阿立哌唑的谱学研究

对抗精神分裂症新药阿立哌唑的紫外光谱(UV)、红外光谱(IR)、核磁共振谱(NMR)以及质谱(MS)进行了解析。根据该化合物的紫外光谱探讨了其在溶液中的存在形式,讨论了红外光谱的特征吸收峰所对应的官能团的振动形式以及质谱的特征同位素离子峰,利用1H—1H cosy,HSQC,HMBC等二维核磁共振技术推断并确证了该化合物的结构,对NMR谱信号进行了归属,并根据化学位移、偶合常数以及二维相关谱分析了该化合物结构中的10个不同的亚甲基。     

Development of a novel RP‐HPLC method for the efficient separation of aripiprazole and its nine impurities

The development of an RP‐HPLC method for the separation of aripiprazole and its nine impurities was performed with the use of partial least squares regression, response surface plot methodology, and chromatographic response function. The HPLC retention times and computed molecular parameters of the aripiprazole and its nine impurities were further used for the quantitative structure–retention relationship (QSRR) study. The QSRR model, R²: 0.899, Q²: 0.832, root mean square error of estimation: 4.761, root mean square error of prediction: 6.614, was developed. Very good agreement between the predicted and observed retention times (t_R) for three additional aripiprazole impurities (TC1–TC3) indicated the high prediction potential of the QSRR model for t_R evaluation of other aripiprazole impurities and metabolites. The developed HPLC method is the first reported method for the efficient separation of aripiprazole and its nine impurities, which could be used for the analysis of an additional three aripiprazole impurities (TC1–TC3).     

A sensitive column-switching HPLC method for aripiprazole and dehydroaripiprazole and its application to human pharmacokinetic studies

A simple and sensitive column‐switching HPLC‐UV method was developed for the simultaneous determination of aripiprazole, a novel atypical antipsychotic drug, and its active metabolite, dehydroaripiprazole in human plasma. Aripiprazole, its active metabolite and 7‐[5‐[4‐(3‐chloro‐2‐methylphenyl)‐1‐piperazinyl]pentyloxy]‐3,4‐dihydro‐2(1H)‐quinolinone (OPC‐14558) as an internal standard were extracted from 1 mL of plasma using a mixture of chloroform/n‐heptane (3:7, v/v), and the extract was injected into a column I (TSK BSA‐ODS/S precolumn, 5 μm) for cleanup and column II (C₁₈ STR ODS‐II analytical column, 5 μm) for separation. Peaks were detected with an UV detector set at a wavelength of 254 nm, and the total time for chromatographic separation was ～20 min. Mean absolute recoveries were 74.0 and 74.7% for aripiprazole and dehydroaripiprazole, respectively. Intra‐ and inter‐day CVs were less than 7.5 and 7.1% for aripiprazole concentrations ranging from 2 to 600 ng/mL, and 9.2 and 4.5% for dehydroaripiprazole concentrations ranging from 2 to 160 ng/mL. The validated concentration ranges for this method were 1–500 ng/mL and the limits of detection were 0.5 ng/mL for both aripiprazole and dehydroaripiprazole. This method was applied to pharmacokinetic study in human volunteers and patients taking aripiprazole.     

Aripiprazole Loaded Polymeric Biodegradable Microspheres: Formulation and In Vitro Characterization

In the present study, we attempted to prepare biodegradable microspheres of polylactic acid containing aripiprazole in order to achieve its controlled release profile suitable for parenteral administration. Biodegradable microspheres were prepared by solvent evaporation method using methylene dichloride as a solvent. The optimization of various formulation variables (e.g., stirring speed, and polymer:drug ratio, stabilizer concentration) to obtain spherical particles was also investigated. The optimized product was further characterized for various in vitro attributes, such as particle size and its distribution, encapsulation efficiency, surface properties, percentage yield, and in vitro release. Changing the ratio of polymer, stabilizers, and leaching agent (sodium chloride) affected the entrapment efficiency and release rate of aripiprazole. The release quantum was 88.41% when stirring rate was 2000 rpm and it was further increased to 94.65% when stirring speed was increased to 3000 rpm (Formulation E). Drug entrapment of microspheres was increased by increasing the concentration of PVP and maximum entrapment (62.35%) was obtained at 4% concentration of PVP (Formulation E). Spherical particles with good surface characteristics were obtained at stirring rate 3000 rpm and drug:polymer ratio 1:10.     

阿立哌唑的合成

以2,3-二氯苯胺为原料,经3步亲核取代反应合成了阿立哌唑。3步反应的收率分别为83%,91%和90%;总收率68%。阿立哌唑的结构经1H NMR,IR和元素分析表征。     

Identification of degradation impurities in aripiprazole oral solution using LC–MS and development of validated stability indicating method for assay and content of two preservatives by RP-HPLC

A simple and simultaneous reverse phase high-performance liquid chromatographic method was developed for the quantification of aripiprazole (ARI) and two preservatives, namely, methyl paraben and propyl paraben in ARI oral solution. The method was developed on ACE C18 (4.6?×?250?mm, 5?µm) column using gradient elution of 0.1% v/v trifluoroacetic acid in water and acetonitrile as mobile phase components. Flow rate of 1.0?mL/min and 30°C column temperature were used for the method at quantification wavelength of 254?nm. The developed method was validated in accordance with International Conference on Harmonization guideline for various parameters. Forced degradation study was conducted in acid, base, peroxide, heat, and light stress conditions. ARI was found to degrade in oxidation, acid hydrolysis, and heat while it was stable under the remaining conditions. Specificity of the method was verified using Photo Diode Array (PDA) detector by evaluating purity of peaks from degradation samples. Major degradation impurities formed during stress study were identified using liquid chromatography–mass spectrometry method. The present method was useful for determining the content of all the three main analytes present in the oral solution without interference from degradation impurities. The method was robust under the deliberately modified conditions.     

Simultaneous determination of aripiprazole and its active metabolite,dehydroaripiprazole, in plasma by capillary electrophoresis combining on‐column field‐amplified sample injection and application in schizophrenia

A sensitive high‐performance CZE combining on‐column field‐amplified sample injection (FASI) has been developed for simultaneous determination of aripiprazole and its active metabolite, dehydroaripiprazole, in human plasma. A sample pretreatment by means of liquid–liquid extraction (LLE) (diethyl ether) with subsequent quantitation by FASI‐CZE was used. The separation of aripiprazole and dehydroaripiprazole was performed using a BGE containing 150 mM phosphate buffer (pH 3.5) with 40% methanol and 0.02% PVA as a dynamic coating to reduce interaction of analytes with the capillary wall. Before sample loading, a methanol plug (0.3 psi, 6 s) was injected to permit FASI for stacking. The samples were injected electrokinetically (10 kV, 30 s) to introduce sample cations and the applied voltage was 20 kV with on‐column detection at 214 nm. Several parameters affecting the separation and sensitivity of the drug and its active metabolite were studied, including reconstitution solvent, organic modifier, pH and concentration of phosphate buffer. The linear ranges of the method for test drug and its active metabolite, in plasma using amlodipine as an internal standard, were over the range 5.0–100.0 ng/mL. One female volunteer (25 years old) was orally administered a single dose of 10 mg aripiprazole (Abilify^®, Otsuka) and blood samples were drawn over a 60 h period for pharmacokinetic study. The method was also applied to monitor the concentration of aripiprazole and dehydroaripiprazole in plasma collected after oral administration of 20 or 30 mg aripiprazole (Abilify^®, Otsuka) daily at steady state in one schizophrenic patient.     

LC–ESI–MS for Rapid and Sensitive Determination of Aripiprazole in Human Plasma

A rapid, sensitive, and accurate high-performance liquid-chromatographic–mass spectrometric (HPLC–MS) method, with estazolam as internal standard, has been developed and validated for determination of aripiprazole in human plasma. After liquid–liquid extraction the compound was analyzed by HPLC on a C₁₈ column, with acetonitrile—30 mm ammonium acetate containing 0.1% formic acid, 58:42 (v/v), as mobile phase, coupled with electrospray ionization mass spectrometry (ESI-MS). The protonated analyte was quantified by selected-ion recording (SIR) with a quadrupole mass spectrometer in positive-ion mode. Calibration plots were linear over the concentration range 19.9–1119.6 ng mL⁻¹. Intra-day and inter-day precision (CV%) and accuracy (RE%) for quality-control samples (37.3, 124.4, and 622.0 ng mL⁻¹) ranged between 2.5 and 9.0% and between 1.3 and 3.5%, respectively. Extraction recovery of aripiprazole from plasma was in the range 75.8–84.1%. The method enables rapid, sensitive, precise, and accurate measurement of the concentration of aripiprazole in human plasma.