Although the systematic study of crystallization afforded high impact results in the 19th century (e.g. Liebig, Wöhler, Pasteur, Ostwald), the concept of crystal engineering has only evolved from an oxymoron(1) to mainstream acceptance over the past two decades. Today there is growing momentum that has been engendered by the success of crystal engineering in areas such as pharmaceutical cocrystals (see CGD Network Structures of the week, SOTWs, #s 9 and 21) and metal-organic materials (see SOTWs 2, 4, 6, 7, 12, 16, 17, 18, 19, 20, 22). In both instances, the crystal engineer can preselect molecules from a library of chemical building blocks that are amenable to crystal engineering. Such an approach limits what can be studied but the modular nature of the products affords at once an enormous diversity of composition coupled with a degree of control over the resulting crystal structure. However, it is not always possible to preselect the composition of a crystal as exemplified by active pharmaceutical ingredients, APIs. There is a great deal of activity in the field of API crystal form screening and much of it can be traced to ranitidine HCl, otherwise known as Zantac®, which was the subject of a series of litigations over a crystal form patent and at one time was the biggest blockbuster drug in the world (see SOTW3). That a new API crystal form is novel, not obvious and has utility means that it meets the key criteria for patentability and the crystal form patent of an API is to all intents and purposes the underpinning of innovation in the pharmaceutical industry. This is because the crystal form of the API is delivered to the patient and most typically the crystal form patent is what protects the exclusivity of an API. However, although novelty and utility are quite facile to prove, obviousness is somewhat more subjective and is a moving target as the science of crystal engineering evolves.
This discussion will address several questions about crystallization that remain unanswered or partially answered with a focus upon “obviousness” and how it applies to crystal forms. In the past several months I have had the pleasure of attending a series of conferences (the first Gordon Conference on Crystal Engineering, the Growing World of Crystal Forms and the 2010 Polymorphism and Crystallization Conference) that have afforded me a snapshot of the science, technology and patent landscape of API crystal forms. The questions to be posed in this discussion might summarize the state of the art concerning crystal forms and/or they could be a composite of listening to and/or discussing the subject with a diverse range of people from industry, academia and the US and European patent offices. In some cases there was considerable debate about these questions.
Question 1. Is it obvious that a compound will be crystalline? Perhaps this is the most basic question of all. We have all encountered compounds that are hard to crystallize, but are there any small molecule compounds out there that cannot be crystallized? I have personally crystallized more than a thousand compounds and, even when powders are obtained from via crystallization, I do not recall having encountered a compound coming out of solution as an amorphous form. I have also used mechanochemistry to convert mixtures of crystalline cocrystal formers into microcrystalline cocrystals, a process that I still find counterintuitive. I
Are there indeed any examples of “uncrystallizable” small molecule compounds? I would certainly like to know about them and perhaps investigate them in depth. Comments or suggestions?
(1) Maddox, JS. "Crystals from First Principles", Nature, 1988, 335, 201.