Water activity and pharmaceuticals

Water activity and pharmaceuticals

The pharmaceutical industry has been measuring moisture for decades because most formulators think water is the enemy of API stability.  Research shows they’re only partly right.

Water activity and shelf life in pharmaceuticals

Moisture is how much water is in a product.  Water activity (aw) measures the water’s energy level.  The energy level is much better correlated to reactions that affect pharmaceuticals.  Consider these three issues:

  1. API hydrolysis
  2. Crystallization that affects dissolution rates
  3. Caking/clumping of powders

All of these are time-dependent reactions with rates influenced by water activity.  For example, USP 1112 specifically states that water activity can be used to reduce degradation of API formulations susceptible to hydrolysis.

Knowing the water activity of pharmaceuticals (proteins, drugs, creams, powders, and excipients) is essential to obtain a dosage form with optimal chemical, physical, microbial, and shelf-life properties. Water activity influences the chemical stability, microbial stability, flow properties, compaction, hardness, and dissolution rate of dosage forms of pharmaceuticals, proteins, biopharmaceuticals, nutraceuticals, and phytochemicals.

Correlation with microbial growth

The purpose of the International Conference on Harmonization (ICH) is to provide guidance in establishing quality testing and batch release programs (Hussong 2009). It emphasizes that quality testing programs should be risk-based and supported by science. Testing procedures and acceptance criteria for drug release programs are outlined in ICH Q6A. Instructions on best methods for determining microbiological attributes are found in Decision Trees #6 and #8. In both decision trees, the need for microbial limits testing is based on whether the product is inherently “dry” enough to not support microbial growth.

Often, the assumption in the pharmaceutical industry is that this dryness can be established using moisture content, or amount of water in a product, usually through a Karl Fischer analysis. However, since the work of Scott in the 1950’s, it has been well established that it is water activity, or the energy of water, that actually determines whether or not microorganisms can access the water in a system (Scott 1957). Therefore, the “dryness” referenced in the decision trees of ICH Q6A should be measured using water activity.

Microorganisms have a limiting water activity below which they cannot grow. Knowledge of the behavior of microorganisms at different water activity levels is important in meeting Federal Food, Drug and Cosmetic Laws.  This chart lists the growth-limits of common microorganisms in pharmaceutical products. Designing a product with a water activity below these growth-limits will keep a product microbially safe.

Range of awMicroorganisms Generally
Inhibited by Lowest aw
in This Range
Consumer and
Pharmaceutical Products
Generally Within this Range
1.00–0.95Pseudomonas, Escherichia,
Proteus, Shigells, Klebsiella,
Bacillus, Clostridium
perfringens, some yeasts
Antacid suspension, hair gel,
anti-inflammatory ointment,
clorhexidine gel, cough syrup,
topical cream, oral liquid
suspension, shampoo
0.95–0.91Salmonella, C. botulinum,
Serratia, Lactobacillus,
Pediococcus, some molds,
yeasts (Rhodotorula, Pichia),
Vibrio parahaemolyticus
Gel anti-inflammatory
(topical use), laxative,
neurotonic syrup,
potassium gluconate (elixir)
0.91–0.87Many yeasts (Candida,
Torulopsis, Hansenula),
Micrococcus
Anti-inflammatory suspension,
cough suppressant, mucolitic
elixir, nasal spray, oral liquid
0.87–0.80Most molds (mycotoxigenic
penicillia), Staphyloccocus
aureus, most Saccharomyces
(bailii) spp., Debaryomyces
Anti-inflammatory cream,
bactericidal cream, canker sore
gel (oral), citrobioflavonoide
and vitamin C syrup, epileptic
syrup, lactulose syrup (laxative)
0.80–0.75Most halophilic bacteria,
mycotoxigenic aspergilli
High fructose corn syrup,
soap (regular)
0.75–0.65Xerophilic molds (Aspergillus
chevalieri, A. candidus,
Wallemia sebi), Saccharomyces
bisporus
Topical ointment,
soap (with glycerin)
0.65–0.60Osmophilic yeasts
(Saccharomyces rouxii), few
molds (Aspergillus echinulatus,
Monascus bisporus)
Honey
0.60–0.50No microbial proliferationAnalgesic (gelatin capsules)
liquid, analgesic (gelatin
capsules) gelatin, anti-micotic
powder
0.50–0.40No microbial proliferationAnalgesic, anti-allergic,
antibiotic pills (cefacillin), antimigraine
pills, aspirin, cough
drop (liquid center), dry powder
inhaler, pancreatin tablets
0.40–0.30No microbial proliferationCompressed tablet, lip balm,
liquid-filled capsule, powderfilled
capsule, soft-gel liquidfilled
capsule, multivitamin
tablets, vitamin C tablets
0.30–0.20No microbial proliferationHard shell capsule, rectal
suppositories, rectal ointment
<0.10No microbial proliferationPropellant-based metered
dose inhaler
Table 1. Water activity and growth of microorganisms for consumer and pharmaceutical products (adapted from Water Activity Applications in the Pharmaceutical Industry).

Water activity for product stability

Protein, enzyme and biopharmaceutical stability are influenced significantly by water activity. Great care must be taken to prevent aggregation under pharmaceutically relevant conditions. Most proteins, enzymes, and biopharmaceuticals must maintain integrity to remain active. In order to maintain the correct dosage and prevent dissolution, aggregation and conformational changes, it is important to maintain critical water activity levels

FIND CRITICAL WATER ACTIVITY LIMITS

How to use isotherms to discover where your product is most stable and find the points beyond which it cakes, clumps, or develops other negative attributes

Establish component compatibility

The importance of water activity as opposed to total water is shown by preformulation compatibility studies involving moisture-sensitive drugs. Hygroscopic excipients (starch, cellulose, and magaldrate) have successfully been formulated for use with moisture sensitive drugs. The excipients may preferentially bind moisture and make the dosage form less susceptible to changes in relative humidity during manufacture, shipment, storage, or patient use, thus extending shelf-life. This is also applicable to other polymer systems of pharmaceutical interest, such as proteins (gelatin, keratin) and various synthetic hydrogels.

Prevent moisture migration

Moisture migration is another quality issue that can be explained and resolved using water activity. Gelcaps provide a classic example of the challenges posed by moisture migration.  Sometimes the capsules crack while sitting in packaging, rendering the product unsuitable. This happens because the water activity of the powder and capsule are different, so moisture leaves the gelcap and enters the powder.  Water activity, not moisture content, is the driving force for migration.

Improve strength properties in solid dosage forms

Water activity of powders affects the flow, caking, compaction and strength properties of solid dosage forms. Water activity is used in the study of shelf-life, aging, and packaging requirements of pharmaceuticals. It is also used in designing and developing coating technology. Understanding the response of solid dosage forms to changing environments helps set formulation and packaging requirements.

Water activity: a better way to measure moisture

Water activity is an alternative water measurement that provides essential information about the energy or availability of water in a product. Numerous scientific investigations demonstrate that water activity is a better predictor of product safety and stability than total amount of water. And with the publication of USP Method <1112>, water activity is now considered a viable option in the pharmaceutical industry.

Measuring water activity is fast and easy

The Series 4TE provides rapid water activity measurement of powders, granulations, creams, fluids, or tablets for pharmaceuticals, biopharmaceuticals, nutraceuticals, and phytochemicals.

Related references

Enigl, Davin C., and Kent M. Sorrells. “Water activity and self-preserving formulas.” Cosmetic Science And Technology Series (1997): 45-74. Article link.

Friedel, R. R. “The application of water activity measurement to microbiological attributes testing of raw materials used in the manufacture of nonsterile pharmaceutical products.” In Pharmacopeial forum, vol. 25, no. 5, pp. 8974-8981. United States Pharmacopeial Convention, 1999. Article link.

Heidemann, D. R., and P. J. Jarosz. “Preformulation Studies Involving Uptake in Solid Dosage Forms.” Pharmaceutical Research 8, no. 3. (1991): 292-97. Article link.

Pader, Morton. Oral hygiene products and practice. Dekker, 1988. Book link.

Pader, M. “Glycerine in oral care products.” Cosmetic science and technology series 11 (1991): 381-393. Article link.

MEASURE WATER ACTIVITY IN 5 MINUTES

Not a “quick mode” reading, but a direct measure of water activity to 0.003. No calibration, no approximation