Are You Getting into Bad Habits?

In my first job, working on the chemistry of organic conducting compounds, I became fascinated by the way compounds crystallised and whether they crystallised in more than one form (polymorphism). Often the compounds I was working on, 9,10-disubstituted anthracenes, would crystallise initially in beautiful fluorescent plates, but if they were further recrystallised to remove more impurities, they would eventually crystallise as long needles. The two different habits were, however, not different polymorphs, but were the same crystal structure in the unit cell. The impurities present at very low amounts in solution (below 0.1% in many cases) were sufficient to inhibit growth in one direction and prevent needle formation.

A similar phenomenon can occur when dealing with polymorphs and solvates. The impurities in solution can prevent the most stable form from crystallising when the compound is first made, and it is often in late development, when the compound has been made in much purer state after extensive development, that a new form appears for the first time, and it may be quite difficult to make the original form – this phenomenon, known as “a disappearing polymorph” is quite common in industry. (I prefer the term “appearing polymorph” since it is the appearance of the new form rather than the disappearance of the old form which may cause problems.)

The phenomenon has been widely discussed and for a fascinating discussion it is best to read the articles by Prof Joel Bernstein from Israel. His book, entitled “Polymorphism in Molecular Crystals” was published in 2002 (Oxford), is probably the best place to start. He also has a chapter on the implications for patents and infringement of patents, which makes for fascinating reading.

The most recent book to be published on polymorphism and related topics came out late in 2006 (“Polymorphism in the Pharmaceuticals Industry” edited by R Hilfiger, Wiley-VCH) and is a multi-author work covering a wide range of relevant topics including analytical methods. For those interested in this fascinating topic, this latest book is recommended as the most up-to-date viewpoint, written from an industrial perspective.
Another recent article which gives an industrial perspective is entitled “Achieving Polymorph Selectivity in the Crystallisation of Pharmaceutical Solids: Basic Considerations and Recent Advances”. This is authored by Susan Reutzel-Edens from Lilly, Indianapolis, who is a well-known expert in the field, and was published in Current Opinion in Drug Discovery and Development, 2006, 9(6), 806-815.

Of course, an even better way to learn about this topic from a process chemistry viewpoint is to attend Scientific Update’s courses, which have been highly rated by attendees and are very popular. This year’s courses will be held in India, Barcelona and Princeton – see the website for more details.
The pictures below show crystals of the the two forms of the anti-AIDS drug lamivudine (Epivir, 3TC, GlaxoSmithKline).

Trevor Laird

Biocatalysis: A Renaissance

The literature on the use of biocatalysts in process R&D is expanding and new books on the subject have appeared regularly throughout the last 5 years. For a comprehensive listing of all the biotransformations used in industry, chemists and engineers should consult the second edition of “Industrial Biotransformations” by A Liese, K Seelbach and C Wandrey. This is an outstanding work for process R&D chemists and engineers since it gives full details, where available, for each process including plant diagrams, space-time-yields, and annual tonnage.

The most recent book is edited by Ramesh Patel, who is based in the process R&D Dept of Bristol-Myers-Squibb. This new multi-author work, “Biocatalysis in the Pharmaceutical and Biotechnology Industries”, CRC Press, 2006 covers a wide range of topics but, to my mind, is not as industrially focussed as the title suggests. For those wanting a more industrially-relevant book why not dip into Patel’s earlier text.

“Stereoselective Biocatalysis”. Alternatively, the most recent edition of Dave Ager’s “Handbook of Chiral Chemicals”, Marcel Dekker, 2006 has some excellent review chapters on industrial biocatalysis, especially the one by Scott Laneman.

Trevor Laird