Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin

Hongbo Chen; Hongyun Xu; Chenguang Wang; Hyunho Kang; Christy L. Haynes; Mahesh K. Mahanthappa; Changquan Calvin Sun

doi:10.1021/acs.cgd.0c00876

Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin

Hongbo Chen, Hongyun Xu, Chenguang Wang, Hyunho Kang, Christy L. Haynes, Mahesh K. Mahanthappa, Changquan Calvin Sun

Pharmaceutics

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

The successful development of tablet formulations of many active pharmaceutical ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability, tabletability) and dissolution characteristics. Here, we report a novel quasi-emulsion solvent diffusion cocrystallization (QESD-CC) method as an integrated crystal and particle engineering approach for successful generation of spherical cocrystal agglomerates of the poorly soluble drug indomethacin (IMC) and the sweet cocrystallization agent saccharin (SAC). The QESD-CC process consists of two distinct steps: (1) formation of a transient emulsion containing solvated IMC and SAC and (2) subsequent precipitation of IMC-SAC cocrystals from the emulsion as hollow spherical particles. Solution 1H NMR analyses and computational modeling studies indicated that hydroxypropyl methylcellulose (HPMC) preferentially interacts with the SAC molecules through hydrogen bonds, thus driving the polymer to form a shell that stabilizes the transient emulsion droplets and coats the resulting particles. Spherical QESD-CC particles exhibited excellent flowability, while the HPMC coating and microsize primary crystals led to excellent tabletability. Outstanding manufacturability and high cocrystal solubility thus enabled the successful development of a high-drug-loading tablet formulation comprising 46.3 wt % IMC.

Original language	English (US)
Pages (from-to)	6752-6762
Number of pages	11
Journal	Crystal Growth and Design
Volume	20
Issue number	10
DOIs	https://doi.org/10.1021/acs.cgd.0c00876
State	Published - Oct 7 2020

Bibliographical note

Funding Information:
H.C. was partially supported by the David Grant and Marilyn Grant Fellowship in Physical Pharmacy (2019-2020), Department of Pharmaceutics, University of Minnesota. H.X. and M.K.M. gratefully acknowledge National Science Foundation DMR-1708874. Contributions from H.K. and C.L.H. were supported by the National Science Foundation under the Center for Sustainable Nanotechnology, CHE-1503408; the CSN is part of the Centers for Chemical Innovation Program. SEM analyses were performed in the College of Science and Engineering Characterization Facility at the University of Minnesota, which receives partial support from National Science Foundation through the UMN MRSEC (DMR-1420013). Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nano Coordinated Infrastructure Network (NNCI) under Award ECCS-1542202. We thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported in this paper. URL: http://www.msi.umn.edu .

Publisher Copyright:
© 2020 American Chemical Society.

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title = "Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin",

abstract = "The successful development of tablet formulations of many active pharmaceutical ingredients (APIs) is challenged by their poor manufacturability (e.g., flowability, tabletability) and dissolution characteristics. Here, we report a novel quasi-emulsion solvent diffusion cocrystallization (QESD-CC) method as an integrated crystal and particle engineering approach for successful generation of spherical cocrystal agglomerates of the poorly soluble drug indomethacin (IMC) and the sweet cocrystallization agent saccharin (SAC). The QESD-CC process consists of two distinct steps: (1) formation of a transient emulsion containing solvated IMC and SAC and (2) subsequent precipitation of IMC-SAC cocrystals from the emulsion as hollow spherical particles. Solution 1H NMR analyses and computational modeling studies indicated that hydroxypropyl methylcellulose (HPMC) preferentially interacts with the SAC molecules through hydrogen bonds, thus driving the polymer to form a shell that stabilizes the transient emulsion droplets and coats the resulting particles. Spherical QESD-CC particles exhibited excellent flowability, while the HPMC coating and microsize primary crystals led to excellent tabletability. Outstanding manufacturability and high cocrystal solubility thus enabled the successful development of a high-drug-loading tablet formulation comprising 46.3 wt % IMC. ",

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Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin

Abstract

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