ReviewA review of high shear wet granulation for better process understanding, control and product development
Graphical abstract
Introduction
Granulation is a well-known technology used to prepare granules of certain shapes and sizes from materials in the state of a powder, melting liquid, or aqueous solution, which has been widely used in pharmaceutical industry, agriculture, chemistry, and food production [1]. In the pharmaceutical field, which is the focus of this review, granulation is considered as a critical unit operation for solid dosage form manufacturing processes, especially in the preparation of tablets and capsules [2,3]. Tablets represent the most popular drug delivery system [4]. Compared with simple powders, granules possess more controllable and acceptable attributes [1,5], which are conducive to reducing dustiness, improving flowability, minimizing ingredient segregation, improving content uniformity, improving the dissolution rate, and increasing the mechanical strength of tablets [[6], [7], [8], [9], [10]]. These granule properties not only determine whether the downstream processes and scale-up production can be carried out successfully, but also have important influences on the final products, such as dissolution behavior and the therapeutic effect [11].
Currently, granulation technologies are classified as wet and dry types, depending on whether or not a liquid binder is used in the granulation process. Wet granulation technologies mainly include high shear wet granulation (HSWG), twin-screw granulation (TSG), fluid-bed granulation (FBG), and fluid-bed melt granulation. Among these methods, HSWG is one of the most widely applied granule product development technologies [12,13]. The HSWG process generally includes the following steps: (a) Addition and dry mixing of the material powders, (b) addition of a liquid binder (either a binder solution or a solvent) into the powder mixtures at a lower impeller and chopper speed, and (c) wet massing with both the impeller and chopper running at a high speed (this can be varied depending on the product). In the process, powder flow is initiated by the momentum transfer from the impeller to the powder mixtures and propagated by a series of collisions among the particles and between the particles and the equipment [14]. HSWG offers several advantages over other granulation methods, such as a good mixing effect, short processing time, high drug loading rate, high efficiency, low energy consumption, reduction of process dust, and full closure [1,5,15]. HSWG is also promising with respect to switching towards continuous processing as the rapid performance of mixing, wetting, agglomeration, and discharge in the same equipment. However, it also has shortcomings, such as chemical degradation of thermally sensitive materials, mechanical degradation of fragile particles, and the formation of clumps caused by over-wetting [16,17]. Despite increased research into HSWG in recent years, this process is still considered to be one of the most complicated and multivariate pharmaceutical processes [18], and is influenced by a large number of variables derived from equipment, formulations, and processes. Additionally, in many practical cases, the granulation process is still carried out mostly by relying on an empirical basis and judgment because of a lack of science and engineering expertise pertaining to granulation, especially with regards to end point determination and scale-up. These complications make it more challenging to effectively control the HSWG process and achieve the desired granule properties.
Understanding and control of the granulation process plays a critical role in achieving the desired attributes of the final granule products and improves production efficiency. The traditional Quality by Testing (QbT) approach of drug development relies on the detection and rejection of unqualified batches, which might lead to sub-optimal product quality [19]. In recent years, with the application of advanced concepts or methods in the pharmaceutical industry, such as Quality by Design (QbD), process analysis technology (PAT), and mathematical modeling and simulation, researchers have gained a deeper understanding of the complex HSWG process and its source of variation. Moreover, these approaches are necessary to facilitate the development of control strategies for the granulation process. As an active drug development strategy, QbD has started to be adopted by the pharmaceutical industry in recent years [20,21]. This approach emphasizes a comprehensive and thorough understanding of the relations among the material properties, production process, and product properties from product design to industrial production, which helps to ensure consistent product quality. In that framework, it emphasizes that quality is a built-in property rather than a measured test of the final product [22]. To provide effective technical support for the implementation of QbD, many PAT approaches, such as near-infrared spectroscopy, Raman spectroscopy, capacitance measurement, focused beam reflection measurement, spatial filtering velocity, and acoustic emission, are recommended [23]. Using these technologies, high-risk variables that are crucial to the final product quality can be monitored inline in real-time at a micro-level. In addition, mathematical modeling and simulation have also attracted attention, because they can effectively capture the detailed information of particle dynamics during the HSWG process, which are helpful to strengthen the physical understanding of the HSWG mechanism at macro, meso and micro levels.
In this review, various aspects of HSWG, such as the granulation mechanism, factors affecting the granulation process, in-line monitoring technologies, mathematical modeling and simulation are analyzed and discussed in detail. The review also introduces the application of the QbD concept in HSWG process control. Overall, the main purpose of this review is to provide comprehensive guidance for formulation scientists to better understand and control the HSWG process and then improve product development.
Section snippets
Granulation mechanism
In-depth understanding of the granulation mechanism is crucial to implement effective process control and predict the final product attributes. Classically, granule formation in HSWG is divided into three distinct stages: (a) Wetting and nucleation, (b) growth and consolidation, and (c) attrition and breakage [24]. The distribution of the binder liquid on the surface of the powder bed is the first step in HSWG, and then nucleation begins with the formation of an initial nucleus of particles.
Factors affecting the granulation process
The HSWG process is influenced by the factors such as equipment, formulation design, and process parameters, and these factors ultimately determine the relevant properties of the granules. These related influencing factors still need to be optimized separately because of the complexity of variables involved in the granulation process and the uniqueness of product requirements. Thus, a better understanding of the source of process variables is the key to further improving the control of the
Process monitoring technologies
Traditional drug development and production practices rely on a series of off-line tests (carried out after the completion of processes) to determine whether the product attributes meet the requirements. These off-line methods are very accurate; however, laboratory analyses are expensive and time consuming, and they cannot provide real-time in-line information of the granule state during the granulation process. Currently, the US Food and Drug Administration (FDA) and other regulatory
Mathematical modeling and simulation
In recent years, the application of mathematical modeling and simulation in the description of the kinetics of the HSWG process has increased and now plays an important role. Its advantages are mainly reflected in the ability to better analyze system dynamics and explore deeply the mechanical relationship between microscopic particles and the experimental environment in the granulation process, which is helpful for theoretical exploration, permitting the formulation of effective control
Application of Quality by Design (QbD) in HSWG process control
QbD provides a systematic approach to understanding the source of formulation and process variables, and for implementing effective process control. Its development and promotion in the pharmaceutical field were mainly the result of the report “Pharmaceutical Quality for the 21st Century: A Risk Based Approach” issued by the FDA in 2004 [218]. Since then, pharmaceutical guidelines on QbD have been issued successively, such as the International Conference on Harmonization (ICH) documents Q8–Q12 [
Conclusion and future challenges
HSWG is a sophisticated and widely used granule design technology in the pharmaceutical industry, with many advantages, as shown by a considerable proportion of oral solid dosage forms manufactured using this process that are authorized for marketing. Nevertheless, it is often regarded as an art rather than a science because of the large number of process variables, which make it difficult to achieve the desired properties of the target products [10]. Therefore, it is important to improve our
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References (237)
- et al.
Model-based analysis of high shear wet granulation from batch to continuous processes in pharmaceutical production–a critical review
Eur. J. Pharm. Biopharm.
(2013) - et al.
The effect of binder concentration and dry mixing time on granules, tablet characteristics and content uniformity of low dose drug in high shear wet granulation
Journal of Drug Delivery Science and Technology
(2017) - et al.
Scale-up of a high shear wet granulation process using a nucleation regime map approach
Particuology
(2017) - et al.
Characterisation of granule structure and strength made in a high shear granulator
Powder Technol.
(2009) - et al.
Statistical analysis and comparison of a continuous high shear granulator with a twin screw granulator: effect of process parameters on critical granule attributes and granulation mechanisms
Int. J. Pharm.
(2016) - et al.
Measurement of the axial dispersion coefficient of powders in a rotating cylinder: dependence on bulk flow properties
Powder Technol.
(2016) - et al.
Process analytical tools for monitoring, understanding, and control of pharmaceutical fluidized bed granulation: a review
Eur. J. Pharm. Biopharm.
(2013) - et al.
Possibility of monitoring granulation by analyzing the amount of hydroxypropylcellulose, a binder on the surface of granules, using ToF-SIMS
Int. J. Pharm.
(2015) - et al.
Real-time assessment of granule densification in high shear wet granulation and application to scale-up of a placebo and a brivanib alaninate formulation
J. Pharm. Sci.
(2015) - et al.
A new approach to high-shear mixer granulation using positron emission particle tracking
Chem. Eng. Sci.
(2011)