Implications of changes in physical state of drugs in poly(lactide-co-glycolide) matrices upon exposure to moisture and release medium

Abstract

The objective of this study was to investigate the influence of the drug physical state (dissolved or dispersed) in poly(lactide-co-glycolide) (PLGA) on drug release and potential changes in physical state upon contact with moisture or release medium. PLGA matrices containing risperidone, ibuprofen or dexamethasone were prepared as films by solvent casting or as implants by hot melt extrusion. The physical state of the drugs in the polymer was examined by DSC and polarized light microscopy and the in-vitro drug release was compared for different drug physical states.Incubation of drug-PLGA matrices at 40 °C/75% RH (relative humidity) resulted in a decrease in microclimate pH in the PLGA matrices upon moisture uptake, dissolving initially dispersed risperidone because of an increased drug solubility in the matrix. In contrast, initially dissolved ibuprofen precipitated in the matrix because of a decrease in drug solubility at lower pH values and a fast water uptake. Dexamethasone did not show any change of physical state under the same conditions; the drug is barely soluble in the dry matrix and its solubility is not pH dependent. Risperidone was released faster from PLGA matrices with dissolved versus dispersed drug, substantially reducing the lag time. The crystallization process of ibuprofen could be inhibited by the use of a higher molecular weight PLGA grade. The inhibition resulted in a faster release from solid solution than from the corresponding solid dispersion. However, ibuprofen, which was deliberately precipitated on the surface of a PLGA matrix by incubation at 40 °C/75% RH, was able to bridge the lag time and led to a linearization of a typical PLGA release profile.In conclusion, a change in the physical state of the drug in PLGA affects the drug release profile. A change can be induced by incubation at 40 °C/75% RH. Furthermore, moisture contact and storage conditions of PLGA drug delivery systems should be carefully considered during handling to avoid undesired drug release changes.