Experts' Opinion

Dr. Michael Gruß                   

"Intrinsic physico-chemical Properties and other specific characteristics of a Drug Substance (API) formulated in a Drug Product determine the efficacy and efficiency of medical treatment.

If you perform crystallization experiments with an active moiety alone under various conditions, you may get polymorphs. But you cannot yield salts or co-crystals of the active moiety doing such experiments. If an additional component (e.g. fumaric acid) is added to the active moiety, the result of the experiments may be a co-crystal, a salt, a combination of both, or just a physical mixture of the components. And all of these may appear in polymorphic forms.

The distinction between neutral or charged molecules forming co-crystals, solvates, or salts is first of all man-made categorization, i.e. classification. There exists a variety of combinations between neutral molecules, salts, co-crystals and solvates in the solid state. This fact complicates clear classification based on a scientific base. Further, all compounds may form polymorphs.

Co-crystals, salts and solvates cover a broad range of physical properties, e.g. with respect to solubility. Co-crystal or salt or solvate forming agents may have themselves a specific toxicological profile and may thus interact with the human body. So, what differentiates co-crystals from salts? It is the category to which the type of the chemical bond is assigned: non-ionic or ionic. And what differentiates co-crystals from solvates? It is the category to which the co-forming agent is assigned according to the melting point: solid or liquid. What differentiates co-crystals from polymorphs? Or what is common? Isn’t that like comparing apples with pears? Co-crystals may appear in different polymorphic forms. The same applies for salts.

The FDA/CDER DRAFT GUIDANCE dated August 2016 proposes to regulatory classify (i.e. categorize) co-crystals like polymorphs. I would suggest to read the referenced ANDA "Pharmaceutical Solid Polymorphism". While doing that, try to substitute the word "polymorph" by "co-crystal". Do you recognize any difference when you instead substitute the word "polymorph" by "salt"? Doing that I struggled a bit about “Polymorphic forms of a drug substance differ in internal-solid structure, but not in chemical structure” in paragraph IV (“sameness”). "Naming of Drug Product Containing Salt Drug Substances" another FDA/CDER guidance document dated June 2015 might be interesting reading in this context as well.

Categorizing simplifies making decisions for downstream processing. Furthermore, fewer choices enable faster decisions. Considering today's complex development and registration processes all means shortening timelines from invention to market entry are doubtlessly welcome. The more consistent the assignment of a compound to a category is with our current scientific understanding, the better will downstream processes fit to the intended purpose. What is the intended purpose? Above all ensuring safety and efficacy for the patient. Secondly, accepted and harmonized registration processes and successful development leading to cheaper and better medical treatment."  

 

Prof. Dr. Joop H. ter Horst   

"A recent article by E. Grothe et al. on classification of cocrystals, salts and solvates shows that in the case of 3 or more components a large fraction of the crystalline compounds should be classified as co-crystal salts, salt solvates, co-crystal solvates, or even co-crystal solvate salts*. This is bound to create classification problems in the more complex multicomponent future."  

*E. Grothe, H. Meekes, E. Vlieg, J. H. ter Horst, and R. de Gelder, Cryst. Growth Des., 2016, 16 (6), 3237–3243

 

Dr. Martin Viertelhaus      

"The new FDA’s draft guidance on the classification of pharmaceutical co-crystals is good news: In this draft, the FDA recommends to classify co-crystals similar to a polymorph of the same active ingredient. With this change, FDA and EMEA consider co-crystals in a similar way. I hope this will support the use of co-crystals in life science formulations (pharma, agro, food, …). Now it should be easier to benefit from the improved properties of co-crystals of actives, which lead to products with e.g. lower amount of active ingredient, higher efficacy and safety, lower requirements for packaging, storage and more convenient application."