Merck System

The Merck system can be extended to the asymmetric synthesis of a-hydroxy ketones by using oxygen as electrophile (Scheme 18) (47). The hydroperoxide intermediates are reduced by triethyl phosphite. The sense of asymmetric induction is again consistent with the ion-paired, 7r-stacked assembly model given in Scheme 13. 

Systemic reactions are less severe than with diethylcarbama2ine. The most commonly seen reactions are fever, rash, and lymph-node pain or swelling. Suppressive ivermectin therapy consists of a single oral dose every 6—18 months. The required duration of suppressive therapy is unknown, probably at least three years (36). Ivermectin is available from the CDC Dmg Service on request. It is manufactured by Merck Sharp and Dohme in the United States and England. 

In principle, on-line SPE-LC can be automated quite easily as well, for instance, by using Such programmable on-line SPE instrumentation as the Prospekt (Spark Holland) or the OSP-2 (Merck) which have the capability to switch to a fresh disposable pre-column for every sample. Several relevant applications in the biomedical field have been described in which these devices have been used. Eor example, a fully automated system comprising an autosampler, a Prospekt and an LC with a UV... 

The Novasep team in 1994, successfully resolved 2 kg of racemic binaphthol per day on a Pirkle-Type 3,5-DNBPG CSP (Merck KGaA, Germany) using a Licosep 8-200 SMB system (Summary report on the BRITE-EURAM project BRE2-CT92-0337). 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

F. 6 Schematic representation of HPLC-HPTLC coupling by means of the OSP-2 system (Merck) for post-column enrichment of the column eluate fractions. 

Figure 4.20 Schematic of laboratory-scale reaction system with a slit-type interdigital micro mixer as central element, used at Merck site [134],...

Note System Cellulose layer (0.1 mm, Merck Art. 5716) developing solvent p.e.-acetone (80 20) the presence or absence of structural features is indicated. 

Note System layer silica gel 60 F254 (0.25 mm, Merck Art. 5716) developing solvent ethyl acetate-formic acid-acetic acid-water (100 11 11 27). 

System 1 cellulose (0.1 mm, Merck) HCl-formic acid-water (7 51 42). 

System 2 cellulose (0.1 nun, Merck) HCl—formic acid-water (19 19 62). 

As previously described, Eq. 6 contains two constants characteristic of the system and the sample, feo and S, which can be determined by two chromatographic mns differing only in tc. These two values allow to calculate log fe using Eq. 4. However, because there is no empirical solution, values of log few and S have to be computed by iteration. Such procedures are included in several commercially available LC software packages, such as Drylab (Rheodyne, CA, USA), Chromsword (Merck, Darmstadt, Germany), ACD/LC simulator (Advanced Chemical Development, Toronto, Canada) or Osiris (Datalys, Grenoble, Erance). This approach was comprehensively described and successfully applied for accurate log P determination of several solutes with diverse chemical structures [9, 12, 43, 50]. 

Using fundamentally the same concepts as those embodied in the push-pull system, ALZA scientists along with those at Merck have commercialized... 

Woodfield, A., J. Fountain and P. Borren (1997), Money Medicines an Economic Analysis of Reference Pricing and Related Public-sector Cost-containment Systems for Pharmaceuticals with Special Reference to New Zealand, New Zealand Merck Sharp Dome. 

Figure 6.8 Chromatographic columns. The glass column illustrated in (a) is manufactured by Merck. A wide variety of columns (ranging in size from 1 ml to several litres, and constructed from glass/plastic or stainless steel) are available from this and a number of other manufacturers (e.g. Bio-Rad and Pharmacia Biotech), (b) Process-scale chromatographic system. This particular system is utilized by a UK-based biotech company in the manufacture of a (protein) drug for clinical trials. The actual column is positioned to the left of picture...

A high performance tic system has been developped for the in-process-control (28) using Merck silica gel HPTLC plates, no. 5628, as the stationary phase and tetrahydrofuran/ chloroform/n-heptane/methanol/conc. ammonia 20 20 57 7 1 per volume as the mobile phase. The chromatography (6 cm ascending) is carried out without preceding chamber saturation. 

A specific assay of bromocriptine mesilate in the dosage form may be carried out by tic followed by uv-spectrophotometry (26)(The system can also serve for identification purposes). The drug substance is extracted with methanol in the absence of light, the chromatographic conditions are Merck plates F 254, mobile phase dichloromethane/dioxane/ ethanol abs./conc. ammonia 180 15 5 0.1 per volume. 

Commercially available fully automated online SPE systems include Prospekt, Prospekt-2, and Symbiosis systems (Spark Holland, the Netherlands) and Merck s OSP-2 (Darmstadt). Figure 10.2 shows a Symbiosis (Kuklenyik et al. 2005) two-cartridge, single analytical column online SPE... 

Phenyl (Cohesive Technologies), the polymer-based Oasis HLB (Waters), the Cyclone (Cohesive Technologies), and the porous graphitized carbon-based Hypercarb (ThermoHypersil, Cheshire, UK) Cohesive s 2300 system was the HTLC component. Merck s monolithic reversed-phased Chromolith Speed ROD (RP-C18 (50 x 4.6 mm) served as the analytical column. The Oasis HLB, Cyclone TFC, and Hypercarb yielded the best retention capacity and good elution efficiency and volume. Recovery was 42 to 94% with a sample volume of 10 mL. Run time was 14 min. LODs were 0.4 to 13 ng/L for most compounds. 

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