Stabilization of the Metastable α-Form of Indomethacin Induced by the Addition of 2-Hydroxypropyl-β-Cyclodextrin, Causing Supersaturation (Spring) and Its Sustaining Deployment (Parachute).

The purpose of this study is to find that a small amount of 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) can produce a parachute effect on indomethacin (INM). From the examination of dissolution curves and concentration after several days, the supersaturation of INM was observed for the mixtures containing HP-β-CD at a molar ratio ≤ 0.5, and the sustained deployment of supersaturation was found not only in equimolar mixtures but also in mixtures with a shortage of HP-β-CD. In the solid state, it was compared the physical properties of INM/HP-β-CD mixtures using two different mixing methods and determined the stoichiometry of INM and HP-β-CD. Differential scanning calorimetry (DSC) revealed that the polymorphs of INM were converted by HP-β-CD into an amorphous state. Furthermore, X-ray powder diffraction (XRPD) and DSC-XRPD demonstrated that INM crystals from the INM/HP-β-CD mixture prepared from an EtOH solution were metastable. In conclusion, these phenomena may be considered the "spring" and "parachute" effects of mixtures with a shortage of HP-β-CD, as they depended on the presence of the metastable α-form of INM. The addition of 1/3 to 1/20 equivalents of HP-β-CD to INM enhanced INM solubility. Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Citation

Ayako Wada-Hirai, Shota Shimizu, Risa Ichii, Chihiro Tsunoda, Ryosuke Hiroshige, Momoko Fujita, Ying-Peng Li, Yohsuke Shimada, Yuta Otsuka, Satoru Goto. Stabilization of the Metastable α-Form of Indomethacin Induced by the Addition of 2-Hydroxypropyl-β-Cyclodextrin, Causing Supersaturation (Spring) and Its Sustaining Deployment (Parachute). Journal of pharmaceutical sciences. 2021 Nov;110(11):3623-3630

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PMID: 34364701

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