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Predicting Greenness Scores

This excellent paper from BMS describes a method for predicting the process mass intensity (PMI) for a given chemical step or for a whole synthesis, and thus provides a new way to compare synthetic routes even at the design stage. At the heart of this approach is an internal database of PMI scores for 15

Impurities Guidelines

Permissible limits for impurities during clinical development has always been a grey area. Existing guidelines, specifically ICH Q3A only formally apply to marketed products. How factors such as duration of clinical trials have never been effectively addressed.

Risk Analysis for Quality by Design (QbD) (part 1)

Whereas process parameter risk quantification is conducted using mathematical calculations (Monte Carlo simulations) based on a process model, risk analysis is a semi-subjective methodology, of value for both early, as well as for late process development work. Herein we will focus on early process development, when little experimental information is available. In spite of its

Particle Size Control in Batch Crystallisation of Pyrazinamide on Different Scales

In the past, the particle size of finished APIs was mostly controlled by processes such as milling and micronization, but this often creates fines and can lead to formulation issues for some compounds. More recently companies are trying to control the particle size of the product as part of the crystallisation process (not forgetting that

Iron Catalysis in Organic Synthesis – A Critical Assessment of What it Takes To Make This Base Metal a Multitasking Champion

Industrial homogeneous catalytic processes are dominated by the use of expensive precious metals and rely on very efficient catalytic cycles for their cost effectiveness. Many of the processes carried out with precious metals are also achieved by iron catalysis, but often other processes compete and these chemistries have not been so widely used in industry,

To Telescope or Not to Telescope

Meanwhile in another presentation from the 4th Winter Process Conference this time from Alexandra Parker of AstraZeneca discussed the development of the manufacturing route to make Lesinurad (Zurampic) a selective uric acid reabsorption inhibitor approved for treatment of hyperuricemia associated with gout in combination with a xanthine oxidase inhibitor (XOI) in patients unable to achieve

Tautomeric Polymers

We are always taught that molecules which can exist in a number of existing tautomeric forms may be prone to polymorph formation as a result, but I came across a real example at our recent Winter Process Conference held at the University of Strathclyde in Glasgow in a presentation from Ivan Marziano of Pfizer. The

Alkyne to Alkene Reduction

The Lindlar reduction of alkynes to alkenes is well known but does not always work as well as we would like, so any new method for carrying out this potentially useful reduction is always of interest. Grela and a co-worker found that Hoveyda-Grubbs HG metathesis catalysts in the presence of NaH (20 mol %) and

Improving the Substrate Scope of the Kumada-Corriu Cross Coupling Reaction

The Ni or Pd catalysed Kumada-Corriu reaction between an aryl halide and a Grignard reagent is one of the original cross coupling reactions, and we all know that the Grignard reagent can react with suitable functional groups, such as carbonyls, on the aryl halide which limits it’s applicability.  Buchwald1 and Knochel2 have shown that by

Regioselective Chlorination of Phenols

Normally when one chlorinates a phenol one would expect to see perhaps 8:1 to 10:1 regioselectivity in favour of the para-isomer, but in this paper using N-chlorosuccinimide as the chlorinating agent, using the correct thiourea catalyst can give up to much better regioselectivity for either the o-chloro or p-chloro isomer depending on the thiourea catalysts