Evaluation of lead compounds targeted for use in a conventional solid oral formulation commonly employs drug-modification strategies that are focused on improving drug solubility. This is based on the recognition that the drug must be in a solution state to be absorbed across the gastrointestinal (GI) tract. Maximizing the amount of drug that dissolves and remains dissolved as it travels through the GI tract provides an increased likelihood that the absorption and bioavailability of the drug will be maximized.
The early phases of development are often accompanied by efforts to profile the physicochemical properties of the drug and attempts to measure its dissolution rate and solubility behavior to model the in vivo performance of the drug (1). Predictive tools have been used to develop a general understanding of these attributes (2, 3). Empirical measurements (e.g., kinetic solubility and intrinsic dissolution rate), however, remain a mainstay. Data that reveal poor or suboptimal solubility/dissolution rate do not necessarily preclude the advancement of a drug. A progression strategy, however, often will need to explore an alternative delivery mode or modification on the drug substance as a means of enhancing solubility and bioavailability. The latter is often times the most straightforward and cost-effective approach. The options available for consideration require an understanding of how the molecule behaves (e.g., solubility and precipitation) in different regions of the GI tract. Some understanding on the intended formulation dose levels also can be helpful in evaluating potential options.When combined with knowledge of the pKa of the compound and its intrinsic solubility, it generally becomes clearer whether a salt can be used to afford an improvement in properties that can lead to an improvement in bioavailability (4). For molecules that have the potential to form stable salts, salt-screen studies are typically the most effective approach at surveying a wide range of acids, bases, and crystallization conditions. The screen also can be achieved in a material-efficient manner, an ever-important consideration during early development.
Salt-screening studies performed using a solid-form technology platform (Optiform, Catalent Pharma Solutions) allow multiple diversity elements to be used in a high-throughput operation, which in turn maximizes the likelihood of producing and discovering crystalline salts. Diversity elements important to consider when screening for salts and available with the Optiform platform include acid–base stoichiometry, the method of drug dosing (e.g., dosing the drug as a solid or a solution), the method of counter-ion dosing (e.g., as a solid or a solution), crystallization solvent selection, and crystallization mode (e.g., cooling and antisolvent addition). Initial evaluation of the solubility of the parent as well as the feasibility of generating crystalline hydrochloride or sodium salts in a small set of experiments offer insight into potential solvents that can be used and provide a guide on the appropriate crystallization method. Effective mixing combined with a sample/vial format that permits individual samples to be cherry-picked from the array, isolated, and characterized using high-throughput isolation and analysis provides a material- and time-efficient screening methodology.
For molecules that are either unionizable or do not form stable salts, cocrystals are often considered as a means of delivering a crystalline material that has the potential to enhance bioavailability in comparison to the free form of the compound. Similar to salt screening, identifying a suitable cocrystal requires combining the API with a stoichiometric amount of a second compound that is both a solid at room temperature and generally regarded as safe (GRAS). These combinations can be effectively constructed using the Optiform technology platform. The stoichiometric combinations are subjected to slurry-based ripening studies, solvent-drop grinding, and/or solution-based experiments as a means of promoting cocrystal formation. The ripening and solution-based experiments can be supported, in their entirety by the Optiform platform. High-throughput solvent-drop grinding, however, requires the use of specialized milling equipment. High-throughput milling techniques have been partnered with the Optiform platform to show the effectiveness of the combination in conducting cocrystallization studies (5).
If neither salts nor cocrystal modifications can be successfully obtained, then the free form of the compound can be modified to impart a change in the solubility and dissolution rate and, correspondingly, the bioavailability of the compound. This modification can be achieved by size reduction to increase surface area through various means, including mechanical milling under ambient or cryostatic conditions. Conversion of the highly ordered crystalline state to a solid form that has low (i.e., poorly crystalline) or negligible long-range order (i.e., amorphous) is an approach generally considered to improve bioavailability. This option can be explored by performing a range of crystallization studies on the free form of the drug substance, typically by employing experiments that lend themselves to producing less ordered or highly energetic forms (e.g., fast desupersaturation methods). Other techniques that can produce amorphous materials include lyophilization, spray-drying, and/or rapid solvent evaporation. In almost all cases, knowledge of the drug solubility is required to allow for a well-designed study. Optiform technology platform uses the solubility information to create experimental designs and execute those designs in a parallel manner.
David Igo*, PhD, is director, and Stephen Carino,
PhD, is a principal scientist, both of Optiform Technologies, Catalent Pharma Solutions, 160 Pharma Drive, Morrisville, NC, [email protected]
* To whom all correspondence should be directed.
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2. C.A. Lipinski et al., Adv. Drug Delivery Rev. 46 (1–3), 3-26 (2000).
3. S. R. Carino, D.C. Sperry, and M. Hawley, J. Pharm. Sci. 99 (9), 3923–3930 (2010).
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5. S. Bysouth, J.A. Bis, and D.H. Igo, Int. J. of Pharm. 11 (1–2), 169–171 (2011).