Formulation Trials: Why Small Weighing Errors Can Affect R&D Outcomes

Achieving reliable results in formulation research requires careful control of the variables involved throughout the process. Among these, the quantities of ingredients used can be particularly important, as small deviations may influence the outcome of a trial. Accurate weighing is therefore an essential part of the process, particularly when working with active pharmaceutical ingredients (APIs) and other components (Fritsch, 2021). This is especially relevant as formulation work increasingly involves more potent ingredients, where the margin for error narrows further.

Why Errors Don’t Stay Small: The Ripple Effect of Inaccurate Weighing

Measurement uncertainty can influence an entire analytical process, from the initial measurement through every result that depends on it. When weighing measurements carry uncertainty, that uncertainty can propagate through subsequent calculations and formulation results. Over repeated formulation trials, these small differences can affect potency and the degree to which one batch matches the next. The smaller the target quantity, the less room there is for error. This makes it more challenging for researchers to reproduce findings or determine the true cause of a change.

What Can Throw Off Balance Readings: Key Factors to Consider

While the precision of an analytical balance can be strongly influenced by balance settings and environmental conditions (Popa-Burke et al., 2013), other aspects of the weighing process can also affect the outcome. Let’s take a closer look at the key factors:

Environmental Factors

• Air currents: Drafts from doors, vents, or foot traffic push against the pan before a reading can settle.
• Temperature fluctuations: Changes in room or sample temperature create small convection currents and can expand or contract the balance’s components.
• Humidity: High humidity can cause hygroscopic samples to absorb moisture, while low humidity can encourage static buildup, potentially producing unstable or inaccurate readings.
• Vibration: Foot traffic or nearby equipment could introduce mechanical noise, disrupting stability.
• Magnetic and electrical interference: Magnetic samples or nearby magnetic fields can interfere with certain high-resolution weighing systems, while inadequate grounding or static buildup can cause unstable readings.

Operational and Sample Factors

• Weighing technique: Container handling, taring, sample placement, and allowing the balance reading to stabilize can all influence the result.
• Sample quantity: The smaller the quantity being weighed, the greater the relative impact of a given weighing error.
• Hygroscopic or volatile samples: These may gain or lose mass while exposed to the environment, causing the measured weight to change over time.
• Temperature acclimation: Weighing a sample before it reaches room temperature can contribute to balance drift and unstable readings.
• Static charge: Plastic containers and powders can accumulate electrostatic charge, leading to unstable or inaccurate readings.
• Off-center loading: Placing a sample away from the center of the pan can introduce measurable weighing errors.
• Contamination: Dust, residue, or fingerprints on the weighing pan or container can add unwanted mass, affecting the measurement.

Instrument Factors

• Leveling: An unlevel balance shifts the load off the axis its sensor is built to measure.
• Analytical Balance Calibration and Performance: Scale calibration alone does not determine suitability for small samples. Repeatability, measurement uncertainty, minimum weight, and the required weighing tolerance should also be considered.

Weighing Small Quantities: Where Accuracy Matters Most

Thidarat Kwangten. “Two lab technicians in white coats and blue gloves conducting chemical analysis with analytical balance in laboratory.” Shutterstock image #2787858429.

The significance of weighing error depends on the quantity being weighed, the required accuracy, balance performance, and environmental and procedural factors. For larger quantities, a small absolute difference may represent only a small percentage of the target weight. With very small quantities, even a small weighing error can make a big difference.

This is why weighing practices that appear adequate for routine measurements may not provide the same level of control when working with small quantities of APIs, excipients, or other formulation components. Researchers should therefore consider whether the balance-and-weighing procedure is appropriate for the actual quantities used in the trial, rather than relying solely on the analytical balance’s displayed resolution. 

How to Minimize Weighing Errors in Formulation R&D: Best Practices

Reducing weighing variability starts with controlling the conditions under which measurements are made. Researchers can:

• Use a balance appropriate for the quantities being measured, with selection guided by your lab needs.
• Verify that the balance is properly leveled and within its calibration or performance-check requirements.
• Minimize drafts, vibration, temperature fluctuations, and sources of static.
• Allow samples and containers to reach appropriate temperature equilibrium before weighing.
• Use consistent handling and weighing techniques between operators.
• Minimize exposure of hygroscopic or volatile materials during weighing.
• Keep the balance and weighing area clean and free from contamination.
• Allow readings to stabilize before recording the result.

While these practices do not eliminate measurement uncertainty, they can reduce variability and improve consistency between formulation trials. 

References

1. Fritsch, K. (2021). Metrology of weighing in the pharmaceutical industry. Measurement: Sensors, 18, 100262. https://doi.org/10.1016/j.measen.2021.100262
2. Popa-Burke, I., Novick, S., Mantilla, M., & McGrath, K. (2013). Analysis of compound weighing precision in drug discovery. Journal of Biomolecular Screening, 18(3), 331–340. https://doi.org/10.1177/1087057112461152
3. Across International. (2024, July 13). Selecting the right analytical balance: A comprehensive guide. Across International.https://www.acrossinternational.com.au/blog/analytical-balances-15/selecting-the-right-analytical-balance-a-comprehensive-guide-11

About the Author

Nikolas Scott

Nikolas holds a Bachelor of Science in Microbiology and a Master’s degree in Biomedical and Health Science from Monash University. His academic background includes a research project and thesis conducted at the CMML lab in Monash Parkville, as well as an internship in research commercialization. Professionally, Nikolas has experience in the human clinical trial industry and currently serves as a Technical Sales Specialist at Across International AU.