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

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Solid-State Chemistry

Background:

• Early-stage assessment of active pharmaceutical ingredient (API) polymorphic forms is crucial for drug development.
• Limited API availability often constrains traditional assessment methods requiring large sample volumes.
• Existing methods like compaction simulators and texture analyzers (TA) necessitate significant API quantities.

Purpose of the Study:

• To evaluate the diamond anvil cell (DAC) as a material-sparing technique for assessing pressure-induced polymorphic transitions in APIs.
• To investigate the impact of pressure on Hydrochlorothiazide (HCT) using minimal API quantities.
• To compare the efficacy of DAC with conventional methods for polymorphic screening.

Main Methods:

• Utilized a diamond anvil cell (DAC) for high-pressure studies on microgram quantities of Hydrochlorothiazide (HCT) as a model API.
• Employed Raman spectroscopy for real-time monitoring of polymorphic form changes within the DAC.
• Correlated DAC findings with data from texture analyzer (TA) and X-ray powder diffraction (XRPD).

Main Results:

• A polymorphic transition was observed at 300 MPa in the DAC, consistent with TA results (500 MPa).
• X-ray powder diffraction (XRPD) indicated that trituration can revert the API to its original phase.
• The DAC successfully detected polymorphic transitions within the tableting compression range, requiring significantly less material than TA.

Conclusions:

• The diamond anvil cell (DAC) is an effective material-sparing technique for assessing pressure-induced polymorphic transitions in APIs.
• DAC enables real-time monitoring of polymorphic changes during compression, crucial for early-stage drug development.
• This method is particularly advantageous when API availability is limited, offering a preferred approach for polymorphic screening.