Major Source of Error in QSPR Prediction of Intrinsic Thermodynamic Solubility of Drugs: Solid vs Nonsolid State Contributions?

Abstract

The main purpose of this study is to define the major limiting factor in the accuracy of the quantitative structure-property relationship (QSPR) models of the thermodynamic intrinsic aqueous solubility of the drug-like compounds. For doing this, the thermodynamic intrinsic aqueous solubility property was suggested to be indirectly "measured" from the contributions of solid state, ΔGfus, and nonsolid state, ΔGmix, properties, which are estimated by the corresponding QSPR models. The QSPR models of ΔGfus and ΔGmix properties were built based on a set of drug-like compounds with available accurate measurements of fusion and thermodynamic solubility properties. For consistency ΔGfus and ΔGmix models were developed using similar algorithms and descriptor sets, and validated against the similar test compounds. Analysis of the relative performances of these two QSPR models clearly demonstrates that it is the solid state contribution which is the limiting factor in the accuracy and predictive power of the QSPR models of the thermodynamic intrinsic solubility. The performed analysis outlines a necessity of development of new descriptor sets for an accurate description of the long-range order (periodicity) phenomenon in the crystalline state. The proposed approach to the analysis of limitations and suggestions for improvement of QSPR-type models may be generalized to other applications in the pharmaceutical industry.

Solution Conformations Explain the Chameleonic Behaviour of Macrocyclic Drugs

“…p K a values, Table ). In view of the high solubilities, and as it is difficult to develop predictive models for solubility, it was not studied further. We instead focused on the cell permeability of the four drugs.…”

Pharmaceutical salts of emoxypine with dicarboxylic acids

“…First, a combined experimental and theoretical study should be conducted in order to assess the influence of the molecular and crystal structures on pharmaceutically relevant properties. There are approaches linking the solubility of pharmaceutical crystals with its melting point (Perlovich, 2014;Abramov, 2015) and theoretical lattice energy evaluated by solid-state density functional theory (DFT) (Voronin et al, 2016). The literature survey of multicomponent crystals of dicarboxylic acids with various APIs conducted in our earlier work (Manin et al, 2015) has shown the influence of the melting point and carbon chain length of the salt/cocrystal former on the potential solubility of the API.…”

Are the Sublimation Thermodynamics of Organic Molecules Predictable?

“…In recent years, it has been suggested that up to 40% of new drug molecules are effectively insoluble 15 and up to 75% are classified as having low solubility by the Biopharmaceutics Classification System (BCS). 16,9 At the lead optimization stage, it is not practical to carry out experimental determinations of thermodynamic solubility on large libraries of compounds. As a result, computational methods are employed to make predictions of numerous properties including solubility.…”

“…9 The creation of standard experimental datasets for solubility prediction is on-going. 25 There are methods which apply physically motivated fitted equations 12 or full calculations from first principles 11,26 to solubility prediction.…”