Quantification of crystalline forms in active pharmaceutical ingredient and tablets by X-ray powder diffraction

Area of Science:

• Pharmaceutical Science
• Solid-State Chemistry

Background:

• A Merck development compound exhibited multiple crystalline forms (polymorphs, hydrates, solvates).
• The most stable crystalline form at room temperature was selected for pharmaceutical development.
• Form conversion was observed in tablets under specific storage conditions (40°C/75% RH).

Purpose of the Study:

• To develop and apply an X-ray powder diffraction (XRPD) method.
• To quantify the relative amounts of two crystalline forms in the active pharmaceutical ingredient (API) and final drug product.
• To monitor and understand the crystalline form conversion during stability studies.

Main Methods:

• Characterization of polymorphic forms.
• Development of an X-ray powder diffraction (XRPD) method.
• Stability studies under accelerated conditions (40°C/75% RH).

Main Results:

• An XRPD method was successfully developed and applied to quantify crystalline forms in both API and tablets.
• Crystalline form conversion was detected in tablets but not in the API alone under tested conditions.
• Monitoring revealed changes in crystalline form composition over time in the formulated tablets.

Conclusions:

• The developed XRPD method is suitable for monitoring crystalline form changes in pharmaceutical formulations.
• The formulation excipients may play a role in the observed crystalline form conversion.
• Further investigation into the conversion mechanism is warranted.