Crystal Engineering - American Chemical Society

Crystal Engineering - American Chemical 24, 2016 - (AP...

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Use of the term "Crystal Engineering" in the regulatory and patent literature of pharmaceutical solid forms. Some comments. Gautam R. Desiraju, and Ashwini Nangia Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01070 • Publication Date (Web): 24 Aug 2016 Downloaded from on August 25, 2016

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Use of the term "Crystal Engineering" in the regulatory and patent literature of pharmaceutical solid forms. Some comments.

Gautam R. Desiraju* and Ashwini Nangia* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India ([email protected]) CSIR-National Chemical Laboratory, Dr.Homi Bhabha Road, Pune 411 008, India ([email protected])

While terms like “polymorph”, “solvate” and “cocrystal” are used regularly in legal contexts, the term “crystal engineering” does not figure so often. Some possible reasons for this observation are suggested.

Polymorphism has always been a well-known phenomenon in the solid state chemistry community, yet in early years, it remained distinct from the typical pharmaceutical research domain. Times have surely changed. Ever since the celebrated Zantac® and Ritonavir® cases in the 1990s, the importance of studying and understanding the properties of solid forms of drugs has become increasingly acknowledged in the pharmaceutical industry.1 Of course, solid forms of drugs have always been known and most of the market pertains to solid forms, as tablets or ointments, rather than to injections. Salts have been traditionally popular as more soluble variations of a drug because of their higher solubility. However, once these albeit unusual examples demonstrated the drastic financial implications of different solid state properties, there was a sea change in the drug development mind set, with a new focus at the regulatory agencies both in research groups devoted specifically to drug polymorphism and in commercial groups .

The study of solid forms of active pharmaceutical ingredients (API) has become a major endeavour in academia and industry today, and given the IP implications, neither brand nor generic companies can afford to ignore solid form properties. Assessment of these properties is now best done early, in the pre-formulation drug development and commercialization timeline. All other things being equal, no brand company wants a lead or development candidate saddled with a troublesome solid-state property that must be formulated-around unnecessarily. Likewise, generics routinely consider other polymorphs for design-around purposes, and craft their formulations accordingly. The introduction of the 1 ACS Paragon Plus Environment

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term “pharmaceutical cocrystal” in the early 2000s started to further cross-pollinate the drug and formulation worlds by recognizing that drug behaviour could be further shaped by, and in effect, intimately formulating at a near-molecular level.2-5

While the study of these solid state properties has become a routine occurrence, the field recognizes its practitioners are highly specialized, with advanced instrumental and technical backup that is not generally available to one and all in the pharmaceutical industry. Several well-known commercial companies acquired this expertise to permit pharmaceutical companies to outsource this analysis. The margins of error when identifying and differentiating different crystal types can be very fine. In any event, the knowledge base has expanded so that terms like “polymorph”, “salt”, “hydrate”, “solvate” and “cocrystal” are commonly used and understood in the industry today.

In the academic community, the umbrella discipline that has brought all these activities onto a common platform is the subject of crystal engineering. This is defined as the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding in the design of new solids with desired physical and chemical properties.6 The subject employs crystallography, spectroscopy and computation, and around 500 research groups are engaged in this subject in academic institutions worldwide. Journals like this and others regularly feature papers based on crystal engineering of drug solid forms. The subject is attractive to scientists who work with pharmaceutical compounds and who come from a variety of disciplines because it addresses two critical issues: (i) the design of a particular solid state structure and (ii) targeting a particular property through the designed structure. Crystal engineering of pharmaceutical compounds then may be conveniently divided into two interconnected parts: (i) structure design and (ii) property design.This having been said, there still seems to be a certain amount of unfamiliarity with the term “crystal engineering” in the pharmaceutical industry, especially with what can actually be done with a certain expertise in the subject.

Crystal engineering principles have been around for decades, and have focused since earlier times on methodologies for inducing crystallization (including of different crystal types that were, e.g., energetically more favourable); ensuring control over production solution systems to reliably and repeatedly generate an acceptable solid-state form; and predicting the molecular structures and features likely to generate different crystal forms. The 2 ACS Paragon Plus Environment

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authors of this commentary have been engaged separately in the use of crystal engineering methods as applied to pharmaceutical solid forms to achieve more targeted crystal outcomes for a little more than a decade. We have regularly studied the patent literature, legal documents, judgements and related material and have participated in the legal process from time to time. In informal discussions with each other and with others in the field, we had noted that while terms like “polymorph”, “hydrate”, “solvate” and more latterly, “cocrystal” are used regularly in these legal contexts, the term “crystal engineering” figures but rarely. We decided to look more closely into the matter.

Data were retrieved from Google Patents. We found 33092, 33323 and 6536 references to “polymorph(s)”, “salt(s)” and “cocrystal(s)” since 2000. There is no doubt that these terms are very popular indeed in the patent literature. The term “crystal engineering”, however, features only 1091 times since 2000. A number of patents that use this term pertain to BaTiO3 and other related inorganics. We estimate that the term “crystal engineering” has been used in the organic context around 700 times since 2000 in patents. Interestingly, the term was used overall 884 and 605 times since 2005 and 2010 but an increasing proportion of these usages pertain to organic crystal engineering and more specifically to pharmaceutical compounds. There is little doubt that the considerable research activity in academic laboratories since 2000 on the crystal engineering of pharmaceutical solids has led to this corresponding increase in the use of the term “crystal engineering” in pharmaceutical patents during the last decade. Similar trends are seen in multi-term searches: “crystal engineering” + “polymorph” yielded 340, 283 and 218 hits post 2000, 2005 and 2010; for “crystal engineering” + “salt” the numbers are 599, 516 and 368; for “crystal engineering” and “cocrystal” the numbers are 329, 297 and 230. It may be noted that while the numbers for polymorph, salt and cocrystal are very different in the global sample (33092, 33323 and 6536), they become quite uniform under the crystal engineering umbrella (340, 590, 329). Clearly most of these patents pertain to solid forms of pharmaceutical compounds. These data raise some questions: (i) are the crystal engineering numbers really small? (ii) if so, what could be the reasons for the limited use of the term in patents? Let us take up these questions in turn.

The numbers are indeed small. Assuming that the “cocrystal” term only entered the pharmaceutical literature in 2004, and also that the “salt” term is being used in the pharmaceutical crystal engineering context for only around the same time, there is little doubt 3 ACS Paragon Plus Environment

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that the “polymorph” term, which has been an integral part of crystal engineering for around 25 years, and which has been used heavily in patents by itself, did not draw in the “crystal engineering” term more frequently into patents. “Polymorph” occurs 33092 times since 2000, but “polymorph” + “crystal engineering” occurs only 340 times.

It must be admitted that the idea of polymorph design was little appreciated in the 1990s. But the field rapidly developed to identify polymorphs and techniques likely to generate them. More interesting from an academic point of view is how to pre-design a particular polymorph structure, with the molecules oriented in precise conditions in threedimensional space in a manner analogous to how we can use known chemical reactions to assemble a molecular structure of groups attached in a particular way. In the 1990s and even early 2000s, the concept of crystal structure prediction (CSP) was still nascent.7 CSP is a much more sophisticated technique today but even so, it seems unlikely to us that the prediction of a crystal structure and property of an unknown polymorph (like say aspirin form II8) would constitute grounds for rejection of a potential patent application for a new form were it to have been isolated experimentally. In balance, we feel that the number of usages of the term “crystal engineering” in patents since 2000 is rather small considering the large numbers of papers in the open literature, during this time period, that use the term in their titles and abstracts.

What could be the reasons for this lack of usage of the “crystal engineering” term in patents? It should be recognized that in the patent field, a foundational threshold includes the premise that something must be unknown, or surprising. In the Zantac® and other patent litigation, brand companies (and, unfortunately, sometimes their experts) have considerable financial incentives to tout any uncertainty in crystal generation as a massive and thus patentworthy development obstacle. For example, the notion that a particular polymorph can suddenly disappear and not appear again appears mysterious, but it has no real scientific basis and can only serve to muddle a complex issue.7 In the case of Ritonavir® which was a poster child both for the “disappearance” and “reappearance” of a polymorph, all that seems to have been required was crystal form screening. Once this was done, the so-called mystery as to how to control the solid forms was readily solved.9 It was not even a scientific issue. All of this lessens the desirability to concede that the techniques used to generate a particular polymorph or pseudopolymorph10 involve application of crystal engineering principles. It is generally conceded that it is much easier to predict if a particular drug molecule will form a 4 ACS Paragon Plus Environment

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hydrate11 or a solvate12 than it is to predict if it will form a polymorph. Considering the importance of hydrates and solvates in brand company patents, might this be an inhibiting factor towards the use of the “crystal engineering” phrase? The word “engineering” signifies that there is a systematic approach to a problem—and when routine, that can indicate obviousness. Is this why patent authors avoid it? Is it that the term has not been defined by the FDA unlike “polymorph”, “salt” and “cocrystal” and is therefore in this sense avoidable? Regarding the first question, there is no dearth of patents that use the word “engineering” in a global sense. Engineering simply means the activity in which one can put forth a plan of construction and then execute it. There is no prior guarantee that either the plan or the execution will work although one tries one’s best to get a successful outcome. But obviousness in the patent sense does not require a guarantee of absolute predictability. And, there is nothing stopping patent authors from noting that they applied routine crystal engineering techniques that did not work, and hence required a non-obvious approach to produce a given crystal that has properties that render it sufficiently unique versus other crystal forms of the drug. The fact that the FDA has not defined crystal engineering formally could have a bearing on the non-usage of the term in patents, even though regulatory and legal concerns are quite separate, but this does not seem to us to be a convincing enough reason. We also note that polymorph patents tend to come later in time than molecule patents, and hence are not likely to be challenged until a drug medicine is on the market, and even then typically not for a period of at least 5 years after first commercial marketing in the United States. Assuming a new chemical entity takes 3-10 years to secure final FDA approval, that could in turn represent a 10-15 year lag time before the generic and legal challenges begin to occur. The present situation for solid form patents may be likened to the period when product patents were issued for new drug molecules. It is possible that when process patents appear for these solid forms, the use of the “crystal engineering” term may follow naturally.In the end, it is possible that the term “crystal engineering” will enter the patent and legal literature more frequently in the future, as the age of the patent filings start to catch up with where the literature is today. In this instance, truly, only time can tell.

Note added in proof: We are just now aware of the revised draft guidelines from the FDA for the regulatory classification of pharmaceutical cocrystals, which state that "pharmaceutical co-crystals have opened up opportunities for engineering solid-state forms beyond conventional solid-state forms of an active pharmaceutical ingredient (API), such as salts and polymorphs." The hyphen in the word “co-crystal” is from the FDA document. The formal 5 ACS Paragon Plus Environment

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mention of the phrase "engineering of solid-state forms" by the FDA will surely impinge on many of the issues we have discussed in this perspective!

Both authors thank the DST (New Delhi) for the award of respective J. C. Bose fellowships



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Why have pharmaceutical patents shied away from the term “Crystal Engineering”?

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