The use of positron emission particle tracking (PEPT) to study milling of roll-compacted microcystalline cellulose ribbons

© 2015. Milling is a critical process for controlling the properties of the granules produced by roll compaction. In the current study, the positron emission particle tracking (PEPT) technique was used to examine the milling kinematics of roll-compacted ribbons at various milling speeds. Microcrystalline cellulose (MCC, Avicel PH-102) was used as the model feed material and a radioactive particle (tracer) was mixed with the MCC powder and roll-compacted to form sample ribbons. They were then milled using an oscillating mill at various speeds and the kinematics of the ribbons (trajectory, velocity, and occupancy) were quantitatively determined using PEPT. A close examination of the PEPT data reveals that, for milling MCC PH-102 ribbons using the oscillating mill considered in this study, the milling speed plays an important role: at low values, the milling process is dominated by cooperative motion of the ribbons with the blade (i.e. the speeds of the ribbons and the blade are similar, and the ribbons move along with the blade) and the ribbons are milled primarily by abrasion; as the speed increases the ribbons undergo more random motion involving collisions that results in an increase in ribbon breakage and hence an increase in the milling efficiency. It is shown that the PEPT technique is a useful technique for examining milling kinematics of roll-compacted ribbons

INDUSTRIAL CASE STUDY ON APPLICATION OF ROLLER COMPACTION MODELLING FOR SCALE UP AND TECHNOLOGY TRANSFER

Dry granulation of pharmaceutical powders by the roller compaction process is gaining increasing popularity in the pharmaceutical industry for its simplicity, cost, potential stability benefits and continuous processing options. The Johanson model for dry granulation process by roller compaction is well established in the scientific literature. Its applicability and limitations have been demonstrated. In this work we focus on the application of the model in an industrial environment and highlights how the application of roller compaction modelling in combination with experimental data can guide the successful scale up and equipment transfer. This work is focused on how the model can inform the DoE design and decision-making process to set parameters and choose operating ranges. In this work, the pilot phase data (Bepex with roll width 30 cm without vacuum de-aeration) was used to model the roller compaction force range on a commercial scale (Bepex with roll width 50 cm with vacuum de-aeration) using the relationship between Pmax and porosity. The predictions helped to establish a good roller compaction process parameter range with wider range for roller compaction force and roll gap, which enabled the production of tablets without work hardening effects and good tablet quality, meeting all the in-process control specifications resulting in free-flowing and compactible granules. These granules ensure that there are no tablet defects such as capping, lamination and sticking. This work demonstrates potential applicability of mechanistic modelling using Johanson model for scale-up from lab scale to commercial roller compaction process settings

COMPARATIVE ANALYSIS OF POROSITY MEASUREMENT TECHNIQUES USING PHARMACEUTICAL MATERIALS

Roller compaction or dry granulation is one of the techniques used to improve the flow properties of pharmaceutical materials where direct compaction of tablets is not possible. It is often preferred over wet granulation due to faster processing times, handling moisture sensitive compounds and lower energy consumption. Ribbons are produced during roller compaction and ribbon porosity is considered a critical intermediate attribute. Ribbon porosity measurements are often used to scale-up, transfer processes and validate roller compactor modelling and simulations. Various ribbon porosity measurement techniques exist, each with it is own advantages and challenges. The most used techniques in the pharmaceutical industry for ribbon porosity measurements are envelope volume using the Geopyc technique, mercury porosimeter and X-ray Microtomography. However, there are ongoing research activities to find innovative techniques which are simple, faster, non-destructive, precise and accurate. In this study, the Laser triangulation technique is used for the evaluation of the ribbon porosity and results are compared with the commonly used technique for comparison of the results and its suitability as an at-site measurement technique. In the initial experiments, riblets were manufactured using a Stylone compaction simulator using Microcrystalline Cellulose (MCC) as the model excipient. In this investigation, ribbons were produced using commercially available roller compactors namely Gerteis Minipactor and Bepex Pharmapactor. Ribbons were manufactured using a roller compactor using MCC for further evaluation of the techniques. Experimental compound A was used in the active formulation and further studies were carried out in pilot and launch scales to generate ribbons for further comparison of the technique and assess the suitability of each measuring technique to quantify the porosity data. This paper discusses in detail the importance of the roller compaction process and ribbon porosity as critical intermediate material attributes, different porosity measurement techniques, results obtained and comparative analysis of the data generated

Effect of particle size on the dispersion behavior of magnesium stearate blended with microcrystalline cellulose.

The majority of tablets manufactured contain lubricants to reduce friction during ejection. However, especially for plastically deforming materials, e.g., microcrystalline cellulose (MCC), the internal addition of lubricants is known to reduce tablet tensile strength. This reduction is caused by the surface coverage by lubricant particles, the extent of which depends on both process and formulation parameters. Previously published models to predict the lubrication effect on mechanical strength do not account for changes in the excipient particle size. In this study, the impact of both lubricant concentration and mixing time on the tensile strength of tablets consisting of three different grades of MCC and four grades of magnesium stearate (MgSt) was evaluated. By taking into account the particle size of the applied excipients, a unifying relationship between the theoretically estimated surface coverage and compactibility reduction was identified. Evaluating the dispersion kinetics of MgSt as a function of time reveals a substantial impact of the initial surface coverage on the dispersion rate, while the minimal tensile strength was found to be comparable for the majority of formulations. In summary, the presented work extends the knowledge of lubricant dispersion and facilitates the reduction of necessary experiments during the development of new tablet formulations

The effects of lubrication on roll compaction, ribbon milling and tabletting

Lubricants are commonly used in the pharmaceutical industry to prevent adhesion and improve the efficiency of roll compaction and tabletting. The aim of the current work is to develop an improved understanding of the mechanisms involved. Two commonly used pharmaceutical excipients, microcrystalline cellulose (MCC) and di-calcium phosphate dihydrate (DCPD), were selected as the model feed powders with magnesium stearate (MgSt) as the lubricant. An instrumented roll compactor was used, the ribbons were milled using an oscillating mill and the granules were compressed into tablets. The wall and internal friction angles of the feed powders were measured and related to the performance of the roll compaction that was characterised by the nip angle and maximum pressure. The milling performance was related to the fracture energy of the ribbons. The tabletting was assessed by the density and strength of the tablets. A qualitative interpretation of the data was developed and the practical implications of the work are considered. It was also shown that the bulk lubrication results in the reduction in internal friction for MCC but not for DCPD. The wall friction of DCPD is reduced by both bulk and wall lubrication unlike MCC for which the friction coefficient is essentially unchanged. The behaviour of the powders in roll compaction can be ascribed to the variation of the frictional properties due to lubrication. It is found that wall lubrication does not affect either the nip angle or the maximum roll pressure during roll compaction of MCC, but for DCPD the nip angle and maximum pressure are reduced with wall lubrication. In addition, the nip angle and the maximum pressure during roll compaction of MCC and DCPD are reduced with bulk lubrication. Furthermore, bulk lubrication causes reduction in the bonding properties and hence the tensile strength for MCC, but not for DCPD.</p

Enhanced multi-component model to consider the lubricant effect on compressibility and compactibility.

Modeling of structural and mechanical tablet properties consisting of multiple components, based on a minimum of experimental data is of high interest, in order to minimize time- and cost-intensive experimental trials in the development of new tablet formulations. The majority of commonly available models use the compressibility and compactibility of constituent components and establish mixing rules between those components, in order to predict the tablet properties of formulations containing multiple components. However, their applicability is limited to single materials, which form intact tablets (e.g. lactose, cellulose) and therefore, they cannot be applied for lubricants. Lubricants are required in the majority of industrial tablet formulations and usually influence the mechanical strength of tablets. This study combines the multi-component compaction model of Reynolds et al. (2017) with a recently published lubrication model (Puckhaber et al. 2020) to describe the impact of multiple components on a formulation consisting of two diluents and a lubricant. By that, this model combination displays a meaningful extension of existing compaction models and allows the systematic prediction of properties of lubricated multi-component tablets

Design Space Estimation of the Roller Compaction Process

Roller compaction (RC) is a continuous process for solid dosage form manufacturing within the pharmaceutical industry achieving similar goals as wet granulation while avoiding liquid exposure. From a quality by design perspective, the aim of the present study was to demonstrate the applicability of statistical design of experiments (DoE) and multivariate modeling principles to identify the Design Space of a roller compaction process using a predictive risk-based approach. For this purpose, a reduced central composite face-centered (CCF) design was used to evaluate the influence of roll compaction process variables (roll force, roll speed, gap width, and screen size) on the different intermediate and final products (ribbons, granules, and tablets) obtained after roll compaction, milling, and tableting. After developing a regression model for each response, optimal settings were found which comply with the response criteria. Finally, a predictive risk based approach using Monte Carlo simulation of the factor variability and its influence on the responses was applied which fulfill the criteria for the responses in a space where there is a low risk for failure. Responses were as follows: granule throughput, ribbon porosity, granules particle size, and tablets tensile strength. The multivariate method orthogonal partial least-squares (OPLS) was used to model product dependencies between process steps e.g. granule properties with tablet properties. Those results confirmed that the tensile strength reduction, known to affect plastic materials when roll compacted, was not prominent when using brittle materials. While direct compression qualities are frequently used for roll compacted drug products because of their excellent flowability and good compaction properties, this study confirmed earlier findings that granules from these qualities were more poor flowing than the corresponding powder blend

Ten years of the manufacturing classification system: a review of literature applications and an extension of the framework to continuous manufacture

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent