Co-Crystal Formation of Antibiotic Nitrofurantoin Drug and Melamine Co-Former Based on a Vibrational Spectroscopic Study.

Ziming Zhang,Yong Du,Jiadan Xue,Qiang Cai,Jianjun Liu,Jianyuan Qin

doi:10.3390/pharmaceutics11020056

Ziming Zhang, Yong Du + Show 4 more

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https://doi.org/10.3390/pharmaceutics11020056

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Abstract

The co-crystallization of active pharmaceutical ingredients (APIs) has received increasing attention due to the modulation of the relative physicochemical properties of APIs such as low solubility, weak permeability and relatively inferior oral bioavailability. Crystal engineering plays a decisive role in the systematic design and synthesis of co-crystals by means of exerting control on the inter-molecular interactions. The characterization and detection of such co-crystal formations plays an essential role in the field of pharmaceutical research and development. In this work, nitrofurantoin (NF), melamine (MELA) and their hydrated co-crystal form were characterized and analyzed by using terahertz time-domain spectroscopy (THz-TDS) and Raman vibrational spectroscopy. According to the experimental THz spectra, the hydrated co-crystal form has characteristic absorption peaks at 0.67, 1.05, 1.50 and 1.73 THz, while the THz spectra for the two raw parent materials (NF and MELA) are quite different within this spectral region. Similar observations were made from the experimental Raman vibrational spectra results. Density functional theory (DFT) calculation was performed to help determine the major vibrational modes of the hydrated co-crystal between nitrofurantoin and melamine, as well as identify the structural changes due to inter- and/or intra-molecular hydrogen bonding motifs between NF and MELA. The results of the theoretical frequency calculations corroborate the THz and Raman experimental spectra. The characteristic bands of the NF–MELA-hydrated co-crystal between nitrofurantoin and melamine were also determined based on the DFT simulated calculation. The reported results in this work provide us with a wealth of structural information and a unique vibrational spectroscopic method for characterizing the composition of specific co-crystals and inter-molecular hydrogen bonding interactions upon pharmaceutical co-crystallization.

Highlights

Nitrofurantoin (NF, with its molecular structure shown in Figure 1) is a widely used antibacterial drug for the oral treatment of urinary tract infections [1,2]
It could be primarily suggested that it is the effects of hydrogen bonding and the water molecule that lead to the structure change of the unit cells between the above two raw materials, along with the formation of the NF–MELA-hydrated co-crystal that results in the differences observed in the THz spectra between the NF–MELA-hydrated co-crystal and its parent compounds
The vibrational spectra of solid-state NF, MELA and their hydrated co-crystal form were measured with terahertz time-domain spectroscopy (THz-TDS) and Raman vibrational spectroscopy

Summary

Introduction

Nitrofurantoin (NF, with its molecular structure shown in Figure 1) is a widely used antibacterial drug for the oral treatment of urinary tract infections [1,2]. This drug is on the World Health Organization Model List of essential medicines and belongs to the Class IV drugs according to the Biopharmaceutics Classification System (BCS), that is, it shows low solubility, weak permeability and relatively inferior bioavailability [3]. TThhee ccoo--ccrryyssttaalllliizzaattiioonn aanndd ssaalltt ffoorrmmaattiioonn ooff AAPPIIss aarree ccoommmmoonn mmeetthhooddss ttoo mmoodduullaattee rreellaattiivvee pphhyyssiiccoocchheemmiiccaallpproroppeertriteiesssuscuhchasassolsuobluilbitiyl,itsyt,absitlaitbyiloitryboiorabviaoilaavbaiilliatybi[l1it0y–1[21]0.–I1n2f]a. Fguroruthpesrm[13o,r1e4,].thFeurrethiseramgorreea, tthneuremibseargorfeaptonteunmtibaelrnoofnp-ototexnicticaol -ncorny-sttoaxl ifcocrom-cerryss(tCalCfoFrsm) tehrast(CcoCuFlsd) btheaut sceodulidn bceo-ucsreydstainl fcoor-mcraytsitoanl sfo[r1m5]a. tiTohnes m[1o5]s.tTimhepmorotastntimadpvoratnatnatgaedovfatnhteagceo-ocfrythsetaclso-icsrtyhsatatltshies cthhaatntgheescohcacnugrerisnogccinurtrhiengcriynstthalepcraycsktianlgpoafckthinegspofecthifiecspderucigficcodurludglceoaudltdoliemadprtoovimedpvroavrieadtivoanroiafttiohne coofrrtehsepocnodrirnegspAoPnId’sinpghyAsiPcoI’cshepmhiycasilcporcohpeemrtiiceasl, wphroerpeearstitehse, awcthiveereiansgrethdeienatcatinvdethienrgarpeeduietinctefafencdt othfetrhaepderuutigcaerfefegcetnoefrtahlelydnroutginarfleugeennceerda[ll1y6]n.ot influenced [16]

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