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.

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.

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.

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).

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'.

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.

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.

New Development in Understanding Drug-Polymer Interactions in Pharmaceutical Amorphous Solid Dispersions from Solid-State Nuclear Magnetic Resonance.

Pharmaceutical amorphous solid dispersions (ASDs) represent a widely used technology to increase the bioavailability of active pharmaceutical ingredients (APIs). ASDs are based on an amorphous API dispersed in a polymer, and their stability is driven by the presence of strong intermolecular interactions between these two species (e.g.

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.

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

Graphical Abstract.

Drug-Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy.

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.

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.

Solid state nuclear magnetic resonance studies of hydroxypropylmethylcellulose acetyl succinate polymer, a useful carrier in pharmaceutical solid dispersions.

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.

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.

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.

Sticking and Picking in Pharmaceutical Tablet Compression: An IQ Consortium Review.

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.

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.

Measuring the sticking of mefenamic acid powders on stainless steel surface.

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.

Use of similarity scoring in the development of oral solid dosage forms.

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.

Effect of milling temperatures on surface area, surface energy and cohesion of pharmaceutical powders.

Particle bulk and surface properties are influenced by the powder processing routes. This study demonstrates the effect of milling temperatures on the particle surface properties, particularly surface energy and surface area, and ultimately on powder cohesion. An active pharmaceutical ingredient (API) of industrial relevance (brivanib alaninate, BA) was used to demonstrate the effect of two different, but most commonly used milling temperatures (cryogenic vs.

Investigation into process-induced de-aggregation of cohesive micronised API particles.

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.

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.