Dry powder inhalers: Physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol

Abstract

The purpose of this work was to evaluate the physicochemical and inhalation characteristics of different size fractions of a promising carrier, i.e., freeze-dried mannitol (FDM). FDM was prepared and sieved into four size fractions. FDMs were then characterized in terms of micromeritic, solid-state and bulk properties. Dry powder inhaler (DPI) formulations were prepared using salbutamol sulphate (SS) and then evaluated in terms of drug content homogeneity and in vitro aerosolization performance. The results showed that the crystalline state of mannitol was maintained following freeze-drying for all size fractions of FDM. All FDM particles showed elongated morphology and contained mixtures of α-, β- and δ-mannitol. In comparison to small FDM particles, FDMs with larger particle sizes demonstrated narrower size distributions, higher bulk and tap densities, lower porosities and better flowability. Regardless of particle size, all FDMs generated a significantly higher (2.2-2.9-fold increase) fine particle fraction (FPF, 37.5 ± 0.9%-48.6 ± 2.8%) of SS in comparison to commercial mannitol. The FPFs of SS were related to the shape descriptors of FDM particles; however, FPFs did not prove quantitative apparent relationships with either particle size or powder bulk descriptors. Large FDM particles were more favourable than smaller particles because they produced DPI formulations with better flowability, better drug content homogeneity, lower amounts of the drug depositing on the throat and contained lower fine-particle-mannitol. Optimized stable DPI formulations with superior physicochemical and pharmaceutical properties can be achieved using larger particles of freeze-dried mannitol (FDM).

On the effects of blending, physicochemical properties, and their interactions on the performance of carrier-based dry powders for inhalation — A review

“…In an early computer simulation study, carrier particles of the largest size and the narrowest size distribution possible were shown to produce adhesive mixtures with the greatest stability [133]. Later, the improved blending homogeneity for adhesive mixtures containing larger carrier particles was supported in experimental studies carried out by Kaialy et al on adhesive mixtures containing various size-fractions of α-lactose monohydrate [84], spherical spray dried mannitol [64], and elongated freeze-dried mannitol [80] (Fig. 8a).…”

“…In the present study, the influence of blending time (5 min to 90 min) on drug content homogeneity, drug-carrier adhesion, and drug aerosolisation performance of salbutamol sulphate (SS, d 50% , 3.1 μm)-lactose (α-lactose monohydrate, 63 μm to 90 μm) adhesive mixtures at a drug:carrier ratio of 1:67.5 w:w were evaluated. The blending was performed using a Turbula™ mixer (Maschinenfabrik, Basel, Switzerland) at a fixed speed of (90 to 100) rpm in laboratory conditions (22°C, 50% RH) in a cylindrical aluminium mixing vessel with a volume of 48 cm 3 [80]. The results showed the coefficient of variation (CV) of SS content to decrease with increasing blending time from 5 min to 90 min (Fig.…”

“…8. Coefficient of variation (CV) of drug (SS or BUD) content in relation to the volume mean diameter of freeze-dried mannitol (FDM) [80], spray-dried mannitol (SMD) [64], and α-lactose monohydrate (LAC) [18]. than smaller carrier particles due to their greater momentum (Fig.…”

Combined control of morphology and polymorph in spray drying of mannitol for dry powder inhalation

“…The tap and bulk densities increased with increasing concentration of NH 4 HCO 3 . Further, the measured values of CI (>40%) and H (>1.6) indicate an extremely poor flow ability [17,36]; however, commercial mannitol and spray-dried mannitol had similarly poor flow properties. The measured outlet temperature was 65 , and did not change with the concentration of NH 4 HCO 3 in the feed solution.…”

“…4) revealed a single melting peak at 168.9 ± 1 , indicating the presence of either -mannitol or -mannitol [36]; no melting events appeared in the DSC curve at approximately 155 (the melting point of -mannitol). Therefore, the presence of -mannitol was excluded.…”