Quality by design: A systematic and rapid liquid chromatography and mass spectrometry method for eprosartan mesylate and its related impurities using a superficially porous particle column

The present work describes the systematic development of a robust, precise, and rapid reversed‐phase liquid chromatography method for the simultaneous determination of eprosartan mesylate and its six impurities using quality‐by‐design principles. The method was developed in two phases, screening and optimization. During the screening phase, the most suitable stationary phase, organic modifier, and pH were identified. The optimization was performed for secondary influential parameters—column temperature, gradient time, and flow rate using eight experiments—to examine multifactorial effects of parameters on the critical resolution and generated design space representing the robust region. A verification experiment was performed within the working design space and the model was found to be accurate. This study also describes other operating features of the column packed with superficially porous particles that allow very fast separations at pressures available in most liquid chromatography instruments. Successful chromatographic separation was achieved in less than 7 min using a fused‐core C₁₈ (100 mm × 2.1 mm, 2.6 μm) column with linear gradient elution of 10 mM ammonium formate (pH 3.0) and acetonitrile as the mobile phase. The method was validated for specificity, linearity, accuracy, precision, and robustness in compliance with the International Conference on Harmonization Q2 (R1) guidelines. The impurities were identified by liquid chromatography with mass spectrometry.     

Transition metal-catalyzed regio- and stereoselective aminobromination of olefins with TsNH2 and NBS as nitrogen and bromine sources

[reaction: see text] A new synthetic procedure for aminohalogenation of olefins has been developed for the preparation of vicinal haloamine derivatives in high yields by using Cu, Mn, or V catalysts with p-toluenesulfonamide (TsNH(2)) and N-bromosuccinimide (NBS) as nitrogen and bromine sources, respectively. Unprecedented regio- and stereoselectivity (anti:syn > 99:1) toward the aminohalogenation process is shown for olefinic substrates as well as transition metal catalysts.     

Manufacturer cooperation in supplier development under risk

Supplier development involves efforts undertaken by manufacturing firms to improve their suppliers’ capabilities and performance. These improvement efforts can be targeted at a variety of areas such as quality management, product development, and cost reduction. Since supplier development requires investments on the part of the manufacturer, it is important to optimally allocate investment dollars among multiple suppliers to minimize risk while maintaining an acceptable level of return. This paper presents a set of optimization models that address this issue. We consider two scenarios: single-manufacturer and multiple suppliers (SMMS) and two-manufacturer and multiple suppliers (TMMS). In the SMMS case, we suggest optimal investments in various suppliers by effectively considering risk and return. The TMMS case investigates whether manufacturers with differing capabilities could gain risk reduction benefits from cooperating with each other in supplier development. Through illustrative applications, we identify conditions in which both cooperation and non-cooperation are beneficial for manufacturers. Under conditions of cooperation, we propose optimal investments for manufacturers to achieve high levels of risk reduction benefits.     

Enantioselective HPLC resolution of synthetic intermediates of armodafinil and related substances

Armodafinil is a unique psychostimulant recently approved by the US Food and Drug Administration for the treatment of narcolepsy. The chromatographic resolution of its chiral intermediates including related substances in the total synthesis of armodafinil was studied on polysaccharide-based stationary phases, viz. cellulose tris-(3,5-dimethylphenylcarbamate) (Chiralcel OD-H) and amylose tris-(3,5-dimethylphenylcarbamate) (Chiralpak AD-H) by HPLC. The effects of 1-propanol, 2-propanol, ethanol, and trifluoroacetic acid added to the mobile phase and of column temperature on resolution were studied. A good separation was achieved on cellulose-based Chiralcel OD-H column compared to amylose-based Chiralpak AD-H. The effects of structural features of the solutes and solvents on discrimination between the enantiomers were examined. Baseline separation with R(s) >1.38 was obtained using a mobile phase containing n-hexane-ethanol-TFA (75:25:0.15 v/v/v). Detection was carried out at 225 nm with photodiode array detector while identification of enantiomers was accomplished by a polarimetric detector connected in series. The method was found to be suitable not only for process development of armodafinil but also for determination of the enantiomeric purity of bulk drugs and pharmaceuticals.     

An organo-catalytic approach to the enantioselective synthesis of (R)-selegiline

An efficient enantioselective synthesis of (R)-selegiline has been achieved by two routes, via proline-catalyzed α-aminooxylation as well as α-amination of phenylpropanaldehyde as the key step.     

On thek-cut subgraph polytope

We consider the problem of finding a minimum-cost set ofk pairwise-disjoint (s, t)-cuts in a graph. For non-negative costs, this problem was solved independently by Nishihara and Inoue, and Wagner. Both solutions involve formulating the problem as a linear-programming problem. In this paper, we give new polyhedral interpretations of the problem. Relationships to the path formulation of the maximum-flow problem are also established.Corresponding author.     

Automated statistical experimental design approach for rapid separation of coenzyme Q10 and identification of its biotechnological process related impurities using UHPLC and UHPLC–APCI‐MS

A novel ultra high performance liquid chromatography method development strategy was ameliorated by applying quality by design approach. The developed systematic approach was divided into five steps (i) Analytical Target Profile, (ii) Critical Quality Attributes, (iii) Risk Assessments of Critical parameters using design of experiments (screening and optimization phases), (iv) Generation of design space, and (v) Process Capability Analysis (Cp) for robustness study using Monte Carlo simulation. The complete quality‐by‐design‐based method development was made automated and expedited by employing sub‐2 μm particles column with an ultra high performance liquid chromatography system. Successful chromatographic separation of the Coenzyme Q10 from its biotechnological process related impurities was achieved on a Waters Acquity phenyl hexyl (100 mm × 2.1 mm, 1.7 μm) column with gradient elution of 10 mM ammonium acetate buffer (pH 4.0) and a mixture of acetonitrile/2‐propanol (1:1) as the mobile phase. Through this study, fast and organized method development workflow was developed and robustness of the method was also demonstrated. The method was validated for specificity, linearity, accuracy, precision, and robustness in compliance to the International Conference on Harmonization, Q2 (R1) guidelines. The impurities were identified by atmospheric pressure chemical ionization‐mass spectrometry technique. Further, the in silico toxicity of impurities was analyzed using TOPKAT and DEREK software.