Computer-Aided Discovery of New Solubility-Enhancing Drug Delivery System.

Eugene N Muratov,Judyta Cielecka-Piontek,Mikołaj Mizera,Alexander Tropsha,Vinicius M Alves

doi:10.3390/biom10060913

Abstract

The poor aqueous solubility of active pharmaceutical ingredients (APIs) places a limit on their therapeutic potential. Cyclodextrins (CDs) have been shown to improve the solubility of APIs, but the magnitude of the improvement depends on the structure of both the CDs and APIs. We have developed quantitative structure–property relationship (QSPR) models that predict the stability of the complexes formed by a popular poorly soluble antibiotic, cefuroxime axetil (CA) and different CDs. We applied this model to five CA–CD systems not included in the modeling set. Two out of three systems predicted to have poor stability and poor CA solubility, and both CA–CD systems predicted to have high stability and high CA solubility were confirmed experimentally. One of the CDs that significantly improved CA solubility, methyl-βCD, is described here for the first time, and we propose this CD as a novel promising excipient. Computational approaches and models developed and validated in this study could help accelerate the development of multifunctional CDs-based formulations.

Highlights

Poor solubility of active pharmaceutical substances (API) places a significant limitation on their clinical use
APIs with low solubility belong to groups II and IV in the Biopharmaceutics Classification System (BCS)
We have successfully developed predictive models for assessing the stability of a broad range of API-CD systems

Summary

Introduction

Poor solubility of active pharmaceutical substances (API) places a significant limitation on their clinical use. This issue affects nearly 40% of currently marketed APIs, resulting in their low bioavailability and the necessity of increased API doses. This issue is persistent: it has been estimated that 90% of APIs currently under development are poorly soluble [1,2]. APIs with low solubility belong to groups II and IV in the Biopharmaceutics Classification System (BCS). BCS II substances are poorly soluble and have high permeability, whereas group IV substances are poorly soluble and have low permeability. Optimizing pharmaceutical formulations toward greater solubility may substantially improve their bioavailability

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