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c-Kheurart_10-15_Masters 12/30/13 1:55 PM Page 11 January 2014 11 Tablets & Capsules and recognize development risks as soon as possible [2]. Key criteria in assessing an NME's development potential include economic factors, such as ease of manufacture and market size; pharmacological considerations, such as therapeutic ratio, toxicity, and how the compound interacts with other APIs; and physical characteristics, such as solubility [1]. Solubility, which refers to the concentration of a solute in a saturated solution at a defined temperature and pressure, is key to a drug product's efficiency [3]. For a drug product to exert its therapeutic effect, it must be soluble in an aqueous environment. This quality ensures that the API will dissolve in intestinal fluids and provide sufficient concentration to induce absorption in the GI tract [4]. The oral delivery of low-solubility drug products is associated with slow dissolution rates, low and variable bioavailability, and a higher potential for food effect [2]. Hence, API candidates with promising pharmacodynamics may be rejected as lead molecules due to poor solubility. Unfortunately, approximately 40 percent of all NMEs exhibit this quality [5], meaning that they are classified as either Class II (low solubility, high permeability) or Class IV (low solubility, low permeability) in the Biopharmaceutics Classification System (BCS). Factors that cause poor solubility include high crystallinity and hydrophobicity [2]. The latter is a characteristic more commonly found in leads obtained via highthroughput screening (HTS) because those NMEs tend to have higher molecular weights than do leads acquired during the pre-HTS era [6]. HTS allows for exponentially faster screening at a fraction of the cost of conventional techniques, and it has thus become a major paradigm of drug discovery [7]. As a result, new formulation strategies are required to achieve acceptable bioavailability. Liquid-filled hard capsules (LFHCs) offer a platform for managing the successful transition from a low-solubility, to-be-abandoned molecule to a potent bioactive drug product. The means to do so, however, are restricted by the API's physicochemical properties, which—aside from poor water solubility—may also include a low melting point (causing it to stick to tooling surfaces), a critical stability profile, and a short half-life [8]. Formulators can use a wide array of solubilizers, co-solvents, surfactants, and emulsifying agents to achieve favorable pharmacokinetics. For instance, an API's rate of release from hard capsules filled with semi-solid excipients can be controlled by using excipients with different hydrophilic-lipophilic balance (HLB) values, as demonstrated by an experiment in which the in vitro release rate of salicylic acid from a mixture of lipid excipients (Gelucire from Gattefossé) was found to be directly proportional to the HLB value of the composition of the fill material [9]. Generous use of any one excipient is limited, however, by permissible-daily-intake standards, individual solubilizing capacities, and potential interactions with the capsule wall: The fill material must not degrade or leak through the gelatin shell. So the challenge is to find a for- mulation approach that enables the judicious selection of excipients by type and use level. This article summarizes how an excipient-mixture approach was able to enhance the solubility, in vitro dissolution, and bioavailability profile of a low-solubility (0.5 milligram per milliliter (mg/mL)) BCS Class II compound, thereby enabling researchers to establish a reasonable spread of prototype formulations in order to conduct in vivo studies in animals. Methodology Stage 1: Vehicle screening studies. In the first set of trials, the API was dissolved in a variety of excipients that were either liquid or semi-solid at ambient temperature, using an approximate API-to-excipient ratio of 1-to-90. The solutions were then visually evaluated for clarity and sonicated for 30 minutes to further agitate the particles. A clear solution was not achieved, however, indicating that none of the excipients adequately dissolved the API. Consequently, no further studies were conducted at ambient temperature. Subsequent trials involved dissolving the API in a variety of excipients at elevated temperatures (~65°C ±5°C) through the application of indirect heat (using a water bath and hot plate) accompanied by intermittent stirring. Some of the excipients were semi-solid at room temperature but melted at temperatures exceeding 55°C. An approximate API-to-excipient ratio of 1-to-90—also expressed as ~1.1 percent w/w API—was again used. See Table 1 for a list of the excipients evaluated at higher temperatures. Based on initial solubility studies of the excipient preparations used to make self-emulsifying lipid formulations (SELFs), preparations 27C, 27D, 27F, and 27H were heated gradually from 65° to 115°C. It was observed that the API dissolved incrementally as the temperature increased. At temperatures higher than 65°C, however, some excipients degraded, so 65°C became the target temperature in further studies. Stage 2: A mixture approach to study solubility at elevated temperatures. Select excipients were mixed in various proportions (Table 2). The API was then dissolved in each mixture and each was assessed to gauge solubility improvement. Similar to the solubility process used for individual excipients, indirect heat was applied to melt the excipients and/or disperse the API. A temperature of approximately 65°C was maintained throughout the evaluation process, and the quantity of API used was gradually increased depending on the solubilization capacity of the mixture. Stage 3: Selection of an optimal mixture. Based on the literature and a visual evaluation of the API's solubility in various excipients and excipient mixtures, it was hypothesized that a combination of two or more select excipients (Imwitor 308, Gelucire 44/14, vitamin E TPGS, hydroxypropyl beta cyclodextrin, and propylene glycol) would yield a formulation with the desired in vitro dissolution profile and in vivo bioavailability characteristics. Among these five excipients, Gelucire 44/14 was con-