Published: June 02, 2011 r2011 American Chemical Society 1372 dx.doi.org/10.1021/mp200205z | Mol. Pharmaceutics 2011, 8, 1372–1380 ARTICLE pubs.acs.org/molecularpharmaceutics Insights into the Early Dissolution Events of Amlodipine Using UV Imaging and Raman Spectroscopy Johan P. Boetker, † Marja Savolainen, † Vishal Koradia, †,‡ Fang Tian, † Thomas Rades, § Anette M€ ullertz, † Claus Cornett, † Jukka Rantanen, † and Jesper Østergaard* ,† † Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark § School of Pharmacy, University of Otago, 18 Frederick Street, Dunedin 9054, New Zealand b S Supporting Information ’ INTRODUCTION The increasing number of poorly water-soluble drug candi- dates has sparked a high interest in exploring formulation approaches involving the optimization of solid-state properties including the use of high energy solid forms such as amorphous systems, solid dispersions or different polymorphs, in order to increase the dissolution rate. These systems often contain thermodynamically metastable or even unstable forms of the active ingredient, and a full understanding of the factors affecting product performance can be challenging. 1,2 When the surface of such systems is exposed to a solvent, phase transformations may occur. 3À5 Furthermore, the drug release from such samples is often governed by a complex interplay between dissolution and recrystallization (nucleation and crystal growth). This behavior may be further complicated by pH effects, surfactants, ions and other components present in the gastrointestinal (GI) tract. 6,7 The development of bio- and physicochemically relevant dis- solution methods is therefore important to better understand and predict dosage form performance. 6À17 Traditional dissolution testing methodologies are based solely on bulk solution concentration measurements as a function of time. 18,19 These approaches suffer from delayed responses due to the need for accumulation of the solution concentration. The absence of simultaneous real-time information regarding the solution concentration and the solid-state composition makes the detection of solid-state changes during dissolution difficult since these often commence almost instantaneously. 20 Hence, the lack of real-time information may preclude the possibility for understanding the behavior of a formulation. A recent editorial has underlined the necessity for the development of new analytical tools that can increase the understanding of complex dissolution behavior. 21 Imaging techniques such as FT-IR, NIR and magnetic resonance imaging (MRI) have been used for studying dissolution processes. 22À25 However, FT-IR and NIR imaging are water sensitive, restricting their use in aqueous media, although the utilization of attenuated total reflectance (ATR) accessories has enabled the investigation of aqueous solutions with FT-IR imaging. 26,27 Coherent anti-Stokes Raman scattering (CARS) for three-dimensional imaging is a new emerging technique. 28 CARS has recently been applied to imaging of lipid-based oral dosage forms. 29 However, CARS suffers from nonlinear concen- tration dependence, 30 and the quantitative interpretation of CARS imaging may be difficult when applied to nonlipid imaging. 31 Received: April 19, 2011 Accepted: June 2, 2011 Revised: June 1, 2011 ABSTRACT: Traditional dissolution testing determines drug release to the bulk, but does not enable an understanding of the events happening close to the surface of a solid or a tablet. UV imaging is a new imaging approach that can be used to study the dissolution behavior of chemical compounds. The UV imaging instrumentation offers recording of absorbance maps with a high spatial and temporal resolution which facilitates the abundant collection of information regarding the evolving solution concentrations. In this study, UV imaging was used to visualize the dissolution behavior of amlodipine besylate (amorphous and dihydrate forms) and amlodipine free base. The dissolution of amlodipine besylate was faster from the amorphous form than from the crystalline forms. The UV imaging investigations suggested that a solvent mediated phase transformation occurred for the amorphous amlodipine besylate and the amlodipine free base samples. Raman spectroscopy was used to confirm and probe the changes at the solid surface occurring upon contact with the dissolution media and verified the recrystallization of the amorphous form to the monohydrate. The combination of UV imaging and Raman spectroscopy is an efficient tool to obtain a deeper insight into the early events of the dissolution process. KEYWORDS: amorphous, crystalline, dissolution, Raman spectroscopy, solid-state transformation, UV imaging