Process intensification of pharmaceutical powder blending at commercial throughputs by utilizing semi-continuous mini-blending


Process intensification involves the miniaturization of equipment while retaining process throughput and performance. The pharmaceutical industry can benefit from this approach especially during drug product development, where the availability of active pharmaceutical ingredients (API) is often limited. It reduces the need for process scale up, as equipment used during product development and commercial production is identical. However, applications of process intensification for processing pharmaceutical powders are limited so far. Here we show that semi-continuous mini-blending can be utilized for process intensification of blending of API and excipients. Uniform blending at commercially relevant throughputs was achieved through mini-blends with a volume of less than ten liters. Our results demonstrate that blending speed, cycle time and blender fill level can be optimized without compromising blending performance. Acceptable blend uniformity is obtained over a broad range of operating parameters, by choosing the right excipients. The optimized throughput of the mini-blending process is in line with the desired throughput of a commercial Continuous Direct Compression (CDC) process.


Process intensification (PI) traditionally involves the physical miniaturization of process equipment or reduction of the number of unit operations, while retaining process throughput and performance (Reay et al., 2013; Zhang et al., 2021). Its fundamental concept is based on process volume reduction, resulting in enhanced mixing and heat/mass transfer. Industrial development in PI has resulted in novel equipment with higher production capacity per unit vessel volume (Wang et al., 2017). Such equipment includes both reactive equipment, such as microreactors or oscillatory baffled reactors, as well as non-reactive processing equipment, such as mixing devices.

The focus of PI has mainly been on processes involving liquids and gases. PI applications for the processing of solids are limited, as fouling and equipment blockages can occur due to the presence of solids in comparably small confinements (Wang et al., 2017). Appropriately designed equipment is therefore key for intensifying industrially-relevant solid processes. The handling of solids, and powders in particular, is an important process in many industries such as the pharmaceutical and food industry. In these sectors, powder processing involves a variety of unit operations including dosing, blending, granulation, filling and compression. These unit operations are generally performed in batch-wise processes at large scale of production in the order of tens to hundreds of kilograms. PI of such operations can greatly reduce the production footprint, improve flexibility in scale of manufacturing and support rapid, material sparing development of new products by reducing scale up needs to deliver commercial throughputs.

Generally, the objective of PI in powder processing is transforming traditional batch processes to continuous ones. This reduces processing times and improves energy efficiency (Wang et al., 2017). Powder blending is a unit operation that is conventionally carried out in a large scale tumble blending process. This results in limited flexibility in terms of the scale of production as the batch size is determined by blender dimensions (Roth et al., 2017). In the pharmaceutical industry, the main goal of a powder blending process is to generate a uniform blend of the active pharmaceutical ingredient (API) and excipients. Uniformity of the powder blend is crucial to ensure accurate and consistent dosing of the API in the final dosage form. Achieving uniform blending can be challenging, as differences in powder material properties (e.g. particle size) can cause segregation during blending (Alexander et al., 2003; Shenoy et al., 2015; Tang and Puri, 2007). This results in poor content uniformity and drives the need for scale up trials. Process intensification of a powder blending process could reduce segregation potential by minimizing the scale of mixing and reducing the number of scale up steps to allow commercial manufacturing throughput.

Continuous powder blenders have been developed as a small-scale alternative for traditional batch blenders (Pernenkil and Cooney, 2006). With a volume in the order of several liters and residence times in the order of seconds to minutes, they are an excellent example of PI. It has indeed been shown that the segregation potential is greatly reduced in continuous powder blending compared to batch blending (Lakio et al., 2017; Oka et al., 2017). Furthermore, continuous blending has also been shown effective in producing uniform blends of API’s and pharmaceutical excipients (Jaspers et al., 2022, Jaspers et al., 2021; Lakio et al., 2017). However, implementation of continuous powder blending, and continuous processing in general, in the pharmaceutical industry is still limited due to both regulatory and technical challenges (Vanhoorne and Vervaet, 2020). The technical limitations include management of fluctuations in feeding of individual ingredients (Bostijn et al., 2019; Jaspers et al., 2021), build-up of material in process equipment (Kauppinen et al., 2019) and challenges with content uniformity of formulations with low API dosage (Karttunen et al., 2019; Van Snick et al., 2017). Furthermore, a drawback of fully continuous processing in product development is the product consumption during start-up and ramp down of the system. This is especially an issue when commercial production volumes are small, as well as during product and process development where the availability of API is limited. A continuous process also requires the development of complex full line disturbance tracking and rejection strategies, as disturbances are guaranteed during refill of feeders.

To overcome the challenges of continuous powder blending while maintaining the advantages of PI, a semi-continuous mini-blender can be implemented. This mini-blender consists of a small-scale batch blender with a volume of approximately 10 l, combined with gravimetric feeders for dosing of API and excipients. The small volume of the mini-blender allows for process intensification of the blending process through enhanced mixing efficiency, resulting in reduced blending times (Bautista et al., 2022). The enhanced mixing efficiency is achieved by applying high rotational speeds of up to 300 rpm, equivalent to a Froude number up to 12. This is much higher than what can be achieved in a conventional batch powder blending process, where typical Froude numbers are below 1.0 (Muzzio and Alexander, 2005). In a semi-continuous mini-blending process, feeding, blending and discharge of the blend are carried out repeatedly at a set frequency, which allows continuous compression of the blend into tablets (Bautista et al., 2022). A major benefit of this semi-continuous approach is the averaging out of feeder fluctuations due to discrete dispensing of raw materials. The weight dispensed by each feeder exactly corresponds to the mass of each component in that particular mini-blend. Furthermore, refill of the feeders occurs during blending and therefore feeders are always dispensing under gravimetric control. This makes the process especially suitable for low-dose formulations which are sensitive to feeding fluctuations in a continuous process. Another benefit is the absence of a process start-up and ramp down phase, resulting in high yields and reduced amounts of API required during development. Finally, there is no need for scale up as the equipment used during development and commercial production is identical.

The objective of the current study is to demonstrate process intensification of the blending of API and excipients using a semi-continuous mini-blender. To this end, potentially critical process parameters; blending speed and blender fill level, are varied and blend uniformity of the resulting powder blends is tested. Blending is performed for formulations with low and medium API dosage and varying direct compression (DC) grades of lactose as the major excipient. The results of this study reveal the critical parameters that determine performance of the mini-blending operation. It is found that uniform blends of API and excipients are obtained over a broad range of process settings, indicating a robust blending process of the API with DC-grade excipients. By optimizing blending speed, the time required per blending cycle can be reduced, which results in an intensification of the blending process. Together with a tailored blender fill level and optimized excipient selection, this leads to a maximized throughput of the mini-blending process. This optimized throughput is in line with the throughput required for a commercial CDC process. These results show the potential of semi-continuous mini-blending for blending of API and excipients at small scale, while achieving a commercially relevant process throughput.

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Spray dried lactose (SuperTab® 11SD), anhydrous lactose (SuperTab® 21AN), agglomerated lactose (SuperTab® 30GR), microcrystalline cellulose (MCC, Pharmacel® 102) and croscarmellose sodium (CCS, Primellose®) were obtained from DFE Pharma (Goch, Germany). Paracetamol fine powder grade was purchased from Mallinckrodt Inc. (Raleigh, NC, USA).

Maarten Jaspers, Florian Tegel, Timo P. Roelofs, Fabian Starsich, Yunfei Li Song, Bernhard Meir, Richard Elkes, Bastiaan H.J. Dickhoff, Process intensification of pharmaceutical powder blending at commercial throughputs by utilizing semi-continuous mini-blending, International Journal of Pharmaceutics: X, Volume 8, 2024, 100264, ISSN 2590-1567,

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