Compatibility of selected active pharmaceutical ingredients with poly(D, L-lactide-co-glycolide): Computational and experimental study

Biodegradable polyesters have emerged as a promising class of polymers for the development of efficient drug delivery systems for various treatments (including cancer treatment) due to their biocompatibility, low toxicity, and controlled drug release. This study presents a computational and experimental evaluation of the compatibility of selected model active pharmaceutical ingredients (APIs) with poly(D, L-lactide-co-glycolide) (PLGA), which is a key parameter to designing drug delivery systems based on amorphous solid dispersions (ASDs) and polymeric micro- or nanoparticles. PLGA with different molar ratios of the monomer units, i.e., lactide to glycolide ratio of 50:50 (PLGA50) or 75:25 (PLGA75), were investigated as polymeric carriers for the following model APIs: ibuprofen (IBU), paracetamol (PARA), naproxen (NAP), and indomethacin (IND). The phase diagrams obtained by a combination of calorimetric measurements and modeling using the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS) demonstrated low solubility of the model APIs in the studied copolymers at storage temperature (25 °C). The amorphous-amorphous phase separation was predicted by the PC-SAFT EOS for all API–PLGA systems and experimentally detected for the IBU–PLGA50, IBU–PLGA75, and NAP–PLGA75 systems. To investigate the physical stability of the API–PLGA systems and their link to the constructed phase diagrams, API–PLGA75 formulations were prepared using a melting process, and their solid-state properties were monitored over time. Of the analyzed API–PLGA75 formulations, only IND–PLGA75 remained in the amorphous state after 20 weeks of storage under dry conditions at 25 °C, while the other formulations recrystallized rapidly after preparation (IBU–PLGA75 and NAP–PLGA75) or after a limited storage period (PARA–PLGA75), reflecting poor compatibility of the investigated APIs with the PLGA copolymers and limited kinetic stabilization, as predicted from the constructed phase diagrams. Another important output of this work is the evaluation of the pure predictions of phase diagrams using the PC-SAFT EOS and its performance in ranking API–polymer compatibility.

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