Investigating the Energetic Relaxation of Milled Budesonide

PURPOSE:

For inhalation delivery platforms, it is common to micronize drug substances to reduce particle sizes. These high-energy processes often change surface morphology, increase defect sites, or decrease crystallinity. It is important to understand how these high-energy sites relax over time at different storage/exposure conditions. This study monitors the surface chemistry of a milled budesonide sample after exposure to 52% relative humidity and 25 °C as a function of exposure time using Inverse Gas Chromatography (IGC).

METHODS:

Crystalline budesonide was milled using a high-speed grinder. Then, the sample was stored in a dessiccator over a saturated salt solution of magnesium nitrate at 25 °C, resulting in an environment of 52% relative humidity. The surface energy and Lewis acid-base properties of the budesonide were measured using IGC at different exposure times. IGC is a common technique for quickly and accurately measuring surface energetics for a wide range of solid materials.

RESULTS AND DISCUSSION:

Initially, the surface energy values measured on the milled budesonide indicated the surface was at a higher energy than crystalline budesonide. Cleary, milling caused some surface disorder. After exposure to 52% RH and 25 °C conditions, the surface basicity (electron donor capacity) dropped precipitously while the dispersive surface energy remained relatively constant. After 30 days at 52% RH/25 °C, the surface energy began to decrease. Dynamic gravimetric Vapor Sorption (DVS) results confirmed that water vapor does not cause amorphous budesonide to crystallize via a plasticization mechanism. Therefore, the milled budesonide relaxed to a lower energy state below the glass transition when exposed to 52% RH at 25 °C.

CONCLUSIONS:

IGC was used to monitor the surface properties of milled budesonide as a function of exposure time to 52% RH and 25 °C. The surface relaxed over time to a lower energy state, without showing moisture-induced crystallization.