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Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.

Quality control is of critical importance in manufacturing of lyophilized drug product, which is accomplished by monitoring the process parameters. The residual gas analyzer has emerged as a useful tool in determination of endpoint for primary and secondary drying in lyophilization process as well as leak detection in vacuum systems. This study presents the application of in situ RGA to quantify outgassing rates of species released from aqueous inorganic and organic ammonium salt formulations throughout the freeze-drying process. The determination of ammonia outgassing conditions aids in ensuring product quality where ammonia release is an indication for loss of co-solvent or degradation of active pharmaceutical ingredients (APIs). Data analysis methods are developed to determine ammonia presence under various process conditions. In-situ real time monitoring of vapor dynamics enables RGA to be used as a tool to characterize counter-ion loss throughout the freeze-drying cycle.

Understanding and predicting the flow of bulk pharmaceutical materials could be key in enabling pharmaceutical manufacturing by continuous direct compression (CDC). This study examines whether, by taking powder and bulk measurements, and using statistical modelling, it would be possible to predict the flow of a range of materials likely to be used in CDC. More than 100 materials were selected for study, from four pharmaceutical companies. Particle properties were measured by static image analysis, powder surface area and surface energy techniques, and flow by shear cell measurements. The data was then analysed, and a range of statistical modelling techniques were used to build predictive models for flow. Using the results from static image analysis, a model could be built which allowed the prediction of likely flow in a shear cell, which can be related to performance in a CDC system. Only a small amount of powder was required for the image analysis. Surface area did not add to the precision of the model, and the available surface energy technique did not correlate with flow. A small sample of powder can be examined by static image analysis, and this data can be used to give an early read on likely flow of a material in a CDC system or other pharmaceutical process, allowing early intervention (if necessary) to improve the characteristics of a material, early in development.

Graphical Abstract.

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug-polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings. At low drug loading (

The attrition of drug particles during the process of dry granulation, which may (or may not) be incorporated into granules, could be an important factor in determining the subsequent performance of that granulation, including key factors such as sticking to punches and bio-performance of the dosage form. It has previously been demonstrated that such attrition occurs in one common dry granulation process train; however, the fate of these comminuted particles in granules was not determined. An understanding of the phenomena of attrition and incorporation into granule will improve our ability to understand the performance of granulated systems, ultimately leading to an improvement in our ability to optimize and model the process. Unique feeding mechanisms, geometry, and milling systems of roller compaction equipment mean that attrition could be more or less substantial for any given equipment train. In this work, we examined attrition of API particles and their incorporation into granule in an equipment train from Gerteis, a commonly used equipment train for dry granulation. The results demonstrate that comminuted drug particles can exist free in post-milling blends of roller compaction equipment trains. This information can help better understand the performance of the granulations, and be incorporated into mechanistic models to optimize such processes.

Sticking and picking during tablet manufacture has received increasing interest recently, as it causes tablet defects, downtime in manufacturing, and yield losses. The capricious nature of the problem means that it can appear at any stage of the development cycle, even when it has been deemed as low risk by models, tests, and previous experience. In many cases, the problem manifests when transferring the process from one manufacturing site to another. Site transfers are more common now than in previous times because of the multinational nature of drug product manufacturing and the need for redundancy in manufacturing networks. Sticking is a multifactorial problem, so one single “fix” is unlikely to solve it completely, and “solutions” addressing one problem may exacerbate another. A broad-based strategy involving the API, formulation, tablet tooling, and the manufacturing process is the most likely approach to provide a robust and lasting solution. When faced with a sticking problem for the first or subsequent time, the formulator should address, in a structured way, a range of possible causes and remedies. In this article, we focus on current research and practice; on some of the common causes of sticking; mitigation and resolution strategies and solutions; and possible future directions in research.

In the oral solid dosage form space, material physical properties have a strong impact on the behaviour of the formulation during processing. The ability to identify materials with similar characteristics (and thus expected to exhibit similar behaviour) within the company's portfolio can help accelerate drug development by enabling early assessment and prediction of potential challenges associated with the powder properties of a new active pharmaceutical ingredient. Such developments will aid the production of robust dosage forms, in an efficient manner. Similarity scoring metrics are widely used in a number of scientific fields. This study proposes a practical implementation of this methodology within pharmaceutical development. The developed similarity metrics is based on the Mahalanobis distance. Scanning electron microscopy was used to confirm morphological similarity between the reference material and the closest matches identified by the metrics proposed. The results show that the metrics proposed are able to successfully identify material with similar physical properties.

Hydroxypropylmethylcellulose (HPMC) acetyl succinate (HPMC-AS) is a key polymer used for the enablement of amorphous solid dispersions (ASDs) in oral solid dosage forms. Choice of the appropriate grade within the material is often made empirically by the manufacturer of small-scale formulations, followed by extensive real time stability. A key factor in understanding and predicting the performance of an ASD is related to the presence of hydrogen (or other) bonds between the polymer and active pharmaceutical ingredient (API), which will increase stability over the parameters captured by miscibility and predicted by the Gordon-Taylor equation. Solid state nuclear magnetic resonance (NMR) is particularly well equipped to probe spatial proximities, for example, between polymer and API; however, in the case of HPMC-AS, these interactions have been sometimes difficult to identity as the carbon-13 NMR spectra assignment is yet to be firmly established. Using feedstock, selectively substituted HPMC polymers, and NMR editing experiments, we propose here a comprehensive understanding of the chemical structure of HPMC-AS and a definitive spectral assignment of the 13 C NMR spectra of this polymer. The NMR data also capture the molar ratios of the acetate and succinate moieties present in HPMC-AS of various grades without the need for post treatment required by chromatography methods commonly use in pharmacopoeia. This knowledge will allow the prediction and measurement of interactions between polymers and APIs and therefore a rational choice of polymer grade to enhance the solid state stability of ASDs.

The aim of this study was to investigate the capability of X-ray microtomography to obtain information relating to powder characteristics such as wall thickness and solid volume fraction for hollow, polymer-stabilised spray dried dispersion (SDD) particles. SDDs of varying particle properties, with respect to shell wall thickness and degree of particle collapse, were utilised to assess the capability of the approach. The results demonstrate that the approach can provide insight into the morphological characteristics of these hollow particles, and thereby a means to understand/predict the processability and performance characteristics of the bulk material. Quantitative assessments of particle wall thickness, particle/void volume and thereby solid volume fraction were also demonstrated to be achievable. The analysis was also shown to be able to qualitatively assess the impact of the drying rate on the morphological nature of the particle surfaces, thus providing further insight into the final particle shape. The approach demonstrated a practical means to access potentially important particle characteristics for SDD materials which, in addition to the standard bulk powder measurements such as particle size and bulk density, may enable a better understanding of such materials, and their impact on downstream processability and dosage form performance.

The aim of this study was to determine the location of attrition of formulated API particles within a powder feed system using a Morphologi G3-ID system, an image analyzer with integrated Raman capability enabling classification of particles with respect to their chemistry, to extract the API size distribution from the blended sample. The study also aimed to investigate the impact of other process variables, such as feed screw speed, on the extent of attrition observed. The study demonstrated that attrition occurs in two zones of the powder feed system, at the bottom of the hopper at the interface with the feed screw, and also within the feed screw itself. In the situation of the attrition at the bottom of the hopper variations in the hopper fill level were not observed to change the extent of attrition observed. Variation of the feed screw speed was observed to affect the extent of API attrition, with the particle size within the formulation observed to decrease with increasing speed. The findings highlight that an understanding of the impact of unit processes, and variations in the associated processing conditions, is vital in order to fully understand the behavior and performance of pharmaceutical dosage forms.

A key part of the Risk Assessment of excipients is to understand how raw material variability could (or does) contribute to differences in performance of the drug product. Here we demonstrate an approach which achieves the necessary understanding for a complex, functional, excipient. Multivariate analysis (MVA) of the certificates of analysis of an ethylcellulose aqueous dispersion (Surelease) formulation revealed low overall variability of the properties of the systems. Review of the scores plot to highlight batches manufactured using the same ethylcellulose raw material in the formulation, indicated that these batches tend to be more closely related than other randomly selected batches. This variability could result in potential differences in the quality of drug product lots made from these batches. Manufacture of a model drug product from Surelease batches coated using different lots of starting material revealed small differences in the release of a model drug, which could be detected by certain model dependent dissolution modelling techniques, but they were not observed when using model-independent techniques. This illustrates that the techniques are suitable for detecting and understanding excipient variability, but that, in this case, the product was still robust.

The concept of “molecular inflation”1, where the molecular weight of patented and marketed drugs is increasing (as is their molecular complexity), is now demonstrated to be a reality. At the same t...

During formulation development, significant resources and effort are dedicated to understanding pharmaceutical material properties and how they impact on drug product performance. Scientists routinely generate large, complex data sets which have specific analysis requirements to fully unlock the information they contain. Multivariate analysis methods are ideally suited to this task and this chapter describes how they can be applied during development of a tablet formulation for the spray-dried dispersion (SDD) of a low-solubility drug. In the first case study, these methods were applied to elucidate the relationships between the SDD properties and key performance indicators (flow, compactibility, and dissolution) which will inform future work towards the definition of the control strategy. In the second case study, a novel approach is proposed to facilitate a better understanding of the SDD particle morphology from the light transmission data collected routinely using an image-based particle characterization method.

The Pharmaceutical Industry has large amounts of data available to it. Much of this data is available from analytical instruments which have the capability and precision to dig deeper into processes, and provide unprecedented understanding of these processes. The process of turning this information into knowledge could conceivably be carried out by a number of routes, including statistical data analysis. Although a number of statistical data analysis techniques could carry out this transformation, one technique; multivariate data analysis (MVA) has become the primary technique in this arena. Transparency, reproducibility and an ability to conform to regulatory directives have all contributed to this current situation, and this chapter explains how.

The aim of this study was to assess the impact of unit processes on the de-aggregation of a cohesive micronised API within a pharmaceutical formulation using near-infrared chemical imaging. The impact on the primary API particles was also investigated using an image-based particle characterization system with integrated Raman analysis. The blended material was shown to contain large, API rich domains which were distributed in-homogeneously across the sample, suggesting that the blending process was not aggressive enough to disperse aggregates of micronised drug particles. Cone milling, routinely used to improve the homogeneity of such cohesive formulations, was observed to substantially reduce the number and size of API rich domains; however, several smaller API domains survived the milling process. Conveyance of the cone milled formulation through the Alexanderwerk WP120 powder feed system completely dispersed all remaining aggregates. Importantly, powder feed transmission of the un-milled formulation was observed to produce an equally homogeneous API distribution. The size of the micronised primary drug particles remained unchanged during powder feed transmission. These findings provide further evidence that this powder feed system does induce shear, and is in fact better able to disperse aggregates of a cohesive micronised API within a blend than the blend-mill-blend step.

This study reports an experimental approach to determine the contribution from two different components of surface energy on cohesion. A method to tailor the surface chemistry of mefenamic acid via silanization is established and the role of surface energy on cohesion is investigated. Silanization was used as a method to functionalize mefenamic acid surfaces with four different functional end groups resulting in an ascending order of the dispersive component of surface energy. Furthermore, four haloalkane functional end groups were grafted on to the surface of mefenamic acid, resulting in varying levels of acid-base component of surface energy, while maintaining constant dispersive component of surface energy. A proportional increase in cohesion was observed with increases in both dispersive as well as acid-base components of surface energy. Contributions from dispersive and acid-base surface energy on cohesion were determined using an iterative approach. Due to the contribution from acid-base surface energy, cohesion was found to increase ∼11.7× compared to the contribution from dispersive surface energy. Here, we provide an approach to deconvolute the contribution from two different components of surface energy on cohesion, which has the potential of predicting powder flow behavior and ultimately controlling powder cohesion.

In a Quality by Design (QbD) development environment the effect of early process parameters on downstream manufacturing parameters, and the ultimate effect on drug product quality, need to be understood. For poorly soluble drugs, size reduction is frequently employed to obtain consistent in-vivo exposures. As a result, micronization is a key early stage processing step for many active pharmaceutical ingredients (APIs). This paper demonstrates the effect of varying micronization conditions on an API for which micronization is deemed necessary to ensure consistent drug delivery after human administration. Material micronized to different extents are confirmed as different by surface area, surface energy, particle size analysis, bulk density and surface adhesion measurements. These material characteristics can be correlated with the outcomes from a key processing step, blending. The evolution of the blending process is followed using PAT techniques, so that an overall understanding of the relationship between particle properties and blend uniformity can be demonstrated. Execution of such a study during drug development can enable selection of the appropriate control strategy to ensure production of API in the desired range where consistent optimal bioavailability and downstream processability are achieved.

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.

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.

An analysis of the free acid form of the HIV-1 attachment inhibitor prodrug BMS-663068-01 revealed a reversible moisture sorption event in the 42%–46% relative humidity (RH) range. An existing single-crystal analysis indicated that these observations were due to the formation of a nonstoichiometric channel hydrate. This effect was reproducible on repeated cycles, suggesting that the material's structural integrity was not compromised because of the inter conversion process. Small, reversible, and predictable changes in the atomic structure were observed by solid-state nuclear magnetic resonance (ssNMR). Atomic force microscopy (AFM) and environmental scanning electron microscopy (ESEM) could discern changes in surface topography as a function of RH. Surface cracks were visible at 25% RH, most of which disappeared at 60% RH. This change was reversible on reducing the RH, with cracks reappearing in the same locations. A reduction in surface roughness was seen at high humidity, which was consistent with the uptake of moisture causing surface swelling. The observations by AFM/ESEM were consistent with the atomic alterations seen with ssNMR. Changes in unit cell dimensions are not uncommon with channel hydrates as the crystal lattice expands or contracts when the crystal structure absorbs/desorbs water, but concomitant, reversible surface morphology property changes have not been widely reported.

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.

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 (D(pS)), 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 D(pS) 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.

Blending of active pharmaceutical ingredient (API) and excipients is a pre-requisite to the dry manufacture of solid dosage forms intended for oral use, whether or not granulation steps are employed prior to compaction. Excipients and API are known to be subject to tribo-electric charging, against each other and the materials in which the blends are manufactured (e.g. stainless steel 316). This study aimed to assess and compare the magnitude of tribo-electric charging of excipients and API using a material-sparing technique. Intra-sample variability in tribo-electric charging was found to be generally low. The results showed that excipients had lower charge levels and smaller variability as compared to the API materials. Some of the APIs tested charged extensively to the levels in excess of ± 150 nC/g. It was also found that the extent of particle adhesion to surfaces of the container walls for charged API was considerably greater compared to the excipients. These results suggest that the extent and variability of tribo-electric charging of APIs is the predominant contributor to variability in electrostatic charge of pharmaceutical blends and to any related formulation issues. It is therefore reasonable to conclude that, to control the electrostatic properties of a formulation, it is a priority to control the particle properties of the API.

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.

This study investigates the impact of micronization on the measured surface energy characteristics of an active pharmaceutical ingredient (API), Ibipinabant, by inverse gas chromatography (IGC) using both a fixed probe concentration, commonly used in standard IGC methods, and a fixed probe surface coverage approach applied by the surface energy analyzer (SEA), a next generation IGC system. The IGC measurements indicate an initial increase in surface energy, going from un-micronized to micronized, followed by a reduction in surface energy with increasing micronization extent. This was attributable to the change in the retention behaviour of the dispersive probes as a consequence of the change in the probe surface coverage rather than a change in the actual surface energy of the materials being analysed. It was observed in the SEA data that micronization leads to an increase in the measured dispersive surface energy of the drug substance with increasing micronization extent. The increase in surface energy is primarily due to the generation of new, higher energy interaction sites, although a small additional increase is also observed which is related to the increase in the number and distribution of high energy sites. The results demonstrate that in order to obtain comparable surface energetic data between batches with varied surface area, and presumably between different materials, results should be obtained at a specific, and constant, probe surface coverage.

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.

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.

We report the case of BMS-488043-PVP solid dispersions which when analysed using modulated DSC showed compliance with the Gordon–Taylor model, confirming ideal mixing behaviour of the two components. The nature or presence of stabilising interactions between drug and PVP could not be confirmed using this technique. Use of FT-IR, Raman and solid-state NMR spectroscopy confirmed the presence of stabilising hydrogen bond interactions between the drug and PVP. Similar interactions are present as intermolecular bonds in the crystalline and pure amorphous drug system. The Gordon–Taylor equation, as it is not predictive of the presence of intermolecular bonds such as hydrogen bonding in an amorphous dispersion, may underestimate the likely physical stability of solid dispersions which are produced and stabilised by these interactions. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3456–3468, 2009

Surface energy data for samples of microcrystalline cellulose have been obtained using two techniques: capillary intrusion and inverse gas chromatography. Ten microcrystalline cellulose materials, studied using capillary intrusion, showed significant differences in the measured surface energetics (in terms of total surface energy and the acid–base characteristics of the cellulose surface), with variations noted between the seven different manufacturers who produced the microcrystalline cellulose samples. The surface energy data from capillary intrusion was similar to data obtained using inverse gas chromatography with the column maintained at 44% relative humidity for the three samples of microcrystalline cellulose studied. This suggests that capillary intrusion may be a suitable method to study the surface energy of pharmaceutical samples.

This study proposes an approach for quantifying the amount of pharmaceutical powder adhering (quality attribute) to the metals surfaces. The effect of surface roughness (detrimental attribute) on the amount of powder sticking to a stainless steel surface for a model pharmaceutical material is also qualitatively determined. Methodology to quantify powder adhesion to surfaces utilises a texture analyser and HPLC. The approach was validated to qualitatively investigate effect of metal surface roughness on adhesion of mefenamic acid. An increase in metal surface roughness resulted in an increase in cohesion. By increasing the average roughness from 289nm to 407nm, a 2.5 fold increase in amount adhering to metal was observed, highlighting the role of surface roughness on adhesion. The simplicity in experimental design with no requirement of specialised equipment and operational ease makes the approach very easy to adopt. Further, ease in interpreting results makes this methodology very attractive.

WOS: 000222117700023, The main objective of this study was to investigate the possible use of zirconia as a material for the manufacture of punches and dies for use in tableting machines and to study its effect on ejection of tablets made from different formulations. In order to achieve this objective, the compaction properties of three commercially available direct compression excipients were examined with the help of a compaction simulator, over a range of compaction pressures using steel and zirconia tooling. The data obtained for all materials indicated that, for a particular compression speed, the work required to eject the tablet from the die, i.e., the work needed to overcome die wall friction during ejection, was lower in zirconia tooling than steel tooling. Scanning electron microscopy (SEM) was employed to investigate the excipients powders and compact surfaces for contrasting particle morphology before and after compaction. Electron probe microanalysis (EPMA) was also carried out on the representative tablets compacted at high speed using zirconia tooling and no shedding of zirconia into the tablets was detected

The influence of relative humidity (RH) on the cohesion properties of three drugs: salbutamol sulphate (SS), triamcinolone acetonide (TAA), and disodium cromoglycate (DSCG) was investigated using the atomic force microscope (AFM) colloidal probe technique. Micronized drug particles were mounted in heat-sensitive epoxy resin for immobilization. Multiple AFM force-distance curves were conducted between each drug probe and the immobilized drug particulates at 15, 45, and 75% RH using Force-Volume imaging. Clear variations in the cohesion profile with respect to RH were observed for all three micronized drugs. The calculated force and energy of cohesion to separate either micronized SS or DSCG increased as humidity was raised from 15 to 75% RH, suggesting capillary forces become a dominating factor at elevated RH. In comparison, the separation force and energy for micronized TAA particles decreased with increased RH. This behavior may be attributed to long-range attractive electrostatic interactions, which were observed in the approach cycle of the AFM force-distance curves. These observations correlated well with previous aerosolization studies of the three micronized drugs.

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.

Bulk density can be a key indicator of performance, and may influence choice of formulation route of materials in pharmaceutical development. During early development, the cost of API’s can be expensive and the availability of material for powder property analysis is limited. The aim of this work was to investigate a suitable small-scale, low material requirement, bulk density test which would provide comparable data to the recommended large volume USP test. Materials with a range of morphological characteristics typically seen in the pharmaceutical industry were assessed to ensure that methods were suitably robust. It was found that the USP II “low volume” test does not give equivalent results to other tests in the USP, across the range of materials. An alternative test based on the FT4 powder rheometer at a scale of 25 mL gave results equivalent to the large volume USP I standard test. The use of smaller 10-mL methods was also found to give acceptable results for materials that were considered well-behaved but were more variable with difficult to handle materials with low bulk density.

The role of surface properties, influenced by particle processing, in particle-particle interactions (powder cohesion) is investigated in this study. Wetting behaviour of mefenamic acid was found to be anisotropic by sessile drop contact angle measurements on macroscopic (>1cm) single crystals, with variations in contact angle of water from 56.3° to 92.0°. This is attributed to variations in surface chemical functionality at specific facets, and confirmed using X-ray photoelectron spectroscopy (XPS). Using a finite dilution inverse gas chromatography (FD-IGC) approach, the surface energy heterogeneity of powders was determined. The surface energy profile of different mefenamic acid crystal habits was directly related to the relative exposure of different crystal facets. Cohesion, determined by a uniaxial compression test, was also found to relate to surface energy of the powders. By employing a surface modification (silanisation) approach, the contribution from crystal shape from surface area and surface energy was decoupled. By "normalising" contribution from surface energy and surface area, needle shaped crystals were found to be ∼2.5× more cohesive compared to elongated plates or hexagonal cuboid shapes crystals.

Surface area and surface energy of pharmaceutical powders are affected by milling and may influence formulation, performance and handling. This study aims to decouple the contribution of surface area and surface energy, and to quantify each of these factors, on cohesion.Mefenamic acid was processed by cryogenic milling. Surface energy heterogeneity was determined using a Surface Energy Analyser (SEA) and cohesion measured using a uniaxial compression test. To decouple the surface area and surface energy contributions, milled mefenamic acid was "normalised" by silanisation with methyl groups, confirmed using X-ray Photoelectron Spectroscopy.Both dispersive and acid-base surface energies were found to increase with increasing milling time. Cohesion was also found to increase with increasing milling time. Silanised mefenamic acid possessed a homogenous surface with a surface energy of 33.1 ± 1.4 mJ/m(2) , for all milled samples. The cohesion for silanised mefenamic acid was greatly reduced, and the difference in the cohesion can be attributed solely to the increase in surface area. For mefenamic acid, the contribution from surface energy and surface area on cohesion was quantified to be 57% and 43%, respectively.Here, we report an approach for decoupling and quantifying the contribution from surface area and surface energy on powder cohesion.

The purpose of this study was to rapidly determine, without the use of extensive animal studies, whether biological activity is retained after spray drying insulin with two excipients, lactose and xanthan gum. This was achieved by the detection of protein kinase B (PKB), which is activated by phosphorylation in response to insulin binding to cellular receptors. A myeloid cell line was cultured and stimulated with the reconstituted insulin powders. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was then utilised to allow in-vitro detection of phosphorylated PKB using an anti-phospho-PKB antibody. A single band specific to phosphorylated PKB was found on the Western blots, indicating that the active conformation of insulin was retained when spray dried in combination with lactose and with xanthan gum over the spray-drying inlet temperature range of 110–170°C. Evidence of inactivation/denaturation was observed when insulin was spray dried at an inlet temperature of 200°C. The assay may be of use as a more rapid and economic means to screen insulin formulations for inhalation and other purposes as opposed to conventional monitoring of blood glucose levels in animals.

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of ∼1 μm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the “micronized” nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12–76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1160–1169, 2000

The mechanical properties of compacts of unlubricated microcrystalline cellulose and silicified microcrystalline cellulose were evaluated using the diametric tensile test. The results suggested that, under comparable testing conditions, compacts of silicified microcrystalline cellulose exhibited greater strength than those of microcrystalline cellulose. In addition to enhanced strength, silicified microcrystalline cellulose compacts exhibited greater stiffness and required considerably more energy for tensile failure to occur. Comparison of the data with that obtained for a dry blend of silicon dioxide/microcrystalline cellulose suggested that the functionality benefits of silicification were not due to a simple composite material model.

When considering the development of potential controlled-release pulmonary drug delivery systems, there is at present no standard method available for the assessment of in vitro drug release profiles necessary to understand how the drug might release following deposition in the lungs. For this purpose, the twin-stage impinger (TSI), apparatus A of the BP, has been redesigned and tested. This modified TSI was found capable of discriminating between drug release rates from conventional and different dry powder formulations consisting of model controlled-release excipients, providing information related to (a) drug diffusion properties of controlled-release dry powder blends with different excipient components and (b) the effect of varying drug concentration within a given formulation.

The use of computational fluid dynamics (CFD) in the design of a pharmaceutical processor is described. A simple computational model of the process vessel was developed using a single-phase flow. The results of this preliminary study showed good agreement with experimental tests. The model was further developed to consider the effect of solid particles on the processes occurring within a single vessel pharmaceutical processor. Having obtained converged solutions, the model was used to optimize the design of the processor. The model was used to develop new designs of the vessel. The design optimization was done on the basis of comparisons with conventional pharmaceutical processing equipment. Optimization of the process parameters is important, as they are known to affect the functionality of the final product. The study reported here discusses one step in the design process, showing how changes to the inlet configuration can be modelled to show the potential for improved performance.

Silicified microcrystalline cellulose (SMCC) is a novel tableting excipient which has been reported to exhibit improved binding capability as a material and in formulations. The material is also reported to show improved resistance to the deleterious effects of magnesium stearate compared with conventional microcrystalline cellulose. To understand the improvement in functionality of silicified microcrystalline cellulose the location of silicon dioxide in SMCC was investigated by studying particle surfaces and cross-sections using scanning electron microscopy together with electron probe micro-analysis. The results suggest that silicon dioxide is primarily located in the surface of SMCC. Some silicon dioxide was detected in the internal regions of some particles.

This study introduces a motionless novel single vessel powder processor designed to carry out all of the unit operations in the preparation of powders for tableting. The processor used controllable fluid dynamics to provide the energy for each unit operation. The vessel design was evaluated using a computational fluid dynamics model which indicated the flow necessary for the intended processing operations to take place. The processor performance was evaluated experimentally for two unit processes: particle size reduction and dry powder mixing. The processor was found capable of reducing the size of lactose granules from a median particle diameter of 459 microm to a median particle diameter of 182 microm within 5 min under optimal process conditions. It was found that a formulation containing lactose granules (373 microm median particle diameter) and a model drug, sodium chloride (30 microm), could be mixed to an improved degree of homogeneity in comparison with equivalent powders blended using a conventional turbulent tumbling technique. It was concluded that a processor having controllable fluid dynamics offered the potential to perform multi-task processing of powders.

Silicified microcrystalline cellulose (SMCC) has been compared with a standard grade of microcrystalline cellulose (MCC) using several physicochemical techniques in order to elucidate any chemical or polymorphic changes in the material that could be attributed to the silicification process. Samples of SMCC, MCC and dry and wet mixes of MCC and silicon dioxide were analysed using FT-IR, 13 C NMR, powder X-ray diffraction, mercury porosimetry, helium pycnometry and scanning electron microscopy together with particle size analysis and deaggregation studies. Analysis of the data obtained from these methods suggested that there were no discernible chemical or polymorphic differences between the samples, indicating that the `silicification' process produces a material which is chemically and physically very similar to standard MCC.