volume is determined and used for this purpose. For example, the f of iodoform with respect to cocoa butter is 3.6, indicating that 3.6 g of iodoform occupies the same volume as 1 g cocoa butter. Therefore, f can also be defined as the ratio of the density of the active drug to that of the base. For suppositories with a large density difference or with a high active content, it is necessary to determine the f value. When the density of the active drug and the base is known, f can be calculated using the following equation:
On the other hand, when the density of the active drug and the base is unknown, f can be calculated using the following equation,
（1）
where W is the weight of the active ingredient in each suppository, G is the weight of the pure base suppository, M is weight of the suppository with X% of the active ingredient.
Based on the displacement value，the amount of base (E) to be added in each suppository can be calculated using the following equation:
(2)
It is important to note that the same drug substance has the different displacement values for different bases. Therefore, the base type should be specified when mentioning the displacement value.
For quality control of suppository, weight variation, melting time, overall appearance, and hardness should be checked as prescribed in the Chinese Pharmacopoeia (2005). Moreover, some other non-compendial parameters should be tested, such as homogeneity, particle size, softening temperature, dissolution and bioavailability.
3. METHODS
3.1 Measurement of the displacement value
Using aspirin as the model drug, determine its displacement value for semi-synthesis glycerides.
3.1.1 Procedures
a) Prepare molded suppositories with base material alone: Weigh 10 g of semi-synthesis glycerides and transfer it into a porcelain casserole, heat the dish using a water bath. Remove the dish from the water bath when 2/3 of the base has melted and stir to complete melting. When the base is cooled down close to its congealing point, pour the melt into the cavities of the lubricated mold and allow the melt continue to cool and congeal for forming suppositories. After trimming, remove the formed suppositories from the mold. Weigh each suppository and determine the average weight G (g) of the blank suppositories.
b) Prepare aspirin containing suppositories: Weigh 6 g of semi-synthesis glycerides and transfer it into a porcelain casserole, heat the dish using a water bath. Remove the dish from the water bath when 2/3 of the base has melted and stir to complete melting. Weigh 3 g of aspirin powder (which was passed through a 100 mesh-screen), incorporate the powder into the melted base by small amounts, and mix until uniform. When the base is cooled down close to its congealing point, pour the melt into the cavities of the lubricated mold and allow the melt to cool and congeal into suppositories. After trimming, remove the formed suppositories from the mold. Weigh each suppository and determine the average weight of aspirin containing suppositories M（g）, the amount of drug in the suppository is : W=M·X%, where X% is the percentage of aspirin in the base.
c) Calculate the displacement value (density factor): use equation (1) to calculate f value of aspirin versus semi-synthesis glyceride by using the determined values of G and M in (a) and (b).
3.1.2 Notes
a) Semisynthetic glyceride is a fatty base and its volume increases with the increase of temperature. Pay attention to the temperature of the mixture before pouring it into the cavity of the mold. If the temperature is too high, there may be the formation of a matrix with a hollow center or a recessed dip. If an undissolved or suspended drug in the mixture is denser than the base, it has a tendency to settle. In this case, constant stirring, even during pouring, is required. Otherwise, the suppositories formed in the cavities towards the end of the pouring process may contain a higher drug contents. The solid drug can remain suspended if the pouring is performed just above the congealing point of the base, at which the base is not too fluid. When filling the cavities in the mold, the pouring must be continuous to prevent the layering effect. To ensure a completely filled mold upon congealing, the melt is poured to a level slightly above the surface of the mold. This is done to prevent the formation of recessed dips at both ends of the suppository during the cooling and congealing process. The mold is usually placed in the refrigerator to accelerate hardening.
b) To ensure accuracy of the measured f value, the same mold should be used to prepare the base suppositories and the drug containing suppositories.
3.1.3 Based on the f value, calculate the amount of base needed to prepare the following formulation:
Aspirin 3.0g
Semisynthetic glyceride q.s.
Cone-shaped rectal suppository 5 pieces
3.2 Preparation of glycerin suppositories
3.2.1 Formulation
Glycerin 10 g
Stearic acid 0.8 g
Sodium hydroxide 0.12 g
Distilled water 1.4 mL
Cone-shaped rectal suppository 5 pieces
3.2.2 Procedures
Weigh the specified amounts of glycerin and heat to 100℃ using a water bath. Add the fine powder of stearic acid, sodium hydroxide and distilled water, stir constantly, and continue heating at 85～95℃ until the mixture is clear. When the base is still hot, pour the melt carefully into the cavities of the lubricated molds and allow the melt to cool and congeal into suppositories. After trimming, remove the formed suppositories from the mold.
3.2.3 Quality test
a) The suppository should be colorless/ almost colorless and transparent or semi-transparent.
b) Measure the weight variation
c) Test the melting time of the prepared suppositories.
3.3 Preparation of chlorhexidinie acetate(醋酸氯己定) suppositories
3.3.1 Formulation
Chlorhexidinie acetate(Pass 100 mesh screen) 0.25 g
Tween-80 1.0 g (ρ:1.06～1.09)
Borneol spirit 2.5 mL
Glycerin 32.0 g
Gelatin 9.0 g
Distilled water add to 50.0mL
Vaginal suppository (Duck tongue shape) 10 pieces
3.3.2 Procedures
a) Preparation of borneol spirit: Weigh 0.5 g of borneol and dilute to 25 mL with 95% ethanol.
b) Preparation of glycerin-gelatin solution：Weigh the predetermined amount of gelatin and transfer it into a pre-weighed porcelain casserole followed by adding 1.5~2 times of distilled water for the soaking of the gelatin until softened. Pour out the excess amount of water and heat the dish using a water bath to yield a molten gelatin solution. Subsequently, add the predetermined amount of glycerin (weighed), heat and stir the mixture continuously to evaporate the water until the prescribed weight was obtained (net weight appro. 46.25 g).
c) Preparation of suppositories：Mix the specified amount of chlorhexidinie acetate, Tween-80 and borneal spirit until uniform, then add the mixture into the glycerin-gelatin solution prepared in (b) and stir until uniform. When the mixture is still hot, pour the melt into the cavities of the lubricated mold, allowing the melt to cool down and eventually congeal into suppositories. After trimming, remove the formed suppositories from the mold.
3.3.3．Notes
a) An appropriate amount of water should be added to the gelatin to allow for proper swelling before heating, otherwise, longer time is needed for mixing and there may be undissolved gelatin pieces or granules remaining in the solution.
b) While stirring the mixture in (a), it is important to avoid the introduction of air bubbles.
c) Water content in the glycerin-gelatin base is critical and should be controlled. Proper control of the evaporation of water to attain the prescribe water content is important to avoid making the suppositories too soft or too hard.
3.3.4 Test and evaluation
Appearance：a pharmaceutically acceptable suppository product should have a smooth surface without bubbles, is light yellow in color, transparent, and with a good elasticity.
3.4 Preparation of matrine(苦参碱) suppositories
3.4.1 Formulation
Matrine 0.25 g
Borneol spirit 2.5 mL
Polyoxyl（40）stearate 47 g
Vaginal suppository (Duck tongue shape) 10 pieces
3.4.2 Procedures
Mix matrine and borneol spirit until uniform followed by adding the mixture into melted polyoxyl (40) stearate (in the water bath) under constant stirring. When the mixture is still hot, pour the melt in the cavities of the lubricated mold, allowing the melt to cool down and congeal into suppositories. After trimming, remove the formed suppositories from the mold.
3.4.3 Test and evaluation
Appearance: a pharmaceutically acceptable suppository product should have a smooth surface without bubbles, is light yellow in color and transparent.
4. RESULTS AND DISCUSSION
4.1 Record the displacement value of aspirin for semisynthetic glyceride. Discuss in what cases displacement value should be determined for suppositories preparation.
4.2. Record the test results in Table 1.
Table 1. Test results of the four different types of suppositories
Name Appearance Weight (g)Aspirin suppositories
Glycerol suppositories
Chlorhexidinie acetate suppositories
Matrine suppositories
5. QUESTIONS
a) Discuss the precautions you should take during the preparation of aspirin suppositories by the molding method.
b) Why was the glycerol-gelatin base selected to prepare chlorhexidinie acetate suppositories? Describe the precautions you should take.
c) What is the difference between the preparation method for traditional Chinese medicine suppositories and suppositories containing chemical drugs?
References
[1] H. C. Ansel, N. G. Popovich and L. V. Allen, Jr. Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th ed., Williams and Wilkins, Baltimore, 2005.
[2] M.E. Aulton. Pharmaceutics: The science of dosage form design. 1988.
(Shirui MAO）
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