PREPARATION OF SUPPOSITORIES

INTRODUCTION

Suppository ShapesSuppositories are medicated, solid bodies of various sizes and shapes suitable for introduction into body cavities. The medicament is incorporated into a base such as cocoa butter which melts at body temperature, or into one such as glycerinated gelatin or PEG which slowly dissolves in the mucous secretions. Suppositories are suited particularly for producing local action, but may also be used to produce a systemic effect or to exert a mechanical effect to facilitate emptying the lower bowel.

The ideal suppository base should be nontoxic, nonirritating, inert, compatible with medicaments, and easily formed by compression or molding. It should also dissolve or disintegrate in the presence of mucous secretions or melt at body temperature to allow for the release of the medication. As with the ointment bases, suppository base composition plays an important role in both the rate and extent of release of medications.

SUPPOSITORY BASES

Suppository bases may be conveniently classified as according to their composition and physical properties:

1. Oleaginous Bases include Theobroma Oil and synthetic triglyceride mixtures.
  1. Cocoa ButterTheobroma Oil or cocoa butter is used as a suppository base because, in large measure, it fulfills the requirements of an ideal base. At ordinary room temperatures of 15° to 25°C (59° to 77°F), it is a hard, amorphous solid, but at 30° to 35°C (86° to 95°F), i.e., at body temperature, it melts to a bland, nonirritating oil. Thus in warm climates, theobroma oil suppositories should be refrigerated.

    Particular attention must be given to two factors when preparing suppositories with cocoa butter base. First, this base must not be heated above 35°C (95°F) because cocoa butter is a polymorphic compound and if overheated will convert to a metastable structure that melts in the 25° to 30°C (77° to 86°F) range. Thus, the finished suppositories would melt at room temperature and not be usable.

    The second factor is the change in melting point caused by adding certain drugs to cocoa butter suppositories. For example, chloral hydrate and phenol tend to lower the melting point. It may be necessary to add spermaceti or beeswax to raise the melting point of finished suppositories back to the desired range.

  2. The newer synthetic triglycerides consist of hydrogenated vegetable oils. Their advantage over cocoa butter is that they do not exhibit polymorphism. They are, however, more expensive. Some of the bases are single entity formulations. Some of the names may denote a series of bases. In a series, the bases are varied to give a range of melting points. For example, Fattibase® is a single entity base that consists of triglycerides from palm, palm kernel, and coconut oils. Wecobee® is a series of bases. Wecobee FS, M, R, and S are all made from triglycerides of coconut oil. But FS has a melting point range of 39.4 to 40.5°C, M has a range of 33.3 to 36.0°C, R has a range of 33.9 to 35.0°C, and S has a range of 38.0 to 40.5°C. Other triglyceride type bases include Dehydag®, Hydrokote®, Suppocire®, and Witepsol®.

2. Water Soluble/Water Miscible Bases are those containing glycerinated gelatin or the polyethylene glycol (PEG) polymers.

  1. Glycerinated Gelatin is a useful suppository base, particularly for vaginal suppositories. It is suitable for use with a wide range of medicaments including alkaloids, boric acid, and zinc oxide. Glycerinated gelatin suppositories are translucent, resilient, gelatinous solids that tend to dissolve or disperse slowly in mucous secretions to provide prolonged release of active ingredients.

    Suppositories made with glycerinated gelatin must be kept in well-closed containers in a cool place since they will absorb and dissolve in atmospheric moisture. In addition, those intended for extended shelf-life should have a preservative added, such as methylparaben or propylparaben, or a suitable combination of the two. To facilitate administration, glycerinated gelatin suppositories should be dipped in water just before use.

    Different Suppository Bases
  2. Polyethylene Glycol Polymers have received much attention as suppository bases in recent years because they possess many desirable properties. They are chemically stable, nonirritating, miscible with water and mucous secretions, and can be formulated, either by molding or compression, in a wide range of hardness and melting point. Like glycerinated gelatin, they do not melt at body temperature, but dissolve to provide a more prolonged release than theobroma oil.

    Certain polyethylene glycol polymers may be used singly as suppository bases but, more commonly, formulas call for compounds of two or more molecular weights mixed in various proportions as needed to yield a finished product of satisfactory hardness and dissolution time.

    Since the water miscible suppositories dissolve in body fluids and need not be formulated to melt at body temperature, they can be formulated with much higher melting points and thus may be safely stored at room temperature.

    Examples of various PEGs used in suppository bases are:

    1450 30%
    8000 70%
    1450 1.96 gm
    3350 200 mg
    300 60%
    8000 40%
    300 48%
    6000 52%
    1000 95%
    3350 5%
    1000 75%
    3350 25%
    300 10%
    1540 65%
    3350 25%
    Silica Gel 25 mg
    PEG 1450 2.3 gm

METHODS OF PREPARATION

Suppositories can be extemporaneously prepared by one of three methods.

1. Hand Rolling is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base. It has the advantage of avoiding the necessity of heating the cocoa butter. A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape.

Effective hand rolling requires considerable practice and skill. The suppository "pipe" or cylinder tends to crack or hollow in the center, especially when the mass is insufficiently kneaded and softened.

2. Compression Molding is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold. The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to omit a portion of the suppository base, based on the density factors of the active ingredients.

3. Fusion Molding involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. The mixture is removed from the heat and poured into a suppository mold. When the mixture has congealed, the suppositories are removed from the mold. The fusion method can be used with all types of suppositories and must be used with most of them.

Learn all about using suppository molds and packaging

Suppositories are generally made from solid ingredients and drugs which are measured by weight. When they are mixed, melted, and poured into suppository mold cavities, they occupy a volume – the volume of the mold cavity. Since the components are measured by weight but compounded by volume, density calculations and mold calibrations are required to provide accurate doses.

When a drug is placed in a suppository base, it will displace an amount of base as a function of its density. If the drug has the same density as the base, it will displace an equivalent weight of the base. If the density of the drug is greater than that of the base, it will displace a proportionally smaller weight of the base. Density factors for common drugs in cocoa butter are available in standard reference texts. The density factor is used to determine how much of a base will be displaced by a drug. The relationship is:

For example, aspirin has a density factor in cocoa butter of 1.3 (see Remington's). If a suppository is to contain 0.3 g of aspirin, it will replace 0.3 g ÷ 1.3 or 0.23 g of cocoa butter. If the blank suppository (suppository without the drug) weighed 2 g, then 2 g - 0.23 g or 1.77 g of cocoa butter will be needed for each suppository, and the suppository will weigh 1.77 g + 0.3 g = 2.07 g. So if a pharmacist was making 12 aspirin suppositories using cocoa butter as the base, he would weigh 1.77 g × 12 or 21.24 g of cocoa butter and 0.3 g × 12 or 3.6 g of aspirin.

The weight of the blank suppository is easily determined. A portion of the suppository base is melted, poured into the suppository mold and allowed to congeal. The suppositories are removed from the mold, and the total weight of the suppositories is determined. The average weight of the blank suppository is determined by dividing the total weight by the number of suppositories.

Some example density factors of drugs in cocoa butter are shown in the table below (see Remington's):

Aspirin 1.3
Barbital 1.2
Bismuth salicylate 4.5
Chloral hydrate 1.3
Cocaine hydrochloride 1.3
Codeine phosphate 1.1
Diphenhydramine hydrochloride 1.3
Morphine hydrochloride 1.6
Phenobarbital 1.2
Zinc Oxide 4.0

 

When the Density Factor is Not Known  

When bases other than cocoa butter are used, or when the density factor for a drug in cocoa butter is not known, then the density factor can be estimated by calculation or experimentally determined by the double casting technique.

Estimation by Calculation
One method to determine the density factor of a drug in a base other than cocoa butter requires the use of the ratio of a blank suppository of the non-cocoa butter base to a blank suppository of the cocoa butter base. This information is generally obtained by calibrating the mold first with one base and then the other base.

As an example of the method, a mold was calibrated with the PEG base and the average blank suppository weighed 2.24 grams. The same mold was calibrated with cocoa butter and those blank suppositories weighed 1.87 grams on average. Therefore, the ratio of the two weights was:

If 200 mg of aspirin is to be incorporated into each PEG suppository, it is necessary to determine how much PEG base will be displaced by the aspirin. That displacement amount can be calculated as follows:

For each PEG suppository to be formulated, 0.2 g of aspirin and 2.06 g (2.24 - 0.18 g = 2.06) of the PEG base will be needed.

Double Casting Technique

The total quantity of drug is mixed with an amount of base which is inadequate to fill the number of cavities. The mixture is poured into the mold, partially filling each cavity, and the remaining portion of the cavities are filled with the melted blank base. The cooled suppositories are then removed, remelted, mixed, and recast to evenly distribute the active ingredient. By recording the necessary information, the pharmacist can determine the weight of base displaced by the drug and then calculate the density factor.

Note: a portion of the formula will be lost during this process, so you should always prepare for 2 extra suppositories to ensure that you have enough mixture for the desired number of suppositories.
Double Casting Image

Sample calculation of density factor

Using a particular mold, the average weight of a plain cocoa butter suppository was found to be 2.0 g. Using the same mold, cocoa butter suppositories, each containing 300 mg of drug A, were found to weigh 2.1 g each. So,

weight of suppository of cocoa butter = 2.0 g
weight of drug in each medicated suppository = 0.3 g
weight of suppository with drug and cocoa butter = 2.1 g
weight of base in medicated suppository = 2.1 g - 0.3 g = 1.8 g
weight of base displaced = 2.0 g - 1.8 g = 0.2 g

Therefore, density factor of drug A = 0.3 g ÷ 0.2 g = 1.5

Now, knowing the density factor for the drug, the pharmacist can make calculations for a batch of suppositories. To prepare 10 suppositories:

weight of drug A needed = 10 suppositories × 300 mg/suppository = 3000 mg = 3.0 g
weight of base needed for plain suppositories = 10 suppositories × 2.0 g/suppository = 20.0 g
weight of base displaced by 3 g drug A = 3.0 g ÷ 1.5 = 2.0 g
weight of base needed for medicated suppositories = 20.0 g - 2.0 g = 18.0 g