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Cocrystals can enable the formulation of solid dosage drugs, but the FDA's final guidelines have left concerns about how their use could impact development timelines, the drug product manufacturing process, and the intellectual property position of products containing cocrystals.
Active pharmaceutical ingredients (APIs) are most conveniently developed and delivered as solid dosage forms that contain a single crystalline form of an API. Cocrystals alter the physical properties of APIs without chemical modification of the API while retaining the benefits of a crystalline solid form. For compounds that do not form useful salts and still require improved physical properties, such as solubility or stability, cocrystals may provide a viable solution. A cocrystal may thus represent a crystal form with better pharmacokinetic properties, and therefore a better market opportunity.
In April 2013, however, FDA issued its final regulatory guidance on cocrystals, including the classification of a pharmaceutical cocrystal as a “drug product intermediate.” This classification may help some product development strategies while, at least in the short term, it may limit the ability to use cocrystals efficiently in other cases.
Improved pharmacokinetic properties and more
“The selection of a specific crystal form for a given API is a profoundly important step from clinical, legal and regulatory perspectives: the dissolution rate and intrinsic solubility of different crystal forms is variable and can strongly influence bioavailability; stability to temperature and humidity are critically dependent upon crystal packing; and the unpredictability (i.e. lack of obviousness) of crystal structures and physical properties means that there are legal issues and challenges in terms of obtaining and maintaining patent protection for an API,” says Ning Shan, director of preclinical development at Thar Pharmaceuticals.
Highly lipophilic APIs have dissolution problems that may be overcome using a cocrystal because the new crystalline lattice being formed often has very different dissolution properties compared to those of the crystals of the API alone, according to Chris Frampton, chief scientific officer of SAFC Pharmorphix. The formation of a new crystal lattice with a pharmaceutically acceptable coformer often enables other issues, such as compaction problems and difficulties with hygroscopicity, to be overcome. In addition, for nonionizable APIs, for which it is not possible to make a salt, the option to form a cocrystal can be advantageous over finding alternative formulation methods or changing the API molecular structure to include the acid or base functionality required for salt formation, which can have an impact on the activity of the API. In addition, increasingly, adds Frampton, cocrystals are also being seen as a lifecycle management tool, because their use can delay or divert generic competition.
Choosing the right coformer
If a cocrystal is to be used, it clearly must have physical properties that offer key improvements over the properties of the API itself. “Cocrystals have been used to create crystalline forms of APIs that were previously known in only amorphous forms, improve melting points, enable improved chemical purity, reduce chemical degradation when exposed to light, remove the risk of hydrate formation in a formulation, and improve the solubility to enable higher bioavailability,” says Scott L. Childs, president and CSO of Renovo Research. For Frampton, improved stability is one of the most desirable attributes of a cocrystal API. “The physical stability, chemical stability, and melting point can all be tuned to achieve a new form that is more desirable than the crystal form of the API alone,” he explains.
In addition, the preferred cocrystal will not only meet the physical property improvement requirements, but also contain a "pharmaceutically acceptable" coformer that is nontoxic, has a high weight percent of API compared to coformer, be chemically and physically stable under all relevant conditions, be manufacturable using low-cost approaches in existing production equipment, and remain stable over the shelf life of the product.
Inexperience and need for screening pose challenges
While cocrystals offer many potential benefits, it is important to recognize that they have not yet been fully embraced or adopted by the industry, according to Childs. There are both skeptics and advocates. It is his opinion that cocrystals are viewed as a “last resort” in some laboratories, and this perception will persist in many minds until FDA approves a product containing a cocrystal that delivers improved performance. “I am convinced, however, that the first FDA-approved cocrystal product is an issue of 'when' and not 'if'’,” he asserts.
Shan adds that the requirement in the FDA guidance that the developer of a cocrystal drug product must provide “assurance that complete dissociation of the API from its excipient occurs prior to reaching the site of action for pharmacological activity” could be a real challenge. He also notes that the prediction of cocrystal structures remains semiempirical, but he anticipates that with more powerful computational equipment, better calculation approaches and estimations will be possible.
The difficulties that are faced with respect to the selection of appropriate coformers for a given API is a real challenge, agrees Frampton. “The one thing we cannot do is predict the outcome of the properties of cocrystals until they are generated. Although we can recognize that there might be an interaction between the API and a conformer, there is no guarantee that this interaction will lead to cocrystal formation, or if the cocrystals that do form will have desirable properties. A lot of screening is required, and sometimes what we get does not reflect the crystal lattice we intended.” He does note, though, that with respect to melting points, he has found that a lower melting point coformer will tend to reduce the melting point of the cocrystal while a higher melting point conformer will increase it.
Of course, Frampton also points out that this lack of predictability is necessary to some degree. “As soon as it is possible to predict cocrystal structures, we have a problem. Patent applications for salt forms are already being questioned on the grounds that they are predictable and obvious due to the pKa of the API and the limited list of pharmaceutically acceptable salt formers. The lure of the cocrystal remains the questionable and unexpected successful outcome.”
New formulating, analytical and modeling techniques
There have been some advances in various techniques and technologies that are beginning to address some of these issued. Shan points to the solvent-drop grinding process as a way to manage mechanochemistry issues and advances in computational chemistry that are enabling improved crystal structure prediction.
At SAFC Pharmorphix, the ability to perform crystal structure analyses on really small crystals has been very advantageous. “Knowing the crystal structure makes it possible to see how the two materials come together to form a supramolecular complex. Then we can go back to our list of potential coformers, tune them slightly, and follow an iterative process to develop the optimum cocrystal,” observes Frampton.
Renovo, meanwhile, has developed a new approach to formulating cocrystals that uses the improved cocrystal solubility more effectively. Traditionally, as is commonly done with salts, cocrystals are used in in-vitro and in-vivo pre-clinical studies as "neat" material (pure crystalline powder), according to Childs. This approach is not optimal because cocrystals are highly susceptible to solvent-mediated transformation into the poorly soluble form of the API when dosed as neat material.
“We have developed our new approach, demonstrated with a danazol cocrystal, that utilizes solubilizing excipients and precipitation inhibitors to create an optimal supersaturation level and controlled dissolution event,” Childs explains. The model system achieved a 10-X increase in the area under the concentration time curve (AUC) in animal studies using the formulation, compared to only a 1.7-X increase in the AUC using the neat cocrystal solid. “The results of this study suggest that the appropriate formulation of cocrystals can be an important part of the cocrystal development process,” he concludes.
Unknown impact of FDA guidance
While the European Medicines Agency and the Ministry of Health, Labor, and Welfare in Japan have not published any official guides with respect to cocrystal development, FDA’s final guidance was issued in April 2013 (1).
The most important aspects of the guidance, according to Frampton, are that FDA determined that a cocrystal is a drug product intermediate, and it defined two types of interactions.
First, the coformer used to make the cocrystal is defined as an excipient, which can form a simple physical mixture with the API or interact with the API on the molecular level within the crystal lattice. Frampton compares the latter interaction to that of an API incorporated into a cyclodextrin excipient to enhance bioavailability and solubility, in which the API sits within the barrel of the beta-cyclodextrin. For salt forms, on the other hand, where it is important to know where the proton sits in a complex and if it has been transferred to the API because if that occurs, the salt form is no longer considered to be the ‘same’ API from a regulatory perspective.
“Many in the industry find it quite surprising that FDA has not regarded cocrystals as new APIs because the properties can vary widely from one coformer to another. It also makes it easier for generics companies to compete with branded products by utilizing these materials,” Frampton comments. “Indeed, the guidance leaves a number of open questions and perhaps some concerns within the pharmaceutical industry about how the use of a cocrystal could impact development timelines, the drug product manufacturing process, and the intellectual property position of a product containing a cocrystal,” adds Childs.
First, cocrysals are treated like the polymorphs of a drug, rather than as salts. As polymorphs they are considered to be the ‘same’ API, whereas different salts are treated as different APIs from a regulatory perspective. Secondly, drug product intermediates have different regulatory reporting requirements than salts or polymorphs. Finally, there are IP issues. Because cocrystals are considered to be, in effect, the same drug substance, generic-drug companies can introduce them as competitive products that are still considered to be the same API, whereas the use of a different salt would not be substitutable as the same active ingredient.
Shan does point out, though, that a cocrystal still has the same active ingredient as the original drug. “Even so, under the patent protection of the original drug, a cocrystal version of the same drug cannot circumvent the original patent,” he notes. “However, a cocrystal with desired properties can be patented, intellectual-property protected, and marketed, as mentioned previously in the context of lifecycle management.”
Much more to come
“The current perception of cocrystals is analogous to that of amorphous materials during the period when that technology was emerging. While the basic understanding of cocrystals as materials has advanced at a steady pace, there are important questions remaining concerning the regulatory issues, impact of the coformer molecule on toxicology studies, the ability to produce some cocrystals at scale, the cost of production if advanced formulation is needed, and the ability of crystal form IP protection to enable product exclusivity,” says Childs
“All of these areas have been addressed to some degree in the available literature, but I would caution anyone who thinks that cocrystals will remain an inferior solid form, and that the real impact of cocrystals has yet to be demonstrated. With the appropriate time, effort, and investment, our ability to effectively use cocrystals to create improved pharmaceutical products will reach the point where cocrystals will be a desirable and useful solid form rather than a ‘last resort’”, he continues.
“I envision the ability of cocrystals, in specific situations, to be able to compete directly with amorphous dispersions in terms of efficacy but create a superior product because of the lower risk and improved stability of the crystalline state compared to the amorphous state,” Childs concludes.
1. FDA, Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals (Rockville, MD, April 2013), http://www.fda.gov/downloads/Drugs/Guidances/UCM281764.pdf, accessed June 20, 2013.