Salt / Cocrystal/ Continuum?

A cocrystal consists of two or more different molecules, typically a drug molecule (API) and a coformer, bound together through non-covalent interactions like hydrogen bonding. The molecules (components) co-exist in a crystal lattice with definite stichometry. Whereas if the bond between two molecules is ionic (involving proton transfer), then it is called a salt form.

This edition focuses on the importance of cocrystal/salt classification in the regulatory & patent landscape and ways to achieve a definitive classification. Though there are many guiding principles for this classification, the subject is still evolving and being debated within the scientific fraternity. While a detailed discussion of cocrystals is beyond the scope of this edition, I have attempted to cover key concepts relevant from regulatory and patent perspectives at a high level, along with some notable references.

Regulatory and Patent Implications:

In the context of generic drugs, exploring cocrystals presents a promising strategy to circumvent drug polymorph patents, offering numerous benefits, such as customizable physicochemical properties. It is crucial, however, to definitively establish that a multi-component system is indeed a cocrystal rather than a salt. This distinction is pivotal because cocrystals are regarded similarly to hydrates, solvates, and polymorphs-they are considered the "same" drug entity and do not require additional safety data for regulatory approval under the generic pathway (505(j)) in the US market. On the other hand, salts of drugs are classified as "not the same" entities, necessitating a different regulatory pathway (505(b)(2)) under the US FDA. This pathway typically requires additional safety data for approval.

Like polymorphs, cocrystals are patentable. Many pharmaceutical products in the market have active ingredients in multi-component solid forms. Sometimes, knowing the class of a patented API solid form opens new avenues for alternative solid forms' development, circumventing the patent. In summary, the classification determines the regulatory & legal pathway for generic drug development and influences strategic decisions in drug development and market entry.

Rules of classification:

Rule No. 1: ΔpKa, the pKa difference between the API and coformer.

?As per USFDA guidance on cocrystals [1]

The ΔpKa?rule is commonly applied by chemists and crystal engineers [2]

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*Salt-cocrystal continuum:

Between these two distinct forms (salts and cocrystals), there exists a continuum where the multi-component system exhibits characteristics that lie somewhere between the pure salt and cocrystal forms. These intermediates can possess varying degrees of ionic and non-covalent interactions, influencing their physicochemical properties such as solubility, stability, and bioavailability.

In most real-time cases, we encounter ambiguous scenarios where it is difficult to predict the classification using ΔpKa alone. In such instances, we must employ orthogonal techniques to gather more evidence for further confirmation.

These orthogonal techniques are employed to precisely locate the H-atom (proton) between both molecules (API and coformer). We can use standalone or combinations of techniques such as infrared (FTIR) [3], X-ray photoelectron spectroscopy (XPS) [4], solid-state nuclear magnetic resonance spectroscopy (SSNMR) [5], and X-ray diffraction [6]. These are some of the most used techniques. The spectroscopic techniques help predict based on the spectral changes of the groups that involve proton transfers, whereas X-ray diffraction helps with prediction based on the bond angles and bond distances of the hydrogen atom. Due to its size, it is quite challenging to position H-atoms precisely during the crystal structure-solving step. Recent studies have reported that using spectroscopic and X-ray diffraction data, together with computational methods, has proven to be more effective in precisely locating H-atoms.

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Rule No. 2: Substantial dissociation

There should be substantial dissociation of the drug from its co-crystal form before reaching the site of pharmacological activity. For this, in vitro evaluation based on dissolution and/or solubility is to be conducted. Often, a chromatographic-based measurement area is used, in which we expect to get two distinct peaks of both components, and measured concentrations of the components should prove the complete dissociation.

Rule No. 3: Same crystal lattice.

Both components of the system (API and coformer) must be present in the same crystal lattice/unit cell. Single X-ray diffraction studies provide the most direct evidence for confirming whether both components are present in the same unit cell. However, when single-crystal X-ray data generation is not feasible due to constraints such as the inability to develop a sizable crystal for single-crystal XRD measurement, alternative techniques such as structure determination from powder diffraction (SDPD) or electron diffraction can be explored.

Disclaimer: The information provided in this article reflects solely my personal views and does not represent the views or opinions of my current or past organizations. Pharmaceutical professionals are advised to exercise their own judgment and consult the most recent guidance from regulatory agencies when making decisions regarding product quality & registration.

?References:

1.???? Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, Feb 2018, USFDA.

2.???? Cruz-Cabeza AJ, Lusi M, Wheatcroft HP, Bond AD. The role of solvation in proton transfer reactions: implications for predicting salt/co-crystal formation using the Δp K a rule. Faraday Discussions. 2022;235:446-66.

3.???? da Silva CC, Guimar?es FF, Ribeiro L, Martins FT. Salt or cocrystal of salt? Probing the nature of multicomponent crystal forms with infrared spectroscopy. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2016 Oct 5;167:89-95.

4.???? Tothadi S, Shaikh TR, Gupta S, Dandela R, Vinod CP, Nangia AK. Can we identify the salt–cocrystal continuum state using XPS?. Crystal Growth & Design. 2021 Jan 14;21(2):735-47.

5.???? Zhao L, Hanrahan MP, Chakravarty P, DiPasquale AG, Sirois LE, Nagapudi K, Lubach JW, Rossini AJ. Characterization of pharmaceutical cocrystals and salts by dynamic nuclear polarization-enhanced solid-state NMR spectroscopy. Crystal Growth & Design. 2018 Feb 15;18(4):2588-601.

6.???? Aaker?y CB, Fasulo ME, Desper J. Cocrystal or salt: does it really matter?. Molecular Pharmaceutics. 2007 Jun 4;4(3):317-22.