Characterisation of rac- and (R)- PZQ Amine

PZQ Phase Diagram v1.pdf13.06 KB
PZQAmine DSC raw data.pdf219.67 KB

A start has finally been made on determining the phase diagram for PZQAmine from 0 to 100% ee, based upon melting point determination of known % w/w mixtures of racemicand single enantiomer PZQAmine.  Samples of the latter were provided by Michael early this year. 
The "version 1" phase diagram is attached, along with a second file containing the raw data.  Note that the data has been generated from mixtures of racemic and (R)- PZQAmine, and the data simply "mirrored" into the (S)- rich region of the diagram.  The ee of the supplied (R)- amine has been taken as stated (97% ee) and not rechecked.
Explanation:  Whilst the "pure" racemate and (R)- enantiomer show sharp melting point behaviour typical of pure materials, mixtures of the two exhibit melting point depression.  When this reaches a minimum the mixture is known as the eutectic.  By using DSC (differential scanning calorimetry) to observe the melting event in detail, two melting endotherms can be observed for most of the mixtures.  The onset of melting is determined graphically from the DSC, and is more informative than the temperature of the endotherm peaks.  These data can be plotted to map out the phase diagram, which is of relevance because melting point is a surrogate for solubility, and hence the behaviour of these materials during recrystallisation. 
I will next be attempting to improve the resolution of the DSC method by adjusting the scan rate, so as to better define the location of the eutectic point.  For the present it is clear that crystallisation of PZQAmine mixtures with below 50% ee will deliver racemic crystals, whereas mixtures of above 95% ee can be crystallised up to enantio-purity. 
It is therefore important at present not to convert the diastereomeric salt to free amine until confident that the salt is of at least 95% ee. 
Best regards, Nick

XRPD patterns of rac- and (R)- PZQAmine

PZQAmine XRPDs.pdf631.14 KB

The attached file contains X-ray powder diffraction patterns (XRPDs) for racemic and (R)- PZQAmine, as well as a mixture of the two.  These confirm that (as is often the case) the racemic compound and the single enantiomer have different crystal structures.  This is consistant with the phase diagram for PZQ Amine gathered from the melting point of mixtures of the two.
Thanks to Jana Galbraith (Almac Sciences Physical Sciences Dept) for recording these patterns.