Reviewing the Impact of Powder Cohesion on Continuous Direct Compression (CDC) Performance

Abstract

The pharmaceutical industry is undergoing a paradigm shift towards continuous processing from batch, where continuous direct compression (CDC) is considered to offer the most straightforward implementation amongst powder processes due to the relatively low number of unit operations or handling steps. Due to the nature of continuous processing, the bulk properties of the formulation will require sufficient flowability and tabletability in order to be processed and transported effectively to and from each unit operation. Powder cohesion presents one of the greatest obstacles to the CDC process as it inhibits powder flow. As a result, there have been many studies investigating potential manners in which to overcome the effects of cohesion with, to date, little consideration of how these controls may affect downstream unit operations. The aim of this literature review is to explore and consolidate this literature, considering the impact of powder cohesion and cohesion control measures on the three-unit operations of the CDC process (feeding, mixing, and tabletting). This review will also cover the consequences of implementing such control measures whilst highlighting subject matter which could be of value for future research to better understand how to manage cohesive powders for CDC manufacture.

Introduction

The pharmaceutical industry is currently undergoing a paradigm shift from batch to continuous processing in order to improve manufacturing efficiency [1]. Continuous direct compression (CDC) (Figure 1) is considered highly efficient because of the reduced number of unit operations involved [2,3]; however, there currently exists only a limited range of formulations for which it is viable. Suitable formulations will generally have low drug load, a need for adequate flowability (as the material has to be transported through the system), and have sufficient tabletability, for the CDC process to work [4].

There are several critical material attributes (CMAs) which impact the flow of pharmaceutical powders and hence the successful formulation of oral solid dosage forms, of which cohesion is thought to be the most significant [5]. Powder cohesion refers to the affinity of particles to adhere to each other. It manifests in the bulk as resistance to powder flow often accompanied by adhesive behaviour, which refers to the tendency of a material to bind to surfaces and other materials [6]. Factors which contribute to cohesion include:

• Liquid bridges (liquid bridges will not be discussed in this literature review as there already exist comprehensive reviews of this topic [7,8,9]). Our focus in the present work will also be on the effect of cohesion in CDC processes rather than the causes of cohesion) [10];
• Van der Waals forces [11];
• Electrostatic forces [12];
• Frictional charging during handling [13];
• Particle shape and size [3].

Although humidity is controlled in a GMP environment, moisture is still present in the air and can be adsorbed and or absorbed into the powders, increasing cohesivity [14,15,16]. This increase in local moisture content in powders results in transient, complex interactions between powder surfaces and water, resulting in higher cohesion and decreased flowability [14,15,16]. Therefore, for every instance where good flowability is desired, an increase in humidity will have a negative effect. On the other hand, with compaction, there is evidence that some moisture can produce higher-strength tablets. However, too much moisture impacts the tablet strength negatively [17]. Thus, the positive effect of humidity, during tabletting, is largely outweighed by its negative effect across all the other unit operations in the CDC process. Therefore, generally or where suitable, moisture content should be kept to a minimum. In the interest of the review, relative humidity will be discussed when it is the only variable suited to solving an issue, for instance mitigating the triboelectric effect during powder feeding (Section 2). Furthermore, there are additional reviews [8,9] which discuss the influence of humidity on powder cohesion.

Active pharmaceutical ingredients (APIs) are typically the components of tablet formulations that give rise to handling issues, due to their often very high cohesivity, low bulk density, and highly aspherical geometries, in turn resulting in undesirable operating performance for CDC [6,18]. Many APIs are needle-like and very fine (<10 μm) resulting in a high contact area and cohesion (and thus poor flowability), whereas excipients are typically coarser and have a more favourable (spherical) particle shape, leading to better flowability. This difference in flow properties is perhaps unsurprising, as excipients are inactive substances whose purpose is to aid the formulation process by supporting or enhancing the stability and tabletability [19] of a pharmaceutical dosage form; as such, cohesive excipients would be omitted during the experimental design stages [20] as they are much easier to replace than APIs. Based on the above, it is clear that a high concentration of API may heavily affect the processability of powders, rendering the CDC manufacturing route non-viable [21].

In spite of the above, cohesion is not always a negative influence on CDC operations. In some instances, moderate cohesion has been found to aid the proper functioning of a given unit operation. For example, during powder feeding the addition of nano-sized silica was shown to result in reduced adhesion to feeder surfaces and improved powder flow as will be discussed later in this review [6,22]. However, in most cases of high cohesivity, flow is inhibited [23,24], which is problematic for feeding [25], mixing [26] and die filling [27,28]. Conversely, during the tabletting stage, powder cohesivity (specifically interparticle adhesion) is generally desirable, inviting smaller particle sizes and higher surface energy powders [29,30,31,32,33,34,35,36].

There are three main ways in which cohesion can be managed in tablet production:
1. Formulation modification, through the introduction of glidants or lubricants [37].
2. Operational process changes which are documented in many different studies for each unit operation [38].
3. Granulation, which also manages cohesion as poor flowing powder fines are made into coarser more uniform agglomerates. (This is beyond the scope of this literature review as this unit operation is not a part of CDC processes [39]).

However, most literature does not consider how cohesion controls impact downstream unit operations. As far as the authors are aware there are no literature reviews that encompass the mitigation of the effects of cohesion and how those controls may affect certain unit operations. Therefore, the primary aim of this literature review is to explore and consolidate current knowledge concerning the impact of powder cohesion and cohesion control measures on all unit operations in the CDC process (feeding, mixing and compression), discuss the consequences of cohesion control measures implemented, and establish what further studies could be valuably conducted in the future.

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Following excipients are mentioned in the study besides other: Magnesium Stearate, Lactose 

Jones-Salkey, O.; Chu, Z.; Ingram, A.; Windows-Yule, C.R.K. Reviewing the Impact of Powder Cohesion on Continuous Direct Compression (CDC) Performance. Pharmaceutics 2023, 15, 1587. https://doi.org/10.3390/pharmaceutics15061587

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