Investigation On Crystal Structures Of Nitrogen Heterocyclic Drugs Based On Characteristic Spectral Techniques

Terahertz time-domain spectroscopy(THz-TDS)is a promising tool in studying molecular configuration and inter-molecular interaction effects.Fourier transform Raman(FT-Raman)spectra has been demonstrated to be an effective probe of intra-molecular vibrational modes of chemical bonds and functional groups.Nitrogen heterocyclic drugs,such as nitrofurantoin and pyrazinamide-isoniazid hyphenated drugs,would yield unique,molecularly-specific vibrational spectra within these two characteristic spectra.Therefore,the crystal structure can be identified.To investigate the effect of hydrogen bonding among the crystal structure of nitrogen heterocyclic drugs and related co-crystals,theoretical analysis and experimental results were obtained.The pyrazinamide detection limit in THz region was acquired based on the relationship between the content of pyrazinamide in the hyphenated drugs and both parameters of absorption coefficient and refractive index.Nitrofurantoin,an antibacterial with poor water solubility,has polymorphism forms.It is well documented that nitrofurantoin is sensitive to hydrate.THz-TDS and FT-Raman spectroscopic techniques were utilized to analyze the structures of nitrofurantoin and its hydrates.The difference in THz spectrum is much more significant than in Raman spectrum.Co-crystal has a remarkable ability to enhance the solubility of nitrofurantoin.Nitrofurantoin was chosen as active pharmaceutical ingredient(API)while 3-aminobenzoic acid(3ABA),4-aminobenzoic acid(4ABA),maleic acid(MA),fumaric acid(FA)and urea were used as the co-crystal formers(CCF).Their fingerprint spectra were obtained by THz-TDS.The optimized geometries and vibrational spectra of these model compounds were performed with the density functional theory(DFT)calculation.The crystal structures could be judged and confirmed by the degree of agreement between theoretical analysis and experimental results.To deeply analyze the dynamic forming process with grinding time,nitrofurantoin-4ABA co-crystal was chosen as an example.Certain relevance between scattering peaks and grinding time from mixture to co-crystal was also found by FT-Raman.The result manifested dynamic information of co-crystal forming process could be real-timely monitored by fingerprint spectral techniques.Hyphenated drugs reduced the risk of emergence of drug resistance.Excessive use of pyrazinamide resulted in liver toxicity.It is necessary to control the dosage of pyrazinamide in hyphenated drugs.The isoniazid and two polymorphs of pyrazinamide were inspected by THz-TDS.Their theoretical simulation indicated that molecular geometries of pyrazinamide were dimer.Terahertz spectrum of isoniazid revealed its molecular geometry was single molecule.There was a good linear relationship between the content of hyphenated drugs and both parameters of absorption coefficient and refractive index.The paper used the single linear regression(SLR)mode and partial least squares regression(PLSR)mode to complete quantitative analysis in hyphenated drugs.The detection limit of pyrazinamide concentration of absorption coefficient in PLSR mode was 0.7660%,which was one over ten of the SLR.The calculation showed that the PLS mode had better result.