Quality by Design approach in the development of a solvent-modified micellar electrokinetic chromatography method: Finding the design space for the determination of amitriptyline and its impurities

A solvent-modified micellar electrokinetic chromatography method was set up for the simultaneous determination of the tricyclic antidepressant amitriptyline (AMI) and its main impurities. The method was developed following Quality by Design (QbD) principles according to ICH Guideline Q8(R2). QbD approach made it possible to find the design space (DS), where quality was assured. After a scouting phase, aimed at selecting a suitable capillary electrophoresis pseudostationary phase, risk assessment tools were employed to define the critical process parameters (CPPs) to be considered in a screening phase (applied voltage, concentration and pH of the background electrolyte, concentration of the surfactant sodium dodecyl sulphate, of the cosurfactant n-butanol and of the organic modifiers acetonitrile and urea). The effects of the seven selected CPPs on critical quality attributes (CQAs), namely resolution values between critical peak pairs and analysis time, were investigated throughout the knowledge space by means of a symmetric screening matrix. Response surface study was then carried out on four selected CPPs by applying a Doehlert Design. Monte-Carlo simulations were performed in order to estimate the probability of meeting the desired specifications on CQAs, and thus to define the DS by means of a risk of failure map. Additional points at the edges of the DS were tested in order to verify the requirements for CQAs to be fulfilled. A control strategy was implemented by defining system suitability tests. The developed method was validated following ICH Guideline Q2(R1), including robustness assessment by Plackett–Burman design, and was applied to the analysis of real samples of amitriptyline coated tablets.     

The rapid detection and identification of the impurities of simvastatin using high resolution sub 2 microm particle LC coupled to hybrid quadrupole time of flight MS operating with alternating high-low collision energy

The profiling and identification of impurities in raw pharmaceuticals or finished drug product is an essential part of the pharmaceutical manufacturing process. Critical to this process is the ability to confirm known, expected impurities and identify new impurities. LC coupled to electrospray MS is a powerful tool that has been employed for the identification of impurities, natural products, drug metabolites, and proteins. In this study, we show how sub 2 microm porous particle LC has been coupled to hybrid quadrupole orthogonal TOF mass spectrometer to profile and identify the impurities of the common cholesterol lowering drug simvastatin. The hybrid quadrupole TOF mass spectrometer was operated by alternating the collision cell energies to allow for the rapid, facile conformation of the identity of impurities. Using this process it was possible to identify all of the common impurities of simvastatin in a single 10 min run. During the analysis a new impurity of simvastatin was detected and identified as the saturated ring form of simvastatin.     

The effect of calcium cations on the precipitation of barium sulfate 2: calcium ions in the presence of organic additives

Calcium ions have been implicated in changing the precipitation of barium sulfate when organic additives are present, although whether it inhibits or promotes nucleation and/or growth has been disputed in the literature. We conducted a thorough investigation into the effect of calcium when additives are present and show that calcium cations do indeed promote nucleation of barium sulfate particles when compared to the appropriate control. This result is independent of the analytical method (conductivity or turbidity) used to assess precipitation. The nucleation promotion produces no change in the crystal morphology, thus morphology is not always a good indicator of nucleation or growth behavior. The extent of nucleation promotion depends on the functional group of the additive.     

A面(11-20)ZnO薄膜中杂质的偏振PL谱研究

本文通过分析A面(11-20)ZnO薄膜的低温PL(光致发光)光谱偏振特性来研究ZnO光致发光谱中杂质峰的来源。低温(4 K)下观察到476、479 nm两处新的杂质峰以及390 nm处激子峰,根据两个杂质峰的偏振特性,初步判定476nm峰来源于氧空位能级到价带轻空穴的跃迁,479 nm峰来源于氧空位价带重空穴的跃迁。     

原子吸收光谱法测定电解金属锰中微量金属杂质元素

本文用盐酸溶解样品,火焰原子吸收光谱法测定电解金属锰中K,Na,Ca,Mg,Fe,石墨炉原子吸收光谱法测定其中的Cr,Cu,Co,Ni含量。对测定条件进行了实验,找出最佳溶样方法和酸度,对共存元素的干扰有排除亦进行了试验,获得了满意的效果。该法简便、快速、准确,加标回收率为88.9%-108.7%之间,相对标准偏差为0.6%-6.7%,标准曲线法、标准加入法结果与对照结果相吻合,适用于电解金属锰样品金属杂质元素的分析。     

Identification of l‐carnitine and its impurities in food supplement formulations by online column‐switching liquid chromatography coupled with linear ion trap mass spectrometry

The identification of impurities in l‐ carnitine by mass spectrometry is difficult because derivative reagents or ion pair reagents are usually used to separate and increase the retention of l‐ carnitine on the reversed‐phase column. In this study, four impurities including 3‐chloro‐2‐hydroxy‐N,N,N‐trimethylpropan‐1‐aminium, 3‐cyano‐2‐hydroxy‐N,N,N‐trimethylpropan‐1‐aminium, 3‐carboxy‐N,N,N‐trimethylprop‐2‐en‐1‐aminium, and 4‐chloro‐2,3,4‐trihydroxy‐N,N,N‐trimethylbutan‐1‐aminium were identified in l‐ carnitine and its tablets by using two‐dimensional column‐switching high‐performance liquid chromatography coupled with linear ion trap mass spectrometry. The first column was a C₈ column at a flow rate of 0.15 mL/min; the detection wavelength was 220 nm. The second column was an Acclaim Q1 column using a gradient elution program with aqueous 30 mM ammonium acetate (pH 5.0) and acetonitrile as the mobile phase at a flow rate of 0.5 mL/min. The mass fragmentation patterns and structural assignments of impurities were studied, and the quantitative validation of three impurities was further investigated. The linearity (r ²) was found to be >0.99, with ranges from 0.2 to 50 ng/mL and 0.1 to 10 ng/mL. The method was used successfully for determination of impurities in five samples of l‐ carnitine and tablets.