Robust Process Scale-Up Leveraging Design of Experiments to Map Active Pharmaceutical Ingredient Humid Drying Parameter Space

Abstract

Sugammadex is a modified γ-cyclodextrin active pharmaceutical ingredient (API) that is used as a reversal agent for neuromuscular blockade drugs in general anesthesia. The open structure of the cyclodextrin molecule yields a multitude of solid forms, and to date, more than 12 different mixed methanol solvate/hydrate forms have been characterized. Historically, the kinetic form (type 1) was manufactured to ensure that the solids could be dried successfully using only heat and vacuum to meet the specifications for residual solvents. Isolation of the thermodynamic form (type 2) was avoided due to the inability to remove process solvents to desired levels during drying and the subsequent need to rework the solids. To meet increasing product demand through improved robustness, the process was redesigned to manufacture the thermodynamic form (type 2). Therefore, an improved drying process had to be developed to enable meeting residual solvent levels of the final API at a large scale. Small-scale drying experiments were performed using a custom, in-house, process analytical technology-enabled drying platform to visualize the real-time evolution of the process solvents and water from the solids and to monitor form change. The mechanism for solvent removal in this case was found to be unique since it was independent of API crystallinity. The key element for successful drying was the displacement of solvent by water molecules, regardless of whether the crystal structure remained intact or collapsed. A predictive model was developed through design of experiments including three-factor interactions of drying humidity, temperature, and pressure, and the model was used to define the operating space to ensure successful drying. The humid drying conditions identified in this study were implemented across scales to ensure that residual solvent specifications were achieved regardless of the crystalline form generated.

Copper-Catalyzed, Aerobic Oxidation of Hydrazone in a Three-Phase Packed Bed Reactor

“…Simultaneously varying these parameters in a body-centered design allowed us to efficiently investigate how each variable influenced the others, along with aryldiazoacetate yield. Several studies have utilized this approach to successfully optimize flow processes, especially for industrial and pharmaceutical applications. − …”

New Bench-Scale Method To Elucidate Active Pharmaceutical Ingredient Drying Mechanisms

“…Methodologies, described in the literature using small scale flow cells, 2,18,20 Integration of different flow cells into the established experimental drying platform enabled rapid generation of data and interrogation of the processing space under well controlled conditions of temperature, pressure, drying gas flow rate, and relative humidity. The methods were material sparing, requiring only 0.5−10 g of wet solids per experiment, and minimized sampling requirements using various in-line process analytical technologies including mass spectrometry (MS) using a Proline Dycor system (Ametek, Pittsburg, PA), near infrared spectrometry (NIR) using a diffuse reflectance probe connected to an Antaris MX Process Analyzer (Thermo Fisher Scientific, Waltham, MA).…”

“…Methodologies, described in the literature using small scale flow cells, ,, were applied here to conduct experiments in Drying Process Development Laboratory in Rahway, NJ, USA. Integration of different flow cells into the established experimental drying platform enabled rapid generation of data and interrogation of the processing space under well controlled conditions of temperature, pressure, drying gas flow rate, and relative humidity.…”

“…Drying is an important unit operation in the pharmaceutical industry and because of the complex nature of the compounds under development, the variety of drying behaviors encountered, and the specific critical attributes targeted, researchers in the field have developed many different tools to study the aspects of interest. − For drying kinetics, these include experimental methods ranging from small scale dynamic vapor sorption chambers and flow cells to larger scale pilot plant agitated dryers and, in some cases, mechanistic models are provided. − Often, to minimize system disturbances and material requirements, in-line process analytical technology is used to supplement or in lieu of off-line testing of in process samples. Common examples include near infrared (NIR) or RAMAN probes, in contact with the solids, to determine the solvent content or physical form of the solids as well as mass spectroscopy to monitor components leaving in off gas streams. − The current work introduces another experimental tool for inclusion in the drying process development toolbox.…”