PHYSICOCHEMICAL STABILITY OF CRYSTALLINE SUGARS AND THEIR SPRAY-DRIEDFORMS - DEPENDENCE UPON RELATIVE-HUMIDITY AND SUITABILITY FOR USE IN POWDER INHALERS

Lactose, trehalose, sucrose, and mannitol were purchased in crystallin e form and fractionated by sieving. Coarse (125-212 mu m) and fine (44 -74 mu m) free-flowing fractions were selected as typical of drug carr iers in dry-powder inhalers. In addition, one batch of each sugar was spray-dried to form a respirable powder (> 50% [w/w] < 5 mu m). Both f ractions and the spray-dried powders were characterized before and aft er storage for 30 days at < 23%, 23%, 52%, 75% and 93% relative humidi ty (RH) at 25 degrees C. Moisture uptake was determined by thermogravi metric analysis (TGA) validated by Karl Fischer titration. Sieve fract ions (before storage at different RHs) and spray-dried materials (befo re and after storage) were further characterized by differential scann ing calorimetry (DSC) and x-ray powder diffraction (XRPD). All crystal line sieve fractions (except sucrose at 93% RH) were stable at 25 degr ees C and showed insignificant moisture uptake when exposed to each re lative humidity for 30 days. Sucrose dissolved in sorbed moisture at 9 3% RH. Spray-dried lactose, sucrose, and trehalose, which were collect ed in the amorphous form, showed moisture uptake, without recrystalliz ation, when held for 30 days at 23% RH. These sugars recrystallized as sintered masses and became undispersible at greater than or equal to 52% RH. Spray-dried mannitol was apparently 100% crystalline when coll ected 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.