In Silico Solid State Perturbation for Solubility Improvement

Abstract

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 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.

A Free Energy Perturbation Approach to Estimate the Intrinsic Solubilities of Drug-like Small Molecules

“…Computed solubility is in good agreement with the experimental data obtained from public datasets, compared here for two published experimental datasets (14,15). The overall R2 between computed and measured logS is 0.5, and mean unsigned error is 0.6 in logS.…”

A Free Energy Perturbation Approach to Estimate the Intrinsic Solubilities of Drug-like Small Molecules

“…Figure 2 Computed solubility is in good agreement with the experimental data obtained from public datasets, compared here for two published experimental datasets (14,15). The overall R2 between computed and measured logS is 0.5, and mean unsigned error is 0.6 in logS.…”

Low solubility in drug development: de-convoluting the relative importance of solvation and crystal packing

“…An advantage of the QSPR model is that it can be applied during the design phase to rapidly estimate how a proposed molecular modification might impact the packing stability. It is interesting to note that a number of papers highlight this area as a key focus including attempts to use in‐silico perturbations in predicted solid‐state structures to estimate the overall trend in intrinsic solubility for selected sets of molecules [35]…”

“…It is interesting to note that a number of papers highlight this area as a key focus including attempts to use in-silico perturbations in predicted solid-state structures to estimate the overall trend in intrinsic solubility for selected sets of molecules. [35] An emerging theme in medicinal chemistry is the use of matched molecular pairs to explore the impact of minor structural modifications on physicochemical properties such as solubility. [6] In Table 2, there are some selected molecular pairs that allow us to explore the relative and combined impact of mixing and packing energy differences.…”