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Title: Direct Precipitation of Micron-Size Salbutamol Sulphate by Antisolvent Crystallization
Authors: XIE SHUYI
Keywords: Direct precipitation, Salbutamol sulphate, Antisolvent crystallization, Surfactants, Polymeric additives, Semi-batch crystallization
Issue Date: 9-Jul-2010
Citation: XIE SHUYI (2010-07-09). Direct Precipitation of Micron-Size Salbutamol Sulphate by Antisolvent Crystallization. ScholarBank@NUS Repository.
Abstract: Particle size is a key factor for inhalation drug powder as it determines the dosing efficiency, drug deposition in various regions, and the systemic absorption. This work aims to propose a direct approach to produce drug particles of desired size (between 1 and 5 ?m) through antisolvent crystallization in the presence of surfactants and polymeric additives. Salbutamol sulphate (SS) was used as the model drug compound. Several candidate antisolvents were screened via studying particle morphology, particle size and agglomeration of crystal products in order to determine the proper antisolvent used in the subsequent experiments. Hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP K25), lecithin (from soybean) and Span 85 were investigated as the additives applied in antisolvent crystallization. Among them PVP K25 showed the strongest effect on crystal growth inhibition. By adding PVP K25 into the SS solution, the habit of SS crystallized was modified and the crystal size was reduced to less than 10 microns. The inhibition mechanism for the selected polymers and surfactants were then further studied on the basis of the predicted morphology of SS and the possible intermolecular interaction of the additives with a developing SS crystal in solution. It is proposed that PVP has a higher propensity to form hydrogen bonds with the functional groups that are exposed at the crystal surface. This is supported by the evidence based on the effects of PVP concentration and molecular weight on SS crystallization, together with the trends of dispersive surface energy of crystallized SS particles. A process study of semi-batch antisolvent crystallization was subsequently conducted. It has shown that the final size of the crystalline product was sensitive to the operating parameters such as feeding rate of antisolvent, stirring speed, and addition of PVP. Furthermore, it was found that nucleation was retarded and particle population was enhanced by adding PVP into the crystallization process. These findings verified the previous proposed inhibition mechanism.
Appears in Collections:Ph.D Theses (Open)

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