Control of poorly soluble drug dissolution in conditions simulating the gastrointestinal tract flow .2. Cocompression of drugs with buffers

The objective of this study was to determine the primary formulation properties that affect the dissolution rate of poorly soluble nondisintegrating drugs. This work focused on compression of orally administered acidic drugs with ionizable buffers. Naproxen was used as the poorly soluble model drug, and calcium salts of carbonic, citric, and phosphoric acids were used as formulation buffers. Gastrointestinal tract (GI) dissolution was simulated in a laminar flow apparatus by exposing a drug/buffer tablet to aqueous solution of a given pH at a constant flow rate. Although formulation with a buffer resulted in reduced available drug surface area, the absolute drug dissolution rate and flux increased with increased buffer content to a maximum from tablets having equal weights of drug and buffer. This buffer-induced enhancement was seen not only in GI tract simulation (pH 7), but also at pH 2 (stomach conditions), where acidic drugs remain in their poorly soluble form upon dissolution. The flux increase was much greater than that achieved by using the same amount of an inert excipient in the solid formulation. Dissolution rates were also increased by decreased drug and buffer particle sizes and increased fluid flow rate. Drug dissolution rates were inversely proportional to intrinsic buffer solubilities: The model drug actually dissolved fastest when the buffer solubility was lower than that of the drug. Dissolution rates were apparently insensitive to the relative proximity of the drug and buffer ionization constants.