The current phase of drug development is witnessing an oncoming crisis due to the combined effects of increasing research and developmental costs, decreasing number of new drug molecules being launched, several blockbuster drugs falling off the patent cliff, and a high proportion of advanced drug candidates exhibiting poor aqueous solubility. The traditional approach of salt formulation to improve drug solubility applies to a narrow set and is unsuccessful with molecules that lack ionisable functional groups, have sensitive moieties that are prone to decomposition and racemization, and/or are not sufficiently acidic or basic to enable salt formation. Also the amorphous forms of active substances are prone to conversion to stable crystalline forms compromising the solubility.
The importance of crystal engineering studies in the pharmaceutical industry to address these concerns has started to be re-appreciated with the advent of cocrystals. These appeared very recently - about a decade back. Crystalline materials derive their properties from the structural molecular arrangement and so any alteration in the placement or interactions with other molecules impacts the crystals properties. This is particularly tapped for the fabrication of pharmaceutical cocrystals with an ultimate goal of improvement of their solubility and hence absorption and bioavailability. The solubility is majorly influenced by lowering the lattice energy and increasing the solvent interactions while fabricating cocrystals. Thus, we can infer that pharmaceutical cocrystals represent an opportunity to diversify the number of crystal forms of a given active pharmaceutical ingredient (API) and in turn fine tune or even customize its physicochemical and pharmacokinetic properties without the formation or breakage of covalent bonds.
As mentioned before, the overall motivation for investigating pharmaceutical cocrystals as an alternative approach during drug development is the adjustment of the physiochemical properties to improve the overall stability and efficacy of a dosage form. The engineering enables modification of the important physico-chemical properties (Fig.1) such as dissolution rate, hygroscopicity, morphology, compaction, powder flow properties, chemical stability and melting point – primarily of interest to pharmaceutical technologists. This is a significant development, since the desired properties are tailored by binding two substances into a single crystal without chemical modification of the active component.
An important constituent of cocrystals is a cocrystal former which through complexation with the API leads to a non-ionic supramolecular complex. Hence, pharmaceutical cocrystals are defined as a stochiometric multi-component system comprising an active pharmaceutical ingredient with a pharmaceutically acceptable co-crystal former connected by non-covalent interactions. The wide range of coformer properties and interactions in the solid and solution phases provides numerous opportunities to play with properties of the final product. Commonly encountered coformers are dibasic acids like succinic, malic and malonic acid; saccharin, nicotinamide, glutaric acid, oxalic acid, salicylic acid etc. Since the complexation here is with neutral molecules, as opposed to ions, additional advantages may be drawn in terms of structural diversity, broadening the scope of intellectual property and rejuvenation of old API’s; particularly when the options for forming pharmaceutically viable salts are limited or for non-ionizable species where they are nil. This makes the technology particularly enticing to pharmaceutical companies looking forward to not only derive scientific but also regulatory benefits.
Cocrystals involve several types of interactions between the two entities forming a crystal lattice, including p-p stacking, vander waals interactions, ion-pairing, hydrophobic interactions, halogen binding, other non-specific interactions and most importantly – hydrogen bonding. There are various methods by which cocrystals may be prepared and have been summarised in Fig. 1. Traditionally, mechanical grinding, solvent drop grinding, melt crystallization and solution based methods have been employed. With extensive research going on in the area currently, additional superior strategies are also being explored. Among these, supercritical fluid technologies, fast evaporation, anti-solvent addition, sonication based methods, microwave assisted cocrystallization, melt extrusion and compression techniques are taking shape.
One of the main challenges in pharmaceutical cocrystal development is the selection of coformers that are compatible with a particular API. A general approach to coformer selection is by “tactless” cocrystal screening, whereby a predetermined library of pharmaceutically acceptable/approved compounds is used to attempt cocrystallization. The most appropriate cocrystal candidate with superior physicochemical and pharmacological properties can then be developed into a dosage form. The number of possible combinations and methods even using GRAS co-crystal formers is staggeringly large and represents a considerable practical limitation.
However recent efforts have turned to a more rational understanding of the interactions between the API and prospective coformer leading to a more scientific approach. Intelligent choice of co-crystal former, assisted by computational crystal structure calculation, is likely to become the approach of choice. Probably, future research may demand conformers specifically designed for a certain active delving further into the lattice engineering. At the VBP Lab, Institute of Chemical Technology, we bear an expertise in systematic formulation development and technology transfer of cocrystal engineering.
Various studies have been reported in the literature suggesting the potential of cocrystals as the next generation modified-API. To mention a few, Carbamazepine, Fluoxetine.HCl, Indomethacin, Curcumin, Itraconazole have justified the superiority of cocrystals in terms of improved solubility, stability and bioavailability. However, till date no commercial pharmaceutical co-crystal has yet been approved for sale as a drug substance and it will perhaps be a brave drug company with deep pockets that undertakes the first ‘test case’.
Progress in the application of co-crystals in commercial dosage forms is currently limited by an uncertain regulatory framework and to some extent by relatively minor differences of opinion concerning nomenclature. However the scenario is also positively driven by the increasing numbers of reports and patents covering applications of pharmaceutical co-crystals. Among many recent patents relating to potential commercial co-crystal products, the possibility of combining two active ingredients in a single co-crystal is an interesting one and has been claimed in the co-crystallisation of quercetin (a plant-derived flavonoid, used as a nutritional supplement and reputed to have anticancer properties) with antidiabetic agents such as metformin or tolazamide. The combination drug system has been suggested to have physical properties and biological activity that are distinct from the individual properties of the two components. Also, a novel NSAID/opioid co-crystal of celecoxib and tramadol has already cleared phase-II clinical trials.
A key question concerning the practical application of a cocrystal of a commercial API is whether the co-crystal is in some sense a physical mixture and hence might fall within current compendial guidelines or whether the co-crystal should be regarded as a new chemical entity with all the concomitant safety and toxicological testing such substances require. The FDA has recently (Dec 2011) released draft guidance on the regulatory classification of pharmaceutical co-crystals for applicants for New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs).
Co-crystal formation offers tremendous scope for controlled modification of key pharmaceutical properties such as habit, bulk density, solubility, compressibility, friability, melting point, hygroscopy, and dissolution rate. Given current levels of interest, coupled with the trend towards increasing molecular weight, hydrophobicity, and hence poor dissolution characteristics of recently developed drug substances, it seems only a matter of time before a successful co-crystal NDA comes about.
On a concluding note, with ESTEVE’s R&D’s positive phase-II clinical data of co-crystal formulation of celecoxib and tramadol (E-58425) , we are not far from seeing cocrystals push the salt and metastable polymorphic forms of API’s from the market.
(Ammar Arsiwala is Research Associate, Preshita Desai is an INSPIRE Research Fellow, Bhagyashree Bachhav is a final year B. Tech student and Vandana Patravale is Professor of Pharmaceutics, Institute of Chemical Technology, Mumbai)