Chemicals case study
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Molecular Modeling Of The Crystal Cleavage Of
Drugs And Pharmaceutical Excipients
Industry Sector
The cleavage properties of crystals are important in materials processing.
Pharmaceutical
Fragmentation procedures, such as milling or compaction, often cause materials to fracture preferentially along slip planes. In crystalline powders, this not
Organization
merely increases the total surface area, but also changes the relative exposure
University of Bradford
of different crystal faces. For example, the exposure of the slip plane can be
enhanced. Furthermore, the morphology of the particles can be altered, which
Key Product
in turn affects the powder flow properties.
Morphology
Various computational algorithms have been applied to the prediction of crystal growth and crystal morphology.
1-3
Researchers at the University of
Bradford extended these methods to investigate the cleavage behavior of
eight drugs and pharmaceutical excipients, including aspirin, DL-mannitol,
paracetamol (acetaminophen) form I, DL-ibuprofen, DL-ketoprofen, carbamazepine form III, beta-lactose, and tolbutamide.
4
1
Based on the growth morphology model, attachment energy, the energy
released on the attachment of a growth slice to a growing crystal surface, is
associated with the growth of a crystal face. The most probable growth layer
on a given face is the one bound most weakly to the crystal face. Such layer
has the smallest attachment energy of all possible layers that could be
Morphology of aspirin
obtained by cleaving the crystal parallel to that face. Therefore, attachment
energies may be used to predict the most probable cleavage plane based on
the assumption that the surface with the smallest attachment energy will be
the preferred cleavage surface.
5
With this in mind, the researchers used Accelrys' Morphology module
6
7
and the DREIDING and COMPASS force fields to calculate the attachment
energies for the eight experimental crystal structures with and without
geometry optimization. These attachment energies were then used
to predict the most probable cleavage or slip planes and are tabulated
in Table 1. The prediction agreed quite well with experimental observations.
For example, Aspirin is known experimentally to cleave on (100) and
(001),
8
with
(100)
9
being
the
preferred
cleavage
plane.
The (100) and (001) planes respectively have the smallest and second smallest
attachment energies, which are consistent with the observed cleavage.
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Tel: 81 3 3578 3861
{100} cleavage planes of
aspirin
Chemicals case study continued
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There are only two materials, paracetamol and ketoprofen, for which COMPASS and DREIDING differ in identifying surfaces with the smallest and second smallest attachment energy. Paracetamol has relatively small energy differences between the three weakest planes as calculated by either force field.
However, ketoprofen (100) is found to be the most weakly bound plane with
-1
COMPASS, but is 21 or 25 kJ mol (unoptimized or optimized structures respectively) more strongly bound than the weakest plane obtained using DREIDING, which in contrast is (010). Cleavage on (010) appears more reasonable as
it would avoid severing hydrogen bonds.
hkl
DREIDING
DREIDING
Unoptimized Optimized
COMPASS
COMPASS
Unoptimized Optimized
001
-80 C
-93 C
-73 C
-83 C
100
-120
-133
-86
-87
100
-21 C
-23 C
-22 C
-26 C
001
-43
-45
-45
-46
DL-Mannitol (Pna21)
Aspirin (P21/c)
Paracetamol form I (P21/a)
010
-56 C
-55 C
-63
-63
110
67
-72
-56 C
-58 C
201
68
-74
-57 C
-57 C
100
-20 C
-20 C
-19 C
-19 C
001
-66
-66
-61
-63
010
-51 C
-53 C
-54
-55
110
-55
-59
-58
-59
001
-61
-63
-68
-65
100
-72
-78
-44 C
-51 C
DL-Ibuprofen (P21/c)
DL-Ketoprofen (P-1)
Carbamazepine form III (P21/c)
110
-61 C
-66 C
-65 C
-68 C
001
-66
-72
-72
-78
100
-109 C
-150 C
-101 C
-133 C
110
-148
-201
-122
-143
100
-37 C
-36 C
-32 C
-33 C
110
-68
-74
-59
-64
β-Lactose (P2 )
1
Tolbutamide (Pna21)
-1
Table 1 Attachment energies. Energies are in KJ mol . The most probable cleavage
planes are labelled C.
Chemicals case study continued
This study confirms the validity of using attachment energies for the prediction of cleavage or slip planes in a range of drugs and excipients. Structural
optimization has little impact on the attachment energy calculations. The
choice of force fields usually makes no difference to the predicted most probable cleavage planes.
References
1. Docherty, R.; Clydesdale, G.; Roberts, K.J.; Bennema, P., J. Phys. D: Appl. Phys.,
24, 89 (1991).
2. Donnay, J. D. H.; Harker, D., Am. Mineral. 22, 463 (1937).
3. Grimbergen, R. F. P., Bennema, P.; Meekes H., Acta Cryst. A54 (1998).
4. Osborn, J., York, P., 14th Int. Symp. Ind. Cryst. 1999. Cambridge, UK.
5. Robert, R.J., Rowe, R.C., York, P. J. Mater. Sci. 29, 2289 (1994).
6. Mayo, S.L., Olafson, B.D., Goddard, W.A., J. Phys. Chem. 94, 8897 (1990).
7. H. Sun, J. Phys. Chem. B. 102, 7338-7364 (1998).
8. Winchell, A.N, The Optical Properties of Organic Compouns, 2nd Ed. (1954).
9. Masaki, N., Machida, K., Kado, H., Yokoyama, K., Tohda, T., Chem. Pharm. Bull.
39, 1899 (1991).
Molecular Modeling Of The Crystal Cleavage Of Drugs And Pharmaceutical Excipients
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