Research Paper Investigations on the Humidity-Induced Transformations of Salbutamol Sulphate Particles Coated with L-Leucine Janne Raula, 1,7 Frank Thielmann, 2 Jarno Kansikas, 3 Sami Hietala, 4 Minna Annala, 5 Jukka Seppälä, 5 Anna Lähde, 1 and Esko I. Kauppinen 1,6 Received December 4, 2007; accepted April 28, 2008 Purpose. 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. Methods. 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). Results. 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. Conclusion. 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 WORDS: crystallization; humidity; L-leucine coating; salbutamol sulphate; stability. INTRODUCTION The crystalline form of a drug is of great importance for maintaining its chemical and physical stability during storage. Although an amorphous material as compared to the corre- sponding crystalline state shows enhanced dissolution and bioavailability due to the high internal energy and specific volume, it may convert to the crystalline state either sponta- neously and/or with the aid of external stimuli (1–3). An amorphous material is thermodynamically metastable, which may, during processing or in the final dosage form, cause instability of drug release and dosing as a result of phase transformation (4). This should be taken into account, especially in humid conditions, since an amorphous material is usually notably more hygroscopic than its crystalline form. However, the crystallization of an amorphous material can conventionally be prevented by storing it below the glass- transition temperature (T g ), by avoiding exposure to moisture or by elevating the T g of the system with the aid of added excipients (5–7). Therefore, it is of the utmost importance to control the crystalline form of the drug during the various stages of its development and storage. Various pharmaceutical formulation techniques, such as drug polymorphs, solvates and phase transitions, significantly affect the final crystalline form of a drug. For instance, spray- drying (8,9) and lyophilisation (10) processes often lead to the formation of the amorphous form of a drug. Also processes such as grinding, milling, granulation, drying, precipitation and compaction, in which stress is applied to large crystals, may result in a fractionation of the amorphous state. This may cause instability problems, such as polymorphic changes and the 0724-8741/08/0000-0001/0 # 2008 Springer Science + Business Media, LLC Pharmaceutical Research ( # 2008) DOI: 10.1007/s11095-008-9613-4 1 NanoMaterials Group, Laboratory of Physics and Center for New Materials, Helsinki University of Technology (TKK), P.O. Box 5100, 02015 TKK, Finland. 2 Surface Measurement Systems Ltd., 3 Warple Mews, Warple Way, London W3 0RF, UK. 3 Laboratory of Inorganic Chemistry, University of Helsinki, P.O. Box 55, Helsinki 00014, Finland. 4 Laboratory of Polymer Chemistry, University of Helsinki, P.O. Box 55, Helsinki 00014, Finland. 5 Laboratory of Polymer Technology, Helsinki University of Technol- ogy (TKK), P.O. Box 6100, 02015 TKK, Finland. 6 VTT Biotechnology (VTT), P.O. Box 1000, 02044, Espoo Finland. 7 To whom correspondence should be addressed. (e-mail: janne. raula@tkk.fi)