Moisture Analysis in the Pharmaceutical Industry

Moisture is a critical parameter in the manufacture of bulk solid pharmaceuticals. The manufacturing process of expensive drugs is often complicated, and during a process that has critical stages which occur over several days, fast and accurate determination of moisture content is essential.

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Generally, moisture analysis needs to be performed in product and process development, as well as during manufacturing to specify and control the maximum allowable moisture content at each step. Knowing the moisture content at each step is part of the very careful process control required during manufacture.

Excessive or deficient moisture content can adversely impact the physical properties of a pharmaceutical product, which in turn affect the chemical reactivity and binding properties that define the product’s shelf-life. In addition, pharmaceutical products may contain compounds that are harmful by skin contact or inhalation and the moisture content is key to the crystallization, agglomeration and the chemical form of these compounds during tablet manufacture. Moisture analysis is thus a routine quality check in the pharmaceutical industry.

Several drying methods have been employed for moisture analyses, including mathematical determination based on infrared detection and chemical titration. The Karl Fischer technique involves adding a reagent to the sample that reacts with the water present to produce a non-conductive chemical. However, this only provides a reliable measure of moisture content if most of the moisture is due to water. A sample containing little water, but high levels of other volatiles, will provide a low moisture reading in a Karl Fischer titration, when in fact it still contains a significant amount of moisture.

For this reason, thermogravimetric moisture balances are typically used for determining the moisture content of pharmaceuticals. Thermogravimetric analysis is a complete, accurate and responsive method of moisture determination based on the loss-on-drying principle. It determines moisture content in terms of the extent of weight loss that occurs as the sample is heated. Heating causes weight loss as the volatile components vaporize. The difference in weight from the pre-heating value is continually calculated and recorded by a precision balance.

Why is Moisture Analysis Important?

There is a huge list of properties of pharmaceutical products that are influenced by moisture content, and directly affect how tablets are made. These include chemical stability, crystal structure, compaction, powder flow, lubricity, dissolution rate, and polymer film permeability.

The presence of moisture affects the consistency and stability of tablets. Too much moisture will cause an agglomeration of powder particles and a poor crumbly tablet; too little moisture will cause the tablet to fall apart. Powdered excipients may fail to flow if they are too wet, and some active pharmaceutical ingredients (APIs) might crystallize or change form if there is too much moisture. Solid dosage forms are produced using a huge number of processes including freeze drying, fluid bed drying, compaction, granulation, and extrusion. All of these operations depend on the amount and the state of water present. Moisture can also influence the chemical/physical properties of individual active ingredients and excipients.

That is why it is essential to analyze moisture content during manufacture and understand how moisture content affects each individual step during process development in order to establish specifications and parameter limits.

Hydrophobic drugs are very often formulated with the addition of hydrophilic polymers to produce miscible blends that are called amorphous solid dispersions. The way moisture interacts in these blends is an important consideration, from the perspective of stability and processing. Moisture issues include:

• Flow of API and excipients not as expected because of moisture content
• Variations in weighing batches of raw materials or finished tablets
• Clogging or caking in process equipment
• Moisture-permeable containers for packaging, and stability of the contents
• The undesirable effect of moisture on chemical stability (e.g. antibiotic hydrolysis) and physical stability (e.g. change of dissolution rate)
• Hydrolytic degradation of drugs with functional groups such as esters, amides, lactones, or lactams, including many polymers
• The angle of repose in a powder or granulate not being as expected. Water can bridge gaps between particles, which changes electrostatic attraction, and ultimately affects powder flow characteristics.

For manufacturers, it is essential to consider the impact of moisture in bulk materials as well as the finished product. Moisture content fluctuates from batch-to-batch, and to achieve consistency in formulation there must be a reliable method to determine moisture content accurately. To be effective, moisture determination methods must be fast, repeatable, and precise.

Infrared Loss-on-Drying Moisture Analysis

The thermogravimetric method of moisture analysis is generally accepted as the most reliable. Although various means of heating the sample have been used to try and improve accuracy, infrared radiation remains one of the most popular drying techniques.

On exposure of the sample to infrared radiation, the surface of the sample is heated first. The energy is then conducted from the surface through the entire volume of the sample. This time for the heat to conduct throughout the entire sample has been the limiting factor of traditional infrared loss-on-drying moisture analyzers. If the sample has high dielectric properties, the drying time will increase. This effect is compounded by the partial reflection of the infrared energy, preventing efficient heat transfer.

Since effective moisture determination is dependent on the speed at which measurements are obtained, this absorption delay makes it unfeasible to determine the moisture content of high-moisture samples using traditional infrared loss-on-drying analyzers in a production environment.

In addition, it is not possible to ensure that the heat has effectively permeated through the entire sample since the temperature measurement is made in the cavity rather than in the sample itself. This carries the risk that moisture remains in the middle of the sample, giving an underestimation of the moisture content. Conversely, the surface of the sample continues to be heated for the entire time needed for the heat to be absorbed throughout the sample, which could result in scorching of these areas.

Furthermore, the analyzers cannot be used directly on the production line, due to the requirement for a fume hood to remove the water vapor and other volatiles. This necessitates a delay while samples are transported to the analyzer, so any production parameters which require real-time feedback will not be optimally controlled, potentially impacting product quality and variability.

Heating using halogen elements has been adopted in preference to traditional infrared loss-on-drying moisture analyzers since the optimal heating temperature can be achieved more quickly. Halogen drying, however, still carries the risk of uneven heat exposure which can undermine the results obtained.

The development of novel technologies to overcome the shortcomings of traditional loss-on-drying moisture analyzers has given rise to second-generation infrared moisture analyzers, such as the SMART Q™, that provide fast and reliable moisture determination on the production line.

The SMART Q

The SMART Q^™ is the most rugged and technologically advanced moisture analyzer available. It is up to 3 times faster than comparable infrared and halogen drying systems.

The rapid moisture balancing achieved with the SMART Q^™ has been made possible by the incorporation of unique technology. An advanced infrared sensor ensures that the temperature of the entire sample is measured, rather than just the cavity temperature. This direct sample measurement allows for better control and improved accuracy and precision.

Temperature control is further enhanced by the inclusion of a patented honeycomb lattice that provides collimated infrared irradiation for rapid and even sample heating, thereby avoiding stray light. The pre-programmed heating protocols make it possible to achieve selective moisture reduction that can be observed in real-time if required.

In addition, its innovative design means that no cooldown period is required between tests, providing further time savings. With the SMART Q^™, reliable, repeatable results can be obtained in only 5 minutes.

The SMART Q^™ is ideal for testing a range of dry products with up to 15% moisture content, including powders, tablets, gel coatings, and excipients, with 0.001% moisture resolution. Such capabilities are well suited for direct moisture analysis in the pharmaceutical industry.

The rapid and accurate measurement of moisture content provided by the SMART Q^™ makes it a valuable tool for pharmaceutical quality control procedures. Furthermore, the novel active ventilation system of the SMART Q^™ allows fumes to be safely routed away so it does not need to be positioned in a fume hood. Consequently, the SMART Q can easily be incorporated into at-line manufacturing quality control systems.

In a recent study on pharmaceutical materials including paracetamol, gelatin, and vitamin C, the average dry time for the SMART Q was approximately 5 minutes without a cavity pre-heat. The SMART Q was able to analyze moisture content with an average difference of 0.003% compared to reference oven results obtained over 8 hours at 100 °C with desiccation. This demonstrates the speed, precision, and reliability of the SMART Q in these applications.

For even more rapid results than this, the SMART Q also has the ability to be upgraded to a faster test time system called the SMART 6 by incorporating microwave heating technology in addition to infrared. The key benefits of the SMART Q include:

• Fastest analysis on the market with no cool-down between tests for rapid turnaround
• At-line testing proximity
• Ease of use with no interference from the nature of the sample
• A four-figure balance for precision
• A direct loss on drying method with no requirement for calibration
• Temperature preprograming

Conclusion

The SMART Q represents the state-of-the-art for loss on drying methodology in the pharmaceutical and food industries and is fully able to provide equivalence with USP 731. With the ability to test a wide range of pharmaceutical materials with up to 15% moisture content – using an analytical-grade 4 figure balance for 0.001% moisture precision – the SMART Q provides real benefits for pharmaceutical testing.

Advanced design feature includes a sealed cavity design so that fumes can be safely channeled into an exhaust vent with no need for a fume hood; direct sample temperature measurements using an infrared sensor; rapid testing because no-cool-down is required between measurements; preprogrammed heating methods and no cavity pre-heat requirement. In summary, the SMART Q is the ideal system for moisture testing of dry pharmaceutical materials at-line in a production environment.

References

1. J. C. Callahan, G. W. Cleary, M. Elefant, G. Kaplan, T. Kensler & R. A. Nash (1982) Equilibrium Moisture Content of Pharmaceutical Excipients, Drug Development and Industrial Pharmacy, 8:3, 355-369
2. Alfred C. F. Rumondor, et al., Analysis of the moisture sorption behavior of amorphous drug-polymer blends, Volume117, Issue2, 15 July 2010, Pages 1055-1063
3. Cook, I., Ward, K. and Duncan, D. (2008) ‘Freeze dried cakes – Where is the water?’, Conference on Freeze Drying of Pharmaceuticals and Biologicals Breckenridge, Colorado.
4. Ileleji KE, Garcia AA, Kingsly AR, Clementson CL, Comparison of standard moisture loss-on-drying methods for the determination of moisture content of corn distillers dried grains with solubles. J AOAC Int. 2010 May-Jun;93(3):825-32
5. CEM application note: AP0165. Rapid & Precise Moisture Analysis for Healthcare Products