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      Inline Determination of Residence Time Distribution in Hot-Melt-Extrusion

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          Abstract

          In the framework of Quality-by-Design (QbD), the inline determination of process parameters or quality attributes of a product using sufficient process analytical technology (PAT) is a center piece for the establishment of continuous processes as a standard pharmaceutical technology. In this context, Twin-Screw-Extrusion (TSE) processes, such as Hot-Melt-Extrusion (HME), are one key aspect of current research. The main benefit of this process technology is the combination of different unit operations. Several of these sub-processes are linked to the Residence Time Distribution (RTD) of the material within the apparatus. In this study a UV/Vis spectrophotometer from ColVisTec was tested regarding the suitability for the inline determination of the RTD of an HME process. Two different measuring positions within a co-rotating Twin-Screw-Extruder were compared to an offline HPLC–UV as reference method. The obtained results were overall in good agreement and therefore the inline UV/Vis spectrophotometer is suitable for the determination of the RTD in TSE. An influence of the measuring position on repeatability was found and has to be taken into consideration for the implementation of PATs. An effect of the required amount of marker on process rheology is not likely due to the low Limit-of-Quantification (LoQ).

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          Most cited references 24

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          Melt extrusion: from process to drug delivery technology.

          Starting from the plastic industry, today melt extrusion has found its place in the array of pharmaceutical manufacturing operations. This article reviews the process technology with regard to the set up and specific elements of the extruder as well as its application. Melt extrusion processes are currently applied in the pharmaceutical field for the manufacture of a variety of dosage forms and formulations such as granules, pellets, tablets, suppositories, implants, stents, transdermal systems and ophthalmic inserts. As a specific area the manufacture of solid dispersions, in particular, solid molecular dispersions using the melt extrusion process is reviewed. Melt extrusion is considered to be an efficient technology in this field with particular advantages over solvent processes like co-precipitation. Potential drawbacks like the influence of heat stress and shear forces on the drug active have been overcome in a number of examples with drugs of different chemical structure. Examples of suitable excipients and recent findings like self-emulsifying preparations are presented. The article concludes with a number of published examples of melt extrudates applying the principle of solid molecular dispersions. Improved bioavailability was achieved again demonstrating the value of the technology as a drug delivery tool.
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            Stability of polyethylene oxide in matrix tablets prepared by hot-melt extrusion.

            The thermal stability of polyethylene oxide (PEO) in sustained release tablets prepared by hot-melt extrusion was investigated. The weight average molecular weight of the polymer was studied using gel permeation chromatography. The chemical stability of PEO was found to be dependent on both the storage and processing temperature, and the molecular weight of the polymer. Storage of the polymer above its melting point significantly increased polymer degradation, and the degradation process was accelerated as the molecular weight was reduced. The thermal stability of PEO MW = 1,000,000 (PEO 1 M) in sustained release chlropheniramine maleate (CPM) tablets prepared by hot-melt extrusion was found to depend on the processing temperature and screw speed. Lower molecular weight PEO MW = 100,000 (PEO 100 K) was demonstrated to be a suitable processing aid for PEO 1 M. Incorporation of PEO 100 K reduced degradation of PEO 1 M and did not alter the release rate of CPM. Vitamin E, Vitamin E Succinate and Vitamin E TPGS were found to be suitable stabilizers for PEO, however, ascorbic acid was shown to degrade the polymer in solution. Thermal analysis demonstrated that Vitamin E Succinate and Vitamin E TPGS were dispersed at the molecular level in hot-melt extruded tablets. Solubilized Vitamin E Succinate and Vitamin E TPGS suppressed the melting point of the polyethylene oxide. Drug release rates from hot-melt extruded tablets stabilized with antioxidants were found to be dependent on the hydrophilic nature of the antioxidant.
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              Novel delivery device for monolithical solid oral dosage forms for personalized medicine.

              There is an evident need for solid oral dosage forms allowing patients' tailor-made dosing due to variations in metabolization or small therapeutic indexes of drug substances. The objective of this work is the development of a device equipped with a novel solid dosage form, containing carvedilol as model drug, for the delivery of monolithical drug carriers in individual doses. The device was developed and constructed enabling an exact feed rate and dose adjustment by a cutting mechanism. A twin-screw extruder was used for producing cylindrical solid dosage forms. Divided doses were characterized by mass variation, cutting behavior and drug dissolution in order to investigate their applicability for practical use. Different formulations could be extruded obtaining straight cylindrical rods, which are divisible in exact slices by using the novel device. Forces below 20 N were needed to divide doses which comply with pharmacopoeial specification "conformity of mass". The developed formulations exhibit a sustained release of carvedilol within a range from 7 up to 16 h. A novel system consisting of a device and a cylindrical dosage form was developed. Patients' individual doses can be applied as monolithical solid dosage forms for oral use.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                15 April 2018
                June 2018
                : 10
                : 2
                Affiliations
                [1 ]Institute of Solids Process Engineering, TU Dortmund University, Dortmund 44227, Germany; jens.wesholowski@ 123456tu-dortmund.de
                [2 ]ColVisTec AG, Berlin 12489, Germany; a.berghaus@ 123456colvistec.de
                Author notes
                [* ]Correspondence: markus.thommes@ 123456tu-dortmund.de ; Tel.: +49-231-755-5954
                pharmaceutics-10-00049
                10.3390/pharmaceutics10020049
                6027324
                29662034
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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