Dissolution enhancement of gliclazide using in situ micronization by solvent change method J. Varshosaz a, ⁎, R. Talari a,b , S.A. Mostafavi a , A. Nokhodchi c,d a Isfahan Pharmaceutical Sciences Research Center, and Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran b School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran c Medway School of Pharmacy, The Universities of Kent and Greenwich, Central Ave., Chathman Maritime, Kent ME4 4TB, England, United Kingdom d Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran ABSTRACT ARTICLE INFO Article history: Received 6 May 2007 Received in revised form 16 January 2008 Accepted 29 February 2008 Available online 18 March 2008 Keywords: Micronization Gliclazide Solubility DSC XRD FTIR Gliclazide (GL) is a second-generation sulphonylurea, widely used for the treatment of non-insulin dependent diabetes mellitus. The low water-solubility of GL leads to a low dissolution rate and variable bioavailability. The aim of this study was to enhance the dissolution rate of GL by the preparation of micron-sized particles using a solvent change method. The in situ micronization process was carried out using solvent change method in the presence of HPMC or Brij 35 (0.05 or 0.1 g) as stabilizing agents. GL (0.5 or 1 g) was dissolved in acetone and the stabilizing agent in water (as non-solvent). The non-solvent was poured rapidly into the drug solution under stirring at 26,000 rpm by an ultra-homogenizer, and the resultant was freeze-dried. The crystalline shape of GL changed from rod-shape to diamond- or cube-shape. The FTIR and DSC results showed no interaction between the drug and the stabilizers. Presence of sharp peaks in the XRD diffractograms of microcrystals with 10 times smaller height than untreated crystals indicates that a crystalline habit modification has occurred in the microcrystals without any polymorphic changes. The particle size was reduced about 50 times and the dissolution efficiency of GL at 15 min (DE 15 %) was increased about 4 times. © 2008 Elsevier B.V. All rights reserved. 1. Introduction Many drugs are poorly soluble or insoluble in water, which results in poor bioavailability because the solubility of a drug is an important factor in determining the rate and extent of its absorption [1]. For class II-drugs, according to the biopharmaceutics classification system [2], the dissolution rate is the limiting factor for the drug absorption rate. Also for class IV-drugs the dissolution rate can be the limiting factor. An enhancement in the dissolution rate of these drugs can increase the blood-levels to a clinically suitable level. One way to improve the dissolution rate is to reduce particle size, which increases the total surface area [3]. Several methods of reducing particle size have been suggested. Physical methods such as milling and grinding [4] are successful in particle size reduction; however the particle size uniformity is not achieved. A common particle size reduction method for hydrophobic drugs is microcrystallization [5]. A common method for increasing the dissolution rate is to form a high specific surface area by micronization. The process which is usually used to obtain small particles is the disruption of large crystals. Chaumeil [6] de- scribes the improvement in dissolution rate and in bioavailability by micronization of sparingly water-soluble drugs using jar mills and fluid energy mills. The micronization process using mills is extremely inefficient [7] due to a high energy input. On the other hand, dis- ruptions in the crystal lattice can cause physical or chemical instability [8,9], because disordered regions in the resulting product are ther- modynamically unstable. Surface energy changes can also influence processing properties such as the powder flow. Micronized powders with a higher energetic surface show poorer flow properties [10]. Due to their high specific surface, micronized particles are often agglom- erated [11]. Micron-sized spherical particles can be prepared by spray- drying of a drug solution. Spray-dried drugs, which are amorphous, show a smaller and more homogeneous particle size and, for in- halation process a higher respirable fraction than mechanically micro- nized drugs [12,13]. However, even spray-dried amorphous drugs show only incomplete dispersion, indicated by a fine particle fraction [14]. Because of the disadvantages of milling process techniques were developed that produce the drug directly in the optimal particle size. However, the preparation and stabilization of small particles are not easy because of their tendency to grow. Because of the high structure that must be created, the established methods need high amounts of Powder Technology 187 (2008) 222–230 ⁎ Corresponding author. E-mail address: varshosaz@pharm.mui.ac.ir (J. Varshosaz). 0032-5910/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2008.02.018 Contents lists available at ScienceDirect Powder Technology journal homepage: www.elsevier.com/locate/powtec