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Markl D.,University of Cambridge | Sauerwein J.,University of Cambridge | Goodwin D.J.,Research Frontiers | van Den Ban S.,GSK Global Manufacturing and Supply | Zeitler J.A.,University of Cambridge
Pharmaceutical Research | Year: 2017

Purpose: The aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale. Methods: Samples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch. Results: The disintegration time (R2 = 0.86) and API dissolved after 15 min (R2 = 0.96) linearly correlates with the effective refractive index, neff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of neff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, αeff, we observed a better correlation with dissolution after 20 min (R2 = 0.96) and a weaker correlation with disintegration (R2 = 0.83) compared to neff. Conclusion: The measurements of neff and αeff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets. © 2017 The Author(s)

van Den Ban S.,GSK Global Manufacturing and Supply | Goodwin D.J.,Research Frontiers
Pharmaceutical Research | Year: 2017

Purpose: The impact of granule densification in high-shear wet granulation on tabletting and product performance was investigated, at pharmaceutical production scale. Product performance criteria need to be balanced with the need to deliver manufacturability criteria to assure robust industrial scale tablet manufacturing processes. A Quality by Design approach was used to determine in-process control specifications for tabletting, propose a design space for disintegration and dissolution, and to understand the permitted operating limits and required controls for an industrial tabletting process. Methods: Granules of varying density (filling density) were made by varying water amount added, spray rate, and wet massing time in a design of experiment (DoE) approach. Granules were compressed into tablets to a range of thicknesses to obtain tablets of varying breaking force. Disintegration and dissolution performance was evaluated for the tablets made. The impact of granule filling density on tabletting was rationalised with compressibility, tabletability and compactibility. Results: Tabletting and product performance criteria provided competing requirements for porosity. An increase in granule filling density impacted tabletability and compactability and limited the ability to achieve tablets of adequate mechanical strength. An increase in tablet solid fraction (decreased porosity) impacted disintegration and dissolution. An attribute-based design space for disintegration and dissolution was specified to achieve both product performance and manufacturability. Conclusion: The method of granulation and resulting granule filling density is a key design consideration to achieve both product performance and manufacturability required for modern industrial scale pharmaceutical product manufacture and distribution. © 2017 Springer Science+Business Media New York

van den Ban S.,GSK Global Manufacturing and Supply | Goodwin D.J.,Research Frontiers
Powder Technology | Year: 2016

Control over batch fluid bed drying processes is important to assure product of uniform moisture content as the level of residual moisture can impact further processing and final product performance and stability. Entrainment during batch fluidised bed drying can potentially result in non-uniformity of the product moisture content and impact reliability of the process endpoint. A two stage inlet air flow batch drying process was defined to minimise the impact of entrainment on product uniformity. The two stage batch fluid bed drying process reduced the level of entrainment observed. This enables the implementation of a relatively straightforward differential temperature technique based on a temperature sensor only to reliably indicate drying endpoint. © 2016 Elsevier B.V.

Pitt K.G.,GSK Global Manufacturing and Supply | Webber R.J.,GSK Global Manufacturing and Supply | Hill K.A.,GSK Global Manufacturing and Supply | Dey D.,Gamlen Tableting Ltd | Gamlen M.J.,Gamlen Tableting Ltd
Powder Technology | Year: 2013

Small scale compaction studies which utilise equipment representative of commercial scale tablet presses can be used to develop process understanding of pharmaceutical formulations using minimal quantities of material. In this study the scalability of compressibility (solid fraction vs. compaction pressure), tabletability (tensile strength vs. compaction pressure), compactibility (tensile strength vs. solid fraction) and ejection shear stress was examined over an eight-fold range in tablet size. Tablets of two representative commercially manufactured formulations were compressed and compared using a small scale compaction press and large scale industrial press. Different tablet sizes and shapes were produced from the two types of press. One formulation was manufactured by direction compression and the other by wet granulation. Generally, good agreement was found across the scales for all the measures assessed. In addition, the measurement of ejection shear stress data on the small scale was able to accurately predict tablet failure on commercial rotary presses. © 2013 Elsevier B.V. All rights reserved.

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