Applications for Water Activity and
Sorption Isotherms in
Pharmaceuticals
Decagon Devices, Inc.
Moisture Content
Ratio of water mass to dry or total sample mass
Typically determined by weigh, dry, weigh method
Relative...
Water Activity
A measure of the energy status of the water in a sample
water vapor pressure of sample

aw = ——————————————...
Water Activity Definition
aw = p/po

Pharmaceutical
1. Equilibrium
2. Constant T & P
WaterMoleculeDemostration.wmv
Chilled Mirror Dew Point
Fan

Primary method of
measuring vapor
pressure (not calibrated)
Highest accuracy
±0.003aw
Rapid ...
Water Activities of Common
Pharmaceutical Products
Product

Water
Activity

Product

Water
Activity

Compressed Tablet

0....
Water Activity Applications
Microbial Growth
API Degradation and Dissolution
Gel Coating Integrity

7
International Conference on
Harmonization
Purpose of ICH is to harmonize guidelines and
establish risk-based quality progr...
International Conference on
Harmonisation (ICH)
ICH Decision Tree #6
Is the drug substance
or excipient capable of
support...
How do you determine if a product
is “dry”
No correlation between moisture content
and microbial growth (Scott 1957)
“Dry”...
USP Method <1112>

(Official Aug 2006)

The determination of the water activity of non-sterile
pharmaceutical dosage forms...
Microbial Growth
Scott (1953 & 1957) showed that
microorganisms have a limiting water
activity level below which they will...
Water Activity vs. Microbial Growth
Every microorganism has a water activity level
below which it cannot grow.
There are n...
Water Activity as a CPP for API
Degradation and Dissolution
Moisture Migration
Two distinct regions at different aw
Water ...
Water Activity as a CPP for Gel Coating
Integrity

Show Videos Here
Isotherm:
The functional relationship between water
activity and water content of a sample at a
specified temperature
AquaLab Vapor Sorption Analyzer
Water activity from
chilled mirror dew point
Precision balance weighs
sample for water con...
AquaLab Vapor Sorption Analyzer
Automatically controls or adjusts
sample water activity from 0.03
to 0.95
Measures sample ...
Moisture Sorption Isotherm
Each product has its
own unique moisture
sorption isotherm – due
to different interactions
(col...
Temperature
Temperature must
be specified and
held constant.
The effect of
temperature on the
moisture sorption
isotherm f...
Static and Dynamic on 1 sample

*Microcrystalline Cellulose at 25C
Static and Dynamic Comparison

* Microcrystalline Cellulose at 25C
Commercializing Pharmaceuticals
NME’s

Formulation

Applications
Shelf Life
Excipient Selection
Packaging Performance
Coat...
Isotherm Applications
Glass Transition
Deliquescence
Crystallization
Isotherms of Mixtures
Temperature Abuse
Packaging Cal...
Water Activity and Glass Transition for
Setting CCPs
Large number of
water binding sites
become available

Limited Water
B...
Determining Deliquescence Point

Deliquescence
Point

*Sucrose
Glass Transition and
Crystallization Measurement

Crystallization

Glass Transition Inflection Point

* Spray Dried Milk P...
Modeling Temperature Abuse
Water activity is
temperature
dependent
Most products have
a lower water activity
value at lowe...
Example of Ingredient Mixing
DLP Combined Isotherm
i = mass fraction of component i
wi = moisture content of component i....
Package Performance Calculations
〈 = slope of the isotherm (g/g)

Water activity under specific conditions

awo = initial ...
Conclusions
Understanding water activity and isotherms
can help in the process of formulating
pharmaceuticals
Water activi...
Thank you
Who Uses Isotherms and for What?
Companies
Kraft
General Mills
Glaxo-Smith Kline
Quaker
Meade Johnson
Nestle Pet Care

Use...
Dynamic Isotherm Only

No Crystallization or Kinetics

Glass Transition Inflection Point

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

* Spray Dried Milk Powder at 25C
Package Calculations
Water Activity and Shelf Life Prediction
Time constant

Shelf life prediction of packaging

ha= 0.60
...
Package Calculations
Package Conductance Prediction from
Measurements
Time constant

Determine package conductance

ha= 0....
Package Calculations
Package Conductance Prediction from WVTR
(water vapor transmission rate) (ASTM-E96)
Conversion for 10...
Package Calculations
Required Package Conductance for 1 year Shelf Life
Time constant

Determine required package conducta...
Overview
Definitions
Instruments
Applications

40
How can we use isotherms?
Chemical stability
monolayer moisture
content

Shelf life estimation
Product formulation
Dry ing...
Upcoming SlideShare
Loading in …5
×

Applications for Water Activity and Sorption Isotherms in Pharmaceuticals

2,303 views
2,024 views

Published on

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.

Published in: Education, Technology, Business
0 Comments
3 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,303
On SlideShare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
87
Comments
0
Likes
3
Embeds 0
No embeds

No notes for slide

Applications for Water Activity and Sorption Isotherms in Pharmaceuticals

  1. 1. Applications for Water Activity and Sorption Isotherms in Pharmaceuticals Decagon Devices, Inc.
  2. 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. 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. 4. Water Activity Definition aw = p/po Pharmaceutical 1. Equilibrium 2. Constant T & P WaterMoleculeDemostration.wmv
  5. 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. 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. 7. Water Activity Applications Microbial Growth API Degradation and Dissolution Gel Coating Integrity 7
  8. 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. 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. 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. 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. 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. 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. 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. 15. Water Activity as a CPP for Gel Coating Integrity Show Videos Here
  16. 16. Isotherm: The functional relationship between water activity and water content of a sample at a specified temperature
  17. 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. 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. 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. 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. 21. Static and Dynamic on 1 sample *Microcrystalline Cellulose at 25C
  22. 22. Static and Dynamic Comparison * Microcrystalline Cellulose at 25C
  23. 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. 24. Isotherm Applications Glass Transition Deliquescence Crystallization Isotherms of Mixtures Temperature Abuse Packaging Calculations 24
  25. 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. 26. Determining Deliquescence Point Deliquescence Point *Sucrose
  27. 27. Glass Transition and Crystallization Measurement Crystallization Glass Transition Inflection Point * Spray Dried Milk Powder at 25C
  28. 28. Modeling Temperature Abuse Water activity is temperature dependent Most products have a lower water activity value at lower temperature. Clausius-Clapeyron relationship:
  29. 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. 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. 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. 32. Thank you
  33. 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. 34. Dynamic Isotherm Only No Crystallization or Kinetics Glass Transition Inflection Point * Spray Dried Milk Powder at 25C
  35. 35. Static Isotherm Only Kinetics of Sorption and Diffusion Crystallization * Spray Dried Milk Powder at 25C
  36. 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. 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. 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. 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. 40. Overview Definitions Instruments Applications 40
  41. 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

×