Name: Suppository Bases, Hard Fat
CAS No: Hard fat triglyceride ester
BP: Hard Fat PhEur: Hard Fat USP-NF: Hard Fat
Adeps neutralis; adeps solidus; Akosoft; Akosol; Cremao CS-34; Cremao CS-36; hydrogenated vegetable glycerides; Massa Estarinum; Massupol; Novata; semisynthetic glycerides; Suppocire; Wecobee; Witepsol.
Hard fat triglyceride ester
Hard fat suppository bases consist mainly of mixtures of the triglyceride esters of the higher saturated fatty acids (C8H17COOH to C18H37COOH) along with varying proportions of mono- and diglycerides. Special grades may contain additives such as beeswax, lecithin, polysorbates, ethoxylated fatty alcohols, and ethoxylated partial fatty glycerides.
The primary application of hard fat suppository bases, or semisynthetic glycerides, is as a vehicle for the rectal or vaginal administration of a variety of drugs, either to exert local effects or to achieve systemic absorption. Selection of a suppository base cannot usually be made in the absence of knowledge of the physicochemical properties and intrinsic thermodynamic activity of the drug substance. Other drug-related factors that can affect release and absorption and which must therefore be considered are the particle size distribution of insoluble solids, the oil : water partition coefficient, and the dissociation constant. The displacement value should also be known, as well as the ratio of drug to base. Properties of the suppository base that may or may not be modified by the drug, or that can influence drug release, are the melting characteristics, chemical reactivity, and rheology. The presence of additives in the base can also affect performance. Melting characteristics Fatty-based suppositories intended for systemic use should liquefy at just below body temperature. Softening or dispersion may be adequate for suppositories intended for local action or modified release. High-melting-point bases may be indicated for fat-soluble drugs that tend to depress the melting point of bases or for suppositories used in warm climates. Drugs that dissolve in bases when hot may create problems if they deposit as crystals of different form or increased size on cooling or on storage. Low-melting-point bases, particularly those that melt to liquids of low viscosity, can be of value when large volumes of insoluble substances are to be incorporated; there is a risk of sedimentation in such instances. An important factor during processing is the time required for setting. This is affected by the temperature difference between the melting point and the solidification point.(1,2) Chemical reactivity Although the use of bases with low hydroxyl values (low partial ester content) is indicated to minimize the risk of interaction with chemically reactive compounds, formulators should be aware that hydroxyl values are also related to hydrophilic properties, which, in turn, can modify both release and absorption rates. Bases with low hydroxyl values tend to be less plastic than those with higher values and, if cooled rapidly, may become excessively brittle. Peroxide values give a measure of the resistance of the base to oxidation and are a guide to the onset of rancidity. Rheology The viscosity of the melted base can affect the uniformity of distribution of suspended solids during manufacture. It can also influence the release and absorption of the drug in the rectum. Further reduction in the particle size of insoluble solids is the method of choice to minimize the risk of sedimentation. However, the presence of a high content of fine, suspended particles is likely to increase viscosity. It may also make pouring difficult, delay melting, and induce brittleness on solidification. Additives are sometimes included to modify rheological properties and to maintain homogeneity, e.g. microcrystalline wax, but the extent of their effect on drug release should first be assessed. Release from a base in which viscosity has been enhanced by an added thickener may vary and be related to the aqueous solubility of the drug itself. Additives Some grades of commercial bases already contain additives, and these are usually identified by the manufacturers by means of suitable letters and numbers. Additives may also be incorporated by formulators. Properties of suppositories that have been modified and additives or types of additives that have been used are shown in Table I. Water is undesirable as an additive because it enhances hydrolysis and the potential for a chemical reaction between constituents of the suppository. In low concentration, water plays little part in drug release and can serve as a medium for microbial growth.
A white or almost white, practically odorless, waxy, brittle mass. When heated to 508C it melts to give a colorless or slightly yellowish liquid
See Table II.
Acid value see Table III. Color number 43 for Massa Estarinum (iodine color index); 43 for Suppocire excluding L grades (Gardener scale); 45 for Suppocire L grades (Gardener scale); 43 for Witepsol (iodine color index). Density 0.955–0.975 g/cm3 for Massa Estarinum at 208C; 0.950–0.960 g/cm3 for Suppocire at 208C; 0.950–0.980 g/cm3 for Witepsol at 208C. Heat of melting (22–408C) 145 J/g/8C for Massa Estarinum; 100–130 J/g/8C for Suppocire; 145 J/g/8C for Witepsol. Hydroxyl value see Table III. Iodine value see Table III. Melting point see Table III. Moisture content 40.2% w/w for Massa Estarinum; <0.5% w/w for Suppocire; 40.2% w/w for Witepsol. Peroxide value 43 for Massa Estarinum; 41.2 for Suppocire; 43 for Witepsol. Saponification value see Table III. Solidification point see Table III. Solubility Freely soluble in carbon tetrachloride, chloroform, ether, toluene, and xylene; slightly soluble in warm ethanol; practically insoluble in water. Specific heat 2.6 J/g/8C for Massa Estarinum; 1.7–2.5 J/g/8C for Suppocire; 2.6 J/g/8C for Witepsol. Unsaponifiable matter see Table III.
Hard fat suppository bases are fairly stable toward oxidation and hydrolysis, with the iodine value being a measure of their resistance to oxidation and rancidity. Water content is usually low and deterioration due to hygroscopicity rarely occurs. Melting characteristics, hardness, and drug-release profiles alter with time, and the melting point may rise by more than 1.08C after storage for several months. Owing to the complexity of bases, elucidation of the mechanisms that induce these changes on aging is difficult. Evidence has been presented(3) that supports a finite transition from amorphous to crystalline forms in which polymorphism may or may not contribute, whereas other workers have found melting point changes to be closely associated with the conversion of triglycerides to more stable polymorphic forms.(4) Before melting point determinations are made, bases are ‘conditioned’ to a stable crystalline form. Suppository bases should be stored protected from light in an airtight container at a temperature at least 58C less than their stated melting point. Refrigeration is usually recommended for molded suppositories. Suppositories that are not effectively packaged may develop a ‘bloom’ of powdery crystals at the surface. This is usually due to the presence of high-melting-point components in the base and can often be overcome by using a different base. Alternatively, the base can be precrystallized prior to pouring, since the crystals will cause a quick and complete crystallization into its end crystal form. This process is called ‘tempering.’
Incompatibilities with suppository bases are not now extensively reported in the literature. The occurrence of a chemical reaction between a hard fat suppository base and a drug is relatively rare, but any potential for such a reaction may be indicated by the magnitude of the hydroxyl value of the base. The risk of hydrolysis of aspirin, for example, may be reduced by the use of a base with a low hydroxyl value (<5) and, additionally, by minimization of the water content of both the base and the aspirin. There is evidence that aminophylline reacts with the glycerides in some hard fat bases to form diamides. On aging or exposure to elevated temperatures, degradation is accompanied by hardening and suppositories tend to exhibit a marked increase in melting point. The ethylenediamine content is also reduced.(5,6) Certain fat-soluble medications, such as chloral hydrate, may depress the melting point when incorporated into a base. Similarly, when large amounts of an active substance, either solid or liquid, have to be dispersed into a base, the rheological characteristics of the resultant suppository may be changed, with concomitant effects on release and absorption. Careful selection of bases or the inclusion of additives may therefore be necessary
The most common method of manufacture involves the hydrolysis of natural vegetable oils such as coconut or palm kernel oil, followed by fractional distillation of the free fatty acids produced. The C8 to C18 fractions are then hydrogenated and reesterified under controlled conditions with glycerin to form a mixture of tri-,di-, and monoglycerides of the required characteristics and hydroxyl value. This process is used for Witepsol. In an alternative procedure, coconut or palm kernel oil is directly hydrogenated and then subjected to an interesterification either with itself or with glycerin to form a mixture of tri-, di-, and monoglycerides of the required characteristics and hydroxyl value, e.g. Suppocire.
Suppository bases are generally regarded as nontoxic and nonirritant materials when used in rectal formulations. However, animal studies have suggested that some bases, particularly those types with a high hydroxyl value, may be irritant to the rectal mucosa.(7
Observe normal precautions appropriate to the circumstances and quantity of material handled. There is a slight fire hazard on exposure to heat or flame.
Included in the FDA Inactive Ingredients Database (rectal and vaginal preparations). Included in nonparenteral medicines licensed in the UK
Glycerin; medium-chain triglycerides; polyethylene glycol; theobroma oil. Theobroma oil CAS number [8002-31-1] Synonyms Cocoa butter; oleum cacao; oleum theobromatis. Appearance A yellowish or white, brittle solid with a slight odor of cocoa. Melting point 31–348C Solubility Freely soluble in chloroform, ether, and petroleum spirit; soluble in boiling ethanol; slightly soluble in ethanol (95%). Stability and storage conditions Heating theobroma oil to more than 368C during the preparation of suppositories can result in an appreciable lowering of the solidification point owing to the formation of metastable states; this may lead to difficulties in the setting of the suppository. Theobroma oil should be stored at a temperature not exceeding 258C. Comments Theobroma oil is a fat of natural origin used as a suppository base. It comprises a mixture of the triglycerides of saturated and unsaturated fatty acids, in which the unsaturated acid is preferentially situated on the 2-position of the glyceride. Theobroma oil is also a major ingredient of chocolate.