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The Influence of Milling on the Dissolution Performance of Simvastatin
Solid State Group, School of Pharmacy, University of Otago, 18 Frederick Street, 9016 Dunedin, New Zealand
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, 70210 Kuopio, Finland
Pharmaceutical Development, Boehringer Ingelheim Vetmedica GmbH, Binger Str. 173, 55216 Ingelheim am Rhein, Germany
Department of Chemistry, MacDiarmid Institute for Advanced Materials and Nanotechnology, University of Otago, Union Place West, 9016 Dunedin, New Zealand
* Author to whom correspondence should be addressed.
Received: 2 December 2010; in revised form: 13 December 2010 / Accepted: 16 December 2010 / Published: 17 December 2010
Abstract: Particle size reduction is a simple means to enhance the dissolution rate of poorly water soluble BCS-class II and IV drugs. However, the major drawback of this process is the possible introduction of process induced disorder. Drugs with different molecular arrangements may exhibit altered properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors, as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed by scanning electron microscopy (SEM) and image analysis. Process induced disorder was determined by partial least squares (PLS) regression modeling of respective X-ray powder diffractograms (XRPD) and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were milling frequency, milling time and ball quantity at a set drug load, out of which milling frequency was found to be the most important factor for particle size as well as process induced disorder. Milling frequency and milling time exhibited an interaction effect on the responses. The optimum milling settings using the maximum number of milling balls (60 balls with 4 mm diameter) was determined to be at a milling frequency of 21 Hz and a milling time of 36 min with a resulting primary particle size of 1.4 μm and a process induced disorder of 6.1% (assessed by Raman spectroscopy) and 8.4% (assessed by XRPD), at a set optimization limit of < 2 μm for particle size and < 10% for process induced disorder. This optimum was tested experimentally and the process induced disorder was determined to be 6.9% (± 2.2) by Raman spectroscopy and 7.8% (± 2.3) by XRPD. Subsequent intrinsic dissolution testing revealed that the process induced disorder was negligible with regard to the dissolution rate. The predicted primary particle size of 1.4 μm could be confirmed experimentally, but due to agglomeration of the primary particles a dissolution rate advantage was not shown, highlighting the importance of dissolution testing at an early stage of drug development.
Keywords: dissolution rate; ball milling; process induced disorder; response surface modeling; simvastatin
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Zimper, U.; Aaltonen, J.; Krauel-Goellner, K.; Gordon, K.C.; Strachan, C.J.; Rades, T. The Influence of Milling on the Dissolution Performance of Simvastatin. Pharmaceutics 2010, 2, 419-431.
Zimper U, Aaltonen J, Krauel-Goellner K, Gordon KC, Strachan CJ, Rades T. The Influence of Milling on the Dissolution Performance of Simvastatin. Pharmaceutics. 2010; 2(4):419-431.
Zimper, Ulrike; Aaltonen, Jaakko; Krauel-Goellner, Karen; Gordon, Keith C.; Strachan, Clare J.; Rades, Thomas. 2010. "The Influence of Milling on the Dissolution Performance of Simvastatin." Pharmaceutics 2, no. 4: 419-431.