Using Polymer Technology to Enhance Bioavailability - Pharmaceutical Technology

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Using Polymer Technology to Enhance Bioavailability
The authors review seven polymer classes that can be used to prepare solid-dispersion formulations.

Pharmaceutical Technology
pp. s37-s42

For solid-dispersion applications, the aromatic carboxylic acids in the phthalyl ester substituent groups are capable of donating strong hydrogen bonds to APIs with hydrogen-bond accepting groups. Hydrogen bond donating of the aromatic-carboxylic acid can be further stabilized with an aromatic ring and the ester functionality. Like hypromellose and HPMCASs, the aliphatic–hydroxyl groups of the natural cellulose and the synthetic 2-hydroxypropoxyl groups can also donate hydrogen bond to APIs with hydrogen-bond accepting groups. These hydrogen bonds, however, are not as strong as the aromatic stabilized hydrogen bonds from the phthalyl–ester substituent groups. The ester groups in the phthalyl–ester substituent groups are capable of accepting hydrogen bonds from APIs to stabilize the solid dispersion. The hydrogen-bond accepting carbonyl group of the ester can resonance stabilize the carboxylic acid hydrogen bond donating group through the aromatic phthalate. The hydrogen-bond donating and accepting properties of hypromellose phthalates make these polymers useful for several API functional groups.

Hypromellose phthalates are insoluble in dichlormethane, methanol, isopropanol, ethyl acetate, and ethanol but demonstrates desired solubility in acetone, tetrahydrofuran, mixtures of dichloromethane and methanol, mixtures of dichloromethane and ethanol, and mixtures of acetone and methanol (1). The insolubility of hypromellose phthalate in single-solvent systems makes it challenging to conduct simple drug-compatibility studies and spray-drying applications. However, solvent mixtures can be effectively prepared for commercial spray drying by using proper spray-drying optimization.

HP-50 and HP-55 have glass-transition temperatures of 150 and 145 C, respectively (6). Hypromellose phthalates remain chemically and physically stable at room temperature for several years but are susceptible to hydrolysis under elevated temperature and humidity conditions (1). Limited information is available regarding hypromellose-phthalate stability during hot-melt extrusion under high shear or high temperature. A plasticizer or an API with plasticizing attributes may be necessary to effectively melt extrude hypromellose phthalates.

Cellulose acetate phthalate. Cellulose acetate phthalate (CAP) is a natural cellulose that is synthetically modified. Half of the CAP hydroxyl groups are acetylated and approximately one quarter are esterified (one of the two acid groups is phthalic and the other acid group remains free). CAP is used in oral pharmaceutical formulations as an enteric coating material. CAP concentrations in oral formulations are typically limited to 0.5 to 0.9% of tablet core weight (1). Much higher concentrations are typically required to prepare stable solid dispersions.

CAP is practically insoluble in water, alcohols, and chlorinated and nonchloronated hydrocarbons. CAP, however, demonstrates good solubility in acetone, methanol, ethanol, and several solvent mixtures, including acetone and water, acetone and ethanol, acetone and isopropanol, acetone and methanol, acetone and dichloromethane, dichloromethane and ethanol, ethyl acetate and ethanol, and ethyl acetate and isopropanol (1).

Figure 3: Hypromellose, hypromellose phthalates, hypromellose acetate succinates, and cellulose acetate phthalates.
CAP has a glass-transition temperature of 175 C but is reportedly compatible with various plasticizers, including acetylated monoglyceride, butyl phthalybutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalylethyl glycolate, glycerin, propylene glycol, triacetin, triacetin citrate and tripropionin (7). A 20% (w/w) addition of diethyl phthalate, triacetin, or acetylated monoglyceride reduces the glass-transition temperature of the CAP to 100 C, 95 C, and 163 C, respectively (7). CAP, like other phthalates, is susceptible to hydrolysis under high temperature and high humidity (1). The high glass transition temperature and chemical instability of the polymer makes plasticizing necessary for hot-melt extruding the material. Limited information is available on hot-melt extrusion conditions for CAP.

Polymethylacrylates. Polymethacrylates are synthetic cationic and anionic polymers of dimethylaminoethyl methacrylates, methacrylic acid, and methacrylic acid esters in varying ratios. Polymethacrylates are commercially available for use as film forming agents, tablet binders, and tablet diluents (1). Four of these polymers have been studied for solid-dispersion technology, including: cationic methacrylate, methacrylic acid copolymer Type A, Type B, and Type C.


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