Introduction of combinatorial chemistry and high-throughput screening in drug discovery and development have led to poor solubility of the potential drug candidate. According to a recent survey, one third of the new compounds synthesised in medicinal chemistry lab have an aqueous solubility less than 10 µg/ml, while another one third have solubility between 10 to 100 µg/ml. Solubility of the remaining new compounds synthesised in medicinal chemistry laboratory have solubility of more than 100 µg/ml. This had led to an ever-increasing interest in the solubilisation approaches for sparingly and/or poorly soluble drugs. Poor solubility of a pharma compound is a challenging issue in drug discovery and development. Therefore, an improvement in solubility by various techniques is pivotal for the successful development of a potential drug candidate.
A number of solubilisation methods, either alone or in combination, have been utilised to improve the solubility, especially in drugs having solubility limited bioavailability.
Micronisation
Micronisation is the process of reducing the particle size of a solid to 2-5 µm to increase its surface area, leading to an improvement in the dissolution rate. Noyes-Whitney equation expresses the direct correlation between the dissolution rate and surface area of particles.
Particle size reduction has often been used as an adjuvant technique to the other techniques of solubilisation. Traditionally, particle size reduction is carried out by milling process. But the heat generated during grinding process may lead to degradation of the thermolabile compounds. The technique also creates problem in controlling the formation of sub-micron sized particles. Conversely, methods like spray drying offers a good control over particle size and generate porous particles having a high surface area that consequently improves the solubility of a compound. Upcoming particle formation processes involve the use of supercritical carbon dioxide (SC-CO2) that is most often referred to as ‘supercritical antisolvent system’ (SAS) and ‘rapid expansion of supercritical solutions’. The technique is useful for micronisation of thermolabile materials and provides particles of size less than 500 nm in diameter.
Particle size reduction to nanosize level produces sub-micron colloidal dispersion with increased intrinsic solubility and dissolution rate. Nanonisation increases the amorphous fraction of the particle or even creates completely amorphous particles. A number of nanosizing techniques are utilised to improve the solubility of poorly soluble drugs.
Crystal habit modification
Crystal habit modification could be used for improving the solubility, dissolution rate and subsequent bioavailability of poorly soluble drugs. Knowledge of the crystallisation process can be applied to confer crystal habit modification in crystalline materials. Exposure of different crystal faces determines the nature of those faces, which in turn influence the wettability and subsequent dissolution of an active pharmaceutical ingredient. Crystal habit modification of a poorly soluble drug can be done by using different solvents, additives and crystallisation conditions. For example, dissolution rate of rod shaped particles of dipyridamole crystallised from benzene was faster as compared to the rectangular needle shaped crystals produced using methanol.
Polymorphism & pseudo-polymorphism
A drug candidate may exhibit different crystalline solid states with no concomitant change in the molecular structure. This phenomenon is known as polymorphism. Here the different solid states are designated as the polymorphs. For a drug that exists in multiple polymorphic forms, the polymorph with the highest order of crystallinity is the most stable form, i.e., with least amount of free energy and consequently possesses least solubility. Conversely, metastable or amorphous forms of drug possess high amount of free energy and higher solubility. In certain cases, solvent molecules are entrapped in the crystal structure, known as pseudo-polymorphs and the phenomenon as pseudo-polymorphism. Like polymorphs, solvates have different physical properties and from polymorphs of pure solute, with resulting differences in solubility.
Lipid formulations
Lipidic systems are isotropic mixtures of oils, surfactants and/or co-solvents. A number of drugs have been formulated as lipidic system in emulsion form as self-emulsifying drug delivery systems (SEDDS) or self-emulsifying drug delivery systems (SMEDDS) and contain water-soluble surfactants and/or co-solvents. Upon mild agitation followed by dilution in aqueous media, these systems can form fine oil-in-water (o/w) emulsions. While SEDDS produce emulsions with a droplet size between 100 and 300 nm, SMEDDS form transparent micro-emulsions with a droplet size of less than 50 nm. The use of the lipidic components decreases the critical micellar concentration (CMC) and increases the size and the solubilisation capacity of the micelles.
Prodrug
Prodrug can be defined as a bio-reversible chemical derivative of an active parent drug. It utilises a chemical derivatisation of poorly water-soluble drugs to improve its solubility, permeability and consequent bioavailability. Generally two types of strategies are used for solubilising the drugs, based on the nature of the physicochemical limitation to oral drug delivery and the properties of biological reconversion sites. These techniques are drug derivatisation with a pro-moiety designed to decrease the drug’s melting point and/or introduce an ionisable group [esterification of a drug hydroxyl, amine or carboxyl group with a moiety (pro-group) designed to introduce an ionisable function] or to reduce the intermolecular interactions responsible for low solubility. A number of drugs have been converted to their prodrug forms to improve their solubility.
Miscellaneous approaches
Apart from the conventional approaches, newer technique like adsorption of drug onto high surface area carrier, liquisolid compaction technique and co-grinding with excipients have also been reported to enhance the solubility of poorly soluble drugs. The dissolution rate of the carbamazepine and nifedipine was improved by adsorbing solutions of the drugs in hydrophilic solvents onto carriers with large surface area. This was accomplished by dissolving the drug in methanol or the non-toxic hydrophilic liquids PEG 400 or 2-pyrrolidone and adsorbing these solutions onto the surface of silica or cross-linked polyvinylpyrrolidone. Similarly, co-grinding with various excipients, including lactose monohydrate, cornstarch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and sodium lauryl sulphate have been reported to improve the solubility of drugs, including albendazole, danazol and felodipine.
Conclusion
Solubilisation of sparingly and/or poorly soluble drugs is a critical component of the drug discovery and development pathway of a potential drug candidate. A number of solubilisation approaches, including micronisation, complexation, salt and prodrugs formation are available to enhance their solubility. In certain cases, however, it is not possible to improve the solubility using single approach, wherein, a combination of two or more approach may be undertaken.
(The authors are with Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research)