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In order to solve the problems of out-of-date synthesis process and lag-behind quality control standards of naphazoline hydrochloride,the synthesis process of aimed product was studied.According to the relevant regulation of ICH Q11 on the development and manufacture of drug substances,the modified synthesis route was designed to control the generation of impurities based on the concept of quality by design.Using 1-naphthylacetic acid as the starting material,the target compound was obtained through amidation reaction,amide dehydration reaction,catalytic addition-cyclization reaction and salt formation reaction.The results show as follows:In the amidation reaction,using dichloromethane as the solvent,n[KG-*4](1-naphthylacetic acid[BF])[BFQ]∶n[KG-*4](di-tert-butyl dicarbonate[BF])[BFQ]∶n[KG-*4](ammonia)[KG-*4]=1∶12∶12,the yield is 886％;In the dehydration reaction and the addition-cyclization reaction,N,N-dimethylformamide is used as the solvent,the workup procedure is simple and the intermediate purity is high;In the salt formation reaction,n[KG-*4](naphazoline free base[BF])[BFQ]∶n[KG-*4](36％ hydrochloric acid)[KG-*3]=1∶148,the yield is 901％.The overall yield of the four-step reaction after optimization of the reaction conditions was 5083%.The four impurities listed in the European Pharmacopoeia were not detected in the product,and no new impurities were produced.The synthesis process have advantages of mild reaction condition and operational simplicity,so the result provide a theoretical basis for the industrial production of naphazoline hydrochloride.

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• Hirshfeld surface analysis of NPZ was discussed. • The structural characteristics of dominant facets were analyzed. • The crystal morphologies of NPZ in different binary solvents were predicted by the MAE model. • Predicted crystal habits were compared with the experimental shapes. • Intermolecular interactions of solvent and crystal facets were revealed by molecular simulation. The crystal morphologies of naphazoline hydrochloride (NPZ) in vacuum and binary solvent conditions (methanol + ethyl acetate, methanol + ethanol, methanol + isopropanol and 2-moxyethanol + isopropanol) were investigated by the molecular dynamic (MD) simulation and experiments. The Hirshfeld surface (HS) analysis was employed to explore the interactions in the crystal structure of NPZ, and results revealed that H···H and H···Cl/Cl···H contacts were primary contributing interactions. The attachment energy (AE) model was utilized to simulate the crystal habit of NPZ in vacuum based on the single crystal data, resulting in the identification of six morphological crystal facets. Also, the structural characteristics of dominant crystal faces were analyzed. The crystal morphologies of NPZ in different binary solvents were predicted using the modified attachment energy (MAE) model. The simulation results indicated that the solvent adsorption processes on the crystal surfaces were exothermic, and {0 0 2} face had largest morphological importance in all solvent systems. Furthermore, the experimental morphology of NPZ obtained from the methanol + ethyl acetate system was consistent with the crystal habit predicted by MAE model, which was plate-shape. On this basis, the intermolecular interactions between solvent molecules and {0 0 2} as well as {1 1––1} facets were analyzed detailly by radial distribution function (RDF) and mean square displacement (MSD), respectively. The RDF analysis indicated that N atoms of {0 0 2} face formed hydrogen bonds with O atoms of solvent molecules, resulting in an evident change in the total facet area of this face. Moreover, MSD analysis demonstrated that the absorptions of solvent molecules on the {1 1––1} face were the main factor affecting the growth rate of this crystal surface. [ABSTRACT FROM AUTHOR]

Four accurate and sensitive methods were developed and validated for determination of naphazoline hydrochloride (NAP) and chlorpheniramine maleate (CLO) in the presence of naphazoline hydrochloride alkaline degradation product (NAP Deg). The first method is a spectrophotometric one , where NAP was determined by the fourth derivative (D4) spectrophotometric method by measuring the peak amplitude at 302 nm, while CLO was determined by the second derivative of the ratio spectra (DD2) spectrophotometric method at 276.4 nm. The second method is a chemometric-assisted spectrophotometric method in which partial least squares (PLS-1) and partial component regression (PCR) were used for the determination of NAP, CLO and NAP Deg using the information contained in their absorption spectra of ternary mixture. The third method is a TLC-densitometric one where NAP, CLO and NAP Deg were separated using HPTLC silica gel F254 plates using ethyl acetate:methanol:ammonia: (8:2:0.5, by volume) as the developing system followed by densitometric measurement at 245 nm. The fourth method is HPLC method where NAP, CLO and NAP Deg were separated using ODS C18 column and a mobile phase consisting of 0.1 M KH2PO4 (pH = 7):methanol (55:45 v/v) delivered at 1.5 mL min−1 followed by UV detection at 265 nm. The proposed methods have been successfully applied to the analysis of NAP and CLO in pharmaceutical formulations without interference from the dosage form additives and the results were statistically compared with a reported method.

Background A simple, rapid, and accurate stability-indicating reverse phase liquid chromatographic method was developed and validated for the simultaneous determination of pheniramine maleate and naphazoline hydrochloride in bulk drugs and pharmaceutical formulations. Results Optimum chromatographic separations among pheniramine maleate, naphazoline hydrochloride and stress-induced degradation products have been achieved within 10 minutes by using an Agilent zorbax eclipse XDB C18 column (150 mm × 4.6 mm, 5 μm) as the stationary phase with a mobile phase consisted of 10 mM phosphate buffer pH 2.8 containing 0.5% triethlamine and methanol (68:32, v/v) at a flow rate of 1 mL min-1. Detection was performed at 280 nm using a diode array detector. Theoretical plates for pheniramine maleate and naphazoline hydrochloride were calculated to be 6762 and 6475, respectively. The method was validated in accordance with ICH guidelines with respect to linearity, accuracy, precision, robustness, specificity, limit of detection and quantitation. Regression analysis showed good correlations (R2 > 0.999) for pheniramine maleate in the concentration range of 150-1200 μg mL-1 and naphazoline hydrochloride in 12.5-100 μg mL-1. The method results in excellent separation of both the analytes and degradation products. The peak purity factor is ⩽980 for both analytes after all types of stress, indicating complete separation of both analyte peaks from the stress induced degradation products. Conclusions Overall, the proposed stability-indicating method was suitable for routine quality control and drug analysis of pheniramine maleate and naphazoline hydrochloride in pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

The construction and performance characteristics of new sensitive and selective in situ modified screen printed (ISPE) and carbon paste (ICPE) electrodes for determination of naphazoline hydrochloride (NPZ-HCl) have been developed. The electrodes under investigation show potentiometric response for NPZ-HCl in the concentration range from 7.0×10–7 to 1.0×10–2 M at 25°C and the electrode response is independent of pH in the range of 3.1–7.9. These sensors have slope values of 59.7±0.6 and 59.2±0.2mVdecade−1 with detection limit values of 5.6×10–7 and 5.9×10–7 M NPZ-HCl using ISPE and ICPE, respectively. These electrodes show fast response time of 4–7s and 5–8s and exhibits lifetimes of 28 and 30 days for ISPE and ICPE, respectively. Selectivity for NPZ-HCl with respect to a number of interfering materials was also investigated. It was found that there is no interference from the investigated inorganic cations, anions, sugars and other pharmaceutical excipients. The proposed sensors were applied for the determination of NPZ-HCl in pharmaceutical formulation using the direct potentiometric method. It showed a mean average recovery of 100.2% and 102.6% for ISPE and ICPE, respectively. The obtained results using the proposed sensors were in good agreement with those obtained using the official method. The proposed sensors show significantly high selectivity, response time, accuracy, precision, limit of detection (LOD) and limit of quantification (LOQ) compared with other proposed methods. [ABSTRACT FROM AUTHOR]

Abstract: Four accurate and sensitive methods were developed and validated for determination of naphazoline hydrochloride (NAP) and chlorpheniramine maleate (CLO) in the presence of naphazoline hydrochloride alkaline degradation product (NAP Deg). The first method is a spectrophotometric one , where NAP was determined by the fourth derivative (D4) spectrophotometric method by measuring the peak amplitude at 302nm, while CLO was determined by the second derivative of the ratio spectra (DD2) spectrophotometric method at 276.4nm. The second method is a chemometric-assisted spectrophotometric method in which partial least squares (PLS-1) and partial component regression (PCR) were used for the determination of NAP, CLO and NAP Deg using the information contained in their absorption spectra of ternary mixture. The third method is a TLC-densitometric one where NAP, CLO and NAP Deg were separated using HPTLC silica gel F254 plates using ethyl acetate:methanol:ammonia: (8:2:0.5, by volume) as the developing system followed by densitometric measurement at 245nm. The fourth method is HPLC method where NAP, CLO and NAP Deg were separated using ODS C18 column and a mobile phase consisting of 0.1M KH2PO4 (pH=7):methanol (55:45 v/v) delivered at 1.5mLmin−1 followed by UV detection at 265nm. The proposed methods have been successfully applied to the analysis of NAP and CLO in pharmaceutical formulations without interference from the dosage form additives and the results were statistically compared with a reported method. [Copyright &y& Elsevier]

Validated spectrophotometric and chemometric methods were developed tbr determination of Naphazoline Hydrochloride (NAP), Chlorpheniramine maleate (CLO) and Methylene blue (MB) in their ternary mixture. Method A was a spectrophotometric method, where NAP and MB were determined using second derivative (D²) spectrophoto metric method using the peak amplitudes at 299 nm and 337 nm for NAP and MB respectively, while CLO was determined using second derivative ratio (DD²) spectrophotometric method using the peak amplitude at 276.6 nm. Method B used the chemometric techniques; principal component regression (PCR) and partial least squares (PLS) for determination of NAP, CLO and MB using the information contained in the absorption spectra of their ternary mixture solutions. The proposed methods have been successfully applied for the analysis of NAP, CLO and MB in their pharmaceutical formulation and the obtained results were statistically compared with the reported methods. [ABSTRACT FROM AUTHOR]

The purpose of this work was to measure the equilibrium solubility of naphazoline hydrochloride (NPZ) in different mono-solvents ranged from 278.15 K to 323.15 K by a laser monitoring method. In this research, N -methyl pyrrolidone (NMP), n -propanol, 2-butoxyethanol, ethanol, 2-methoxyethanol, N , N -dimethylformamide (DMF), methanol, ethylene glycol (EG), isopropanol, 2-propoxyethanol and 2-ethoxyethanol were selected as the experimental solvents. The results indicated that solubility data of NPZ in 11 neat solvents increased with the increase of temperature. At 298.15 K, the maximum solubility was observed in EG (5.028e-2), followed by 2-methoxyethanol (2.460e-2), methanol (2.429e-2), 2-ethoxyethanol (7.788e-3), ethanol (6.391e-3), 2-propoxyethanol (4.216e-3), n -propanol (3.373e-3), 2-butoxyethanol (3.144e-3), DMF (2.348e-3), NMP (2.002e-3) and isopropanol (1.689e-3). Moreover, the solvent polarity, radial distribution function (RDF) and solvent effect (KAT-LSER model) were implemented to investigate the impact of solute-solvent interactions on solubility behavior of NPZ. The results demonstrated that the whole dissolution behavior of NPZ in organic solvents was a complicated process, and the solvent-solute interactions were associated with hydrogen bond acidity and dipolarity/polarizability of solvent. Besides, the NRTL-SAC, Two-Suffix Margules, Wilson, NRTL and UNIQUAC models were employed to fit experimental solubility data. Deviation analysis revealed that the Wilson model reflected the best agreement between measured data and calculated values with the minimum mean values of average relative deviation (100ARD, 0.9144) and root-mean square deviation (104RMSD, 1.062). Furthermore, the positive entropy changes and negative values of Gibbs energy changes showed that mixing and dissolution process of NPZ in 11 neat solvents were confirmed to entropy-driven and spontaneous. • The solubility of NPZ was studied in eleven neat solvents. • Molecular dynamic simulation and KAT-LSER model were implemented to investigate the solute-solvent interactions. • Five thermodynamic models were used to fit experimental solubility data. • Thermodynamic properties of NPZ were calculated and discussed. [ABSTRACT FROM AUTHOR]

Laser monitoring technique was used for the determination of solid-liquid equilibrium solubility of naphazoline hydrochloride (NPZ) in four binary solvents (methanol + ethanol, methanol + isopropanol, 2-methoxyethanol + isopropanol and methanol + ethyl acetate) at T = (278.15–323.15) K and pressure p = 0.1 MPa. In all cases, solubility of NPZ raised with the increment of temperature. The results also indicated that the addition of positive solvents (methanol or 2-methoxyethanol) on the solution of binary solvent mixtures led to increasing solubility of NPZ in all studied binary solvents. The solute-solvent interaction and solvent-solvent interaction were investigated using radial distribution function (RDF). The RDF results revealed that the change of solvent composition varied as the solute-solvent interplay and solvent-solvent interaction, thereby causing the difference of NPZ solubility. Additionally, the measured data was successfully correlated with the Margules, NRTL and UNIQUAC model to investigate theoretically the solubility of NPZ. Computational results proved that the lower mean values of average relative deviation (100 ARD) and root-mean square deviation (104 RMSD) were obtained to be (1.675) and (2.338) for calculating the solubility of NPZ in investigated systems, further implying that the UNIQUAC model reflected the most accurate descriptions. Using the experimental solubility data, the changes of thermodynamic properties as enthalpy (Δ mix H and Δ dis H), entropy (Δ mix S and Δ dis S) and Gibbs free energy (Δ mix G and Δ dis G) of mixing and dissolution processes were calculated to investigate the solvation behavior of NPZ in studied systems. It was concluded from positive values of entropy and negative values of Gibbs energy change that the mixing and dissolution processes of NPZ in all studied mixed solvents were entropy-driven and spontaneous. • Solubility of naphazoline hydrochloride in four binary solvents was measured. • Solubility values were fitted with NRTL, Margules and UNIQUAC models. • Molecular simulations were provided to explain the solubility behavior in (methanol + ethyl acetate) system. • Thermodynamic properties were calculated by UNIQUAC model. [ABSTRACT FROM AUTHOR]