Applications for Water Activity and Sorption Isotherms in Pharmaceuticals
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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
- 1. Applications for Water Activity and Sorption Isotherms in Pharmaceuticals Decagon Devices, Inc.
- 2. 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
- 3. Water Activity A measure of the energy status of the water in a sample water vapor pressure of sample aw = —————————————————— saturation vapor pressure @ sample temp. The work required to remove water from the sample is
- 4. Water Activity Definition aw = p/po Pharmaceutical 1. Equilibrium 2. Constant T & P WaterMoleculeDemostration.wmv
- 5. Chilled Mirror Dew Point Fan Primary method of measuring vapor pressure (not calibrated) Highest accuracy ±0.003aw Rapid measurement <5 minutes Measures entire aw range (0.03 – 1.0aw) High reliability Optical Sensor Mirror Infrared Sensor Sample
- 6. 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
- 7. Water Activity Applications Microbial Growth API Degradation and Dissolution Gel Coating Integrity 7
- 8. 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 extrinsic properties of the ingredients and finished product These guidelines provide the opportunity to minimize microbial testing based on “dry” conditions
- 9. International Conference on Harmonisation (ICH) ICH Decision Tree #6 Is the drug substance or excipient capable of supporting microbial growth? No Provide Supporting data. Microbial limits acceptance criteria and testing may not be necessary ICH Decision Tree #8 Is the drug product a dry dosage form? Yes Does Scientific evidence demonstrate growth inhibitory properties of the drug product? Yes Microbial limits acceptance criteria and testing may not be necessary
- 10. 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 be determined by water activity USP <1112>
- 11. 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 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.
- 12. 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.
- 13. 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 0.91 0.86 0.88 0.80 0.70 0.62 0.61 0.60 Microorganisms Gram Negative Bacteria Gram Positive Bacteria Yeast (practical limit) Production of mycotoxins Molds (practical limit) Osmophilic yeast Xerophilic molds Absolute limit for all growth
- 14. 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. 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
- 15. Water Activity as a CPP for Gel Coating Integrity Show Videos Here
- 16. Isotherm: The functional relationship between water activity and water content of a sample at a specified temperature
- 17. AquaLab Vapor Sorption Analyzer Water activity from chilled mirror dew point Precision balance weighs 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) Dry Air Wet Air Fan Optical Sensor Mirror Infrared Sensor Sample Precision Balance
- 18. 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 0.001 Controls sample temperature between 15 and 60 C. Automatically obtains adsorption, desorption and scanning isotherms
- 19. 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.
- 20. Temperature Temperature must be specified and held constant. The effect of temperature on the moisture sorption isotherm 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.
- 21. Static and Dynamic on 1 sample *Microcrystalline Cellulose at 25C
- 22. Static and Dynamic Comparison * Microcrystalline Cellulose at 25C
- 23. Commercializing Pharmaceuticals NME’s Formulation Applications Shelf Life Excipient Selection Packaging Performance Coating/Capsule Use Manufacturability Product Performance Sales Measurements Sorption Kinetics Crystallization Glass Transition Combined Isotherms Hygroscopicity Temperature Abuse Data Microbial Growth Potential
- 24. Isotherm Applications Glass Transition Deliquescence Crystallization Isotherms of Mixtures Temperature Abuse Packaging Calculations 24
- 25. Water Activity and Glass Transition for Setting CCPs Large number of water binding sites become available Limited Water Binding Sites Caking, Clumping, Crystallization, Loss of Texture RHc Critical Water Activity Amorphous Metastable State *Spray Dried Milk Powder
- 27. Glass Transition and Crystallization Measurement Crystallization Glass Transition Inflection Point * Spray Dried Milk Powder at 25C
- 28. Modeling Temperature Abuse Water activity is temperature dependent Most products have a lower water activity value at lower temperature. Clausius-Clapeyron relationship:
- 29. 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
- 30. Package Performance Calculations 〈 = slope of the isotherm (g/g) Water activity under specific conditions awo = initial water activity awc = critical water activity pa = atmospheric pressure (kPa) Time Constant Shelf life prediction of packaging 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 Package Conductance t = Time in package, = Time constant
- 31. Conclusions Understanding water activity and isotherms can help in the process of formulating pharmaceuticals 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
- 32. Thank you
- 33. Who Uses Isotherms and for What? Companies Kraft General Mills Glaxo-Smith Kline Quaker Meade Johnson Nestle Pet Care Uses Ingredient mixing, powder flow, product formulation, DUO Ingredient mixing, product formulation, deliquescence Excipient stability, glass transition, moisture migration, API stability Ingredient mixing, product formulation, deliquescence Powder flow, caking, chemical stability, glass transition, DUO Powder flow, caking, chemical stability, glass transition,
- 34. Dynamic Isotherm Only No Crystallization or Kinetics Glass Transition Inflection Point * Spray Dried Milk Powder at 25C
- 35. Static Isotherm Only Kinetics of Sorption and Diffusion Crystallization * Spray Dried Milk Powder at 25C
- 36. 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
- 37. 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 〈 = 0.026 g/g pa = 100kPa M = 10 g, es = 3kPa (25°C) A = 0.054 m2
- 38. Package Calculations Package Conductance Prediction from WVTR (water vapor transmission rate) (ASTM-E96) Conversion for 100 F, 90% RH ha= 0.90 es = 6.55 kPa (100°F) 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
- 39. Package Calculations Required Package Conductance for 1 year Shelf Life Time constant Determine required package conductance Common Resealable Plastic Package= 6.0 g m-2 days-1 ha= 0.60 awo = 0.10 awc = 0.43 t = 365 days 〈 = 0.026 g/g pa = 100kPa M = 10 g, es = 3kPa A = 0.054 m2
- 41. How can we use isotherms? Chemical stability monolayer moisture 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