Engineering Codrug Solid Forms: Mechanochemical Synthesis of an Indomethacin–Caffeine System

Abstract

This article reports on the preparation and solid-state characterization of an indomethacin–caffeine drug–drug cocrystal (or codrug) in a 1:1 stoichiometry. These two active ingredients are frequently coadministered as part of a therapy against strong migraines, in a commercially available fixed dose combination formulation. The X-ray crystal structure of the codrug is characterized by a hydrogen bond interaction between the carboxylic moiety of indomethacin and the purinic nitrogen atom of caffeine. The combination of multinuclear and multidimensional solid-state NMR measurements (1H MAS, 13C and 15N CPMAS, 1H DQ MAS, 13C–1H HETCOR, 14N–1H J- and D-HMQC), as well as IR data, provided spectroscopic evidence about the hydrogen atom position along the hydrogen bond axis, thereby confirming the neutral nature of the cocrystal. Furthermore, dissolution kinetic tests revealed superior bioavailability of indomethacin in the codrug compared to indomethacin alone and to an indomethacin–caffeine physical mixture. On the other hand, the melting point of indomethacin was slightly lower in the cocrystal rather than in the pure drug.

Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

“…The crystal engineering approach, i.e., the rational design and synthesis of new crystal forms [ 1 ], is viable for any molecule that is employed in the solid state, ranging from pigments to explosives [ 2 ], from pharmaceuticals to energy storage materials [ 3 ]. In the case of active pharmaceutical ingredients (APIs), crystal engineering has proved to be successful in modulating and improving their performances in terms of water solubility [ 4 , 5 ], dissolution rate [ 6 , 7 ], hygroscopicity [ 8 ], thermal stability [ 9 ], flow properties [ 10 ], etc. An important point of this strategy is the fact that some APIs are often doomed to obsolescence because of their poor biopharmaceutical and/or physicochemical properties [ 11 ].…”

“…The latter, in particular, are more and more commonly pursued as an alternative to salts in the quest for performance enhancement of APIs, because cocrystallization offers greater opportunities than salification: (i) it is viable for molecules that do not display any ionizable moiety; (ii) the possible coformers (i.e., molecules selected to cocrystallize with the API) are more numerous than the possible counterions; (iii) cocrystallization can significantly improve the solubility of the APIs without altering their permeability. As of today, many pharmaceutical cocrystals have been successfully prepared and reported in the literature [ 7 , 16 , 17 , 18 , 19 , 20 ].…”

Determination of the 15N chemical shift anisotropy in natural abundance samples by proton‐detected 3D solid‐state NMR under ultrafast MAS of 70 kHz

“…The recent introduction of probes that can reach stunningly high‐spinning speeds of up to 110 kHz has considerably contributed to significant improvements in solid‐state NMR. Besides, additional enhancement in sensitivity and resolution, thanks to efficiently suppressed homonuclear 1 H– 1 H dipolar interaction, ultrafast MAS regime allows the practical use of “solution‐like” proton‐detected correlation experiments, making measurements on cost‐effective natural abundance samples possible . Moreover, because such high rates can be achieved by notably reducing the diameter of the rotor and the volume of sample within it, this simplifies the analyses on systems for which large amounts are not feasible or difficult to obtain.…”

“…However, the averaging of CSA leads to a loss of important information about conformation, molecular structure, and intermolecular and intramolecular hydrogen bonding, which is essential to get deeper insights on systems like proteins, drugs, and materials. Hence, during the years, a large number of different approaches have been developed to firstly recouple 13 C and 15 N CSA in the indirect dimension without sacrificing the valuable benefits provided by MAS in the direct dimension. [1][2][3][4][5][6][7][8][9] The whole idea behind the recoupling is to make use of a synchronized radio frequency (rf) field irradiation, which would interfere with MAS averaging.…”

“…Besides, additional enhancement in sensitivity and resolution, thanks to efficiently suppressed homonuclear 1 H-1 H dipolar interaction, ultrafast MAS regime allows the practical use of "solution-like" proton-detected correlation experiments, making measurements on cost-effective natural abundance samples possible. [10][11][12][13][14][15][16][17][18][19] Moreover, because such high rates can be achieved by notably reducing the diameter of the rotor and the volume of sample within it, this simplifies the analyses on systems for which large amounts are not feasible or difficult to obtain. Several examples can be found in site-specific 1 H CSA measurement by novel 2D/3D proton-detected recoupling sequences under such spinning regime.…”