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Commercial-scale Production of Cyclodextrin ComplexesJeffrey L. Tate1, James A Rehkopf2

1NanoSonic Products, Inc., Alachua, FL 32615Jeffrey_Tate@nanosonicproducts.com

2Pulse Combustion Systems, Payson, AZ 85541

ABSTRACT SUMMARY:Pulse combustion drying enables production of

freeze-dry quality powders from labile biologicalsolutions. The production of powdered thymol-hydroxypropyl beta cyclodextrin complex using PulseCombustion Drying was demonstrated.

INTRODUCTION:Cyclodextrin complexes allow normally insoluble

materials like lipids to be water-soluble. For thisreason cyclodextrins and cyclodextrin derivatives areattractive excipients in the formulation of lipophilicpharmaceuticals and nutritional products.Cyclodextrins form complexes with lipids as a resultof a thermodynamic equilibrium between the host

cyclodextrin molecule and the guest lipophilic activeingredient that is being made soluble. Production ofcommercially useful quantities of cyclodextrincomplexes, >10 kg to MT's, is challenging becauseof the fragile nature of the thermodynamic interactionbetween host and guest molecules. Pulsecombustion drying offers the ability to create a largevolume of complex in aqueous solution andcontinuously dry it to a flowable powder in one step.This process allows the complexes to remain intactand freely soluble after drying.

EXPERIMENTAL METHODS:

The insoluble and odiferous botanical oil, thymol,was combined with a 25% w/w aqueous solution ofhydroxypropyl beta cyclodextrin. The resultingsolution was mixed using a high shear mixer forapproximately 60 minutes at room temperature. Thesolution was then filtered through a paper filter. Thefiltered solution was loaded into the feed vessel of aP-0.1 Pulse Combustion Dryer.

Pulse drying was conducted using an inlettemperature of 95020F and outlet temperature of1505F. Outlet temperature was controlled byautomated adjustment of dryer feed using a feedforward control scheme.

Dried powder was collected using a cycloneprecipitator fitted with a pneumatically tight pair ofslide valves.

Product yield and quality were evaluated afterdrying and collection were completed.

RESULTS AND DISCUSSION:The aqueous solution of thymol-hydroxypropyl

beta cyclodextrin complex was visibly clear andstable after filtration. It exhibited a very strong thymolaroma without any visible evidence of uncomplexed

thymol separation after standing for 24 hours at roomtemperature. This indicates that a stable thymol-

hydroxypropyl beta cyclodextrin complex waspresent in the aqueous solution.

Feeding of the dryer was without incident. A finewhite powder formed and collection began withinseconds of the introduction of complex-containingfeed to the dryer. Inspection of the dryer after theprocess revealed no visible residue on the dryerwalls or cone surfaces at the bottom of the dryingchamber.

More than 90% of the introduced solid materialwas collected as powder as determined by a massbalance of the entire process.

The powder produced was fine and free flowing.

Microscopic examination revealed a sphericalparticle with the appearance of a glass bead.

When placed in water, the powder dissolvedfreely with agitation. On preparation of a 25% w/waqueous solution, the resulting clear solution had astrong thymol aroma. The aqueous solutionremained clear with a strong thymol aroma afterstanding for 24 hours at room temperature. Therewas no visible separation of thymol. This indicatesthe presence of a stable thymol-hydroxypropyl betacyclodextrin complex.

CONCLUSION:

From this work the authors conclude that PulseCombustion Drying allows the commercial-scaleproduction of cyclodextrin complexes as drypowders. The complexes retain their characteristicwater solubility after drying, indicating that the fragilethermodynamic association between cyclodextrinand guest molecule is preserved in the dryingprocess.

REFERENCES: A.A. Putnam, F.E. Belles, J.A.C. Kentfield, PulseCombustion, Progress in Energy and CombustionScience, V12:1, 1986, pp 43-79.

T. Higuguchi, K.A. Connors, Phase-SolubilityTechniques, Advances in Analytical Chemistry andInstrumentation, V4, 1965, pp 117-212.