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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.
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Applications for Water Activity and Sorption Isotherms in
Pharmaceuticals
Decagon Devices, Inc.
Pharmaceuticals
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
Water Activity
aw = ——————————————————water vapor pressure of sample
saturation vapor pressure @ sample temp.
� A measure of the energy status of the water in a sample
saturation vapor pressure @ sample temp.
� The work required to remove water from the sample is
Water Activity Definitionaw = p/po
1. Equilibrium2. Constant T & P
WaterMoleculeDemostration.wmv
Pharmaceutical
Chilled Mirror Dew Point
� Primary method of measuring vapor pressure (not calibrated)
� Highest accuracy ±0.003a
Infrared SensorMirror
Optical SensorFan
±0.003aw
� Rapid measurement <5 minutes
� Measures entire awrange (0.03 – 1.0aw)
� High reliability
Sample
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
Water Activity Applications
� Microbial Growth
� API Degradation and Dissolution
� Gel Coating Integrity
7
� Gel Coating Integrity
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 �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
International Conference on Harmonisation (ICH)
Is the drug substance or excipient capable of supporting microbial
Provide Supporting data. Microbial limits acceptance criteria and testing may not
No
ICH Decision Tree #6
supporting microbial growth?
criteria and testing may not be necessary
Is the drug product a dry dosage form?
Yes
Does Scientific evidence demonstrate growth inhibitory properties of the drug product?
YesMicrobial limits acceptance criteria and testing may not be necessary
ICH Decision Tree #8
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 � “Dry” in terms of microbial stability can only be determined by water activity
�USP <1112>
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 hydrolysisproduct 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.
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.
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 Microorganisms0.91 Gram Negative Bacteria0.91 Gram Negative Bacteria0.86 Gram Positive Bacteria0.88 Yeast (practical limit)0.80 Production of mycotoxins0.70 Molds (practical limit)0.62 Osmophilic yeast0.61 Xerophilic molds0.60 Absolute limit for all growth
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 lowwater activity. water activity.
� Driving force for watermigration 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
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 content
Optical SensorFan
Dry Air Wet Air
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)
Infrared SensorMirror
Sample
Precision Balance
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 0.001mg, and water activity to 0.001
� Controls sample temperature between 15 and 60 C.
� Automatically obtains adsorption, desorption and scanning isotherms
Moisture Sorption Isotherm
Each product has its own unique moisture sorption isotherm – due to different interactions to different interactions (colligative, capillary, and surface effects) between the water and the solid components at different moisture contents.
�Temperature must be specified and held constant.
�The effect of
Temperature
�The effect of temperature on the moisture sorption isotherm follows the Clausius-Clapeyron 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.
Static and Dynamic on 1 sample
*Microcrystalline Cellulose at 25C
Static and Dynamic Comparison
* Microcrystalline Cellulose at 25C
Commercializing Pharmaceuticals
NME’s Formulation Sales
MeasurementsApplications
Shelf LifeExcipient SelectionPackaging PerformanceCoating/Capsule UseManufacturabilityProduct Performance
Sorption KineticsCrystallization
Glass TransitionCombined Isotherms
HygroscopicityTemperature Abuse Data
Microbial Growth Potential
MeasurementsApplications
Isotherm Applications
� Glass Transition� Deliquescence � Crystallization
24
� Crystallization� Isotherms of Mixtures� Temperature Abuse� Packaging Calculations
24
Water Activity and Glass Transition for Setting CCPs
Caking, Clumping,
Large number of water binding sites become available
*Spray Dried Milk Powder
RHc Critical Water Activity
Amorphous Metastable State
Caking, Clumping, Crystallization, Loss
of TextureLimited Water Binding Sites
Determining Deliquescence Point
*Sucrose
Deliquescence Point
Glass Transition and Crystallization Measurement
Crystallization
* Spray Dried Milk Powder at 25C
Glass Transition Inflection Point
Crystallization
Modeling Temperature Abuse
� Water activity is temperature dependent
� Most products have � Most products have a lower water activity value at lower temperature.
� Clausius-Clapeyron relationship:
Example of Ingredient MixingDLP 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
Package Performance Calculations⟨ = slope of the isotherm (g/g)
awo = initial water activity
awc = critical water activity
pa = atmospheric pressure (kPa)
M = total mass of product inside the package (g)
e = saturation water vapor pressure at
Water activity under specific conditions
Time Constant
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,
t = Time in package,
= Time constant
Shelf life prediction of packaging
Determine Package Conductance
Conclusions
� Understanding water activity and isotherms can help in the process of formulating pharmaceuticals
� Water activity is the best way to monitor � 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
Thank you
Who Uses Isotherms and for What?
Companies Uses
KraftIngredient mixing, powder flow,
product formulation, DUO
General MillsIngredient mixing, product formulation, deliquescenceformulation, deliquescence
Glaxo-Smith KlineExcipient stability, glass transition,
moisture migration, API stability
QuakerIngredient mixing, product formulation, deliquescence
Meade JohnsonPowder flow, caking, chemical stability, glass transition, DUO
Nestle Pet CarePowder flow, caking, chemical
stability, glass transition,
Dynamic Isotherm Only
No Crystallization or Kinetics
Glass Transition Inflection Point
* Spray Dried Milk Powder at 25C
Static Isotherm Only
Crystallization
Kinetics of Sorption and Diffusion
* Spray Dried Milk Powder at 25C
Package Calculations ha= 0.60 awo = 0.10 awc = 0.43 ⟨ = 0.026 g/gpa = 100kPa M = 10 g, es = 3kPa A = 0.054 m2
gv = 6.93x10-5 g m-2 s-1
Time constant
Water Activity and Shelf Life Prediction
Shelf life prediction of packaging
Package Calculationsha= 0.90 awo = 0.10awf = 0.32awc = 0.43t = 20 days ⟨ = 0.026 g/gpa = 100kPa M = 10 g,
Time constant
Package Conductance Prediction from Measurements
es = 3kPa (25°C)A = 0.054 m2
Determine package conductance
Package Calculations
ha= 0.90 es = 6.55 kPa (100°F)
Package Conductance Prediction from WVTR (water vapor transmission rate) (ASTM-E96)
Conversion for 100 F, 90% RH
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
Package Calculationsha= 0.60 awo = 0.10 awc = 0.43t = 365 days ⟨ = 0.026 g/gpa = 100kPa M = 10 g, es = 3kPa
Time constant
Required Package Conductance for 1 year Shelf Life
sA = 0.054 m2
Determine required package conductance
Common Resealable Plastic Package= 6.0 g m-2 days-1
Overview
� Definitions� Instruments� Applications
40
� Applications
40
How can we use isotherms?
� Chemical stability� monolayer moisture
content
� Shelf life estimation
� Moisture content or awprediction
� Physical Changes� Glass transition� Shelf life estimation
� Product formulation
� Dry ingredient mixing
� Temperature effects on aw
� Glass transition� Crystallization
� Deliquescence
� Stickiness
� Packaging design
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