Author:

Keywords:

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

Abstract:

PURPOSE We recently found that indomethacin (IMC) effectively inhibits the crystallization of polyethylene glycol 6000 (PEG).1-2 However, the fate of IMC upon solidification was unelucidated. The aim of this work was to investigate the crystallization of IMC in dispersions with PEG. METHODS Dispersions of PEG and IMC were prepared by heating the mixture of the two components to above the melting point of IMC, followed by cooling the melt. The samples were stored at various conditions and characterized by differential scanning calorimetry and X-ray diffraction (XRD). RESULTS At room temperature, the drug in dispersions containing less than 50% IMC crystallized as the α-form whereas the sample containing 60% drug loading exhibited completely new XRD diffactogram which corresponds to a new polymorph of IMC (τ-form) with Bragg peaks inconsistent to any reported IMC polymorphs. τ-IMC is metastable relative to the α-form as τ-to-α phase transformation occured during storage. The formation of metastable τ-form from 60% IMC dispersions, which is in accordance with the Ostwald step rule, is due to the high mobility of the drug molecules in the liquid mixture that is in turn originating from the significant crystallization inhibition effect of IMC on PEG. In samples with drug loading below 50%, PEG crystallized more rapidly, leading to the lower mobility of IMC molecules in solid matrices and hence the crystallization of the drug as the more stable α-form. When stored at 40°C, the crystallization of PEG was impeded due to the lower degree of supercooling and consequently, the mobility of IMC molecules in 50% drug dispersions increased and the drug crystallized as the τ-polymorph. As the storage temperature rose to 55°C, the movement of the drug molecules became too rapid that the crystallization of IMC did not follow the Ostwald step rule any longer, illustrating by the formation of the α-form in 60% drug loading sample and even the most stable γ-polymorph in dispersions containing 50% IMC. The same pattern of IMC polymorph formation was also observed for dispersions of the drug in liquid PEG. CONCLUSION The study highlights the complex nature in the crystallization behavior of active pharmaceutical indredients which is driven by molecular mobility. This should be taken into account during preparation and storage to produce solid dispersions with consistent and reproducible performance. REFERENCES 1. Van Duong, T. et al. Crystallization kinetics of indomethacin/polyethylene glycol dispersions containing high drug loadings, Molecular Pharmaceutics 12 (7), 2493-2504 (2015). 2. Van Duong, T. et al. Spectroscopic investigation of the formation and disruption of hydrogen bonds in pharmaceutical semi-crystalline dispersions, Molecular Pharmaceutics 14 (5), 1726–1741 (2017).