Introduction
Testing for moisture in lyophilized materials has well documented benefits to ensuring quality and shelf life. It has been previously demonstrated that the Computrac® Vapor Pro® Rx is a perfect fit for testing for moisture in lyophilized samples. The samples can be tested in the lyophilization vials without ever being exposed to ambient air. The relative humidity sensor in the instrument is sensitive enough to allow for sample sizes as small as 5 mg. Most importantly, the testing procedure itself is dead simple.
The Computrac® Vapor Pro® Rx uses a thermoset polymer capacitor that has a selective response when in the presence of water, the same way that many RH sensors work in traditional settings such as houses, laboratory controlled environments, and dry boxes. A material is sealed in a sample vial, and then transported into an oven with inert gas blown through it. As the material gets hot, water vapor is evolved and carried to the sensor via the carrier gas. The sensor is exposed to the water vapor and a measurable change in the relative humidity of the sensor chamber takes place. This change in relative humidity can be directly converted to total micrograms of water passing the sensor. No solvent and no material processing for lyophilized pharmaceuticals are necessary for analysis.
Moisture in Lyophilization Closures
One often overlooked source of possible drug quality degradation is in the lyophilization stopper or closure itself. The closure is the primary barrier between the lyophilized material and the atmosphere. If this barrier is breached, the loss in quality of the sample material can be severe and rapid. Controlling the moisture in the closure is of paramount importance to the efficacy of the barrier, and the shelf life of the material it is supposed to protect. The closure may release moisture over time which can result in drug degradation especially in materials with extremely low cake weights. Careful drying of the lyophilization closure can increase the stability of the drug product over time.
Currently the standard method for testing for moisture in a lyophilization closure is by coulometric Karl Fischer titration. This method calls for a batch of closures to be cut into pieces, and a representative sample of those cut stoppers is to be tested for moisture in a coulometric Karl Fischer titrator with oven attachment. This method is good for mitigating the effects of small variances between stoppers on the final moisture analysis result. However, cutting the stoppers involves an extra step before testing, and introduces a possible safety hazard. KF titration has the additional drawback of using toxic reagents and solvents and normally needs specially trained personnel for operation and maintenance.
The obvious solution to these issues is to develop a new method that does not require a KF or cutting of the stoppers. Arizona Instrument LLC, in conjunction with some of our customers in the pharmaceutical industry, has developed a method for testing closures on the Computrac® Vapor Pro® Rx that uses whole uncut stoppers. Not only is the method easier to perform than the Karl Fischer equivalent, the results obtained compared favorably to the KF testing of the same lots.
Test Results
In the data below, five stopper samples of varying moisture content , size and composition were tested on both the KF coulometric titrator with oven attachment and the Computrac® Vapor Pro® Rx. For the Karl Fischer titration, the four closures were cut into eight pieces of relatively equal size. The cut pieces were mixed and five pieces were randomly selected for testing in the KF titrator. For Computrac® Vapor Pro® Rx testing, a single stopper was tested intact for each analysis. No additional sample preparation was performed before analysis.
Across all samples, the Computrac® performed as well as the Karl Fischer titration. The Vapor Pro® analysis results were within 65 ppm of the Karl Fischer for all samples, and the average result on the Vapor Pro® was within the KF margin of error for all tests. The Vapor Pro® had the added benefit of shorter test times (~ 30 minutes) on average than the Karl Fischer (~ 60 minutes).
Conclusion
The Computrac® Vapor Pro® Rx is an excellent alternative to Karl Fischer titration offering equivalent results, easier usage, and faster test times than the Karl Fischer when testing lyophilization closures. The instrument is highly durable, and since it uses no solvents or reagents, it is a greener alternative to Karl Fischer analysis.