I thought I would thank everyone for taking a look at my last post, “You could add a little bit of soap to that”. My site is picking up quite a few visits since I started posting again. Today’s post is not a synthesis one ( I do have one of those). It might be the next post. I saw this paper and couldn’t resist.
We are all accustomed to all the acronyms that NMR spectroscopists have given some of the pulse sequences they have designed. COSY, NOESY, HETCOR and many others. Had you heard of CLASSIC NMR ? (Is that what I always do ? Errr. Nope) CLASSIC stands for Combined Liquid- And Solid-State In-situ Crystallization NMR. Like everyone else, I had used NMR for structure elucidation and confirmation, sometimes to roughly determine residual solvent levels in the drug material I was synthesizing. This technique is used to acquire more information on crystallizations. I am almost certain there are a few process chemists that would be interested in this.
The article, “CLASSIC NMR”: An In-Situ NMR Strategy for Mapping the Time-Evolution of Crystallization Processes by Combined Liquid-State and Solid-State Measurements” by Colan E. Hughes, P. Andrew Williams, and Kenneth D. M. Harris, Angew. Chem. Int. Ed. 2014, 53, 8939 –8943 2014, DOI: 10.1002/anie.201404266 seems quite interesting.
Using two different pulse sequences, one that is invisible to solvent and the other that is invisible to the solid, seems logical. The pulse sequences are alternating during the experiment. This method purports to provide information on the first solid particles in the crystallization to be identified and allows the evolution of different polymorphs to be identified as a function of time. (Sounds pretty valuable to me) Apparently, you can perform this technique with any solid-state NMR spectrometer. I didn’t have access to one several years ago, but perhaps, you do now.
I haven’t seen a solid state NMR of polymorphs. You could tell the differences from Form I to V for this particular molecule. But what would it look like with a more complex molecule ? That’s what I would like to know. This could provide great information on API crystallizations. It looks like they were performing a crystallization from one solvent, where I might want to use a solvent/anti-solvent system. Additionally, it would be nice to see what effect a seed crystal had on the crystallization. I think it is a good step in the right direction, though. Very encouraging !!
The CLASSIC NMR strategy is applied here in 13C NMR studies of crystallization of m-ABA from dimethyl sulfoxide DMSO-d6 using a Bruker AVANCE III spectrometer. The solution was initially held at 120 °C for 1 h to ensure complete dissolution, then cooled to 33 °C over ca. 15 mins. The CLASSIC NMR strategy was then applied over 15 h. The time to record each spectrum was 38.4 mins for 13C CPMAS and 6.4 mins for 13C direct-excitation. Thus, the effective time resolution for the CLASSIC NMR study was 44.8 mins.
The paper describes how only Form I was formed during the crystallization from DMSO (not too interesting), but a recrystallization in methanol shows that in the early stages of the crystallization, Form I is present before a polymorphic transition occurs to Form III, the final form from methanol.
It would be nice to see something a little more complex. Hopefully, it will be adopted as a technique to probe crystallizations.
I will be back soon with another post. You always free to comment, follow me on Twitter (@DevelopProcess), Google Plus, LinkedIn. Have a great week !!!