Solid‐state Solubility Influences Encapsulation and Release of Hydrophobic Drugs from PLGA/PLA Nanoparticles

Abstract

Biodegradable nanoparticles formulated from poly(D,L‐lactide‐co‐glycolide) (PLGA) and polylactide (PLA) polymers are being extensively investigated for various drug delivery applications. In this study, we hypothesize that the solid‐state solubility of hydrophobic drugs in polymers could influence their encapsulation and release from nanoparticles. Dexamethasone and flutamide were used as model hydrophobic drugs. A simple, semiquantitative method based on drug–polymer phase separation was developed to determine the solid‐state drug–polymer solubility. Nanoparticles using PLGA/PLA polymers were formulated using an emulsion–solvent evaporation technique, and were characterized for size, drug loading, and in vitro release. X‐ray powder diffraction (XRD) and differential scanning calorimetry (DSC) were used to determine the physical state of the encapsulated drug. Results demonstrated that the solid‐state drug–polymer solubility depends on the polymer composition, molecular weight, and end‐functional groups (ester or carboxyl) in polymer chains. Higher solid‐state drug–polymer solubility resulted in higher drug encapsulation in nanoparticles, but followed an inverse correlation with the percent cumulative drug released. The XRD and DSC analyses demonstrated that the drug encapsulated in nanoparticles was present in the form of a molecular dispersion (dissolved state) in the polymer, whereas in microparticles, the drug was present in both molecular dispersion and crystalline forms. In conclusion, the solid‐state drug–polymer solubility affects the nanoparticle characteristics, and thus could be used as an important preformulation parameter. © 2004 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 93:1804–1814, 2004