X-Ray Diffraction and Theoretical Calculation–Supported Formation of Polymorphic Cocrystals Discovered Through Thermal Methods: A Case Study

Zhengzheng Zhou, Mónica Calatayud, Julia Contreras-García, Liang Li, Henry H.Y. Tong, Ying Zheng

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Polymorphism commonly exists in the preparation of cocrystals and has attracted widespread attention from both the pharmaceutical industry and academia. However, few studies have examined how to discover polymorphic cocrystals and their potential formation mechanism. In this study, we report the novel discovery of salicylic acid: 3-nitrobenzamide (SA-3NBZ) polymorphic cocrystals by thermal methods. The formation mechanism is elucidated based on theoretical calculations. SA-3NBZ polymorphic cocrystals with molar ratio of 1:1 and 2:2 were discovered using the combination of differential scanning calorimetry and hot stage microscopy. Single-crystal X-ray diffraction analysis confirmed this discovery. Density functional theory calculations corrected with dispersion were conducted to illustrate the energetic stabilization of SA polymorphic cocrystals. Compared with the starting materials, formation of the cocrystals at 1:1 and 2:2 present a weak stabilization with overall energy reduction of −0.01 and −0.05 eV/molecule, respectively. The calculated noncovalent interactions index further suggests that intralayer hydrogen bonds and van der Waals forces contribute to these weak interactions. The density functional theory calculations are in good agreement with the X-ray diffraction data. Hence, thermal analysis is a simple and reliable method to discover polymorphic cocrystals.

Original languageEnglish
Pages (from-to)3340-3347
Number of pages8
JournalJournal of Pharmaceutical Sciences
Volume108
Issue number10
DOIs
Publication statusPublished - Oct 2019

Keywords

  • cocrystal
  • density functional theory (DFT)
  • modulated temperature DSC (MTDSC)
  • polymorphism
  • salicylic acid
  • thermal methods

Fingerprint

Dive into the research topics of 'X-Ray Diffraction and Theoretical Calculation–Supported Formation of Polymorphic Cocrystals Discovered Through Thermal Methods: A Case Study'. Together they form a unique fingerprint.

Cite this