The AAPS Journal

, Volume 15, Issue 3, pp 728–743 | Cite as

Engineered Mannitol Ternary Additives Improve Dispersion of Lactose–Salbutamol Sulphate Dry Powder Inhalations

  • Waseem Kaialy
  • Ali Nokhodchi
Research Article


The aim of this study was to evaluate the influence of novel engineered fine mannitol particles (4.7%, w/w) on the performance of lactose–salbutamol sulphate dry powder inhaler (DPI) formulations to obtain promising aerosolisation properties. The results showed that the more elongated the fine mannitol particles, the weaker the drug–carrier adhesion, the better the drug content homogeneity, the higher the amount of drug expected to be delivered to the lower airways and the higher the total DPI formulation desirability. Linear relationships were established showing that mannitol particles with a more elongated shape generated powders with broader size distributions and that were less uniform in shape. The weaker the drug–carrier adhesion, the higher the fine particle fraction of the drug is upon aerosolisation. It is believed that more elongated fine mannitol particles reduce the number of drug–carrier and drug–drug physical contact points and increase the ability of the drug particles to travel into the lower airways. Additionally, a lower drug–carrier contact area, lower drug–carrier press-on forces and easier drug–carrier detachment are suggested in the case of formulations containing more elongated fine mannitol particles. Ternary ‘drug-coarse carrier-elongated fine ternary component’ DPI formulations were more favourable than both ‘drug-coarse carrier’ and ‘drug-elongated coarse carrier’ binary formulations. This study provides a comprehensive approach for formulators to overcome the undesirable properties of dry powder inhalers, as both improved aerosolisation performance and reasonable flow characteristics were obtained using only a small amount of elongated engineered fine mannitol particles.


added fines adhesive mixtures engineered fine mannitol formulation performance ternary component 



Acetone crystallised mannitol


Aspect ratio


Cooling crystallised mannitol


Carr’s index


Commercial mannitol


Cutoff diameter


Coefficient of variation


Particle diameter at 10% volume distribution


Particle diameter at 50% volume distribution (median diameter)


Particle diameter at 90% volume distribution


Theoretical aerodynamic diameter


Geometric diameter (volume mean diameter)


Desirability function


Ethanol crystallised mannitol


Emitted dose


Overall desirability function


Dry powder inhaler


Differential scanning calorimetry


Fine mannitol particles


Fine particle fraction


Fine particle aggregates


Flatness ratio


Geometric standard deviation


Hausner ratio

I + M

Inhaler with mouthpiece adaptor


Impaction loss


Induction port (throat)


Mean diameter


Mass median aerodynamic diameter


Multistage liquid impinger


Relative humidity


Particle size distribution


Recovered dose


Spray dried mannitol


Standard error


Scanning electron microscope


Shape factor


Supplementary material


Salbutamol sulphate


Powder X-ray diffraction


True density



Waseem Kaialy thanks Dr. Ian Slipper (University of Greenwich) for taking the SEM images. The reviewers are thanked for their valuable comments.

Supplementary material

12248_2013_9476_MOESM1_ESM.docx (1.5 mb)
ESM 1 (DOCX 1.53 MB)


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Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  1. 1.Chemistry and Drug Delivery Group, Medway School of PharmacyUniversity of KentKentUK
  2. 2.Pharmaceutics and Pharmaceutical Technology Department, School of PharmacyUniversity of DamascusDamascusSyria
  3. 3.Drug Applied Research Center and Faculty of PharmacyTabriz University of Medical SciencesTabrizIran

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