Formation of composite drug–polymer particles by co-precipitation during the rapid expansion of supercritical fluids

In modern medicine oral application of solid forms is the preferential way. Thus, in pharmaceutical applications size, shape and morphology of the solid particles are important because they can affect the bioavailability of drug particles. Since the bioavailability of orally applied drugs depends on the rate of dissolution and absorption, methods to increase the rate of dissolution are often necessary to reach significant blood levels. A promising way to increase the dissolution rate is the reduction of particle size. Recent investigations show, that the rapid expansion of supercritical solutions (RESS) enables the formation of submicron particles of thermally labile drugs and dissolution studies demonstrate that submicron drugs are characterized by a significantly higher dissolution rate. However, active ingredients in the micro- or sub-micro range are very difficult to be included in solid dosage forms. To overcome this, the co-precipitation during the rapid expansion of supercritical solutions (CORESS) was used to produce composite particles. In CORESS both, the drug and the biodegradable polymer are dissolved in supercritical CO2, followed by the rapid expansion of the ternary mixture. This leads to the simultaneous co-precipitation of the solutes, resulting in the different morphologies and composition profiles for the composite particles.In the present work, the micronisation of two pure polymers by RESS and the formation of composite l-poly(lactic acid)–phytosterol particles formed by CORESS were investigated. These experiments showed the feasibility of CORESS to enable the formation of submicron composite particles with different solutes. Prior to the CORESS-experiments, the phase behaviour of CO2/phytosterol and of CO2/l-poly(lactic acid) were investigated. The melting temperature of the pure solutes under CO2 pressure and the solubility of phytosterol in CO2 were also measured.