Abstract
An automated parallel crystallisation search for physical forms of carbamazepine, covering 66 solvents and five crystallisation protocols, identified three anhydrous polymorphs (forms I-III), one hydrate and eight organic solvates, including the single-crystal structures of three previously unreported solvates (N,N-dimethylformamide (1:1); hemi-furfural; hemi-1,4-dioxane). Correlation of physical form outcome with the crystallisation conditions demonstrated that the solvent adopts a relatively nonspecific role in determining which polymorph is obtained, and that the previously reported effect of a polymer template facilitating the formation of form IV could not be reproduced by solvent crystallisation alone. In the accompanying computational search, approximately half of the energetically feasible predicted crystal structures exhibit the C=(OH)-H-...-N R-2(2)(8)dimer motif that is observed in the known polymorphs, with the most stable correctly corresponding to form III. Most of the other energetically feasible structures, including the global minimum, have a C=(OH)-H-...-N C(4) chain hydrogen bond motif. No such chain structures were observed in this or any other previously published work, suggesting that kinetic, rather than thermodynamic, factors determine which of the energetically feasible crystal structures are observed experimentally, with the kinetics apparently favouring nucleation of crystal structures based on the CBZ-CBZ R-2(2)(8) motif. (c) 2006 Wiley-Liss, Inc.
| Language | English |
|---|---|
| Pages | 1918-1930 |
| Number of pages | 13 |
| Journal | Journal of Pharmaceutical Sciences |
| Volume | 95 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 2006 |
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Keywords
- crystal structure prediction
- solid state
- polymorphism
- crystallisation
- hydrates/solvates
- X-ray powder diffractometry
- crystal structure
- multivariate analysis
- SMALL ORGANIC-MOLECULES
- distributed multipole
- polymorph selection
- solvent
- blind test
- nucleation
Cite this
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An automated parallel crystallisation search for predicted crystal structures and packing motifs of carbamazepine. / Florence, Alastair J.; Johnston, Andrea; Price, Sarah L.; Nowell, Harriott; Kennedy, Alan R.; Shankland, Norman.
In: Journal of Pharmaceutical Sciences, Vol. 95, No. 9, 09.2006, p. 1918-1930.Research output: Contribution to journal › Article
TY - JOUR
T1 - An automated parallel crystallisation search for predicted crystal structures and packing motifs of carbamazepine
AU - Florence, Alastair J.
AU - Johnston, Andrea
AU - Price, Sarah L.
AU - Nowell, Harriott
AU - Kennedy, Alan R.
AU - Shankland, Norman
PY - 2006/9
Y1 - 2006/9
N2 - An automated parallel crystallisation search for physical forms of carbamazepine, covering 66 solvents and five crystallisation protocols, identified three anhydrous polymorphs (forms I-III), one hydrate and eight organic solvates, including the single-crystal structures of three previously unreported solvates (N,N-dimethylformamide (1:1); hemi-furfural; hemi-1,4-dioxane). Correlation of physical form outcome with the crystallisation conditions demonstrated that the solvent adopts a relatively nonspecific role in determining which polymorph is obtained, and that the previously reported effect of a polymer template facilitating the formation of form IV could not be reproduced by solvent crystallisation alone. In the accompanying computational search, approximately half of the energetically feasible predicted crystal structures exhibit the C=(OH)-H-...-N R-2(2)(8)dimer motif that is observed in the known polymorphs, with the most stable correctly corresponding to form III. Most of the other energetically feasible structures, including the global minimum, have a C=(OH)-H-...-N C(4) chain hydrogen bond motif. No such chain structures were observed in this or any other previously published work, suggesting that kinetic, rather than thermodynamic, factors determine which of the energetically feasible crystal structures are observed experimentally, with the kinetics apparently favouring nucleation of crystal structures based on the CBZ-CBZ R-2(2)(8) motif. (c) 2006 Wiley-Liss, Inc.
AB - An automated parallel crystallisation search for physical forms of carbamazepine, covering 66 solvents and five crystallisation protocols, identified three anhydrous polymorphs (forms I-III), one hydrate and eight organic solvates, including the single-crystal structures of three previously unreported solvates (N,N-dimethylformamide (1:1); hemi-furfural; hemi-1,4-dioxane). Correlation of physical form outcome with the crystallisation conditions demonstrated that the solvent adopts a relatively nonspecific role in determining which polymorph is obtained, and that the previously reported effect of a polymer template facilitating the formation of form IV could not be reproduced by solvent crystallisation alone. In the accompanying computational search, approximately half of the energetically feasible predicted crystal structures exhibit the C=(OH)-H-...-N R-2(2)(8)dimer motif that is observed in the known polymorphs, with the most stable correctly corresponding to form III. Most of the other energetically feasible structures, including the global minimum, have a C=(OH)-H-...-N C(4) chain hydrogen bond motif. No such chain structures were observed in this or any other previously published work, suggesting that kinetic, rather than thermodynamic, factors determine which of the energetically feasible crystal structures are observed experimentally, with the kinetics apparently favouring nucleation of crystal structures based on the CBZ-CBZ R-2(2)(8) motif. (c) 2006 Wiley-Liss, Inc.
KW - crystal structure prediction
KW - solid state
KW - polymorphism
KW - crystallisation
KW - hydrates/solvates
KW - X-ray powder diffractometry
KW - crystal structure
KW - multivariate analysis
KW - SMALL ORGANIC-MOLECULES
KW - distributed multipole
KW - polymorph selection
KW - solvent
KW - blind test
KW - nucleation
U2 - 10.1002/jps.20647
DO - 10.1002/jps.20647
M3 - Article
VL - 95
SP - 1918
EP - 1930
JO - Journal of Pharmaceutical Sciences
T2 - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 9
ER -