EVALUATION OF COMPOUND RE-PRECIPITATION FROM SALT SOLUTION FORMULATIONS : A NOVEL SCREENING TOOL FOR DISCOVERY SUPPORT

A novel tool was developed to optimize the selection of drug development candidates and identify, in an early discovery phase, potential issues for the development of formulations suitable for the preclinical and clinical trials. In the preclinical laboratories, the intravenous (IV) formulation intended for the preliminary “in vivo” assessment of the animal pharmacokinetics is always a challenge. In this early stage, the restricted timelines, the limited compound availability, the incomplete physico-chemical characterization and, quite often, the low water solubility of discovery compounds are important limits and impediments to develop an IV formulation screening. To overcome these limitations and to be able to formulate the discovery compounds the pharmaceutical scientists have to be aware of and understand some common solubilization strategies. pH adjustment and soluble salt formation, cosolvents, complexation, surfactants, emulsion, micelles and nano-microparticulate suspensions are the most frequently used formulation approaches. Among these methods, the pH adjustment and the soluble salt formation of an ionisable compound is the most biologically and clinically acceptable. An “in situ salt formation technique” is in house available for compounds with weak basic properties: this technique consists in a direct salification of a weak base powder with an equimolar quantity of strong acid. A potential drawback of this formulation approach is the occurrence of re-precipitation of the weak base upon dilution in the bloodstream at pH 7.4. The work described in this poster was aimed at setting-up and optimizing a fast automated screen for the “in vitro” evaluation of the potential “in vivo” re-precipitation. The results of this re-precipitation test were correlated with the solubility of the compounds in aqueous buffer at pH 7 and outcomes were obtained allowing to predict the potential “in vivo” re-precipitation