Abstract-Structure and spectroscopic characterization of pharmaceutical co-crystal formation between acetazolamide and 4-hydroxybenzoic acid

Yaguo Wang, Jiadan Xue, Jianyuan Qin, Jianjun Liu, Yong Du

https://www.sciencedirect.com/science/article/pii/S138614251930469X

Co-crystals have great potential for drug research and development because the formation of co-crystal is accompanied by changes inter-molecular interactions between starting materials that enable to improve both physical and chemical properties of active pharmaceutical ingredients. In order to provide a more profound insight into the structural changes of specific drugs upon co-crystallization, spectroscopic characterization of solid-state acetazolamide (ACZ), 4-hydroxybenzoic acid (4HBA) and their co-crystal prepared by mechanical grinding approach has been performed with spectral techniques including terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy. Experimental THz spectra show that the ACZ-4HBA co-crystal has a few significantly different absorption peaks in 0.82, 1.16, 1.28 and 1.64 THz respectively compared with parent materials in the frequency region from 0.2 to 1.8 THz. Likewise, such differences between the co-crystal and starting compounds could also be characterized by Raman vibrational spectra. Moreover, density functional theory (DFT) calculations were performed to simulate structures and vibrational modes of three kind of possible co-crystal theoretical forms (form I, II and III) between ACZ and 4HBA. Theoretical results and THz/Raman vibrational spectra of ACZ-4HBA co-crystal show that the 4HBA links to the thiadiazole acetamide fragment of ACZ via the double-bridged heterodimeric synthon C(N)NH⋯HOOC inter-molecular hydrogen bonding interaction establishing the theoretical form I, which is more consistent with experimental observations than other two co-crystal forms. These results provide rich information and unique method for characterizing the composition of co-crystal structures and also inter-molecular interactions shown within pharmaceutical co-crystallization process at the molecular level.

Abstract-Structural investigation of a 2:1 co-crystal between diflunisal and isonicotinamide based on terahertz and Raman spectroscopy

Yaguo Wang, Jiadan Xue, Qiqi Wang, Shunji Jin, Ziming Zhang, Zhi Hong, Yong Du

https://www.x-mol.com/paper/5593201

In order to characterize molecular structure changes of drugs upon co-crystallization by means of spectroscopic techniques, vibrational spectra of solid-state diflunisal (DIF), isonicotinamide (ISO) and their 2:1 co-crystal have been investigated by using terahertz time-domain spectroscopy (THz-TDS) and Raman spectroscopy. A 2:1 DIF-ISO co-crystal between DIF and ISO has been synthesized by slow solution crystallization from ethanol. The experimental THz spectroscopy shows that the co-crystal has a few significantly different absorption peaks compared with raw parent materials within the frequency region from 0.2 to 1.6 THz. Likewise, some differences of vibrational spectra between the co-crystal and starting compounds could also be characterized by Raman spectral results. Density functional theory (DFT) was used to simulate optimized structures and vibrational modes of two kind of possible co-crystal theoretical forms (form I and II) between DIF and ISO. Theoretical co-crystal form I is shown with 2:1 theoretical binary-adduct formed by carboxylic acid-amide and carboxylic acid-pyridine under inter-molecular hydrogen bonding. Theoretical co-crystal form II has a similar structure as form I, meanwhile the only difference is that O63 atom simultaneously forms hydrogen bond with H33 and H64. Also the hydroxyl –OH and carboxyl group –COOH establish molecular heterocycle under intra-molecular hydrogen bonds in both forms. The theoretical results show that both THz and Raman spectra of co-crystal form II between DIF and ISO is more consistent with the experimental observations than those of co-crystal form I. These results provide us with a wealth of information and unique method for characterizing the composition of co-crystal structures and also inter-molecular hydrogen bonding interactions shown within pharmaceutical co-crystallization at the molecular level.

Abstract-Investigation into tautomeric polymorphism of 2-thiobarbituric acid using experimental vibrational spectroscopy combined with DFT theoretical simulation

Qiqi Wang, Jiadan Xue, Yaguo Wang, Shunji Jin, Qi Zhang, Yong Du,

https://www.sciencedirect.com/science/article/pii/S1386142518305687

Vibrational modes of 2-thiobarbituric acid (TBA) tautomeric polymorphs (form I, II and IV) were characterized by terahertz time-domain spectroscopy (THz-TDS) and Raman spectral techniques. The experimental results indicate that both vibrational spectroscopy techniques could be used to recognize the above TBA three tautomeric forms clearly. Experimental THz spectral results show that each of TBA tautomeric polymorphs has distinctive fingerprint peaks in the terahertz region. Raman spectra also show similar results about differences of TBA tautomeric polymorphs, but not significant as that of terahertz spectra since Raman-active vibrational modes are mostly from intra-molecular interaction of various functional groups within the specific molecule while that of terahertz region is more sensitive to inter-molecular interaction within crystalline unit cells. In addition, density functional theory (DFT) was used to simulate the optimized structures and vibrational modes of these three TBA tautomeric forms. The characteristic vibrational modes of TBA polymorphs are assigned comparing the simulated DFT results with experimental vibrational spectra. The results provide fundamental benchmark for the study of pharmaceutical polymorphism based on both Raman and terahertz vibrational spectroscopic techniques combined with theoretical simulations.

Abstract-Raman and Terahertz Spectroscopic Investigation of Cocrystal Formation Involving Antibiotic Nitrofurantoin Drug and Coformer 4-aminobenzoic Acid

Yong Du ^1,* ,Qiang Cai ¹

,Jiadan Xue ²

 andQi Zhang ¹

¹

Centre for THz Research, China Jiliang University, Hangzhou 310018, China

²

Department of Chemisty, Zhejiang Sci-Tech University, Hangzhou 310018, China

^*

Author to whom correspondence should be addressed.

Academic Editor: Srinivasulu Aitipamula

http://www.mdpi.com/2073-4352/6/12/164

Cocrystallization could improve most physicochemical properties of specific active pharmaceutical ingredients, which has great potential in pharmaceutical development. In this study, the cocrystal of nitrofurantoin and 4-aminobenzoic acid was prepared with solid-state (solvent-free or green-chemistry) grinding approach, and the above cocrystal has been characterized by Raman and terahertz vibrational spectroscopic techniques. Spectral results show that the vibrational modes of the cocrystal within the whole spectral region are different from those of the corresponding parent materials. The dynamic process of such pharmaceutical cocrystal formation has also been monitored directly with Raman spectra. These results offer us unique means for characterizing the cocrystal conformation from the molecule-level, and provides us with rich information about the reaction dynamic of cocrystal formation within pharmaceutical fields. View Full-Text