A novel in silico scale-up approach for hot melt extrusion processes

Matić, Josip; Witschnigg, Andreas; Zagler, Michaela; Eder, Simone; Khinast, Johannes G.

doi:10.1016/j.ces.2019.04.016

Cited by 18 publications

(19 citation statements)

References 19 publications

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“…This is an important result: although higher SMEC values generally result in higher API degradations, SMEC does not seem to be a good descriptor of the process and product quality equivalence. Therefore, it is not advisable to use it for scale-up, as suggested by many authors and discussed in one of our previous papers ( Matić et al 2019 ). Moreover, even in case C with the same barrel temperature profile (profile I), the resulting SMEC values differ by a factor of two while the API degradation is similar.…”

Section: Resultsmentioning

confidence: 97%

“…As part of the process control and simulation validation efforts, the process torque, SMEC and RTD were captured, analyzed and compared to the values obtained in the 1D HME simulations. A detailed analysis can provide valuable insights into the process, showing the effect of the process settings on the filling degree, the melt temperature and the pressure profile (see our earlier work ( Matić et al 2019 )). A comparison between the experimental and in silico values is important for validating the simulations, including the A1 and A2 values used to parametrize the screws, and the parametrization of the formulation obtained via the material's measurements.…”

Section: Resultsmentioning

confidence: 99%

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Towards predicting the product quality in hot-melt extrusion: Small scale extrusion

Matić

Alva

Witschnigg

et al. 2020

International Journal of Pharmaceutics: X

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In product development, it is crucial to choose the appropriate drug manufacturing route accurately and timely and to ensure that the technique selected is suitable for achieving the desired product quality. Guided by the QbD principles, the pharmaceutical industry is currently transitioning from batch to continuous manufacturing. In this context, process understanding and prediction are becoming even more important. With regard to hot melt extrusion, the process setup, optimization and scale-up in early stages of product development are particularly challenging due to poor process understanding, complex product-process relationship and a small amount of premix available for extensive experimental studies. Hence, automated, quick and reliable process setup and scale-up requires simulation tools that are accurate enough to capture the process and determine the product-process relationships. To this end, the effect of process settings on the degradation of the active pharmaceutical ingredient (API) in a lab-scale Leistritz ZSE12 extruder was investigated. As part of the presented study, the limitations of traditional process analysis using integral process values were investigated, together with the potential that simulations may have in predicting the process performance and the product quality. The results of our investigation indicate that the average melt temperatures and the exposure times in specific zones along the screw configuration correlate well with the API degradation values and can be used as potent process design criteria to simplify the process development.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Towards predicting the product quality in hot-melt extrusion: Small scale extrusion

Matić

Alva

Witschnigg

et al. 2020

International Journal of Pharmaceutics: X

Self Cite

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“…Since the processed formulations are binary mixtures, a screw configuration that does not introduce extensive amount of shear was selected ( Figure 1 a). The arrangement and choice of the kneading blocks guaranteed a soft back-conveying section with enhanced distributive mixing capabilities, allowing a sufficient local residence time for melting the formulations [ 38 , 39 , 40 ]. Consequently, any potential API agglomerate that may have formed in the hopper breaks up, which guarantees a uniform API distribution in the polymer matrix.…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, any potential API agglomerate that may have formed in the hopper breaks up, which guarantees a uniform API distribution in the polymer matrix. In addition, in order to prevent any thermal degradation, two consecutive mixing elements were chosen to increase distributive mixing without introducing high viscous dissipation [ 22 , 38 , 40 ]. All open barrels for side/top feeding (barrel 4 and 5 in Figure 1 a) or de-gassing (barrel 6 and 9 in Figure 1 a) remained closed by closing inserts.…”

Section: Methodsmentioning

confidence: 99%

“…Conveying elements with a continuous and unbroken geometry, such as GFA and GFF elements, have a continuous melt transport. In contrast, kneading elements have a discontinuous geometry with typically four or five kneading blocks designed to break up, stretch and fold the flow in order to facilitate sufficient distributive and dispersive mixing and to increase the residence time [22,38,40,67]. This inevitably leads to local accelerated and decelerated flow with lower material transport than that in the conveying elements, which is also valid for the solvent flow during the solvent-based cleaning sequence.…”

Section: Api Cleaningmentioning

confidence: 99%

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Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion

et al. 2020

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To avoid any type of cross-contamination, residue-free production equipment is of utmost importance in the pharmaceutical industry. The equipment cleaning for continuous processes such as hot melt extrusion (HME), which has recently gained popularity in pharmaceutical applications, necessitates extensive manual labour and costs. The present work tackles the HME cleaning issue by investigating two cleaning strategies following the extrusion of polymeric formulations of a hormonal drug and for a sustained release formulation of a poorly soluble drug. First, an in-line quantification by means of UV–Vis spectroscopy was successfully implemented to assess very low active pharmaceutical ingredient (API) concentrations in the extrudates during a cleaning procedure for the first time. Secondly, a novel in-situ solvent-based cleaning approach was developed and its usability was evaluated and compared to a polymer-based cleaning sequence. Comparing the in-line data to typical swab and rinse tests of the process equipment indicated that inaccessible parts of the equipment were still contaminated after the polymer-based cleaning procedure, although no API was detected in the extrudate. Nevertheless, the novel solvent-based cleaning approach proved to be suitable for removing API residue from the majority of problematic equipment parts and can potentially enable a full API cleaning-in-place of a pharmaceutical extruder for the first time.

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Numerical Investigation of the Local Shear Rate in a Twin‐Screw Extruder for the Continuous Processing of Li‐Ion Battery Electrode Slurries

Gonzalez

Nirschl

2023

Energy Tech

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The mixing step for electrode slurry preparation in the manufacture of batteries is highly relevant because it directly affects the downstream production processes and the performance of the battery cells. In this work, a study of the flow behavior and material strain in a twin‐screw extruder is carried out to analyze its efficiency for continuous battery slurry processing. Here, individual elements of the extruder screw are simulated using the smoothed particle hydrodynamics method. Based on the resulting flow profiles, a dimensionless analysis is used to validate the calculations. Hence, the local shear rate and pressure profiles are evaluated for different screw geometries. The effects of the screw design and process setup are discussed, to accordingly improve the mixing process.

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A novel in silico scale-up approach for hot melt extrusion processes

Cited by 18 publications

References 19 publications

Towards predicting the product quality in hot-melt extrusion: Small scale extrusion

Towards predicting the product quality in hot-melt extrusion: Small scale extrusion

Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion

Numerical Investigation of the Local Shear Rate in a Twin‐Screw Extruder for the Continuous Processing of Li‐Ion Battery Electrode Slurries

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