Author:

Keywords:

crystallization, solid dispersions, molecular mobility, indomethacin, polyethylene glycol, Ostwald step rule

Abstract:

INTRODUCTION Solid dispersion (SD) of an active pharmaceutical ingredient (API) and a carrier is a powerful strategy to overcome the limited solubility and dissolution rate of poorly water soluble APIs. As the carrier normally constitutes the largest part of the formulation, its characteristics greatly contribute to the performance of SD. However, studies on SD have mainly focused on how carriers affect the properties of APIs. There have been only few studies dealing with the influence of APIs and preparation process on the properties of the carriers in the system. For amorphous carriers, the modifications in their conformation might lead to significant differences in the API stabilization and supersaturation maintenance effect of the carriers. The story becomes even more complicated with semi-crystalline carriers like polyethylene glycol (PEG). Therefore, thorough understanding of behaviors of both APIs and carriers is important for preparation of SD with consistent and reproducible quality. MATERIALS AND METHODS Dispersions of polyethylene glycol 6000 (PEG) and indomethacin (IMC) were prepared by heating the mixture of the two components to above the melting point of IMC, followed by solidification of the melt. The samples were stored at different conditions and characterized by X-ray powder diffraction (XRPD), Raman microscopy and polarized light microscopy. RESULTS Increasing the drug loading resulted in slower crystallization of PEG and faster crystallization of IMC, except the sample containing 70% IMC showing the highest crystallization rate of both components. In dispersions containing ≤ 50% IMC, the drug crystallized as the α-form whereas samples containing higher drug loadings (≥ 60%) exhibited new XRPD peaks. In the latter cases, Raman spectra show that most PEG signals weakened or disappeared while IMC displayed peaks that are inconsistent to signals of α- and -form of IMC. We hypothesize that in PEG-IMC dispersions containing high drug loadings, a co-crystal of IMC and PEG was generated. Raman spectroscopy indicates the segregation of IMC from co-crystal upon crystallization. The co-crystal is metastable as IMC transforms into the α-form upon storage. By controlling the composition of the dispersions and the storage conditions, IMC can be obtained as co-crystal with PEG, α - or γ-form. CONCLUSIONS This study highlights the complex nature in crystallization of semi-crystalline dispersions, which should be taken into account during preparation and storage to produce SD with consistent and reproducible performance.