In Silico Solid State Perturbation for Solubility Improvement

QC 20140604
Solubility 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 insilico 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.

Kloo, LarsKTH,Tillämpad fysikalisk kemi,KTH Royal Institute of Technology, Sweden(Swepub:kth)u1jrdr1m (author)
Rosdahl, JanKTH,Tillämpad fysikalisk kemi,KTH Royal Institute of Technology, Sweden(Swepub:kth)u1r4rexr (author)
Svensson, Per H.RISE,KTH,Tillämpad fysikalisk kemi,Analys och fastfas,KTH Royal Institute of Technology, Sweden(Swepub:ri)PerHSv@ri.se (author)
Adroit Science AB, SwedenTillämpad fysikalisk kemi (creator_code:org_t)

By the author/editor: Briggner, Lars-E ...; Kloo, Lars; Rosdahl, Jan; Svensson, Per H.

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...; and Physical Chemist ...

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