(337bs) Spectroscopic Characterization and Assignments of Nifedipine Via Computational Modeling and Experiment (FTIR, Raman, and ssNMR) and Comparisons to an Amorphous Solid

chemistry, chemical engineering, explosives, pharmaceuticals, calorimetry, amorphous solids, spray-drying, spectroscopy, solid-state NMR, Raman, FTIR, UV-VIS, dielectric relaxation, crystallization, glasses, energetic materials

Density Functional Theory (DFT) calculations are used to determine the optimized geometry and spectroscopic signatures for the pharmaceutical compound nifedipine (NIF). The results show an excellent agreement between the experimental crystal structure and the geometry optimized at the B3LYP/6-311G++ level of theory. Experimental Fourier Transform Infrared (FTIR)and Raman spectra of nifedipine were recorded in the regions 4000 to 600 cm^-1 and 4000 to 200 cm^-1, respectively. The calculated vibrational frequencies are compared with experimental FTIR and FT Raman spectra, and assignments are made for the different vibrational modes with good agreement. ¹³C NMR chemical shifts are also computed and they compared well to the experimental solid-state NMR spectra. In addition, the frontier molecular orbitals are investigated using theoretical calculations. The results are also compared to the spectra of NIF-based amorphous solid dispersions (ASD) composed of different cellulose-based polymers (hydroxy methyl propyl cellulose acetate succinate (HPMCAS) (results not shown here) and nitrocellulose (NC)). Spectroscopic characterization allows for interpretation of potential intermolecular interactions taking place in the ASD, and these interactions are useful for relating a polymer’s relative miscibility and contribution to the overall stability of a specific ASD.

NIF is a member of a class of pharmaceutical compounds known as 1,4-dihydropyridine calcium channel blockers. These types of drugs primarily function by blocking calcium (Ca²⁺) ions in the blood from traversing across the cell membranes of smooth muscular systems (e.g., arteries, intestines), which ultimately relaxes the muscles by preventing contraction. Regarding the circulatory system, this results in an increase in the diameters of different arteries, which serves to both reduce blood pressure (i.e., reduce hypertension) and increase the flow of blood and oxygen to the heart (i.e., alleviate angina). NIF is most commonly used as a vasodilator for treating angina [1], but the nature of the calcium channel blocking mechanism has also led to the use of NIF in other treatments as well, such as: hypertension in pregnancies [2], premature labor [3-5], kidney stone expulsion [6], Raynaud’s phenomenon [7], enhanced respiration [8], swallowing due to swollen esophagus [9], and hemorrhoids. [10]

NIF is also commonly utilized as a pharmaceutical research standard for studies related to improving bioavailability. NIF, like many pharmaceutical drugs, is relatively nonpolar, which makes it difficult to dissolve within aqueous environments (e.g., the bloodstream). [11,12] To overcome this general limitation, a commonly pursued option is to administer drugs in the form of an amorphous solid. [13] However, achieving long term stabilization of the amorphous form is challenging since small organic molecules tend to rapidly crystallize from the supercooled state at room temperature. [14] This tendency can be potentially overcome via the production of co-amorphous mixtures containing a polymeric stabilizer that prevents drug crystallization. [15] This polymer/drug combination is collectively referred to as an amorphous solid dispersion (ASD), and the mechanism of enhanced stabilization of the active pharmaceutical ingredient (API) is becoming more widely attributed to intermolecular interactions. [16] NIF, in particular, has a relatively high melting point (~170-175 ^oC), which makes it easier to form a stable glass at room temperature, as well as having many functional groups that can interact with an adjacent polymer to generate long lasting ASDs.

Vibrational spectroscopic techniques, such as Fourier-transform infrared (FTIR) and Raman spectroscopies, have been useful tools in understanding and characterizing intermolecular interactions. [16-20] The spectroscopic assignments for NIF can be used as a reference to improve the understanding of intermolecular interactions between polymers and drug molecules in ASDs. The use of computational modeling has provided further insight into the relationship between structure and spectroscopy, where all possible vibrational modes of a molecule can be calculated, visualized, and assigned to different functional groups or groups of atoms. [21] Another technique commonly utilized for characterizing ASD interactions is solid-state nuclear magnetic resonance (ssNMR) spectroscopy [22-24], and the isotropic chemical shifts can be calculated and used to help interpret experimental ssNMR spectra. This information can be used to identify which specific carbon positions are impacted by intermolecular interactions between NIF and a specific polymer (commonly a cellulose derivative) in ASDs. [25-27] Furthermore, a combination of these four different types of techniques allows for a much more complete and robust characterization of in situ intermolecular interactions in ASD systems.

In this study, we have applied density functional theory (DFT) calculations to determine the optimized geometry and vibrational spectra of a single NIF molecule. The theoretical bond lengths and angles are compared to those found in the experimental crystal structure. [28] We then go on to compute and assign all of NIF’s vibrational modes related to its specific functional groups or molecular fragments. We note that Chan et al. previously reported some basic vibrational assignments of different NIF polymorphs based on their Raman spectra, but their characterization lacked the rigorous details provided by computational modeling. [20] Through a combination of experimental FTIR, Raman, XRD [28], and ssNMR spectroscopies and a comparison to computed properties from DFT, we provide a complete atomic-level analysis of NIF’s molecular structure and obtain excellent agreement between theory and experiment. For the ASD experiments, IMI characterization is performed via Raman, FTIR, and ssNMR, and ASD stability is characterized via DSC, dielectric relaxation spectroscopy (DRS), and powder XRD.

Bibliography

[1] Zhang, J.; Chen, Y.; Sun, Y.; Wang, R.; Zhang, J.; Jia, Z. Drug Delivery 2018, 25 (1), 1175-1181.

[2] Clark, S. M.; Dunn, H. E.; Hankins, G. D. V. Seminars in Perinatology 2015, 39 (7), 548-555.

[3] Kashanian, M.; Bahasadri, S.; Zolali, B. International Journal of Gynecology & Obstetrics 2011, 113 (3)

[4] de Heus, R.; Mulder, E. J. H.; Visser, G. H. A. Int. J. Women’s Health 2010, 2, 137-142.

[5] Filgueira, G. C. d. O.; Filgueira, O. A. S.; Carvalho, D. M.; Marques, M. P.; Moisés, E. C. D.; Duarte, G.; Lanchote, V. L.; Cavalli, R. C. British Journal of Clinical Pharmacology 2017, 83 (7), 1571-1579,

[6] Porpiglia, F.; Destefanis, P.; Fiori, C.; Fontana, D. Urology 2000, 56 (4), 579-582.

[7] Khan, K. M.; Patel, J. B.; Schaefer, T. J. Nifedipine. In StatPearls, StatPearls Publishing, 2022.

[8] Rubini, A.; Catena, V.; del Monte, D.; Bosco, G. Journal of Enzyme Inhibition and Medicinal Chemistry 2017, 32 (1), 1-4.

[9] Richter, J. E.; Dalton, C. B.; Bradley, L. A.; Castell, D. O. Gastroenterology 1987, 93 (1), 21-28.

[10] Chrysos, E.; Xynos, E.; Tzovaras, G.; Zoras, O. J.; Tsiaoussis, J.; Vassilakis, S. J. Diseases of the Colon & Rectum 1996, 39 (2).

[11] Yasam, V. R.; Jakki, S. L.; Natarajan, J.; Venkatachalam, S.; Kuppusamy, G.; Sood, S.; Jain, K. Drug Delivery 2016, 23 (2), 619-630. DOI: 10.3109/10717544.2014.931484.

[12] Devarakonda, B.; Hill, R. A.; de Villiers, M. M. International Journal of Pharmaceutics 2004, 284 (1), 133-140.

[13] Chavan, R. B.; Thipparaboina, R.; Kumar, D.; Shastri, N. R. RSC Advances 2016, 6 (81), 77569-77576, 10.1039/C6RA19746A.

[14 Raina, S. A.; Van Eerdenbrugh, B.; Alonzo, D. E.; Mo, H.; Zhang, G. G. Z.; Gao, Y.; Taylor, L. S. Journal of Pharmaceutical Sciences 2015, 104 (6), 1981-1992.

[15] Baghel, S.; Cathcart, H.; O'Reilly, N. J. Journal of Pharmaceutical Sciences 2016, 105 (9), 2527-2544.

[16] Ricarte, R. G.; Van Zee, N. J.; Li, Z.; Johnson, L. M.; Lodge, T. P.; Hillmyer, M. A. Molecular Pharmaceutics 2019, 16 (10), 4089-4103.

[17] Meng, F.; Trivino, A.; Prasad, D.; Chauhan, H. European Journal of Pharmaceutical Sciences 2015, 71, 12-24.

[18] Chauhan, H.; Hui-Gu, C.; Atef, E. Journal of Pharmaceutical Sciences 2013, 102 (6), 1924-1935.

[19] Prasad, D.; Chauhan, H.; Atef, E. Journal of Pharmaceutical Sciences 2014, 103 (11), 3511-3523.

[20] Chan, K. L. A.; Fleming, O. S.; Kazarian, S. G.; Vassou, D.; Chryssikos, G. D.; Gionis, V. Journal of Raman Spectroscopy 2004, 35 (5), 353-359.

[21] Mariappan, G.; Sundaraganesan, N. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 2014, 117, 604-613.

[22] Ueda, K.; Yamazoe, C.; Yasuda, Y.; Higashi, K.; Kawakami, K.; Moribe, K. Molecular Pharmaceutics 2018, 15 (9), 4099-4109.

[23] Lu, X.; Huang, C.; Lowinger, M. B.; Yang, F.; Xu, W.; Brown, C. D.; Hesk, D.; Koynov, A.; Schenck, L.; Su, Y. Molecular Pharmaceutics 2019, 16 (6), 2579-2589.

[24] Paudel, A.; Geppi, M.; Mooter, G. V. d. Journal of Pharmaceutical Sciences 2014, 103 (9), 2635-2662.

[25] Heinz, A.; Strachan, C. J.; Gordon, K. C.; Rades, T. Journal of Pharmacy and Pharmacology 2009, 61 (8), 971-988.

[26] Cilurzo, F.; Minghetti, P.; Casiraghi, A.; Montanari, L. International Journal of Pharmaceutics 2002, 242 (1), 313-317.

[27] Vippagunta, S. R.; Maul, K. A.; Tallavajhala, S.; Grant, D. J. W. International Journal of Pharmaceutics 2002, 236 (1), 111-123.

[28] Bortolotti, M.; Lonardelli, I.; Pepponi, G. Acta Crystallogr B 2011, 67 (Pt 4), 357-364.