This thesis describes some of the physical, chemical and biopharmaceutical properties of a poorly soluble salicylate, salicylsalicylic acid (SSA). In the introduction influences on drug absorption from the gastro-intestinal tract are described. These influences are of physical, chemical, physiological and pharmaceutical origin and are discussed with respect to drugs that are known to exhibit a poor or variable absorption that is limited by their solubility and dissolution behaviour. Methods for improving gastro-intestinal absorption of such drugs are introduced and the advantages of their coprecipitate formation with polyvinylpyrrolidone (PVP) and various bile acids, cholic (CA) and deoxycholic (DOCA) are reviewed. Salicylsalicylic acid is presented as a drug suggested to show dissolution rate-limited absorption and was considered as a suitable model for investigating the influences of various pharmaceutical and formulatory manoeuvres on its absorption. The experimental sections are divided according to in vitro and in vivo disciplines. The in vitro studies describe the characterization of SSA with respect to purity, particle size distribution and surface area, crystallinity, melting point, solubility, pKa, partition coefficient, stability, dissolution rate and the influence of different media on its recrystallisation. These studies showed the drug to exhibit poor solubility and high stability in acidic media and established a relationship between particle size and dissolution rate. Parameters relevant to the pH-partition hypothesis indicated that, provided SSA was in solution, then its absorption would occur throughout the entire gastro-intestinal tract. The preparation of SSA coprecipitates and admixtures with PVP, CA and DOCA are described together with their subsequent characterisation for purity, crystallinity and, in the case of the SSA:CA systems, their in vitro dissolution. In vivo studies are preceded by an introduction to some basic pharmacokinetic concepts and the methods of pharmacokinetic analyses used in this thesis. Investigations were performed in man to establish a correlation between plasma and saliva salicylate levels following oral doses of SSA. This correlation was not shown and, following a report of the limited studies carried out in man, the majority of this section deals with studies in the rat. Various pharmacokinetic criteria were established between the dose of SSA given by intravenous and oral routes. The drug was formulated as a suspension and the influences of suspending agent and particle size were ascertained. A relationship between in vitro dissolution rate and in vivo absorption for material of varying particle sizes was established and, in an attempt to improve bioavailability, the absorption of SSA from coprecipitates and admixtures with PVP, CA and DOCA was determined. These formulatory manoeuvres met with varied success; indeed, only the SSA:CA 1:1 systems significantly improved drug availability. These studies are discussed with respect to the literature and suggestions for further work are presented.
|Date of Award||1977|