5. REFERENCES 6. ACKNOWLEDGEMENTS - uni-bonn.de · 2014-04-03 · Th. Kipping, H. Rein Department...
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Th. Kipping, H. Rein Department of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany (email: [email protected]) 1. INTRODUCTION Right now hot-melt extrusion is gaining more and more interest in pharmaceutical industry. One of the main advantages, apart from improving the bioavailability of an API, is the possibility to move away from batch processing towards continuous production. The main aspect of this work involves the implementation of a dynamic fly-knife cutting machine into the production line in order to cut the semi-finished strands into biplanar, tablet-like solid dosage forms. Special focus is laid on the production of fast dissolving gum arabic extrudates, which due to their immediately release show a great potential for buccal administration. In contrast starch-based extrudates provide an extended retard formulation. Depending on swelling processes in the matrix a variation of the amylose- amylopectin ratio can modify the release (Fig. 4 d, e). All samples were stored in a climatic chamber according to ICH-Q1A guideline (subtropical and Mediterranean climates). Additionally products were analyzed concerning uniformity of mass, content uniformity, tensile strength, glass transition temperature and dissolution behavior. 2. MATERIALS AND METHODS Extrusion was carried out by using a Leistritz twin screw extruder type ZSE 27 HP-PH (Nürnberg, Germany). The cutting machine type Dynamat 20 was provided and further developed by Metzner (Neu Ulm, Germany). Data acquisition was done by using the LexiumCT software from Schneider Electric (Paris, France). Analytical devices: X-ray diffractometer PW1830/40, Panalytical (Almelo, Netherlands) Scanning electron microscope S2460, Hitachi (Tokyo, Japan) Dynamic mechanical analyzer Eplexor 100 N, Gabo (Ahlden, Germany) Texture Analyzer TA.HDi, stable micro systems (Godalming, United Kingdom) 3.2 Temperature influence Determining glass transition temperatures (Tgs) of the extruded material is an important aspect concerning available cutting temperatures of the strands as well as estimating the storage stability of the products. Tg should at least be 50 K above storage temperature to prevent molecular movements inside a solid solution [2]. Starch based products show a sufficient stability. For gum arabic a long-term storage might be more problematic (Fig.2). For each material the cutting temperature has to be individually adjusted. SEM pictures in Fig.3 demonstrate occurring problems caused by inadequately tempered material. The melt accumulates on the surface of the blade and leaves a trace of solidified material. Fig.2: Glass transition temperatures of different starch- and gum arabic-based extrudates; plasticizing effect of API addition (n = 2) Fig.3: SEM pictures of cut corn starch-placebo extrudates; cutting temperature set too high (~ 60 °C) 3.3 Content uniformity / uniformity of mass / dissolution studies Considering an industrial application of this technique, an important aspect will be the ability to provide content uniformity. Fig.4 a) and c) show the exemplary results of different extrudates containing 10% of paracetamol. The in relative terms lower amount of API can be linked to water addition during the process. No segregation tendencies or possible drug degradation could be observed. For the start-stop mode an adequate uniformity of mass is achieved. Texture Analyzer TA.HDi, stable micro systems (Godalming, United Kingdom) Automatic Dissolution tester type PTW S, Pharmatest (Hainburg, Germany) Fig.1: Schematic overview of the production line 3. RESULTS 3.1 Extrusion characteristics Physical parameters of placebo extrudates are shown in Tab.1. There are considerable differences while comparing the mean specific energy input (MSEI) of the different starches. Largest differences are observed between Eurylon 7, a high amylose corn starch (0,488 kW*h/kg) and Waxilys 200, an amylose-free starch containing a high amount of amylopectin (1.292 kW*h/kg). Variations in die-swelling can be explained by different molecular weights of the starch components [1]. Tab.1: Physical properties of different placebo extrudates. 2011 AAPS Annual Meeting and Exposition October 23 - 27 Fig. 4: Content uniformity of starch-based (a) and gum arabic-based extrudates (b); percentage related to mean value, n = 30; Uniformity of mass corn starch placebo (c), n = 100; dissolution profiles: starches (lidocaine 10 %) (d); gum arabic with an increasing amount of paracetamol (e), medium 0.1 N HCl 3.4 Mechanical stability Fig.5: Tensile strength measurements of different extrudates (different starches; gum arabic) Fig.6: Pictures of the tested products; different starches with addition of lidocaine (10%): left to right: Corn Starch, Eurylon 7, Pea Starch, Potato Starch, Waxilys 200 (height: 3 mm) 4. DISCUSSION / OUTLOOK In a first attempt the application of this new technique provided a continuous and reliable process. High values for tensile strength indicate a secured prolonged release, avoiding unexpected burst effects. For some materials there only remains a small time window for placing a cut. It can be extended by integrating a temperature control unit into the production line. Further modifications of the cutting machine will be necessary in order to obey GMP-conformity. An automation of the whole process will be unavoidable for establishing the system on the market. An interesting opportunity would be the installation of a contact-free loop control, delivering signals directly to the cutting machine. 5. REFERENCES [1] H. Liu et al. Thermal processing of starch-based polymers, Progress in Polymer Science 34 (2009) 1348-1368 [2] B.C. Hancock et al. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures, Pharmaceutical Research 12 (1995) 799-806 6. ACKNOWLEDGEMENTS Great thanks go to Leistritz Extrusionstechnik GmbH (Nürnberg, Germany) and Metzner Maschinenbau GmbH (Neu Ulm, Germany) for the excellent cooperation. A big thank you also goes to Roquette (Lestrem, France) for providing a large variety of different starches. Basic Substances Feeding rate (Material) [kg/h] Feeding rate (Water) [kg/h] Extrusion speed [cm/min] Rotation Speed [rpm] MSEI [kW*h/kg] Die swelling Density [g/cm 3 ] Corn Starch 1.4 0.31 51.8 150 1.046 1.31 1.477 Eurylon ® 7 1.4 0.40 109.8 150 0.488 0.89 1.490 Potato Starch 1.4 0.27 45.0 150 0.955 1.35 1.409 Waxilys ® 200 1,4 0.28 41.9 175 1.211 1.29 1.425 Pea Starch 1.4 0.31 42.8 150 0.876 1.34 1.509 Instant GumAA 0.8 0.19 36.3 75 0.343 1.21 1.486 c) d) height: 1,5 mm Mechanical stability was tested by calculating the tensile strength of the biplanar extrudates. Extremely high crushing strength is needed to break the starch-based extrudates (up to 1000 N for potato starch) gum arabic-based extrudates show much lower breaking strength (100 N - 300 N). API addition decreases the stability of the products. a) b) c) d) e)
Transcript of 5. REFERENCES 6. ACKNOWLEDGEMENTS - uni-bonn.de · 2014-04-03 · Th. Kipping, H. Rein Department...
Th. Kipping, H. Rein Department of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Str. 3, 53121 Bonn, Germany (email: [email protected])
1. INTRODUCTIONRight now hot-melt extrusion is gaining more and more interest in pharmaceutical industry.One of the main advantages, apart from improving the bioavailability of an API, is thepossibility to move away from batch processing towards continuous production. The mainaspect of this work involves the implementation of a dynamic fly-knife cutting machine intothe production line in order to cut the semi-finished strands into biplanar, tablet-like soliddosage forms. Special focus is laid on the production of fast dissolving gum arabicextrudates, which due to their immediately release show a great potential for buccaladministration. In contrast starch-based extrudates provide an extended retardformulation. Depending on swelling processes in the matrix a variation of the amylose-amylopectin ratio can modify the release (Fig. 4 d, e). All samples were stored in a climaticchamber according to ICH-Q1A guideline (subtropical and Mediterranean climates).Additionally products were analyzed concerning uniformity of mass, content uniformity,tensile strength, glass transition temperature and dissolution behavior.
2. MATERIALS AND METHODSExtrusion was carried out by using a Leistritz twin screw extruder type ZSE 27 HP-PH(Nürnberg, Germany). The cutting machine type Dynamat 20 was provided and furtherdeveloped by Metzner (Neu Ulm, Germany). Data acquisition was done by using theLexiumCT software from Schneider Electric (Paris, France).Analytical devices:X-ray diffractometer PW1830/40, Panalytical (Almelo, Netherlands)Scanning electron microscope S2460, Hitachi (Tokyo, Japan)Dynamic mechanical analyzer Eplexor 100 N, Gabo (Ahlden, Germany)Texture Analyzer TA.HDi, stable micro systems (Godalming, United Kingdom)
3.2 Temperature influenceDetermining glass transition temperatures (Tgs) of the extruded material is an important aspect concerning available cutting temperatures of the strands as well as estimating the storagestability of the products. Tg should at least be 50 K above storage temperature to prevent molecular movements inside a solid solution [2]. Starch based products show a sufficientstability. For gum arabic a long-term storage might be more problematic (Fig.2). For each material the cutting temperature has to be individually adjusted. SEM pictures in Fig.3demonstrate occurring problems caused by inadequately tempered material. The melt accumulates on the surface of the blade and leaves a trace of solidified material.
Fig.2: Glass transition temperatures of different starch- and gum arabic-based extrudates; plasticizing effect of API addition (n = 2) Fig.3: SEM pictures of cut corn starch-placebo extrudates; cutting temperature set too high (~ 60 °C)
3.3 Content uniformity / uniformity of mass / dissolution studiesConsidering an industrial application of this technique, an important aspect will be the ability to provide content uniformity. Fig.4 a) and c) show the exemplary results of differentextrudates containing 10% of paracetamol. The in relative terms lower amount of API can be linked to water addition during the process. No segregation tendencies or possible drugdegradation could be observed. For the start-stop mode an adequate uniformity of mass is achieved.
Texture Analyzer TA.HDi, stable micro systems (Godalming, United Kingdom)Automatic Dissolution tester type PTW S, Pharmatest (Hainburg, Germany)
Fig.1: Schematic overview of the production line
3. RESULTS3.1 Extrusion characteristicsPhysical parameters of placebo extrudates are shown in Tab.1. There are considerabledifferences while comparing the mean specific energy input (MSEI) of the differentstarches. Largest differences are observed between Eurylon 7, a high amylose corn starch(0,488 kW*h/kg) and Waxilys 200, an amylose-free starch containing a high amount ofamylopectin (1.292 kW*h/kg). Variations in die-swelling can be explained by differentmolecular weights of the starch components [1].
Tab.1: Physical properties of different placebo extrudates.
2011 AAPS Annual Meeting and Exposition October 23 - 27
Fig. 4: Content uniformity of starch-based (a) and gum arabic-based extrudates (b); percentage related to mean value, n = 30; Uniformity of mass corn starch placebo (c), n = 100; dissolution profiles: starches (lidocaine 10 %) (d); gum arabic with an increasing amount of paracetamol (e), medium 0.1 N HCl
3.4 Mechanical stability
Fig.5: Tensile strength measurements of different extrudates (different starches; gum arabic) Fig.6: Pictures of the tested products; different starches with addition of lidocaine (10%): left to right: Corn Starch, Eurylon 7, Pea Starch, Potato Starch, Waxilys 200 (height: 3 mm)
4. DISCUSSION / OUTLOOKIn a first attempt the application of this new technique provided a continuous and reliable process. High values for tensile strength indicate a secured prolonged release, avoidingunexpected burst effects. For some materials there only remains a small time window for placing a cut. It can be extended by integrating a temperature control unit into the productionline. Further modifications of the cutting machine will be necessary in order to obey GMP-conformity. An automation of the whole process will be unavoidable for establishing the systemon the market. An interesting opportunity would be the installation of a contact-free loop control, delivering signals directly to the cutting machine.
5. REFERENCES[1] H. Liu et al. Thermal processing of starch-based polymers, Progress in Polymer Science 34 (2009) 1348-1368[2] B.C. Hancock et al. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures, Pharmaceutical Research 12 (1995) 799-806
6. ACKNOWLEDGEMENTSGreat thanks go to Leistritz Extrusionstechnik GmbH (Nürnberg, Germany) and Metzner Maschinenbau GmbH (Neu Ulm, Germany) for the excellent cooperation. A big thank you alsogoes to Roquette (Lestrem, France) for providing a large variety of different starches.
Basic Substances
Feeding rate (Material)
[kg/h]
Feeding rate (Water) [kg/h]
Extrusion speed
[cm/min]
Rotation Speed [rpm]
MSEI [kW*h/kg]
Die swelling
Density[g/cm3]
Corn Starch 1.4 0.31 51.8 150 1.046 1.31 1.477
Eurylon®7 1.4 0.40 109.8 150 0.488 0.89 1.490
Potato Starch 1.4 0.27 45.0 150 0.955 1.35 1.409
Waxilys®200 1,4 0.28 41.9 175 1.211 1.29 1.425
Pea Starch 1.4 0.31 42.8 150 0.876 1.34 1.509
Instant Gum AA 0.8 0.19 36.3 75 0.343 1.21 1.486
c) d) height: 1,5 mm
Mechanical stability was tested by calculating the tensile strength of the biplanar extrudates. Extremely highcrushing strength is needed to break the starch-based extrudates (up to 1000 N for potato starch) gumarabic-based extrudates show much lower breaking strength (100 N - 300 N). API addition decreases thestability of the products.
a) b) c) d) e)
