The biopharmaceutical properties of solid dosage forms -- The stability of p-aminosalicylic acid and sodium p-aminosalicylate in tablets

A product must comply with pharmacopeial specifications at all times. If the drug in the tablet degrades to a therapeutically inactive (and sometimes toxic) substance, the patient will not receive the correct amount of drug and, more important, may be adversely affected by the degradation product. The stability characteristics of four products containing either p-aminosalicylic acid or sodium aminosalicylate were, therefore, determined in this laboratory. The products were selected at random and are currently being sold to pharmacies and hospitals in Canada. The products were analyzed and their disintegration times determined. All products complied with existing specifications. The products were then stored in a Vapor-Temp Controlled Humidity Chamber at various temperatures (30°C. to 60°C.) and at 65 % and 90 % relative humidity for varying periods of time. Tablets were withdrawn from the chamber at various times and analyzed. Using the data so obtained, rate constants were calculated for each product stored at the two basic conditions, that is, at 65 % and 90 % relative humidity. Products 1 and 4 were not affected by the environmental conditions in the humidity chamber. However, the drug in Products 5 and 7 degraded quickly to m-aminophenol when the tablets were exposed to temperatures in excess of 40°C and a relative humidity of 90 %. Product 7, in particular, was very susceptible to both heat and moisture. The product would, therefore, be unacceptable to the profession. It contains buffers and it is assumed that these substances are responsible for the product's instability. This then is a good example of poor product development. The data accumulated during this investigation was analyzed mathematically and it was concluded that the pseudo first-order reaction equation may be used to explain the degradation process. Arrhenius plots (that is, plots of the logarithm of the rate constant versus the reciprocal of the absolute temperature) were prepared for Products 5 and 7. On the basis of these plots, product stability at various temperatures and a relative humidity of 90 % was determined. As an example, Product 7 will contain only 90% of the drug claimed on the label if it is stored at a temperature of 25°C and a relative humidity of 90% for 70 days. Values at other temperatures and for Product 5 are given in this thesis. The data obtained during this investigation suggests that the following stability specification may be used to quickly evaluate a product containing p-Aminosalicylic acid or its sodium salt. Place 20 tablets in a petrie dish and transfer to a humidity chamber adjusted to 40°C and a relative humidity of 90%. Store in the chamber for ten days. Remove and assay the tablets. The mean potency of the 20 tablets must be not less than 90 % of the amount claimed on the label. The drug in products which do not meet this specification would degrade to m-aminophenol even if it is stored at normal temperatures for relatively short periods of time. Product 7 falls into this category. This study shows that humidity must be taken into consideration in any investigation on product stability. Moreover, it is not enough to determine the stability of the drug as such. The excipients (and other drugs combined with the anti-tubercular in the same dosage form) can influence the degradation process in the tablet. This abstract represents the true contents of the thesis submitted.

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