Is This The Newest Trend For Controlling Polymorphism ?: A New Strategy of Transforming Pharmaceutical Crystal Forms (OLD)

This was a post from my old website PHARMNBIOFUEL.COM that was posted on 2011-02-19.  I am currently working on getting some new information on the website, but during this time, I have a few posts from the old website that are quite interesting.    I have a few things on the go, plus RBC Bluesfest is happening.

Hi Everyone.  Hope everyone’s research is going well.  Sometimes, you are perusing the journals and you come across the occasional paper that you know everyone should know about.  Perhaps it is the latest, greatest technique, synthesis, isolation etc. and people should be made aware of it or it may fade into that big pile of papers on your desk or you don’t find out about it until the most inappropriate time.  Today, this paper is to all the process chemists in the pharmaceutical industry that have ever worked on polymorphs.  That is, probably, every process chemist out there.  It can be the ultimate source of frustration, something that can take unreasonable amounts of time to solve, has no clear set of rules to it and can require heating to high temperatures, different solvents, long drying times and the list goes on.  This paper, that is in fact the title of this post, “A New Strategy of Transforming Pharmaceutical Crystal Forms”, by Jerry L. Atwood et al, J. Am. Chem. Soc.2011133 (5), pp 1399–1404, DOI: 10.1021/ja107617m is one of those papers that I think will be important to my pharmaceutical colleagues.  I know, when I was working on a crystallization for one of our drug candidates, there was a period of uncertainty until the x-ray diffraction data came back.  Did I get the right crystal form or was I going back to the drawing board (perhaps, picking another suitable solvent out of my list )?  The paper talks about only two drugs that are currently on the market, clarithomycin and lansoprazole.  Their chemical structures are provided below.



Clarithomycin is marketed under the brand-name Biaxin and is a semi-synthetic antibiotic where Lansoprazole (also No. 8 in its class) is a proton-pump inhibitor that is marketed under the name Prevacid (I have heard of this one, at least).  I had no idea about some of the new research that is ongoing to control polymorphs, such as the utilization of extreme pressures or utilization of supercritical fluids; this is mainly due to the fact I have been away a few years from working in the pharmaceutical industry.  When I came across this paper, I was impressed by the novelty of using pressurized carbon dioxide to transform crystal forms.  To set the stage for this paper, there has to be some appreciation how the crystal form is controlled (or formed) now as a marketable product.


Clarithomycin has 5 crystal forms: 0, I, II, III and IV of which II is the form used in formulation.  Form II is converted from Form I by heating at 110-115 °C for 18 hours.  Form 0 is prepared as a solvate of clarithomycin using such solvents as ethanol (which is preferred), isopropanol, tetrahydrofuran or isopropyl acetate.  Form II is the thermodynamically stable form.

I am going to show the schematic to show how you could convert one form to the other (I was hoping not to need the schematic, but decided you need it).


What is completely novel about this paper is that they used 350 psi CO2 to convert form 0 to form II without even going through form II.  I am at a loss for words.  Do you mean that we might be using pressure vessels to convert crystal forms in the future ?  It certainly would seem a lot more “green” than using more solvent, wouldn’t it ?  The author had tried a list of other gases and found success with carbon dioxide.  The author does speculate how carbon dioxide may affect the transformation, but I won’t rewrite it.  Take a look at the paper.  There is XRD evidence behind the author’s claims.  What I also found compelling was their second case, Lansoprazole.

Lansoprazole is marketed as the solvent-free form of the product.  The ethanol hydrate is the easiest to prepare.  The hydrate is difficult to attain solvent-free, even with vacuum drying due to susceptibility of decomposition.  The hydrate is stable at low temperature (0 C or lower) for 1 year.  Even exposure to air in an open container will cause decomposition to occur.  With the difficulty of this control of crystal form, you might be able to see the advantage of using 500 psi to convert from the solvate to the solvent-free form.  They were able to achieve conversion after applying 500 psi CO2 for 2 days, followed by a reintroduction of another 500 psi of CO2.

I apologize for the lack of pictures, but the paper is only a few pages itself and I didn’t want to reproduce anything.  I think it is worthy of a look, especially after those challenging weeks, where you have to spend more time working on a crystallization to get the right form.  Have a good week and I will be back with something else of note. Ciao !!


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