Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Physical Chemistry

Background:

• Drug bioavailability is often limited by poor solubility, necessitating solubility enhancement strategies.
• Drug salt disproportionation can lead to a significant drop in solubility during absorption, impacting bioavailability.
• Limited salt and cocrystal options exist for certain drug molecules with bioavailability challenges.

Purpose of the Study:

• To investigate the use of a pH modifier as a disproportionation retardant in tablet formulations.
• To enhance the solubility and bioavailability of a drug molecule facing disproportionation risks.
• To develop an innovative risk-mitigating strategy for salt disproportionation in pharmaceutical formulations.

Main Methods:

• Utilized Raman spectroscopy with chemometrics and quantitative X-ray diffraction for stress testing.
• Investigated disproportionation phenomena under controlled stress conditions.
• Employed fumaric acid as a microenvironmental pH modulator in tablet formulations.

Main Results:

• Fumaric acid demonstrated a synergistic advantage in preventing disproportionation for both high-risk (HCl) and moderate-risk (maleate) scenarios.
• The interaction of fumaric acid with the freebase released during disproportionation formed a more soluble hemifumarate species.
• This hemifumarate formation helped maintain elevated drug solubility, mitigating the solubility drop during the 'parachute' phase.

Conclusions:

• A novel utilization of a pH modifier (fumaric acid) as a disproportionation retardant in tablet formulations was reported.
• This approach effectively mediates the solubility drop during drug absorption, offering a potential risk-mitigating strategy for salt disproportionation.
• The findings demonstrate an innovative technique using compendial excipients to improve drug solubility and bioavailability.