Racemization of ketorolac in aqueous solution

Area of Science:

• Pharmaceutical Chemistry
• Physical Chemistry
• Drug Stability

Background:

• Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) commonly used for pain management.
• Understanding the racemization kinetics of ketorolac is crucial for developing stable pharmaceutical formulations.
• Previous studies have indicated potential stability issues with ketorolac formulations.

Purpose of the Study:

• To investigate the racemization of ketorolac in aqueous buffered solutions.
• To identify the catalytic species influencing ketorolac degradation.
• To determine optimal conditions for enhancing the stability of single-isomer ketorolac formulations.

Main Methods:

• Racemization studies were conducted in aqueous buffered solutions at controlled temperatures (25°C and 80°C).
• Reaction kinetics were analyzed across a range of pH values to determine the pH-rate profile.
• Stability (T90 values) of ketorolac tromethamine solutions was assessed under various conditions and buffer systems.

Main Results:

• A U-shaped pH-rate profile was observed for ketorolac racemization at 80°C, with maximum stability between pH 3.0-7.5.
• A 1.5% (R)-ketorolac tromethamine solution at pH 7.4 and 25°C exhibited a T90 value of 8 months.
• Phosphate buffer systems demonstrated superior stabilization, yielding formulations with a T90 exceeding 2 years.

Conclusions:

• Ketorolac racemization is significantly influenced by pH and temperature.
• Alternative salt forms and buffer systems, particularly phosphate buffers, are essential for achieving stable single-isomer ketorolac formulations.
• Optimized formulations can achieve extended shelf-life, crucial for therapeutic efficacy and patient safety.