Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

Daniel Markl,Daniel J Goodwin,Johanna Sauerwein,J Axel Zeitler,Sander Van Den Ban

doi:10.1007/s11095-017-2108-4

Daniel Markl, Daniel J Goodwin + Show 3 more

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https://doi.org/10.1007/s11095-017-2108-4

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Journal: Pharmaceutical research	Publication Date: Feb 2, 2017
Citations: 53	License type: open-access

Affiliation: University of Cambridge

Abstract

ABSTRACTPurposeThe 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.MethodsSamples 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.ResultsThe 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.ConclusionThe 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.

Highlights

Processing of active pharmaceutical ingredients (APIs) into convenient dosage forms for effective drug administration places great demands on excipients, the formulation and the processes used in pharmaceutical production
As outlined above, within the inherent limitations of the disintegration testing and the limitations of using dissolution testing results based on cumulative batch data, both tablet thickness and neff show good correlations for the tablets under investigation with the disintegration time and the API dissolved after 15 min
This study demonstrates the potential of terahertz spectroscopy as an important process monitoring or quality control tool for pharmaceutical tablets prepared by wet granulation and compaction

Summary

Introduction

Processing of active pharmaceutical ingredients (APIs) into convenient dosage forms for effective drug administration places great demands on excipients, the formulation and the processes used in pharmaceutical production. One of the key processes is powder compaction to form interparticulate bonds, i.e., solid bridges, intermolecular bonds, mechanical interlocking The strength of these bonds and the arrangement of the particles in the tablet are affected by the material properties (e.g., particle shape, particle size distribution, elasticity/plasticity/brittleness of particles) and the process configuration (e.g., compression speed and force, granulation and drying parameters). The pore structure defines the capillary and viscous forces which govern the ingress of gastrointestinal fluids into the tablet upon administration and initiate the disruption of the particle bonds. Such pore structures are typically characterised by the relative void space in the tablet, i.e. the porosity, which is the fraction of the volume of voids over the total volume of the tablet. The porosity of a tablet is one of the most important contributors to tablet disintegration and it is directly influenced by the process configuration, such as compaction force and compression speed [2, 3]

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