Commercial-scale Production of Cyclodextrin Complexes

Jeffrey L. Tate1, James A Rehkopf2 NanoSonic Products, Inc., Alachua, FL 32615 Jeffrey_Tate@nanosonicproducts.com 2 Pulse Combustion Systems, Payson, AZ 85541
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ABSTRACT SUMMARY: Pulse combustion drying enables production of freeze-dry quality powders from labile biological solutions. The production of powdered thymolhydroxypropyl beta cyclodextrin complex using Pulse Combustion Drying was demonstrated. INTRODUCTION: Cyclodextrin complexes allow normally insoluble materials like lipids to be water-soluble. For this reason cyclodextrins and cyclodextrin derivatives are attractive excipients in the formulation of lipophilic pharmaceuticals and nutritional products. Cyclodextrins form complexes with lipids as a result of a thermodynamic equilibrium between the host cyclodextrin molecule and the guest lipophilic active ingredient that is being made soluble. Production of commercially useful quantities of cyclodextrin complexes, >10 kg to MT's, is challenging because of the fragile nature of the thermodynamic interaction between host and guest molecules. Pulse combustion drying offers the ability to create a large volume of complex in aqueous solution and continuously dry it to a flowable powder in one step. This process allows the complexes to remain intact and freely soluble after drying. EXPERIMENTAL METHODS: The insoluble and odiferous botanical oil, thymol, was combined with a 25% w/w aqueous solution of hydroxypropyl beta cyclodextrin. The resulting solution was mixed using a high shear mixer for approximately 60 minutes at room temperature. The solution was then filtered through a paper filter. The filtered solution was loaded into the feed vessel of a P-0.1 Pulse Combustion Dryer. Pulse drying was conducted using an inlet temperature of 95020F and outlet temperature of 1505F. Outlet temperature was controlled by automated adjustment of dryer feed using a feed forward control scheme. Dried powder was collected using a cyclone precipitator fitted with a pneumatically tight pair of slide valves. Product yield and quality were evaluated after drying and collection were completed. RESULTS AND DISCUSSION: The aqueous solution of thymol-hydroxypropyl beta cyclodextrin complex was visibly clear and stable after filtration. It exhibited a very strong thymol aroma without any visible evidence of uncomplexed

thymol separation after standing for 24 hours at room temperature. This indicates that a stable thymolhydroxypropyl beta cyclodextrin complex was present in the aqueous solution. Feeding of the dryer was without incident. A fine white powder formed and collection began within seconds of the introduction of complex-containing feed to the dryer. Inspection of the dryer after the process revealed no visible residue on the dryer walls or cone surfaces at the bottom of the drying chamber. More than 90% of the introduced solid material was collected as powder as determined by a mass balance of the entire process. The powder produced was fine and free flowing. Microscopic examination revealed a spherical particle with the appearance of a glass bead. When placed in water, the powder dissolved freely with agitation. On preparation of a 25% w/w aqueous solution, the resulting clear solution had a strong thymol aroma. The aqueous solution remained clear with a strong thymol aroma after standing for 24 hours at room temperature. There was no visible separation of thymol. This indicates the presence of a stable thymol-hydroxypropyl beta cyclodextrin complex. CONCLUSION: From this work the authors conclude that Pulse Combustion Drying allows the commercial-scale production of cyclodextrin complexes as dry powders. The complexes retain their characteristic water solubility after drying, indicating that the fragile thermodynamic association between cyclodextrin and guest molecule is preserved in the drying process. REFERENCES: A.A. Putnam, F.E. Belles, J.A.C. Kentfield, Pulse Combustion, Progress in Energy and Combustion Science, V12:1, 1986, pp 43-79. T. Higuguchi, K.A. Connors, Phase-Solubility Techniques, Advances in Analytical Chemistry and Instrumentation, V4, 1965, pp 117-212.