Understanding Polymorphic Control of Pharmaceuticals Using lmidazolium-Based Ionic Liquid Mixtures as Crystallization Directing Agents
authors Martins, ICB; Gomes, JRB; Duarte, MT; Mafra, L
nationality International
journal CRYSTAL GROWTH & DESIGN
keywords SOLID-STATE; GABAPENTIN; DESIGN; FORMS; INGREDIENTS; SEPARATION; SOLVENTS
abstract Imidazolium-based room temperature ionic liquids (RTILs) were tested to assess their ability to control molecular polymorphic behavior. Mixtures of RTILs with distinct cation/anion combinations revealed promising capabilities in directing the crystallization process toward less stable polymorphs. In our tests, gabapentin (GBP) neuroleptic drug was used as a case study, as it is a well know polymorphic active pharmaceutical ingredient. For the first time, pure "bulk" GBP Form IV, a highly unstable polymorph, was isolated through RTILs. Forms were maintained over time, once they were kept soaked, opening new perspectives for the method presented here. Molecular dynamics (MD) simulations clearly supported the results. In this work the polymorphic behavior of GBP is controlled recurring to the use of different pure imidazolium-based RTILs or mixtures, as crystallization solvents. Molecular dynamics simulations clearly supported the results showing that specific H((addic)((C4/C6mim)))center dot center dot center dot O-carboxylate interaction between GBP and RTILs drives the formation of Form IV. For the first time, pure "bulk" GBP Form IV, a highly unstable polymorph, was isolated. These results showed the importance of these "directing agents" in the polymorphic process as well as the importance of using MD simulations in predicting the "designed" crystallization environment for the "desired" polymorph.
publisher AMER CHEMICAL SOC
issn 1528-7483
year published 2017
volume 17
issue 2
beginning page 428
ending page 432
digital object identifier (doi) 10.1021/acs.cgd.6b01798
web of science category Chemistry, Multidisciplinary; Crystallography; Materials Science, Multidisciplinary
subject category Chemistry; Crystallography; Materials Science
unique article identifier WOS:000393354100005
  ciceco authors
  impact metrics
times cited (wos core): 2
journal impact factor (jcr 2016): 4.055
5 year journal impact factor (jcr 2016): 4.054
category normalized journal impact factor percentile (jcr 2016): 81.179
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