Nanoprecipitation of Poly(methyl methacrylate)-Based Nanoparticles: Effect of the Molar Mass and Polymer Behavior Igor Y. Perevyazko, 1,2 Antje Vollrath, 1,2 Christian Pietsch, 1,2,3 Stephanie Schubert, 1,2,4 Georgy M. Pavlov, 1,2 Ulrich S. Schubert 1,2,3 1 Laboratory of Organic and Macromolecular Chemistry (IOMC) Friedrich-Schiller-University, D-07743 Jena, Germany 2 Jena Center for Soft Matter (JCSM), Friedrich-Schiller-University, D-07743 Jena, Germany 3 Dutch Polymer Institute (DPI), Eindhoven 5600 AX, The Netherlands 4 Institute of Pharmacy, Department of Pharmaceutical Technology, Friedrich-Schiller-University, D-07743 Jena, Germany Correspondence to: U. S. Schubert (E-mail: ulrich.schubert@uni-jena.de) Received 8 March 2012; accepted 14 March 2012; published online DOI: 10.1002/pola.26071 ABSTRACT: The current investigation describes in detail the influence of the polymer molar mass as well as polymer-sol- vent interactions on the formation of nanoparticles using the nanoprecipitation methodology. For this purpose, a homolo- gous series of poly(methyl methacrylate)s with molar masses ranging from 7,700 to 274,000 g mol 1 was prepared. Subse- quently nanoprecipitation was performed in an automated and systematic manner using liquid handling robots and a variation of different initial concentrations of the polymers and solvent/ nonsolvent ratios. To elucidate information about the polymer behavior in the solvents used for the nanoprecipitation proce- dure (acetone, tetrahydrofuran), intrinsic viscosity measure- ments were performed. The nanoparticle formulations were examined in terms of particle size and size distribution, particle shape as well as zeta-potential. The conditions for the prepara- tion of stable and uniform nanoparticles, regardless of molar mass and hydrodynamic volume of the initial polymer, were determined. V C 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 000: 000–000, 2012 KEYWORDS: nanoparticles; nanoprecipitation; molar mass; PMMA; synthetic polymers; ultracentrifugation; viscosity INTRODUCTION Polymeric nanoparticles have been exten- sively studied in the last decades as potential drug delivery devices. Nanoparticle formation using the nanoprecipitation method 1 is nowadays a commonly used technique. Among the numerous other manufacturing methods, it is known to be a very simple and convenient way for the production of polymeric nanoparticles with desired sizes. 2,3 A variety of different polymers can be used, such as poly(lactide-co-glyco- lide), 4 poly(e-caprolactone), 5 poly(acrylics), poly(styrene), poly(methyl methacrylat) (PMMA), and its different copoly- mers as well as various amphiphilic block copolymers. 6–9 Nanoprecipitation represents a process based on the diffu- sion of the organic solution (i.e., polymer solvent) into an aqueous phase leading to the precipitation of the polymer into small colloidal particles. The formation of nanoparticles by the process complies with the nucleation theory and con- sists of several steps like particle nucleation, molecular growing, and aggregation. 10,11 Stable nanoparticle suspen- sions are only formed applying specific conditions, which promote a supersaturation of polymer molecules in a ternary polymer/solvent/nonsolvent system and shifts it into a metastable region (Ouzo region). 9,11–13 This region is located between the binodal (miscibility limit curve) and spinodal (stability limit curve) on a three component phase diagram based on the hydrophobic solute, the solvent, and the non- solvent. The resulting properties of the particles primarily depend on the polymer behavior in the organic phase but also on the nature and ratio of the external phase as well as on concentration and nature of the used surfactants. 14–18 It could be shown repeatedly that the particle size is strongly affected by the initial polymer concentration: higher concen- trations lead to an increasing number of molecules per vol- ume of the solvent, which, in turn, leads to the formation of larger particles. At the same time, the ratio between solvent and nonsolvent was found to have a more complex, nonlin- ear influence on the size of the particles. 9,18,19 Thorough investigation of the molar mass influence on the production of biodegradable nanoparticles based on poly(lactic acid) was first presented by Legrand et al. 16 This study was designed to determine in detail and to extend the under- standing of the effect of the polymer characteristics, in par- ticular the molar mass, on the nanoprecipitation results of synthetic polymers. For this purpose, PMMA samples were investigated in a wide range of molar masses (between M w V C 2012 Wiley Periodicals, Inc. WWW.MATERIALSVIEWS.COM JOURNAL OF POLYMER SCIENCE PART A: POLYMER CHEMISTRY 2012, 000, 000–000 1 JOURNAL OF POLYMER SCIENCE WWW.POLYMERCHEMISTRY.ORG ARTICLE