Original Research PaperContinuous high-shear granulation: Mechanistic understanding of the influence of process parameters on critical quality attributes via elucidating the internal physical and chemical microstructure
Graphical abstract
Introduction
In recent years, due to the increasing demand for solid dosage forms and expiring patents of drug molecules, there is a critical need to accelerate and de-risk process and product development. In such a context, continuous manufacturing has been drawing considerable attention by virtue of its intrinsic advantages [1], [2]. It enables the prospect of curtailing capital expenditure with smaller equipment footprint and elimination of intermediate storage, and facilitating process design and understanding with less scale-up issues. In addition, risk mitigation and enhanced product quality can be accrued with integration of process analytical technologies for automated real-time quality monitoring and control [3]. More importantly, regulatory authorities, such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), also encourage and incentivize pharmaceutical industry to adopt such a paradigm transformation from conventional batch processing to more futuristic and advantageous continuous processing [4].
Wet granulation has been one of the most prevalent unit operations in tablet manufacturing. It creates interparticle bonds and promotes granule growth with the induction of liquid binder and mechanical shear forces in the system [5]. By combining formulation design with process optimization, particle characteristics can be modified, which herein exerts an impact on the performance of finished product. Key primary properties of granules are size distribution and porosity that dominate a wide spectrum of secondary properties, such as flow properties, strength and compressibility [6]. Pharmaceutical quality by design (QbD) principles framed by ICH Q8, Q9 and Q10 guidelines underline that product and process understanding and control predicated on sound science and quality risk management are of essence to increase process capability and robustness, enhance efficiencies of product development and manufacturing, accomplish performance-based quality specifications etc. Those efforts are made to ensure consistent satisfaction of predefined quality target product profiles and eventually build rather than test quality into the end product [7], [8].
To identify, monitor and control the critical sources of variability in continuous wet granulation processes, correlations between critical material attributes, critical process parameters and critical quality attributes have been extensively examined and reported in literature over the past few years [9], [10], [11], [12], [13]. Willecke et al. (2018) implemented a novel approach to explore the influence of overarching excipient characteristics on granule and tablet attributes by combining Design of Experiments (DoE) with principal component analysis [14]. With the aid of near-infrared chemical imaging, Kumar et al. (2016) investigated the residence time and liquid distributions under different combinations of process and equipment design parameters [15]. Screw speed was found to be the most dominant variable in enhancing axial mixing and granulation yield accompanied by reduced mean residence time. EI Hagrasy et al. (2013) delved into the fundamental granulation rate processes with different screw configurations in the kneading section. 90° neutral and 30° reverse offset angles of kneading elements featured the two extremes of granulation mechanisms: breakage followed by layering, and shear-elongation and breakage followed by layering, respectively [16].
While the intrinsic dissolution rates of active ingredient are determined by the chemical nature of the compound itself, tablet microstructure carrying information about the history of manufacturing process enables additional degrees of freedom to modulate the dosage form bioavailability [17]. It is an essential factor that is closely intertwined with the mechanical strength, friability, disintegration, and drug dissolution and release kinetics of the finished product. One of the microstructures that has been studied by other researchers focused on the intra-granular physical structure at microscopic scale and its influence on spatial distribution of solid particles and void space within the tablet after compaction [18], [19], [20], [21]. Typically, the observed relationship is that an increase in granule porosity is associated with a reduction in granule strength but greater compatibility, subsequently leading to faster tablet disintegration and dissolution. However, high porosity may result in unacceptably friable tablet with low elastic modulus and tensile strength, which, in turn, causes sub-potency and poor product quality during processing and handling. Some other contributions shed light on the implication of formulation microstructure at a comparable length scale concerning the homogeneity of interactive mixture or distribution of agglomerates formed by cohesive hydrophobic drug particulates on blend dissolution [22], [23], [24], [25]. In absence of proper dispersion or de-agglomeration processing prior to the dissolution testing, particles formed coherent masses and manifested significant slower dissolution rate on account of reduced surface area exposed to the dissolution medium. Therefore, a better understanding of the interplay between material properties and process conditions is of paramount importance to engineer the microstructure that is further conducive to diagnosing deficiencies, avoiding pitfalls and ensuring consistent quality in product development [26], [27].
There has been very limited research heretofore carried out to implement QbD methodologies towards continuous wet granulation processes. Our previously published work systematically investigated a continuous high-shear granulation system, Lӧdige CoriMix® CM5, with the focus on bridging knowledge gap between critical process variables and granule properties [18]. This present study continued the investigation to further include final drug product in the parametric analysis with emphasis on understanding the role of microstructure in modulating the performance of immediate release tablets. DoE, multivariate data analysis and complementary imaging techniques were combined to (1) reveal the interplay between key process parameters, intermediate properties and final drug product attributes, (2) elucidate the underlying dissolution mechanisms accompanied by distinct tablet physical microstructures, and (3) gain in-depth insight into the influence of tablet drug agglomerate size distribution (chemical microstructure) on release kinetics.
Section snippets
Materials
The low-dose formulation comprised 8% (w/w) semi-fine acetaminophen (APAP, Mallinckrodt Inc, Raleigh, NC), 44.75% (w/w) α-lactose monohydrate 200 M (Foremost Farms USA, Baraboo, WI, USA), 44.75% (w/w) microcrystalline cellulose (MCC, Avicel® PH101, FMC Biopolymer, Philadelphia, PA) and 2.5% (w/w) polyvinylpyrrolidone (PVP K29-32, Fisher Scientific, Pittsburgh, PA). The dry binder addition method was adopted, i.e., PVP was premixed with other ingredients as dry powders. Distilled water as
Multiple linear regression models for granule and tablet properties
In the present study, multiple linear regression models were developed posterior to the completion of DoE experiments to correlate the properties or responses to the processing conditions or regressors. The raw data of granule and tablet properties were provided in Tables S1 and S2. The selection of optimum terms included in each model necessitated striking a balance between parsimony (fewer independent variables if possible) and accuracy (more independent variables if requisite). Forward
Conclusions
In this study, DoE and multivariate data analysis were used to comprehensively investigate the continuous high-shear granulation process. L/S ratio and impeller rotation speed showed predominant effect over powder feeding rate on the underlying granulation rate processes that further determined the critical attributes of granules and tablets. L/S ratio mainly controlled the particle degree of liquid saturation while rotation speed was a key factor of adjusting the mechanical shear input. The
Acknowledgement
The authors would like to thank Rutgers University Engineering Research Center for Structured Organic Particulate Systems for funding this work. We also gratefully acknowledge Scott Tandy from H2Optx, Inc for experimental suggestions and instrument training.
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