Re: “Crystal Engineering in the Regulatory and Patent Literature of

Editorial pubs.acs.org/crystal

Re: “Crystal Engineering in the Regulatory and Patent Literature of Pharmaceutical Solid Forms”

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discussion is focused on scientific versus regulatory literature on organic pharmaceuticals. Filing a patent on an invention is not that different from submitting a scientific paper. An introduction, i.e., the state-ofthe-art, is provided, followed by a discussion of results; a detailed experimental part is added, literature is cited, and a clear statement of what is considered new and worth of publication is “claimed”. Not that different, except for some prerequisites. According to the United States Patent and Trademark Office (USPTO5), inventions, in order to be patentable, must be (i) novel, (ii) nonobvious, and (iii) useful; for the European Patent Office (EPO6) inventions, to be patentable, must (i) be new, (ii) involve an inventive step, and (iii) be industrially applicable. In all cases inventions must relate to a product, a process, or a use. Novelty and nonobviousness are requirements also of scientific publications, but they are judged on different bases with respect to a patent applications mainly because of meaning attributed to the concept of “prior art”, another pillar of patent literature. “Prior art”, cites EPO, “is any evidence that your invention is already known. Prior art does not need to exist physically or be commercially available. It is enough that someone, somewhere, sometime previously has described or shown or made something that contains a use of technology that is very similar to your invention. [...] A piece of technology that is centuries old can be prior art. [...] Anything can be prior art.”7 On the same subject, USPTO says: “The subject matter sought to be patented must be sufficiently different from what has been used or described before that it may be said to be non-obvious to a person having ordinary skill in the area of technology related to the invention.”8 The “prior art” in a scientific paper is the collection of all previously published information necessary to understand how the new results were obtained and useful to put them in the perspective of other people’s work. On these premises, we can now get back to crystal engineering. In his seminal book in 1989 Gautam Desiraju defined crystal engineering 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”.9 Indeed, most crystal engineering strategies are conceived and carried out on the basis of what is already known about the intermolecular bonding capacity of functional groups or ligands. This type of “prior art” knowledge relies vastly on the possibility of sharing the results that thousands of scientists worldwide have deposited in databases and/or described in papers, theses, reports, and orally transmitted at conferences. On the basis of this collectively available knowledge, the practitioner conceives experiments (which can also be “in silico”10) aimed at controlling the aggregation of molecules/ ions/complexes in a predictable way in order to obtain a target

his contribution was prompted in response to the recent Perspective by Desiraju and Nangia (hereafter DN).1 The somewhat unconventional format used here is consistent with scientific discourse in general and the nature of an Editorial comment. Following an initial exchange of views the four authors opted on adopting a format historically employed in written discourse−namely, presenting the views of various commentators together in the same textual offering. Likewise, each of the authors of this contribution wishes to comment individually on the DN Perspective, but we wish to contain the comments in one publication to be read, considered, and cited together rather than individually. As a result, each comment is self-contained, with its own text and references cited at the end. Dario Braga and Fabrizia Grepioni Comment. In a recent editorial Desiraju and Nangia address the question of the limited use of the term “crystal engineering” in the regulatory and patent literature of pharmaceutical solid forms. Conversely, the same term appears to be very well rooted in the scientific literature. This is witnessed, inter alia, by the existence of successful journals devoted to crystal engineering published by two of the most important learned chemical societies in the world, the American Chemical Society (this journal) and the Royal Society of Chemistry (CrystEngComm). Since both industrial and academic researchers interested in solid formulations of drugs (but also of pigments, nutraceuticals, agrochemicals, etc.) publish papers and file patents, the lower popularity of the term crystal engineering in intellectual property with respect to the scientific literature must originate from the different requirements of the two types of dissemination tools. Let us see first how the ACS and RSC crystal engineering journals define their scopes: (1) “The aim of Crystal Growth & Design is to stimulate crossfertilization of knowledge among scientists and engineers working in the fields of crystal growth, crystal engineering, and the industrial application of crystalline materials. [...] Synergistic approaches originating from different disciplines and technologies and integrating the fields of crystal growth, crystal engineering, intermolecular interactions, and industrial application are encouraged [...]”.2 (2) “CrystEngComm is the journal for innovative research covering all aspects of crystal engineering, the design, including synthesis of crystals and crystal growth, synthesis and evaluation of solid-state materials with desired properties[...]”.3 Unsurprisingly, these journals, as well as many others published by the same and other publishers, contain many explicit references to “crystal engineering”. Figure 1 shows the occurrence of papers containing the terms “crystal engineering” in the title, abstract, and keywords and the number of citations of such papers over time (source WoS4). Besides there is, of course, a very large occurrence of terms referring to crystal forms, e.g., solvates, polymorphs, co-crystals, ionic co-crystals, molecular salts, etc. Coordination polymers and metal organic frameworks, although occupying the largest portion of the crystal engineering area, will not be considered in the following because this © 2017 American Chemical Society

Published: March 1, 2017 933

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Figure 1. Occurrence of papers containing the terms “crystal engineering” in the title, abstract, and keyword and the number of citations of such papers over time (source WoS4).

significant differences in intrinsic dissolution rates which affect the safety profile of the drug.23,24 The discovery of polymorphs and solvates clashes with the crystal engineering paradigm but often leads, sometimes unexpectedly, to surprising and innovative properties. In summary, in our opinion, “crystal engineering” does not appear so often in the regulatory and patent literature of pharmaceutical solid forms because a crystal engineering project should have a predictable outcome. Paradoxically, it is the failure of the predictability paradigm that often affords results worthy of intellectual property protection. On the other hand, crystal engineering has increased our awareness of the complexity of “crystal making” and of the number of factors that come to play when molecules begin to aggregate and precipitate out from a solution, or solidify from a melt, or combine in the solid-state, etc. The fact that the kinetic− thermodynamic dualism resists the deterministic approach gives us more food for thought and opportunities for new discoveries. Angelo Gavezzotti Comments. The present contribution is a commentary on the Perspective Article by G. R. Desiraju and A. Nangia (henceforth DN) in this Journal, on “Use of the Term ‘Crystal Engineering’ in the Regulatory and Patent Literature of Pharmaceutical Solid Forms”, where the authors provide personal opinions on many matters in organic solid state chemistry. The present author is not an expert in patenting and has (thankfully) no experience of litigation. However, personal opinions in print (1) must be set in a clear statement rather than allusion or surmising, (2) must be based on sound facts, and (3) must refrain from involving unaware third parties, especially in what concerns personal reputation. The following considerations are provided only because in many places the Perspective fails to comply with these rules. DN embrace an entire solid-state community under the “umbrella” of crystal engineering. For the understanding of intermolecular interactions, it is rather quantum chemistry that has provided quantitative benchmarks25 and very efficient methods for harnessing the physics of crystal cohesion.26,27 DN reckon 500 research groups engaged in the subject: for intermolecular interactions and analysis of solids, that number is too small by an order of magnitude; for counting reproducible protocols in materials design, that number is on the order of a few units.28 DN claim an experience in “the use of crystal engineering methods as applied to pharmaceutical solid forms”which, when, or where exactly, is not said in transparent quotation. Incidentally, the Perspective, and indeed the whole crystal engineering business, seem to assume that knowing the structure automatically leads to cashing in the properties. Not quite so:

crystal structure and target properties. Therefore, crystal engineering is not a “result”, or an “outcome”, or a “discovery” per se; rather crystal engineering is a scientific process rooted on a crucial predictability paradigm. Polymorphism,11−13 i.e., the possible existence of more than one crystal form for a given crystalline substance, seems to contradict such predictive capacity or desire. Careful experimental screening never fully guarantees that a new form will not appear at some later stage or under unexpected circumstances, perhaps displacing an old one. On the other hand, in silico prediction, though increasingly powerful, is not necessarily accompanied by success in polymorph obtainment, as thermodynamic stability is often challenged by kinetics. The number of examples of unexpected appearance/ disappearance of polymorphs, beside the overquoted case of ritonavir, is very large.14 Explorers of the land of crystal forms know that the territory is vastly uncharted. The concept of “disappearing polymorphs”14 serves to remind researchers that even the most thorough and/or automated (high throughput) polymorph screening cannot guarantee that the crystal structure corresponding to the absolute free energy minimum has been discovered. This reasoning applies also to one of the successful recent manifestations of molecular crystal engineering, namely, cocrystals preparation.15,16 The predictability paradigm is the basis on which the aggregation of two or more different molecules in the same crystal is planned. However, co-crystals are affected by polymorphism just as well as single molecule crystals are.17−19 This “uncertainty principle” holds also in the case of solvates.20 Nobody can predict whether a solvate or solvates (hydrate or hydrates) will actually precipitate out when a new species is crystallized from solution, or whether on changing solvent/ mixture of solvents other types of solvates or an unsolvate species will be formed. Solvates, in their turn, can be polymorphic and can also be nonstoichiometric. The difference in properties among solvates and between solvates and unsolvates may be as dramatic as those between polymorphic forms, often even larger. It has been shown that the solubility in water of anhydrates and hydrates can be significantly different.21 For instance, the solubilities of anhydrous caffeine, carbamazepine, sulfaguanidine (49.7, 0.424, and 1.30 mg/mL, respectively) decrease to significantly lower values when these compounds are in the form of hydrates (21.8, 0.139, and 1.07 mg/mL, respectively).22 As a recent example of high impact, we may cite rifaximin, an antibiotic patented by Alfa Wassermann, which has been shown to form a series of nonstoichiometric hydrates with very 934

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some unsubstantiated or incorrectly documentedthat we believe warrant correction and/or clarification. We deal first with the authors’ description of the term “crystal engineering” and then with the general theme of the paper. DN state that “the umbrella discipline ... of crystal engineering” is “the design of new solids with desired physical and chemical properties”. In his 1989 book Crystal Engineering: The Design of Organic Solids, Desiraju9 defined crystal engineering “as the understanding of intermolecular interactions in the context of crystal packing and in the utilization of such understanding in the design of new solids with desired physical and chemical properties”. This is very different from the definition of an “umbrella discipline” as described in the recent Perspective. Furthermore, DN did not cite a single example of the a priori design and subsequent preparation (without failure) of a solid with desired chemical and physical properties (no support for the authors’ assertion that “around 500 research groups are engaged in this subject worldwide” was provided.) Having followed the course of “crystal engineering” over much of its existence,33 it is clear to me that the plethora of activities that fall under the umbrella of “crystal engineering” in molecular crystals have not led to a single invention. To the credit of practitioners in these activities, there has indeed developed a much greater understanding of the interactions between molecules and even the possibility of creating certain patterns or even possibly predictable patterns in one or two dimensions. This Journal may, as DN state, regularly feature papers under the banner of “crystal engineering”. However, none of them has come close to proving that they have succeeded, in DN’s words, in the “(i) design of a particular solid state structure” or that they have “(ii) target[ed] a particular property through the designed structure” in the true engineering sense. In view of this essentially complete lack of success as the discipline is defined, it is not at all surprising that there is “a certain amount of unfamiliarity with the term ‘crystal engineering’ in the pharmaceutical industry”. As defined by practitioners, it simply has not proven to be of use to the pharmaceutical industry. Even if DN’s current definition of crystal engineering were accepted, it does not necessarily follow that “reliably and repeatedly generating an acceptable solid state form is a component of that discipline [i.e., of crystal engineering]”. Rather, that activity describes control of crystallization and is not based on design. That control is virtually always obtained by experimentation and laboratory, pilot, and/or manufacturing adjustments, balancing thermodynamic and kinetics effects. It has not been demonstrated that control can be obtained by any design principles, including those in the DN paper. Indeed, DN essentially admit this failure, by noting that crystal engineering deals with “predicting the molecular structures and features likely to generate dif ferent crystal forms” (emphasis added). At this current level of prediction and control, the discipline can hardly claim to carry out engineering. In this context, it is important to point out that terminology is adopted by a discipline or society not because of the cleverness of its originator, but because it aids in fostering understanding and communication. In crystallography, a recent outstanding example is the term “quasicrystals” and in organic chemistry the term “synthons”, which was adopted from E. J. Corey34 and widely employed in a slightly different context by one of the authors of the paper under discussion.35 According to that paper, the term “crystal engineering” has not achieved a wide level of acceptance in the patent and regulatory literature, a prime reason

properties like dissolution and solubility (pharmaceuticals), charge hopping (solar cells), energy transport (explosives), and charge transfer (conductivity and pigment color) are still quite difficult to assess directly from crystal structure. DN touch briefly upon crystal structure prediction (CSP) by computer, an enterprise still requiring enormous amounts of ingenuity and supercomputing power.29 Crystal structure guessing by drawing prospective intermolecular bonds is also impervious because molecular synthesis and crystal synthesis are different universes.30 DN quickly dismiss a possible role of CSP in priority claims. No doubt the availability of a new experimental form would prevail over the proposal of a computationally predicted one, but other things being equal, an exhaustive theoretical search over crystal phase space stands much more chances of being relevant than vague crystal engineering claims. CSP protocols are anyway a separate subject from crystal engineering and are making their way (if still quite expensive) in the field of pharmaceutical crystals.10,31 DN say in passing that expert scientists called in court to testify over patent litigations “have consistent financial incentives to tout any uncertainty in crystal generation”. There are most certainly financial incentives in the business and denying it would be naive. But DN’s wording (“consistent”, “tout”), together with the absence of conditionals (e.g., some experts may have...”) is disturbing. DN implicitly criticize a paper by Bernstein and Dunitz,32 entitled “Disappearing polymorphs”. There is however no citation of the criticized paper, preventing the casual reader from hearing the other bell. That paper and indeed the whole subject deal with one of the many phenomena proving that applied crystal engineering is at least discontinuous. DN state that the topic “has no real scientific basis”, an improper expression in any scientific debate, as if charging the authors, the Editor of Accounts of Chemical Research, and its referees of incompetence. DN also state that the case “can only serve to muddle a complex issue”: some may counter that as far as muddling a complex issue is concerned, crystal engineering in patents is exactly what is needed. In a final statement DN suggest that crystal engineering may find more recognition in the future, as if blaming patent authorities for being somewhat slow in “catching up” with the topic. To borrow DN’s wording, as of today crystal engineering is indeed an umbrella, or a widely accepted and very fashionable trademark, that hundreds of serious research groups may (or may not) append to their published work, as well as an appealing banner under which several journals publish very significant papers. But trying to upgrade what is still mostly a verbal provision to a productive discipline in itself is hardly advisible. Eventually, who would want to patent an umbrella? Joel Bernstein Comments. We wish to comment on the recent Perspective in this Journal by Desiraju and Nangia (henceforth DN) titled “Use of the Term ‘Crystal Engineering’ in the Regulatory and Patent Literature of Pharmaceutical Solid Forms”.1 The authors begin by noting the fact (which is later supposedly substantiated by their searches of the United States patents) that “the term ‘crystal engineering’ does not figure so often” in patents as, say “polymorph”, “solvate”, and “co-crystal”. They conclude the Perspective by suggesting that “it is possible that the term ‘crystal engineering’ will enter the patent and legal literature more frequently in the future”. Between these two editorial pronouncements there are many observations and comments 935

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applications and the patent examiners have found no reason, let alone any need, to use the term in writing or prosecuting patents. DN state that “‘engineering’ signifies that there is a systematic approach to the problemand when routine, that can indicate obviousness. Is that why patent authors avoid it?” The answer is a resounding “No!” The issue of obviousness in the context of crystal forms is more complex than the authors’ somewhat simplistic statement that “obviousness in the patent sense does not require a guarantee of absolute predictability”. (We have recently discussed it in detail elsewhere40 so will not dwell on it here). As previously, there simply is no reason to use the term in patents. As we have discussed in detail elsewhere,41 a crystal form screen is not by any stretch of the imagination routine. Every compound is a new situation. Even compounds having very similar chemical structures exhibit different crystallization behaviors and different crystal form landscapes.42 The nonobviousness of a crystal structure and the unpredictability of the crystal form landscape were explicitly recognized by the United States District Court of Delaware in a recent patent litigation:43 “...evidence at trial further demonstrated that the crystal structure itself is fundamentally unpredictable...Even if there were a way of predicting that a compound would be polymorphic and what the crystal structures might be, the evidence presented shows that person of skill would not know how to make a specific polymorph or predict its properties.” This opinion was further strengthened by an even more recent decision.44 Indeed, DN admit that “There is no prior guarantee that either the plan or the execution will work...” The crucial point is that even the most experienced practitioners in organic solid state chemistry can not simply look at a molecular formula, put forth a plan to investigate, and determine without experimentation the crystal form landscape. As noted in the introduction above, the DN paper contains a number of other points on which we wish to comment. First, the statement by the authors of the DN paper that “Polymorphism has always been a well-known phenomenon in the solid-state community” is partially true at best. The classic cases of calcite and aragonite or diamond and graphite were wellknown, but the facts indicate that the phenomenon was pretty much ignored by virtually everyone in the organic solid state and pharmaceutical communities until the “celebrated Zantac and Ritonavir cases”. Arguably the key general modern reference on polymorphism even today is Walter McCrone’s chapter in the landmark three volume 1960s opus on Physics and Chemistry of the Organic Solid State.45 As shown in Figure 2 the chapter was

being that there have been no inventions employing crystal engineering. Viewed in that light, “crystal engineering” has no relevance to patents, which are fundamentally different from peer reviewed scientific publications. The purpose of scientific literature is to inform the scientific (and often general) public about advances in science. It has also served as a vehicle for teaching, for exploring new ideas and new theories, for presenting data for which there is no current explanation, and for proposing theories for examination and acceptance or rejection by the scientific community. Traditionally, especially in the older German chemical literature, failed experiments were often described in order to give the reader additional understanding of how the final reported result was achieved. (Very few modern journal editors will permit such excursions into failed experiments due to the limitations on the number of annual printed pages.) On the other hand, a purpose of patents is to provide the framework for the protection of inventions.36 In the United States, patents are enshrined in the original constitution of 1787, as stated in Article 1, section 8, clause 8: The Congress shall have power... To promote the progress of science and useful arts, by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries. The granting of exclusivity to inventors is one side of the social contract embodied in a patent. The quid pro quo is the responsibility of the inventor to teach (enable) the public how to make and use the invention, which knowledge may serve as a basis for further inventions and/or which may be used freely after the patent has expired (currently 20 years from the first U.S. effective filing date plus any patent term adjustment and/or extension to which the patent may be entitled).37 Unlike in a scientific publication, there is no requirement for a patent to describe how the invention was achieved, or to explain how and why it works. The inventor simply has to teach the reader how to make and use the invention. In return for that information, the inventor is granted exclusivity, that is, the right to prevent others from using that invention for a certain term. The observation in the DN paper that “there is nothing stopping patent authors from noting that they applied routine crystal engineering techniques that did not work...” is inappositepatent applications do not require this information. Indeed, a patent application need not disclose, and preferably omits, what is well-known to those skilled in the art.38 Furthermore, patent applicants can submit evidence, such as evidence of unpredictability, in response to any rejections that may be made by the U.S. Patent and Trademark Office. Whether or not the examiner is convinced that the applicants have made a case, that information becomes part of the prosecution record in the file wrapper (which is available to the public) but generally is not included in the patent.39 A classic example of this is highlighted by the words and works of Thomas Edisonarguably an American folk hero and perhaps the quintessential inventor, with 1093 patents: “I have not failed. I’ve just found 10,000 ways that won’t work.” His patent for the electric light bulb (U.S. Patent No. 223818) describes none of the over 1500 failed experiments carried out in pursuit of that invention, nor any of the reasoning (if there was any) behind the eventual successful invention; it is described in a document comprised of two pages and a single diagram. Since there have been no inventions employing crystal engineering, it is understandable why the drafters of patent

Figure 2. Annual citations of W. C. McCrone’s 1965 chapter on “Polymorphism”.

barely cited prior to 1990, with some years totally devoid of any citations. Some additional earlier significant publications on polymorphism were similarly ignored. The paper of Martin Buerger, considered one of the “fathers” of crystallography, coauthored with M. C. Bloom published in 193746 has a total of 15 citations prior to 1990, with the first citation regarding a 936

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The authors’ denial of established science continues: “...the notion that a particular polymorph can suddenly disappear and not appear again appears mysterious, but has no real scientific basis and can only serve to muddle a complex issue”. The genesis of our recognition of the phenomenon of disappearing polymorphs and the paper in Accounts of Chemical Research with that title32 has been described.53 I believe that Jack Dunitz and I provided the scientific basis for this phenomenon, and to the best of my knowledge not one of the ∼800 papers that have cited that paper has taken issue with the phenomenon as lacking “scientific basis”. I will point out here that having attempted to describe and explain the phenomenon we stressed in the last sentence of that paper that “...we believe that once a particular polymorph has been obtained, it is always possible to obtain it again; it is only a matter of finding the right experimental conditions” (italics in original). Scientifically, this is simply a matter of stating the obvious: if a particular crystal form had been obtained and identified, then it occupies a specific region of phase space. When first, and subsequently crystallized, that region of phase space was accessed by a combination, or perhaps even a variety of combinations of crystallization conditions, governed by the kinetic conditions of the crystallization. The appearance of a new crystal form, very often under apparently the same crystallization conditions, doesn’t mean that the previous form has disappeared irreversibly from the face of the earth. Rather, it means that the same region of phase space must be reached by a different route, viz. by developing a different set of crystallization conditions. This is not idle rationalization. In the Accounts paper itself32 we described the recovery of Form I of dichlorobenzylideneaniline earlier in my laboratory.54 But to prove the point about recovering disappeared polymorphs, we carried out a complete study of one of the examples therein, benzocaine/picrate, and learned to prepare and characterize four forms, including two polymorphs (one of which had disappeared), a monohydrate, and 2:1 complex.55 The Accounts paper had also been prompted by an example in Jack Dunitz’s lab, p′-methylchalcone, reported by Weygand in 1929 to have 13 polymorphs.56 In Jack’s lab once the stable form had been prepared, all succeeding crystallization experiments yielded only the stable form. In Beer Sheva, Jan-Olav Henck prepared the compound via a simple condensation reaction, and obtained five of Weygand’s metastable forms at nine different reaction conditions.57 Subsequent to the Accounts paper the disappeared polymorph of 1,2,3,5-tetra-O-D-ribofuranose was also prepared (not without difficulty) by a Hungarian group.58 Thus, there is nothing mysterious about disappearing polymorphs. Moreover, as documented in a recent review, they are a recurring problem in the pharmaceutical industry.14,59 They don’t serve to “muddle a complex issue”; rather, they provide challenges to solid state chemists to learn to control the crystallization process by employing the scientific methods of investigating, mastering, and controlling the kinetics and thermodynamics of that process. Regarding Ritonavir, DN have totally misrepresented the sequence of events and the “ready” solution of the problem. Briefly, it will be recalled that in 1998 Abbott Laboratories reported that after 240 production batches and two years on the market a new, more stable solid form of the material appeared.60 Attempts to avoid the crystallization of the new form proved fruitless. Attempts to manufacture the material in Italy or in a newly built facility in Puerto Rico similarly yielded only the new form.

molecular compound (albeit an explosive) in 1994. Walter McCrone’s 1956 book Fusion Methods in Chemical Microscopy,47 which contains many examples of polymorphism and methods for studying polymorphic systems, was cited 40 times prior to 1991, with only 8 of those citations related to polymorphism. A particularly rich source of information on polymorphism in pharmaceuticals, Kuhnert-Brandstatter’s 1971 book Thermomicroscopy in the Analysis of Pharmaceuticals48 was cited only 8 times up to 1991, with 6 of those being self-citations. The 1986 FDA Guidance on drug substances stated that appropriate analytical procedures should be used to detect solid forms, and that it is the applicant’s responsibility to control the crystal form of the drug substance. Although this publication may have increased awareness in the pharmaceutical industry in the five-year interim prior to the Zantac litigation, its influence on the academic community is at best difficult to assess. Accordingly, the DN paper’s statement that “Polymorphism has always been a wellknown phenomenon in the solid-state community” is belied by historical facts. DN also state 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.” No literature is cited to support this statement. Given the unpredictability of multiple crystal forms, the phrase “likely to generate them” is factually unsupportable, and polymorphism can still be considered very much the nemesis of crystal engineering.49 Further, while drawing a parallel between crystal engineering and chemical synthesis is attractive, it is important to remind readers of a significant distinction between these two chemical pursuitsand our understanding and control over themis the difference between chemical bonds and intermolecular interactions. The former, directional and relatively energetic, are quite well understood as the result of a century and a half of research, while the latter are less directed and of much lower energy, hence still less understood.50 It is worthy of note in this context that patents on the synthesis of new compounds, using well established methods to reach a definable goal, are routinely granted, while patents on new (and unpredictable) solid forms are often the subject of considerable debate and resistance of patent authorities. In addition, the DN paper’s discussion of aspirin Form II is misleading. The authors of ref 8 in DN51 did indeed “predict” its crystal structure, although it was not the lowest energy polymorph predicted, but save for the structure solution and the relative energies, they said nothing about the properties of any potential new form or how to obtain it. In an attempt to provide the “the reasons for this lack of usage of the ‘crystal engineering’ term in patents,” the DN paper cites specifically the Zantac and other patent litigations (without including any references), noting that “brand companies (and unfortunately, sometimes their experts) have considerable financial incentives to tout any uncertainty in crystal generation as a massive and thus patent-worthy development obstacle.” This ignores the fact that generation of a new crystal form invention is deemed by the law to be patent-worthy. It also ignores the fact that, as noted above, determining the crystal form landscape is a continuing challenge for every single drug throughout the course of its lifetime.52 New forms are not obvious or predictable; their properties can and very often do differ and are also not predictable. Hence, crystal generation is a massive and patentworthy development obstacle. 937

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While Abbott’s efforts at crystal form screening prior to, or following launch, are not a matter of public record, their efforts subsequent to the appearance of the more stable form are (or at least were) available61 and served as another proof of the scientific basis for this phenomenon. Following considerable effort, Abbott did determine the cause of the unpredicted and undesirable more stable form.62,63 In fact, one might speculate that if that form had appeared much earlier in the course of the development of the drug (as suggested by DN) its lack of therapeutic efficacy may have prevented it from ever being launched on the market. By implication DN suggest that the Zantac (ranitidine hydrochloride) case also lacks “real scientific basis”. We have also described the events surrounding the unplanned, unpredicted, and unwanted serendipitous appearance of Form 2 of the compound nearly four years after it was first synthesized.64,65 Since this took place when the compound was in pilot plant development, management initially insisted on going back to Form 1. No amount of effort or experimentation succeeded for nearly five years. Glaxo subsequently did learn how to make Form 1 consistently and robustly. Although the API in Glaxo’s Zantac is still Form 2 of ranitidine hydrochloride, for which the patent expired in 2002, a number of generic companies also managed to create conditions to prepare Form 1 consistently and robustly, and they went on the market with that form in 1997, upon the expiration of the Form 1 patent. None of these research efforts were trivial, and all of them are based on solid, and often sophisticated science, thus proving the point we made in the last sentence of the 1995 Accounts paper. Finally, having been involved in a number of patent litigations over the past 25 years, I feel compelled to object to the authors so casually questioning the integrity and motives of fellow scientists who have served as expert witnesses in these litigations. Many of our most distinguished colleagues have served in the capacity of expert witnesses in courts around the world.66 Yes, patents involve financial incentive; that is part of the qui pro quo. And the patent system has been a major catalyst in the Industrial Revolution. But that does not mean the financial incentive is a determining factor in the behavior of expert witnesses. In closing we note that regarding the attempt to engineer a crystal and/or its properties even DN admit “There is no prior guarantee that either the plan of the execution will work...” The crucial point is that no one can simply look at a molecular formula and put forth a plan to investigate and determine, without experimentation, the crystal form landscape, prescribe the experimental methods for accessing the specific regions in which forms are located, or predict a priori what the properties of those crystal forms would be; that process has not yet been engineered.

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Faculty of Science, New York University Shanghai, Pudong New Area, Shanghai 200122, China

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Joel Bernstein: 0000-0001-9104-8461

Notes

Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.

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ACKNOWLEDGMENTS J.B. is grateful to a number of colleagues for stimulating and enlightening discussions on these issues, in particular, Dr. Susan Reutzel-Edens, Dr. Jill MacAlpine, Professor Bruce Foxman, and the authors of the two other commentaries in this contribution, Professors Angelo Gavezzotti, Dario Braga, and Fabrizia Grepioni. They follow in the tradition of a number of distinguished scientists in this field (some of whom are cited herein) who have influenced him over the course of many years.

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REFERENCES

(1) Desiraju, G. R.; Nangia, A. Cryst. Growth Des. 2016, 16, 5585− 5586. (2) http://pubs.acs.org/page/cgdefu/about.html. (3) http://www.rsc.org/journals-books-databases/about-journals/ crystengcomm/. (4) http://thomsonreuters.com/en/products-services/scholarlyscientific-research/scholarly-search-and-discovery/web-of-science. html. (5) http://www.uspto.gov/. (6) https://www.epo.org/. (7) https://www.epo.org/learning-events/materials/inventorshandbook/novelty/prior-art.html. (8) https://www.uspto.gov/patents-getting-started/generalinformation-concerning-patents. (9) Desiraju, G. R. Crystal Engineering: The Design of Organic Solids; Materials Science Monographs 54; Elsevier: Amsterdam, NL, 1989. (10) Price, S. L. Chem. Soc. Rev. 2014, 43, 2098−2111. (11) McCrone, W. C. Polymorphism in Physics and Chemistry of the Organic Solid State; Fox, D.; Labes, M. M.; Weissemberg, A., Eds.; Interscience: New York, 1965; Vol. II, p 726. (12) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: New York, 2002. (13) Brittain, H. G. Polymorphism in Pharmaceutical Solids; Marcel Dekker, Inc.: New York, USA, 1999. (14) Bucar, D. K.; Lancaster, R. W.; Bernstein, J. Angew. Chem., Int. Ed. 2015, 54, 6972−6993. (15) Duggirala, N. K.; Perry, M. L.; Almarsson, O.; Zaworotko, M. J. Chem. Commun. 2016, 52, 640−655. (16) Wouters, J., Quéré, L., Eds. Pharmaceutical Salts and Co-Crystals RSC Drug Discovery Series; Royal Society of Chemistry: Cambridge, U.K., 2012. (17) Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2014, 16, 3451−3465. (18) O’ Nolan, D.; Perry, M. L.; Zaworotko, M. J. Cryst. Growth Des. 2016, 16, 2211−2217. (19) Eddleston, M. D.; Sivachelvam, S.; Jones, W. CrystEngComm 2013, 15, 175−181. (20) Griesser, U. J. In Polymorphism: In the Pharmaceutical Industry; Hilfiker, R., Ed.; Wiley-VCH: Germany, 2006; pp 211−233. (21) Gift, A. D.; Luner, P. E.; Luedeman, L.; Taylor, L. S. J. Pharm. Sci. 2008, 97, 5198−5211. (22) Khankari, R. K.; Grant, D. J. W. Thermochim. Acta 1995, 248, 61− 79.

Dario Braga Fabrizia Grepioni

Ciamician Department, University of Bologna, Bologna, Italy

Angelo Gavezzotti

Dipartimento di Chimica, Università di Milano, via Venezian 21, 20133 Milano, Italy

Joel Bernstein*

Department of Chemistry (Emeritus), Ben-Gurion University of the Negev, Beer Sheva, Israel 84120 Faculty of Science, New York University Abu Dhabi, P.O. Box 129188, Abu Dhabi, United Arab Emirates 938

DOI: 10.1021/acs.cgd.6b01485 Cryst. Growth Des. 2017, 17, 933−939

Crystal Growth & Design

Editorial

(45) McCrone, W. C. Polymorphism. In Physics and Chemistry of the Organic Solid State; Fox, D., Labes, M. M., Weissberger, A., Eds.; Wiley Interscience: New York, 1965; Vol. 2, pp 725−767. (46) Buerger, M. J.; Bloom, M. C. Z. Kristallogr. - Cryst. Mater. 1937, 96, 182−200. (47) McCrone, M. C. Fusion Methods in Chemical Microscopy; Interscience Publishers: New York, 1957. (48) Kuhnert-Brandstätter, M. Thermomicroscopy in the Analysis of Pharmaceuticals. In International Series of Monographs in Analytical Chemistry; Belcher, R., Freiser, M., Eds; Pergamon: Oxford, 1971; Vol. 45. (49) Braga, D.; Curzi, M.; Dichiarante, E.; Giafredda, S. L.; Grepioni, F.; Maini, L.; Paino, G.; Pettereson, A.; Polito, M. In Engineering of Crystalline Materials Properties; Novoa, J. J.; D. Braga, D., L Addadi, L., Eds.; Springer (in cooperation with NATO Public Diplomacy Division): Dordrecht, 2008; pp 131−156. (50) Dunitz, J. D. IUCrJ 2015, 2, 157−158. (51) Ouvrard, C.; Price, S. L. Cryst. Growth Des. 2004, 4, 1119−1127. (52) Erdemir, D.; Lee, A. Y.; Myerson, A. S. Curr. Opin. Drug Disc. Develop. 2007, 10, 746−755 and references therein. (53) Bernstein, J. Trans. Am. Crystallogr. Assoc. 2013, BI, 87−96. (54) Bar, I.; Bernstein, J. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1982, 38, 121−125. (55) Henck, J.-O.; Bernstein, J.; Ellern, A.; Boese, R. J. Am. Chem. Soc. 2001, 123, 1834−1841. (56) See refs 45 and 46 in ref 32. (57) Bernstein, J.; Henck, J.-O. Cryst. Eng. 1998, 1, 119−128. (58) Bombicz, P.; Czugler, M.; Tellgren, R.; Kalman, A. Angew. Chem., Int. Ed. 2003, 42, 1957−1960. (59) Newman, A. Org. Process Res. Dev. 2013, 17, 457−471 and references therein.. (60) Anon. The Pharmaceutical Journal, 261, August 1, 1998. (61) The web site for the International Association of Physicians for Aids Care is www.iapac.org. Abbott held a number of press conferences to try to explain the appearance of the new form to the public shortly after it appeared. The transcripts of those press conferences were on this site for about two years. They have since been removed. (62) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, J.; Morris, J. Pharm. Res. 2001, 18, 859−866. (63) Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.; Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.; Bauer, P.; Donaubauer, J.; Narayanan, B. A.; Soldani, M.; Riley, D.; McFarland, K. Org. Process Res. Dev. 2000, 4, 413−417. (64) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, UK, 2002, Chapter 10. (65) Bernstein, J. Polymorphism and Patents from a Chemist’s Point of View. In Polymorphism in Pharmaceutical Technology; Hilfiker, R., Ed.; Elsevier: Amsterdam, 2006; pp 365−384. (66) In alphabetical order, we list but a few of the distinguished members of the solid state organic chemical community who have been recruited to testify in patent litigations in a number of different countries, inevitably finding themselves on opposite sides of the courtroom: Jerry Atwood, Sir Jack Baldwin, Simon Bates, Dario Braga, David Bugay, Stephen Byrn, Michael Cima, Bill David, Jack Dunitz, Michael Glazer, Jenny Glusker, David Grant, Frank Herbstein , Mark Hollingsworth, Ron Jenkins, Bart Kahr, Bill Lipscomb, Tobin Marks, Adam Matzger, Michael McBride, Alan Myerson, Kenneth Morris, Kevin Roberts, Robin Rogers, Dean Smith, Bob Snyder, Pat Stahly, Jonathan Steed, Peter Stephens, Stephen Tarling, Terry Threlfall, Mike Zaworotko.

(23) Viscomi, G. C.; Campana, M.; Barbanti, M.; Grepioni, F.; Polito, M.; Confortini, D.; Rosini, G.; Righi, P.; Cannata, V.; Braga, D. CrystEngComm 2008, 10, 1074−1081. (24) Braga, D.; Grepioni, F.; Chelazzi, L.; Campana, M.; Confortini, D.; Viscomi, G. C. CrystEngComm 2012, 14, 6404−6411. (25) See for example Jurecka, P.; Sponer, J.; Cerny, J.; Hobza, P. J. Phys. Chem. Chem. Phys. 2006, 8, 1985. (26) See www.crystal.unito.it for a serious analysis of crystal structure and properties. (27) See for a review Gavezzotti, A. Molecular Aggregation, 2nd ed.; Oxford University Press: Oxford, 2013; Chapter 12. (28) A few examples: Aakeröy, C. B.; Wijethunga, T. K.; Desper, J.; Dakovic, M. Cryst. Growth Des. 2015, 15, 3853. Braga, D.; Grepioni, F.; Maini, L. Chem. Commun. 2010, 46, 6232. (29) Cruz-Cabeza, A. J. Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 2016, 72, 437. (30) Gavezzotti, A. New J. Chem. 2016, 40, 6848. (31) See for example www.avmatsim.de, a for-profit company, and references therein. (32) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28, 193. (33) I vividly recall the evening Gerhard Schmidt group seminar I attended early in 1970 at the Weizmann Institute as a fresh postdoctoral fellow when I first heard the phrase “crystal engineering”. As an accomplished synthetic organic chemist and X-ray crystallographer, Schmidt was riding the crest of his 1960s successes with the topochemical photoreactions in the solid state. But the organic chemist in him longed for a method to “engineer” crystals to obtain the desired crystal structure to enable the synthesis of predesigned molecules using those topochemical principles. Thus the desire to “engineer” crystals. The concept apparently may not have been of his creation. In the 1950s a leading crystallographer Ray Pepinsky at Penn State coined the phrase. Pepinsky, R. Phys. Rev. 1955, 100, 971. Pepinsky’s laboratory was very much a mecca for crystallographers at that time since he had built an analogue computer to carry out the then tedious calculations of Fourier transforms to generate electron densities. Schmidt had been one of the “pilgrims” to Pepinsky’s laboratory. (34) Corey, E. J. Pure Appl. Chem. 1967, 14, 30−37. (35) Desiraju, G. R. Angew. Chem., Int. Ed. Engl. 1995, 34, 2311−2327. (36) Grubb, P. W. Patents for Chemicals, Pharmaceuticals and Biotechnology, 3rd ed.; Oxford University Press: Oxford, 1999. (37) Thomas, J. R. Pharmaceutical Patent Law; The Bureau of National Affairs, Inc.: Washington, D.C., 2005. (38) Manual of Patent Examining Procedures, Section 2164; USPTO: Alexandra, VA, 2015; https://www.uspto.gov/web/offices/pac/mpep2100.html. (39) It is also worth pointing out here that, at least in U.S. patent law, an inventor can call his invention anything he desires. The name or designation is not a crucial issueit does not define the invention. How to manufacture and use of the invention are described in the specifications of the patent, and the invention for which the inventor wishes to obtain exclusivity is described in the claims. If the creator of a co-crystal wanted for some reason to call it, say, ROBERT, there is nothing in the patent law to prevent him from doing so, as long as ROBERT is sufficiently described in the patent to be enabled to the person of skill in the art. (40) Bernstein, J.; MacAlpine, J. Pharmaceutical Crystal Forms and Crystal Form Novelty and Obviousness. In Polymorphism in Pharmaceutical Technology, 2nd; Hilfiker, R.; von Raumer, M., Eds.; Wiley-VCH: Weinheim, 2016. (41) Cruz-Cabeza, A. J.; Reutzel-Edens, S.; Bernstein, J. Chem. Soc. Rev. 2015, 44, 8619−8635. (42) See e.g., Nauha, E.; Ojala, A.; Nissinen, M.; Saxell, H. CrystEngComm 2011, 13, 4956−4964. (43) Cephalon, Inc., Cephalon France, and Teva Sante SAS v. Watson Laboratories, Inc., et al. Case 1:10-md-02200-GMS, United States District Court District of Delaware, 2013. (44) Depomed and Grunenthal GmbH v. Activis Elizabeth et al. Case 2:13-CV-04507-CCC-MF, Civil Action No. 13-45-7 (CCC-MF). 939

DOI: 10.1021/acs.cgd.6b01485 Cryst. Growth Des. 2017, 17, 933−939