Interpretación de valores de aw e p wisotermas de sorción de humedad

en medicamentosen medicamentos

FRANCESC FERRER Dr Eng. Agrònom.

SDM-UB, Barcelona, 11 Desembre 2012.

Humedad

CONTENIDO: (g agua / g ms)

MÉTODOS DE DETERMINACIÓNK l Fi hKarl FischerPérdida de masa por desecación

Farmacopea, Desarrollo, Control de Calidad

CONTENIDO TOTAL DE AGUANo relacionado directamente con el efecto del agua sobreprocesos físicos químicos y microbiológicosprocesos físicos, químicos y microbiológicos

Formas del agua en un producto sólido

LIBRE (Solvent & Free water)• Presente en los poros y espacios vacios• Actúa como agente dipersante , solvente en componentesg p , pcristalinos, desarrollo microbiano• Móvil

ADOSRBIDA (adsorbed water)• En la superficie del material (surface interaction)• Forma multicapas en la matríz (capilar)Forma multicapas en la matríz (capilar)• Móvil

LIGADA (bound water)LIGADA (bound water) • Monocapa de moléculas de agua• Ligada químicamente por puentes de H (cristalización, estructural )estructural,…)•No móvil Modelo BET

Actividad de agua (aw)Medida del estado energético del agua en una muestra

Trabajo necesario para disponer del agua para procesosfísicos, químicos y microbiológicos

Humedad Relativa de Equilibrio (HRE)

a = p/paw = p/po

W t A ti it D fi itiWater Activity Definitiona p/paw = p/po

1. Equilibrium2 C t t T & P

Pharmaceutical

2. Constant T & PWaterMoleculeDemostration.wmv

Isoterma de sorción de humedadIsoterma de sorción de humedad

Ligada -monocapa

Adsorbida -Multicapap

Libre y solvente

Valores típicos de a enValores típicos de aw en medicamentos

Producto aw Product o aw

Extracto vegetal seco Líquido oral 0.90

Granulado 0.31

Comprimido

Crema 0.815

humedad vs. aw

aw fácilmente medibles: 0,001aw

h d d fá il t dibl 0 1 (0 01%)humedad fácilmente medibles: 0,1mg (0,01%)

M did dMedida de aw

Punto de rocio (chilled mirror dew point). Infrared SensorMirror

Optical SensorFan

mirror dew point). Medida directa de p y po Exactitud: ±0.003aw Rapidez: <5 minutos Intervalo: (0.03 – 1.0aw) Alta repetibilidad y

Sample

Alta repetibilidad y fiabilidad

AOAC

B P á ti d didBuenas Prácticas de medida

Verificación y ajuste de la lectura de aw

Humedad relativa ambiental y tiempo de medida

Método de preparación de la muestra

Control de temperatura

aw y las normativas

International Conference on Harmonization (ICH) – intentar minimizar el número de análisis(ICH) – intentar minimizar el número de análisismicrobiológicos en el CC an base a si el producto está +/- secoproducto está +/ seco

USP <1112>USP 1112

Farmacopea

GMPs internas

HR ( ) Las moléculas deg

HR (p, po) Las moléculas de agua se mueven

HRE (p, po)

gv

(p po)

aw & isoterma

agin

g

aw & isotermapack

a

Producto, cobertura, IA, excipiente

Procesos afectados por cambiosProcesos afectados por cambiosde la aww

Mov de agua a (t) niveles críticos aMov. de agua aw(t) niveles críticos aw procesos de degradación

Desarrollo microbiano

D d ió fí i í i d l IA d lDegradación físico-química de los IA y de la calidad de las formulaciones

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¿Qué necesitamos medir?Actividad de aguaIsoterma de sorciónCondiciones ambientales (T y HR)g del packaginggv del packaging.

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Aplicacionesaw como barrera (hurdle) para asegurarque no habrá desarrollo microbianoq

Estabilidad y condiciones deEstabilidad y condiciones de almacenamiento de excipientes y IA

Evitar migración de humedad entre componentes de una formulación

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.

Desarrollo microbianoDesarrollo microbianoS tt (1953 & 1957) bó lScott (1953 & 1957) comprobó que los microorganismos tienen un nivel críticode aw por debajo del cual no se desarrollan

a (y no el contenido de humedad) es elaw (y no el contenido de humedad) es el parámetro barrera (Hurdle).

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.

Actividad de agua vs DesarrolloActividad de agua vs. Desarrollomicrobianoc ob a o

aw limit Microorganisms0.91 Gram Negative Bacteriag0.86 Gram Positive Bacteria0.88 Yeast (practical limit)0 80 P d ti f t i0.80 Production of mycotoxins0.70 Molds (practical limit)0.62 Osmophilic yeast0.62 Osmophilic yeast0.61 Xerophilic molds0.60 Absolute limit for all growth

Water Activity as a CPP for APIWater Activity as a CPP for API Degradation and DissolutionMoisture Migration Two distinct regions at different aw

Water moves from areas of high water activity to areas of lowwater activitywater 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 stickyCauses coatings to crack or become sticky

Water Activity as a CPP for Gel CoatingWater Activity as a CPP for Gel Coating Integrity

Show Videos HereShow Videos Here

Isotherm:Isotherm:The functional relationship between water pactivity and water content of a sample at a specified temperaturep p

AquaLab Vapor Sorption Analyzer

Water activity from chilled mirror dew point

Dry Air Wet Air

chilled mirror dew point Precision balance weighs

sample for water contentOptical Sensor

Fan

sample for water content Dry and wet air flow for

St ti i th ilib t

Infrared SensorMirror

Static isotherm - equilibrate samples at a set aw

Dynamic isotherm - add or SampleDynamic isotherm add or remove water for fast, high resolution isotherm (DDI)

Precision Balance

AquaLab Vapor Sorption AnalyzerAquaLab Vapor Sorption Analyzer

Automatically controls or adjusts sample water activity from 0.03 to 0.95to 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 gisotherms

Moisture Sorption Isotherm

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

TemperatureTemperature

Temperature must be specified andbe specified and held constant.The effect of temperature on the moisture sorption

fisotherm follows the Clausius-ClapeyronClapeyron 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

C i li i Ph ti lCommercializing Pharmaceuticals

NME’s Formulation Sales

MeasurementsApplications

Shelf Life Sorption Kinetics

MeasurementsApplications

Shelf LifeExcipient SelectionPackaging Performance

CrystallizationGlass Transition

Combined Isothermsg gCoating/Capsule UseManufacturabilityP d t P f

Combined IsothermsHygroscopicity

Temperature Abuse DataProduct Performance Temperature Abuse DataMicrobial Growth Potential

Isotherm Applications

Glass Transition Deliquescence

Cr stalli ation Crystallization Isotherms of Mixtures Temperature Abuse Packaging Calculations

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Water Activity and Glass Transition forWater Activity and Glass Transition for Setting CCPs

Large number of water binding sites

Caking Clumping

water binding sites become available

Caking, Clumping, Crystallization, Loss

of TextureLimited Water Binding Sites

RHc Critical Water Activity

Amorphous Metastable State

Binding Sites

Amorphous Metastable State

*Spray Dried Milk Powder

Determining Deliquescence Point

Deliquescence PointPoint

*S*Sucrose

Glass Transition andGlass Transition and Crystallization Measurementy

C t lli tiCrystallization

Glass Transition Inflection Point

* Spray Dried Milk Powder at 25C

Modeling Temperature Abuse

Water activity is ytemperature dependent Most prod cts ha e Most products have a lower water activity value at lower temperature.

Clausius-Clapeyron l ti hirelationship:

Example of Ingredient MixingExample 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)))χeq ( ( w(eq)))

b3’ = ∑Φib3i , b2’ = ∑Φib2i , b1’ = ∑Φib1i , b0’ = ∑Φib0i

P k P f C l l tiPackage Performance Calculations = slope of the isotherm (g/g)

a = initial water activityW t ti it d ifi diti awo initial water activity

awc = critical water activity

pa = atmospheric pressure (kPa)

Water activity under specific conditions

M = total mass of product inside the package (g)

e = saturation water vapor pressure at

Time Constant

es = saturation water vapor pressure at package temperature (kPa)

A = package surface area (m2) Shelf life prediction of packaging

gv = package conductance (g m-2 s-1)

ha= Humidity of air, D t i P k C d t t = Time in package,

= Time constant

Determine Package Conductance

Conclusions

Understanding water activity and isotherms can help in the process of formulating pharmaceuticalsW t ti it i th b t t it Water activity is the best way to monitor moisture in pharmaceuticals

The AquaLab Vapor Sorption Analyzer The AquaLab Vapor Sorption Analyzer provides an easy and fast method for determining either static or dynamic isothermsdetermining either static or dynamic isotherms

Isotherms have applications in predicting chemical and physical stability, product mixing, p y y, p g,packaging

Thank you

Who Uses Isotherms and for What?Companies Uses

Ingredient mixing powder flowKraft Ingredient mixing, powder flow, product formulation, DUO

General Mills Ingredient mixing, product formulation deliquescenceformulation, deliquescence

Glaxo-Smith Kline Excipient stability, glass transition, moisture migration, API stability

I di t i i d tQuaker Ingredient mixing, product formulation, deliquescence

Meade Johnson Powder flow, caking, chemical Meade Johnson stability, glass transition, DUO

Nestle Pet Care Powder flow, caking, chemical stability, glass transition,y g

Dynamic Isotherm OnlyDynamic Isotherm Only

No Crystallization or Kinetics

Glass Transition Inflection Point

* Spray Dried Milk Powder at 25C

Static Isotherm OnlyStatic Isotherm OnlyKinetics of Sorption and Diffusion

Crystallization

* Spray Dried Milk Powder at 25C

Package Calculations ha= 0.60 Package Calculations aawo = 0.10 awc = 0.43 = 0.026 g/gWater Activity and Shelf Life Predictionpa = 100kPa M = 10 g, es = 3kPa

Time constant

A = 0.054 m2

gv = 6.93x10-5 g m-2 s-1

Shelf life prediction of packaging

Package CalculationsPackage Calculationsha= 0.90 awo = 0.10

Package Conductance Prediction from Measurements awo 0.10

awf = 0.32awc = 0.43t = 20 days

Time constant

Measurements

y = 0.026 g/gpa = 100kPa M = 10 g, es = 3kPa (25°C)A = 0.054 m2

Determine package conductanceDetermine package conductance

Package CalculationsPackage CalculationsPackage Conductance Prediction from WVTR g(water vapor transmission rate) (ASTM-E96)

C f %ha= 0.90 es = 6.55 kPa (100°F)

Conversion for 100 F, 90% RH

package conductance for WVTR of 0 35 g m-2 day-1package conductance for WVTR of 0.35 g m day

Note: WVTR values are evaporation values, but can be converted to conductance values using the temperature and humidity testing conditions

Package Calculations ha= 0.60 awo = 0.10Req ired Package Cond ctance for 1 ear Shelf Life awo 0.10 awc = 0.43t = 365 days = 0.026 g/gTime constant

Required Package Conductance for 1 year Shelf Life

g gpa = 100kPa M = 10 g, es = 3kPaA = 0.054 m2

Determine required package conductance

Common Resealable Plastic Package= 6.0 g m-2 days-1Common Resealable Plastic Package 6.0 g m days

Overview

Definitions Instruments

Applications Applications

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H i th ?How can we use isotherms?

Chemical stabilityl i t

Moisture content or awprediction monolayer moisture

content

Shelf life estimation

prediction Physical Changes Glass transitionShelf life estimation

Product formulation Dry ingredient mixing

Glass transition Crystallization DeliquescenceDry ingredient mixing

Temperature effects on aw

Stickiness

Packaging designon aw