Drug-Drug Binary Solids of Nitrofurantoin and Trimethoprim: Crystal Engineering and Pharmaceutical Properties.

With the aim of developing multidrug solids through a tuned crystal engineering approach, we have selected two antiurinary infective drugs, namely, nitrofurantoin (NF) and trimethoprim (TMP) and isolated eight binary drug-drug solid solvates along with a nonsolvated cocrystal. Crystal structure analyses were performed for eight of these solids and rationalized in terms of known supramolecular synthons formed by pyrimidine, imide, and amine functionalities. Notably, the TMP-NF anhydrous cocrystal and its ionic cocrystal hydrate exhibit enhanced equilibrium solubilities compared to pure NF or the simple NF hydrate. Furthermore, the ionic cocrystal hydrate exhibits greater antibacterial activity against the Gram-negative bacteria, E. coli, compared to the parent TMP and NF at the lowest concentration of 3.9 µg/mL. This study indicates initial pathways using the cocrystal methodology that would help to eventually arrive at an antiurinary cocrystal with optimal properties.

Sonochemical degradation of trimethoprim in water matrices: Effect of operating conditions, identification of transformation products and toxicity assessment.

The sonochemical degradation of trimethoprim (TMP), a widely used antibiotic, in various water matrices was investigated. The effect of several parameters, such as initial TMP concentration (0.5-3 mg/L), actual power density (20-60 W/L), initial solution pH (3-10), inorganic ions, humic acid and water matrix on degradation kinetics was examined. The pseudo-first order degradation rate of TMP was found to increase with increasing power density and decreasing pH, water complexity (ultrapure water > bottled water > secondary wastewater) and initial TMP concentration. TMP degradation is accompanied by the formation of several transformation products (TPs) as evidenced by LC-QToF-MS analysis. Nine such TPs were successfully identified and their time-trend profiles during degradation were followed. An in silico toxicity evaluation was performed showing that several TPs could potentially be more toxic than the parent compound towards Daphnia magna, Pimephales promelas and Pseudokirchneriella subcapitata.

Exposure to sub-inhibitory ciprofloxacin and nitrofurantoin concentrations increases recA gene expression in uropathogenic Escherichia coli: The role of RecA protein as a drug target.

Sub-inhibitory concentrations (sub-MIC) of antimicrobial agents can lead to genetic changes in bacteria, modulating the expression of genes related to bacterial stress and leading to drug resistance. Herein we describe the impact of sub-MIC of ciprofloxacin and nitrofurantoin on three uropathogenic Escherichia coli strains. Disk-diffusion assays with different antimicrobial agents were tested to detect phenotype alterations, and quantitative real-time PCR (qRT-PCR) was performed to analyze the expression of ompF and recA genes. Significant reduction on the susceptibility to ciprofloxacin and nitrofurantoin was detected on disk diffusion test. The qRT-PCR results revealed a 1.2-4.7 increase in recA expression in all E. coli studied, while the ompF expression varied. Because RecA was pointed as an important component to the development of drug resistance, molecular docking studies were performed with three experimentally known inhibitors of this enzyme. These studies aimed to understand the inhibitory binding mode of such compounds. The results confirmed the ADP/ATP binding site as a potential site of inhibitor recognition and a binding mode based on π-stacking interactions with Tyr103 and hydrogen bonds with Tyr264. These findings can be useful for guiding the search and design of new antimicrobial agents, mainly concerning the treatment of infections with resistant bacterial strains.

L-Methionine associated with Hibiscus sabdariffa and Boswellia serrata extracts are not inferior to antibiotic treatment for symptoms relief in patients affected by recurrent uncomplicated urinary tract infections: Focus on antibiotic-sparing approach.

OBJECTIVE: To evaluate the efficacy of a phytotherapic combination of L-Methionine associated with Hibiscus sabdariffa and Boswellia serrata for treatment of acute episodes of uncomplicated urinary tract infections (UTI) in women affected by recurrent UTIs. MATERIALS AND METHODS: In this randomized phase III clinical trial, adult females with uncomplicated UTI were enrolled into one of the following treatment groups: Group A: phytotherapic combination 1 tablet in the morning and 1 tablet in the evening for 7 days; Group B: Short term antibiotic treatment according to international guidelines recommendations. At baseline, all patients were evaluated by a urologist and quality of life (QoL) questionnaires and mid-stream urine culture. Same clinical and laboratory investigations were repeated at each follow-up visit. RESULTS: Forty-six patients were enrolled in Group A and 47 in Group B. At the first follow-up (30 days), both groups showed a statistically significant improvement in quality of life scores as compared with baseline assessment [Group A: (QoL 94.3 VS 98.5 p < 0.001); Group B: (QoL 94.5 VS 98.7 p < 0.001)]. An improvement from baseline was also seen at the second followup evaluation after 3 months [Group A: (QoL 94.3 VS 99.1 p < 0.001); Group B: (QoL 94.5 VS 98.1 p < 0.001)]. At the second follow-up visit, a statistically significant difference in QoL was reported between the two groups (99.1 VS 98.1; p < 0.003) and a transition from UTI to asymptomatic bacteriuria (ABU) was observed 12 of 46 (26%) patients in Group A, while no patients in Group B demonstrated ABU (p = 0.007). CONCLUSIONS: Here, we demonstrated that this phytotherapic combination is able, in comparison to antibiotic treatment, to improve patients quality of life, reducing symptoms in acute setting and preventing the recurrences. Interestingly, a significantly higher proportion of patients in the phytotherapy group had ABU after three months. Our findings are of great interest in an antibiotic stewardship perspective.

Nitrofurantoin hydrolytic degradation in the environment.

Occurrence of pharmaceuticals, especially antibiotics in the environment increased attention to their environmental fate. Hydrolysis is one of two abiotic processes by which compounds are degraded in the environment. According to authors knowledge this is the first study investigating hydrolytic degradation of nitrofurantoin at pH-values normally found in the environment. Nitrofurantoin hydrolytic degradation appeared to be much slower at acidic (pH 4) solution compared to neutral (pH 7) and alkaline (pH 9) solutions at all three investigated temperatures (20 °C, 40 °C and 60 °C). In all cases nitrofurantoin hydrolysis followed the first-order kinetics with half-lives ranged from 0.5 days at pH 9 and 60 °C to 3.9 years at pH 4 and 20 °C. Temperature dependence of the hydrolysis rate constant was quantified by Arrhenius equation; obtained Ea values were as follows: 100.7 kJ mol-1 at pH 4, 111.2 kJ mol-1 at pH 7 and 102.3 kJ mol-1 at pH 9. Increase in hydrolysis rate constants for each 10 °C increase in temperature were 3.4, 3.9 and 3.5 at pH 4, pH 7 and pH 9, respectively. The structures of hydrolytic degradation products were determined and degradation pathways were suggested. Three main processes occurred depending on pH-values: protonation of the nitrofurantoin followed by cleavage of the NN single bond, heterocyclic non-aromatic ring cleavage, and reduction of the non-aromatic heterocyclic ring.

High-throughput identification and rational design of synergistic small-molecule pairs for combating and bypassing antibiotic resistance.

Antibiotic-resistant infections kill approximately 23,000 people and cost $20,000,000,000 each year in the United States alone despite the widespread use of small-molecule antimicrobial combination therapy. Antibiotic combinations typically have an additive effect: the efficacy of the combination matches the sum of the efficacies of each antibiotic when used alone. Small molecules can also act synergistically when the efficacy of the combination is greater than the additive efficacy. However, synergistic combinations are rare and have been historically difficult to identify. High-throughput identification of synergistic pairs is limited by the scale of potential combinations: a modest collection of 1,000 small molecules involves 1 million pairwise combinations. Here, we describe a high-throughput method for rapid identification of synergistic small-molecule pairs, the overlap2 method (O2M). O2M extracts patterns from chemical-genetic datasets, which are created when a collection of mutants is grown in the presence of hundreds of different small molecules, producing a precise set of phenotypes induced by each small molecule across the mutant set. The identification of mutants that show the same phenotype when treated with known synergistic molecules allows us to pinpoint additional molecule combinations that also act synergistically. As a proof of concept, we focus on combinations with the antibiotics trimethoprim and sulfamethizole, which had been standard treatment against urinary tract infections until widespread resistance decreased efficacy. Using O2M, we screened a library of 2,000 small molecules and identified several that synergize with the antibiotic trimethoprim and/or sulfamethizole. The most potent of these synergistic interactions is with the antiviral drug azidothymidine (AZT). We then demonstrate that understanding the molecular mechanism underlying small-molecule synergistic interactions allows the rational design of additional combinations that bypass drug resistance. Trimethoprim and sulfamethizole are both folate biosynthesis inhibitors. We find that this activity disrupts nucleotide homeostasis, which blocks DNA replication in the presence of AZT. Building on these data, we show that other small molecules that disrupt nucleotide homeostasis through other mechanisms (hydroxyurea and floxuridine) also act synergistically with AZT. These novel combinations inhibit the growth and virulence of trimethoprim-resistant clinical Escherichia coli and Klebsiella pneumoniae isolates, suggesting that they may be able to be rapidly advanced into clinical use. In sum, we present a generalizable method to screen for novel synergistic combinations, to identify particular mechanisms resulting in synergy, and to use the mechanistic knowledge to rationally design new combinations that bypass drug resistance.

Modeling the biotransformation of trimethoprim in biological nutrient removal system.

A pilot scale biological nutrient removal (BNR) process, batch experiments and modeling exercises were employed to investigate the removal and biotransformation of trimethoprim (TMP) in a BNR activated sludge process. The concentrations of the active microbial groups - ammonia oxidizing bacteria (AOB), ordinary heterotrophic organisms (OHOs) and polyphosphate accumulating organisms (PAOs) - in the BNR bioreactor were quantified through modeling of the pilot bioreactor. The overall TMP removal efficiency for the pilot BNR process was 64 ± 14% while the TMP biotransformation efficiencies in the anaerobic, anoxic and aerobic zones were 22 ± 20%, 27 ± 8% and 36 ± 5% respectively. Batch tests with and without nitrification inhibition showed that AOB played a role in the biotransformation of TMP in BNR activated sludge. A pseudo first order model which incorporated the contributions of PAOs, OHOs and AOB to the overall biodegradation of TMP was found to describe the biodegradation of TMP in batch tests with and without nitrification inhibition. This model showed that PAOs, OHOs and AOB contributed towards the biotransformation of TMP in aerobic BNR activated sludge with the biotransformation rate constants following the trend of kAOB > kOHOs > kPAOs.

Degradation of flumequine in aqueous solution by persulfate activated with common methods and polyhydroquinone-coated magnetite/multi-walled carbon nanotubes catalysts.

In recent years, flumequine (FLU) has been ubiquitously detected in surface waters and municipal wastewaters. In light of its potential negative impacts to aquatic species, growing concern has been arisen for the removal of this antibiotic from natural waters. In this study, the kinetics, degradation mechanisms and pathways of aqueous FLU by persulfate (PS) oxidation were systematically determined. Three common activation methods, including heat, Fe(2+) and Cu(2+), and a novel heterogeneous catalyst, namely, polyhydroquinone-coated magnetite/multi-walled carbon nanotubes (Fe3O4/MWCNTs/PHQ), were investigated to activate PS for FLU removal. It was found that these three common activators enhanced FLU degradation obviously, while several influencing factors, such as solution pH, inorganic ions (especially HCO3(-) at 5 mmol/L) and dissolved organic matter extracts, exerted their different effects on FLU removal. The catalysts were characterized, and an efficient catalytic degradation performance, high stability and excellent reusability were observed. The measured total organic carbon levels suggested that FLU can be effectively mineralized by using the catalysts. Radical mechanism was studied by combination of the quenching tests and electron paramagnetic resonance analysis. It was assumed that sulfate radicals predominated in the activation of PS with Fe3O4/MWCNTs/PHQ for FLU removal, while hydroxyl radicals also contributed to the catalytic oxidation process. In addition, a total of fifteen reaction intermediates of FLU were identified, from which two possible pathways were proposed involving hydroxylation, decarbonylation and ring opening. Overall, this study represented a systematical evaluation regarding the transformation process of FLU by PS, and showed that the heterogeneous catalysts can efficiently activate PS for FLU removal from the water environment.

Nitrofurantoin enteric pellets with high bioavailability based on aciform crystalline formation by wet milling.

The aim of the present study was to grind nitrofurantoin (NF) with HPMC solution and to determine the dissolution and bioavailability of the enteric pellets prepared with the NF cogrounds and other excipients. During milling, crystalline transformation occurred--the aciform microcrystalline monohydrate II replaced the coarse crystal anhydrate ß and the particle size markedly reduced. In vitro test demonstrated that the enteric pellets prepared with NF cogrounds (4 h) revealed a faster dissolution than the commercial tablet and 50% was released within 30 min in the basic medium. Finally, an in vivo test was conducted in beagle dogs. The Cmax and AUC(0 → 24) of the pellets were 2.19 ± 0.74 µg/ml and 6.73 ± 4.71 µg/ml h, respectively, while the corresponding values were 0.49 ± 0.42 µg/ml and 1.38 ± 1.17 µg/ml h for the tablet. Thus, the bioavailability of the pellets was increased significantly. In conclusion, the wet grinding that reduced the particle size and created the microcrystalline played a major role in the acceleration of the dissolution of NF and, consequently, enhanced the bioavailability, and the wet grinding process offers an alternative approach to improve the dissolution and bioavailability of drugs with poor aqueous solubility.

Poly(L-lactide) and poly(butylene succinate) immiscible blends: from electrospinning to biologically active materials.

For the first time the preparation of defect-free fibers from immiscible blends of high molar mass poly(lactic acid) (PLA) and poly(butylene succinate) (PBS) in the whole range of the polyester weight ratios is shown. Electrospinning using the solvent-nonsolvent approach proved most appropriate. Moreover, electrospinning revealed crucial for the obtaining of PLA/PBS materials maintaining integrity. DSC and XRD analyses attested for a plasticizing effect and for increased PLA crystallinity at PBS addition to PLA. The mechanical properties of the PLA/PBS mats were controlled by the alignment of the fibers and changed from plastic to brittle materials upon increasing the PBS content. Drug loading and tests against pathogenic microorganisms suggested that the obtained mats can find application as antibacterial fibrous materials.

Non linear optical analyses of hexamine: phenol cocrystals based on hydrogen bonding: a comparative study.

Fourier-Transform Infrared (FT-IR) spectroscopy supported by Raman spectroscopy has been employed to explain the conventional and unconventional hydrogen bonding present in the 4,4'thiodiphenol: hexamine and 4,4'sulfonyldiphenol: hexamine cocrystals. The possible internal and external vibrational modes are predicted through factor group analysis. Influence of intra molecular charge transfer (ICT) interaction caused by the strong ionic ground state hydrogen bonding between charged species, giving rise to a non centro symmetric structure which is a criterion for second harmonic generation (SHG) efficiency has been discussed. Intense low wave number hydrogen bond vibrations in Raman which arise due to electron-phonon coupling are analyzed. Optical quality of adducts is identified through UV-Vis analysis. The second harmonic generation efficiency of both adducts is determined by Kurtz-Perry method.

Quantitation of nitrofurantoin in human plasma by liquid chromatography tandem mass spectrometry.

A reliable, selective and sensitive LC-MS/MS assay has been proposed for the determination of nitrofurantoin in human plasma. The analyte and nitrofurazone were extracted from 100 µL of human plasma via SPE on Strata-X 33 µm extraction cartridges. Chromatography was done on a BDS Hypersil C18 (100 mm × 4.6 mm, 5 µm) column under isocratic conditions. Quantitation was done using the multiple reaction monitoring (MRM) mode for deprotonated precursor to product ion transitions of nitrofurantoin (m/z 237.0 → 151.8) and nitrofurazone (m/z 197.0 → 123.9). The limit of detection and the lowest limit of quantitation of the method were 0.25 ng mL-1 and 5.00 ng mL-1, respectively, with a linear dynamic range of 5.00-1500 ng mL-1 for nitrofurantoin. The intra- -batch and inter-batch precision (RSD, %) was ≤ 5.8 %, while the mean extraction recovery was > 92 %. The method was successfully applied to a bioequivalence study of a 100 mg nitrofurantoin capsule formulation in 36 healthy subjects.

Superiority of solar Fenton oxidation over TiO2 photocatalysis for the degradation of trimethoprim in secondary treated effluents.

The overall aim of this work was to examine the degradation of trimethoprim (TMP), which is an antibacterial agent, during the application of two advanced oxidation process (AOP) systems in secondary treated domestic effluents. The homogeneous solar Fenton process (hv/Fe(2+)/H2O2) and heterogeneous photocatalysis with titanium dioxide (TiO2) suspensions were tested. It was found that the degradation of TMP depends on several parameters such as the amount of iron salt and H2O2, concentration of TiO2, pH of solution, solar irradiation, temperature and initial substrate concentration. The optimum dosages of Fe(2+) and H2O2 for homogeneous ([Fe(2+)] = 5 mg L(-1), [H2O2] = 3.062 mmol L(-1)) and TiO2 ([TiO2] = 3 g L(-1)) for heterogeneous photocatalysis were established. The study indicated that the degradation of TMP during the solar Fenton process is described by a pseudo-first-order reaction and the substrate degradation during the heterogeneous photocatalysis by the Langmuir-Hinshelwood kinetics. The toxicity of the treated samples was evaluated using a Daphnia magna bioassay and was finally decreased by both processes. The results indicated that solar Fenton is more effective than the solar TiO2 process, yielding complete degradation of the examined substrate within 30 min of illumination and dissolved organic carbon (DOC) reduction of about 44% whereas the respective values for the TiO2 process were ∼70% degradation of TMP within 120 min of treatment and 13% DOC removal.

Heterogeneous degradation of precipitated hexamine from wastewater by catalytic function of silicotungstic acid in the presence of H2O2 and H2O2/Fe2+.

The industrial wastewater produced by hexamine plants is considered as a major environmental polluting factor due to resistance to biodegradation. So the treatment of such wastewater is required. In this work, the removal of hexamine from wastewater and its degradation have been studied. Hexamine was precipitated through formation of an insoluble and stable compound with silicotungstic acid. The oxidative heterogeneous degradation of precipitated hexamine was carried out with hydrogen peroxide (H(2)O(2)) aqueous solution and H(2)O(2)/Fe(2+) under the catalysis of silicotungstic acid. The operating conditions including amount of precipitate, hydrogen peroxide and ferrous ion dosage, temperature, time and pH were optimized by evaluating the removal of total organic carbon from system. A total organic carbon conversion higher than 70% was achieved in the presence of H(2)O(2)/Fe(2+). The experimental results showed that hexamine can be effectively degraded with H(2)O(2) and H(2)O(2)/Fe(2+) under the catalysis of silicotungstic acid. It was interesting that the solution of dissolved precipitate with H(2)O(2) can re-react with hexamine after the removal of excess hydrogen peroxide. This observation indicates the catalysis role of silicotungstic acid in the degradation of hexamine. A kinetic analysis based on total organic carbon reduction was carried out. The two steps mechanism was proposed for the degradation of hexamine.

Development and validation of a spectrophotometric method for quantitative determination of new preservatives from pharmaceutical forms.

AIM: A spectrophotometric UV-VIS fast, sensitive and simple method was developed for quantitative determination of two new antimicrobial preservatives (oxi-acetyl-mandelic acid and oxi-propionyl mandelic acid) and validated according to validation quides. MATERIAL AND METHODS: The absorption spectra were recorded at 200-400 nm, and the absorbances were measured at 256 nm for oxi-acetyl mandelic acid and 258 nm for oxipropionyl mandelic acid. Optimum working conditions were established and the method was validated. The developed and validated method was applied to determine these two preservatives from ointments, in which the preservatives were incorporated. RESULTS: The method has a good linearity in the concentration range 0.1-1.5 mg/ml (for oxi-acetyl mandelic acid) and 0.1-1 mg/ml (for oxi-propionyl mandelic acid). The RSD for the precision of the method was 0.96328 for oxiacetyl mandelic acid and 0.797612 for oxi-propionyl mandelic acid. The relative standard deviation was 0.726367% for oxi-acetyl mandelic acid and 0.726234% for oxipropionyl mandelic acid. In the ointment samples, the concentration of oxi-acetyl mandelic acid and oxi-propionyl mandelic acid were within the limits specified by pharmacopoeia for ointments. CONCLUSIONS: The developed and validated spectrophotometric method, for the determination of oxi-acetyl mandelic acid and oxi-propionyl mandelic acid is simple, easy to perform, fast and cost effective.

Vibrational spectroscopic and DFT study of trimethoprim.

Structural investigations by different vibrational spectroscopic methods: FTIR, FT-Raman and surface-enhanced Raman scattering (SERS) spectroscopy, as well as density functional theory (DFT) calculations were performed on trimethoprim (5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine). A reliable assignment of vibrational IR, Raman and SERS bands was possible by a proper choice of model used in quantum chemical calculations. Based on SERS spectrum analysis it is shown that the molecule is adsorbed on the silver surface through the pyrimidine ring, in a perpendicular orientation. Two theoretical models were used in order to simulate the silver surface and the interaction with trimethoprim molecule, the accuracy of the models being evaluated by comparing the predicted bands position of the two complexes with the SERS result.

Spectroscopic investigation on the mechanism of formation of molecular complexes of albendazole and trimethoprim with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

UV-vis, (1)H NMR, FT-IR, mass and fluorescence spectral techniques were employed to investigate the mechanism of interaction of albendazole and trimethoprim with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and to characterize the reaction products. The interaction of DDQ with trimethoprim (TMP) and albenadazole (ALB) were found to proceed through the formation of donor-acceptor complex, containing DDQ radical anion and its conversion to the product. Fluorescence quenching studies indicated that the interaction between the donors and the acceptor are spontaneous and the interaction of TMP-DDQ (binding constant=2.9×10(5)) is found to be stronger than that the ALB-DDQ (binding constant=3×10(3)) system. Also, the binding constant increased with an increase in polarity of the medium indicating the involvement of radical anion as intermediate.

Oxidation of trimethoprim by ferrate(VI): kinetics, products, and antibacterial activity.

Kinetics, stoichiometry, and products of the oxidation of trimethoprim (TMP), one of the most commonly detected antibacterial agents in surface waters and municipal wastewaters, by ferrate(VI) (Fe(VI)) were determined. The pH dependent second-order rate constants of the reactions of Fe(VI) with TMP were examined using acid-base properties of Fe(VI) and TMP. The kinetics of reactions of diaminopyrimidine (DAP) and trimethoxytoluene (TMT) with Fe(VI) were also determined to understand the reactivity of Fe(VI) with TMP. Oxidation products of the reactions of Fe(VI) with TMP and DAP were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Reaction pathways of oxidation of TMP by Fe(VI) are proposed to demonstrate the cleavage of the TMP molecule to ultimately result in 3,4,5,-trimethoxybenzaldehyde and 2,4-dinitropyrimidine as among the final identified products. The oxidized products mixture exhibited no antibacterial activity against E. coli after complete consumption of TMP. Removal of TMP in the secondary effluent by Fe(VI) was achieved.

Nitrofurantoin-p-aminobenzoic acid cocrystal: hydration stability and dissolution rate studies.

Nitrofurantoin (NF) drug is known to transform to a hydrate form in aqueous medium. The hydration stability and dissolution rate of a few cocrystals of NF were compared with that of its stable ß polymorph and hydrate form II. Hydrogen bonding and molecular packing in the novel cocrystal structures were analyzed. Pharmaceutical cocrystals of NF with p-aminobenzoic acid (PABA) and urea showed superior physicochemical properties compared with the known L-arginine salt hydrate. All the solid-state adducts were characterized by single-crystal X-ray diffraction, X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis. NF-PABA cocrystal was found to be superior among the compounds studied in terms of minimal transformation to NF hydrate and comparable dissolution rate to the reference drug.

Integrated approach to study the dehydration kinetics of nitrofurantoin monohydrate.

There is a need for thorough knowledge of solid-state transformations in order to implement quality by design (QbD) methodology in drug development. The present study was aimed at gaining a mechanistic understanding of the dehydration of nitrofurantoin monohydrate II (NF-MH). The dehydration was studied using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), and variable temperature X-ray powder diffraction (VT-XRPD). Isothermal TGA data were used to study dehydration kinetics using model-fitting and model-free approaches. Model-fitting analysis indicated a good fit for several models derived from nucleation-growth and/or geometric contraction mechanisms. However, based on visual observations during HSM, Avrami-Erofeyev equations A3 and A4, indicating nucleation-growth phenomenon, were found to be the most suitable kinetic models. HSM showed initiation of dehydration with random nucleation, and nuclei coalesced with the progress of dehydration reaction. VT-XRPD revealed formation of anhydrate beta form on dehydration of NF-MH. The phenomenon of random nucleation is justified based on the crystal structure of NF-MH, which showed presence of water molecules in an isolated manner, prohibiting directional dehydration. It was found that supplementary information from HSM and VT-XRPD can be valuable to gain a better understanding of dehydration from formal solid-state kinetics analysis.