Simultaneous optimization of mobile phase composition and pH using retention modeling and experimental design.

Chromatographic methods are progressing continuously. Increasing sample complexity and safety expectations lead to higher regulatory demands, hence challenges in liquid chromatography analysis are rising, even today, when faster and faster chromatographic systems are extensively employed and become widely accessible for successful method development. The goal of this study was to investigate the impact of mobile phase influences as important factors of selectivity tuning in method development. This would mitigate mobile phase-related robustness issues throughout the method's lifecycle. To discover and understand these effects, a new module of chromatographic modeling software DryLab (ver. 4.3.4. beta) was introduced and a special experimental design (DoE) was tested, allowing the simultaneous optimization of solvent-dependent parameters, such as gradient time (tG), ternary eluent composition (tC) and pH, requiring 18 input experiments (2 × 3 × 3 = 18). Additionally, the model creation, using a UPLC system and a narrow bore column (50 × 2.1 mm), the entire experimental work could be finished in 2-3 hours. To demonstrate the applicability of this new design, amlodipine and its related pharmacopoeia impurities (A-H) were subjected to be used in a case study. Predicted vs. Experimental (or Verification) runs showed excellent agreement, average retention time deviations were typically less than 1 s. Modelled robustness testing was also performed, elucidating all important mobile phase and instrument parameters that could influence a method's lifetime performance. Furthermore, as the in silico robustness testing is the least time consuming part of the method development process, it can be used extensively to evaluate robustness even at the very early part in stage 1 of the Method Life Cycle (MLC).

Exploring better column selectivity choices in ultra-high performance liquid chromatography using quality by design principles.

An older method for amlodipine was reworked with the goal to reduce the analysis time of 60min below 6min. To select the best column for short and robust analysis, 9 different UHPLC column chemistries were investigated using 3-dimensional resolution spaces based on 12 experiments using modelling software. The main variables used were gradient time (tG), temperature (T) and the pH of eluent A. The best critical resolution was calculated and located in a 3-dimensional space in an automated fashion and the corresponding best experiments were carried out. The work (9×12=108 runs) was finished with an UHPLC instrument in less than 24h. The comparison between predictions and real experiments showed an excellent correlation with differences typically less than 0.04min (<3s) in average, although the set points were located at quite different conditions on gradient times, pH's and temperatures for the individual columns. All columns could perform the required baseline separation at their individual best working points with satisfactory results.

Retention modelling in ternary solvent-strength gradient elution reversed-phase chromatography using 30 mm columns.

An optimization strategy for ternary solvent-strength gradient elution RP chromatography is described in which a two-dimensional model of gradient time (2 levels) against ternary proportions of organic modifiers (4 levels) was constructed. From the resolution surface the optimum ratio of organic modifiers could be selected. Excellent retention time and acceptable peak width and resolution simulations were obtained. The separation could be further optimized from the same input data by using a standard one-dimensional model in order to optimize for gradient slope, duration and shape. Excellent retention time and acceptable peak width and resolution simulations were obtained (< 1, 2 and 6% error, respectively).

[Sponsoring of physicians in private practice]. / Sponsoring niedergelassener Arzte.

The financing of advanced medical training for physicians by the pharmaceutical industry has been the subject of legal discussions for more than two decades. Recent legal changes have renewed the importance of industry sponsoring. At the 106th national convention of the German physicians, the model ordinance for the German medical profession ("Musterberufsordnung für die deutschen Arztinnen und Arzte-MBO-A") has been reformed, and for the first time individual physicians are now permitted, under certain circumstances, to receive financial support from sponsors to participate in medical-training events. A recent legal reform to modernize the healthcare system ("GKV-Modernisierungsgesetz"--GMG) obliges physicians to observe the law that regulates advertising of medicinal products ("Heilmittelwerbegesetz"--HWG); consequently, the physicians can commit a misdemeanor when accepting prohibited financial support. This essay discusses the implications of this legal reform for the most important types of commercially-sponsored medical training. The GMG reform has introduced an obligation for physicians to absolve continuous medical training, however the resulting legal situation has not changed the requirement that this training remain free of commercial interests.