These crystalline molecules are still poorly understood; but their properties hint at significant opportunities to improve solid-state pharmaceutical products.

by Raymond E Peck, CEO of VxP Pharma

Not all pharmaceutical compounds offer ideal physical and pharmacokinetic properties. For example, some may not form useful salts, or may lack stability or solubility. One common solution is to chemically modify the active pharmaceutical ingredient (API); but for APIs delivered as solid dosage forms, a better alternative is the formation of cocrystals. These additional crystalline forms of the API, formed during a modified manufacturing process, can improve the pharmacokinetic properties of the API, creating a more marketable form of the drug.

Cocrystals have been used to improve APIs in a wide range of ways. Some have been used to create crystalline forms of formerly amorphous compounds. Others have served to improve the chemical purity of compounds, raise melting points, strengthen resistance to degradation by light, boost solubility, to remove the risk of hydrate formation, and even to increase the bioavailability of the drug. For all these reasons, the development of a cocrystal form of an API are worth investigating.

However, the formation of cocrystals requires a coformer: a chemical that triggers the cocrystal of the API to take shape in addition to the original crystalline form. These coformers must maintain the pharmaceutical efficacy of the drug, and must be nontoxic. The end product must also have a high weight percent of API relative to coformer, and must remain physically and chemically stable, while also being manufacturable at a reasonable cost.

These challenges require considerable expertise on the part of any pharmaceutical developer or contract manufacturing organization (CMO) involved in the creation of cocrystals. The following concerns are especially pertinent in today’s development landscape.

Lack of empirical cocrystal predictability presents challenges, as well as opportunities.

New technologies offer hope of improved control over cocrystals in the near future.

New technologies offer hope of improved control over cocrystals in the near future.

Although the benefits of cocrystals are now widely recognized in the pharmaceutical sector, a good deal of skepticism remains; and cocrystals have not been widely adopted on a practical level. Some laboratory directors even view cocrystals as a “last resort” to compensate for defects in an API, rather than as a potential improvement that could increase the market viability of a product. The lack of clear guidance on cocrystals from the US Food and Drug Administration (FDA), along with the current lack of empirical methods for predicting cocrystal structure, have further fueled this uncertainty.

On a practical level, he difficulty of predicting cocrystal formation makes it difficult to select appropriate coformers for each API. Until the cocrystals have actually formed, it is simply not possible for current technology to predict their properties. While some methods have shown promising results (for example, a coformer with a higher melting point tends to raise the melting point of the resulting cocrystal) the fact remains that extensive screening is necessary to select cocrystalline forms that offer desirable modifications of the original API. The new crystalline lattice of a cocrystalline form may also present additional challenges, such as issues with compaction, dissolution, and hygroscopicity. This has proven to be an issue of particular concern with APIs that are highly lipophilic.

However, many of these hurdles are technological rather than theoretical. As the power of computational equipment continues to increase, calculations will become clearer, and it may soon be entirely possible to predict and produce specific cocrystals on demand. In fact, today’s lack of empirical cocrystal predictability may actually present an opportunity for pharmaceutical developers. Just as polymorphs of many APIs remain unpatented, most cocrystalline APIs are not “predictable and obvious” enough to qualify as intellectual property. Thus, unexpected successes in cocrystal development may prove to be well worth the investment.

New technologies offer hope of improved control over cocrystals in the near future.

Pharmaceutical developers and CMOs will soon begin to produce cocrystals at scale.

Pharmaceutical developers and CMOs will soon begin to produce cocrystals at scale.

An array of new technologies and techniques have taken promising steps toward the resolution of some of these concerns. One example is the solvent-drop grinding process, which delivers tighter control over the mechanochemistry of crystals. Still more promising is an innovation on the conventional approach to forming cocrystals. Instead of creating the crystals from pure crystalline powder, which makes them vulnerable to breaking down as soon as they’re introduced into a solvent, this new technique forms crystals in the presence of precipitation inhibitors and solubilizing excipients, to create a superior supersaturation level that results in more stable cocrystals.

With the help of the latest chemical computation software, engineers are also beginning to see improvements in their ability to predict cocrystal formation. New tools can perform structural analysis of very small cocrystals, enabling researchers to analyze the resulting supramolecular complex, and iteratively select alternative coformers that will bring that complex’s structure closer to the ideal. More directed experimentation in this vein is likely to discover even more impactful uses for cocrystals, as further pharmaceutical benefits become apparent.

As the fundamental understanding of cocrystal formation continues to advance, new tools for more rapid selection and screening of cocrystals, and for computerized recommendation of more ideal coformers, will begin to appear on the market within the next several years. Just as engineers can use computer software to predict useful polymorphs with some degree of reliability, they will soon be able to digitally test coformers and predict their results in cocrystal formation. Such innovations will streamline the development pipeline, enabling engineers to rapidly pinpoint the most useful coformers with minimal investment in time and material resources.

With the help of tools like these, pharmaceutical developers and CMOs will very likely begin to produce cocrystals at scale, for the express purpose of performing product improvement research. And once this cocrystal experimentation trend begins to take hold, pharma firms will unlock significant improvements to their existing solid-state drug products, and will begin to capitalize on those innovations. The first companies that develop the ability to consistently predict cocrystal structure and properties, meanwhile, will have grounds to make intellectual property claims, securing significant market share while locking competitors out of the development of profitable coformers. Firms whose engineers already possess expertise in cocrystal creation will be ideally positioned to control this emerging marketplace.

In addition to being a writer and speaker, Raymond E Peck is the Founder and CEO of VxP Pharma Services and VxP Biologics, both based in Indianapolis Indiana.

By |2018-02-07T09:27:17+00:00October 25th, 2017|Formulation Development & Clinical Trial Materials|

About the Author:

Ray Peck