The pharmaceutical industry has been measuring moisture for decades. Why? Because most people think water is the enemy of API stability. Turns out they're only partly right.

1. Applications for Water Activity and
Sorption Isotherms in
Pharmaceuticals
Decagon Devices, Inc.

2. Moisture Content
Ratio of water mass to dry or total sample mass
Typically determined by weigh, dry, weigh method
Relative values can be accurate, but the absolute
value of water content is not knowable because
zero water content is arbitrarily (empirically)
determined

3. Water Activity
A measure of the energy status of the water in a sample
water vapor pressure of sample
aw = ——————————————————
saturation vapor pressure @ sample temp.
The work required to remove water from the sample is

4. Water Activity Definition
aw = p/po
Pharmaceutical
1. Equilibrium
2. Constant T & P
WaterMoleculeDemostration.wmv

5. Chilled Mirror Dew Point
Fan
Primary method of
measuring vapor
pressure (not calibrated)
Highest accuracy
±0.003aw
Rapid measurement <5
minutes
Measures entire aw
range (0.03 – 1.0aw)
High reliability
Optical Sensor
Mirror
Infrared Sensor
Sample

6. Water Activities of Common
Pharmaceutical Products
Product
Water
Activity
Product
Water
Activity
Compressed Tablet
0.39
MCC
0.30
Liquid Filled Capsule
0.38
High Fructose Corn
Syrup
0.74
Lip Balm
0.36
Anti-Bacterial
Cream
0.84
Powder Capsule
0.31
Oral liquid
0.90

7. Water Activity Applications
Microbial Growth
API Degradation and Dissolution
Gel Coating Integrity
7

8. International Conference on
Harmonization
Purpose of ICH is to harmonize guidelines and
establish risk-based quality programs based
on science
Need to understand the critical intrinsic and
extrinsic properties of the ingredients and
finished product
These guidelines provide the opportunity to
minimize microbial testing based on “dry”
conditions

9. International Conference on
Harmonisation (ICH)
ICH Decision Tree #6
Is the drug substance
or excipient capable of
supporting microbial
growth?
No
Provide Supporting data.
Microbial limits acceptance
criteria and testing may not
be necessary
ICH Decision Tree #8
Is the drug
product a
dry dosage
form?
Yes
Does Scientific
evidence demonstrate
growth inhibitory
properties of the drug
product?
Yes
Microbial limits
acceptance
criteria and testing
may not be
necessary

10. How do you determine if a product
is “dry”
No correlation between moisture content
and microbial growth (Scott 1957)
“Dry” in terms of microbial stability can only
be determined by water activity
USP <1112>

11. USP Method <1112>
(Official Aug 2006)
The determination of the water activity of non-sterile
pharmaceutical dosage forms aids in the decisions relating to
the following:
Optimizing product formulations to improve antimicrobial effectiveness of
preservative systems,
Reducing the degradation of active pharmaceutical ingredients within
product formulations susceptible to chemical hydrolysis
Reducing the susceptibility of formulations (especially liquids, ointments,
lotions, and creams) to microbial contamination
Providing a tool for the rationale for reducing the frequency of microbial
limit testing and screening for objectionable microorganisms for product
release and stability testing using methods contained in the general test
chapter Microbial Limit Tests <61>
Now a information chapter, but with time will hopefully become an
methods chapter.
USP-NF (2006) Vol 29(2):3802-3803.

12. Microbial Growth
Scott (1953 & 1957) showed that
microorganisms have a limiting water
activity level below which they will not
grow.
Water activity, not water content,
determines the lower limit of available
water for microbial growth.
Scott,W.J. 1953. Water relations of Staphylococcus aureus at 30ºC. Aust. J. Biol. Sci. 6:549-564.
Scott,W.J. 1957. Water relations of food spoilage microorganisms. Adv Food Res 7:83-127.

13. Water Activity vs. Microbial Growth
Every microorganism has a water activity level
below which it cannot grow.
There are no such correlations to moisture content
aw limit
0.91
0.86
0.88
0.80
0.70
0.62
0.61
0.60
Microorganisms
Gram Negative Bacteria
Gram Positive Bacteria
Yeast (practical limit)
Production of mycotoxins
Molds (practical limit)
Osmophilic yeast
Xerophilic molds
Absolute limit for all growth

14. Water Activity as a CPP for API
Degradation and Dissolution
Moisture Migration
Two distinct regions at different aw
Water moves from areas of high water
activity to areas of low
water activity.
Driving force for water
migration directly
related to aw difference.
Rate of migration depends on
structure/diffusion properties.
Can lead to Excipient/Drug interactions and
increased degradation of API
Causes coatings to crack or become sticky

15. Water Activity as a CPP for Gel Coating
Integrity
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16. Isotherm:
The functional relationship between water
activity and water content of a sample at a
specified temperature

17. AquaLab Vapor Sorption Analyzer
Water activity from
chilled mirror dew point
Precision balance weighs
sample for water content
Dry and wet air flow for
Static isotherm - equilibrate
samples at a set aw
Dynamic isotherm - add or
remove water for fast, high
resolution isotherm (DDI)
Dry Air
Wet Air
Fan
Optical Sensor
Mirror
Infrared Sensor
Sample
Precision Balance

18. AquaLab Vapor Sorption Analyzer
Automatically controls or adjusts
sample water activity from 0.03
to 0.95
Measures sample mass to 0.1
mg, and water activity to 0.001
Controls sample temperature
between 15 and 60 C.
Automatically obtains adsorption,
desorption and scanning
isotherms

19. Moisture Sorption Isotherm
Each product has its
own unique moisture
sorption isotherm – due
to different interactions
(colligative, capillary,
and surface effects)
between the water and
the solid components
at different moisture
contents.

20. Temperature
Temperature must
be specified and
held constant.
The effect of
temperature on the
moisture sorption
isotherm follows
the ClausiusClapeyron
equation.
Desorption isotherms of potato slices at various temperatures.
From Gorling, P. (1958) in Fundamental Aspects of the
Dehydrationof Foodstuffs. Society of Chemical Industry, London,
pp 42-53.

21. Static and Dynamic on 1 sample
*Microcrystalline Cellulose at 25C

22. Static and Dynamic Comparison
* Microcrystalline Cellulose at 25C

23. Commercializing Pharmaceuticals
NME’s
Formulation
Applications
Shelf Life
Excipient Selection
Packaging Performance
Coating/Capsule Use
Manufacturability
Product Performance
Sales
Measurements
Sorption Kinetics
Crystallization
Glass Transition
Combined Isotherms
Hygroscopicity
Temperature Abuse Data
Microbial Growth Potential

24. Isotherm Applications
Glass Transition
Deliquescence
Crystallization
Isotherms of Mixtures
Temperature Abuse
Packaging Calculations
24

25. Water Activity and Glass Transition for
Setting CCPs
Large number of
water binding sites
become available
Limited Water
Binding Sites
Caking, Clumping,
Crystallization, Loss
of Texture
RHc Critical Water Activity
Amorphous Metastable State
*Spray Dried Milk Powder

26. Determining Deliquescence Point
Deliquescence
Point
*Sucrose

27. Glass Transition and
Crystallization Measurement
Crystallization
Glass Transition Inflection Point
* Spray Dried Milk Powder at 25C

28. Modeling Temperature Abuse
Water activity is
temperature
dependent
Most products have
a lower water activity
value at lower
temperature.
Clausius-Clapeyron
relationship:

29. Example of Ingredient Mixing
DLP Combined Isotherm
i = mass fraction of component i
wi = moisture content of component i.
Where b3, b2, b1, and b0 are empirical constants from the
DLP isotherm model and χ is ln(-ln(aw))
Where b3’, b2‘, b1‘, and b0’ are the DLP constants for the
combined isotherm and χeq is ln(-ln(aw(eq)))
b3’ = ∑Φib3i , b2’ = ∑Φib2i , b1’ = ∑Φib1i , b0’ = ∑Φib0i

30. Package Performance Calculations
〈 = slope of the isotherm (g/g)
Water activity under specific conditions
awo = initial water activity
awc = critical water activity
pa = atmospheric pressure (kPa)
Time Constant
Shelf life prediction of packaging
M = total mass of product inside the package
(g)
es = saturation water vapor pressure at
package temperature (kPa)
A = package surface area (m2)
gv = package conductance (g m-2 s-1)
ha= Humidity of air,
Determine Package Conductance
t = Time in package,
 = Time constant

31. Conclusions
Understanding water activity and isotherms
can help in the process of formulating
pharmaceuticals
Water activity is the best way to monitor
moisture in pharmaceuticals
The AquaLab Vapor Sorption Analyzer
provides an easy and fast method for
determining either static or dynamic isotherms
Isotherms have applications in predicting
chemical and physical stability, product mixing,
packaging

32. Thank you

33. Who Uses Isotherms and for What?
Companies
Kraft
General Mills
Glaxo-Smith Kline
Quaker
Meade Johnson
Nestle Pet Care
Uses
Ingredient mixing, powder flow,
product formulation, DUO
Ingredient mixing, product
formulation, deliquescence
Excipient stability, glass transition,
moisture migration, API stability
Ingredient mixing, product
formulation, deliquescence
Powder flow, caking, chemical
stability, glass transition, DUO
Powder flow, caking, chemical
stability, glass transition,

34. Dynamic Isotherm Only
No Crystallization or Kinetics
Glass Transition Inflection Point
* Spray Dried Milk Powder at 25C

35. Static Isotherm Only
Kinetics of Sorption and Diffusion
Crystallization
* Spray Dried Milk Powder at 25C

36. Package Calculations
Water Activity and Shelf Life Prediction
Time constant
Shelf life prediction of packaging
ha= 0.60
awo = 0.10
awc = 0.43
〈 = 0.026 g/g
pa = 100kPa
M = 10 g,
es = 3kPa
A = 0.054 m2
gv = 6.93x10-5 g m-2 s-1

37. Package Calculations
Package Conductance Prediction from
Measurements
Time constant
Determine package conductance
ha= 0.90
awo = 0.10
awf = 0.32
awc = 0.43
t = 20 days
〈 = 0.026 g/g
pa = 100kPa
M = 10 g,
es = 3kPa (25°C)
A = 0.054 m2

38. Package Calculations
Package Conductance Prediction from WVTR
(water vapor transmission rate) (ASTM-E96)
Conversion for 100 F, 90% RH
ha= 0.90
es = 6.55 kPa (100°F)
package conductance for WVTR of 0.35 g m-2 day-1
Note: WVTR values are evaporation values, but can be converted to
conductance values using the temperature and humidity testing conditions

39. Package Calculations
Required Package Conductance for 1 year Shelf Life
Time constant
Determine required package conductance
Common Resealable Plastic Package= 6.0 g m-2 days-1
ha= 0.60
awo = 0.10
awc = 0.43
t = 365 days
〈 = 0.026 g/g
pa = 100kPa
M = 10 g,
es = 3kPa
A = 0.054 m2

40. Overview
Definitions
Instruments
Applications
40

41. How can we use isotherms?
Chemical stability
monolayer moisture
content
Shelf life estimation
Product formulation
Dry ingredient mixing
Temperature effects
on aw
Moisture content or aw
prediction
Physical Changes
Glass transition
Crystallization
Deliquescence
Stickiness
Packaging design