Crystal engineering of active pharmaceutical ingredients helps improve solubility and dissolution rates

Drug molecules with limited aqueous solubility are becoming increasingly prevalent in the research and development portfolios of discovery focussed pharmaceutical companies. Molecules of this type can provide a number of challenges in pharmaceutical development and may potentially lead to slow dissolution in biological fluids, insufficient and inconsistent systemic exposure and consequent sub-optimal efficacy in patients, particularly when delivered via the oral route of administration. Advances in the pharmaceutical sciences have led to the establishment of a number of approaches for addressing the issues of low aqueous solubility. These strategies for improving and maximizing dissolution rate include micronisation to produce increased surface area for dissolution, the use of salt forms with enhanced dissolution profiles, solubilisation of drugs in co-solvents and micellar solutions, complexation with cyclodextrins and the use of lipidic systems for the delivery of lipophilic drugs.

Although these techniques have been shown to be effective at enhancing oral bioavailability, the success of these approaches is dependent at times on the specific physicochemical nature of the molecules being studied. Solubilisation technologies such as micellar systems are reliant on the acceptable solubility and compatibility of therapeutic molecules in a limited range of pharmaceutically acceptable excipients, whilst the increasing number of weakly ionisable and neutral molecules entering development constrains the opportunities for salt formation as a method of improving dissolution rate. Furthermore, whilst micronisation increases the dissolution rate of drugs through increased surface area, it does not increase equilibrium solubility. Often for drugs with very low aqueous solubility, the achieved increase in dissolution rate is insufficient to provide adequate enhancement of bioavailability. The potential for increased Van der Waals interactions and electrostatic attraction between ultrafine particles can also act to reduce the effective surface area for dissolution and therefore limit improvements in bioavailability.
Crystal engineering approaches, which can potentially be applied to a wide range of crystalline materials, offer an alternative and potentially fruitful method for improving the solubility, dissolution rate and subsequent bioavailability of poorly soluble drugs. The ability to engineer materials with suitable dissolution characteristics, whilst maintaining suitable physical and chemical stability provides a strong driver for the utilisation of new and existing crystal engineering approaches to drug delivery system design. The challenges of low aqueous solubility provide an ideal situation for the application of crystal engineering techniques for improving bioavailability, whilst also developing stable and robust pharmaceutical products. The potential utility of crystal engineering as an approach for designing efficacious dosage forms for poorly soluble drugs is constantly reviewed and applications, benefits and drawbacks of this strategies are analysed.

Crystal engineering is taken as the design of molecular solids in the broadest sense with the aim of tailoring specific physical or chemical properties, which may be used to manipulate the solubility and/or dissolution rate of the parent molecular components in the crystalline state. At the centre of these available approaches is the need to change surface and molecular assembly in equilibrium with a solution. Consequently, the recent developments in the study of molecular solids and topical issues such as habit modification, polymorphism, solvation, co-crystal formation (particularly, co-crystallisation) and surface modification, can help achieve good success rates and can become an emerging area of strategic importance to the pharmaceutical sector.

 The principles of crystal engineering are typically used to control crystal size, shape and crystalline form. Although the primary focus considers the crystalline state, the utility of amorphous materials, and their use in enhancing drug dissolution and bioavailability is also important. The precise control of crystallite size and shape provides notable improvements in the dissolution rate of hydrophobic active pharmaceutical ingredients (APIs). 

The crystal and particle engineering strategies have notable potential to strengthen the available methods for addressing problems of low aqueous solubility of drug substances. These methods are applicable not only to molecules of a specific physical and chemical nature, but to a wide range of crystalline materials, although a comprehensive knowledge of drugs at the molecular level is required to determine the appropriate approach to improving solubility and dissolution rate.

The controlled production of ultrafine particles, particularly at sizes below 1 μm is becoming a favoured strategy for the pharmaceutical industry. In addition to the established comminution methods available to the formulator, new and emerging methods of controlled crystallisation provide an opportunity to produce highly pure crystalline drugs with narrow size distribution and desirable morphology. Although there are few disclosed examples of success in human subjects, there is sufficient evidence to demonstrate the potential benefits on dissolution in aqueous environments.

The formation of molecular complexes and co-crystals is becoming increasingly important as an alternative to salt formation, particularly for neutral compounds or those having weakly ionizable groups. Despite lack of precedence in marketed products and concerns about the safety and toxicity of co-crystal forming agents, there is growing interest and activity in this area, which aims to increase the understanding of co-crystal formation and methods of preparation.

Although, with some recent developments in crystal and particle engineering, established approaches such as the use of high-energy amorphous and metastable crystalline forms is still widespread. In particular substantial advancements in methods for isolating metastable crystalline have been achieved since the early days of chloramphenicol palmitate, whilst a greater understanding of the production and stabilisation of amorphous forms is also leading to a revolution in their use.

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