Editorial pubs.acs.org/OPRD
Special Feature Section: Polymorphism and Crystallisation
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An unusual topic in this special feature relates to the chemical integrity of polymorphs, with examples chosen from the patent literature to illustrate the issues discussed. The paper emphasises the need not only to look at XRPD data but also to support the identification of new forms with other spectroscopic information to ensure that the structural integrity has not changed. Two papers focus on solubility measurements, one with a thought-provoking analysis and the other with a case study involving measurement of solubility of a rapidly transforming metastable form. Several papers are concerned with control of crystallisation processes and subsequent downstream activities such as filtering and drying. Inevitably control strategies these days include process analytical technology (PAT) to monitor the crystallisation process, and one paper shows how this can also be used to help to define design space in this and subsequent unit operations. A number of papers describe case studies on a single molecule and its crystal forms. One of these is a compound in which the crystallisation of a cocrystal form enabled purification of the API, whereas another describes the reasons for the choice of a cocrystal as the preferred form for manufacture, even when other forms such as salts were available. Solid-state interconversion of forms during a drying process forms part of another interesting paper. Chemists who have worked for many years in organic chemistry usually say that the most difficult substances to crystallise are carbohydrates, so it is pertinent to include a paper on the crystallisation of sugars, particularly owing to the increased importance of carbohydrates in discovery chemistry. Whilst reviewing an undergraduate text on organic chemistry this week, I noticed that two monosaccharides are still listed as syrups, presumably having never been crystallised before. This is a chicken and egg situation since the materials may never have been crystallised because they are impure, and the reason they are impure is because they do not crystallise. Perhaps a more theoretical understanding of carbohydrate crystallisation might assist with design of appropriate crystallisation conditions for a particular carbohydrate crystal form. If so, anyone interested in the subject should read the paper in this issue from Pfizer on computational approaches to support solid form selection. Polymorphism and crystallisation are multidisciplinary subjects, where expertise from many sources can influence the thinking. It is good to have received so many papers from such a wide variety of institutions and departments, and I thank all those who have contributed to this special section.
he subjects of polymorphism and the crystallisation and other downstream processes that produce polymorphs, solvates, hydrates, and cocrystals are increasingly important in industry, particularly in the production of high added-value products with extremely tight specifications, such as pharmaceuticals. Crystallisation is the most important unit operation for impurity removal, and control of the crystallisation to produce the desired crystal form with the appropriate stability and properties for further formulation is a topic of considerable value to industry. More and more intermediates and final products are shown to be polymorphic or to form cocrystals, solvates, or hydrates with suitable molecules. Compounds with four different components (e.g., active ingredient, cocrystal former, solvent, and water) have recently been made, stretching our understanding of the thermodynamics and kinetics of the crystallisation process. I wonder whether the type of structures currently being examined in industry, with lots of conformational flexibility coupled with a number of heterocyclic rings and hydrogen bond donors/acceptors means that polymorphism/solvation is inevitable. The identification of lots of polymorphs/solvates could also result from the more comprehensive screening for different forms, now routine in industry. The generic pharmaceutical industry is expert at finding new crystal forms (by very extensive screening from unusual solvents, for example) of existing substances which can, in some jurisdictions, be patented. The response from the discovers of new molecules is therefore to screen for all possible forms (and patent them) prior to launch of a new product. However, new forms surprisingly do appear during development and sometimes after launch despite previous extensive screening. As far as I recall from reading the papers in the special feature section, no appearing/disappearing polymorph issues are mentioned, but there have been such problems mentioned in recent papers in the last 12 months in Organic Process Research & Development (OPR&D). The fundamentals of crystallisation, as delineated in academic laboratories, underpin the knowledge required to develop robust processes, allowing chemists and engineers to develop an understanding of nucleation and crystal growth as well as the kinetics of interconversion of the different forms of the substance being studied or manufactured. There is no doubt that this is a subject where the collaboration beween the universities, research institutes, and industry has been extremely fruitful. This special feature section of OPR&D is the fifth we have published on the subject of Polymorphism and Crystallisation, the last being in 2009. It contains a mixture of academic and industrial studies, sometimes with a close collaboration between a university and an industrial partner. The section begins with a couple of interesting review articles both illustrating industrial perspectives; one on crystallisation and monitoring of the crystallisation process, the other on solid form screening. © 2013 American Chemical Society
Trevor Laird, Editor, OPR&D Special Issue: Polymorphism and Crystallization 2013 Published: February 18, 2013 443
dx.doi.org/10.1021/op4000303 | Org. Process Res. Dev. 2013, 17, 443−444
Organic Process Research & Development
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Editorial
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Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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dx.doi.org/10.1021/op4000303 | Org. Process Res. Dev. 2013, 17, 443−444
