Role of Water in the Physical Stability of Solid Dosage Formulations SARI AIRAKSINEN, 1 MILJA KARJALAINEN, 1 ANNA SHEVCHENKO, 2 SARI WESTERMARCK, 2 ELLA LEPPA ¨ NEN, 2 JUKKA RANTANEN, 3 JOUKO YLIRUUSI 1,3 1 Pharmaceutical Technology Division, Faculty of Pharmacy, University of Helsinki, Finland 2 Orion Pharma, Orionintie 1, Espoo, Finland 3 Viikki Drug Discovery Technology Center (DDTC), University of Helsinki, Finland Received 21 December 2004; revised 3 May 2005; accepted 4 May 2005 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20411 ABSTRACT: The interaction of moisture with pharmaceutical solids is highly crucial to an understanding of water-based processes, for example, manufacturing processes or prediction of solid dosage form stability and shelf life. Both the active pharmaceutical ingredient (API) and excipients in the formulation have different moisture sorption properties that can result in unexpected processing-induced phase transitions and they can affect solid-state phase transitions in the final dosage forms. The character of excipient effects on the stability of formulation. Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The aim of the present study was to investigate the water sorption properties of different excipients, model the sorption isotherms, examine the phase transitions, and identify differences of excipients in solid dosage form stability using dynamic vapor sorption analysis, near-infrared spectroscopy, and X-ray diffraction methods. The thermal processing was carried out with a variable temperature X-ray powder diffractometer to compare the dehydration behavior of wet excipients and evaluate solid- state properties during heating. These results showed that despite some limitations, moisture sorption isotherms of excipients are useful in predicting solid-state stability, interactions at early stages of formulation development, and effects of moisture on physicochemical properties of the final dosage forms. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2147– 2165, 2005 Keywords: dynamic vapor sorption; excipients; near-infrared (NIR) spectroscopy; phase transition; sorption isotherms; X-ray powder diffraction INTRODUCTION Pharmaceutical solids may come in contact with water during manufacturing processes and some moisture could remain as the residual water from processing in solid oral dosage forms. Moreover, they may be exposed to water during storage at high relative humidity (RH) or in a dosage form consisting of materials that contain water and are capable of transferring it to other ingredients. 1 The physical and chemical properties of pharma- ceutical solids are critically dependent on the presence of moisture, for example, flow, compac- tion, dissolution, stability, storage, processing into formulations, and final product packing. 2 The association between moisture and solid materials was described as one in which the mois- ture is adsorbed as monolayers or multilayers or may be present as condensed water at the surface. 3 Water can interact with crystalline solids by JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 10, OCTOBER 2005 2147 Correspondence to: Sari Airaksinen (Telephone: þ358-9- 191 59164; Fax: þ358-9-191 59144; E-mail: sari.airaksinen@helsinki.fi) Journal of Pharmaceutical Sciences, Vol. 94, 2147–2165 (2005) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association