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Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients

Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients
Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients
Co-crystal screening is routinely undertaken using high-throughput solution growth. We report a low- to medium-throughput approach, encompassing both a melt and solution crystallization step as a route to the identification of co-crystals. Prior to solution studies, a melt growth step was included utilizing the Kofler mixed fusion method. This method allowed elucidation of the thermodynamic landscape within the binary phase diagram and was found to increase overall screening efficiency. The pharmaceutically acceptable adduct nicotinamide was selected and screened against a small set of active pharmaceutical ingredients (APIs) (ibuprofen (both the racemic compound (R/S) and S-enantiomer), fenbufen, flurbiprofen (R/S), ketoprofen (R/S), paracetamol, piracetam, and salicylic acid) as part of a larger systematic study of synthon stability. From the screen, three new co-crystal systems have been identified (ibuprofen (R/S and S) and salicylic acid) and their crystal structures determined. Because of poor crystal growth synchrotron radiation was required for structure solution of the S-ibuprofen nicotinamide co-crystal. Two further potential systems have also been discovered (fenbufen and flurbiprofen), but crystals suitable for structure determination have yet to be obtained. A greater ability to control crystallization kinetics is required to yield phase-pure single-crystalline material for full verification of this crystal engineering strategy.
sulfathiazole, z'-greater-than-1, design, solubility, multiple molecules, cambridge structural database, polymorphism, cocrystals, acetaminophen, solid-state
1528-7483
1697-1712
Berry, D.J.
df2e93b1-43f2-401b-9047-1ce7429201bf
Seaton, C.C.
8b16f972-7997-4e85-8afb-e39d12203d98
Clegg, W.
a29c8e43-b6a6-4db7-9ce2-e44da8792cb5
Harrington, R.W.
e912893d-1846-4f66-8f20-b810e7aef239
Coles, S.J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Horton, P.N.
154c8930-bfc3-495b-ad4a-8a278d5da3a5
Hursthouse, M.B.
57a2ddf9-b1b3-4f38-bfe9-ef2f526388da
Storey, R.
b8bc48de-b9b0-4297-bafc-c3ae9e823ad7
Jones, W.
c18f6cea-13e4-4c34-b280-f95cf8c6dd12
Friscic, T.
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Blagden, N.
d129206f-57ce-4292-9c3f-abe9669e5e82
Berry, D.J.
df2e93b1-43f2-401b-9047-1ce7429201bf
Seaton, C.C.
8b16f972-7997-4e85-8afb-e39d12203d98
Clegg, W.
a29c8e43-b6a6-4db7-9ce2-e44da8792cb5
Harrington, R.W.
e912893d-1846-4f66-8f20-b810e7aef239
Coles, S.J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Horton, P.N.
154c8930-bfc3-495b-ad4a-8a278d5da3a5
Hursthouse, M.B.
57a2ddf9-b1b3-4f38-bfe9-ef2f526388da
Storey, R.
b8bc48de-b9b0-4297-bafc-c3ae9e823ad7
Jones, W.
c18f6cea-13e4-4c34-b280-f95cf8c6dd12
Friscic, T.
2396e6bb-91d7-456f-9806-8c3b51f2564d
Blagden, N.
d129206f-57ce-4292-9c3f-abe9669e5e82

Berry, D.J., Seaton, C.C., Clegg, W., Harrington, R.W., Coles, S.J., Horton, P.N., Hursthouse, M.B., Storey, R., Jones, W., Friscic, T. and Blagden, N. (2008) Applying hot-stage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients. Crystal Growth & Design, 8 (5), 1697-1712. (doi:10.1021/cg800035w).

Record type: Article

Abstract

Co-crystal screening is routinely undertaken using high-throughput solution growth. We report a low- to medium-throughput approach, encompassing both a melt and solution crystallization step as a route to the identification of co-crystals. Prior to solution studies, a melt growth step was included utilizing the Kofler mixed fusion method. This method allowed elucidation of the thermodynamic landscape within the binary phase diagram and was found to increase overall screening efficiency. The pharmaceutically acceptable adduct nicotinamide was selected and screened against a small set of active pharmaceutical ingredients (APIs) (ibuprofen (both the racemic compound (R/S) and S-enantiomer), fenbufen, flurbiprofen (R/S), ketoprofen (R/S), paracetamol, piracetam, and salicylic acid) as part of a larger systematic study of synthon stability. From the screen, three new co-crystal systems have been identified (ibuprofen (R/S and S) and salicylic acid) and their crystal structures determined. Because of poor crystal growth synchrotron radiation was required for structure solution of the S-ibuprofen nicotinamide co-crystal. Two further potential systems have also been discovered (fenbufen and flurbiprofen), but crystals suitable for structure determination have yet to be obtained. A greater ability to control crystallization kinetics is required to yield phase-pure single-crystalline material for full verification of this crystal engineering strategy.

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More information

e-pub ahead of print date: 7 May 2008
Published date: May 2008
Keywords: sulfathiazole, z'-greater-than-1, design, solubility, multiple molecules, cambridge structural database, polymorphism, cocrystals, acetaminophen, solid-state
Organisations: Chemistry

Identifiers

Local EPrints ID: 54425
URI: https://eprints.soton.ac.uk/id/eprint/54425
ISSN: 1528-7483
PURE UUID: a5488900-7a6d-4bd2-8d6f-33290c7d08d8
ORCID for S.J. Coles: ORCID iD orcid.org/0000-0001-8414-9272
ORCID for P.N. Horton: ORCID iD orcid.org/0000-0001-8886-2016

Catalogue record

Date deposited: 05 Aug 2008
Last modified: 19 Nov 2019 01:53

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Contributors

Author: D.J. Berry
Author: C.C. Seaton
Author: W. Clegg
Author: R.W. Harrington
Author: S.J. Coles ORCID iD
Author: P.N. Horton ORCID iD
Author: M.B. Hursthouse
Author: R. Storey
Author: W. Jones
Author: T. Friscic
Author: N. Blagden

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