Spray Drying of Mannitol as a Drug Carrier—The Impact of Process Parameters on Product Properties

Abstract

Powders intended for the use in dry powder inhalers have to fulfill specific product properties, which must be closely controlled in order to ensure reproducible and efficient dosing. Spray drying is an ideal technique for the preparation of such powders for several reasons. The aim of this work was to investigate the influence of spray-drying process parameters on relevant product properties, namely, surface topography, size, breaking strength, and polymorphism of mannitol carrier particles intended for the use in dry powder inhalers. In order to address this question, a full-factorial design with four factors at two levels was used. The four factors were feed concentration (10 and 20% [w/w]), gas heater temperature (170 and 190°C), feed rate (10 and 20 L/h), and atomizer rotation speed (6,300 and 8,100 rpm). The liquid spray was carefully analyzed to better understand the dependence of the particle size of the final product on the former droplet size. High gas heater temperatures and low feed rates, corresponding to high outlet temperatures of the dryer (96–98°C), led to smoother particles with surfaces consisting of smaller crystals compared to those achieved at low outlet temperatures (74–75°C), due to lower gas heater temperatures and higher feed rates. A high solution concentration of the feed also resulted in the formation of comparably rougher surfaces than a low feed concentration. Spray-dried particles showed a volume-weighted mean particle size of 71.4–90.0 µm and narrow particle size distributions. The mean particle size was influenced by the atomizer rotation speed and feed concentration. Higher rotation speeds and lower feed concentrations resulted in smaller particles. Breaking strength of the dried particles was significantly influenced by gas heater temperature and feed rate. High gas heater temperatures increased the breaking strength, whereas high feed rates decreased it. No influence of the process parameters on the polymorphism was observed. All products were crystalline, consisting of at least 96.9% of mannitol crystal modification I.

Keywords:

• Breaking strength
• Carrier particles
• Crystallization
• Design of experiments
• Dry powder inhaler
• Mannitol
• Particle size
• Spray drying
• Surface roughness

ACKNOWLEDGMENTS

The authors thank Roquette Frères (Lestrem, France) for providing mannitol and the German research foundation (DFG) for the grant within the priority program SPP 1423 “Prozess-Spray”. The authors also would like to thank Prof. Herwig Friedl, Graz University of Technology, for his helpful comments and suggestions regarding the statistical analysis of the data.

Notes

^a A, feed concentration; B, gas heater temperature; C, mannitol solution feed rate; D, atomization rotation speed. −, Low; o, center; +, high.

R ² values are given to indicate the quality of fit of the statistical models to the experimental values (also see Statistical Design section). Parameters of significance are in bold. No model for polymorphism is given because there was no significant influence of process parameters on polymorphism.

This article was part of the 17th International Drying Symposium (IDS2010), held October 3–6, 2010, in Magdeburg, Germany. Other articles from IDS2010 were published in special issues of Drying Technology, 29(13) and 29(16).