Tuesday, March 03, 2009

Semi-automated measurement of solubility using NMR

Over the past few days Andrew Lang and I have been discussing ways of streamlining the measurement of non-aqueous solubilities using NMR. Inspired by David Strumfels' VBA code on Excel to automatically measure kinetics, Andy found a way to directly extract the integration values from the H NMR spectra hosted on our server in JCAMP-DX format.

We have set up a Google Spreadsheet (see ONSC-EXP062B for an example) that automatically calculates solubility based on information that the researcher provides. What is required:
  • A link to the NMR spectrum (the HTML file linking to the JCAMP-DX file)
  • Density and molecular weight of the solute
  • Density and molecular weight of the solvent
  • A range in the solute to integrate with the number of corresponding Hs
  • A range in the solvent to integrate with the number of corresponding Hs
The spreadsheet calculates the molar ratio of the solute to solvent then the molarity by making use of the assumption that the volumes of the two components are additive. The volume of solids is typically not available experimentally but ChemSpider gives a reasonable prediction. We have been using this assumption to convert published solubility values from g solute/ 100 g solvent to molar. In order to prevent taxing the server, once the measurements are computed they are stored in a database so that the spectrum and calculations don't have to be performed again.

The beauty of this approach is that there are no volume measurements. A saturated solution is made then, generally diluted in a deuterated solvent. When using an internal standard the volume of the saturated solution and the volume (or weight) of the standard must be known exactly. It is often difficult to micropipette some solvents and there is always the possibility of making an error in the handling of the micropipette. In general the fewer variables there are the more likely the results will be reproducible.

This is method can save a lot of time but it is not as automated as it could be. The densities must be looked up manually, although the molecular weight is automatically calculated from the common name using a web service by Rajarshi Guha run directly from within Google Spreadsheets. It also requires students to define solvent and solute ranges manually. All of the input cells are colored green, the output red and the intermediate calculations are in yellow.

However, once a range for a solute or solvent (and corresponding number of hydrogens) has been determined it can be used as a handy default and we will be collecting these and storing them in this sheet.

Does this mean that students don't need to think anymore?

Used properly, this system should actually elevate the level of thinking, in much the same way that the calculator did not remove the need for thought in data analysis. It just removed a lot of the tedium of manually calculating square roots and all of the associated sources of error in manual calculations of that type.

Students should use this tool to handle more measurements - faster - and think about their results in aggregate form. The ability to detect systematic errors becomes an essential skill to be developed. Also students need to spot problematic results quickly, for example where solvent and solute peaks overlap - or where there are baseline anomalies.

Of course even these last issues of quality can control can probably be automated to a large extent and we will report on this as we go. For example, it is conceivable that the NMR of a solute and solvent can be predicted or looked up automatically (on ChemSpider for example) and probable peak overlaps could be flagged. Software could also probably detect a mislabeling error.

At this point, we are getting closer to scientific progress by machine-to-machine communication on the free open read/write web. All we would need are a few groups around the world who see the value in endeavors such as this and donate a part of their NMR autosampling time. I am sure we could come up with simple ways of automatically converting files on their local computers to JCAMP-DX format and automatically upload them. We also need people to make up saturated solutions - but with the decoupling of tasks in this new workflow - these don't necessarily have to be the same people who process the NMR spectra.

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