Condensation-based method for generating aerosol particles of cocrystals
A.A. Protasov, A.M. Baklanov, E.A. Losev, G.G. Dultseva, S.V. Valiulin
V.V. Voevodsky Institute of Chemical Kinetics and Combustion of the Siberian Branch of the RAS, Novosibirsk, Russia
Keywords: aerosol, co-crystal, succinic acid, isoniazid, binary nucleation
Abstract
Cocrystals are commonly obtained using solid-phase or liquid-phase methods, though in the case if these methods are employed to develop cocrystalline pharmaceutical dosage forms, difficulties related to the control of mixture compositions and dosing accuracy arise. In the present work, we describe condensation-based method for generating aerosol particles of cocrystals formed by isoniazid, a known antituberculous remedy, and succininc acid. This method allows obtaining a pharmaceutical dosage form for delivery through inhalation with the high accuracy of dosage control. Inhalation delivery of isoniazid in the form of cocrystal can overcome the drug resistance of the mycobacteria by making high local concentration of the drug directly in the affected organ. The binary nucleation of the vapors of isoniazid and succinic acid in a horizontal flow thermal condensation reactor is investigated. The nucleation zone was determined using the method of supersaturated vapor shutoff. The composition of thus obtained cocrystals was determined by the full-profile X-ray diffraction. The conditions for generating cocrystals in a high yield have been selected, and nucleation rate was measured. The dose for inhalation delivery to laboratory animals under optimal conditions of binary nucleation is assessed. The results allow developing pharmaceutical dosage forms for delivery through inhalation with high accuracy of dosage control to treat pulmonary tuberculosis, including its drug-resistant forms.
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