Physico-Chemical and Technological Properties of Sodium Naproxen Granules Prepared in a High-Shear Mixer-Granulator PIERA DI MARTINO, LEDJAN MALAJ, ROBERTA CENSI, SANTE MARTELLI Pharmaceutical Technology Laboratory, Department of Chemistry, University of Camerino, Via S. Agostino, 62032 Camerino, Italy Received 20 June 2007; revised 12 February 2008; accepted 27 February 2008 Published online 8 April 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21400 ABSTRACT: In the present work, authors produced tablets of anhydrous sodium naproxen by wet granulation using a high-shear mixer-granulator. Drug hydrated to the tetrahydrated form, as observed by X-ray powder diffractometry. After wet granula- tion, authors then performed two different drying procedures, obtaining granules of different water content and crystallographic characteristics. The first procedure dried granules in the high-shear mixer-granulator by applying vacuum at room temperature (batch A), while the second employed the same apparatus and time, under vacuum at 408C (batch B). X-ray powder diffractometry revealed that the sodium naproxen (SN) contained in batch A granules was a mixture of dihydrated and tetrahydrated forms (as demonstrated by the coexistence of peaks typical of both hydrated forms), while that of batch B granules was a mixture of monohydrated and tetrahydrated forms. This means that differences in drying procedures could lead to products of different crystallographic properties. The behavior under compression was evaluated, revealing that batch A offered the best tabletability and compressibility. These results make it possible to conclude that differences in the crystallographic properties and water content of SN are such that different hydration/drying processes can alter the drug crystal form and thus the tabletability of the resulting granules. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5263–5273, 2008 Keywords: sodium naproxen; hydration; wet granulation; high-shear mixer- granulator; tabletability; compressibility INTRODUCTION Numerous pharmaceutical compounds exist as crystalline hydrates, 1 and can be classified ac- cording to the various states of water association with solids. 2 Drug substance exposure to water during several pharmaceutical operations is of great relevance, particularly with wet granula- tion, as particle growth occurs by liquid bridging of powders. 3 Water exposure can cause changes in the crystal lattice, such that during the sub- sequent drying step generally associated with these processes, the drug substance does not fully dehydrate to the complete anhydrous form of the starting material. Several studies report examples of structural changes as a consequence of wet granulation. 4–7 The structural changes related to the hydration/ dehydration process can strongly affect drug tech- nological performance and bioavailability. Cabri et al. 8 reported that cefdinir tableting behavior and dissolution profiles are different when the Correspondence to: Piera Di Martino (Telephone: þ39-0737- 402215; fax: þ39-0737-637345; E-mail: piera.dimartino@unicam.it) Journal of Pharmaceutical Sciences, Vol. 97, 5263–5273 (2008) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 12, DECEMBER 2008 5263