Coupling between chemical reactivity and structural relaxation in pharmaceutical glasses

Area of Science:

• Physical Chemistry
• Materials Science
• Pharmaceutical Sciences

Background:

• Chemical degradation in amorphous systems is influenced by molecular mobility.
• Structural relaxation describes molecular motions in glassy states.
• Understanding the link between degradation and relaxation is crucial for drug stability.

Purpose of the Study:

• To investigate the hypothesis that molecular motions driving chemical degradation in glassy amorphous systems are governed by structural relaxation.
• To assess the degree of coupling between chemical reactivity and structural relaxation in model systems.
• To determine how molecular motion requirements affect this coupling.

Main Methods:

• Amorphous drugs and mixtures were prepared via lyophilization.
• Physical properties were characterized using optical microscopy and differential scanning calorimetry.
• Chemical degradation was quantified using high-performance liquid chromatography (HPLC), and molecular mobility was measured using isothermal microcalorimetry.

Main Results:

• Pure amorphous cephalosporins showed a weak correlation between degradation rates and structural relaxation times.
• Sucrose addition to a cephalosporin drug improved stability but reduced glass transition temperature (T(g)) and relaxation time, indicating no correlation in mixtures.
• Ethacrynate sodium dimer formation rate showed stronger coupling to relaxation time constants in mixtures.

Conclusions:

• The coupling between chemical degradation and structural relaxation in glasses depends on the molecular motion requirements of the rate-limiting step.
• Chemical changes involving significant molecular motion, including translation, are more strongly coupled to structural relaxation.
• Stabilization of cefoxitin sodium by sucrose, despite lowered T(g) and relaxation time, suggests other molecular motions influence chemical reactivity in glasses.