A new method for the continuous production of single dosed controlled release matrix systems based on hot-melt extruded starch; analysis of relevant process parameters and implementation of an in-process control
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V | 15 Jan 2013
T Kipping and H Rein
PURPOSE: In the present study we evaluated a novel processing technique for the continuous production of hotmelt extruded controlled release matrix systems. A cutting technique derived from plastics industry, where it is widely used for cutting of cables and wires was adapted into the production line. Extruded strands were shaped by a rotary-fly cutter. Special focus is laid on the development of a process analytical technology by evaluating signals obtained from the servo control of the rotary fly cutter. The intention is to provide a better insight into the production process and to offer the ability to detect small variations in process-variables. MATERIALS AND METHODS: A co-rotating twin-screw extruder ZSE 27 HP-PH from Leistritz (Nürnberg, Germany) was used to plasticize the starch; critical extrusion parameters were recorded. Still elastic strands were shaped by a rotary fly-cutter type Dynamat 20 from Metzner (Neu-Ulm, Germany). Properties of the final products were analyzed via digital image analysis to point out critical parameters influencing the quality. Important aspects were uniformity of diameter, height, roundness, weight and variations in the cutting angle. Stability of the products was measured by friability tests and by determining the crushing strength of the final products. Drug loading studies up to 70% were performed to evaluate the capacity of the matrix and to prove the technological feasibility. Changes in viscosities during API addition were analyzed by a Haake Minilab capillary rheometer. X-ray studies were performed to investigate molecular structures of the matrices. RESULTS: External shapes of the products were highly affected by die-swelling of the melt. Reliable reproducibility concerning uniformity of mass could be achieved even for high production rates (>2500 cuts/min). Both mechanical strength and die swelling of the products could be linked to the ratio of amylose to amylopectin. Formulations containing up to 70% of API could still be processed. Viscosity measurements revealed the plasticizing effect caused by API addition. Dissolution data proved the suitability of extruded starch matrices as a sustained release dosage form. Monitoring of consumed energies during the cutting process could be linked to changes in viscosity. The established PAT system enables the detection of small variations in material properties and can be an important tool to further improve process stability.
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