Capturing The Advantages Of Co-Crystals

Jul 01, 2010
Volume 22, Issue 7

Dana Hoff/Getty Images
Pharmaceutical developers typically prefer their bioactive molecules to be produced and delivered to the patient in a crystalline form, primarily because of the intrinsic stability and acceptable manufacturability of crystalline materials. The vast majority of marketed APIs are molecular crystals. Such crystals are composed of molecules held together by various non-covalent forces, which makes it possible to view them as solid-state supermolecules (or supramolecules).1 The supramolecular nature of APIs dictates that their properties are modulated by the intramolecular and intermolecular interactions, manifested as the unique molecular conformation and crystal packing. That is why collective crystal properties are different from (although closely related to) the molecular properties of their building blocks — single molecules.1 This provides the fundamental explanation for dissimilarities, which are often considerable, in physicochemical properties among various solid state forms of a given API and also allows one to adopt the principles of supramolecular chemistry to the design of functional pharmaceutical materials.

The growing recognition of this concept within the pharmaceutical industry is being demonstrated by a rapidly emerging class of API solids — pharmaceutical co-crystals.2,3 This novel type of pharmaceutical material raises a number of questions that pharmaceutical manufacturers are posing to academia. A key questions is: How can we bring together two fields, crystal engineering and pharmaceutical sciences, in order to capture the advantages of pharmaceutical co-crystalline materials to enhance the clinical performance of drugs?

Pharmaceutical designer crystals a reality?

Sidebar 1: The key advantages of co-crystals as an alternative solid state form of APIs
Pharmaceutical co-crystals are broadly defined as crystalline materials comprised of an API and one or more unique co-crystal formers, which are solids at room temperature and bound together in the crystal lattice through any type or combination of non-covalent interactions, including hydrogen bonding, van der Waals forces and π-stacking. Owing to their supramolecular organisation, pharmaceutical co-crystals posses the unique feature that beneficially distinguishes them from any other solid state form — polymorphs, salts, solvates or amorphous solids. Explicitly, these multicomponent assemblies can be designed by employing crystal engineering strategies,3,4 which opens enormous possibilities for pharmaceutical developers in terms of tailoring the physical and material properties for the target drug. The most comprehensive list of the key attributes of pharmaceutical co-crystals as a solid state form of APIs is displayed in Sidebar 1.

Figure 1
The caffeine:oxalic acid 2:1 co-crystal is an elegant example of the successful implementation of the crystal engineering strategy for enhancing the physicochemical stability of a moisture-labile API — caffeine anhydrate.5 This example is depicted in Figure 1, which schematically illustrates the key steps involved in a typical crystal engineering experiment.

Sidebar 2: Five things to consider during the co-crystal formers selection process
In terms of both solid-state structure and physicochemical profile, it is co-formers that bring an additional multiplicity into a co-crystalline system. Co-former selection, therefore, is an important initial step in the entire co-crystal engineering process. To increase the probability and at the same time maximise the experimental effectiveness of generating pharmaceutical co-crystalline systems, co-formers should be preliminary evaluated against a set of typical selection criteria, which are listed in Sidebar 2. It should be emphasised, however, that the presence of chemically compatible functional groups in a given system does not guarantee success of the co-crystallisation reaction. Moreover, it is not yet possible to accurately predict if a co-crystal, a eutectic mixture or simply a physical mixture, will result from any particular reaction.6 For this reason, experimental co-crystal screening remains the obligatory step and must be conducted under varied conditions by employing different crystallisation techniques, including solid-based and solution-based methods.7–9

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