Research on the influences of binders on high shear wet granulation and tablet quality

Solid oral dosage forms remain the preferred dosage forms because of their convenience, inexpensive production costs, non-sterile manufacturing, and high patient compliance [1]. Tablets account for approximately 90% of all oral solid dosage forms, and 40% of tablets are produced through a wet granulation intermediate step [2], [3]. In the production of tablets, wet granulation is the most commonly used process since it achieves all the characteristics required for compression, such as good flowability, proper compactibility, and uniform drug distribution [4]. And wet granulation is mainly classified into four types: (i) high shear wet granulation (HSWG), (ii) fluid-bed granulation, (iii) twin-screw granulation, and (iv) melt fluid-bed granulation [3], [5], [6], [7]. Among them, HSWG has the advantages of high efficiency, low energy consumption, being pollution-free and fully enclosed, mixing and granulation integration, and also improves the properties of the granules (e.g., flowability, filler, etc.) as well as tablet properties, such as suitable compactibility. All of these make it a widely used granulation technology at present [8], [9], [10], [11], [12]. In the HSWG process, selecting a suitable binder to agglomerate the powder with the diluent is crucial. In general, the secondary properties of the binder, such as viscosity and glass transition temperature (T_g), resulting from the underlying physicochemical properties such as the chemical structure of the binder and the morphology of the microparticles, will affect the properties of the granules (e.g., granules strength, granules growth, and granules size) [13]. Meanwhile, binder concentration has a significant effect on granules flowability, disintegration time (DT) and tensile strength (TS) of tablets as well as particle size and porosity of granules [14], [15]. In addition, different types and amounts of binder will also affect downstream processing possibilities such as compactibility and DT of tablets. Therefore, an improved understanding of binders is essential for a more effective formulation design for the high shear wet granulation and tableting (HSWG-T).

At present, some studies have reported the impact of binder on granule properties for the HSWG process. For example, Willecke et al. investigated the effect of binders and diluents on product quality using the principal component analysis (PCA) method [16]. The result indicated that the binder properties, such as viscosity and wettability, affected granule quality. However, the amount of binder in the experimental design was not included in the examination [16]. Similarly, Morkhade et al. investigated the effect of different binder solutions and their additions on the granules and tablet attributes by HSWG-T [17]. And the result showed that the granules prepared with polyvinylpyrrolidone (PVP) as a binder were rounder and more brittle than those prepared with hydroxypropyl methylcellulose (HPMC) [17]. Furthermore, Koster et al. compared the effect of molecular weight and liquid-solid ratio (L/S) of six binders on granules in twin-screw wet granulation and found that an increase in the L/S led to an increase in particle size [18]. Although the type of binders selected in this study was comprehensive, the effect of binders on the texture properties of wetting mass, functional properties of the granules, and tablet quality was not examined. In general, these studies revealed that binder type and L/S affect both granule quality during HSWG and downstream processing of tablet. The binders can improve the consolidation of granules and the uniform distribution of APIs during the HSWG-T process. Whether the type of binder or L/S significantly affects the texture properties of wetting mass, and the basic and functional properties of the granules further affect the tablet quality during HSWG-T of herbal extracts as model drugs. Therefore, the effect of different binders on HSWG and tablet quality needs to be further evaluated.

In light of the above, the current study selected the Eucommia ulmoides Oliv. extract powder as a model drug and microcrystalline cellulose (MCC101) as a diluent. Aqueous solutions of six different types of polymers, i.e., copovidone S-630 (PVP/VA S-630), povidone K30 (PVP K30), povidone K90 (PVP K90), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose E5 (HPMC E5), and hydroxypropyl methylcellulose E15 (HPMC E15), were used as the binder to produce granules via HSWG, and these granules were compressed into tablets. Meanwhile, the properties of the binder (e.g., viscosity and surface tension), the texture properties of wetting mass (e.g., hardness, adhesiveness, and cohesiveness), and the granules’ fundamental properties (e.g., particle size, flowability) and functional properties (e.g., compressibility, compactibility, fragmentation, and rearrangement) were systematically investigated. In addition, the tablet quality was analyzed for TS, DT, and friability. Ultimately, PCA and partial least squares (PLS) analyses were performed using the SIMCA 14.1 software to elucidate the effects of different binders and L/S for HSWG and tablet quality.

The Eucommia ulmoides Oliv. extract (Xinyang Shi Mufan Biological Technology Co., Ltd, Xinyang, China) was prepared according to the procedure described in the Chinese Pharmacopoeia (2020 edition). MCC PH 101 was supplied by DFE Pharma (Goch, Germany). PVP/VA S-630, PVP K30, PVP K90, and HPC were supplied by Ashland Pharma (Kentucky, America). HPMC E5 and HPMC E15 were supplied by Anhui Shanhe Pharmaceutical Excipient Co.