Basis Suppo HOPE 2006 (Oleum Cacao) [PDF]

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Suppository Bases, Hard Fat 1



Nonproprietary Names



BP: Hard fat PhEur: Adeps solidus USPNF: Hard fat 2



Synonyms



Adeps neutralis; Akosoft; Akosol; Cremao CS-34; Cremao CS36; hydrogenated vegetable glycerides; Massa estarinum; Massupol; Novata; semisynthetic glycerides; Suppocire; Wecobee; Witepsol. 3



Chemical Name and CAS Registry Number



Hard fat triglyceride esters 4



Empirical Formula and Molecular Weight



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. 5



Structural Formula



where R = H or OC(CH2)nCH3; n = 7–17 Not all Rs can be H at the same time. 6



Functional Category



Suppository base. 7



Applications in Pharmaceutical Formulation or Technology



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-meltingpoint 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



Suppository Bases, Hard Fat 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. Table I:



Selected suppository additives.



Property



Additive



Dispersants (release and/or absorption enhancers) Hygroscopicity (reduced) Hardeners (or increasing melting point)



Surfactants



Plasticizers (or decreasing melting point)



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Colloidal silicon dioxide Beeswax Cetyl alcohol Stearic acid Stearyl alcohol Aluminum monostearate (or di- and tristearate) Bentonite Magnesium stearate Colloidal silicon dioxide Glyceryl monostearate Myristyl alcohol Polysorbate 80 Propylene glycol



Description



A white or almost white, practically odorless, waxy, brittle mass. When heated to 508C it melts to give a colorless or slightly yellowish liquid. 9



Pharmacopeial Specifications



See Table II. Table II:



Pharmacopeial specifications for suppository bases.



Test



PhEur 2005



USPNF 23



Identification Characters Melting range Residue on ignition Total ash Acid value Iodine value Saponification value Hydroxyl value Peroxide value Unsaponifiable matter Alkaline impurities Heavy metals



þ þ 30–458C — 40.05% 40.5 43.0 210–260 450 43.0 40.6% þ 410 ppm



— — 27–448C 40.05% — 41.0 47.0 215–255 470 — 43.0% þ —



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Typical Properties



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;



7 63



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;