Solution Preparation

10 Reasons to Say Goodbye To Inaccurate Concentrations

In the laboratory, there are numerous factors which can introduce error into your processes and lead to Out-of-Specification (OOS) results. But did you know that everyday manual sample processing steps account for up to 50% of such errors in an analytical workflow?

Accurate preparation of samples and standards is a fundamental starting point for any analysis, whether in analytical, quality control or testing labs, in the pharmaceutical, chemical or food industries, to name but a few.

To prepare an accurate solution, a sample or standard must be accurately weighed on an appropriate balance. Then, the precise amount of solvent must be added to make up to the required concentration.

Manual volumetric sample preparation contributes many potential errors to the process. Solution Preparation Solution By switching to automated gravimetric methods, you will not only reduce errors and variability, but will also benefit from increased accuracy, safety and resource savings.

We outline 10 good reasons why you should say goodbye to inaccurate concentrations in your laboratory.

Errors in volumetric sample preparation can lead to out-of-specification results Challenges of traditional methods

Flask-based, volumetric sample • Temperature variation. In addition to error risks, preparation has not changed Volumetric flasks are typically volumetric methods also tend to significantly in decades. The calibrated at 20 °C. However, lead to excessive use of workflow is manual and time flask contents are not always substances and solvents. This is a consuming, and it relies on measured at this specific waste of money, especially when subjective assumptions and temperature. Temperature substances are expensive. steps with high potential for variations of the flask caused by human error. Common challenges reaction, sonication or even • Substance waste. Sample and and sources of variability or dishwashing can contribute standard solutions are prepared

Solution Preparation Solution uncertainty in a typical volumetric to error potential. in volumes far in excess of what workflow include: is required. Only a small • Cross contamination. Cross- proportion is used for the • Operator error. Mistakes during contamination creates risk. analysis. The excess solution is materials or flask selection, However, defining an effective eventually discarded, creating weighing, sample transfer, washing process can be added disposal costs. dilution, and meniscus reading difficult, time-consuming, and make solution preparation highly expensive. variable. • Data errors. OOS results can • Glassware failure. A paper from also arise from incorrect labeling the “National Institute of or incomplete description of Standards and Technology” flask contents. Transcription (NIST) states that new error a common problem when glassware fails to meet Class A manually recording process specifications as often as 50 results. percent of the time.

Pipettes Flasks Volume (ml) Relative % Error Volume (ml) Relative % Error 1 0.60 5 0.40 2 0.30 10 0.20 3 0.33 25 0.12 4 0.25 50 0.10 5 0.20 100 0.08 10 0.20 200 0.05

Table 1: Relative percentage errors for Class A glassware

2 What does gravimetric sample preparation really mean?

There is now a single, easy-to-per- While the principle works with both effort. On that basis alone, this form sample preparation method that manual and automated methods, mass-based method deserves eliminates all these sources of error using a balance equipped with consideration – but that’s just the at once using mass as the basis for the ability to automatically dose beginning. Read on to discover 10 measurement, instead of volume. a solvent based on the mass of important reasons why this gravi- This method requires little more than weighed-in solids means that pre- metric method for preparing accu- the analytical or semi-micro balance cise concentrations are achieved rate solutions belongs in your lab. you already use in your lab. every time with less operator

Weigh sample Record actual weight. Rinse paper. Fill to Calculate Label flask within tolerance Transfer sample to meniscus. Put on concentration onto weigh paper volumetric flask stopper. Invert flask

Weighing errors Transcription errors Subjective, depends Calculation Transcription Time consuming Flask cleanliness on operator training errors errors Flask selection

Figure 1: Volumetric preparation is highly manual, subjective, and variable

Set target Weigh in sample Automated Diluent added Label vial concentration directly in the vial calculation

Required Approximate Calculation based Automated liquid Automated label concentration weight on sample weight and dosing printing target concentration

Figure 2: Automated dosing eliminates subjectivity and variability

3 Why Should I Switch to Gravimetric Sample Preparation?

Gravimetric sample preparation is increases – yet larger flasks 5. Use smaller sample volumes. simply the preparation of a solution require more solvent and sub- The amount of solution by weighing both the sample stance for solution preparation. prepared is not dictated by the and the solvent. It generates an The challenge is in finding the discrete intervals of volumetric accurate concentration. The sample right compromise between error flasks available. Combined with or standard can be weighed into a risk and materials use. Gravi- the lower minimum weight vial (rather than using a volumetric metric solution preparation achievable when using mass- flask) either manually or with eliminates time-consuming based dosing, smaller sample automated dispensing. The correct glassware vs. process needs amounts can be used, smaller

Solution Preparation Solution amount of solvent is calculated and analysis, as only the required solution volumes prepared, and added automatically to achieve a amount of solution is prepared. less material wasted for precise concentration, leading to significant cost savings. accurate and high quality analyses 3. Eliminate subjective readings. from start to finish. Adding liquid by Sources of variability mount 6. Use significantly less solvent. weight based on the actual weight during the solvent addition Gravimetric sample prepa- of the dosed solids helps you: step. First and fore-most, ration ensures that solvent volumetric meniscus reading is addition is precisely calculated 1. Eliminate manual variability. highly subjective and can vary based on actual amounts of Manual volumetric sample from operator to operator. dispensed solid sample. It also preparation is variable and has Mass-based dosing, on the means using much less a high potential for introducing other hand, relies on weight solvent, because the volume errors, as described earlier. A values rather than “eyeballed” prepared is no longer dictated mass-based method estimates. by the volumes of available (gravimetric sample glassware. Solvent use is preparation) avoids these error- 4. Create precise concentrations further reduced due to reduced prone manual steps eliminating quickly, even with manual cleaning of glassware. Time- the need to transfer sample weigh-in. Automated liquid consuming serial dilutions to from a weighing paper to dosing delivers precise reach desired concentrations volumetric flask, and removing concentrations every time, can also be achieved in less the influence of temperature because solvent is added steps. variations. automatically based on the actual weight of weighed-in 7. Stop maintaining expensive 2. Get to work faster. Flask selec- solids. This means manual glassware. Instead of using tion in volumetric workflows powder dosing can be a calibrated volumetric flask requires a thorough process approximate, eliminating time- and volumetric pipettes, pow- understanding. As glassware consuming scooping in or out ders and liquids are dispensed volume decreases, error risk to meet exact targets. into small, disposable vials

4 placed directly on the weighing with electronic transfer, elimi- of time an operator is exposed pan of the XPR Automatic Bal- nates risk of transcription to the solid substance. ance. Disposable vials are far errors. Automated label printing more cost-effective than expen- also ensures data is complete. 10. Reduce or eliminate cross- sive calibrated volumetric contamination risk. Disposable glassware. 9. Reduce or eliminate exposure vials are used just one time, risk. When dispensing solids eliminating the need for a robust 8. Ensure traceability and meet automatically, in combination flask-washing system for expen- compliance requirements. The with automated liquid dispens- sive volumetric glassware, as ability to recall critical meta- ing, substances are dispensed well as the risk of cross-con- data such as when a solution directly into the target vial with tamination that occurs when was prepared and its sample no manual intervention by the cleaning SOPs are not followed. ID is paramount during audits. operator. Sample transfer using When preparing samples using spatulas or weighing papers – mass on a balance, target and the exposure risk that weights, actual weights, and comes with it – is eliminated. achieved concentrations can be Even during manual weigh-in of recorded automatically. Auto- solids, automated liquid dosing mated recording of weight and means weights do not need to concentration measurements, be precise, reducing the amount

5 Gravimetric benefits summarized

Overall, gravimetric sample • Valuable resource savings highly variable, error-prone and preparation utilizing automated • Enhanced ergonomics resource-intensive volumetric liquid dosing offers: • Automated data recording solution preparation.

• Reduced sample processing errors These benefits make automated • Improved concentration accuracy gravimetric sample preparation a • Reduced environmental impact viable, cost-effective alternative to Solution Preparation Solution

6 How to make a shift to mass-based methods

Gravimetric sample preparation solvent addition instead, without Either way, the new method must expresses a concentration in mg/g the need to alter their existing be validated in accordance with instead of mg/ml. SOP’s. USP General Chapter <1225>, as you would for any new method. USP General Chapter <841> If a new procedure involving Specific Gravity was revised in preparation of a solution is written, 2013 (2), enabling gravimetric there are two ways to approach sample preparation to be used for this: pre-existing SOP’s. 1. Document gravimetric solution “Where the density is known, preparation in mg/g as the mass can be converted to volume, method of preparing a or volume converted to mass, by solution of a specific the formula: volume = mass/ concentration. density.” 2. Document preparation of a The statement above allows any solution in mg/g or mg/ml laboratory whose SOP’s are (with the use of specific written in terms of volumetric gravity for conversion between solvent addition, to use gravimetric the two where necessary)

7 References:

1. General Chapter <1251> “Weighing on an Analytical Balance”, Second Supplement to USP36-NF31, June 2013, Rockville, Maryland, Online-Edition

2. General Chapter <841> “Specific Gravity”, First Supplement to USP36-NF31, February 2013, Rockville, Maryland, Online-Edition

3. “Important Technical Guidance on Glassware”, Tom Coleman and Georgia Harris, NIST, August 2005.

4. U.S. Food and Drug Administration. Guidance for Industry: Investigating out-of-specification (OOS) test results for pharmaceutical production. FDA. Available at: www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM070287.pdf.

5. “Gravimetric Sample Preparation Reducing Sample Size and OOS Errors”, Mettler-Toledo GmbH, 2020

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