We offer a classical chiral resolution screening service to identify diastereomeric salts that are effective in the separation of racemic compounds into their single enantiomers, as often required for chiral APIs and intermediates. Chiral purification by crystallization can also be applied with chirally enriched mixtures arising from synthesis.
We have an in-house database of more than 150 chiral resolving agents to select from. This comprehensive list includes chiral acids, bases and coformers, complemented by information such as bulk price, solubility and pKa. As the number of commercial chiral acids with low pKa is limited, we have synthesised a set of strong chiral acids designed to form salts, such as chiral pyridines, that can be included in our chiral screens.
Using our know-how and experience of salt and cocrystal formation, a screen is designed with a subset of resolving agents selected with known synthons to interact with the target racemic molecule. For non-ionizable molecules, a chiral separation via the formation of chiral cocrystals could also be explored as part of a screening strategy.
Screens are typically performed using 20 to 30 mg of racemic mixture per experiment. The crystallization space is explored using multiple solvents (controlled cooling crystallization, liquid assisted grinding, anti-solvent additions, etc.). This approach maximizes the chance of identifying a suitable separating system for your chiral molecules. Our chiral screen service is supported by our solid state expertise in X-Ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA) and analytical team in chiral High Performance Liquid Chromatography (HPLC).
S-naproxen – thermal elliposids shown at 50% probability
Absolute stereochemistry can be confirmed by Single Crystal X-Ray Diffraction (SCXRD) internally by our experts and the information generated can complement the API dossier for FDA filling.
Robustness testing and scale-up of chiral separation are supported in-house. Commercial-scale chiral separation of API and intermediates is available at Veranova GMP and non-GMP facilities.
For molecules that are difficult to separate or purify by crystallization techniques, our Veranova team can also provide chiral chromatography methods for small and large-scale separations, including Supercritical Fluid Chromatography (SFC).
In 2023 Veranova carried out work identifying and exemplifying a chiral resolution of an API intermediate via diastereomeric salt formation.
Problem
The route for synthesis involved a multi-step process, with the final step being purification of an unwanted diastereomer using expensive and time consuming supercritical fluid chromatography (SFC). The aim was to eliminate the need for this separation by introducing a resolution through chiral salt formation into the process.
Scope of work carried out at Veranova
Outcome
The client was presented with an alternative process to expensive SFC purification during the synthesis of their API. The work was completed to tight timelines giving the option for development to be incorporated into their upcoming GMP batch.
Praziquantel (PZQ) is an important racemic drug for the treatment of worm infections. It is a neutral molecule not bearing any functional groups which could allow a classical resolution by diastereomeric salt formation. The separation by cocrystal formation with L-malic acid was first reported in 2016 (Cryst. Growth Des. 2016, 16, 1, 307–314).
Veranova designed and developed a robust separation of praziquantel.
Scope of work carried out by Veranova
We revisited the resolution on a multigram scale in acetone.
Discover new ways to advance your science with Veranova.
Contact us