Miniaturization of Drug Solubility and Dissolution Testings

Solubility and drug dissolution are of crucial importance for drug formulations. Poor water-solubility of drug candidates is a major obstacle in drug development, since the oral route is the most patient convenient and cost effective way to deliver drugs. In some cases the low aqueous solubility may limit the bioavailability when the absorption of the drug is dissolution limited. About 40% of the current lead optimization compounds suffer from poor solubility. Improvements in drug solubility/dissolution testing technologies (e.g. high throughput screening, HTS) can enhance the possibilities of the lead compounds to success in the later stages of drug development process. Typically HTS protocols measure the kinetic solubility involving co-solvents (e.g. dimethyl sulfoxide), which might enhance the in vitro solubility or give erroneous results if the potential drug candidates are eliminated. Also, measurement of dissolution profiles is not available by the present HTS methods. For these reasons, there is a need for improvements in HTS solubility formats. Traditionally the in vitro dissolution tests are studied by pharmacopoeial methods, which are not utilizable in the drug discovery stage because of the large amount of compounds needed. However, dissolution studies at the drug discovery stage could be useful e.g. to classify compounds based on their dissolution rates. In addition, the initial steps of dissolution process might be lost by the regulatory dissolution methods. The aim of this thesis was to miniaturize traditional drug dissolution and solubility testing methods. Systematic down scaling of methods was done towards the development of both equilibrium and kinetic 96-well plate solubility/dissolution methods. Miniaturization of the regulatory dissolution methods and shake-flask solubility measurements on the 96-well plates was successful. 96-well plate methods for equilibrium drug solubilities, as well as for drug dissolution profiles as a function of time, were developed. The former method is the first true equilibrium solubility method, which can be used in the screening of drug solubility and dissolution phenomena at the early stages of drug development process. This method was also tested using fasted state human intestinal fluid as a medium for the first time. Human intestinal fluid and data obtained might turn out to be important for very low water-solubility compounds. Surface tension based microtensiometry was also presented as an alternative method for kinetic HTS of drug solubility properties, e.g. for classifying solubility of compounds not suitable for UVanalysis. Channel flow methodology was introduced enabling especially the kinetic follow-up at the very beginning of the dissolution process. This thesis provides directly applicable new miniaturized methods for the drug solubility and dissolution experiments. These methods enhance the throughput and understanding of drug solubility/dissolution phenomena and profiles in drug discovery and improve success in the later stages of the drug development process.