Scale up of Semisolid Dosage Forms Manufacturing Based on Process Understanding: from Lab to Industrial Scale.

The scale up of production processes is a major challenge in pharmaceutical industry. Using a quality by design approach, upscaling can be based on the design space, which can be assessed on a small scale. In a previous study, the critical process parameters were identified by a definitive screening design on cetomacrogol ointment. In the current study, this lab scale (0.5 kg) study was scaled up to industrial scale (2000 kg, filling 100g tubes at 75 tubes/min). A similar trend for the influence of filling temperature on ointment yield stress was found for lab and industrial scale production. Furthermore, a process window for ointment filling viscosities was established. It was shown that between 26 and 170 Pa.s ointment could be filled into tubes with a low weight variation (< 0.5% RSD) resulting in a product with a yield stress that meets the pre-set criteria. This approach was subsequently verified using several creams and ointments and showed general applicability.

The Role of Excipients in the Stability of Triamcinolone Acetonide in Ointments.

Degradation of triamcinolone acetonide (TCA) in an ointment was investigated. TCA appeared to be concentrated in propylene glycol (PG) which in turn is dispersed in a lanolin-petrolatum mixture. Two predominant degradation products were identified: a 21-aldehyde and a 17-carboxylic acid. The 21-aldehyde is formed after TCA is oxidized by O2, a reaction that is catalyzed by trace metals. Logically, the content of trace metals has a profound effect on the degradation rate. It was shown that trace metals are extracted from lanolin and petrolatum by PG, increasing the concentration in PG. In accordance with these findings, TCA degrades faster in PG that is present in the ointment formulation than in regular PG. The 21-aldehyde was confirmed to be a primary degradation product, while the 17-carboxylic acid was identified as a secondary degradation product. Based on the mechanism of degradation, the ointment can be stabilized by the addition of sodium metabisulfite which was shown to reside also in the PG phase within the ointment.