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We investigated the effect of drug physico-chemical properties on the release of basic drugs from poly( l -lactic acid) (P(L)LA) cylindrical matrices (rods; 10 mm×1 mm diameter). All the rods were revealed to exhibit two-stage diffusion-controlled release profiles resulting from the transformation of P(L)LA from an amorphous to a semicrystalline state in aqueous medium. On the assumption that interactions between polymer carboxyl residues and basic drugs control the drug release rate, we evaluated the strength of these interactions by the drug partition between the polymer and the aqueous medium. In the first release stage, the drugs diffused through the swollen polymer matrix. The polymer–drug interactions shielded the polymer terminal carboxyl residues, thereby resulting in a less hydrated matrix and consequent diminishment of drug diffusion. In the second release stage, the drugs diffused through the water-filled micropores which had developed as a result of polymer crystallization. The stronger polymer–basic drug interactions reduced the drug diffusion rate by decreasing not only the porosity of the matrix, but also the drug partition to the water-filled micropores. It was also found that the fractional drug release rate in the second stage increased with drug content of the rod at the pH where both the polymer carboxyl residues and the drugs were ionized. Since the polymer–drug interactions must be close to saturation with increasing drug content, we believe this result to be due to an increase in the ratio of the drug partition to the water-filled micropores.

Effects of drug content and medium pH on the release of papaverine (PAP) from biodegradable poly(l-lactic acid) [P(L)LA] matrix were investigated to reveal the predominant factors affecting the two-stage diffusion-controlled release mechanism. A drug-dissolved cylindrical matrix (rod; 10 mmx1 mm diameter) was prepared by heat compression method. In the case of a PAP content below 10%, pH was found to have a strong effect on the release rate, and drug content was found to have no effect on the release profile. The release profile consisted of two sequential diffusion stages due to P(L)LA transformation from amorphous to the semicrystalline state prior to release. In the first release stage PAP diffused through the swollen matrix. The release accelerated with increasing medium pH due to an increase in water content in the acidic P(L)LA rod. In the second release stage PAP diffused through the water-filled micropores developed as a result of the polymer crystallization. On the assumption that the drug partition between the polymer and the medium in the micropores affects the diffusion and the partition is controlled by pH, we derived a modified diffusion kinetic equation. The observation that the release decelerated with increasing medium pH can be explained by the derived equation as resulting from the increase in the drug partition to the polymer. In the case where the rods contained more than 15% of PAP, the drug precipitated out as crystals during release. Accordingly, these rods showed a slower release.