The influence of milling of ribbons on selected granule quality attributes and carvedilol release from roller-compacted hypromellose-based matrix tablets

Roller compaction is gaining importance in the pharmaceutical industry. This study evaluates the impact of ribbon milling conditions on properties of granules and compression mixtures and on drug release from hypromellose-based matrix tablets prepared with two different fillers. In the first part of the study, design of experiments (DoE) was utilized to investigate the effect of filler type (lactose and microcrystalline cellulose (MCC)), mill type (oscillating, conical and hammer mill), milling speed and the size of screen apertures on selected attributes (granule particle size distribution (PSD), porosity and shape), and on the compressibility and compactibility of compression mixtures. The effect of DoE factors and selected attributes on the release of carvedilol at different timepoints of the release profile (t = 1–7 h) was further assessed. The study showed that drug release was affected by filler type, mill type, and various attributes; however, their effect proved to be complex and strongly related to granule PSD. Therefore, this effect was minimized in the second part of the study, in which tablets containing the same amount of different particle size fractions of granules were prepared with different mills and fillers. The drug release profiles confirmed that drug release is mainly related to differences in filler type and granule PSD. However, they indicate that with lactose mill type also affected drug release, possibly due to differences identified in particle shape.

Introduction

The importance of roller compaction has been growing recently [1,2]. It is a simple, continuous, energy-efficient, and environmentally friendly technological process that is suitable for a broad spectrum of ingredients, including heat- and moisture-sensitive active pharmaceutical ingredients and excipients [[3], [4], [5], [6], [7], [8], [9]]. During roller compaction, the powder mixture is compacted into ribbons by two counterrotating rolls. The ribbons are further milled to obtain granules, which are incorporated into tablets or capsules. The effects of roller compaction process parameters, such as roll speed, roll pressure, and gap width on granule properties, has been reported in several studies [3,4,8,10]. On the other hand, the effect of milling parameters has been investigated less often, even though it has a major impact on granule properties. Namely, the milling process significantly affects particle size distribution (PSD), which is one of the critical quality attributes of the granulate that can influence the manufacturability and quality of the final product [4,5,8,11]. The PSD of the granulate can also have a major influence on drug release from sustained release tablets obtained with roller compaction [12,13]. The use of roller compaction is also beneficial in manufacturing formulations containing the hydrophilic matrix-forming polymer hypromellose. It can overcome problems associated with other conventional technologies, such as inconsistent drug release profiles due to uneven wetting during wet granulation or content uniformity and flowability issues that may occur when using direct compression [14,15]. Nevertheless, only a few studies have examined the use of roller compaction in manufacturing hypromellose-based matrix tablets. These studies have mostly focused on manufacturability and the effect of various formulation and process parameters on drug release [13,[16], [17], [18], [19]]. None of the studies have examined the effect of the type of mill and milling process parameters on granule and tablet properties.

The number of studies that have examined the effect of milling on the granule properties of immediate release formulations is also limited. Vendola and Hancock [20] compared the effect of milling with a conical mill, oscillating granulator, hammer mill, and roller mill on two formulations. Their study showed that the mill type and PSD did not have a significant impact on the compactibility of tablets. On the other hand, Samanta [21] focused on the effect of conical screen milling parameters on granule characteristics and demonstrated that the type of impeller and the screen have the greatest influence on granule PSD. Sakwanichol et al. [22] investigated properties of granules obtained with an oscillating mill and a roller mill. They showed that different milling parameters affect PSD and flowability; however, they did not observe major differences in the granule properties obtained with both mills. Perez-Gandrillaz et al. [23] further compared different settings for rotating and oscillating motion of the rotor integrated in the milling chamber of the roller compactor. They studied the combined effects of roller compaction process parameters and milling conditions on the amount of fines and tensile strength of tablets. They concluded that the effect of milling was less pronounced than the effect of roller compaction process parameters, and that milling did not have a major effect on the tensile strength of the tablets. However, all the aforementioned studies were carried out on placebo formulations for immediate-release tablets. Therefore, none of the studies examined the formulation and milling effects on prolonged-release formulation, which was the basis of this study.

This study investigated the impact of milling conditions on drug release from hypromellose-based matrix tablets prepared with two different fillers. The goal was to examine whether different milling mechanisms of different mill types have an impact on granule properties and consequently on the release of carvedilol from hypromellose-based matrix tablets, which has not been demonstrated so far. In the first part of the study, design of experiments (DoE) was utilized to statistically evaluate the effect of four categorical factors on selected granule quality attributes and drug release. Filler type and screen aperture sizes were investigated at two levels; that is, granules were prepared with two different fillers: microcrystalline cellulose (MCC), a plastically deforming material, and lactose, which deforms predominantly by fragmentation. In the milling of roller-compacted ribbons, two screen sizes were utilized. In addition, milling was performed using three preselected milling speeds (low, medium, and high). The mill type was assessed at three levels. Three milling devices with different predominant milling mechanisms were selected to study the effect of the mill type: an oscillating, conical, and hammer mill. In an oscillating mill deformation occurs through shear forces; in a conical mill with a round knife, compression occurs during milling; and in a hammer mill reduction of particle size is based on impact between the particles with each other and with the rotor. In the second part of the study, six batches of tablets were manufactured, containing the same amount of different particle size fractions of granules prepared with both fillers and all three mill types. The aim of this part of the study was to further investigate the influence of the filler type and mill type on drug release with a minimized effect of granule size on drug release results.

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Raw Materials

Prolonged-release matrix tablets, which were developed within this study, contained 25 mg of carvedilol (provided by Krka, d.d., Novo mesto, Slovenia), that was used as a model drug. The formulation also contained matrix-forming polymer hypromellose (METHOCEL™, K4M Premium CR grade, Colorcon, USA), lactose monohydrate 200 mesh (DFE Pharma, Germany) or MCC (CEOLUS™ KG802, Asahi Kasei Corporation, Japan) as fillers, magnesium stearate (Faci SpA, Italy) as a lubricant and colloidal silicon dioxide

Aleša Dular Vovko, Tjaša Slak, Zvone Simončič, Franc Vrečer, Grega Hudovornik, The influence of milling of ribbons on selected granule quality attributes and carvedilol release from roller-compacted hypromellose-based matrix tablets,
Journal of Drug Delivery Science and Technology, Volume 98, 2024, 105882, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2024.105882.

Read also our introduction article on Magnesium Stearate here: