Development and Validation of an In‐Line API Quantification Method Using AQbD Principles Based on UV‐Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process

open access journalA key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in Kollidon® VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in‐line analytical procedure was developed using predictive models based on UV‐Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters—in‐process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% β‐expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at ±5%. The method robustness was tested by evaluating the effects of screw speed (150–250 rpm) and feed rate (5–9 g/min) on piroxicam content around 15% w/w. In‐line UV‐Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process

Measurements of effective porosity of pharmaceutical tablets using THz TDS

The pharmaceutical industry requires a rapid nondestructive technique for monitoring porosity of tablets. Here effective porosity of compressed lactose pellets was investigated using THz time-domain spectroscopy (THz TDS)

Measuring open porosity of porous materials using THz-TDS and an index-matching medium

The porosity of porous materials is a critical quality attribute of many products ranging from catalysis and separation technologies to porous paper and pharmaceutical tablets. The open porosity in particular, which reflects the pore space accessible from the surface, is crucial for applications where a fluid needs to access the pores in order to fulfil the functionality of the product. This study presents a methodology that uses terahertz time-domain spectroscopy (THz-TDS) coupled with an index-matching medium to measure the open porosity and analyze scattering losses of powder compacts. The open porosity can be evaluated without the knowledge of the refractive index of the fully dense material. This method is demonstrated for pellets compressed of pharmaceutical-grade lactose powder. Powder was compressed at four different pressures and measured by THz-TDS before and after they were soaked in an index-matching medium, i.e., paraffin. Determining the change in refractive index of the dry and soaked samples enabled the calculation of the open porosity. The results reveal that the open porosity is consistently lower than the total porosity and it decreases with increasing compression pressure. The scattering losses reduce significantly for the soaked samples and the scattering centers (particle and/or pore sizes) are of the order of or somewhat smaller than the terahertz wavelength. This new method facilitates the development of a better understanding of the links between material properties (particles size), pellet properties (open porosity) and performance-related properties, e.g., disintegration and dissolution performance of pharmaceutical tablets

The Effect of Particle Size and Concentration on Low-Frequency Terahertz Scattering in Granular Compacts

Fundamental knowledge of scattering in granular compacts is essential to ensure accuracy of spectroscopic measurements and determine material characteristics such as size and shape of scattering objects. Terahertz time-domain spectroscopy (THz-TDS) was employed to investigate the effect of particle size and concentration on scattering in specially fabricated compacts consisting of borosilicate microspheres in a polytetrafluoroethylene (PTFE) matrix. As expected, increasing particle size leads to an increase in overall scattering contribution. At low concentrations, the scattering contribution increases linearly with concentration. Scattering increases linearly at low concentrations, saturates at higher concentrations with a maximum level depending on particle size, and that the onset of saturation is independent of particle size. The effective refractive index becomes sublinear at high particle concentrations and exceeds the linear model at maximum density, which can cause errors in calculations based on it, such as porosity. The observed phenomena are attributed to the change in the fraction of photons propagating ballistically versus being scattered. At low concentrations, photons travel predominately ballistically through the PTFE matrix. At high concentrations, the photons again propagate ballistically through adjacent glass microspheres. In the intermediate regime, photons are predominately scattered

Non-destructive determination of disintegration time and dissolution in immediate release tablets by terahertz transmission measurements

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

Digital medicines manufacturing (DM2) : AI-driven optimization of oral solid dosage form development

[Abstract not available

Enhancing virtual tablet formulation design

Despite the fact that the pharmaceutical industry has produced tablets for more than a hundred years, the development of a new formulation and the choice of manufacturing processes and excipients is often based on trial-and-error approach. This trail and error approach poses several challenges during tableting ( e.g. low tensile strength, excessive friability, and strain rate sensitivity

In vivo visualization and analysis of 3-D hemodynamics in cerebral aneurysms with flow-sensitized 4-D MR imaging at 3T

Introduction: Blood-flow patterns and wall shear stress (WSS) are considered to play a major role in the development and rupture of cerebral aneurysms. These hemodynamic aspects have been extensively studied in vitro using geometric realistic aneurysm models. The purpose of this study was to evaluate the feasibility of in vivo flow-sensitized 4-D MR imaging for analysis of intraaneurysmal hemodynamics. Methods: Five cerebral aneurysms were examined using ECG-gated, flow-sensitized 4-D MR imaging at 3T in three patients. Postprocessing included quantification of flow velocities, visualization of time-resolved 2-D vector graphs and 3-D particle traces, vortical flow analysis, and estimation of WSS. Flow patterns were analyzed in relation to aneurysm geometry and aspect ratio. Results: Magnitude, spatial and temporal evolution of vortical flow differed markedly among the aneurysms. Particularly unstable vortical flow was demonstrated in a wide-necked parophthalmic ICA aneurysm (high aspect ratio). Relatively stable vortical flow was observed in aneurysms with a lower aspect ratio. Except for a wide-necked cavernous ICA aneurysm (low aspect ratio), WSS was reduced in all aneurysms and showed a high spatial variation. Conclusion: In vivo flow-sensitized 4-D MR imaging can be applied to analyze complex patterns of intraaneurysmal flow. Flow patterns, distribution of flow velocities, and WSS seem to be determined by the vascular geometry of the aneurysm. Temporal and spatial averaging effects are drawbacks of the MR-based analysis of flow patterns as well as the estimation of WSS, particularly in small aneurysms. Further studies are needed to establish a direct link between definitive flow patterns and different aneurysm geometrie

On the role of API in determining porosity, pore structure and bulk modulus of the skeletal material in pharmaceutical tablets formed with MCC as sole excipient

The physical properties and mechanical integrity of pharmaceutical tablets are of major importance when loading with active pharmaceutical ingredient(s) (API) in order to ensure ease of processing, control of dosage and stability during transportation and handling prior to patient consumption. The interaction between API and excipient, acting as functional extender and binder, however, is little understood in this context. The API indomethacin is combined in this study with microcrystalline cellulose (MCC) at increasing loading levels. Tablets from the defined API/MCC ratios are made under conditions of controlled porosity and tablet thickness, resulting from different compression conditions, and thus compaction levels. Mercury intrusion porosimetry is used to establish the accessible pore volume, pore size distribution and, adopting the observed region of elastic intrusion-extrusion at high pressure, an elastic bulk modulus of the skeletal material is recorded. Porosity values are compared to previously published values derived from terahertz (THz) refractive index data obtained from exactly the same tablet sample sets. It is shown that the elastic bulk modulus is dependent on API wt% loading under constant tablet preparation conditions delivering equal dimensions and porosity. The findings are considered of novel value in respect to establishing consistency of tablet production and optimisation of physical properties

Measurement of the Intertablet Coating Uniformity of a Pharmaceutical Pan Coating Process With Combined Terahertz and Optical Coherence Tomography In-Line Sensing.

We present in-line coating thickness measurements acquired simultaneously using two independent sensing modalities: terahertz pulsed imaging (TPI) and optical coherence tomography (OCT). Both techniques are sufficiently fast to resolve the coating thickness of individual pharmaceutical tablets in-situ during the film coating operation and both techniques are direct structural imaging techniques that do not require multivariate calibration. The TPI sensor is suitable to measure coatings greater than 50 μm and can penetrate through thick coatings even in the presence of pigments over a wide range of excipients. Due to the long wavelength, terahertz radiation is not affected by scattering from dust within the coater. In contrast, OCT can resolve coating layers as thin as 20 μm and is capable of measuring the intra-tablet coating uniformity as well as the inter-tablet coating thickness distribution within the coating pan. ¬-However, the OCT technique is less robust when it comes to the compatibility with excipients, dust and potentially the maximum coating thickness that can be resolved. Using a custom built laboratory scale coating unit, the coating thickness measurements were acquired independently by the TPI and OCT sensors throughout a film coating operation. Results of the in-line TPI and OCT measurements were compared against one another and validated with off-line TPI and weight gain measurements. Compared to other process analytical technology (PAT) sensors, such as near-infrared and Raman spectroscopy, the TPI/OCT sensors can resolve the inter-tablet thickness distribution based on sampling a significant fraction of the tablet populations in the process. By combining two complementary sensing modalities it was possible to seamlessly monitor the coating process over the range of film thickness from 20 μm to greater than 250 μm.The authors would like to acknowledge the financial support from UK EPSRC Research Grant EP/L019787/1 and EP/L019922/1. The authors acknowledge BASF for providing the materials used in this study, Colorcon Ltd. (Dartford, UK) for coating process recommendations, Hüttlin GmbH (Bosch Packaging Technology, Schopfheim, Germany) for advice on the coating unit design and the staff of the electronics and mechanical workshops in Department of Chemical Engineering and Biotechnology at University of Cambridge. HL also acknowledges travel support from Joy Welch Educational Charitable Trust