Efficient screening of coformers for active pharmaceutical ingredient cocrystallization
Author(s)
Sugden, Isaac J
Braun, Doris E
Bowskill, David H
Adjiman, Claire S
Pantelides, Constantinos C
Type
Journal Article
Abstract
Controlling the physical properties of solid forms for active pharmaceutical ingredients (APIs) through cocrystallization is an important part of drug product development. However, it is difficult to know a priori which coformers will form cocrystals with a given API, and the current state-of-the-art for cocrystal discovery involves an expensive, time-consuming, and, at the early stages of pharmaceutical development, API material-limited experimental screen. We propose a systematic, high-throughput computational approach primarily aimed at identifying API/coformer pairs that are unlikely to lead to experimentally observable cocrystals and can therefore be eliminated with only a brief experimental check, from any experimental investigation. On the basis of a well-established crystal structure prediction (CSP) methodology, the proposed approach derives its efficiency by not requiring any expensive quantum mechanical calculations beyond those already performed for the CSP investigation of the neat API itself. The approach and assumptions are tested through a computational investigation on 30 potential 1:1 multicomponent systems (cocrystals and solvate) involving 3 active pharmaceutical ingredients and 9 coformers and one solvent. This is complemented with a detailed experimental investigation of all 30 pairs, which led to the discovery of five new cocrystals (three API–coformer combinations, a polymorphic cocrystal example, and one with different stoichiometries) and a cis-aconitic acid polymorph. The computational approach indicates that, for some APIs, a significant proportion of all potential API/coformer pairs could be investigated with only a brief experimental check, thereby saving considerable experimental effort.
Date Issued
2022-06-06
Date Acceptance
2022-06-01
Citation
Crystal Growth & Design, 2022, 22 (7), pp.4513-4527
ISSN
1528-7483
Publisher
American Chemical Society
Start Page
4513
End Page
4527
Journal / Book Title
Crystal Growth & Design
Volume
22
Issue
7
Copyright Statement
© 2022 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0 .
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/35915670
Subjects
AB-INITIO GENERATION
ACCURATE
ACID
Chemistry
Chemistry, Multidisciplinary
Crystallography
CRYSTAL-STRUCTURE PREDICTION
FORCE
INTRAMOLECULAR ENERGY
Materials Science
Materials Science, Multidisciplinary
MINIMIZATION
Physical Sciences
POLYMORPHS
REFINEMENT
REPRESENTATION
Science & Technology
Technology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2022-06-15