SECTION TITLE API
compound precipitation, and solid-liquid phase separation by filtration or centrifugation. Typically, these liquid handling systems which carry out the volumetric dispensing and related activities can be combined with highly sensitive analytical systems, eg, high-performance liquid chromatography or ultra-performance liquid chromatography utilizing generic methodologies and can be applied to automated solubility assessments with throughputs of 10 to 100 compounds per day.32-36
However, one has to bear in mind that this type of kinetic solubility does not answer the question, “to what extent does my compound dissolve?” Instead, this type of kinetic solubility provides the answer to the related question, “to what extent does my compound precipitate?” As most drugs are intended for oral administration, the first question is more relevant during later research phases. The key differentiating point between kinetic solubility—which is obtained using the pre-dissolved compound—and thermodynamic solubility—which is obtained using the solid compound—is given by the fact the kinetic solubility will refer in many cases to the amorphous phase. In a kinetic solubility assay, the compound will have only very limited time to precipitate out and accordingly will be mainly amorphous in nature. As a consequence, solubility will be significantly enhanced compared to thermodynamic solubility (which typically utilizes the crystalline phase).37
The main—and in many cases only—difference between kinetic and thermodynamic solubility assays is the usage of a solid compound instead of DMSO stock solutions. Handling steps for the solid materials are difficult to automate and typically become more labor-intensive and usually constrain the throughput of thermodynamic solubility assays. Importantly, at this stage information on solubility becomes available for the first time with related information on solid state characteristics allowing solubility optimization strategies to commence.37,38
An assessment of solubility by the aforementioned kinetic or thermodynamic solubility assays is limited to generic conditions such as one pre-defined buffer system, typically at neutral pH. To get a physiologically more relevant understanding—especially for orally administered drugs—thermodynamic solubility is measured using biorelevant conditions simulating the prevailing conditions within the gastrointestinal (GI) tract. Initially, this is conducted using different buffers simulating the different pH conditions in the GI tract. These buffers are typically simple inorganic or organic systems, and they permit investigations of pH-dependent solubility of the compound. The solubility of different salt forms can be initially assessed. As an example, for a weak base in the most acidic parts of the GI tract (ie, the stomach), conversion of the parent form to the corresponding hydrochloride salt may take place. Accordingly, solubility, as measured in the thermodynamic assay, will refer to the salt form and not to the parent—and this information will be the physiologically relevant.
Application of Biopharmaceutical
Solubility Approaches As the GI tract is a complicated biological system,39,40
even the
aforementioned approaches to determining pH-dependent solubility do not provide the complete picture of solubility behavior that will underpin drug absorption. As a prerequisite to ensuring adequate bioavailability of a research compound, the prediction of drug absorption becomes critical during late stage preclinical research in combination with formulation development as part of pharmaceutical development. At this stage, further parameters influencing solubility need to be assessed. As a starting point, the influence of bile salts on drug solubility must be assessed. The best way to obtain this information would be using human GI-media in ex vivo settings.41
However, this approach is not
practical for routine research and development. A much more practical way to investigate the impact of bile salts on solubility is provided by the
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use of biorelevant dissolution media, which also can be easily utilized for thermodynamic solubility determinations. Biorelevant dissolution media such as FaSSIF (fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid), FaSGF (fasted state simulated gastric fluid), and FeSGF (fed state simulated gastric fluid) mimic the effect of bile salts, pH, ionic strength, as well as osmolarity of human GI fluids.42 When such biorelevant media have been introduced, preparation of these systems was often a laborious procedure. However, due to the availability of commercial ready-to-use kits, preparation of the media has been simplified and measurements of solubility in these media can be performed with throughput of 10 to 100 compounds per day.43 For many compounds, a significant increase in solubility is seen due to the presence of bile salts. This especially holds true for lipophilic and basic moieties, where increases in solubility can be up to 1 or 2 orders of magnitude. Usage of biorelevant media to determine thermodynamic solubility allows the generation of physiologically relevant data, but also allows the initial assessment of potential food effects (FaSSIF vs. FeSSIF solubility).
At this stage of a project, further physicochemical characterization of research compounds is carried out for a very limited number of candidates and focus on intrinsic or apparent dissolution and the effect of particle size. Technical feasibility of these investigations has been facilitated during the last decade by the development of mini-dissolution apparatus and particle size determination using image analysis,44,45
which provides important information using a few milligrams of the compound. These miniaturized approaches allow the
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