Strategies to improve drug solubility are of crucial importance to the pharmaceutical industry. Advancement of high-throughput screening techniques for lead identification in drug discovery has had the benefit of generating more potential drug candidates, but with this increase in the diversity and number of drug molecules comes challenges (1). Most notably, more leads are being identified with high-molecular weights and lipophilicity and thus have poor water-solubility (1). Industry estimates are that as much as 60% of drugs currently in development may be classified as poorly water-soluble (2). Poor solubility is problematic because of the resulting decrease or variability in bioavailability, which affects clinical efficacy and safety, such as through necessitating higher dosing regimens to achieve therapeutic effects (1). Enhancing bioavailability of poorly water-soluble drugs, therefore, has strong clinical and commercial significance.
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Classifying poorly soluble drugs
The Biopharmaceutics Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability (2). When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption: dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified as follows:
Various approaches can be used to address problems of solubility, such as particle engineering, salt selection, amorphization of the compound, use of surface-active agents or cosolvents, polymeric stabilizers to achieve supersaturation, and solid dispersions and solutions (2). Physical modifications may occur through such techniques as micronization, nanonization, and sonocrystallization (4). Although micronization of powders can be useful to improve solubility, the resulting particle size of drug powders of between 1 and 10 µm to increase the surface area and the dissolution velocity may be insufficient to overcome bioavailability problems of many poorly soluble BCS Class II drugs (4). Nanonization moves beyond micronization to further reduce particle size as a means to increase dissolution rates and bioavailability of poorly water-soluble drugs (4). Nanozination strategies include increasing the surface area-to volume ratios of drug powders, changing crystalline forms, and developing nanomaterials for drug delivery (5).
- Class I: high solubility and high permeability
- Class II: low solubility and high permeability
- Class III: high solubility and low permeability
- Class IV: low solubility and low permeability (3).