Sabiruddin Mirza is Senior Scientist in the Drug Delivery and Nanotechnology Group, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki (Finland).Tel. +358 9 191 59 582 

Sabiruddin Mirza

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).

  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.

  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.

  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?

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,

  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: The key advantages of co-crystals as an alternative solid state form of APIs			

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.

, which schematically illustrates the key steps involved in a typical crystal engineering experiment.  

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 

. 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.

  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.

Sidebar 2: Five things to consider during the co-crystal formers selection process			

With the constantly increasing number of insoluble drug molecules in development pipelines, pharmaceutical companies' needs for new strategies and approaches that enable the reliable solubility enhancement of APIs for a specific drug delivery system are significantly increasing. Indeed, exploring co-crystals of pharmaceuticals is also driven by (although not limited by) the potential to modify their physicochemical properties in terms of solubility and/or dissolution rate. 

In addition to efficacy, one desirable attribute of a pharmaceutical product is its cost effectiveness, which partly explains the traditional conservatism of the entire pharmaceutical industry — in most cases, weighty arguments must exist to convince the pharma industry to adopt a novel tool. In particular, there are a number of conventional approaches already available to address the issues of insufficient aqueous solubility; for instance, salt formation, particle size reduction and crystallinity decrease (amorphisation). So, what extra value can be achieved with the pharmaceutical products containing co-crystals? 

Currently, salt formation is one of the foremost strategies employed by pharmaceutical developers to modify the physicochemical profile of a compound.

  However, this strategy has two significant drawbacks. Firstly, salt formation relies on the presence of one or more ionisable functional groups in the molecule, while many APIs and development compounds lack this chemical feature. Secondly, 

 prediction regarding the existence of a crystalline salt (or salts) of a given compound is impossible. In this context, co-crystallisation can be a feasible alternative to pharmaceutical salts because any type of drug molecules, including neutral molecules, is theoretically capable of forming co-crystals. Moreover, pharmaceutical co-crystals themselves can form salts, as well as exhibit polymorphism and solvatomorphism, which further extends the landscape of solid-state forms of a given API. 

Particle size reduction, particularly nanocrystallisation,

  is another proven approach to enhance the biopharmaceutical performance of APIs, with at least three oral nanocrystalline products being currently marketed — Rapamune (sirolimus; Wyeth/Pfizer), Tricor (fenofibrate; Abbott Laboratories) and Emend (aprepitant; Merck & Co.). The key challenge that hinders widespread commercial implementation of this technology is the potential regrowth of small crystals into larger ones during storage. If inadequately controlled, this phenomenon, also known as Ostwald ripening, may eventually compromise the success of the entire technology. 

In comparison with the exploiting amorphous (high energy) phases of APIs, the indisputable advantage of co-crystallisation for dissolution rate enhancement is avoiding a probable conversion — either during manufacturing, storage, or clinical use — from a meta-stable form to a more stable one in an unpredictable manner. Itraconazole, an extremely water-insoluble antifungal agent, provides an excellent example in this respect. Due to failure of finding a suitable crystalline form, amorphous intraconazol seemed to be the only option and was released to the market as Sporanox (Janssen Pharmaceutica). More recently, however, it has been discovered that co-crystals of 

-itraconazole with various carboxylic acids exhibit a higher solubility and a faster dissolution rate compared with those for the free base.

  Moreover, the dissolution profile of the itraconazole:L-malic acid co-crystals has matched that of Sporanox. 

Overall, the examples described above demonstrate that every advantage must be sought to aid the design of an appropriate crystalline form of an API. Thus, unsurprisingly, pharmaceutical co-crystals are gradually becoming an integrated part of the solid form screening activities of pharmaceutical companies,

  as exemplified by the decision tree presented in 

Finally, it should be pointed out that although bioavailability studies involving pharmaceutical co-crystals are still in their infancy, the case studies reported to date show a great promise with respect to the bioavailability enhancement of poorly soluble APIs.

  More importantly, these studies have demonstrated that even the co-crystals that tend to dissociate 

Patents have always been an imperative tool for the pharmaceutical industry so it is not surprising that intricate patent litigations are among the key issues that have triggered the shift of concerns towards material properties of APIs. Nowadays, the need of thorough investigation and optimisation of physicochemical and material properties for 

 performance, reliable manufacture and the protection of intellectual property is well recognised in the pharmaceutical arena. 

In this context, pharmaceutical co-crystals deserve special attention. Because of a large number of potential co-formers available, co-crystals represent a broad patent space and provide enormous opportunities for companies to boost their pipelines, as well as to manage patents throughout their lifecycle. 

Co-crystals are rapidly emerging in the pharmaceutical arena, especially as a means of enhancing the physicochemical profiles of existing APIs. The uniqueness of pharmaceutical co-crystals as a solid state form is attributable to their susceptibility to supramolecular design. This implies that the functional properties of APIs — including solubility, physical stability and mechanical properties — can potentially be built-in during the co-crystal design. Furthermore, pharmaceutical co-crystals offer an opportunity for companies to significantly expand their intellectual property portfolios. From this perspective, the coming years are thought to be critical for bringing boost products containing pharmaceutical co-crystals to the market. 

The authors thank the Finnish Cultural Foundation and the Academy of Finland for financial support. 

is Senior Scientist in the Pharmaceutical Materials Research Group, Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki (Finland).

is Senior Scientist in the Drug Delivery and Nanotechnology Group, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki (Finland).Tel. +358 9 191 59 582 

11. J-U. A H Junghanns and R. H Müller, 

Articles

How can crystal engineering and pharma sciences be combined to enhance the clinical performance of drugs?