Frequency Modulation Spectroscopy - Pharmaceutical Technology

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Frequency Modulation Spectroscopy
A Novel Nondestructive Approach for Measuring Moisture Activity in Pharmaceutical Samples


Pharmaceutical Technology


Instruments used for comparison in the study. A capacitive sensor (Rotronics Hygrolab III, Rotronic Instrument Corp., Huntington, NY) and a chilled-mirror dew-point analyzer (Aqualab 3TE, Decagon Devices Inc., Pullman, WA) also were evaluated for comparison. For studies conducted with the Rotronics Hygrolab III instrument, samples were placed in the measurement chamber that had been previously placed and thermally equilibrated in an circulated-air oven at the desired temperature. The sensor then was placed on top of the measurement chamber and clamped into place. Following equilibration in the sample chamber headspace, the sensor measured the relative humidity at the temperature of interest.

For the Aqualab 3TE measurements, samples were placed in the measurement chamber that was previously thermally equilibrated at the desired temperature. The samples were allowed to equilibrate, and the relative humidities over the samples were measured.

Results and discussion

Development and application of FMS for water activity measurements. The results illustrated the development and application of the FMS 1400 for water activity measurements in pharmaceutically relevant samples. Data taken from several real examples demonstrated the wide applicability of the moisture activity method for pharmaceutical samples.

We conducted studies on pharmaceutically relevant samples using a FMS sample holder at temperature settings of 25 and 40 C (see Tables I and II). Measurements were taken on vials containing 10 tablets or capsules, a lyophilized product sample, and a single desiccant. The samples were pre-equilibrated as described previously at 10–84% RH. Tables I and II list the manner of headspace-moisture conditioning. Following this conditioning step, FMS measurements were conducted on the samples at 25 and 40 C. Various numbers of samples (N) were prepared for repeat measurements, and the average expected %RH was determined.

In all cases, the difference between the measured RH and the expected RH was within the measurement error expected from the combined sources of sample preparation and instrument bias. The percent relative standard deviation (% RSD) for all measurements also was calculated, and as the data show, the % RSD values for replicate measurements were generally low, ranging from 1–9%. Bias, reported in %RH, also was low and varied from -1 to 1.5 in %RH units. These data demonstrate the capability of the FMS 1400 instrument to measure moisture levels in the headspace over pharmaceutical samples.

The nondestructive examination of moisture levels in a closed container allows for several applications of the FMS 1400 instrument, including the evaluation of the effect of stopper drying on headspace moisture levels for moisture-sensitive lyophilized products, moisture-vapor transmission measurements of pharmaceutical blister packaging (13), seal integrity testing (14), and the real-time determination of equilibration rates of multicomponent pharmaceutical systems (e.g., tablets and desiccant within a sealed package.)


Figure 4: Results of using the Lighthouse FMS 1400 instrument for monitoring moisture redistribution in a two-component system.
We conducted an experiment to monitor the equilibration of a multicomponent system in real time (see Figure 4). Ten 800-mg tablets of a proprietary product (pre-equilibrated at 25 C and 60% RH) were sealed in a vial with 2 g of desiccant. The internal RH in the vial was monitored over time using the FMS 1400 instrument, and the results of three replicate experiments were reported (see Figure 4). The multicomponent desiccant–tablet system equilibrated in less than one day, and moisture levels in the package were brought from ~60% RH to a steady-state level of 10% RH. This example illustrates the value of the nondestructive nature of the FMS 1400 analyzer measurement in that it allows for real-time data generation and may improve understanding about the interaction of moisture in various multicomponent systems.


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