Phase transformations of amlodipine besylate solid forms

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry
• Materials Science

Background:

• Phase transformations, such as hydrate formation and dehydration, are critical during drug product manufacturing and storage.
• Understanding and controlling these solid-form changes is essential for maintaining drug quality attributes.
• Amlodipine besylate (AMB) exhibits multiple solid forms, including anhydrate (AH), monohydrate (MH), dihydrate (DH), and amorphous (AM).

Purpose of the Study:

• To investigate the phase transformations of different solid forms of amlodipine besylate (AMB).
• To develop quantitative models for solid form analysis using spectroscopic techniques.
• To elucidate the kinetics and mechanisms of AMB solid form transformations during processing.

Main Methods:

• Raman and near-infrared (NIR) spectroscopy were employed to monitor solid form changes.
• Multivariate data analysis was used to develop quantification models for AMB solid forms.
• Optical microscopy was utilized to study the kinetics of dissolution, nucleation, and growth during transformations.
• Solubility measurements and wet granulation processes were used to induce and study transformations.

Main Results:

• The anhydrate (AH), monohydrate (MH), and amorphous (AM) forms transformed to the dihydrate (DH) form during solubility measurements.
• The AH to DH transformation was also observed during wet granulation, with significantly faster kinetics compared to solubility experiments.
• Shear forces during wet granulation were identified as a key factor accelerating the AH to DH transformation.
• The DH form persisted after drying in wet granules, resulting in a final mixture of AH and DH.
• Transformation kinetics were primarily limited by nucleation and growth steps.

Conclusions:

• Spectroscopic methods coupled with multivariate analysis are effective for quantifying AMB solid forms.
• Wet granulation processes can significantly influence AMB solid form transformations due to mechanical stress.
• Nucleation and growth are the rate-limiting steps in AMB solid form transformations, impacting drug product stability.