Multidrug Co-Crystals Leading to Improved and Effective Therapeutics in Drug Development


In the last ten years, research has been focused on alternative therapeutic strategies for drug development and one of them is co-crystals. A review of the development, production and future of co-crystals has recenlty been published by Thipparaboina R. and co-workers .

The definition of co-crystals given by the FDA is “solids that are crystalline materials composed of two or more molecules in the same crystal lattice”, usually the interactions between molecules are weak, having non-colavent interactions. The discovery of the first co-crystal structure was quinhydrone complex synthesise by Friedrich Wohler in 1844, he found that this co-crystal was composed of a 1:1 ratio of quinone and hydroquinone. In drug development a co-crystal or multidrug co-crystal (MDC) is an active pharmaceutical ingredient (API) with a neutral compound in the same crystal lattice with non-ionic interactions between the two.

The interest in co-crystals for the pharmaceutical industry has increased in the last ten years, thanks to the development of multidrug co-crystals, for example the recent success of the phase II clinical trial of Celecoxib and Tramadol drugs by ESTEVE and Muldipharma Laboratories GmbH for the treatment of acute pain. There is a large list of existing multidrug co-crystals, their interactions improve solubility and bioavailability in therapeutic treatments. Some examples are, Ethenzamide and Gentisic acid which increase the solubility and dissolution rate (Srinivasulu et al., 2009); Meloxicam and Aspirin that significantly increase bioavailability (Cheney et al., 2011).  Co-crystals give the opportunity to treat a specific group of patients with one drug. The multidrug co-crystal Sildenafil and Aspirin presented dual therapeutic effects, treating erectile dysfunctions in cardiovascular complication patients (Zegarac et al., 2014). The following table lists the multidrug co-crystals developed so far.

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The production of multidrug co-crystals is similar to normal crystallography procedures, however, the success depends on several factors and a deep understanding of both components to co-crystalize. Important factors to consider in the production of MDC are temperature, presence of impurities, rates of evaporation, differential solubility, solvent properties, supersaturation, cooling, etc. Scaling up the production of MDC is feasible and successful, several techniques such as spherical co-crystallization, spray-drying technologies, solvent crystallization, sonic crystallization and others have been used for the production of co-crystals (Fig1).

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In 2013 the Food and Drug Administration (FDA) released a regulatory guideline for the classification of pharmaceutical co-crystals and soon after, in 2014, the European Medicines Agency (EMA) released a paper on the use of co-crystals in pharmaceutical research, however there are no many regulatory guides for the pharmaceutical market. At the moment there are few marketed co-crystal products, such as Entresto (Sacubitril-Valsartan), approved by the FDA in 2015, for the treatment of heart failure, and Lexapro (Escitalopram Oxalate), approved in 2009, for the treatment of major depressive and anxiety disorders. For the pharmaceutical industry it could be quite challenging to patent MDC and their method of production. In addition, every patent office requires different criteria for co-crystals registration. Every year the number of patents granted to multidrug co-crystals by the European Patent Office (EPO) and the United States Patent Office (USPTO) has increased. The patents available currently in MDC are listed in table 2.

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It is a challenge for pharmaceutical research and industry to find appropriate drug co-crystals combinations for the therapeutic and pharmaceutical market. However, several factors need to be considered for the production of MDC, such as incompatibility between compounds, impurities, differential solubility and dose variability. The latter is an important factor to be considered for optimal success of MDC. For example, the common stoichiometry of co-crystals is a 1:1 ratio, however some dose range between drugs are variable and the slight increase of dose of one can modify or cause undesirable side effects to the patient. The development of validated predicted models for MDC is required to avoid pitfalls.

On the other hand, novel treatments for psychiatric disorders and neuropathic pain can be approached with the used of lithium and magnesium salts to form multidrug co-crystals. Also nanotechnology can be used for the production of nano-crystals for drug delivery or clinical applications.

The pharmaceutical industry needs be aware of the different considerations in terms of multidrug co-crystals such as, predicted models, FDA regulations, patents, safety and bioavailability. Although challenging multidrug co-crystals could be a novel approach for developing an effective therapeutic, however the commercial success hasn’t emerged rapidly. There needs to be further investment in research for the development of multidrug co-crystals.

Blog written by Thalia Carreno Velazquez

 

 

References

Cheney, M.L. et al. (2011) Coformer selection in pharmaceutical cocrystal development: a case study of a meloxicam aspirin cocrystal that exhibits enhanced solubility and pharmacokinetics. J. Pharm. Sci. 100, 2172–2181

Srinivasulu, A. et al. (2009) Trimorphs of a pharmaceutical cocrystal involving two active pharmaceutical ingredients: potential relevance to combination drugs. CrystEngComm 11, 1823–1827.

Thipparaboina, R. et al. (2016) Multidrug co-crystals: towards the development of effective therapeutic hybrids. Drug Discov Today 21, 481-490.

Zegarac, M. et al. (2014) A sildenafil cocrystal based on acetylsalicylic acid exhibits an enhanced intrinsic dissolution rate. CrystEngComm 16, 32–35

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