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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 languageEnglish (US)
Pages (from-to)6752-6762
Number of pages11
JournalCrystal Growth and Design
Issue number10
StatePublished - 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: .

How much support was provided by MRSEC?

  • Shared


Dive into the research topics of 'Novel Quasi-Emulsion Solvent Diffusion-Based Spherical Cocrystallization Strategy for Simultaneously Improving the Manufacturability and Dissolution of Indomethacin'. Together they form a unique fingerprint.

Cite this