Frequency Modulation Spectroscopy - Pharmaceutical Technology

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PharmTech Europe

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

Pharmaceutical Technology

n = (ΔI Γ π ÷ I o S x) cm-3

in which ΔI is the change in intensity of light after passing through the container (W/cm2 ), Γ is the full-width at half maximum of the absorption signal (cm-1 ), π is a constant, I o is the incident laser intensity (W/cm2 ), S is the integrated absorption cross section (cm), and x is the container diameter (cm). The measured density in a sample vial is referenced to a standard and displayed as a concentration in percent. The frequency modulated diode laser output is converted to an amplitude modulation after passing through a sample that absorbs at a particular wavelength. The amplitude modulation is detected at radio frequencies and is proportional to moisture concentration.

Materials and sample preparation

Preparation of relative humidity standard. We prepared various saturated salt solutions from USP water and ACS-certified salts (Fisher Scientific, Fair Lawn, NJ) for use as relative humidity standards. To use the samples in a headspace moisture analyzer, the saturated salt solutions were placed in an optically transparent sample vial—comprising a glass vial, a rubber stopper, and an aluminum crimp top—typically used for parenteral pharmaceutical formulations. These relative humidity standards were used for instrument calibration and for examining the performance of the headspace moisture analyzer.

Pharmaceutical sample preparation. Pharmaceutical samples included placebo tablets (comprising microcrystalline cellulose, lactose, and magnesium stearate), a gelatin-encapsulated dry product (comprising proprietary drug, sucrose, microcrystalline cellulose, hydroxypropyl cellulose, and sodium lauryl sulfate), a lyophilized product (comprising proprietary drug, gelatin, mannitol, and citric acid), desiccant (silica gel, Süd-Chemie, Munich, Germany), and a liquid-filled hard gelatin capsule (proprietary drug and lipids). To pre-equilibrate the samples at various relative humidity levels, they were stored in weigh boats (single layer) either in a variable temperature and relative humidity stability chamber (Lunaire, Williamsport, PA) or a desiccator with saturated salt solutions for 4–10 days and then sealed into the same vial–stopper–crimp top vial used to prepare the relative humidity standards.


Figure 3: Schematic of measuring cell for Lighthouse Instruments FMS 1400 device.
Moisture analyzer. A Lighthouse Instruments FMS 1400 headspace moisture analyzer (Lighthouse Instruments, Charlottesville, VA) was used for the frequency modulation studies. The optical head where the sample container is presented (accessible from the top) is continuously purged with nitrogen to eliminate any room air moisture from the measurement region before the experiments. Containers are inserted to the sample holder from the top of the instrument and the measured moisture concentration result is sent to the computer as well as the instrument's front-panel display. The sample holder is jacketed, thus the temperature of the sample holder and the sample can be controlled (see Figure 3).

Typical operation of the instrument was conducted in the following sequence: The sample holder was heated or cooled to the desired measurement temperature. Next, the instrument was calibrated at the measurement temperature using a known activity solution. The water activity reading was graphically monitored in real time to ensure that the vial headspace had reached equilibrium with the sample at the measurement temperature. After the instrument was calibrated, a similar procedure was followed for the actual measurement. Each time the temperature or container was changed or the instrument was shut down, a new calibration was performed.


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