Real-time polymorphic form assessment of pharmaceuticals at tabletting pressures using micro-scale quantities

Assessing polymorphic form changes in active pharmaceutical ingredients (APIs) during the early stage is critical for selecting the best polymorphic form required for drug product development. However, this assessment can be constrained by limited API availability. Present methods to assess risk in industry relies on larger volume equipment such as a compaction simulator or texture analyser (TA) that requires larger quantities of API. In the present study, a diamond anvil cell (DAC) was used, that reduces the quantity of material even further to micrograms to investigate the impact of pressure using Hydrochlorothiazide (HCT) as a model API. The powdered API was directly loaded into the DAC sample chamber without a pressure-transmitting medium (PTM), and Raman spectroscopy was used to monitor form changes. A polymorphic transition begins to be observed at 300 MPa pressure in the DAC that is commensurate with the findings in the TA (500 MPa) from Raman and X-ray powder diffraction (XRPD). XRPD analysis revealed that trituration likely causes a transformation back to the original phase as undisturbed samples can be stored for months. In conclusion, the study highlights the effectiveness of the DAC as a material sparing technique for assessing pressure induced polymorphic transition in APIs at the time of compression enabling a real-time monitoring of the process. The DAC successfully detected the polymorphic transition in tabletting compression range requiring significantly less material than the TA. The minimal consumption of API making DAC a preferred method for polymorphic screening particularly at the early stage of development when material availability is limited.