Investigations into the mechanisms of drug particle detachment from carriers in adhesive mixtures for inhalation

Purpose: To study the effect of carrier payload and flow rate on the drug particle detachment from coarse lactose carriers in an air classifier based test inhaler. Methods: Vibratory and air jet sieved lactose with a size fraction of 250-315 /m was used as a carrier. Mixtures of 0.4 to 4% w/w micronised salmeterol xinafoate with this carrier were prepared by mixing for 10 minutes at 90rpm with a Turbula mixer. The residual amount of drug on the carrier particles retained in the classifier based test inhaler (carrier residue, CR) was determined after each inhalation experiment. Results: The amount of salmeterol (in mg per m2carrier surface area) detached in 3 seconds from the lactose carrier surface in the classifier based test inhaler increases linearly with the initial carrier payload. The degree of linearity increases with increasing flow rate from R2= 0.990 at 20 L/min to R2= 1 at 40 to 60 L/min. Only at 10 L/min linearity is less pronounced. The linear relationship comprises low payload mixtures in which drug particles are primarily attached to the carrier surface by adhesive forces as well as high payload mixtures in which drug particles are primarily bound by cohesive forces. Conclusions: The high degree of linearity at higher flow rates for salmeterol detachment from lactose carrier crystals over the range of carrier payloads tested suggests that any difference in adhesive and cohesive forces is irrelevant to drug particle detachment in effective inhalers.