In Silico Solid State Perturbation for Solubility Improvement

ChemMedChem - Tập 9 Số 4 - Trang 724-726 - 2014
Lars‐Erik Briggner1, Lars Kloo2, Jan Rosdahl2, Per H. Svensson2,3
1Adroit Science AB, Medicon Village, 223 81 Lund (Sweden)
2Division of Applied Physical Chemistry, Royal Institute of Technology, Teknikringen 30, 100 44 Stockholm (Sweden)
3SP Process Development, Technical Research Institute of Sweden, Forskargatan 18, Buildning 341, Box 36, 151 21 Södertälje (Sweden)

Tóm tắt

AbstractSolubility is a frequently recurring issue within pharmaceutical industry, and new methods to proactively resolve this are of fundamental importance. Here, a novel methodology is reported for intrinsic solubility improvement, using in silico prediction of crystal structures, by perturbing key interactions in the crystalline solid state. The methodology was evaluated with a set of benzodiazepine molecules, using the two‐dimensional molecular structure as the only a priori input. The overall trend in intrinsic solubility was correctly predicted for the entire set of benzodiazepines molecules. The results also indicate that, in drug compound series where the melting point is relatively high (i.e., “brick dust” compounds), the reported methodology should be very suitable for identifying strategically important molecular substitutions to improve solubility. As such, this approach could be a useful predictive tool for rational compound design in the early stages of drug development.

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ChemMedChem

Tập 9 Số 4

724-726

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