Successful computationally directed templating of metastable pharmaceutical polymorphs

David H. Case, Vijay K. Srirambhatla, Rui Guo, Rona E. Watson, Louise S. Price, Hector Polyzois, Jeremy K. Cockcroft, Alastair J. Florence, Derek A. Tocher, Sarah L. Price

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

A strategy of using crystal structure prediction (CSP) methods to determine which, if any, isostructural template could facilitate the first crystallization of a predicted polymorph by vapor deposition is extended to the fenamate family. Mefenamic acid (MFA) and tolfenamic acid (TFA) are used as molecules with minimal chemical differences, whereas flufenamic acid (FFA) shows greater differences in the substituents. The three crystal energy landscapes were calculated, and periodic electronic structure calculations were used to confirm the thermodynamic plausibility of possible isostructural polymorphs to experimentally obtainable crystals of the other molecules. As predicted, a new polymorph, TFA form VI, was found by sublimation onto isomorphous MFA form I, using a recently developed technique. MFA and TFA form a continuous solid solution with the structure of MFA I and TFA VI at the limits, but the isomorphous MFA/FFA solid solution does not extended to a new polymorph of FFA. The novel solid solution structure of TFA and FFA was found, and a new isomorphous polymorph TFA VII was found by sublimation onto this new solid solution template. Sublimation of TFA onto a metal surface at the early stage of deposition gave TFA form VIII. We rationalize the formation of new polymorphs of only TFA.
LanguageEnglish
Pages5322-5331
Number of pages10
JournalCrystal Growth and Design
Volume18
Issue number9
Early online date2 Aug 2018
DOIs
Publication statusPublished - 5 Sep 2018

Fingerprint

Polymorphism
Drug products
Mefenamic Acid
acids
Acids
Pharmaceutical Preparations
Solid solutions
Sublimation
solid solutions
sublimation
Fenamates
tolfenamic acid
Crystals
Vapor deposition
Molecules
Crystallization
templates
Electronic structure
Crystal structure
Metals

Keywords

  • crystal structure prediction
  • crystalization
  • polymorph

Cite this

Case, David H. ; Srirambhatla, Vijay K. ; Guo, Rui ; Watson, Rona E. ; Price, Louise S. ; Polyzois, Hector ; Cockcroft, Jeremy K. ; Florence, Alastair J. ; Tocher, Derek A. ; Price, Sarah L. / Successful computationally directed templating of metastable pharmaceutical polymorphs. In: Crystal Growth and Design. 2018 ; Vol. 18, No. 9. pp. 5322-5331.
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Successful computationally directed templating of metastable pharmaceutical polymorphs. / Case, David H.; Srirambhatla, Vijay K.; Guo, Rui; Watson, Rona E.; Price, Louise S.; Polyzois, Hector; Cockcroft, Jeremy K.; Florence, Alastair J.; Tocher, Derek A.; Price, Sarah L.

In: Crystal Growth and Design, Vol. 18, No. 9, 05.09.2018, p. 5322-5331.

Research output: Contribution to journalArticle

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AU - Case, David H.

AU - Srirambhatla, Vijay K.

AU - Guo, Rui

AU - Watson, Rona E.

AU - Price, Louise S.

AU - Polyzois, Hector

AU - Cockcroft, Jeremy K.

AU - Florence, Alastair J.

AU - Tocher, Derek A.

AU - Price, Sarah L.

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N2 - A strategy of using crystal structure prediction (CSP) methods to determine which, if any, isostructural template could facilitate the first crystallization of a predicted polymorph by vapor deposition is extended to the fenamate family. Mefenamic acid (MFA) and tolfenamic acid (TFA) are used as molecules with minimal chemical differences, whereas flufenamic acid (FFA) shows greater differences in the substituents. The three crystal energy landscapes were calculated, and periodic electronic structure calculations were used to confirm the thermodynamic plausibility of possible isostructural polymorphs to experimentally obtainable crystals of the other molecules. As predicted, a new polymorph, TFA form VI, was found by sublimation onto isomorphous MFA form I, using a recently developed technique. MFA and TFA form a continuous solid solution with the structure of MFA I and TFA VI at the limits, but the isomorphous MFA/FFA solid solution does not extended to a new polymorph of FFA. The novel solid solution structure of TFA and FFA was found, and a new isomorphous polymorph TFA VII was found by sublimation onto this new solid solution template. Sublimation of TFA onto a metal surface at the early stage of deposition gave TFA form VIII. We rationalize the formation of new polymorphs of only TFA.

AB - A strategy of using crystal structure prediction (CSP) methods to determine which, if any, isostructural template could facilitate the first crystallization of a predicted polymorph by vapor deposition is extended to the fenamate family. Mefenamic acid (MFA) and tolfenamic acid (TFA) are used as molecules with minimal chemical differences, whereas flufenamic acid (FFA) shows greater differences in the substituents. The three crystal energy landscapes were calculated, and periodic electronic structure calculations were used to confirm the thermodynamic plausibility of possible isostructural polymorphs to experimentally obtainable crystals of the other molecules. As predicted, a new polymorph, TFA form VI, was found by sublimation onto isomorphous MFA form I, using a recently developed technique. MFA and TFA form a continuous solid solution with the structure of MFA I and TFA VI at the limits, but the isomorphous MFA/FFA solid solution does not extended to a new polymorph of FFA. The novel solid solution structure of TFA and FFA was found, and a new isomorphous polymorph TFA VII was found by sublimation onto this new solid solution template. Sublimation of TFA onto a metal surface at the early stage of deposition gave TFA form VIII. We rationalize the formation of new polymorphs of only TFA.

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