Structural Studies Of Polymorphs Of Pharmaceutical Compound Using Solid-State NMR Spectroscopy

It is well known that X-ray single crystal or powder diffraction (XRD) is probably the most powerful tool to study structure of crystalline solids. With the aid of other techniques, such as Raman spectroscopy, thermo-analytical method (DSC) and infrared spectroscopy (IR), one, in principle, can resolve the accurate structure of pure crystals. But in a system with structural defects or with polymorphous forms, the abovementioned techniques are limited, to certain extent. Because it is extremely sensitive to the local electronic environment, solid state NMR spectroscopy (SSNMR) has been widely used to investigate molecular structures of crystalline and amorphous solids. It is well documented that the vast majority of commercial solid pharmaceutical products consist of multiple polymorphs. For amorphous pharmaceutical material, the role of XRD may be limited, because important structural features are often lost due to broadening lines for such samples. The SSNMR, however, often can be utilized to analyze these systems effectively. The characterization of a drug compound using SSNMR methods has been recommended by the FDA in 2007, indicating its ever-increasing importance in the study of pharmaceutical products.One can obtain the isotropic chemical shift by employing the magic angle spinning (MAS) method, to produce NMR spectra in which the resonances of the diluted spin 1/2 nuclei such as 13C and 15N are resolved because of the inherent narrowing. The isotropic chemical shift, an average of three principal values of the chemical shift tensor, is—by far—the most sensitive NMR parameter related to molecular structure in solids. Its value provides a global representation of the local electronic structure. However, the principal values of the chemical shift tensor provide information on the geometry of the electronic distribution about the nuclear center, something that cannot often be directly determined from a simple MAS experiment. To gain a more complete picture of solid structure in polymorphous material, it is critical to determine the principal values of the NMR chemical shift tensor. In principle, analysis of static powder patterns gives the information on these principal values directly, but in system with multiple sites, it becomes difficult to resolve overlapping powder patterns from even a few sites.To obtain detailed geometric information on the electronic structure, a pulse sequence named SUPER is employed and modified to extract a static powder pattern of each nuclear site. With a proper data processing, principal values of each chemical shift tensor can be directly read out from the spectrum, giving a more specific delineation of electronic environment information in the vicinity of nucleus.The complete 13C NMR chemical shift tensors (CST) for the carbon sites of the three polymorphic forms (PI, PII, and PM) of the analgesic drug, piroxicam, are reported. The NMR parameters (isotropic chemical shifts, chemical-shielding anisotropies and asymmetries, and dipolar couplings), X-ray powder diffraction, and density-functional calculations to predict NMR parameters are analyzed in terms of hydrogen bonding and structure in these solids. The integration of all the data gives an improved model of the local solid-state structures of the polymorphs. In particular, the solid-state NMR spectra demonstrate that the asymmetric unit of the monohydrate, PM, contains two zwitterionic piroxicam molecules.With the increased complicity in molecular structure, overlap of spectral resonances is inevitable. A modified 2D-SUPER technique is proposed here to allow independent measurement of the principal values of the chemical-shift tensors of overlapping protonated and unprotonated carbons. The insertion of a dipolar-dephasing period into the sequence causes loss of signal from protonated carbons. The spectrum obtained with this modification allows one to determine the principal values of the unprotonated carbons with high precision. Subsequent fitting of the usual 2D-SUPER spectrum, with the chemical-shift parameters of the unprotonated carbons fixed, gives the parameters of the overlapped resonances of the protonated carbons. As an example, we report the determination of the 3C chemical-shift parameters of the carbons of formⅡof piroxicam. The experimental results are compared with those obtained from calculations using the DFT/GIAO method. Potential applications of this method are also discussed.The results of this research provide a systematic method for investigating polymorphism of solid organic compound. Adding this SSNMR technique to other well-established techniques should help resolve or confirm structures in these more complicated systems, as exemplified by the polymorphic states of piroxicam.