Article | November 18, 2015

Laser-Based Measurements Of Water Activity In Solid Dosage Applications

Laser-Based Measurements Of Water Activity In Solid Dosage Applications

By D.I. Duncan and J.R. Veale

Water activity aw, or the relative humidity inside a package, is commonly measured by manufacturers in industries such as food and pharmaceuticals. The food industry has used water activity testing for more than two decades in development and quality control applications. The FDA and USDA consider water activity a key parameter to control mold, fungus and bacterial growth on packaged foods. Food producers also use water activity measurements in product development to understand how water migrates between the package and the product itself, and between the individual food components.

In the pharmaceutical industry, water activity is a critical quality attribute and a key factor to maintain stability over the shelf life. Since December, 2012, when the United States Pharmacopeia (USP) added a new chapter “Application of Water Activity Determination to Non-sterile Pharmaceutical Products” <1112&GT that defines aw testing for bacterial growth on solid dosage forms, measuring the water activity inside drug packaging is increasing.

Measuring Water Activity in a New Area — Solid Dosages
Historically, pharmaceutical companies measured and reported total water content by Loss on Drying (LOD) or by Karl Fisher electrochemical titration in every batch of solid dosage drug. Now, the industry is trending towards using more aw measurements, since the total water by weight percent does not provide a complete understanding of how different forms of water impact the stability of a solid dosage form. The relationship of total water to water activity is non-linear, that is, for a small change in total water, there is a larger change in aw, and measuring total water may not be the best way to assess several critical factors of the process and final product quality.

It is well recognized that the “most common cause for packaged product failure is instability as a result of moisture uptake,” according to the PQRI Container Closure Working Group. A higher aw during storage can impact many drug properties, so it is an important measurement for the solid dosage industry. Higher aw can degrade the active pharmaceutical ingredient (API), affect tablet hardness and dissolution rate, and change a tablet’s polymorphic form.

Commercial manufacturers have the ability to measure aw in tablets and gel caps at several points during development, production and storage to ensure ongoing stability of a marketed product. Package, formulation, and process development groups, as well as quality control groups and those measuring stability, use aw measurement techniques during crystal morphology, granulation/drying, and tablet press operations, and as a supplement or possible replacement for a Karl Fisher Water Testing system.1

Current Water Activity Measurement Methods
There are two types of commercial systems currently used to measure aw in solid dosage applications. Both involve placing samples in a sealed chamber and measuring the moisture content in the headspace. In solid dosages, water activity is the partial pressure of water in the headspace above the solid dosage form divided by the partial pressure of pure water at the same temperature. This is equivalent to the equilibrium relative humidity (ERH) expressed as a number ranging from 0 to 1.0.

Chilled mirror systems, from vendors such as Aqualab, are a standard, indirect, inexpensive method of measuring water activity. A sample is sealed inside a chamber, so the ERH inside is the same as the water activity in the sample. The chamber has a mirror that is thermoelectrically cooled, an optical sensor that detects when condensation first appears, and an infrared thermometer that measures the dewpoint temperature repeatedly until vapor equilibrium is reached. Water activity is determined from both measuring the dewpoint and the sample surface temperature.

Capacitance film systems, from vendors such as Rotronics, are also an indirect, inexpensive method of determining water activity. Capacitive water activity meters’ sensors have two metal plates with a non-conductive polymer film in between them. Moisture in a sample of air affects the plates’ capacitance (ability to store electric charge). The film collects moisture from the air, causing the voltage between the two plates to change. These voltage changes are quickly and accurately converted into digital readings showing the level of ERH in the air around it, which is the same as the water activity as long as the sensor is calibrated and at the same temperature as the sample. They can require long times to come to equilibrium, and require good temperature control for high accuracy. Also, the sensor must be calibrated using salt solution RH standards.

Dynamic Vapor Sorption systems are also used for measuring water sorption/desorption properties of solids. To detect the water sorption/desorption of a sample, a carrier gas, with a specified RH, flows over a sample that is suspended from a balance or weighing system. The system measures the increase or decrease in mass. By testing at different RH levels, isotherms can be developed.

Lighthouse’s Laser Headspace Measurement Technology: The Newest Option for Making Water Activity Measurements in Oral Solids
Frequency Modulation Spectroscopy (FMS) is a relatively new laser-based technique to measure water activity (% RH) measurements of solid dosage drug product samples. Frequency Modulation Spectroscopy (FMS) is a high sensitivity and high precision measurement technique offering a 104 increase in sensitivity over traditional broad band NIR techniques. In the Lighthouse Instruments FMS-1400H Headspace Moisture Analyzer, light from a near-infrared (NIR) laser at 1400nm is tuned to match an internal absorption frequency of a water vapor molecule and is passed through a sealed glass sample container in the headspace above the product. The amount of laser light absorbed is directly proportional to the water vapor pressure in the gas phase in the headspace (according to Beer’s Law), which in turn can be directly related to the water activity of the pharmaceutical solid. The system reports the moisture content as a partial pressure or %RH.

Calibration is performed using a NaCl saturated salt solution, and system linearity is checked using six other saturated salt solutions over a range of 5% to 90% RH. The FMS-1400H has temperature control inside the sample housing to ensure samples are measured at the correct temperatures, and unlike inexpensive systems, offers a broad range of temperature control from 15C to 50C. The method is non-destructive, meaning samples can be re-used and retested over time, allowing a broad range of moisture activity applications to be measured and offering significant advantages over traditional techniques.

Each measurement uses sealed vials, ensuring a near-zero long-term loss of water content. After the sample holder is heated or cooled to the desired temperature, making a water activity measurement is quick, taking only 5 seconds, and the system allows real-time data generation and graphical monitoring. The FMS-1400 can be used for long-term measurements, and is much more accurate than inexpensive polymer film capacitance & resistance measurement systems with measurement error less than 0.02 aw.

Lighthouse Instruments developed the FMS-1400H in collaboration with a major US Pharma company that uses the instrument as part of its oral solid dosage package development efforts. These systems have been qualified and tested side by side with other water activity analyzers6 and shown to have equivalent or better performance. Linearity studies showed the systems have linearity greater than 0.99%.

As of now, the technology is fully commercialized, installed, validated and released by internal tests at Lighthouse Instruments. It has been deployed, and proven. It has been submitted to regulatory agencies and is an established method that has been used to conduct stability and characterization studies on solid doses. A top five global pharmaceutical company has implemented the FMS-1400 as its standard moisture test for their solid dosage product.

Why Measure aw in Solid Dose Applications With the Lighthouse FMS Method
There are many advantages to measuring aw in solid doses with the FMS technique. The primary is that the measurement is non-destructive, which offers opportunities for cost savings and the ability to use the same sample over time. The actual solid dosage sample remains intact, so manufacturers could perform other tests on it. Compared to other methods which destroy or consume the sample, the FMS measurement technique allows it to be used to test other parameters. For example, it is possible to correlate moisture content with hardness of a coating by making both types of measurements on the same tablet.

If the sample is heated inside the test chamber, it can take up to 30 minutes to reach full equilibrium over the temperate range of 25C to 40C. Samples tested in the FMS- 1400H can be taken directly from environmental chambers at a specifi ed temperature and measured in a heated sample block at the same temperature. The laser measurement itself is fast, taking only a few seconds. The rapid measurement time allows hundreds of measurements per hour.

The Lighthouse FMS-1400 uses sealed vials for each measurement ensuring near-zero long-term loss of water content. Unlike inexpensive polymer fi lm capacitance and resistance measurement systems, the FMS-1400H can tolerate moving from high to low moisture activity samples. It can also control temperature over a wide range, unlike inexpensive systems, ensuring that the water activity is measured at the correct temperature. Unlike polymer fi lm sensors, the FMS-1400H measurement will not be impacted by volatile organic compounds like acetic acid or other compounds created by degradation.

Measuring aw with the FMS-1400 can help develop package performance. Every type of pharmaceutical packaging has a measurable Moisture Vapor Transmission Rate (MVTR). The PQRI Container Closure Working Group measured the water activity of the same product in two different blister packages and 7- and 30-tablet bottles over 180 days, and found that pharmaceutical companies can build a MVTR data set for each packaging option that they will use, making it easier to predict package performance required for each drug.

In quality programs, measuring aw in addition to LOD provides additional information about degradation rates that can impact drug stability and dissolution rates that impact bio-availability, both of which are critical quality factors.

Water may be present in multiple states: Tightly bound monolayers, which are bound inside the crystal structure of the API and include water of hydration, less-strongly bound monolayers, which are held to and absorbed on the hydroscopic surface, and free water.

Free water is not bound but may be within capillaries, pores or open spaces between the solid particles in the formulation. Free water is what will cause stability issues and can change a drug’s chemical properties, and above aw of 0.6 (60% RH), a drug will be in contact with free water.

Pharmaceutical formulation groups measure the crystalline state and degree of hydration during the final wet milling and drying step, and also during accelerated storage studies at elevated temperature and humidity. Most formulation stability studies list the total water content, but few describe the aw of these different crystal states. Measuring aw during long-term stability studies offers more information about the types of water present and is essential to understanding the rate of how a drug changes.

Water content will also impact the compression of a tablet in complex ways. The pharmaceutical industry typically uses a wet milling technology to blend the API and the excipients and then a dryer to set the final water concentration prior to forming tablets. The manufacturing team may measure the total water content of the API and each excipient, but it may be useful to measure the aw at multiple points in the process:

  • Water activity for incoming or as-received for the API and each of multiple excipients
  • Post-granulation water activity
  • Post-drying water activity
  • Post-tableting water activity

Measurements of aw at these points would be simple and easy with the Lighthouse FMS technique using only a few grams of the formulation for each test. The manufacturing team could then compare the aw to the total water of each ingredient or for the formulation batch at each point in the process.

In the Field: Using The Lighthouse FMS Technique
One published formulation development study6 looked at the effect of headspace oxygen concentration and relative humidity (RH) on the oxidative degradation of a model pharmaceutical formulation and used a FMS-1400H to measure the actual versus expected aw. Along with a Mocon destructive oxygen analyzer, headspace testing was done to show the oxidative degradation rate as a function of both oxygen concentration and humidity.

Two model formulations, including a drug substance known to exhibit oxidative degradation, at two different drug/excipient ratios were stored in stoppered glass vials with headspace of low to high oxygen concentrations filled in a glove bag (from 0% to 20.9%). Headspace relative humidity was set by pre-equilibrating the solid-dose drug over saturated salts in a bell jar, and samples were stored at 40°C. The oxidative degradation was quantified as a function of time, for 32 weeks. The results clearly showed dependence of oxidative degradation on headspace oxygen concentration, relative humidity, drug loading, and time.

As a result of these studies, researchers found that reducing the headspace oxygen concentration improved stability, and at what range the most significant protective benefits could be seen (in their case, at very low oxygen concentrations [less than 0.25%]). They were also able to propose package options for each formulation, and concluded that using RH and oxygen control was expected to be beneficial, even in both cases when RH control was not a convenient option or needed to be avoided (e.g., for products encapsulated in gelatin, where low RHs can result in product embrittlement) and when RH control is an option. They were also able to conclude that using oxygen scavengers in bottles as well as inert atmospheric packaging (foil-foil, blister lines) could be options for the achieving pharmaceutical packages with low oxygen concentrations from this study.

In another example, the Lighthouse FMS-1400 was used to measure aw over time and create a stability profile for a tablet that was sealed in a container. The user was able to define a stable region for the tablet when the aw was below 0.7. This in turn helped locate a package material that would maintain the aw level under 0.7.

The Lighthouse FMS method is a rapid and nondestructive technology for water activity measurements. It allowed researchers to collect much more data with their product than with other methods. Repeated measurements could be made on the same material since the technique was nondestructive, allowing cost savings in the number of samples run and easier, quicker measurements with fewer sample logistics to manage. In an industrial quality environment, this non-destructive RH measurement method could be used to determine how much water a tablet can be exposed to and maintain stability over its intended shelf life.

For More Information/Works Cited:
1 L. Synder, Pearson of Eli Lilly. “Implementation of Water Activity Testing to Replace Karl Fisher Water Testing,” PharmTech, Feb-2007.
2 K. Waterman, B. McDonald. “Package Selection for Moisture Protection for Solid, Oral Drug Products,” Journal of Pharmaceteutical Sciences, Vol. 99, No. 11, November 2010.
3 R. Mahajan A. Templeton, R. Reed, R. Chern. “Frequency Modulation Spectroscopy, A Novel Nondestructive Approach for Measuring Moisture Activity,” PharmTech, October, 2005.
4 R. Mahajan, A. Templeton, A. Harman, R. Reed, R. Chern. “The Effect of Inert Atmospheric Packaging on Oxidation Degradation in Formulated Granules,” Pharmaceutical Research, Vol 22, Number 1, January 2005.
5 Ha°kan Wikstro¨m, W. Carroll, and L. Taylor, “Manipulating Theophylline Monohydrate Formation During High-Shear Wet Granulation Through Improved Understanding of the Role of Pharmaceutical Excipients,” Pharmaceutical Research, Vol 25, No 4, April 2008.
6 R. Mahajan, A. Templeton, R. Reed, R. Chern. “Frequency Modulation Spectroscopy, A Novel Nondestructive Approach for Measuring Moisture Activity,” Pharmaceutical Sales PharmTech, Vol. 29 Issue 10, p88 October 2005.

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