Determining the Impact of Roller Compaction Processing Conditions on Granulate and API Properties: Impact of Formulation API Load.

Previous work demonstrated that roller compaction of a 40%w/w theophylline-loaded formulation resulted in granulate consisting of un-compacted fractions which were shown to constitute between 34 and 48%v/v of the granulate dependent on processing conditions. The active pharmaceutical ingredient (API) primary particle size within the un-compacted fraction was also shown to have undergone notable size reduction. The aim of the current work was to test the hypothesis that the observations may be more indicative of the relative compactability of the API due to the formulation being above the percolation threshold. This was done by assessing the impact of varied API loads in the formulation on the non-granulated fraction of the final granulate and the extent of attrition of API particles within the non-granulated fraction. The influence of processing conditions for all formulations was also investigated. The results verify that the observations, both of this study and the previous work, are not a consequence of exceeding the percolation threshold. The volume of un-compacted material within the granulate samples was observed to range between 34.7 and 65.5% depending on the API load and roll pressure, whilst the API attrition was equivalent across all conditions.

Non-contact Laser Interferometer Method to Characterize Tablet Punches: New Methodology to Assess Surface Roughness.

Sticking to tablet punches is a major issue during drug product manufacturing. Research has shown that sticking involves the interrelationship of powder properties, compression force, length of manufacturing runs and punch quality. Here, we present a novel non-destructive methodology to study the surface metrology of punches to monitor them over their lifetime. This investigation used a non-contact laser interferometer to characterise roughness of commercial standard S7 steel punches coated with chrome that were originally used for commercial scale production that developed a sticking issue. During the development, this phenomenon had not been observed and was not considered a scale-up risk. The profilometer was used to examine the complete surface of these punches to investigate whether they met the acceptability criteria based on BS_ISO_18804 tooling standard. To improve data analysis during changeover, a 3D-printed holder was designed to enable analysis with minimal set-up requirements. Upon investigation, the punches were found to be of an unacceptable roughness and, particularly rough areas of the punch surface profiled, correlated well with areas of visually pronounced sticking. This non-destructive method can be used to produce a more detailed characterisation of punch roughness to ensure surfaces are of an acceptable quality after treatment with coatings.

Particle Property Characterization and Data Curation for Effective Powder Property Modeling in the Pharmaceutical Industry.

Computational modeling, machine learning, and statistical data analysis are increasingly utilized to mitigate chemistry, manufacturing, and control failures related to particle properties in solid dosage form manufacture. Advances in particle characterization techniques and computational approaches provide unprecedented opportunities to explore relationships between particle morphology and drug product manufacturability. Achieving this, however, has numerous challenges such as producing and appropriately curating robust particle size and shape data. Addressing these challenges requires a harmonized strategy from material sampling practices, characterization technique selection, and data curation to provide data sets which are informative on material properties. Herein, common sources of error in particle characterization and data compression are reviewed, and a proposal for providing robust particle morphology (size and shape) data to support modeling efforts, approaches for data curation, and the outlook for modeling particle properties are discussed.

Characterization of the Morphological Nature of Hollow Spray Dried Dispersion Particles Using X-ray Submicron-Computed Tomography.

Graphical Abstract.

Determining the Impact of Roller Compaction Processing Conditions on Granule and API Properties.

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.

Multivariate analysis as a method to understand variability in a complex excipient, and its contribution to formulation performance.

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 modeling 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.

Enhanced Understanding of Pharmaceutical Materials Through Advanced Characterisation and Analysis.

The impact of pharmaceutical materials properties on drug product quality and manufacturability is well recognised by the industry. An ongoing effort across industry and academia, the Manufacturing Classification System consortium, aims to gather the existing body of knowledge in a common framework to provide guidance on selection of appropriate manufacturing technologies for a given drug and/or guide optimization of the physical properties of the drug to facilitate manufacturing requirements for a given processing route. Simultaneously, material scientists endeavour to develop characterisation methods such as size, shape, surface area, density, flow and compactibility that enable a stronger understanding of materials powder properties. These properties are routinely tested drug product development and advances in instrumentation and computing power have enabled novel characterisation methods which generate larger, more complex data sets leading to a better understanding of the materials. These methods have specific requirements in terms of data management and analysis. An appropriate data management strategy eliminates time-consuming data collation steps and enables access to data collected for multiple methods and materials simultaneously. Methods ideally suited to extract information from large, complex data sets such as multivariate projection methods allow simpler representation of the variability contained within the data and easier interpretation of the key information it contains. In this review, an overview of the current knowledge and challenges introduced by modern pharmaceutical material characterisation methods is provided. Two case studies illustrate how the incorporation of multivariate analysis into the material sciences workflow facilitates a better understanding of materials.

Determination of process variables affecting drug particle attrition withinmulti-component blends during powder feed transmission.

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.

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

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.

Titanium Dioxide (E171 Grade) and the Search For Replacement Opacifiers and Colorants: Supplier Readiness Survey, Case Studies and Regulatory Perspective.

Titanium dioxide (TiO2) is used primarily as an opacifier in solid dosage forms and is present in the majority of tablet and capsule dosage forms on the market. The IQ* TiO2 Working Group has previously shown that titanium dioxide has unique properties which are necessary for its function in these formulations and noted that, as the potential replacements lack the semi-conductor properties, high refractive index and whiteness of E171, it might be hard to replicate these properties with alternative materials. In this paper we detail the results of readiness surveys and practical assessments that have been conducted with alternative materials by IQ member companies. A range of technical challenges and regulatory hurdles were identified which mean that, in the short term, it may be difficult to replace titanium dioxide with the currently available alternative materials while readily achieving the same drug product quality attributes, especially for some of the marketed formulations that titanium dioxide is currently used for. We note the higher technical complexity, due to the variability, color fading and identified scale up risk, of E171 free film coatings and the likely impact on development costs and timelines. We also highlight several regulatory hurdles that would have to be overcome if a titanium dioxide replacement was required for some markets but was not mandated by others.

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 (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.

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.

In-Process Vapor Composition Monitoring in Application to Lyophilization of Ammonium Salt Formulations.

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.

Morphological distribution mapping: Utilisation of modelling to integrate particle size and shape distributions.

The aim of this work was to develop approaches to utilize whole particle distributions for both particle size and particle shape parameters to map the full range of particle properties in a curated dataset. It is hoped that such an approach may enable a more complete understanding of the particle landscape as a step towards improving the link between particle properties and processing behaviour. A 1-dimensional principal component analysis (PCA) approach was applied to create a 'morphological distribution landscape'. A dataset of imaged APIs, intermediates and excipients encompassing particle size, particle shape (elongation, length and width) and distribution shape was curated between 2008 and 2022. The curated dataset encompassed over 200 different materials, which included over 150 different APIs, and approximately 3500 unique samples. For the purposes of the current work, only API samples were included. The morphological landscape enables differentiation of materials of equivalent size but varying shape and vice versa. It is hoped that this type of approach can be utilised to better understand the influence of particle properties on pharmaceutical processing behaviour and thereby enable scientists to leverage historical knowledge to highlight and mitigate risks associated to materials of similar morphological nature.

Comparative Evaluation of the Powder and Tableting Properties of Regular and Direct Compression Hypromellose from Different Vendors.

Hypromellose, a widely used polymer in the pharmaceutical industry, is available in several grades, depending on the percentage of substitution of the methoxyl and hydroxypropyl groups and molecular weight, and in various functional forms (e.g., suitable for direct compression tableting). These differences can affect their physicomechanical properties, and so this study aims to characterise the particle size and mechanical properties of HPMC K100M polymer grades from four different vendors. Eight polymers (CR and DC grades) were analysed using scanning electron microscopy (SEM) and light microscopy automated image analysis particle characterisation to examine the powder's particle morphology and particle size distribution. Bulk density, tapped density, and true density of the materials were also analysed. Flow was determined using a shear cell tester. Flat-faced polymer compacts were made at five different compression forces and the mechanical properties of the compacts were evaluated to give an indication of the powder's capacity to form a tablet with desirable strength under specific pressures. The results indicated that the CR grades of the polymers displayed a smaller particle size and better mechanical properties compared to the DC grade HPMC K100M polymers. The DC grades, however, had better flow properties than their CR counterparts. The results also suggested some similarities and differences between some of the polymers from the different vendors despite the similarity in substitution level, reminding the user that care and consideration should be given when substitution is required.

An investigation into the impact of magnesium stearate on powder feeding during roller compaction.

A systematic evaluation on the effect of magnesium stearate on the transmission of a placebo formulation from the hopper to the rolls during screw fed roller compaction has been carried out. It is demonstrated that, for a system with two 'knurled' rollers, addition of 0.5% w/w magnesium stearate can lead to a significant increase in ribbon mass throughput, with a consequential increase in roll gap, compared to an unlubricated formulation (manufactured at equivalent process conditions). However, this effect is reduced if one of the rollers is smooth. Roller compaction of a lubricated formulation using two smooth rollers was found to be ineffective due to a reduction in friction at the powder/roll interface, i.e. powder was not drawn through the rollers leading to a blockage in the feeding system. An increase in ribbon mass throughput could also be achieved if the equipment surfaces were pre-lubricated. However this increase was found to be temporary suggesting that the residual magnesium stearate layer was removed from the equipment surfaces. Powder sticking to the equipment surfaces, which is common during pharmaceutical manufacturing, was prevented if magnesium stearate was present either in the blend, or at the roll surface. It is further demonstrated that the influence of the hopper stirrer, which is primarily used to prevent bridge formation in the hopper and help draw powder more evenly into the auger chamber, can lead to further mixing of the formulation, and could therefore affect a change in the lubricity of the carefully blended input material.

The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.

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.

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.

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.