Solid-State Amorphization of Linaprazan by Mechanical Milling and Evidence of Polymorphism JEAN-FRANCOIS WILLART, 1 MORGAN DURAND, 1 LARS-ERIK BRIGGNER, 2 ANKE MARX, 2 FLORENCE DAN ` EDE, 1 MARC DESCAMPS 1 1 Universit´ e Lille Nord de France, F-59000 Lille, USTL, UMET (Unit´ e Mat´ eriaux et Transformations), UMR CNRS 8207 F-59650 Villeneuve d’Ascq, France 2 Pharmaceutical Development, AstraZeneca R&D, M¨ olndal, Sweden Received 18 December 2012; revised 15 March 2013; accepted 9 April 2013 Published online 19 May 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23573 ABSTRACT: In this paper, we study the thermodynamic and structural changes of crystalline linaprazan (a proton pump inhibitor) upon high-energy ball milling at room temperature. The investigations have been performed by differential scanning calorimetry and powder X-ray diffraction. The results indicate that this drug undergoes a direct crystal-to-glass transfor- mation upon milling. Moreover, upon heating, the amorphous material obtained by milling is shown to recrystallize toward two different polymorphs that appear to form a monotropic set. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2214–2220, 2013 Keywords: amorphous; polymorphism; milling; calorimetry (DSC); glass transition; materi- als science; thermodynamics; transformation; X-ray powder diffractometry INTRODUCTION Mechanical milling is frequently used in pharma- ceutical formulation processes to reduce the size of the particles of drugs and excipients. 1 This size re- duction generally improves the apparent solubility, dissolution performance, facilitates the compression of tablets, and enables more accurate dosing of the drugs. However, it is now a widely accepted fact that milling can also change the structural state of the material through an amorphization process. 1,2 This physical change can further improve the apparent sol- ubility of the drug, 3,4 but the intrinsic propensity of the amorphous state to recrystallize may impose diffi- culties to maintain the therapeutic characteristics of the material during storage. 5 Special attention must thus be paid to the possible amorphization of drugs induced by milling. 6 Many fundamental questions, still unresolved, arise from this solid-state amorphization route. One of them is to decide, whether or not, the nature and the properties of the amorphous state obtained by milling are similar to those of the amorphous state produced by the usual thermal quench of the liquid. Correspondence to: Jean-Francois Willart (Telephone: +33-3-20- 43-68-34; E-mail: jean-francois.willart@univ-lille1.fr) Journal of Pharmaceutical Sciences, Vol. 102, 2214–2220 (2013) © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association Possible differences between these two amorphous states concern their physical and chemical stabilities, their energetic level, their local order, their ability to generate new polymorphs upon recrystallization, etc. Linaprazan is a proton pump inhibitor (C 21 H 26 N 4 O 2 ; M w = 366.5 g/mol) developed by AstraZeneca, M¨ olndal, Sweden (Fig. 1). Up to now, little is known about the physical properties of this material. Includ- ing a brief characterization of the vitrification prop- erties by melt quenching, we present here an investi- gation of the structural and thermodynamic changes of crystalline linaprazan upon mechanical milling. EXPERIMENTALS Crystalline linaprazan was provided by AstraZeneca and used without any further purification. The ball milling was performed with a high- energy planetary mill (Pulverisette 7—Fritsch, Idar- Oberstein, Germany) at room temperature (RT). We used ZrO 2 milling jars of 43 cm 3 with seven balls (ø = 15 mm) of the same material. One gram of material was placed in the planetary mill corresponding to a ball–sample weight ratio of 75:1. The rotation speed of the solar disk was set to 400 rpm that corresponds to an average acceleration of the milling balls of 5 g. We took care to alternate milling periods (typically 2214 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, NO. 7, JULY 2013