2013 http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, 2014; 19(8): 911–921 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2013.840844 RESEARCH ARTICLE Investigation into physical–chemical variables affecting the manufacture and dissolution of wet-milled clarithromycin nanoparticles Maliheh Shahbazi Niaz 1 , Daniela Traini 2,3 , Paul M. Young 2,3 , Maliheh Ghadiri 4 , and Ramin Rohanizadeh 4 1 Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 2 Respiratory Technology, Woolcock Institute of Medical Research, Glebe, NSW, Australia, 3 Discipline of Pharmacology, Sydney Medical School, University of Sydney, NSW, Australia, and 4 Advanced Drug Delivery Group, Faculty of Pharmacy, University of Sydney, Australia Abstract A critical problem associated with poor water-soluble drugs is their low and variable bioavailability, which is derived from the slow dissolution and erratic absorption. Nano- formulation has been identified as one approach to enhance the rate and extent of drug absorption for compounds that demonstrate limited water solubility. This study aimed to investigate the physico-chemical variables that affect the manufacture, dissolution and consequent bioavailability of wet-milled clarithromycin (CLA) nanoparticles, a macrolide antibiotic. CLA nanoparticles were prepared using wet milling method followed by freeze- drying. Different stabilizer systems, consisting of surfactants and polymers alone or their combinations were studied to determine the optimum conditions for producing nano-sized CLA particles. In vitro characterizations of the CLA nanoparticles were performed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry and dissolution efficiency test. Results showed that in general the wet milling process did not modify the crystallinity of the CLA nanoparticles. The poloxamers and polyvinyl alcohol (PVA) stabilizers resulted in nanoparticles with the smallest particle size and best dissolution rates. Furthermore, poloxamers F68 and F127, and PVA stabilizers demonstrated the best performance in increasing dissolution efficacy. Keywords Clarithromycin, dissolution efficiency, nanoparticles, stabilizers, wet milling History Received 26 February 2013 Revised 14 August 2013 Accepted 21 August 2013 Published online 4 October 2013 Introduction Orally administered poorly water-soluble drugs suffer from low absorption from the gastrointestinal tract, resulting in their decreased bioavailability. There are different approaches to increase the solubility of this class of compound, including the use of solvent mixtures, complexation with cyclodextrins, devel- opment of solid solutions or preparing emulsion or suspension formulations 1 . The success of these methods is dependent on the specific physico-chemical properties of the drug used 2 and often still has limitations 3 . One approach that can be applied to the majority of drugs in this class is direct particle size reduction. Reduction of the active pharmaceutical ingredient particle size down to the sub-micron range can improve the water solubility of drug, increasing bioavailability without the need for advanced nanotechnology approaches such as polymeric encapsulation or chemical fusion. These nanoparticles, having sizes between a few nm to 1000nm, have a larger surface area to volume ratio, which improves the solubility of particles according to the Noyes- Whitney equation 4,5 and can contain 100% drug without the use of a carrier or excipient material 1 . While drug nanoparticles can be produced by precipitation technology (bottom-up approach 6 ), the combination or milling of larger material to the nano-size may provide a preferred means of processing since it is less dependent on solubility, surface chemistry and crystallization kinetics that are encountered in the bottom-up approaches. Top-down ‘‘nanoization’’ can be achieved using high-pressure homogenization and/or media milling techniques. Both approaches have already been used for the nano-formulation of five marketed oral drug delivery prod- ucts, four of which were fabricated using a wet milling method 3 . While this approach has many advantages over polymeric encapsulation and complexation, ultimately, these milling pro- cesses increase the total surface area of the drug, making them thermodynamically unstable; resulting in a drive to minimize the Gibbs free energy via agglomeration 3 . The addition of ionic or non-ionic stabilizers to the medium may prevent such agglom- eration via electrostatic repulsion or steric interference, respect- ively 5 , with further stabilization being possible via altering the molecular weight, viscosity, surface tension and chemical func- tionality of the suspending media and stabilizers 4 . Although the selection of effective stabilizers is clearly an important issue, available information on the relationship between stabilizers chemistry and nanoparticles stability is still relatively limited. Clarithromycin (CLA), a macrolide antibiotic with molecular structure shown in Figure 1, is a weak base molecule with one dimethylamino moiety as the only ionizable group (pK 9.2) 7 . CLA can be used for the treatment of the upper and lower respiratory tract infections, skin and HIV-related opportunis- tic infections 8–11 . Based on the biopharmaceutical classifica- tion system, CLA is a class II antibiotic, having an acceptable permeability but poor solubility, resulting in a Address for correspondence: Ramin Rohanizadeh, Faculty of Pharmacy (A15), University of Sydney, Sydney, NSW 2006, Australia. E-mail: ramin.rohanizadeh@sydney.edu.au Pharmaceutical Development and Technology Downloaded from informahealthcare.com by University of Sydney on 01/14/14 For personal use only.