PREPARATION, ANALYSIS AND PHARMACODYNAMIC EVALUATION OF POLYMER DRUG SALTS
Abstract
This study of the chemical reaction between commercially available non-toxic acidic polymers with basic amine drugs was undertaken to study the feasibility of using the interacting products primarily as prolonged release agents, in all types of dosage forms. The mechanism of interaction between the acidic polymers and amine drug bases was studied by potentiometric and viscometric titrations of model polymers, with aliphatic and aromatic amines, and amine drug bases. The interaction products of each of the polymers, PVM/MA 169 {poly(methyl vinyl ether/maleic anhydride)}, PVAc-5-L (carboxylated polymer of vinyl acetate) and Acr-525 (acrylic polymer) with dextromethorphan, methapyrilene and phenylpropanolamine bases were prepared. The interaction products of PVM/MA 169 with amphetamine and methaphenilene and PVAc-5-L with methaphenilene were also prepared. Viscometric and potentiometric studies and chemical assays of interacted products showed that the acidic groups in the polymers are neutralized by the basic amine drugs to form polymer drug salts, and the neutralization process generally accounted for the total amount of drug combined to the polymers. Other processes, such as adsorption, complexation, etc., do not play the dominant role in the interaction. Drugs with more than one basic functional group tended to react incompletely with polymers containing dicarboxylic comonomer substituents. In vitro release study of the first nine salts in particulate form, were conducted using a modified U.S.P. dissolution rate method. The dissolution rate of polymer drug salts were unlike simple salts, and after a preliminary induction period, the rate could be best explained by the Higuchi equation for the release of drugs dispersed in solid matrices. The dissolution rate was dependent on the nature of the polymer as well as the drug. PVAc-5-L-dextromethorphan and Acr-525-dextromethorphan salts, in suspension form, were found to be stable to leach-out dissolution when suspended in a vehicle of neutral pH and normal storage conditions. A PVAc-5-L-dextromethorphan polymer drug salt suspension was evaluated in vivo by the histamine vapor test in guinea pigs, and produced a statistically significant duration of increased action of 5.83 hours, compared to 2.25 hours for a free drug suspension. . . . (Author's abstract exceeds stipulated maximum length. Discontinued here with permission of school.) UMI
Degree
Ph.D.
Subject Area
Organic chemistry
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