A Robust, Automated Karl Fischer Titration System - Pharmaceutical Technology

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A Robust, Automated Karl Fischer Titration System
The authors developed a robust, automated system to conduct Karl Fischer moisture assays for lyophilized products.

Pharmaceutical Technology
Volume 33, Issue 11, pp. 52-60

The instrument control software offers the users a limited number of choices. The manual "Control" screen allows the operator to activate certain functions such as the titration-cell wash routine, open and close the titration-cell cap, move the robot arm grippers, control the balance door, and operate the decapping station gripper. The operator thus has sufficient control to handle routine maintenance such as cleaning the titration cell and removing sample tubes that were left in the system after a critical error or an emergency stop. Advanced functions such as control of the robot-arm movements are disabled for safety reasons and can only be accessed through a password-protected administrator login.

The "Run Standards" screen allows the operator to perform titer determination using sodium tartrate. The raw data (volume of titrant dispensed) is obtained from the titrator, the sample mass is obtained from the balance and the titer (mg H2O/mL KF reagent) is calculated and stored by the Focus software. Here, a minimum of three replicates are required. The average value is used for all subsequent sample moisture determination.

The "Run Sample" screen allow users to enter the total number of samples to be analyzed and the number of titrations to be performed before the titration cell is washed. These two user-input parameters are the only ones that directly affect system operation. No product-specific methods exist. All samples are handled and analyzed in the same manner. After each moisture determination, the result is sent to the computer and immediately printed on the attached line printer. To simplify system validation, the authors decided not to include the optional 21 CFR Part 11: Electronic Records, Electronic Signature feature, but this functionality could be added in a future software revision if needed.

The "Mock Run" screen is identical to the "Run Sample" screen, with exception that no titration is performed. This mode is used for system demonstration and training purposes.

System testing

The system was subjected to comprehensive tests, including hardware error checking and recovery. No major difficulties were encountered. Operational testing was simplified by the limited number of user input parameters. This section presents the results from the most relevant studies: the moisture determination of active hygroscopic freeze-dried product from a fully loaded sample rack.

Figure 3: The effect of queue time on sample moisture. The squares and dashed line represent Sample Set 1. The circles and solid line represent Sample Set 2. (IMAGE IS COURTESY OF PHILIPPE LAM)
For these studies, the sample queue times (i.e., the time the samples were on the rack awaiting analysis) were recorded. Figure 3 summarizes the results for two sets of samples consisting of two batches of active material lyophilized in 50-cm3 vials. For the second set, analysis was paused after 4.5 h and resumed 17 h later to increase the queue time.

The data show that, for this product, the sample moisture increases in a linear way as a function of queue time. The increase suggests that the samples absorb environmental moisture, most likely from diffusion though the centrifuge tube wall or the cap closure seal. The absolute overhead moisture present in a 15-mL sample tube under typical laboratory ambient conditions of 21 C and 50 15% relative humidity is approximately 1.4 10-4 mg, an insignificant amount. The moisture-ingress rates for the two sets of samples are 0.018 wt%/h and 0.0095 wt %/h, respectively. This behavior is expected and results from the sample-preparation method selected. Although this small amount of moisture ingress seems to be a shortfall, in practice, analysts prepare 10–20 samples at a time, and samples are added only after most of the initial samples have been tested. Hence, the queue time is typically only a few hours. This minor limitation was deemed an acceptable tradeoff for the convenience afforded by an automated system.


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