Investigations on the Humidity-Induced Transformations of Salbutamol Sulphate Particles Coated with l-Leucine
- 370 Downloads
The crystallization and structural integrity of micron-sized inhalable salbutamol sulphate particles coated with l-leucine by different methods are investigated at different humidities. The influence of the l-leucine coating on the crystallization of salbutamol sulphate beneath the coating layer is explored.
The coated particles are prepared by an aerosol flow reactor method, the formation of the l-leucine coating being controlled by the saturation conditions of the l-leucine. The coating is formed by solute diffusion within a droplet and/or by vapour deposition of l-leucine. The powders are humidified at 0%, 44%, 65% and 75% of relative humidity and the changes in physical properties of the powders are investigated with dynamic vapour sorption analysis (DVS), a differential scanning calorimeter (DSC), and a scanning electron microscope (SEM).
Visual observation show that all the coated particles preserve their structural integrity whereas uncoated salbutamol sulphate particles are unstable at 65% of relative humidity. The coating layer formed by diffusion performs best in terms of its physical stability against moisture and moisture-induced crystallization. The degree of crystallization of salbutamol in the as-prepared powders is within the range 24–35%. The maximum degree of crystallization after drying ranges from 55 to 73% when the salbutamol crystallizes with the aid of moisture. In addition to providing protection against moisture, the l-leucine coating also stabilizes the particle structure against heat at temperatures up to 250°C.
In order to preserve good flowability together with good physical stability, the best coating would contain two l-leucine layers, the inner layer being formed by diffusion (physical stability) and the outer layer by vapour deposition (flowability).
KEY WORDScrystallization humidity l-leucine coating salbutamol sulphate stability
We thank the Academy of Finland for financial support. Graduate student Raita Heiskanen is thanked for assistance with the experimental work.
- 13.D. Begon, P. Guillaume, and M. Kohl. Process for producing fine medicinal substances. WO World IPO 0114036 (2001).Google Scholar
- 14.R. W. Lancaster, H. Sigh, and A. L. Theophilus. Apparatus and process for preparing crystalline particles. WO World IPO 0038811 (2000).Google Scholar
- 16.L.-E. Briggner, K. Bystrom, E. Jakupovic, E. Trofast, and J. Trofast. Pharmaceutical formulation. US Patent 5,874,063 (2002).Google Scholar
- 18.K. D. Kussendrager, and M. J. H. Ellison. Carrier material for dry powder inhalation. WO 02/07705 (2002).Google Scholar
- 21.J. Raula, A. Kuivanen, A. Lähde, and E. I. Kauppinen. Gas-phase synthesis of L-leucine-coated micrometer-sized salbutamol sulphate sodium chloride particles. Powder Technol., DOI 10.1016/j.powtec.2008.03.006 (2008).
- 24.J. Raula, A. Lähde, and E. I. Kauppinen. A novel gas phase method for the combined synthesis and coating of pharmaceutical particles. Pharm. Res. 25:242–245 (2008).Google Scholar
- 29.F. P. Incropera, and D. P. DeWitt. Fundamentals of Heat and Mass Transfer. 5Wiley, New York, 2002, pp. 846–847.Google Scholar
- 31.R. C. Flagan, and J. H. Seinfeld. Fundamentals of Air Pollution Engineering. Prentice Hall, Englewood Cliffs, 1988, p. 542.Google Scholar
- 33.J. Raula, A. Kuivanen, A. Lähde, and E. I. Kauppinen. Synthesis of L-leucine nanoparticles via physical vapor deposition under various saturation conditions. J. Aerosol Sci. 38:1172–1184 (2007).Google Scholar
- 40.S. Budavari, M. J. O’Neil, A. Smith, and P. E. Heckelman (Eds.). The Merck Index, 11th edn., Rahway, USA, 1989, p. 857.Google Scholar
- 47.D. V. Talapin, A. L. Rogach, A. Kornowski, M. Haase, and H. Weller. Highly luminescent monodisperse CdSe and CdSe/ZnS nanocrystals synthesized in a hexadecylamine–trioctylphosphine oxide–trioctylphospine mixture. Nanoletters. 1:207–211 (2001).Google Scholar