Comparative Evaluation of the Powder and Tableting Properties of Regular and Direct Compression Hypromellose from Different Vendors

Hypromellose, a widely used polymer in the pharmaceutical industry, is available in several grades, depending on the percentage of substitution of the methoxyl and hydroxypropyl groups and molecular weight, and in various functional forms (e.g., suitable for direct compression tableting). These differences can affect their physicomechanical properties, and so this study aims to characterise the particle size and mechanical properties of HPMC K100M polymer grades from four different vendors. Eight polymers (CR and DC grades) were analysed using scanning electron microscopy (SEM) and light microscopy automated image analysis particle characterisation to examine the powder’s particle morphology and particle size distribution. Bulk density, tapped density, and true density of the materials were also analysed. Flow was determined using a shear cell tester. Flat-faced polymer compacts were made at five different compression forces and the mechanical properties of the compacts were evaluated to give an indication of the powder’s capacity to form a tablet with desirable strength under specific pressures. The results indicated that the CR grades of the polymers displayed a smaller particle size and better mechanical properties compared to the DC grade HPMC K100M polymers. The DC grades, however, had better flow properties than their CR counterparts. The results also suggested some similarities and differences between some of the polymers from the different vendors despite the similarity in substitution level, reminding the user that care and consideration should be given when substitution is required.

1. Introduction

Hypromellose (hydroxypropyl methylcellulose, HPMC) is a non-ionic, semi-synthetic, inert, viscoelastic hydrophilic polymer existing as a creamy white powder that is tasteless and odourless [1]. It is composed of o-methylated and o-(2-hydroxyl propylated) cellulose, produced from treating alkali cellulose with propylene oxide and chloromethane. Various grades of HPMC are available with differences in their methoxyl and hydroxypropoxyl substitution, viscosity, molecular weight, and particle size distribution. Differences in the percentages of methoxyl and hydroxypropoxyl groups provide for the grade name (e.g., “K” or “E”) or equivalent substitution type (2208 or 2910, respectively) describing the polymer [2]. HPMC is the most widely used cellulose ether in the pharmaceutical industry and has been used as a tablet disintegrant, binder, viscosity-increasing agent, and in extended-release (ER) technology [3,4,5]. It is also used as a suspending and thickening agent in liquid pharmaceuticals [6].

Particle size is one of the essential factors of a material or formulation that can affect the mechanical strength of tablets produced from them. A decrease in the particle size of the powder may result in an increase in tablet tensile strength, especially for plastically deforming materials. Generally, a small particle size allows for a high surface area for bonding, resulting in increased tensile strength under equivalent compaction conditions relative to larger particles. Large particles, which deform via plastic deformation, tend to make weaker tablets compared to small particles, but for brittle materials, this may be less pronounced due to particle fracture under applied pressure creating a new surface for bonding [7].

It is also suggested that compressibility profile, tensile strength, and elastic recovery are affected significantly by the particle size of the HPMC polymer, as it exhibits plastic deformation under compaction [8]. Additionally, powder surface area and particle shape were more important than the degree of the substitution in respect of the compaction behaviour of the polymers [9]. The effect of viscosity grades on the profile of drug release and compaction behaviour has also been investigated. It was observed that the highest viscosity grade polymer studied (HPMC K100M) formed tablets with higher tensile strength compared to the other viscosity grades of the same polymer [10]. It was confirmed that at compression speeds between 15 to 500 mm/s and different compression forces between (5 to 20 kN), HPMC K100M was the more compressible polymer of those studied due to its plasticity in comparison to other grades evaluated [10].

Investigations into the compaction and flow properties of different HPMC grades have confirmed that all non-direct compression grades of HPMC polymers display poor to very poor flowability compared to their direct compression (DC) grades, which showed better flowability due to it having a more rounded, smoother surface and larger particle size [6]. The DC grades of HPMC are made in different processes. According to the Dow Chemical Company, Methocel DC2 polymer is prepared by a process in which the polymer particles are physically modified to reduce fines and enhance the spherical nature of the particles, helping to improve the direct compression process by optimising the powder’s flowability whilst maintaining the other important properties of their controlled-release Methocel regular (CR) grade counterpart [6]. The Ashland Chemical Company manufactures its Benecel DC grade via a co-processing process. Here, the HPMC is co-processed to coat it with silicon dioxide to improve the flowability of the polymer [11,12,13]: the properties of different viscosity grades of this specific DC material have been described relative to the regular material from this manufacturer [12]. Co-processing of MCC with silicon dioxide has been shown to improve the flow and also the compressibility of that material, so it may be logical to consider that it could do so for HPMC [14,15].

The high molecular weight K (HPMC 2208, USP) and E (HPMC 2910, USP) chemistries are frequently used polymers in ER matrix formulations [16] and hence this research focuses on the K chemistry grade of HPMC, specifically the 100,000 mPa.s (K100M) viscosity grades, because they may be preferred in extended-release hydrophilic matrix tablets [17]. Here, the K100M chemistry grades from four different vendors are investigated. Furthermore, the DC counterpart grades, where available, are also investigated to determine if their properties associated with tablet manufacture are equivalent to those for the related CR grades.

It is imperative to ensure that the sources of raw excipients used in manufacturing provide materials of essentially the same characteristics to ensure that the manufacturing process is sufficiently robust to incorporate materials from different sources. This is a key part of quality by design (QbD) and is also necessary for a robust business process. Having only a single source of a material makes a process vulnerable to supply chain shocks, such as the sudden absence from the market of a preferred vendor source.

It is with this motive that the research described in this paper aims to extend prior work to determine if the K100M HPMC grades from different suppliers can be considered to be interchangeable with respect to the drug product manufacturing process. Given that chemistry and viscosity grades are equivalent, it could be considered that the polymer hydration and consequent drug release rate will be equivalent, hence, that behaviour has not been investigated in this work. Recently, the mechanical properties of HPMC from K4M and K100M from three vendors have been investigated, with a focus on compression speed [18]. The DC and CR grades were investigated for one vendor only (Methocel grades of K4M and K100M). The authors found the Benecel and Methocel K100M grades had the best compaction properties [18]. The material attributes of HPMC from two different vendors with a focus on viscosity grades (K4M, K15M, and K100M) have also been explored. Using principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA), the powder and tableting properties were recognised as the differential material attributes for the HPMC samples studied [19].

In this present study, we have investigated similarities and differences between the K100M HPMC grades from four different vendors as well as the different grades of the same polymer from the same supplier (such as DC, CR, and XR) by probing properties such as their flow, compactability, mechanical strength, and an in-depth analysis of their particle properties. This is to ultimately inform a formulator with regard to potential interchangeability between the various grades.

2.1. Materials

HPMC 2208 100,000 mPa.s materials were kindly provided by Colorcon Ltd., Kent, UK (Methocel^TM K100M CR and DC2, referred to as DC from henceforth); Ashland Industries Europe GmbH, Schaffhausen, Switzerland (Benecel^TM K100M PH DC, Benecel^TM K100M PHARM CR and Benecel^TM K100M PHARM XR); Biogrund GmbH, Neukirchner, Hünstetten, Germany (BonuCel^® D 100000 H 2208); and Shin-Etsu Chemical Co., Ltd., Tokyo, Japan (Metolose^® 90SH-100000 and Metolose^® 90SH-100000SR). Materials obtained were typical commercial materials, not specially selected lots, and so were considered representative materials from each vendor for comparative purposes. Exploring lot-to-lot variability from each vendor was not within the scope of the current study.

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Mawla, N.; Alshafiee, M.; Gamble, J.; Tobyn, M.; Liu, L.; Walton, K.; Conway, B.R.; Timmins, P.; Asare-Addo, K. Comparative Evaluation of the Powder and Tableting Properties of Regular and Direct Compression Hypromellose from Different Vendors. Pharmaceutics 2023, 15, 2154.
https://doi.org/10.3390/pharmaceutics15082154

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