interpretación de valores de actividad de agua & isotermas de sorción de humedad en...
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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