Use of inline Raman spectroscopy to understand mechanisms of polymorph formation

The Problem

During pilot scale isolation of a close-to-market API, difficulties were encountered associated with mixtures of polymorphs appearing in the final solid. 

The Breakthrough

Through the use of Raman spectroscopy, a form map was constructed and then leveraged to establish the mechanism of polymorph formation to avoid future batch failures.

The Impact

By understanding and controlling the polymorphic landscape, the optimized processes avoided batch failures during the crucial validation campaigns and ultimately allowed for successful large-scale production of the pivotal medicine. 

Control of the crystalline form of an API is a crucial parameter for many marketed APIs. Quite often, the final stage in manufacturing for solid APIs is focused on crystallisation of the target compound as the desired polymorph.

APC was asked to investigate the final crystallisation step in question and define the conditions for polymorph control, and also to try and define modes of failure to better understand what process parameters acted as levers for creating undesired polymorphs. A reliable library of defined polymorphs and their respective XRDs was already available, which allowed APC’s scientists to create a form map by Raman spectroscopy. Each of the previously observed polymorphs were made in the lab, and the form confirmed by XRD and DSC. The challenge then remained to analyse each isolated polymorph by Raman spectroscopy. Establishing a library of Raman spectra and identifying diagnostic peaks for the key polymorphs was crucial in order to extract the maximum amount of information from each experiment during the process understanding and optimisation phase of the project. 

With the toolbox for polymorph identification in hand, it was then possible to run the crystallisation step with inline Raman and establish the mechanism of polymorph formation. Similarly, several crystallisation processes could be carried out with variation of the many process parameters in order to establish optimum conditions for clean and efficient form transition in the final crystallisation step.

Ultimately, APC established a process for consistent polymorph isolation, along with details of multiple scenarios that could lead to undesired polymorphs. This allowed the team to accurately define the parameter setpoints that would lead to the desired form. A series of large scale crystallisations were then carried out to examine scale sensitive parameters, with mixing values modelled from both the small scale experiments and based on suitability for the forecasted manufacturing vessel. This ensured that when the optimised crystallisation process was transferred to manufacturing, all the necessary parameters were met, and the client was able to produce large amounts of their crucial medicine.