Physicochemical stability of nefopam and nefopam/droperidol solutions in polypropylene syringes for intensive care units.

Introduction: Nefopam has been reported to be effective in postoperative pain control with an opioid-sparing effect, but the use of nefopam can lead to nausea and vomiting. To prevent these side effects, droperidol can be mixed with nefopam. In intensive care units, high concentrations of nefopam and droperidol in syringes can be used with a continuous flow. Objectives: The first objective of this work was to study the physicochemical stability of a nefopam solution 2.5 mg/mL diluted in NaCl 0.9% in polypropylene syringes immediately after preparation and after 6, 24 and 48 hours at room temperature. The second objective was to study the physicochemical stability of mixtures of nefopam 2.5 mg/mL and droperidol 52 µg/mL diluted in NaCl 0.9% in polypropylene syringes at room temperature over 48 hours. Materials and methods: Three syringes for each condition were prepared. For each time of analysis, three samples for each syringe were prepared and analysed by high performance liquid chromatography coupled to photodiode array detection. The method was validated according to the International Conference on Harmonisation Q2(R1). Physical stability was evaluated by visual and subvisual inspection (turbidimetry by UV spectrophotometry). pH values were measured at each time of analysis. Results: Solutions of nefopam at 2.5 mg/mL and the mixture of nefopam 2.5 mg/mL with droperidol 52 µg/mL, diluted in NaCl 0.9%, without protection from light, retained more than 90% of the initial concentration after 48 hours storage at 20-25°C. No modification in visual or subvisual evaluation and pH values were observed. Conclusion: Nefopam solutions at 2.5 mg/mL and the mixture of nefopam 2.5 mg/mL with droperidol 52 µg/mL diluted in NaCl 0.9% were stable over a period of 48 hours at room temperature. These stability data provide additional knowledge to assist intensive care services in daily practice.

A metal organic framework-functionalized monolithic column for enantioseparation of six basic chiral drugs by capillary electrochromatography.

Poly(glycidyl methacrylate)-co-(ethylene dimethacrylate) [poly(GMA-co-EDMA)] monoliths were used as a support to grow a zeolitic imidazolate framework-8 (ZIF-8) via layer-by-layer self-assembly. Pepsin, acting as as chiral selector, was covalently linked to the surface of the amino-modified ZIF-8 through the Schiff base method. The material was characterized by scanning electron microscopy, thermogravimetric analysis, X-ray diffraction, Fourier transform infrared spectroscopy and elemental analysis. The pepsin-ZIF-8-poly(GMA-co-EDMA) column was utilized to the enantioseparation of the racemic forms of hydroxychloroquine (HCQ), chloroquine (CHQ), hydroxyzine (HXY), nefopam (NEF), clenbuterol (CLE) and amlodipine (AML). In comparison with a pepsin-poly(GMA-co-EDMA) monolithic column (without self-assembled ZIF-8 nanoparticles), the resolution is strongly enhanced (HCQ: 0.34 → 2.50; CHQ: 0.45 → 1.97; HXY: 0.39 → 1.43; NEF: 0.27 → 0.81; CLE: 0 → 0.81; AML: 0.16 → 0.72). Effects of self-assembly layers of ZIF-8, pepsin concentration, buffer pH values and applied voltage were investigated with hydroxychloroquine as the model analyte. The reproducibility of run-to-run, day-to-day and column-to-column were explored, and found to be satisfactory. Graphical abstractSchematic representation of capillary electrochromatography (CEC) systems with a pepsin-zeolitic imidazolate framework-8 (ZIF-8) modified poly(glycidyl methacrylate)-co-(ethylene dimethacrylate) [poly(GMA-co-EDMA)] monolithic column as stationary phases for separation of basic racemic drugs. ZIF-8 modified column was prepared via layer-by-layer self-assembly.

Compatibility and stability of binary mixtures of acetaminophen, nefopam, ketoprofen and ketamine in infusion solutions.

BACKGROUND AND OBJECTIVE: Administering various combinations of acetaminophen, ketoprofen, nefopam and ketamine, though sometimes discussed, is expected to provide superior pain relief and reduce opioid analgesic-related side effects. However, some studies have indicated that multimodal analgesia has limited efficacy. We studied the stability of various binary combinations of these four drugs. PATIENTS AND METHODS: The drugs were studied at 25 degrees C. Binary mixtures of acetaminophen, ketoprofen, nefopam and ketamine were produced. Each drug concentration was assessed using a specific high-performance liquid chromatographic technique. Measurements were carried out at T0, +1, +2, +4, +6 and +24 h. A 5% loss of initial concentration was considered to be significant. The changes with time of the concentrations were analysed using linear regression analysis. A P value of less than 0.05 was significant. RESULTS: The four drugs tested in the binary mixtures were stable, showing neither loss of concentration nor degradation products (P > or = 0.05). CONCLUSION: Physicochemical negative interaction is not likely to account for the limited clinical efficacy sometimes reported with binary combinations of these drugs. Coadministration of binary mixtures of acetaminophen, nefopam, ketoprofen and ketamine from the same bottle or infusion bag using the same venous line is demonstrated to be feasible.

[Physico-chemical stability and sterility of non-opioid analgesics in solution]. / Stabilité physicochimique et bactériologique d'associations d'antalgiques de classe I en solution.

OBJECTIVES: The combination of non-opioid analgesic drugs (P: paracetamol, K: ketoprofen and N: nefopam) is currently recommended for postoperative pain control. In practice, these analgesics are often administered in the same solution. We investigated the chemical stability and sterility of three mixtures of analgesics (P+K, P+N and K+N). METHODS: For each mixture, concentrations of active principles were measured using high-performance liquid chromatography over 24 hours. These mixtures were cultured for microbiological colonization. RESULTS: Our study demonstrated chemical and bacteriologic stability of these three mixtures over a 24-hour period. The results allow the use of P+K, P+N and K+N in the same ready to use solution.

Spectrophotometric microdetermination of nefopam, mebevrine and phenylpropanolamine hydrochloride in pharmaceutical formulations using alizarins.

Simple and rapid spectrophotometric procedures have been established for quantitation of nefopam hydrochloride (NF) mebevrine hydrochloride (MB) and phenylpropanolamine hydrochloride (PP). The procedures are based on the reaction between the examined drugs (NF, MB and PP) and alizarin (I), alizarin red S (II), alizarin yellow G (III) and quinalizarin (IV) producing ion-pair complexes which can be measured at the optimum wavelength. The optimization of the reaction conditions is investigated. Beer's law is obeyed in the concentration ranges 0.5-30.0 microg ml(-1). The molar absorptivity, Sandell sensitivity, detection and quantification limits are also calculated. The correlation coefficient was > or =0.9988 (n=6) with a relative standard deviation (R.S.D.) of < or =1.3, for six determinations of 20 microg ml(-1). The methods are successfully applied to the determination of NF, MB and PP in their pharmaceutical formulations.

Degradation mechanism of nefopam in solution under stressed storage conditions.

Nefopam, in pH 2.0 and pH 9.0 solutions, was forcibly degraded at 90 +/- 0.2 degrees C for 60 days. At least eight degradation products from the above solutions were collected from a reverse-phase high performance liquid chromatographic (HPLC) system with a C18 semipreparative column. Some minor peaks were considered insignificant, and no attempt was made to collect and identify their structures. The collected eluents under each major peak were further purified by extraction with methylene chloride from alkaline solutions. Proton nuclear magnetic resonance and fast atom bombardment mass spectroscopy were used to characterize the chemical properties of these degradates. The chemical structures of the major degradation products were proposed as (B) or (C) 2,3-dihydro-2(2'-hydroxyethyl)-N-methyl-1-phenyl-isoindole; (D) or (E) 1-hydroxy-3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine++ +; (F) 2-(N-(2-hydroxyethyl)-N-methylaminomethyl) benzhydrol; (G) 2-(N-(2-hydroxyethyl)-N-methylaminoethyl) benzophenone; (H) 1-hydroxy-3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine++ +, where B and C, D and E, are diasteromers. The possible pathways by which the nefopam degradation proceeded in acidic and basic solutions is postulated as Schemes I and II, respectively. The initial ring-opening process at the site of ether linkage appears to be the rate-determining step of degradation in both acidic and basic solutions.

Stereoisomer differentiation for the analgesic drug nefopam hydrochloride using modeling studies of serotonin uptake area.

Equatorial and axial N-methyl diastereomers of the analgesic drug nefopam hydrochloride were differentiated using a hypothetical model of the serotonin (5-hydroxytryptamine) uptake area. Both diastereomers were placed within the hypothetical model area to form van der Waals interactions involving the phenyl group of nefopam, but only in the case of the equatorial N-methyl epimer was the +N--H bond able to be oriented towards the proposed hydrogen-bonding site. A comparison of equatorial N-methyl nefopam hydrochloride enantiomers in the proposed two-site binding mode points to less severe nonbonding steric interactions for the (+)-(1S,5S)-enantiomer compared with the (-)-(1R,5R)-isomer.

Enantiomer resolution of nefopam hydrochloride, a novel analgesic: a study by liquid chromatography and circular dichroism spectroscopy.

Nefopam, a potent analgesic, has been completely resolved into enantiomers on a preparative scale by low-pressure liquid chromatography on swollen, microcrystalline triacetylcellulose. The enantiomerically pure hydrochlorides were prepared from the base, and the circular dichroism spectra of the free base and the hydrochloride are reported.

Nefopam excretion in human milk.

Human milk and plasma samples were obtained from five healthy nursing mothers who were taking nefopam hydrochloride (60 mg four-hourly) for post-episiotomy pain. Concentrations of nefopam were quantified in milk and plasma paired samples, taken daily from birth for 5 days, by a specific paired-ion reverse phase h.p.l.c. method. Although nefopam was present in human milk in an equivalent concentration to plasma (milk: plasma ratio 1.2 +/- 0.7, mean +/- s.d.), the likely infant exposure was less than 0.05 mg kg-1 day-1 which, on a body weight basis, would be less than 3% of the maternal dose.

Conformation of nefopam hydrochloride, a novel analgesic.

The solid state structures of (+/-)- and (+)-nefopam hydrochloride (3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine hydrochloride, 1) were determined by single crystal X-ray diffraction analysis. (+/-)-Nefopam hydrochloride gave crystals belonging to monoclinic P21/c space group, and at 298 K: a = 11.766 (1) A, b = 7.741 (1) A, c = 16.907 (3) A, beta = 97.43 (1) degrees, V = 1527.0 (7) A3, Z = 4, R = 0.0336, and Rw = 0.0452. (+)-Nefopam hydrochloride monohydrate gave crystals of the orthorhombic P2(1)2(1)2(1) space group, and at 298 K: a = 9.651 (2) A, b = 19.747 (2) A, c = 8.504 (2) A, V = 1620.7(7) A3, Z = 4, R = 0.0432, and Rw = 0.0690 for the (1S,5S)-model. The diastereoisomer found in the chiral crystal was also found in the solid racemic modification: (1S,5S) in the monohydrate of (+)-1 and (1R,5R)/(1S,5S) in (+/-)-1. 1H and 13C[1H] NMR spectroscopy revealed two distinct, major and minor, N-protonated species in CD2Cl2 solution differing in the stereochemistry of the N-methyl group. The molecular structures of the crystals of (+/-)-1 and (+)-1 X H2O (a) indicate a modified boat-chair conformation of the eight-membered ring with an equatorial N-methyl group, caused by two sp2-hybridized ring atoms, and (b) correspond to the stereochemistry of the minor species in solution.