Gavin K. Reynolds

A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms

Abstract This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the “right particles” are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience. This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.

Practical application of roller compaction process modeling

Abstract Very limited work has been reported on comparing the performance of the roller compaction process at different scales. The majority of the approaches highlighted in the literature discuss the applicability of using confined uniaxial compaction for predicting the performance of the roller compaction process. In this paper a method was developed that allows the rolling theory of granular solids developed by Johanson [Johanson, J. R. (1965). A rolling theory for granular solids. ASME, Journal of Applied Mechanics Series E, 32(4), 842–848] to be used to infer the underlying material parameters from small-scale roller compaction experiments for both separation controlled or screw controlled configurations. Once these parameters are determined, the model can be used for predictive process design and scale-up in order to achieve target outputs such as ribbon density and throughput. The peak pressure, predicted by the model, can also be used to present roller compaction of a given formulation from a scale-independent perspective. This approach can be used to justify process parameter and equipment flexibility in the context of a pharmaceutical design space based on a proven acceptable range of peak pressures, or achieving target intermediate quality attributes, such as ribbon density.

Mechanistic Insights into the Dissolution of Spray-Dried Amorphous Solid Dispersions

We have investigated the dissolution mechanisms of spray-dried amorphous solid dispersions of the poorly water-soluble drug felodipine and the water-soluble polymer copovidone using a new combined spectrophotometric and magnetic resonance imaging technique and a mathematical modelling approach. Studies of the dissolution rates of both uncompacted and compacted solid dispersions revealed that compaction leads to a significant decrease in the rate and extent of dissolution and a strong dependence on drug loading, especially for the uncompacted samples. Low drug-loaded compacts [5% and 15% (w/w) felodipine] eroded with linear kinetics at identical rates, pointing to matrix control, whereas for compacts containing a higher proportion of felodipine (≥ 30%, w/w), dissolution performance was dominated by the drug. In these cases, felodipine concentrations were extremely low and the compact swelled rather than eroded. We have developed a mathematical population balance framework to model the processes of particle release, dissolution and crystal growth. This was found to accurately describe the bell-shaped dissolution profiles observed for the compacts containing a low felodipine loading.

Mechanistic modeling of modular co-rotating twin-screw extruders

In this study, we present a one-dimensional (1D) model of the metering zone of a modular, co-rotating twin-screw extruder for pharmaceutical hot melt extrusion (HME). The model accounts for filling ratio, pressure, melt temperature in screw channels and gaps, driving power, torque and the residence time distribution (RTD). It requires two empirical parameters for each screw element to be determined experimentally or numerically using computational fluid dynamics (CFD). The required Nusselt correlation for the heat transfer to the barrel was determined from experimental data. We present results for a fluid with a constant viscosity in comparison to literature data obtained from CFD simulations. Moreover, we show how to incorporate the rheology of a typical, non-Newtonian polymer melt, and present results in comparison to measurements. For both cases, we achieved excellent agreement. Furthermore, we present results for the RTD, based on experimental data from the literature, and found good agreement with simulations, in which the entire HME process was approximated with the metering model, assuming a constant viscosity for the polymer melt.

Granulation of increasingly hydrophobic formulations using a twin screw granulator.

The application of twin screw granulation in the pharmaceutical industry has generated increasing interest due to its suitability for continuous processing. However, an understanding of the impact of formulation properties such as hydrophobicity on intermediate and finished product quality has not yet been established. Hence, the current work investigated the granulation behaviour of three formulations containing increasing amounts of hydrophobic components using a Consigma™-1 twin screw granulator. Process conditions including powder feed rate, liquid to solid ratio, granulation liquid composition and screw configuration were also evaluated. The size of the wet granules was measured in order to enable exploration of granulation behaviour in isolation without confounding effects from downstream processes such as drying. The experimental observations indicated that the granulation process was not sensitive to the powder feed rate. The hydrophobicity led to heterogeneous liquid distribution and hence a relatively large proportion of un-wetted particles. Increasing numbers of kneading elements led to high shear and prolonged residence time, which acted to enhance the distribution of liquid and feeding materials. The bimodal size distributions considered to be characteristic of twin screw granulation were primarily ascribed to the breakage of relatively large granules by the kneading elements.

The combined effect of wet granulation process parameters and dried granule moisture content on tablet quality attributes.

A pharmaceutical compound was used to study the effect of batch wet granulation process parameters in combination with the residual moisture content remaining after drying on granule and tablet quality attributes. The effect of three batch wet granulation process parameters was evaluated using a multivariate experimental design, with a novel constrained design space. Batches were characterised for moisture content, granule density, crushing strength, porosity, disintegration time and dissolution. Mechanisms of the effect of the process parameters on the granule and tablet quality attributes are proposed. Water quantity added during granulation showed a significant effect on granule density and tablet dissolution rate. Mixing time showed a significant effect on tablet crushing strength, and mixing speed showed a significant effect on the distribution of tablet crushing strengths obtained. The residual moisture content remaining after granule drying showed a significant effect on tablet crushing strength. The effect of moisture on tablet tensile strength has been reported before, but not in combination with granulation parameters and granule properties, and the impact on tablet dissolution was not assessed. Correlations between the energy input during granulation, the density of granules produced, and the quality attributes of the final tablets were also identified. Understanding the impact of the granulation and drying process parameters on granule and tablet properties provides a basis for process optimisation and scaling.

Linking Dissolution to Disintegration in Immediate Release Tablets Using Image Analysis and a Population Balance Modelling Approach

ABSTRACTPurposeIn order to achieve an improved understanding of disintegration and dissolution phenomena for an immediate release tablet formulation, a technique to monitor the number and size of particles entrained within the dissolution media was developed in combination with a population balancing model.MethodsTablets were first characterized for crushing force, disintegration time and dissolution performance using standard USP methodologies. The performance of the tablets was then assessed using a new measurement system which links a “QicPic” particle imaging device to a USP dissolution vessel. This system enables us to measure the number and size of particles generated during tablet dissolution. The population balance mathematical model allowed a tablet erosion rate to be manipulated to fit the experimental data.ResultsResults showed that tablets with differing crushing forces showed different dissolution behaviors that could be explained by differing rates of particle release into the dissolution media. These behaviors were then successfully modeled to provide a description of the dissolution and disintegration behavior of the tablets in terms of a tablet erosion rate.ConclusionsA new approach was developed that allowed the description of the dissolution behaviors of the tablets in terms of the rate that they release particles into solution. This was then successfully modeled in terms of a tablet erosion rate.

Investigating the effect of processing parameters on pharmaceutical tablet disintegration using a real-time particle imaging approach

Tablet disintegration is a fundamental parameter that is tested in vitro before a product is released to the market, to give confidence that the tablet will break up in vivo and that active drug will be available for absorption. Variations in tablet properties cause variation in disintegration behaviour. While the standardised pharmacopeial disintegration test can show differences in the speed of disintegration of different tablets, it does not give any mechanistic information about the underlying cause of the difference. With quantifiable disintegration data, and consequently an improved understanding into tablet disintegration, a more knowledge-based approach could be applied to the research and development of future tablet formulations. The aim of the present research was to introduce an alternative method which will enable a better understanding of tablet disintegration using a particle imaging approach. A purpose-built flow cell was employed capable of online observation of tablet disintegration, which can provide information about the changing tablet dimensions and the particles released with time. This additional information can improve the understanding of how different materials and process parameters affect tablet disintegration. Standard USP analysis was also carried out to evaluate and determine whether the flow cell method can suitably differentiate the disintegration behaviour of tablets produced using different processing parameters. Placebo tablets were produced with varying ratios of insoluble and soluble filler (mannitol and MCC, respectively) so that the effect of variation in the formulation can be investigated. To determine the effect of the stress applied during granulation and tableting on tablet disintegration behaviour, analysis was carried out on tablets produced using granular material compressed at 20 or 50bar, where a tableting load of either 15 or 25kN was used. By doing this the tablet disintegration was examined in terms of the tablet porosity by monitoring the tablet area and particle release. It was found that when 20 and 50bar roller compaction pressure was used the USP analysis showed almost identical disintegration times for the consequent tablets. With the flow cell method a greater tablet swelling was observed for the lower pressure followed by steady tablet erosion. Additionally, more particles were released during disintegration due to the smaller granule size distribution within the tablet. When a higher tableting pressure was applied the tablet exhibited a delay in the time taken to reach the maximum swelling area, and slower tablet erosion and particle release were also observed, largely due to the tablet being much denser causing slower water uptake. This was in agreement with the USP analysis data. Overall it was confirmed by using both the standard USP analysis and flow cell method that the tablet porosity affects the tablet disintegration, whereby a more porous tablet disintegrates more slowly. But a more in-depth understanding was obtained using the flow cell method as it was determined that tablets will swell to varying degrees and release particles at different rates depending on the roller compaction and tableting pressure used.

Chapter 1 High shear granulation

Publisher Summary There are typically four main types of wet-agitated granulating equipments, classified by the way the material is agitated: drum granulators, pan granulators, fluidized-bed granulators, and mixer granulators. Mixer granulators or high shear granulators have a wide range of applications in the pharmaceutical, agrochemical, and detergent industries. High shear granulators in general fall into two classes—namely, horizontal axis and vertical axis—and can be either continuously operated or batch operated. High shear granulators use an impeller to vigorously agitate the powder and produce high-density granules. They are commonly found in pharmaceutical, agrochemical, and detergent industries because of their ability to handle difficult feed formulations, including high viscosity binder fluids and fine cohesive powders. Impellers rotate at high speeds (between 100 and 1500 rpm) on either a vertical or horizontal axis to create the agitation required for granulation. Typically, a secondary smaller impeller called a “chopper” is used. This rotates at much higher speeds (around 1500 rpm). The role of the chopper in granulation is currently a matter of debate; it either fractures larger agglomerates or causes growth of smaller agglomerates, depending on the feed properties, operating conditions, and the geometry of the mixer, impeller, and chopper. Binder addition to high shear granulators can be in the form of a liquid spray or can be poured. For melted granulation, binder can be added as a solid to a preheated high shear granulator.

Chapter 21 Breakage in granulation

Publisher Summary The process of granulation is used in a wide range of industries, including mineral processing, agricultural products, detergents, pharmaceuticals, foodstuffs, and specialty chemicals. Typically, fine powders are agglomerated together to form larger particles, or granules. Granules generally have a variety of advantages over fine powders in that they flow well, pose lower environmental hazards, and dissolve or disperse better. This chapter discusses breakage in granulation from a number of different length scale perspectives. At the process scale, breakage is important in enhancing the material distribution and eventual strength of the product granules. Knowledge of how operating parameters and equipment design influence the breakage process can help to improve the properties of the granular products. Granulation in itself is a broad topic. In this case a granule, or agglomerate, refers to a body that consists of constituent particles held together. This chapter defines and discusses three generic types of granules. First, a binderless granule is described, whereby the constituent particles are held together by micro-scale forces, typically van der Waals forces. Second, a solid granule refers to a granule where the constituent particles are held together by solid bonds. Third, a wet granule is described as a granule which contains interstitial liquid. Although these three generic cases could all be described as granules, it is expected that they will exhibit different breakage behavior because of the different nature of the constituent particle bonding forces. At the process scale, studies using high-shear mixer granulators and fluidized-bed granulators are reviewed.