Treating mannitol in a saturated solution of mannitol: a novel approach to modify mannitol crystals for improved drug delivery to the lungs

The aim of this study was to evaluate the influence of treatment of a promising dry powder aerosol carrier (mannitol) on the aerosolization performance of salbutamol sulphate (SS) using a novel approach: treating excess commercial carrier particles in a saturated solution of the same carrier. Commercial mannitol (CM) particles were treated with aqueous mannitol supersaturated solutions (20% and 25% w/v), under stirring, (300 rpm) for either 24 h or 48 h. The results showed that particle treatment did not alter the polymorphic form of mannitol (ß-mannitol); however, all treated mannitol particles demonstrated smoother surface topography and improved aerosolization performance compared to CM in dry powder inhalations. Unlike the concentration of mannitol solution used during treatment, the time of treatment to collect mannitol crystals was an essential key to modify the physical properties of mannitol and its effect on the aerosolization performance. In comparison to mannitol particles treated for 48 h, mannitol particles treated for 24 h demonstrated larger size, more elongated-less regular shape, and smoother surfaces. No apparent relationship was obtained between in vitro aerosolisation behavior of SS with either mannitol particle size or shape descriptors. However, despite their larger size and more irregular-less uniformed shape, treated mannitol particles with smoother surfaces generated drug particles with smaller aerodynamic size and are expected to deliver higher amounts of drug to lower airways. The results demonstrated the potential of treating mannitol particles in aqueous solutions of the same material under controlled conditions to produce mannitol particles promising for dry powder inhaler systems. The results suggested that mannitol particle surface texture properties dominate over both particle size and particle shape of mannitol in terms of determining the aerosolization performance of mannitol. AbbreviationsRaArithmetic mean averageAFMatomic force microscopyCOPDchronic obstructive pulmonary diseaseCMcommercial mannitolD10%particle sizes at 10% volume distributionD50%particle sizes at 10% volume distribution or median diameterD90%particle sizes at 50% volume distributionDSCdifferential scanning calorimetryDPIsdry powder inhalersEMemissionDequiequivalent diameterFPFfine particle fractionFT-IRfourier transform infraredGRASgenerally recognized as safesggeometric standard deviationILimpaction lossIPinduction portI&Minhaler device with its fitted mouthpiece adaptorM20%,24hmannitol particles from 20% mannitol solution after treatment for 24 hM20%,28hmannitol particles from 20% mannitol solution after treatment for 48 hM25%,24hmannitol particles from 25% mannitol solution after treatment for 24 hM25%,28hmannitol particles from 25% mannitol solution after treatment for 48 hMMADmass median aerodynamic diameterMSLImulti stage liquid impingerPSDparticle size distributionRHrelative humidityRErecoveryRqroot mean square averageSSsalbutamol sulphateSEMscanning electron microscopy.© 2013 Elsevier B.V.