Investigation of Solid-State Reactions Using Variable Temperature X-Ray Powder Diffractometry. II. Aminophylline Monohydrate Suneel K. Rastogi, 1,2 Marek Zakrzewski, 3,4 and Raj Suryanarayanan 1,5 Received May 22, 2002; Accepted May 30, 2002 Purpose. The object of this investigation was to demonstrate the utility of X-ray powder diffractometry (XRD) to study the kinetics of a complex pharmaceutical solid-state reaction wherein the reactant, product and intermediate phases were all simultaneously quantified. Methods. Aminophylline monohydrate (I) decomposed to anhydrous theophylline (III) either directly or through an intermediate (anhy- drous aminophylline, II). The reaction kinetics were studied isother- mally at several temperatures ranging from 65 to 100°C. By measur- ing the intensities of the XRD peaks unique to I, II and III, it was possible to simultaneously quantify the 3 phases during the entire reaction. Results. Assuming that all the reaction steps follow first-order kinet- ics, the three equations describing the concentrations of I, II and III as a function of time, were derived. By fitting the experimental data to these equations, it was possible to obtain the rate constants for the three reaction steps. The rate constants were obtained at different temperatures and were used to draw Arrhenius type plots from which the activation energies were determined. At lower temperatures (<80°C), the concentration of the intermediate phase, i.e., II, was low throughout the reaction while at higher temperatures (>90°C), there was rapid formation and accumulation of II during the early stages of the reaction. These differences could be attributed to the fact that k 1 (I → II) had a more pronounced temperature dependence than k 2 (I → III) and k 3 (II → II). The XRD results were confirmed with isothermal thermogravimetry. Conclusions. Variable temperature XRD is a powerful tool to probe reaction kinetics in crystalline pharmaceuticals since it permits simul- taneous quantification of multiple solid phases. KEY WORDS: kinetics; solid-state; theophylline; aminophylline; de- composition; X-ray powder diffractometry. INTRODUCTION The active ingredient and the excipients in a solid dosage form can undergo chemical decomposition as well as physical transformation reactions. Physical transformations include polymorphic transitions, changes in state and degree of sol- vation and alterations in degree of crystallinity. Some types of chemical reactions in solid pharmaceuticals are oxidation, hy- drolysis and photochemical reactions (1–8). These changes can be induced during pharmaceutical processing and/or stor- age and can profoundly influence the performance as well as the shelf-life of dosage forms. The kinetics and mechanism of solid-state reactions are influenced by several factors includ- ing temperature, water vapor pressure, and processing. Differential scanning calorimetry and thermogravimetry have been extensively used to study solid-state decomposition kinetics. However, these techniques have several drawbacks. For example, they do not unambiguously identify crystalline phases (if any) and are not necessarily useful for discerning the reaction mechanism (9). These drawbacks can be over- come by using the technique of X-ray powder diffractometry (XRD). Since the diffraction pattern of each crystalline form of a compound is unique, XRD is particularly suited for the analyses of solid mixtures. Moreover, the intensities of the peaks unique to each phase enable quantitative analyses (10,11). Thus, simultaneous quantification of crystalline reac- tants, products and intermediates (if any) are possible. If an amorphous intermediate is formed, this usually becomes evi- dent from mass balance calculations (12). Thus the technique is ideally suited to understand reaction mechanisms. Several advances in XRD instrumentation and software have greatly facilitated the study of pharmaceutical systems. Variable temperature XRD is a technique where XRD pat- terns are obtained while a sample is subjected to a controlled temperature program. The kinetics of dehydration, racemiza- tion and crystallization reactions have been studied by this technique (12–14). While the dehydration of theophylline monohydrate has been the subject of numerous investiga- tions, only variable temperature XRD revealed the formation of a metastable anhydrate, which then transformed into the stable anhydrate (5). Recently, it has also become possible to control the water vapor pressure in the XRD sample chamber (9,15–17). Another advancement in instrumentation is the po- sition sensitive detector (PSD) which enables very rapid data collection. Finally, reliable data analyses programs have be- come available, which are particularly useful to decompose asymmetric and overlapping X-ray peaks. In an earlier investigation, we had demonstrated the util- ity of variable temperature XRD in the study of simple, one- step decomposition and phase transformation reactions (18). In this project, we have extended the utility of XRD to study more complex solid-state reactions. Theophylline, a broncho- dilator effective in the treatment of asthma, is only slightly soluble in water. Complexation of theophylline with ethylene- diamine to form aminophylline considerably enhances the aqueous solubility. The decomposition of aminophylline was investigated since an understanding of the reaction kinetics and mechanism may facilitate the preparation of stable ami- nophylline formulations. Several solid forms of aminophylline have been reported in the literature including an anhydrate (19), a hemihydrate (20), a monohydrate (20,21), a dihydrate (19) and a hepta hemihydrate (20). The solid-state decomposition of the monohydrate has been investigated using thermogravimetry (21,22). Ishiguro et al. (22) found that the elimination of eth- ylenediamine from aminophylline was a first-order process. Nishigo et al. (21) showed that the decomposition of I is a complex process involving three elementary steps as shown later (Scheme 1). Our studies revealed that the intermediate 1 College of Pharmacy, 308 Harvard St. S.E., University of Minne- sota, Minneapolis, Minnesota 55455. 2 Present address: Forest Laboratories, Inc., 330 Prospect Street, In- wood, New York 11096. 3 Philips Analytical X-ray, Almelo, The Netherlands. 4 Present address: Advanced Solid State Analysis International, Inc., 3B East Lake Road, Danbury, Connecticut 06811. 5 To whom correspondence should be addressed. (e-mail: surya001@ umn.edu) Pharmaceutical Research, Vol. 19, No. 9, September 2002 (© 2002) Research Paper 1265 0724-8741/02/0900-1265/0 © 2002 Plenum Publishing Corporation