Interpretación de valores de actividad de agua & Isotermas de Sorción de humedad en medicamentos
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Interpretación de valores de actividad de agua & Isotermas de Sorción de humedad en medicamentos

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Interpretación de valores de actividad de agua & Isotermas de Sorción de humedad en medicamentos Interpretación de valores de actividad de agua & Isotermas de Sorción de humedad en medicamentos Presentation Transcript

  • Interpretación de valores de aw e p isotermas de sorción de humedad en medicamentos FRANCESC FERRER Dr Eng. Agrònom. SDM-UB, Barcelona, 11 Desembre 2012.
  • Humedad CONTENIDO: (g agua / g ms) MÉTODOS DE DETERMINACIÓN Karl Fischer K l Fi h Pérdida de masa por desecación Farmacopea, Desarrollo, Control de Calidad CONTENIDO TOTAL DE AGUA No relacionado directamente con el efecto del agua sobre procesos físicos químicos y microbiológicos físicos,
  • Formas del agua en un producto sólido LIBRE (Solvent & Free water) • Presente en los poros y espacios vacios • Actúa como agente dipersante , solvente en componentes g p p cristalinos, desarrollo microbiano • Móvil ADOSRBIDA (adsorbed water) • En la superficie del material (surface interaction) • Forma multicapas en la matríz (capilar) • Móvil 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 procesos físicos, químicos y microbiológicos Humedad Relativa de Equilibrio (HRE) aw = p/po
  • Water A ti it D fi iti W t Activity Definition aw = p/po Pharmaceutical 1. Equilibrium 2. Constant T & P 2 C t t WaterMoleculeDemostration.wmv
  • Isoterma de sorción de humedad Ligada monocapa Adsorbida Multicapa p Libre y solvente
  • Valores típicos de aw en medicamentos Producto aw Granulado 0.31 Comprimido Crema 0.815 aw Líquido oral Extracto vegetal seco Product o 0.90
  • humedad vs. aw aw fácilmente medibles: 0,001aw humedad fá il h d d fácilmente medibles: 0 1 t dibl 0,1mg (0 01%) (0,01%)
  • Medida de M did d aw  Punto de rocio (chilled mirror dew point). Medida directa de p y po  Exactitud: ±0.003aw  Rapidez: <5 minutos  Intervalo: (0.03 – 1.0aw)  Alta repetibilidad y fiabilidad AOAC Optical Sensor Mirror Infrared Sensor Sample Fan
  • Buenas P á ti B Prácticas d medida de did  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 microbiológicos en el CC an base a si el producto está +/- seco +/ USP <1112> 1112 Farmacopea GMPs internas
  • HR ( po) (p, gv Las moléculas de agua se mueven packa aging HRE (p, po) (p aw & isoterma aw & isoterma Producto, cobertura, IA, excipiente
  • Procesos afectados por cambios de la aw Mov. Mov de agua  aw(t)  niveles críticos aw  procesos de degradación Desarrollo microbiano Degradación fí i D d ió físico-química d l IA y d l í i de los de la calidad de las formulaciones 13
  • ¿Qué necesitamos medir? Actividad de agua Isoterma de sorción Condiciones ambientales (T y HR) gv del packaging . 14
  • Aplicaciones aw como barrera (hurdle) para asegurar q que no habrá desarrollo microbiano Estabilidad y condiciones de almacenamiento de excipientes y IA Evitar migración de humedad entre componentes de una formulación . 15
  • Desarrollo microbiano Scott S tt (1953 & 1957) comprobó que l bó los microorganismos tienen un nivel crítico de aw por debajo del cual no se desarrollan aw (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 Desarrollo vs. microbiano c ob a o aw limit 0.91 0.86 0.88 0.80 0 80 0.70 0.62 0.61 0.60 Microorganisms Gram Negative Bacteria g Gram Positive Bacteria Yeast (practical limit) Production f P d ti of mycotoxins t i Molds (practical limit) Osmophilic yeast Xerophilic molds 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 low water activity. 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
  • Water Activity as a CPP for Gel Coating Integrity Show Videos Here
  • Isotherm: The functional relationship between water p activity and water content of a sample at a specified temperature p p
  • AquaLab Vapor Sorption Analyzer  Water activity from chilled mirror dew point  Precision balance weighs sample for water content  Dry and wet air flow for Dry Air Wet Air Optical Sensor Mirror Fan Infrared Sensor  St ti isotherm - equilibrate Static i th ilib t samples at a set aw  Dynamic isotherm - add or remove water for fast, high resolution isotherm (DDI) Sample Precision Balance
  • AquaLab Vapor Sorption Analyzer  Automatically controls or adjusts sample water activity from to 0.95 0.03  Measures sample mass to 0.1 mg, and water activity to 0.001  Controls sample temperature between 15 and 60 C.  Automatically obtains adsorption, g desorption and scanning isotherms
  • 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.
  • Temperature Temperature must be specified and held constant. The effect of temperature on the moisture sorption isotherm f 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.
  • Static and Dynamic on 1 sample *Microcrystalline Cellulose at 25C
  • Static and Dynamic Comparison * Microcrystalline Cellulose at 25C
  • Commercializing Ph C i li i Pharmaceuticals ti l NME’s Formulation Applications Shelf Life Excipient Selection Packaging Performance g g Coating/Capsule Use Manufacturability Product Performance P d tP f Sales Measurements Sorption Kinetics Crystallization Glass Transition Combined Isotherms Hygroscopicity Temperature Abuse Data Microbial Growth Potential
  • Isotherm Applications       Glass Transition Deliquescence Crystallization Cr stalli ation Isotherms of Mixtures Temperature Abuse Packaging Calculations 28
  • Water Activity and Glass Transition for Setting CCPs Large number of water binding sites become available Limited Water Binding Sites Caking, Clumping, Caking Clumping Crystallization, Loss of Texture RHc Critical Water Activity Amorphous Metastable State *Spray Dried Milk Powder
  • Determining Deliquescence Point Deliquescence Point *Sucrose *S
  • Glass Transition and Crystallization Measurement y Crystallization C t lli ti Glass Transition Inflection Point * Spray Dried Milk Powder at 25C
  • Modeling Temperature Abuse  Water activity is y temperature dependent  Most prod cts ha e products have a lower water activity value at lower temperature.  Clausius-Clapeyron relationship: l ti hi
  • 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
  • Package P f P k Performance Calculations C isotherml(g/g) l ti  = slope of the Water ti it W t activity under specific conditions d ifi diti awo = initial water activity awc = critical water activity Time Constant Shelf life prediction of packaging pa = atmospheric pressure (kPa) 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 P k D t i Package C d t Conductance t = Time in package,  = Time constant
  • Conclusions  Understanding water activity and isotherms can help in the process of formulating pharmaceuticals  W t activity is the best way to monitor Water ti it i th b t t it 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 p y y, product mixing, g, chemical and physical stability, p packaging
  • Thank you
  • Who Uses Isotherms and for What? Companies Kraft General Mills Glaxo-Smith Kline Quaker Meade Johnson Nestle Pet Care Uses Ingredient mixing powder flow mixing, flow, product formulation, DUO Ingredient mixing, product formulation, formulation deliquescence Excipient stability, glass transition, moisture migration, API stability Ingredient mixing, product I di t i i d t formulation, deliquescence Powder flow, caking, chemical stability, glass transition, DUO Powder flow, caking, chemical stability, glass transition, y g
  • 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 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
  • 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 y  = 0.026 g/g pa = 100kPa M = 10 g, es = 3kPa (25°C) A = 0.054 m2
  • Package Calculations Package Conductance Prediction from WVTR g (water vapor transmission rate) (ASTM-E96) Conversion f 100 F, 90% RH C for % package conductance for WVTR of 0 35 g m-2 day-1 0.35 Note: WVTR values are evaporation values, but can be converted to conductance values using the temperature and humidity testing conditions ha= 0.90 es = 6.55 kPa (100°F)
  • Package Calculations Required Req ired Package Cond ctance for 1 year Shelf Life Conductance ear Time constant Determine required package conductance Common Resealable Plastic Package= 6.0 g m-2 days-1 Package ha= 0.60 awo = 0.10 awc = 0.43 t = 365 days  = 0.026 g/g gg pa = 100kPa M = 10 g, es = 3kPa A = 0.054 m2
  • Overview  Definitions  Instruments  Applications 44
  • How can we use i th H isotherms? ?  Chemical stability  monolayer moisture l i t 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