Process induced transformations during tablet manufacturing: phase transition analysis of caffeine using DSC and low...

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry

Background:

• Understanding API phase transitions during tableting is crucial for drug product stability and efficacy.
• Caffeine Form I is a model Active Pharmaceutical Ingredient (API) commonly used in solid dosage forms.

Purpose of the Study:

• To investigate the phase transition of caffeine Form I to Form II during the tableting process.
• To compare the capabilities of Differential Scanning Calorimetry (DSC) and Micro Raman Spectroscopy (MRS) in analyzing these transitions within tablets.

Main Methods:

• Tableting of caffeine Form I using an instrumented press (70-170 MPa) with plastic flow behavior (Heckel model).
• Quantitative analysis using Differential Scanning Calorimetry (DSC) for macroscopic analysis (10mg).
• Quantitative analysis using low frequency Micro Raman Spectroscopy (MRS) for microscopic mapping (5 μm³ spatial resolution).

Main Results:

• Phase transitions were detected at tablet surfaces, borders, and centers.
• The degree of transition from caffeine Form I to Form II remained relatively constant across applied pressures.
• MRS indicated higher transition degrees (50-60%) compared to DSC (20-35%).
• MRS revealed partial transformation of caffeine Form I particles microscopically throughout the tablets.
• Tablet surfaces exhibited locally higher transition degrees than other regions.

Conclusions:

• Micro Raman Spectroscopy offers valuable microscopic insights into solid-state transformations during tableting, complementing macroscopic DSC analysis.
• Caffeine Form I undergoes consistent, pressure-independent phase transitions during tableting, with localized variations observed.
• The findings highlight the importance of spatially resolved techniques for comprehensive understanding of API behavior in solid dosage forms.