Molecular Mobility and Fragility in Indomethacin: A Thermally Stimulated Depolarization Current Study Nata´ lia T. Correia, 1 Joaquim J. Moura Ramos, 1,4 Marc Descamps, 2 and George Collins 3 Received May 16, 2001; accepted September 6, 2001 Purpose. To show that thermally stimulated depolarization currents (TSDC), which is a dielectric experimental technique relatively un- known in the pharmaceutical scientists community, is a powerful technique to study molecular mobility in pharmaceutical solids, be- low their glass transition temperature (T g ). Indomethacin (T g  42°C) is used as a model compound. Methods. TSDC is used to isolate the individual modes of motion present in indomethacin, in the temperature range between -165°C and +60°C. From the experimental output of the TSDC experiments, the kinetic parameters associated with the different relaxational modes of motion were obtained, which allowed a detailed character- ization of the distribution of relaxation times of the complex relax- ations observed in indomethacin. Results. Two different relaxational processes were detected and char- acterized: the glass transition relaxation, or -process, and a sub-T g relaxation, or secondary process. The lower temperature secondary process presents a very low intensity, a very low activation energy, and a very low degree of cooperativity. The fragility index (Angell’s scale) of indomethacin obtained from TSDC data is m  64, which can be compared with other values reported in the literature and obtained from other experimental techniques. Conclusions. TSDC data indicate that indomethacin is a relatively strong glass former (fragility similar to glycerol but lower than sor- bitol, trehalose, and sucrose). The high-resolution power of the TSDC technique is illustrated by the fact that it detected and char- acterized the secondary relaxation in indomethacin, which was not possible by other techniques. KEY WORDS: glass transition relaxation, secondary relaxations, glassy state, amorphous state. INTRODUCTION It is well known that the dissolution rate and therapeutic activity of a drug depend on its physical state and, particu- larly, on its degree of crystallinity. The significance of the amorphous state in pharmaceutical systems has been under- lined in recent works (1,2). A disordered amorphous material dissolves faster and has a greater solubility than the corre- sponding ordered crystalline solid. As a consequence, the amorphous form of a drug often shows an improved thera- peutic activity. However, the amorphous state is a non- equilibrium state and, consequently, it is unstable. If the mo- lecular motions that originate this instability are not retarded over a meaningful pharmaceutical timescale, a significant variation in some of the key properties of the drug may occur. In this context, the knowledge of the timescales of molecular motions in amorphous systems, i.e., the knowledge of the re- laxation map that characterizes the molecular dynamics in a given material is needed for profiting from the advantages of the amorphous state and is an important requirement for a safe storage and use of amorphous pharmaceutical solids (3). Thermally stimulated depolarization currents (TSDC) is a di- electric technique that is able to probe slow reorientational motions and, consequently, is a very suitable technique to study mobility in solids. However, it is unknown in the com- munity of pharmaceutical scientists. One of the purposes of the present work is to address this community to show how TSDC provides relevant information regarding the different modes of motion present in a given pharmaceutical material. To do so, we chose indomethacin as a model pharmaceutical solid. The fact that the molecular mobility in indomethacin has been studied by several experimental techniques (4–6) allows a comparison between the results provided by the dif- ferent techniques. MATERIALS AND METHODS Indomethacin (1-[4-chlorobenzoyl]-5-methoxy-2-methyl- 1-H-indole-3-acetic acid) was a Sigma product (catalogue number I-7378, lot 77H18461), with a melting point at 160°C obtained by DSC, and it was used without further purifica- tion. Its calorimetric glass transition temperature is reported to be T g  42°C (315.2 K) for a heating rate of 1°C/min (7). TSDC experiments were carried out with a TSC/RMA 9000 instrument (TherMold Partners, Stamford, CT) covering the temperature range between -170 and +400°C. The quan- tity of substance required to prepare the sample is typically 100–300 mg. Before the TSDC experiments, the sample was heated up above the melting point and cooled down fast from the melt below the glass transition temperature to produce the glassy state. Description of a TSDC Experiment In a TSDC experiment, the sample under study is placed between the electrodes of a parallel plane capacitor and is “excited” by polarizing with a dc electric field at a given tem- perature [the polarization temperature (T P )] for a given pe- riod of time [the polarization time (t P )]. This is the first step of a TSDC experiment: the polarization step. The effect of the electric field in the sample is to orient dipoles within the molecular structure, to create in the sample a given amount of polarization. Naturally, because the mo- lecular mobility increases as the temperature increases, the nature and the amount of the polarization created by the electric field depends on the polarization temperature. The second step of a TSDC experiment consists in cool- ing the sample down to a temperature T P  T P - T, in the presence of the electric field, to freeze-in the dipolar orien- tations, i.e., to retain (at least partially) the polarization cre- 1 Centro de Quı´mica-Fı´sica Molecular, Complexo I, IST, Av. Rovisco Pais, 1049-001 Lisboa, Portugal. 2 Laboratoire de Dynamique et Structure des Mate´ riaux Mole´ cu- laires, UFR Physique, Baˆ timent P5, 59655 Villeneuve d’Ascq Ce- dex, France. 3 TherMold Partners, L.P., 652 Glenbrook Road, Stamford, Con- necticut 06906. 4 To whom correspondence should be addressed. (e-mail: mouraramos@ist.utl.pt) Pharmaceutical Research, Vol. 18, No. 12, December 2001 (© 2001) Research Paper 1767 0724-8741/01/1200-1767/0 © 2001 Plenum Publishing Corporation