Dynamic properties of ibuprofen by solid state NMR spectroscopy and relaxometry: from pure active ingredient to formulations.

The molecular dynamics of a solid drug strongly affects its pharmaceutical properties and other important characteristics as solid state degradation. Understanding the mobility of molecular moieties in solid drugs can also lead to a deeper knowledge of the factors responsible for conformational interconversions and solid state reactions [1]. Moreover, dynamics plays an important role in drug-excipient interactions, which significantly affect the release properties. Many active pharmaceutical ingredients (APIs) show a limited and variable bioavailability mainly associated to inadequate biopharmaceutical properties such as aqueous solubility and dissolution rate. The latter is the main factor responsible for the limited efficacy of many biopharmaceutics classification system (BCS) class II and class IV orally administered drugs. In this context, the employment of inorganic matrices, such as mesoporous materials and lamellar anionic clays, for the preparation of host-guest composites is a suitable strategy for improving biopharmaceutical properties [2]. Indeed, some inorganic matrices are able to host drugs into nanometric galleries or pores in a non-crystalline form. In this way rapid dissolution can occur after the contact with the dissolution medium, without the need of a previous modification of the API chemical structure. The characterization of the solid form, chemical environment and dynamic properties of the API in this kind of formulations therefore appears particularly relevant. In this work, the dynamic properties of ibuprofen, a widely used non-steroidal analgesic and anti-inflammatory drug belonging to BCS class II, have been investigated in detail both in pure crystalline forms of the API and in an innovative formulation where ibuprofen is intercalated in a Hydrotalcite (HTlc) clay. In the presented work, the potentialities offered by solid state NMR to study molecular dynamics have been extensively exploited. In particular, fast motional processes, with characteristic frequencies in the range of MHz, were investigated through 13C and 1H longitudinal relaxation times (T1); the intermediate motional region (frequencies in the range of kHz) was studied through 1H longitudinal relaxation time in the rotating frame (T1?) and T1 at low frequencies, and 13C chemical shift anisotropy; insights into the slow motional regime (frequencies in the range of Hz) could be instead obtained by looking at exchange processes affecting in the 13C high-resolution spectrum. A combined analysis of all the data provided qualitative and quantitative information about the motions of the various molecular fragments (phenyl ring, methyl groups, aliphatic chains) [4, 5]. The comparison of spectral and relaxation properties of ibuprofen in its pure form and in formulation with HTlc allowed interesting differences to be highlighted and discussed. In particular, all the NMR experiments revealed a much higher mobility of ibuprofen when it is intercalated in HTlc with respect to the pure compound and a motion involving the whole ibuprofen molecule could be identified and characterized [6]. Acknowledgments This work was supported by the CA15209 COST Action (EURELAX). References [1] S. R. Byrn , W. Xu , A. W. Newman, Chemical reactivity in solid-state pharmaceuticals: formulation implications. Adv. Drug Deliver. Rev. 2001, 48, 115 - 136. [2] L. Perioli, C. Pagano, Inorganic matrices: an answer to low drug solubility problem. Expert Opin. Drug Deliv. 2012, 9, 1559-1572. [3] E. Conterosito, W. Van Beek, L. Palin, G. Croce, L. Perioli, D. Viterbo, G. Gatti, and M. Milanesio, Development of a Fast and Clean Intercalation Method for Organic Molecules into Layered Double Hydroxides. Cryst. Growth Des. 2013, 13, 1162-1169. [4] E. Carignani, S. Borsacchi, M. Geppi, Detailed Characterization of the Dynamics of Ibuprofen in the Solid State by a Multi-Technique NMR Approach. ChemPhysChem, 2011, 12, 974-981. [5] E. Carignani, S. Borsacchi, M. Geppi, Dynamics by Solid-State NMR: Detailed Study of Ibuprofen Na Salt and Comparison with Ibuprofen. J. Phys. Chem. A, 2011, 115, 8783-8790. [6] E. Carignani, S. Borsacchi, P. Blasi, A. Schoubben, M. Geppi, Dynamics of hydrotalcite-intercalated Ibuprofen studied by Solid State NMR. Mol. Pharm. submitted.