Development of an In Vitro Solubility Test as a Tool for Predicting Lung Retention of Poorly Water Soluble Compounds

Stefani Mariarita¹, Cesari Nicola ¹, Corsaletti Roberto¹, Fioni Alessandro¹, Saccani Francesca¹, Volta Roberta¹, Brogin Giandomenico¹ & Puccini Paola¹

¹Chiesi Farmaceutici S.p.A., Largo Belloli 11/A, Parma, 43122, Italy

Summary

Background: The prediction of pulmonary exposure after inhalation of a drug is one of the key objectives for the success of a novel inhalable drug candidate. This study focuses on the determination of an apparent solubility (S_app) value that may be used to study the impact of solubility on the drug candidate lung mean retention time (MRT) in order to support lead candidate selection. Methods: An in vitro solubility test in simulated lung fluid (SLF) was developed to measure S_app. The S_app value was determined by the diffusion of the dissolved amount from a drug-saturated solution through a membrane, which provides the separation between the donor and the receiver (sampling) compartments. In order to evaluate the validity of the test, different compounds with poor water solubility and different solid state were tested. Results: The test can provide different values of S_app for the same compound, based on the different solid states of the powder. The values correlated well with the in vivo lung mean residence time (MRT) after intra-tracheal administration in rats. Conclusion: The S_app value seems promising in predicting the impact of solubility on drug candidate lung MRT in the drug discovery phase.