Scale-Up of pharmaceutical Hot-Melt-Extrusion: Process optimization and transfer

Wesholowski, Jens; Hoppe, Kevin; Nickel, Kathrin; Muehlenfeld, Christian; Thommes, Markus

doi:10.1016/j.ejpb.2019.07.009

Cited by 36 publications

(16 citation statements)

References 26 publications

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“…The residence time was considered the time from the beginning of feeding up to the opening of the recirculation valve when the melt begins to extrude from the die. A residence time of 5 min was selected as this is within the typical range of a hot melt extrusion process and has been found to be suitable for the small-scale equipment used in these experiments . Extrudate rods were cryomilled for 30 s under liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

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Impact of Polymer Type on Thermal Degradation of Amorphous Solid Dispersions Containing Ritonavir

et al. 2021

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High-temperature exposure during hot melt extrusion processing of amorphous solid dispersions may result in thermal degradation of the drug. Polymer type may influence the extent of degradation, although the underlying mechanisms are poorly understood. In this study, the model compound, ritonavir (T m = 126 °C), undergoes thermal degradation upon high-temperature exposure. The extent of degradation of ritonavir in amorphous solid dispersions (ASDs) formulated with poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone) vinyl acetate copolymer (PVP/VA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and hydroxypropyl methylcellulose (HPMC) following isothermal heating and hot melt extrusion was evaluated, and mechanisms related to molecular mobility and intermolecular interactions were assessed. Liquid chromatography–mass spectrometry (LC–MS/MS) studies were used to determine the degradation products and pathways and ultimately the drug–polymer compatibility. The dominant degradation product of ritonavir was the result of a dehydration reaction, which then catalyzed a series of hydrolysis reactions to generate additional degradation products, some newly reported. This reaction series led to accelerated degradation rates with protic polymers, HPMCAS and HPMC, while ASDs with aprotic polymers, PVP and PVP/VA, had reduced degradation rates. This work has implications for understanding mechanisms of thermal degradation and drug–polymer compatibility with respect to the thermal stability of amorphous solid dispersions.

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Section: Methodsmentioning

confidence: 99%

“…A residence time of 5 min was selected as this is within the typical range of a hot melt extrusion process and has been found to be suitable for the small-scale equipment used in these experiments. 18 Extrudate rods were cryomilled for 30 s under liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

Impact of Polymer Type on Thermal Degradation of Amorphous Solid Dispersions Containing Ritonavir

et al. 2021

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“…Galant et al 141 evaluated a continuous TSE process against conventional solvent-batch cocrystallization methods and observed a considerable decrease in numerous sustainability and green chemistry parameters, including energy efficiency, impact on climate change, and human and ecological health, as well as cost due by minimizing excessive reactant consumption and solvent usage while retaining high product selectivity. Wesholowski et al 142 investigated scale-up of a pharmaceutical HME for process optimization and transfer with respect to continuous manufacturing of pharmaceutical materials. TSE is widely used in the synthesis of organic compounds, metal−organic frameworks, and peptides, reaching kilogram per hour scales under solid-state or minimal-solvent conditions.…”

Section: ■ Insight Into the Scaling Up Of Mechanochemical Cocrystalli...mentioning

confidence: 99%

Opportunities and Challenges in Mechanochemical Cocrystallization toward Scaled-Up Pharmaceutical Manufacturing

Madanayake

Manipura

Thakuria

et al. 2023

Org. Process Res. Dev.

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Recently, pharmaceutical cocrystals have gained immense interest because of their potential to tune mechanical, pharmacokinetic, and physicochemical properties of active pharmaceutical ingredients (APIs) while keeping their therapeutic action intact. In this review, cocrystallization is raised as a viable strategy toward commercialized pharmaceutical manufacturing, where attention has been paid to solid-state cocrystal preparation methods and their opportunities and challenges in overall product and process development. A comparative study of cocrystallization in the form of mechanical energy is demonstrated with the aid of SELECT criteria to qualitatively evaluate the synthetic route selection of scalable mechanochemical cocrystallization methods. Remedies and alternatives for the challenges that arise in mechanochemical synthesis of cocrystals are presented in this review, highlighting the commercial perspectives of sustainable, eco-friendly, and less toxic mechanochemical methods.

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“…These hot spots could lead to degradation of thermally sensitive API or polymers, if not addressed through an adaption of process parameters affecting the SME, such as feed rate, screw speed, screw configuration, and/or the general temperature profile of the barrel (12,13). Additionally, these interactions are shifting in relevance among the various scales, complicating the scale-up process even more (14).…”

Section: Introductionmentioning

confidence: 99%

ASD Formation Prior to Material Characterization as Key Parameter for Accurate Measurements and Subsequent Process Simulation for Hot-Melt Extrusion

2022

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Process simulation facilitates scale-up of hot-melt extrusion (HME) and enhances proper understanding of the underlying critical process parameters. However, performing numeric simulations requires profound knowledge of the employed materials’ properties. For example, an accurate description of the compounds’ melt rheology is paramount for proper simulations. Hence, sample preparation needs to be optimized to yield results as predictive as possible. To identify the optimal preparation method for small amplitude oscillatory shear (SAOS) rheological measurements, binary mixtures of hydroxypropylmethylcellulose acetate succinate or methacrylic acid ethyl acrylate copolymer (Eudragit L100-55) together with the model drugs celecoxib and ketoconazole were prepared. The physical powder mixtures were introduced into the SAOS as a compressed tablet or a disk prepared via vacuum compression molding (VCM). Simulations with the derived parameters were conducted and compared to lab-scale extrusion trials. VCM was identified as the ideal preparation method resulting in the highest similarity between simulated and experimental values, while simulation based on conventional powder-based methods insufficiently described the HME process.

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Scale-Up of pharmaceutical Hot-Melt-Extrusion: Process optimization and transfer

Cited by 36 publications

References 26 publications

Impact of Polymer Type on Thermal Degradation of Amorphous Solid Dispersions Containing Ritonavir

Impact of Polymer Type on Thermal Degradation of Amorphous Solid Dispersions Containing Ritonavir

Opportunities and Challenges in Mechanochemical Cocrystallization toward Scaled-Up Pharmaceutical Manufacturing

ASD Formation Prior to Material Characterization as Key Parameter for Accurate Measurements and Subsequent Process Simulation for Hot-Melt Extrusion

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