Physicochemical Stability of Crystalline Sugars and Their Spray-Dried Forms: Dependence upon Relative Humidity and Suitability for Use in Powder Inhalers

Abstract

Lactose, trehalose, sucrose, and mannitol were purchased in crystalline form and fractionated by sieving. Coarse (125-212 µm) and fine (44-74 µm) free-flowing fractions were selected as typical of drug carriers in dry-powder inhalers. In addition, one batch of each sugar was spray-dried to form a respirable powder (> 50% [w/w], < 5 µm). Both fractions and the spray-dried powders were characterized before and after storage for 30 days at < 23%, 23%, 52%, 75% and 93% relative humidity (RH) at 25°C. Moisture uptake was determined by thermogravimetric analysis (TGA) validated by Karl Fischer titration. Sieve fractions (before storage at different RHs) and spray-dried materials (before and after storage) were further characterized by differential scanning calorimetry (DSC) and x-ray powder diffraction (XRPD). All crystalline sieve fractions (except sucrose at 93% RH) were stable at 25°C and showed insignificant moisture uptake when exposed to each relative humidity for 30 days. Sucrose dissolved in sorbed moisture at 93% RH. Spray-dried lactose, sucrose, and trehalose, which were collected in the amorphous form, showed moisture uptake, without recrystallization, when held for 30 days at 23% RH. These sugars recrystallized as sintered masses and became undispersible at ≥ 52% RH. Spray-dried mannitol was apparently 100% crystalline when collected directly from the spray-dryer; it did not show humidity-induced changes.

The physicochemical behavior of each sugar form is discussed as it relates to the sugar's suitability as a powder-inhaler excipient, with both conventional and protein drugs.