WATER-ACTIVITY TESTING Implementation of Water
Activity Testing to Replace Karl
Fischer Water Testing
for Solid Oral-Dosage Forms

Bob Snider, Peihong Liang, and Neil Pearson
For solid oral-
ost pharmacopeial monographs that have proce- dosage forms, water
dures for the measurement of water are based on testing usually is
the measurement of total water either by the KarlFischer titration or by loss on drying. Karl Fis- performed to
cher titrations have dominated the measurement of water control the
in pharmaceutical products for many years. Although the technique is reliable under carefully controlled conditions, it is subject to a variety of problems such as sample han- properties of the
dling and side-reactions that cause erroneous results. Re- sults commonly vary with changes in room relative humid-ity (RH). In addition, general models for describing the effect of water on physical, chemical, and microbiological total water as made with Karl Fischer (KF)
characteristics recognize that different types of water may techniques is not needed and water-activity often
be present (1–3) and that the measurement of total water will provide a better correlation with changes in
may not be the best approach for understanding the effects chemical, physical, or microbiological properties
than KF techniques. In these cases, water activity
According to most common definitions, water can be pres- ent in at least three forms: free water, adsorbed water, and testing can easily replace KF testing.Water-
bound water. Free water is present in the void volume or in activity measurements are nondestructive,
the pores. Free water can serve as a dispersing agent, as a sol- require little labor, and the equipment required is
vent for crystalline compounds, or for microbiological growth.
generally inexpensive. Only a few simple checks
Adsorbed water is located on the surface of the material. Bound are needed to ensure the validity of
water is defined as the water of hydration bound to the prod- measurements. Strategies for implementing water
uct by strong H-bonds. Bound water relates to the monolayerof water molecules, whereas adsorbed water is present in the activity testing are described.
form of multilayers in the matrices. Water also may be pres-ent as a crystal hydrate that effectively is the same as bound At the time of the research, Bob Snider, PhD,* was a
water. An example of another type of water is structural water research advisor with Eli Lilly and Company, bobsnider@ associated with hydrogen bonding between helices of poly- fastmail.fm. Peihong Liang is an analytical chemist
mer in a gel network (4). This explanation follows the the- at Lilly Research Laboratories, Eli Lilly and Company ory of the BET isotherm describing vapor desorption or ad- (Indianapolis, IN), and Neil Pearson is a research
sorption isotherms (3).
scientist at Lilly Research Laboratories, Eli Lilly Canada,Inc. (Toronto, ON, Canada).
When water interacts with solutes and surfaces, it is un- available for other hydration interactions. The term water *To whom all correspondence should be addressed.
activity (a ) describes the (equilibrium) amount of water Submitted: July 13, 2006. Accepted: Oct. 11, 2006.
available for the hydration of materials. Water activity is unit- Keywords: Karl Fischer techniques, solid dosage forms, water testing less and a value of unity indicates pure water, whereas zero Pharmaceutical Technology FEBRUARY 2007

WATER-ACTIVITY TESTING No microbial growth ,0.6 a and capillary water Relative humidity (%) Figure 2: Typical adsorption isotherm for tablet formulation.
Relative humidity (%) the humidity of the air is defined as 60% (a = 0.6) by the Figure 1: Water sorption isotherm.
International Conference on Harmonization under ClimaticZones II, materials with lower a tend to gain water and those indicates the total absence of water molecules. Water activ- with higher a tend to lose water. Most solid oral-dosage ity is the effective mole fraction of water, defined as: forms are produced with water activities of 0.3 to 0.5 andthus gain water in stability studies.
a 5 l x = p/p Use of water activity. The food industry has long used water
activity to control microbial growth and chemical stability.
in which l is the activity coefficient of water, x is the mole Consistent with the US Food and Drug Administration's use fraction of water in the aqueous fraction, p is the partial pres- of water activity in controlling the microbial attributes of sure of water above the material, and p is the partial pres- food (7), water activity also is being used to control the mi- sure of pure water at the same temperature (i.e., the water crobiological properties of pharmaceutical products (8, 9).
activity is equal to the equilibrium relative humidity [ERH]), The growth of most bacteria is inhibited below approxi- expressed as a fraction. The relationship between water ac- mately a 5 0.91. Similarly, most yeasts cease growing below tivity and weight percent water is shown in a sorption a 5 0.87, and most molds stop growing below a 5 0.80.
isotherm (see Figure 1). Figure 1 also shows the hysteresis The absolute limit of microbial growth is approximately observed when the sorption isotherm depends on whether the water is added to the dry material or removed from the The importance of water activity in controlling the micro- wet material. This hysteresis is caused by nonreversible struc- bial properties of pharmaceutical products was added to US tural changes and/or kinetic effects.
Pharmacopeia (USP) Chapter 2023&, "Microbiological At- The sorption isotherm for a formulated drug product is the tributes of Nonsterile Nutritional and Dietary Supplements," result of the combination of the individual-component sorp- and a new USP chapter was written: 1113& "Application of tion isotherms. Sorption isotherms for excipients and the drug Water Activity Determination to Nonsterile Pharmaceutical substance may be used to model the sorption isotherm of the Products." USP Chapter 1113& primarily describes the ap- finished dosage form (5). Figure 2 shows an example of an plication of water-activity measurement for the control of a adsorption isotherm for a typical oral formulation. Two re- nonsterile formulation's microbial attributes, but also men- cently published studies present adsorption and desorption tions the control of chemical degradation. The correlation of isotherms for several common excipients (5–6).
water activity and chemical changes in food also has been in- Materials of differing water activity exhibit time- and vestigated extensively (10). A correspondingly common prac- temperature-dependent water migration from areas with tice in pharmaceutical development is to equilibrate prod- high to low a . For example, a gelatin capsule filled with a ucts at different humidities (water activities) and study their powder that has a different water activity will undergo water degradation rates. Water activity also correlates with changes migration and, at equilibrium, the capsule shell and powder in chemical and physical stability (11, 12). The degradation contents have the same a . For packaged products, the rate of several pharmaceutical products is well modeled by moisture-vapor barrier properties of the packaging become water activity using the BET function (rate is proportional crucial in the rate of moisture loss or gain. In addition, des- to 1/[1 – a ]) (11) as well as other approaches (12–15).
iccants inside a package change the initial water activity as Measurement of water activity.Water activity is determined by
well as the subsequent rate of water activity change. Because the measurement of water in the gas phase immediately sur- Pharmaceutical Technology FEBRUARY 2007
WATER-ACTIVITY TESTING Table I: Examples of required changes in water activity to
double degradation rate.

Change in a
y 5 –0.0348x 1 76.148 Change in water
content to double
degradation rate degradation rate
Cephalosporin degradation (19) y 5 –0.0298x 1 60.34 N-oxide formation (20) Waterman aspirin degradation y 5 –0.0574x 1 34.189 Hydrolysis of nitrazepam (22) Asparatamine degradation (23) y 5 –0.0014x 1 11.329 rounding the sample. The measurement of water activity in foodsis described by AOAC's Official Methods of Analysis, No. 978.18, "Water Activity of Canned Vegetables" (16). The principal tech- Temperature (°C) niques are changes in electrical capacitance or resistance of poly-mer thin films and dew point by chilled mirror. Newer tech- Figure 3: Relative humidity as a function of temperature for
niques include the measurement of water in the headspace either saturated salt solutions used for calibration (only the magnesium spectroscopically (17) or chromatographically (18).
nitrate standard is sensitive to temperature).
Method Number 978.18 also compares various types of instruments. For sensor-type instruments, a typical instru-ment chamber would have a depth of approximately 1.3 cm Although sample transfer can be performed rapidly to min- and a diameter of 4.2 cm. Sufficient sample is needed to fill imize changes to the sample moisture content, moisture still the chamber to the appropriate level (one-half to two-thirds must be absorbed or desorbed from the sample to equilibrate full). Probes also are available for insertion into bulk mate- the measuring chamber's headspace. For a typical sample, the rials or possibly through product packaging. Measurement change in the sample's moisture content during this equili- time is controlled by sensor measurement time (usually a few bration process will not have a significant effect on the accu- minutes) and time for the headspace to equilibrate (the time racy of the sample's final a reading. Air at a temperature of for water activity in the headspace to come into equilibrium 25 8C contains approximately 0.023 mg/mL of water at 100% with the material being tested). Typical equilibration times RH. For a sample at 75% RH, with the external environment vary from 5 to 30 minutes.
at 0% RH and a sample chamber headspace of 6 mL, the sam- The rate of equilibration of the dosage form with the cham- ple must replace only approximately 6 mL 3 0.023 mg/mL 3 ber's headspace depends on several factors, including: (0.75 – 0.10) or 0.01 mg of water. With a sample weight of 2 • the difference in water activity between the dosage form g in the chamber and a water content of 2%, the total amount and the air in the chamber's headspace immediately fol- of water in the sample is 40 mg. In this case, only a very small lowing the sample-transfer process; fraction of the total water is removed from the dosage form • the headspace volume of the measuring chamber contain- to equilibrate the humidity in the headspace (the water con- tent of the sample would drop by less than 0.01%).
• the transfer rates of water within the sample and between Samples that contain very little water or have a very shal- the sample and the gas phase; low slope for the sorption isotherm in the region of interest • the gas-phase diffusion rate for water in the headspace.
will be problematic with regards to bias during equilibration The gas-phase diffusion rate of water is not a significant in the chamber. The use of laser-absorption spectroscopy factor based on the configuration of typical sensor cells. The (which can determine the water activity in the headspace of gas-phase diffusion rate is approximately 0.1 cm2/s and the a sample vial without breaching the seal) would be beneficial largest distance in the chamber is approximately 4 cm. Be- for these types of samples. An example of a product that could cause the sample occupies most of the chamber, the largest be difficult is a lyophilized cake with very low water content.
distance is actually closer to 0.5 cm (from the top of the sam- Nonetheless, the typical capsule or tablet product generally ple to the top of the chamber). The transfer rate of water be- contains a large amount of water and is an excellent candi- tween the sample and the gas phase is related to the specific date for water-activity testing.
sample for evaluation. Depending on the sample, the trans- For most solid oral-dosage forms, the range of interest for fer rates within the sample and between the sample and the water activity is 0.30–0.75. Water-activity measurements are gas phase can vary significantly. Heterogeneous samples such generally precise and accurate to 0.01–0.02 units. Thus, water as intact capsules or coated tablets may have longer equili- activity should be capable of providing 23 levels ([0.75 – bration times than uniform powder samples.
0.30]/0.02) of distinction over this measurement range. Sev- Pharmaceutical Technology FEBRUARY 2007
WATER-ACTIVITY TESTING Table II: Protective filters used with
Over-the-counter tablets of ibuprofen, water-activity instruments from
naproxen, and enteric-coated aspirin Novasina for Capsule B
were obtained from a local retail estab- lishment for evaluation. Two develop-mental capsule formulations also were evaluated. Capsule A was a starch-based formulation and Capsule B contained enteric-coated beads. The water-activity Protects sensor from particles of sample instruments used were from the same manufacturer (Novasina, Pfäffikon, Protects sensor from Switzerland) but obtained from Omn- imark Instrument Corp. (Tempe, AZ).
General chemical filter The names of the two models are theMs1 and the AW Lab.
Protects sensors from Both instruments use the same meas- uring cell and sensor. The AW Lab Oxidizes, reduces model has an additional capability of interfering compounds determining whether the measurementhas reached equilibrium by establish- eral examples of degradation as a func- ing a limit of the change in water activ- tion of water activity are shown in Table ity with time. All measurements were I, and water activity changes of about made using the mechanical prefilter, ex- 0.1–0.2 are needed to double the degra- cept for those made for Capsule B. For dation rate. In a case for which a 0.1 the Capsule B measurements, all of the change in water activity is critical, tighter protective filters listed in Table II were controls of calibration may be needed.
In general, the water activity would be Water-activity standards (saturated controlled at a level well below when sig- salt solutions) were obtained from the nificant degradation occurs. Thus, the instrument supplier. Both Novasina in- examples in Table I represent mostly the struments take into account tempera- worst cases in terms of required accu- ture during calibration as long as the racy. Compared with Karl Fischer water temperature is between 15 8C and 30 8C.
testing, water activity has particular ad- The Novasina instruments do not allow for temperature control. To obtain • the sample is hygroscopic; temperature-effect data, the measuring • the sorption isotherm is relatively flat chamber was placed in a plastic bag and over the region where increased immersed in a water bath. Measurements degradation rates are noted (i.e., were only recorded after the sensor tem- little change in water content); perature reading agreed with the exter- • the amount of total water is high (e.g., nal water-bath temperature.
hydrates) and variability in the meas- Because it is not easy to predict the urement makes discriminating effect of test samples on the instrument changes in water content difficult.
sensor, bracketing readings of water ac- Calibration. Calibration is accom-
tivity standards were performed regu- plished with the use of either saturated larly (one low and one high standard salt solutions or solutions with well- reading during each period of use, typ- characterized water activities. Saturated ically 24 hours).
salt solutions that have reference values The equilibration of dosage forms to traceable to National Institute of Stan- different water activities were per- dards and Technology standards (24) formed to ensure the validity of the are available. Figure 3 shows the effect water-activity measurement. In general, of temperature on some typical water- the same type of salt solutions used in activity standards.
sealed desiccators also were used for cal-ibration. Intact tablets or capsules were Pharmaceutical Technology FEBRUARY 2007
WATER-ACTIVITY TESTING Figure 4: Rate of equilibration of Capsule A.
Figure 5: Rate of equilibration of several solid oral-dosage forms.
equilibrated for 7–14 days. Crushed or in a of .0.01 to 0.02 were not consid- composited dosages were equilibrated ered significant.
for 24 hours.
Sample temperature. If the sample and
Studies requiring RH control were the equilibration chamber are at the performed with a humidity-controlled same temperature, then temperature has glove box (Coy Laboratory Products, a small effect on water activity within Grass Lake, MI).
the temperature range of most labora-tories. The authors previously discussed Results and discussion
the effects of temperature on the water Key operating conditions that were in- activity of the saturated salt standard vestigated include the effects of sample solutions used for calibration. Those ef- temperature, equilibration time, and fects are generally small and taken into sample handling (in particular, the hu- account by the instrument. The effect midity of the environment in which of temperature on solid oral-dosage samples are transferred). In addition, forms was studied for two samples: Cap- the factors affecting the specificity of sule A and naproxen. The observed ef- the sensor must be considered to sup- fects of temperature changes on water port the validation of the technique.
activity were 0.003 and 0.004 a /8C and Based on an earlier discussion, changes were similar to those reported by a man- Pharmaceutical Technology FEBRUARY 2007
ufacturer (25). The small effect of tem- Table III: Effect of sample grinding on measured water activity.
perature is explained by the fact that thechange in the partial pressure of water Error compared with
vapor (p) with temperature for the sam- ple is similar (but not equal) to the mag- Intact ibuprofen tablets (different lot than nitude of the change of the saturation Ibuprofen tablets crushed in a 80% pressure (p ) above pure water. Any relative humidity environment (2 min change in the temperature of a hygro- scopic product automatically causes the Ibuprofen tablets crushed in a 10% product to exchange moisture with the relative humidity environment (2 min air (or gas) that surrounds it. Moisture is exchanged until the partial water-vapor pressure at the product's surfaceand in the air is equal. For this reason,a constant temperature is importantwhen measuring a .
Equilibration time. To understand the
time required for the headspace to comeinto equilibrium with the sample, wateractivity was measured as a function oftime for the products shown in Figures4 and 5. The results for Capsule A indi-cated that equilibration occurred within10 minutes and no significant changesoccurred over the subsequent 12 hours(see Figure 4). Figure 5, which includestwo typical tablet formulations and anenteric-coated aspirin tablet, shows thata 30-minute equilibration time was ap-propriate for the tablet formulations. Alonger equilibration time would beneeded with the enteric-coated formu-lation for the same degree of accuracy.
In general, the authors have used an ac-curacy of 60.02 a as being acceptable.
Another alternative would be to crushthe enteric-coated tablet, but this pro-cedure needs special precautions.
For some instruments, the equilibra- tion time is not a concern. These instru-ments measure the rate of change of awwith time and will indicate a stablereading only when the rate of change isbelow a selected threshold. Other in-struments use a mathematical functionto estimate the final equilibrium value.
The advantage of measuring water ac-tivity on intact tablets is shown in TableIII, in which the water activity of intacttablets is compared with that of crushedtablets under 10% and 80% RH. Thetotal exposure time to the ambient RHwas approximately 2 min (including thetime to crush the tablets with a mortarand pestle). This time was used to sim- Pharmaceutical Technology FEBRUARY 2007
Pharmaceutical Technology FEBRUARY 2007
WATER-ACTIVITY TESTING Table IV: Water activity after equilibration and absolute
error (measured a and theoretical a ).
Low relative humidity (10%) Measured water activity and absolute error
High relative humidity (80%) Table V: Replicate measurements of water activity.
Capsule B
Figure 6: Effect of ambient relative humidity during transfer on rate
of equilibration.
ulate rapidly crushing, weighing, and transferring tablets inalternative methods such as Karl Fischer. Whereas the low humidity only created a small bias, the high humidity cre- ated a large error. There was a larger difference between the sample water activity and the ambient conditions for the high humidity (45% RH higher) versus the low humidity (22% RH lower). The rate of water uptake versus loss is not expected to be the same. A technique for reducing water changes during crushing is to use a device sold to home cus- tomers that sandwiches the sample between two holders, thus reducing contact with the ambient atmosphere.
Sample handling. The effect of ambient humidity on sam-
dards (one low and one high standard check) were used dur- ple handling was assessed by transferring Capsule A in en- ing each period of use (typically 24 hours) to ensure that any vironments of 10% and 80% RH. As shown in Figure 6, the changes in sensor response were readily detected. Potential effect of high or low humidity is to increase the equilibra- interferences also were removed through the use of prefilters.
tion time with little effect on the final measured value. An Interferences from the enteric-coated beads in Capsule B equilibration time of 30 minutes was considered adequate.
caused some difficulty. The problem appeared as a failure of A second issue with sample handling is the equilibration of the check standard and subsequent poor sensor performance water within the dosage unit. For tablets, a blended powder is with respect to drift. The sensor was replaced with a new sen- compressed and there should be little inhomogeneity of water sor, and the authors evaluated each of the chemical filters de- content. For capsules, the powder fill will be at a different water scribed in the experiment section for their ability to prevent activity than the gelatin. A study was undertaken to measure sensor failure. All filters were capable of removing the inter- the time required for equilibration to occur between the fill fering components, but the general chemical filter (activated and the capsule. For dry contents (a 5 0.38) within a wetter carbon) greatly reduced response time and required as much gelatin capsule shell (a 5 0.54), approximately one hour was as an hour for equilibration to occur. The interference arises required to be within 0.01 of the final water-activity value.
from the degradation of the hydroxypropyl methylcellulose The same contents within a very dry shell required approxi- acetate succinate (HPMCAS) polymer to yield acetic and suc- mately three hours to be within 0.01 of the final water-activ- cinic acids. The acetic acid is a known potential interferant ity value. Thus, equilibration within the dosage unit would for this type of measurement cell (26).
only be a concern for in-process testing. For in-process test- Linearity. The general calibration approach ensures a linear
ing, the capsule could be opened, and the capsule shell and response to within 0.01 a over the operating range of the powder could be placed within the testing chamber.
Validation. Specificity.For the Novasina instruments, the sen-
Accuracy. Accuracy at equilibrium is assessed by comparing
sor responds to any polar volatile component that affects the the water activity of equilibrated samples with the theoreti- resistance or the capacitance of the polymer used in the sen- cal water activity (the RH to which the sample was equili- sor. Most pharmaceutical tablets or capsules either will have brated using a controlled humidity chamber). Samples were no solvents or the solvents are removed during the process- equilibrated over the same type of saturated salt solutions ing and drying of the dosage form. Bracketing check stan- used to calibrate the instrument. This approach was evalu- Pharmaceutical Technology FEBRUARY 2007
WATER-ACTIVITY TESTING Table VI: Comparison of instruments for measurement of water activity.
Principle of measurement
Temperature control Equilibration detection Protective filter
Novasina, a division of capacitance and resistance Axair Ltd. (Pfäffikon, Rotronic Instrument Corp.
capacitance and resistance (Huntington, NY) extrapolation modes Decagon Devices, Inc.
Lighthouse Instruments, (Charlottesville, VA) ated with an enteric-coated aspirin tablet and two other tablet of the chamber seal integrity should be evidenced by a fail- formulations as shown in Table IV with a general accuracy ure of standards that are dissimilar from the RH of the room.
of 0.01–0.02 a . The same approach was taken by Mahajan et al., with a similar degree of accuracy (17). As previously Water activity as part of a control strategy
mentioned, a 30-minute equilibration time generally has Water measurements as part of a control strategy generally been adequate for capsules and tablets.
must be quantitative (correcting for water content in a drug Precision. Replicate measurements were made for two tablet
substance) or must be related to a change in a chemical or formulations and one capsule formulation (see Table V). The physical property. For solid oral-dosage forms, water is usu- relative standard deviations for replicate measurements were ally measured because of an adverse effect of water on either chemical stability or a physical attribute of the formulation Instrument qualification of maintenance (Novasina Instrument).
such as drug release. Much of current measurement of water Using the guidelines published in a recent white paper (27), by Karl Fischer testing could be replaced with water-activity water-activity instruments would be Class B, principally re- testing because water activity is easier to measure, less sub- quiring calibration to ensure performance. At the initial in- ject to handling problems, and as good or better at correlat- stallation and every 6 months thereafter, four standards are ing to physical and chemical changes than total water.
checked (0.11, 0.33, 0.75, and 0.90). If the measured results Additional advantages of water activity testing are: are more than 0.02 a outside of the theoretical value, then • One immediately knows whether the sample is likely to the instrument calibration for that standard is changed. Note add or lose water relative to the external environment.
that the 0.53 standard may be used for laboratories with ad- • The risk of microbial growth is assessed readily based on equate temperature control or the reading must be corrected the earlier discussion in which a , 0.6 has no risk for mi- for temperature (see Figure 3). The use of daily bracketing crobial growth.
standards is recommended to ensure that the instrument con- • Samples with water activities approaching the area of the tinues to work properly and that the sample does not affect sorption isotherm where "free" water is present are at a higher risk of adverse chemical or physical effects.
The instrument is operated with the alcohol prefilter, and Where water measurements are part of a regulatory com- records are maintained for the installation of the prefilter.
mitment, water-activity results would need to be related to The replacement of the prefilter depends on the type and Karl Fischer measurements by the sorption isotherm. The number of samples measured, but it should be replaced at specification for water activity then could be set to correspond least every six months. The standards themselves are avail- to the Karl Fischer specification.
able from the vendor with a certificate, and the vendor rec- The establishment of water activity as an analytical proce- ommends a use period of several years. Some water activity dure would generally involve: standards will dry out over time, and some water must be • determining which instruments are most suitable for the added to maintain a saturated suspension. Aqueous, single- intended application (see Table VI); use solution standards also are available from some vendors.
• qualifying the instruments (using white paper [26], cate- The stainless steel chambers also should be cleaned and gory B, calibrate); sanded periodically to remove any rust. The o-ring seal on • using daily check standards; the chamber should be inspected regularly and replaced if • using protective filters for materials with expected volatile any cracking or other defects are noted. A significant failure Pharmaceutical Technology FEBRUARY 2007
WATER-ACTIVITY TESTING • validating methods once they are being used for lot-release Table VII: Options for implementing water-activity
testing as a function of registration status.
Table VI describes some differences in the types of instru- ments. Only representative manufacturers are included.
Product registration status
The approach used by all of the instruments is nondestruc- tive. The instruments vary in the cutoff at low RH, the con- Establish water activity as an trol of temperature, and the detection of the equilibration alternate procedure with a limit based end-point. Measurement time is faster for the laser absorp- on sorption isotherm.
Marketed product with tion and the instruments that extrapolate the detection of the Karl Fischer water test end-point; but, temperature control generally lengthens the If actual water levels are close toregistration limit, then variations in measurement time to 10–30-minutes for all the instruments.
isotherms should be considered.
The Lighthouse instrument would be especially useful forlyophilized formulations because the measurement can be Marketed product with Follow normal practices for changing made on the headspace of the product vial. Reference 16 has no registered Karl more details about differences in cost and applicability.
Fischer water test The control strategy also must be consistent with the reg- 1. Implement with the intent to use ulatory strategy. Table VII summarizes options relative to the water activity as an internal GMP product registration status.
test (e.g., not registered).
Routine control of instrumentation. For the instruments that
registration stability or 2. Correlate Karl Fischer and water activity tests to keep options open, have sample contact with the sensor, bracketing readings of but use water activity as the the standard solutions should be used to ensure that the sen- principal test.
sor is providing accurate results and that the samples did notcontaminate the sensor. The use of a protective filter should salt suspensions also require some maintenance to replace be tracked such that the filter is replaced at least as frequently lost water from evaporation. These standards should be as the manufacturer suggests. Standards that are saturated checked each time they are used.
Pharmaceutical Technology FEBRUARY 2007
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19. B. Snider, "Mass Balance Issues with Low Dose Compounds," pre- wise, water activity also can be used to evaluate the poten- sented at Annual Meeting of the American Association of Pharma- tial effect of water on chemical and physical changes in the ceutical Scientists, Indianapolis, IN, November 2000.
formulation. The Novasina ms1 and AW instruments in par- 20. Unpublished data.
ticular have proven to be sufficiently precise and accurate to 21. K.C. Waterman et al., "Hydrolysis in Pharmaceutical Formulations," measure the water activity of typical solid oral-dosage forms.
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Topics of interest include: 10. P.S. Taoukis, T.P. Labuza, and I.S. Saguy, "Kinetics of Food Dete- rioation and Shelf-Life Prediction" in Food Engineering Practice, K.J.
• biotechnology/large-molecular processes; Valentas, E. Rotstein, and R.P. Singh, Eds. (CRC Press, Boca Raton, • analytical testing; 11. J.T. Carstensen and A. Li Wan Po, "The State of Water in Drug De- • solid-dosage manufacturing; composition in the Moist Solid State: Description and Modeling," • regulatory affairs; Int. J. of Pharm. 83 (1–3), 87–94 (1982).
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Technology‘s Web site (www.pharmtech.com).Please send 15. L. Bell, "Water Activity and Reaction Rates/Physical Properties/ Shelf-Life," IFT Fundamentals of Water Activity Short Course pre- submissions to Kaylynn Chiarello-Ebner, sented at the 2002 Annual Conference of the Institute Food Tech- nologists, Anaheim, CA, 2002.
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Pharmaceutical Technology FEBRUARY 2007

Source: http://optris.be/pdf/water%20activity%20vs%20moisture%20content.pdf


Final Draft of the original manuscript: Yang, X.; Zhao, L.; Almasy, L.; Garamus, V.M.; Zou, A.; Willumeit, R.; Fan, S.: Preparation and characterization of 4-dedimethylamino sancycline (CMT-3) loaded nanostructured lipid carrier (CMT-3/NLC) formulations In: International Journal of Pharmaceutics (2013) Elsevier DOI: 10.1016/j.ijpharm.2013.04.021

Microsoft word - keeping your brain young.doc

Keep Your Brain Young: Read, Be Bilingual, Drink Coffee Stephen Krashen Published in: Language Magazine, October, 2010 My grandfather told me about senility, I'm not worried about that. My grandfather said, "When you become senile, you won't know it." (Bill Cosby) There are three things you can do to stay young mentally and you can do all three at the same time. Read: Older people who read more do better on tests of mental ability. If fact they do a lot better. The standard test used to detect dementia is the MMSE, a short test of arithmetic, memory and spatial relations. A research team (Galluccia et al, 2009) found that older people (average age 84) who said they read novels and non-fiction averaged 27.3 on the MMSE, which is in the normal range (27-30). Those who said they only read newspapers averaged 26, which is just below normal (20-26 = "some impairment), but those who said they did no reading averaged 21, well inside the "impaired" range). Smith (1996) reported that in general older people do not do as well as younger people on reading tests. But older (e.g. age 65 and older) who said they wide variety of types of reading, or genres (e.g. fiction, current affairs or history, religion/inspiration, science/social science/) not only read better than their age-mates who read less widely, but read just as well as younger adults (age 19 to 24) who read just one type of reading material. Smith concludes that " …extensive reading practice may help to ameliorate possible cognitive declines later in life" (p. 217). A popular research design in dementia studies is to test older people who don't have any signs of problems, and then retest them years later, comparing those who develop problems and those who don't, called "prospective" studies. In one prospective study, Verghese et. al. (2003) reported that 68% of those who developed dementia five years after initial testing said they read books or newspapers frequently (at least several times per week), but 86% of those who did not were frequent readers, a significant difference. Geda and colleagues (2009) recently reported similar results.