Nearly every chromatographer needs to do some kind of method development at one time or another. Whether your job is running a routine liquid chromatography (LC) method that needs an occasional "tweak", you need to develop a one-use method to support chemical synthesis, or you need a robust method to monitor a production process, a good understanding of the principles of LC method development are valuable to know. I have titled this series "The Perfect Method", a little tongue-in-cheek, because, at least in my experience, there is no such thing as a "perfect" method — every method I have seen can always be made better. Herein lies the first principle of method development: "better is the enemy of good enough." You can always make the method just a little better, but it comes at a cost of time that you might not be able to afford. Develop a method that is adequate for the job at hand, then stop.

Over the next several issues, we'll look at the subject of LC method development in detail. Before we start, though, let me caution you that this will not be the final, authoritative treatment on LC method development. If method development is a part of your life in the laboratory, your personal library should include reference 1, which I think is the best book ever written on the subject.

Where Are You Going?

We've all heard Lewis Carroll's quote: "If you don't know where you are going, any road will take you there."

This seems to be the attitude many chromatographers take when they start a method development project. There doesn't seem to be a goal in mind, and even if there is one vaguely formulated, it is felt that a trial-and-error approach will eventually get the job done. Trial-and-error ends up more commonly as error-and-error, which wastes valuable time and money. I think that Laurence J. Peter's take on this subject is much more apropos for method development:

"If you don't know where you are going, you will probably end up somewhere else."

And most of us don't have the luxury of extra time to spend exploring possibilities that lead us away from our goal.

So we need a goal. But that can vary widely. If you desire that method mentioned earlier to use as a quick check of the purity of your synthetic product, a 30 min generic gradient will probably do the job — no need for anything fancy. In contrast, if your method will need to support a 10000-sample clinical study, the energy spent in reducing the run time from 6 min to 4 min can well be worth the investment. You could think of a number of different criteria that you might use to help define your goals. Here's a list that we use in one of our method development classes at LC Resources:

• Number of samplers
• Run time
• Number of analytes
• Number of matrices
• Sensitivity
• Reproducibility
• Precision and accuracy
• Concentration range
• Qualitative or quantitative
• Equipment or operator limitations
• Sample preparation requirements
• Validation requirements