Isolation, structure elucidation, and high-performance liquid chromatography quantification of photolytic degradation impurities in acrivastine.

Acrivastine is a second-generation H1-receptor antagonist, and its structure is sensitive to ultraviolet. Four unknown and one reported degradation products can be detected in the ultraviolet radiation solutions of acrivastine. To improve the quality control of acrivastine, the photodegradation impurities were isolated and structurally elucidated. There are four new impurities (1-3 and 5), and one reported compound (4). The isolation strategy was designed as preparative high-performance liquid chromatography using a reversed phase column with volatile acid addition in the mobile phase, combined with preparative thin-layer chromatography using silica gel with alkaline addition in the mobile phase. Using the developed methods, five impurities (1-5) were efficiently purified after two or three chromatography runs with purities > 95%. The structures of compounds 1-5 are elucidated based on spectroscopy analysis of MS, and nuclear magnetic resonance spectroscopy. Using the impurity standard, the high-performance liquid chromatography method was developed and validated. The method was proved to be sensitive, accurate (Recovery% 96.1-107.7%), linear (0.15-0.75 µg/mL, R2 > 0.996), robust, and specific, and it was successfully used to determine the degradation impurities of acrivastine and its formulation.

Identification, synthesis and structural characterization of process related and degradation impurities of acrivastine and validation of HPLC method.

Four impurities (Imp-I-IV) were detected using gradient HPLC method in few laboratory batches of acrivastine in the level of 0.03-0.12% and three impurities (Imp-I-III) were found to be known and one (Imp-IV) was unknown. In forced degradation study, the drug is degraded into four degradation products under oxidation and photolytic conditions. Two impurities (Imp-III and -IV) were concurred with process related impurities whereas Imp-V and -VI were identified as new degradation impurities. Based on LC-ESI/MSn study, the chemical structures of new impurities were presumed as 1-[(2E)-3-(4-methylphenyl)-3-{6-[(1E)-3-oxobut-1-en-1-yl]pyridin-2-yl}prop-2-en-1-yl]pyrrolidin-1-ium-1-olate (Imp-IV), 1-{[3-(4-methylphenyl)-3-{6-[(1E)-3-oxobut-1-en-1-yl]pyridin-2-yl}oxiran-2-yl]methyl}pyrrolidin-1-ium-1-olate (Imp-V) and 2-[2-(4-methylphenyl)-3-[(1-oxidopyrrolidin-1-ium-1-yl)methyl]oxiran-2-yl]-6-[(1E)-3-oxobut-1-en-1-yl]pyridin-1-ium-1-olate (Imp-VI), and confirmed by their synthesis followed by spectroscopic analysis, IR, NMR (1H, 13C) and mass. An efficient and selective high-performance liquid chromatography method has been developed and resolved well the drug related substances on a Phenomenex Gemini C-18 (250×4.6mm, particle size 5µm) column. The mobile phase was composed of sodium dihydrogen phosphate (10mM) and methanol, temperature at 25°C, and a PDA detector set at 254nm used for detection. The method was validated with respect to specificity, linearity, precision, accuracy, and sensitivity and satisfactory results were achieved. Identification, synthesis, characterization of impurities and method validation were first reported in this paper.

Comparison of the Efficacy of Desloratadine Citrate Disodium and Acrivastine Decremental Therapy in the Treatment of Chronic Urticaria / 中国药房

OBJECTIVE:To compare the efficacy and safety of desloratadine citrate disodium and acrivastine decremental thera-py in the treatment of chronic urticaria. METHODS:132 patients with chronic urticaria were randomly divided into group A(62 cases)and group B(70 cases). Group A was orally given 8.8 mg Desloratadine citrate disodium tablet in 12 2 weeks,once a day;8.8 mg in 3-4 weeks,once every 2 days;8.8 mg in 5-6 weeks,once every 3 days;8.8 mg in 7-8 weeks,once every 4 days;and 8.8 mg in 9-10 weeks,once every 5 days. Group B was orally given 8 mg Acrivastine capsule in 12 2 weeks,3 times a day;8 mg in 3-4 weeks,twice a day;8 mg in 5-6 weeks,once a day;8 mg in 7-8 weeks,once every 2 days;and 8 mg in 9-10 weeks, once every 3 days. The treatment course for both groups was 10 weeks. Clinical efficacy,and plasma histamine levels and total scores of signs and symptoms before and after treatment in 2 groups were observed,and recurrence and incidence of adverse reac-tions after 4 weeks of stopping drugs in 2 groups were followed-up. RESULTS:There were no significant difference in the total ef-fective rate and incidence of adverse reactions between 2 groups(P>0.05). After treatment,the total scores of signs and symptoms in 2 groups were significantly lower than before,the difference was statistically significant(P0.05). The recurrence rate in group A was significantly lower than group B,the difference was sta-tistically significant(P<0.05). CONCLUSIONS:Both efficacy and safety of desloratadine citrate disodium and acrivastine decre-mental therapy in the treatment of chronic urticaria are good,however,desloratadine citrate disodium is better than acrivastine in re-ducing recurrence rate.

Development and validation of a rapid stability indicating HPLC-method using monolithic stationary phase and two spectrophotometric methods for determination of antihistaminic acrivastine in capsules.

Simple, rapid and accurate high performance liquid chromatographic (HPLC) and spectrophotometric methods are described for determination of antihistaminic acrivastine in capsules. The first method (method A) is based on accurate, sensitive and stability indicating chromatographic separation method. Chromolith® Performance RP-18e column, a relatively new packing material consisting of monolithic rods of highly porous silica, was used as stationary phase applying isocratic binary mobile phase of ACN and 25 mM NaH2PO4 pH 4.0 in the ratio of 22.5:77.5 at flow rate of 5.0 mL/min and 40°C. A diode array detector was used at 254 nm for detection. The elution time of acrivastine was found to be 2.080±0.032. The second and third methods (methods B and C) are based on the oxidation of acrivastine with excess N-bromosuccinimide (NBS) and determination of the unconsumed NBS with, metol-sulphanilic acid (λmax: 520 nm) or amaranth dye (λmax: 530 nm). The reacted oxidant corresponds to the drug content. Beer's law is obeyed over the concentration range 1.563-50, 2.0-20 and 1.0-10 µg mL(-1) for methods A, B and C, respectively. The limits of detection and quantitation were 0.40, 0.292 and 0.113 µg mL(-1) and 0.782, 0.973 and 0.376 µg mL(-1) for methods A, B and C, respectively. The HPLC method was validated for system suitability, linearity, precision, limits of detection and quantitation, specificity, stability and robustness. Stability tests were done through exposure of the analyte solution for four different stress conditions and the results indicate no interference of degradants with HPLC-method. The proposed methods was favorably applied for determination of acrivastine in capsules formulation. Statistical comparison of the obtained results from the analysis of the studied drug to those of the reported method using t- and F-tests showed no significant difference between them.

Chromatographic separation and spectroscopic characterization of the E/Z isomers of acrivastine.

A reverse phase high performance liquid chromatography (HPLC) method has been developed for the separation of two geometric isomers of Acrivastine using crude reaction mixture. The resolution between two isomers was found more than 2.9. The geometric isomers have been isolated by preparative HPLC and characterized by spectroscopic techniques, such as NMR, infrared, and MS. The developed method has been validated for the determination of Z-isomer in Acrivastine. The limit of detection and limit of quantification of the Z-isomer were 0.05 and 0.2 µg/ml, respectively. The developed method is precise, linear, accurate, rugged and robust for its intended use.

Determination of Acrivastine in Human Plasma by HPLC and Its Pharmacokinetic Study / 中国药房

OBJECTIVE:To establish an HPLC method for the determination of acrivastine in human plasma and study its pharmacokinetics in healthy male volunteers. METHODS:The plasma sample was extracted with acetonitriles and concentrated and quantified with external reference method on a Symmetry ShieldTMPR18 column. The mobile phase was a mixture of acetonitrile-0.2% triethylamine (adjusted pH to 6.8?0.2 by dilute phosphoric acid solution,25∶75) at a flow rate of 1.0 mL?min-1. The column temperature was 35 ℃. The detection wavelength was set at 250 nm. RESULTS:The linear range of acrivastine was 4.687 5～600 ng?mL-1(r=0.999 4). The methodological recovery was 96.14%～98.89%; the intra-day RSD was 1.60%～3.00% and inter-day RSD was 2.03%～6.98%. The concentration-time pharmacokinetic parameters after oral administration of acrivastine capsules were in line with the one-compartment mode. CONCLUSION:The method is simple,sensitive,accurate with high recovery,and it is applicable for the concentration determination and clinical pharmacokinetic study of acrivastine.