Process engineering-aided development of pharmaceutical particles

BUCALÁ, VERÓNICA; CASTRO, SILVINA; PALMA, SANTIAGO; ALEMMANDI, DANIEL; GARCÍA, MAXIMILIANO; PIÑA, JULIANA

San Juan, Puerto Rico

Congreso; Particle Technology Forum, Particulate Processes in the Pharmaceutical Industry II; 2008

International Engineering Conferences Inc, ECI

The production of new pharmaceutical particles is often developed through costly and time-consuming experimentation. However, some basic tools of chemical engineering can be helpful to define the values of operating variables that lead to the required product quality prior to the experimentation stage. By using mass, energy, momentum and population balances, it is possible to obtain the process operating map which allows minimizing experimental and production times, costs and wastes. Solid dispersions are one of the most promising strategies to improve the oral bioavailability of poorly water soluble drugs. They can be defined as molecular mixtures of drugs with hydrophilic carriers. Actually, some experiments are conduced using surfactant as ternary component in these systems. The most frequent concern regarding solid dispersions is the feasibility of manufacturing the process scale up. For this reason, it is very useful to design strategies to attain microparticulate solids dispersions through scalable and reliable industrial methods. In previous works, we have obtained ternary solid dispersions compounded by Indomethacin (antiinflamatory drug) – polyethylene glycol 6000 – ascorbyl palmitate (surfactant) which have evidenced a noticeable improvement on the dissolution rate. The size of the unit of dosage form can significantly affect drug bioavailability. It is well know that multiparticles have more uniform gastro-intestinal transit than dosage units of higher sizes (i.e. tablets). The spray chilling techniques have been successfully used to obtain microparticles since several decades ago and are reliable and cost-effective. In this work, mass and energy balances have been employed to determine the operating variables ranges for a cocurrent spray chilling process to produce microparticles of solid dispersions constituted by different fractions of indomethacin, ascorbyl palmitate and polyethylene glycol 6000. For a given dispersion, the operating variables of the spray chilling system are basically the inlet mass flows and temperatures of the dispersion and cooling and atomization airs. Therefore, diverse combinations of these variables can be selected to obtain the desired product within the operating ranges defined by the equipment manufacturer. In the present work, mass and energy balances have been used to reduce the exploratory regions to perform experiments. The global energy balance together with the assumption of equal outlet dispersion and air temperatures (i.e., an extreme long residence time) allows restricting the operating conditions in an easy way. Even though this tool sets limits on the operating variables values; it is not conservative enough. For this reason, a heterogeneous plug flow model has been developed to represent the heat exchange between the dispersion (as melt droplets or solid particles) and the cooling air. Three process zones have been identified and modeled along the spray chiller: I) the cooling of the molten dispersion from its inlet temperature down to its melting point, II) the solidification of the liquid dispersion at constant temperature, and III) the cooling of the solid dispersion from its fusion temperature down to the microparticles outlet temperature. The developed mathematical tools have been valuable to construct the operating map of the desired process, from which the forbidden working regions can be easily distinguished.