Scale-up of an oil/water cream containing 40% diethylene glycol monoethyl ether

The purpose of this study was to scale up an oil/water (o/w) cream formulat ion containing 40% diethylene glycol monoethyl ether (DGME), developed via 300-g laboratory batches in a 2(5-2) fractional factorial design, to 7-kg b atch sizes in a Brogli-10 homogenizer. The o/w cream was manufactured via a standard phase-inversion process in the Brogli-10 homogenizer. Partitionin g studies of DGME were conducted in test tubes at ambient temperature and a fter 24 hr at 70 degrees C in a convection oven. Phase height was measured by vernier calipers. Microscopy studies of excipients with and without trea tment with water or a DGME/water mixture were conducted with a Nikon micros cope after equilibration at 35 degrees C for 24 hr. During creation of the 7-kg pilot-scale batches, congealed material was observed between the sweep agitation blade and the discharge port, where the Brogli-10 homogenizer is not temperature jacketed. Factors that increased the amount of congealed m aterial were higher temperatures during primary emulsification and longer c ooling times. Partitioning studies revealed that DGME resides in the aqueou s external phase of this formulation. Microscopy studies revealed that DGME in the external phase of this cream has a profound impact on the solubilit y of certain solid, waxy excipients (e.g., cetyl alcohol and polyoxyethylen e-2-stearyl ether) at 35 degrees C. From this study, it appears that DGME r esides in the external phase of the o/w cream. During manufacturing, it is hypothesized that the presence of DGME in the external phase alters the sol ubility of certain solid, waxy excipients in the formula such that they no longer primarily reside in the internal oil phase. On cooling, these materi als precipitate or congeal in the external phase. The fractional factorial experimental design at the 300-g laboratory scale did not predict the issue s encountered during scale-up. Differences between laboratory scale and pil ot plant scale that explain why this phenomenon was not seen during laborat ory scale are differences in cooling times, nonjacketed or "cold spots" in the Brogli-10 homogenizer, and a low proportion of congealed material in re lation to the total batch size (< 1.5%).