Drying an Organic Monohydrate:  Crystal Form Instabilities and a Factory-Scale Drying Scheme to Ensure Monohydrate Preservation

Continuous manufacturing of pharmaceuticals offers such benefits as production flexibility, reduced drug product costs, and improved product quality. Moving toward continuous manufacturing requires suitable small-scale equipment, either by development of new equipment or optimization of existing equipment. In primary manufacturing, particle properties are often altered during crystallization and have to be restored during subsequent processing. Drying a crystallized product is one of the most challenging steps, especially since attrition and agglomeration can occur. To that end, we investigated the drying behavior of a crystalline model compound with moisture levels of up to 10 wt % in a corotating twin-screw extruder. The feed mass flows on a piece of small-scale equipment used for pharmaceutical production varied between 0.5 and 2.0 kg/h. Experiments were conducted to evaluate the drying performance in various process settings. Because of a very narrow and consistent residence time distribution, extrusion drying has the potential for pharmaceutical compound drying. In our study, we successfully accomplished drying of a crystalline product with very little agglomeration and/or attrition in some process settings while preserving a crystal size similar to that of the raw material. The reduction in particle size occurred as a result of long residence times (low extruder screw speed) and a decrease in the residual moisture of the product. The aim of our work was to show the potential of extruder drying as a novel continuous manufacturing process for pharmaceuticals and to enable further process development.

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Continuous Drying of Pharmaceutical Powders Using a Twin-Screw Extruder

Kreimer

Aigner

Lepek

et al. 2018

“…Humidified gas can be employed during the drying of active pharmaceutical ingredients (APIs) when it is necessary to preserve the product as a desired crystalline hydrate or to favorably impact the drying kinetics for the removal of processing solvents. − The process is internally referred to as “humid drying” if the water content of the drying gas is maintained above a critical relative humidity (i.e., water activity) such that the hydrated form is isolated successfully while excess water and other processing solvents are removed to desired levels.…”

Section: Introductionmentioning

confidence: 99%

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

Lamberto

Neuhaus²

2021

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.

“…Adjusting the pH to >6.0 led to contamination with an undesired polymorph or pseudopolymorph, as observed by X-ray powder diffraction (XRPD) (Figure S2). Given that the pKa values were 11.2, 7.7, 3.7, and 0.9 for base and 2.8 for acid, as calculated using ACD/ Percepta, 14 compound 1 may exist mostly as a monohydrochloride in an approximately pH 5.5 aqueous solution. Based on these findings, the target pH was set to 5.5.…”

Section: ■ Introductionmentioning

confidence: 99%

Practical and Scalable Manufacturing Process for Plasma Kallikrein Inhibitor ASP5069

Hirasawa

Kohmura

2020

The plasma kallikrein inhibitor ASP5069 is a promising drug candidate for the treatment of edema and hematoma and for the prevention of bleeding during surgery. Here, we report the development of a practical and scalable process for manufacturing ASP5069 that features a convergent synthetic approach, suppression of impurity formation, effective purification of the amine compound by extraction, improved reproducibility of the reductive amination reaction, and a drying process for the dihydrate form. This process was successfully used to prepare >100 g of ASP5069.