![[Readers Insight] Asking the Questions Right: A Guide to Troubleshooting Consultations in HPLC Method Development](http://www.welch-us.com/cdn/shop/articles/asking-115-1080_e1af459a-8c94-4cee-a7ea-1d8f32e355df_750x.jpg?v=1768532002)
[Readers Insight] Asking the Questions Right: A Guide to Troubleshooting Consultations in HPLC Method Development
Author: Sepuxianyun
Translator's note: This article offers general guidance intended to be broadly useful. Due to culture diversity, some suggestions in this article may not 100% fit the culture in your country. Despite these differences, the principles should remain practically valuable across diverse cultures.
Introduction
Developing HPLC methods is a cornerstone skill for nearly every pharmaceutical scientist. For those just starting their careers, seeking guidance from senior colleagues or supervisors isn't just a necessity, but the fastest path to professional growth.
However, it is common for newcomers to find themselves paralyzed by “question anxiety”, worrying about “I don't know what to ask”, “I'm afraid of asking in a wrong way”, or “I asked, but didn't learn much from it.”
Mastering the science of “asking questions” does more than just get you an answer; it builds your reputation as a sharp, proactive scientist.
The Cost of a Vague Question
“Please help! These two peaks are not separating. How can I fix this?”
As a veteran in the lab, this is what I may often receive from junior analysts, together with a chromatogram of two peaks sitting shoulder to shoulder.
My first instinct is to analyze the molecular structures to identify structural differences. But the junior is also unaware of that information and has to consult process colleagues, wasting half a day. Next, I ask about the column, the mobile phase, and the gradient (and it turns out the method is running at 80% organic in isocratic mode). Then, having realized both x and y axes are not visible in the photo, I ask the junior to take a full screenshot of the chromatogram. Now the problem is clear: the analytes eluted almost immediately, unseparated from the solvent peak in the void volume.
Such a simple issue that could be fixed in minutes took an entire day's consultation. To a junior, it’s a learning curve; to a senior, it’s an avoidable drain on resources.
In this fast-paced world, seniors and leads are results-oriented. If the problem is fixed, the job is done. However, a junior's goal is not just to solve a problem, but to learn the why behind it. To bridge the gap and improve your own capability, it is necessary to learn the art of asking.
Prepare Before You Ask
Preparation clarifies your own thinking and keeps the discussion focused. Before you approach someone, define your problem with surgical precision.
Are you struggling with tailing, an elusive impurity, or a resolution failure? Instead of a vague plea for help, compile a “data package”. For instance, if you have a poor resolution between the main peak and a closely eluting impurity in a related substances method development, do not simply describe it as “a resolution problem”. Instead, describe the full contexts:
- Chemical structures
- Mobile phase composition
- Gradient information
- Column type and dimensions
- Flow rate and column temperature
- Other conditions you have tried, if any
If the information is extensive, use a Document or a Slideshow to organize it. In this way, it might feel like extra work upfront, but allows a senior to spot the bottleneck immediately. It’s far better to spend thirty minutes preparing a clear summary than to spend three days in a “question-and-answer” ping-pong match while your samples sit in the autosampler.
How to Ask: The “Perfect Question” Formula
Now that we are well prepared and begin to ask, be direct and reach the core quickly, as seniors also have their own workload. A highly effective way to structure your request is:
Context + Specific Parameters + Attempted Solutions + The Core Ask.
For example: “Dr. Wang, I’m working on a related substances method for a new API. I’m currently using an Ultisil LP-C18 column (250 × 4.6 mm, 5 μm) with a 20 mM potassium phosphate buffer (pH 3.5) and an acetonitrile. The gradient is 0 min (10% ACN) to 30 min (70% ACN), flow rate is 1.0 mL/min, and column temperature 30 °C. The main peak shows significant tailing. I've tried dropping the pH to 2.5, which helped slightly, but the peak shape is still failing integration criteria. Here are the chromatograms—where do you think the issue lies?”
With this level of clarity, an experienced chromatographer can give an instant, actionable suggestion—switching to an end-capped column like Ultisil XB-C18 or Xtimate C18—saving everyone a week of trial and error.
After the Answer: Turn Solutions into Skills
Solving the immediate problem is not the end of everything. To truly turn an answer into expertise, you need to deconstruct the solution.
First, review the reasoning behind the solution. Why did the column chemistry matter? What interaction was driving the tailing? This kind of analysis builds transferable understanding, making it easier to handle similar issues in the future.
Second, always follow up and provide feedback. If the suggestion worked, a quick “That column fixed the tailing, thanks for the lead!” goes a long way. If it didn't work, let them know what happened so you can troubleshoot the next step together. This follow-up isn't just polite; it’s a sign of professional reliability. It shows you aren't just looking for a “cheat code” but are actually invested in the science.
Building Professional Trust
For a junior analyst, asking questions is more than gaining knowledge; it is also a primary way to build “professional capital”. Approach these interactions with humility, but don't be afraid to ask for clarification if you don't understand a suggestion. Using phrases like, “I want to make sure I follow your logic—could you explain why the pH shift would affect that specific impurity? ” is much more effective than nodding along and making a mistake later.
Growth is Gradual, and That's Normal
Evolving question skills is a gradual growth. Early on, most questions focus on basic instrument settings and concrete operational issues. Over time, they shift toward method optimization strategies, and eventually toward independent problem-solving. There is also no need to resolve everything at once. Ask in stages aligned with your current knowledge and experimental needs. Ultimately, you’ll be the one providing the answers.
In conclusion, the essentials of asking questions effectively in HPLC method development are straightforward: prepare thoroughly, express yourself clearly, reflect after the fact, and remain humble throughout. Each well-considered question not only fixes your chromatogram, but sharpens thinking, deepens understanding, and lays a solid foundation for long-term professional development.