Why is Physical Organic Chemistry Important in Pharmaceutical Chemical Process Development?
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Why is Physical Organic Chemistry Important in Pharmaceutical
Chemical Process Development?
Ian W Ashworth
AstraZeneca Pharmaceutical Technology & Development, Silk Road Business Park,
Charter Way, Macclesfield, SK10 2NA, UK
The uti lity of applying app roaches rooted in physical organ ic chemistry to the development of manufacturing processes f or active pharmaceutical ingredients (A PIs) will be demonstrated through three AstraZeneca case studies . These will illustrate applications to a reaction, work -up a nd to contr ol a reaction occurring during the formation an d c rystallisation of a s alt.
The study of a reaction is exemplified by the investigation of the kinetics and mechanism of a Williamson style ether synthesis . The observed first order kinetics led us to the conclusion that the activation of the alkylating agent to form a reactive intermediate was the rate controlling pr ocess in th is reaction . The consequences of this conclusion in relation to our ability to contr ol the formation of alkylated impuriti es will be discussed.
The work -up phase of a reaction will be illustrated by an investigation of a pH - controlled ex traction. Unexp ectedly we found that we were able to sepa rate unreacted starting mat erial from the product of a Buchwald -Hartwig cou pling re action despite the two compounds having nearly identical p Kas. These observations led us to propose a general equation for the part ition of ionisable molecules as a function of pH and the molecules pa rtition coefficient.
Finally , the potential for chemist ry to occur during crystallisations will be discussed in the light of a fina l API salt formation in methanol. Self -cata lysed esteri fication of the salt forming acid was observed that could lead to the isolat ion of the wrong solid form of the API . Download PDF
Theatre C, Purdie
March 4, 2020
From: 14h00 To: 15h00