Applications for Water Activity and Sorption Isotherms in Pharmaceuticals

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

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� Crystallization� Isotherms of Mixtures� Temperature Abuse� Packaging Calculations

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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

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� 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