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When and why should my API be a new crystalline polymorph, amorphous, a co-crystal, or an alternative salt?

Generic drugs contain an active pharmaceutical ingredient (API) that is similar to the originator product, but might have different and improved characteristics. Extensive development activities are needed in order to define the right chemical process and physical properties.

A different scientific approach contains a long list of challenges, and regulatory and IP rules should be taken into account.

The physical properties of the option you choose may have a major impact on solubility, stability and performance of the drug product. It will also have an influence on your production cost, regulatory procedures and time to market.

In short, the understanding of API characteristics and its behavior, including selected development approach, is necessary when deciding on the best option.

Here is a brief outline of the four options:

New polymorph

Polymorphism is a frequent characteristic of active pharmaceutical ingredients (APIs), and it refers to the ability of substances to crystallize into more than one crystalline forms.

Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure and density.

These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.

From the thermodynamic aspect, the common approach is to select the most stable crystal form for the formulation. However, the thermodynamic metastable crystal with better solubility and bioavailability could also be adopted for pharmaceutical preparation. New polymorphic forms may also exhibit different physical and mechanic properties, including particle size, density, hardness, outflow and compactness.

Generic products may comprise solid substances that have differentiated and improved characteristics over the existing knowledge in the literature. These solid substances can potentially be the subject of patent applications.

New polymorph Afatinib.

Amorphous

The second option is to create an amorphous API.

There are multiple advantages associated with amorphous APIs. They usually have higher solubility than alternative crystalline forms and, in some cases, amorphous APIs may be an alternative to crystalline material that is patent protected.

Having said that, working with amorphous material can also be challenging. You might need to overcome its tendency to recrystallize, absorb significant amounts of humidity, or create side reactions that lead to chemical impurities.

A lack of a crystallization process could also lead to a final API that is not pure enough for use. In some cases, these problems may be solved by having a good control of impurities during the process. Therefore, a robust process is needed, as well as a good R&D team to define it.

Amorphous Eluxadoline.

Co-crystals

Co-crystals are single-phase crystallines that contain two or more solids. One of the compounds is an API, and the other is usually an excipient. Generally, evidence to demonstrate that both the API and co-formers are present in the unit cell should be provided.

Choosing the right conformer, and finding the right conditions to create a stable co-crystal, is challenging. An efficient research plan and a dedicated R&D team are needed to find the right match.

As of  FDA guidelines1, a pharmaceutical co-crystal has a regulatory classification similar to that of a polymorph of the API.  Specifically, it is not regarded as a new API. From a regulatory perspective, drug products that are designed to contain a new co-crystal are considered analogous of a new polymorph of the API.

According to the FDA’s guideline 1, for the classification of co-crystals, If both API and co-former have ionizable functional groups: a co-crystal is required to have a pKa difference between co-formers that is less than 1, thus indicating a non-ionic species and minimal proton sharing. The aim is to distinguish between a salt and a co-crystal. Additionally, substantial dissociation of the API from its co-crystal form should occur before reaching the site of pharmacological activity.

A co-crystal that is composed of two or more APIs, with or without additional inactive co-formers,  will be treated as a fixed-dose combination product and not a new API.

According to the new FDA guidelines, the co-crystal option should only be considered after gathering wide analytical and physical characterization data, showing that a co-crystal is the desirable form.

Examples from the literature show possible advantages that the co-crystal solid might have superior properties compared to the base/acid API, for example when it comes to dissolution rate, solubility, stability, bioavailability and mechanical properties.

Additionally, enhanced processability of APIs during drug product manufacturing can be sometimes an added value when selecting the co-crystal form of API development.

The rationale behind using co-crystals in the context of bioequivalence requirements which is part of ANDA submission is explained by Blagden2, et al who notes that the behavior of co-crystals characterized by a transient improvement in concentration and a subsequent drop, normally to the solubility limits of the free form in that pH environment.

If concentration improvements can be maintained over a bio-relevant timescale then it is strong evidence that a co-crystal phase will possess useful function. Formulation additives can inhibit free form nucleation after dissociation of the co-crystal, providing a ‘parachute’ where one does not naturally exist.

If you have already chosen a coformer, you might be facing several different challenges, such as; crystallization process development, analytical characterization and some regulatory requirements.

There are several cocrystals in development and one of the examples is Baricitinib.

  1. Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER)

Salts

The fourth option is to create a salt. Today, many pharmaceutical drugs are salts due to their solubility properties. Chemical and physical properties and behavior will be determined by the decision on the counter ion.

Just like with amorphous materials, salts may give an advantage of higher solubility compared to a crystalline form of the base/acid. A salt may also be more stable to produce and store than amorphous material.

Preparation of a salt may include additional step of crystallization. This additional step might improve your final material’s purity and physical properties.

However, the process of creating a salt may also be perplexing. After taking the decision regarding the counter ion, finding the right chemical procedure and having the analytical support to show it is a salt, could prove challenging. In addition, salts are filed with the FDA with full reports of investigations of safety and effectiveness as per 505b2 NDA.

Salt of  Nilotinib fumarate

So, what to choose?

Choosing the right form has always been one of the major challenges in generic pharmaceuticals development, especially today when there is a broad range of options available on the market.

Choosing by guess alone is not a good option. The decision should be made in collaboration with a professional team of experts, whether to go with a new polymorph, an amorphous, a co-crystal, or a salt form.

 

Thanks to Masa Rajic Linaric, and Oshrat Frenkel for contributing to this article.

About the author

Maytal Piran is Director of Physical R&D. She leads the solid state global team of product managers and researchers, specializing in API crystal forms, particle & powder properties.