Recrystallization of PZQ

13 Oct
Published by RyanPakula

This information is from a few days previous, but I didn't have the blog all set up then, so here it is now.
 
As the first step in working with praziquantel, I'm looking to simply find some pretty solid conditions for recystallizing the racemate.  Ideally we'd be able to separate the enantiomers via recrystallization of a scalemic sample (which is already reported, vide infra), but later it'll be important that we can at least purify the racemate this way, as opposed to using more expensive methods such as chromatography.
 
Some solvents I don't plan on trying include methyl-tert-butyl ether, methylene chloride, hexane(s), isopropanol, toluene, and acetonitrile, as well as chloroform.  This list is based on two papers I found in my initial search for literature that specifically discusses chromatography and/or recrystallization of PZQ, and chloroform is included because it was used as the eluent in purifying PZQ by column chromatography in this Tetrahedron: Asymmetry paper from 2006.  This J Chromatography B 2009 paper only discusses chromatography, but this J Pharm Sci 2004 paper discusses both chromatography and recrystallization.  In the J Chromatography paper they use a 2:1 v/v mixture of methyl-tert-butyl ether and methylene chloride to extract PZQ from human plasma samples, then later they elute their Chiralpak AD column with 3:1 v/v hexanes/isopropanol.  They also discuss a former publication which had nearly the same success using an acetonitrile/toluene mixture for extraction.  PZQ is also soluble in methanol (they use it as the solvent for standards in the J Chromatography B paper), but it apparently works well enough for recrystallization based on the J Pharm Sci paper.  In this one they dissolve scalemic mixtures in methanol at RT (to give saturated solutions) then chill at 0ºC for a week to form crystals (see pg. 3044).  They provide this helpful graph:
PZQ solubility in MeOH
 
I should mention recrystallization for obtaining enantiopure PZQ: the J Pharm Sci paper reports this on pg. 3045.  After constructing a ternary phase diagram of the two enantiomers and methanol and determining eutectics to exist at 92:8 wt% either direction (saturated at RT), they demonstarte that using a mixture at least this enantiopure (e.g., a solution saturated at room temperature containing 94% R isomer and 6% S isomer would suffice) results in optically pure crystals once cooled to 0ºC for recrystallization.  They used 94% S to obtain pure S crystals, and observed that a 75% S mixture resulted in a "loss of purity in the crystals and enrichment of the mother liquor [with the dominant starting enantiomer]."
 
A few questions I'll throw out there:
1) Does anyone know of ways to crystallize amides nicely?  With amines one can form the conguated acid, but I can't find any similar tricks for amides...
2) Has anyone already had good success recrystallizing PZQ, maybe with a solvent in which you can heat to dissolve PZQ and cool to RT to crash out crystals, rather than dissolve at RT and chill to 0ºC to crash out (as with methanol, mentioned above)?
3) What numbers do people have for the melting points of the racemate and the pure (-)-(R) enantiomer?  From the J Pharm Sci paper I have 136.2ºC for the racemate and 110.6ºC for the pure (-)-(R) enantiomer.  Other numbers I've found are 136-138ºC for the racemate (pg. 13), 108-110ºC for the (+)-(S) enantiomer, and 107-108ºC for the (-)-(R) enantiomer (both pg. 16)(from the original US patent 4,001,411; I think you should be able to view/download it here), 113-115ºC for the pure (-)-(R) enantiomer from the Tetrahedron: Asymmetry paper (though they do cite the 107-108ºC from the patent), 135-137ºC for what is supposedly the (-)-(R) enantiomer (in the J Chem Res 2004 paper with DOI 10.3184/0308234041640564 [it doesn't quite work properly, but if you search google for that, the first link should be the article])(we believe this is either the racemate, or just flat-out wrong), and 136-142ºC for the racemate (from this randomly chosen manufacturer's website).