Mike Tobyn

Investigation into the impact of sub-populations of agglomerates on the particle size distribution and flow properties of conventional microcrystalline cellulose grades

Microcrystalline cellulose (MCC) is regarded as one of the most versatile tablet filler binders, finding a wide use in both granulation and direct compression operations. It has been shown that MCC particle populations consist of a mixture of ‘rod like’ primary particles, and agglomerates, and that the proportion of these primary particles and agglomerates differs within the different grades of materials, contributing to the different bulk properties of these materials. However, the proportion of primary particles and agglomerates has not previously been fully elucidated, and their contribution to the performance factors such as flow explained. In this paper we use a novel microscopy-based characterization technique to demonstrate that the proportion of ‘agglomerates’ in the series of MCC grades between PH101 and PH200 is, by number, very low, but sufficient to perturb a volume-based particle size method by significant amounts.

Physical Stability and Recrystallization Kinetics of Amorphous Ibipinabant Drug Product by Fourier Transform Raman Spectroscopy

The solid-state physical stability and recrystallization kinetics during storage stability are described for an amorphous solid dispersed drug substance, ibipinabant, at a low concentration (1.0%, w/w) in a solid oral dosage form (tablet). The recrystallization behavior of the amorphous ibipinabant-polyvinylpyrrolidone solid dispersion in the tablet product was characterized by Fourier transform (FT) Raman spectroscopy. A partial least-square analysis used for multivariate calibration based on Raman spectra was developed and validated to detect less than 5% (w/w) of the crystalline form (equivalent to less than 0.05% of the total mass of the tablet). The method provided reliable and highly accurate predictive crystallinity assessments after exposure to a variety of stability storage conditions. It was determined that exposure to moisture had a significant impact on the crystallinity of amorphous ibipinabant. The information provided by the method has potential utility for predictive physical stability assessments. Dissolution testing demonstrated that the predicted crystallinity had a direct correlation with this physical property of the drug product. Recrystallization kinetics was measured using FT Raman spectroscopy for the solid dispersion from the tablet product stored at controlled temperature and relative humidity. The measurements were evaluated by application of the Johnson-Mehl-Avrami (JMA) kinetic model to determine recrystallization rate constants and Avrami exponent (n = 2). The analysis showed that the JMA equation could describe the process very well, and indicated that the recrystallization kinetics observed was a two-step process with an induction period (nucleation) followed by rod-like crystal growth.

Formulation and process design for a solid dosage form containing a spray-dried amorphous dispersion of ibipinabant

Amorphous forms of poorly soluble drugs are more frequently being incorporated into solid dispersions for administration and extensive research has led to a reasonable understanding of how these dispersions, although still kinetically unstable, improve stability relative to the pure amorphous form. There remains however a paucity of literature describing the effects on such solid dispersions of subsequent processing into solid dosage forms such as tablets. This paper addresses this area by looking at the effects of the addition of common excipients and different manufacturing routes on the stability of a spray-dried dispersion (SDD) of the cannabinoid CB-1 antagonist, ibipinabant. A marked difference in physical stability of tablets was seen with the different fillers with microcrystalline cellulose (MCC) giving the best stability profile. It was found that minimising the number of compression steps led to improved formulation stability with a direct compression process giving the best results. Increased levels of crystallinity were seen in coated tablets most likely due to the exposure of the amorphous matrix to moisture and heat during the coating process. DSIMS analysis of the SDD particles indicated increased levels of polymer on the surface.

Monitoring and end-point prediction of a small scale wet granulation process using acoustic emission.

A study to establish if acoustic emission could be used to monitor a small scale (120 g batch size) high shear granulation process and predict the process end-point, is reported. The robustness of the prediction model was further assessed by changing process variables. It is demonstrated that the technique is capable of repeatedly producing granules with consistent physical characteristics, such as particle size distribution and bulk density, despite changes in batch size and liquid dose rates. It is demonstrated that the model was affected by changes in impeller speed such that it was unable to identify a process end-point.

Application of imaging based tools for the characterisation of hollow spray dried amorphous dispersion particles.

The aim of this study was to investigate novel approaches to determine spray dried dispersion (SDD) specific particle characteristics through the use of imaging based technologies. The work demonstrates approaches that can be applied in order to access quantitative approximations for powder characteristics for hollow particles, such as SDD. Cryo-SEM has been used to measure the solid volume fraction and/or particle density of SDD particles. Application of this data to understand the impact of spray drying process conditions on SDD powder properties, and their impact on processability and final dosage form quality were investigated. The use of data from a Morphologi G3 image based particle characterisation system was also examined in order to explain both the propensity and extent of attrition within a series of SDD samples, and also demonstrate the use of light transmission data to assess the relative wall thickness of SDD particles. Such approaches demonstrate a means to access potentially useful information that can be linked to important particle characteristics for SDD materials which, in addition to the standard bulk powder measurements such as bulk density, may enable a better understanding of such materials and their impact on downstream processability and final dosage form acceptability.

Multivariate analysis in the pharmaceutical industry: enabling process understanding and improvement in the PAT and QbD era.

Abstract In the pharmaceutical industry, chemometrics is rapidly establishing itself as a tool that can be used at every step of product development and beyond: from early development to commercialization. This set of multivariate analysis methods allows the extraction of information contained in large, complex data sets thus contributing to increase product and process understanding which is at the core of the Food and Drug Administration’s Process Analytical Tools (PAT) Guidance for Industry and the International Conference on Harmonisation’s Pharmaceutical Development guideline (Q8). This review is aimed at providing pharmaceutical industry professionals an introduction to multivariate analysis and how it is being adopted and implemented by companies in the transition from “quality-by-testing” to “quality-by-design”. It starts with an introduction to multivariate analysis and the two methods most commonly used: principal component analysis and partial least squares regression, their advantages, common pitfalls and requirements for their effective use. That is followed with an overview of the diverse areas of application of multivariate analysis in the pharmaceutical industry: from the development of real-time analytical methods to definition of the design space and control strategy, from formulation optimization during development to the application of quality-by-design principles to improve manufacture of existing commercial products.

Investigating the applicability of inverse gas chromatography to binary powdered systems: an application of surface heterogeneity profiles to understanding preferential probe-surface interactions.

The aim of this study was to investigate the applicability of surface energy characterization tools such as inverse gas chromatography for the analysis of binary systems. Drug substance was coated with two grades of silicon dioxide and the surface energy characteristics determined using a surface energy analyser. The results demonstrated that the measured dispersive surface energy of such intermediate samples were as a consequence of probe interactions with both constituent components, however, the degree and order of interaction with each species was related to surface energy heterogeneity and surface availability. A method to predict the degree of probe-surface preferentiality within the intermediate samples was applied to the data, demonstrating to closely match the measured data whilst suggesting notable differences in probe-surface preferentiality. Specific probe interactions were also assessed and the results suggested that probe surface preferentiality was not equivalent to that of the dispersive probes, possibly due to differences in ranges of the dispersive/specific forces. An equivalent physically mixed sample was analysed and the results demonstrated that the measured heterogeneity curve mirrored that of the pure drug substance suggesting that the driver for probe interaction is different for the physically mixed and the coated intermediate samples.

Application of external lubrication during the roller compaction of adhesive pharmaceutical formulations

A novel use of external lubrication has been investigated in which magnesium stearate was applied directly to the roll surface during roller compaction. A scalable parameter; travelling roll distance per shot (DpS), has been defined which ensures that an equal amount of magnesium stearate is applied to the roll surface per rotation at any roll speed. It was found that a formulation containing 20% w/w of either the API Pravastatin or Ibipinabant required a smaller DpS than a placebo formulation in order to prevent roll adherence. The inherent adhesiveness, and hence the required amount of external magnesium stearate to prevent roll adhesion, will depend on the material properties of the formulation. The amount of magnesium stearate transferred from the roll surface to the ribbon was measured using inductively coupled plasma optical emission spectroscopy and was found to be less than 0.01% w/w. This is a significant reduction in magnesium stearate compared to the normal manufacturing procedure of blending 0.25–2.0% w/w within the formulation.The advantage of external lubrication during roller compaction is the significant reduction in magnesium stearate from the formulation which could lead to the production of tablets with superior mechanical properties and faster dissolution times.

Application of image-based particle size and shape characterization systems in the development of small molecule pharmaceuticals.

With the introduction of Quality by Design (QbD) to the pharmaceutical industry, there has been an increased focus on understanding the nature of particles and composites, with the aim of understanding and modeling how they interact in complex systems, leading to robust dosage forms. Particle characterization tools have evolved and now enable a greater level of understanding of powder systems and blends. Tools that can elucidate the size and shape of particulate systems can provide significantly more information about the nature of the particles being analyzed, than a conventional particle size measurement. Although accurate size and shape analysis has always been regarded as the gold standard in understanding the nature of particulate systems, neither imaging systems nor IT infrastructure was sufficiently developed to allow this to be performed with sufficient accuracy in a timely manner. The aim of this review is to provide an insight into developments in the field of size and shape analysis of pharmaceutical systems, and how these can now realistically be used as robust development tools. Examples of current uses of such technologies will be explored as well as investigating future applications such as combined image/spectroscopic analyses to track single components within blended systems.

Monitoring process induced attrition of drug substance particles within formulated blends

The aim of the study was to investigate the impact of unit processing steps such as blending, cone milling and powder feeding systems on the particle size of a formulated API. The particle properties of a single component (API) within formulated samples were tracked using an image based particle characterisation system with an integrated Raman probe. In addition to the primary aim, the impact of excipient selection was also assessed. The study demonstrated the ability to track the size and shape of particles of a single component within a blended system. Process induced attrition can affect significant changes in the size and shape characteristics of the API particles. Whilst blending and cone milling were found to have minimal impact on the API properties, significant particle attrition was induced through transmission of the formulations through a powder feeding system. The impact of excipients within the formulated blends on API attrition propensity was observed to be low. The findings suggest that the propensity for particles to undergo process induced attrition should be taken into consideration when designing a manufacturing process and/or relating initial particle properties to the performance of intermediate or final dosage forms.