SOLID-SOLID INTERACTIONS INVOLVING PHENYL SALICYLATE, METHENAMINE, BENZOIC ACID, ATROPINE SULFATE AND L-HYOSCYAMINE
Abstract
A study was undertaken to detect and identify the possible solid-solid interactions between methenamine, phenyl salicylate, benzoic acid, atropine sulfate and 1-hyoscyamine which are components of a combination urinary tract antibacterial tablet. The volatility of methenamine and methenamine granulations was determined using a dynamic thermogravimetric analysis and a static gravimetric procedure at elevated temperatures. This was of primary concern since no data were available. The results showed that the volatility of methenamine was temperature and time dependent. Significant weight loss of methenamine took place over a thirty day period at 40(DEGREES) and 50(DEGREES)C. However, the incorporation of methenamine in a microcrystalline cellulose-polyvinylpyrrolidone granulation reduced the volatility of methenamine. Various thermal and analytical techniques were utilized to study the solid-solid interactions between the active ingredients by initially evaluating simple physical mixtures. Spectroscopic methods were employed to study the reaction product of methenamine and phenyl salicylate. Thin-layer chromatography and differential scanning calorimetry (DSC) studies demonstrated that phenyl salicylate interacts with 1-hyoscyamine. The DSC and high-pressure liquid chromatography procedures indicated that methenamine reacts with phenyl salicylate to form a yellow degradation product which was insoluble in methanol. Further evaluation of this yellow degradation product indicated that phenyl salicylate was partially hydrolyzed in the presence of a weak base to phenol and salicylic acid. The degradation products in turn reacted with methenamine to form a yellow reaction product. Nuclear magnetic resonance spectra suggested that the yellow degradation product is a polymer. The most significant reaction detrimental to the physical and chemical stability of the tablet containing these ingredients and contributing to the intense yellow color was probably the polymerization reaction between methenamine and phenol. However, the incorporation of phenyl salicylate in a polyvinylpyrrolidone (PVP) solid dispersion prevented the discoloration of tablets containing these ingredients and eliminated the interaction of pheyl salicylate with 1-hyoscyamine and methenamine. A stability indicating high-pressure liquid chromatography assay method for phenyl salicylate was developed and validated . The studies with various granulating agents demonstrated the stabilizing properties of PVP in the compressed tablets containing methenamine, phenyl salicylate, benzoic acid, atropine sulfate and 1-hyoscyamine.
Degree
Ph.D.
Subject Area
Pharmacology
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