Checklist for Developing a Scaled up Step in a Chemical Process

kilomentor | 30 December, 2006 18:55

This site will be presenting strategies for efficiently creating rugged chemical processes. By processes we mean a series of chemical steps and isolations which produce commercially interesting amounts of pure substances- my own experience of 40 years is with pharmaceutical actives. Here we get started by just considering some of the questions which a process chemist asks hinself/herself about a proposed transformation.

If the process involves a crystallization step:

Is a method in place to determine the solvent composition?
Is there a method in place to determine the ratio of volatile solvent to non-volatile residue?
Is there provision to initiate crystal formation? (seeding)
Is there a provision for managed crystal growth?
Is there provision for crystal size assessment?
Is there a study of crystal aging(ripening)? Does the purity change depending on aging?
Is there an IPC to verify that the crystallization is complete and the correct quantity of residual product is left?

Does the process have a filtration process step? If so:

Has the rate of filtration been checked?
Does the solid shrink in diameter size on the filter after removing solvent or does the filter cake crack?
Do your instructions make provision to prevent shrinking or cracking to facilitate washing?
Have you done a split run (reaction mixture is worked in several parts) to assess the effect of inadequate washing of the crystalline mass?
If the filtration uses charcoal or filter-aid- has the substrate been completely removed from the filter material? Do you have an in-process control to assess the quantity in filtrate and the quantity caught in the adsorbant?

In the process is there a concentration step or a distillation? If so:

Has the stability of the hot solution been determined on the time scale of the large reaction?

Does the process have an extraction step(s)? If so:

Are the phases susceptible to emulsion formation (vigorous shaking)?
What provisions for promoting separation are known?
Are the phases very dark and hard to tell apart? What to do?
What about interfacial material? What should be done with it?
Have you reduced the size of the liquid phases as much as possible to increase throughput?

Is there a drying step in the process? If so:

Can the drying be done by azeotropic distillation or passing through a molecular sieve plug to avoid solid drying agents? Is there an IPC to determine completion of drying?