RESUMEN
Reformulation of metered-dose inhalers (MDIs) without the use of chlorofluorocarbon (CFC) propellants presents numerous obstacles because there are no alternative propellants that can serve as immediate replacements for pharmaceutical use. Hydrofluorocarbons (HFCs), hydrochlorofluorocarbons (HCFCs) and hydrocarbons (HCs) are all under consideration as possible alternatives for CFC propellants. However, no single propellant or combination of propellants has been identified with all of the physical-chemical properties of CFCs. Based on their zero ozone depletion potentials, relatively low global warming potentials, non-flammabilities, densities, and vapor pressures, HFA-134a and HFA-227 are the most attractive replacement propellants identified to date. Yet, their use in MDIs will still require: (1) identification of a metering valve with propellant and formulation-compatible gaskets, (2) use of current suspending agents at levels much lower than in present MDIs or identification (and characterization) of new suspending agents, and (3) modification of existing manufacturing technologies. Demonstration of acceptable final product stability, safety and efficacy will be necessary prior to submission to worldwide registration authorities.
Asunto(s)
Propelentes de Aerosoles/normas , Hidrocarburos Fluorados/normas , Nebulizadores y Vaporizadores/normas , Administración por Inhalación , Propelentes de Aerosoles/química , Diseño de Equipo , Humanos , Hidrocarburos Fluorados/químicaRESUMEN
A mass transfer model was developed to describe the dissolution and reaction of an acidic drug, naproxen [(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid], from a rotating disk in buffered solutions. Dissolution in 0.0010 to 0.030 M acetate, citrate, and phosphate buffer solutions, with 0.1 M KCl added, over a pH range of 2 to 8 at 25 degrees C, was investigated. Features of the mass transfer model include: treatment of the mass transfer as a convective diffusion process; use of the buffer reactions and the acid ionization as a single flux boundary condition; the capacity to make accurate a priori predictions without fitting film thicknesses or diffusion coefficients; and the option of considering two limiting cases for the maximal increase in dissolution that could be expected in a reactive buffer and the increase in dissolution in a buffer at maximum buffer capacity.
Asunto(s)
Preparaciones Farmacéuticas/análisis , Tampones (Química) , Fenómenos Químicos , Química Física , Difusión , Concentración de Iones de Hidrógeno , Cinética , Naproxeno/análisis , SolubilidadRESUMEN
A mass transfer model was developed to describe the dissolution and reaction of acidic and basic compounds from a rotating disk in unbuffered water. Dissolution of two carboxylic acids, 2-naphthoic acid (1) and naproxen [(+)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid, 2], and the free base, papaverine (6,7-dimethoxy-1-veratrylisoquinoline, 3), in aqueous solutions (mu = 0.1 with KCI) at 25 degrees C were investigated. An automated dissolution apparatus, which consisted of microcomputer-controlled autoburets, was constructed to monitor and adjust the pH of the aqueous solutions during the experiments. Unique features of the mass transfer model include treatment of mass transfer as a convective diffusion process rather than a stagnant film diffusion only process; treatment of ionization and acid-base reactions as heterogeneous reactions; use of experimental diffusion coefficients for all species, particularly H+ and OH-; and application of boundary conditions that specify flux for surface ionization produced species. The model accurately predicted the dissolution rate assuming the solubility, pKa, and diffusion coefficient of the compound were independently known. The model also predicted pH at the solid-liquid surface, the flux of H+ from the surface, and the contribution of A- to the total acid flux as a function of bulk pH of the aqueous solution.