Continuous twin screw granulation: Impact of binder addition method and surfactants on granulation of a high-dosed, poorly soluble API.

Despite the recent commercialization of several drug products manufactured through continuous manufacturing techniques, knowledge on the formulation aspect of these techniques, such as twin screw wet granulation, is still rather limited. Previous research identified lactose/MCC/HPMC as a robust platform formulation for several model formulations, although granulation of the high-dosed, poorly soluble API mebendazole proved challenging. Therefore, current research evaluated the binder addition method (wet or dry) as well as surfactant (SLS) addition when using PVP, instead of HPMC. Compared to the previous formulation, using HPMC as binder, all four formulations with PVP yielded significantly stronger granules at similar to significantly lower liquid to solid (L/S) ratios. Through the combination of four replicate center composite circumscribed designs, each evaluating the impact of screw speed and L/S ratio on granule quality attributes, the effect of the formulation variables was assessed. Overall, L/S ratio had the most significant impact on granule characteristics whereas the effect of screw speed was negligible. Similar granule quality attributes were obtained for each formulation, although the addition of SLS and wet binder addition significantly reduced the required L/S ratio to achieve the desired characteristics. This significant reduction could prove useful for processing other formulations requiring high amounts of moisture, which could otherwise not be dried at a high throughput due to the limited drying capacity of the dryer unit of the Consigma system.

Continuous twin screw granulation: Robustness of lactose/MCC-based formulations.

In recent years, significant progress has been made in the field of continuous twin screw granulation. However, only limited knowledge is currently available on the impact of active pharmaceutical ingredient (API) properties on granule quality and processability. In this study, the response behavior of four formulations containing APIs (5-10% drug load) with diverse characteristics was compared to the behavior of the corresponding placebo formulation consisting of lactose, microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC). API selection was based on extensive material characterization, combining conventional testing with in silico descriptors. For each formulation, a design of experiments was set up, evaluating the impact of liquid to solid (L/S) ratio and screw speed. Response ranges, response behavior and processability of each of the four formulations proved very similar to the placebo formulation when an appropriate center point L/S ratio was chosen. Hence, this robust placebo formulation could prove useful by decreasing drug product development time and consequently providing patients with a faster access to innovative medicine. Additionally, APIs with similar properties exhibited highly comparable response behavior at similar L/S ratios, indicating the potential use of surrogate APIs in novel drug product development.

Continuous twin screw granulation: A complex interplay between formulation properties, process settings and screw design.

Due to the numerous advantages over batch manufacturing, continuous manufacturing techniques such as twin screw wet granulation are rapidly gaining importance in pharmaceutical production. Since a large knowledge gap on the importance of formulation variables exists, this study systematically assessed the impact of different screw configurations and process settings on eight model formulations, varying in filler type, active pharmaceutical ingredient (API) characteristics and drug load. Although liquid to solid (L/S) ratio was the most influential variable for all formulations, also a large effect of the kneading element thickness was observed. Narrow kneading elements with a length to diameter ratio (L/D) of 1/6 had a significant detrimental effect on granule size, flow and strength compared to 1/4 L/D elements. The effects of kneading element distribution and barrel fill level were less pronounced. At low drug load, both filler types could be used to obtain granules with acceptable critical quality attributes (CQAs) for both APIs. Granulation at high drug load of the poorly soluble, poorly wettable API mebendazole proved challenging as it could not be processed using lactose as filler, in contrast to lactose/MCC. As formulations containing lactose/MCC as filler were less influenced by different screw configurations, process settings and API characteristics than formulations without MCC, lactose/MCC/HPMC was considered a promising platform formulation.