A Systematic Investigation of Process Parameters for Small-Volume Aqueous Suspension Production by the Use of Focused Ultrasonication.

Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.

Estabilidad de haloperidol-butilescopolamina-midazolamen sistemas de infusión continua de 24 horas / No disponible

Objetivo: determinar la estabilidad de la mezcla ternaria haloperidolbutilescopolamina-midazolam para establecer su validez terapéutica. Material y método: se estudiaron mezclas ternarias de haloperidol, butilescopolamina (Br), y midazolam, utilizando como vehículo glucosa 5%, a concentraciones de 0,2 y 0,8 mg/ml para haloperidol. Para los otros dos componentes la concentración (1,2 mg/ml) permaneció invariable. El estudio se realizó bajo condiciones asépticas, a temperatura ambiente, sin fotoprotección, por duplicado y durante un periodo de 84 horas. Como criterios de compatibilidad física: cambio de color, aparición de opalescencia, variación de peso y pH. La estabilidad química de los componentes se evaluó mediante cromatografía líquida de alta resolución ultravioleta-visible. Como parámetro de validez clínica se empleó el T90, considerando para su cálculo el valor obtenido al interpolar el límite inferior del intervalo de confianza del 95% de la recta representativa de la cinética lineal, para una concentración del 90% de la concentración inicial de los componentes. Resultados: los valores de las concentraciones de los componentes se ajustaron a una cinética de orden uno. El valor de T90 obtenido no fue inferior a 72 horas en las mezclas estudiadas. Durante las 84 horas que duró el ensayo ninguna de las mezclas presentó cambio de color, aparición de opalescencia, variación de peso ni de pH. Conclusión: las mezclas intravenosas a las concentraciones estudiadas de haloperidol (hasta 0,8 mg/ml), butilescopolamina (Br) (1,2 mg/ml) y midazolam (1,2 mg/ml), preparadas en glucosa 5%, en sistemas de infusión elastoméricos portátiles, son físicamente compatibles y químicamente estables durante al menos 72 horas (AU)

Objective: to determine the stability of ternary mixtures of haloperidol, midazolam, and scopolamine in order to establish their therapeutic validity. Material and methods: ternary mixtures of haloperidol, scopolamine, and midazolam were prepared in 5% glucose as vehicle at concentrations of 0.2 and 0.8 mg/mL for haloperidol. Concentration (1.2 mg/mL) remained invariable for the other two components. The study was conducted under aseptic conditions, at room temperature, without photoprotection, in duplicate, and during a period of 84 hours. Chemical stability was evaluated by high pressure liquid chromatography, and physical compatibility by changes in colour, development of opalescence, and changes in weight and pH. The T90 parameter was used to establish clinical validity, and was calculated for each drug in the mixture by considering the time at which the 95% one-sided confidence limit for the mean curve intersects 90% of the drug's initial concentration. Results: concentrations were adjusted to a first-order kinetic equation. The value of T90 was obtained after no less than 72 hours in the mixtures studied. During the 84-hour test none of the mixtures developed changes in colour, opalescence, or changes in weight or pH. Conclusion: the intravenous mixtures studied, consistent of haloperidol (up to 0.8 mg/mL), scopolamine (1.2 mg/mL), and midazolam (1.2 mg/mL) prepared in 5% glucose within elastomeric portable infusion systems, are physically compatible and chemically stable for at least 72 hours (AU)