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`Solvent Systems and Their
`Selection in Pharmaceutics
`and Biopharmaceutics
`
`Patrick Augustijns
`Catholic University of Leuven, Belgium
`
`Marcus E. Brewster
`Janssen Pharmaceutica N.V., Beerse, Belgium
`
`MYLAN EXHIBIT 1023
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`iii
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`Patrick Augustijns
`Laboratory for Pharmacotechnology
`and Biopharmacy
`Catholic University of Leuven
`Belgium
`
`Marcus E. Brewster
`Janssen Pharmaceutica N.V.
`Beerse, Belgium
`
`Library of Congress Control Number: 2007924356
`
`ISBN-13: 978-0-387-69149-7
`
`e-ISBN-13: 978-0-387-69154-1
`
`Printed on acid-free paper.
`C(cid:2) 2007 American Association of Pharmaceutical Scientists.
`All rights reserved. This work may not be translated or copied in whole or in part without the written
`permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York,
`NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in
`connection with any form of information storage and retrieval, electronic adaptation, computer
`software, or by similar or dissimilar methodology now known or hereafter developed is forbidden.
`The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are
`not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject
`to proprietary rights.
`
`While the advice and information in this book are believed to be true and accuate at the date of going
`to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any
`errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect
`to the material contained herein.
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`5
`
`Practical Aspects of Solubility
`Determination in Pharmaceutical
`Preformulation
`
`WEI-QIN (TONY) TONG
`Novartis Pharmaceuticals Corporation, Pharmaceutical and
`Analytical Development, One Health Plaza, East Hanover, NJ
`
`Introduction
`Solubility is one of the most important physicochemical properties studied
`during pharmaceutical preformulation. For liquid dosage form development,
`accurate solubility data are essential to ensure the robustness of the finished
`product. For solid dosage forms, solubility data are important in determining if
`an adequate amount of drug is available for absorption in vivo. If a compound
`has a low aqueous solubility, it may be subject to dissolution rate-limited or
`solubility-limited absorption within the gastrointestinal (GI) residence time
`(Lobenberg et al., 2000). The importance of solubility, in biopharmaceutical
`terms, is highlighted by its use in the biopharmaceutics classification system
`(BCS) described by Amidon et al. (1995). This system defines low solubility
`compounds as those whose aqueous solubility in 250 mL of pH 1-7.5 aqueous
`solution is less than the total dose. Solubility data are also used to estimate the
`maximum absorbable dose (MAD) (Johnson and Swindell, 1996). MAD is a
`conceptual tool that relates the solubility requirement for oral absorption to
`the dose, permeability and GI volume and transit time. It is defined as:
`MAD (mg) = S (mg/mL) × Ka (1/min) × SIWV (mL) × SITT (min)
`where S is solubility at pH 6.5 reflecting typical small intestine condition; Ka is the
`trans-intestinal absorption rate constant determined by a rat intestinal perfusion
`experiment; SIWV is the small intestine water volume, generally considered to
`be 250 mL; and SITT is the small intestine transit time, typically about 270 min.
`Solubility is influenced by many variables including temperature, pH (for
`ionizable compounds), solvents used for the solubility determination, state of the
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`Chapter 5: Practical Aspects of Solubility Determination
`
`solid, common ions in the medium, and so on. For poorly soluble compounds,
`determining solubility in the presence of various solubilizing agents presents a
`special set of challenges.
`The aims of this chapter are to summarize solubility determination methods
`commonly used in pharmaceutical preformulation and to discuss various factors
`to be considered in designing and carrying out these solubility studies.
`
`Experimental Methods
`Saturation Shake-Flask Method
`
`The shake-flask method is based on the phase solubility technique that was
`developed 40 years ago and is still the most reliable and widely used method
`for solubility measurement today (Higuchi and Connors, 1965). The method
`can be divided into five steps: sample preparation, equilibration, separation of
`phases, analysis of the saturated solution and residual solid, and data analysis
`and interpretation (Yalkowsky and Banerjee, 1992, Winnike, 2005).
`
`Sample Preparation
`A solubility sample is typically prepared by adding an excess amount of solid to
`the solubility medium in a stoppered flask or vial. The amount added does not
`need to be accurately measured. While it is important to ensure that enough
`material is added so the sample is a suspension, it is also important not to add
`too much material to significantly alter the properties of the solubility medium
`including its pH.
`
`Equilibration
`Depending on the type of agitation used, the drug substance properties, amount
`of material used, and the equilibration method used, the time to reach equilib-
`rium varies. With good agitation, samples generally reach equilibrium reasonably
`quickly, often within 24 hours. However, for poorly soluble compounds, the equi-
`libration time may be unrealistically long due to the poor dissolution rate that
`is further depressed as the equilibrium process advances and the concentration
`in solution gets closer to the solubility. One way to speed up the process is to
`increase the effective surface area for dissolution. This can be achieved by either
`vortexing or sonicating samples prior to equilibration. Creating a supersaturated
`solution may also be helpful in overcoming the problem of a slow dissolution
`rate. This can be achieved by adding a certain amount of amorphous mate-
`rial to the samples, or by cycling the sample temperature to higher and lower
`temperatures during the equilibration process.
`Another challenge for determining solubility of poorly soluble compounds
`is their poor wettability and their tendency to float. Ways to get around this
`problem include using small glass microspheres (Glassperlen) to de-aggregate
`the particles with agitation or sonication, and adding an amount of sodium
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`139
`
`dodecyl sulfate below the critical micelle concentration to serve as a wetting
`agent (L¨otter et al., 1983).
`There is no better way to accurately determine the end point for equilibra-
`tion than by performing an actual analysis. Saturation or equilibrium is consid-
`ered to be achieved when multiple samples assayed after different equilibration
`time periods give the same apparent solubility. If solid-state form transitions oc-
`cur during equilibration, the equilibration time may be longer, especially if the
`solubility differences between various forms are small. To ensure that equilibrium
`is indeed reached, it is a good idea to demonstrate that the same equilibrium
`state (solubility) can be reached from different directions; for example, from
`undersaturation and supersaturation as well as from constant temperature or
`from temperature variation by means of temperature cycling.
`
`Separation of Phases
`Filtration and centrifugation both have been commonly employed to separate
`the saturated solution from the solute phase. Filtration is easily accomplished,
`but filter sorption can be a significant source of error. Generally, filter sorption is
`more significant for hydrophobic and poorly soluble compounds, and obviously
`it is directly proportional to the filter surface area. Typically, pre-rinsing the filter
`with a few milliliters of the saturated solution can remedy the problem. However,
`in some extreme cases where the solubility of the compound is very low, a much
`larger volume may be needed to saturate the filter adsorption sites.
`Centrifugation or ultracentrifugation may be preferable for certain samples
`that are difficult to filter. Solubility samples in co-solvent systems with high vis-
`cosity are such examples. If the solute is less dense than the solubility medium,
`it will float on the surface, making it difficult to sample the solution. This may
`be particularly problematic for compounds with low solubility where a single
`particle carried over to the solution may cause significant overestimation of the
`true solubility.
`Theoretically, the solid should always be separated from the saturated so-
`lution at the equilibrium temperature. Obviously this is more important when
`equilibrium is reached quickly. For poorly soluble compounds, equilibrium is
`typically reached slowly, thus filtration at ambient temperature may not intro-
`duce a significant error.
`Centrifugal filter devices such as the UniPrep r(cid:2)
`filter have become commer-
`cially available in recent years, making it possible to combine both approaches
`(Glomme et al., 2004; Winnike, 2005).
`
`Analysis of the Saturated Solution and Residual Solid
`High performance liquid chromatography (HPLC) is the most commonly used
`analytical tool for the analysis of saturated solutions. Its advantage over the
`ultraviolet method is that it can detect impurities and any instability. A generic
`gradient method can be made readily available that is stability-indicating enough
`for multiple compound analyses without the need to make major adjustments
`in the column or mobile phase.
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`
`When determining the solubility of meta-stable forms, the application of a
`fiber optic probe, which permits the detection of the drug concentration every
`few seconds, may prove to be very useful.
`Examination of the residual solid from solubility samples is one of the most
`important but often overlooked steps in solubility determinations. Powder X-ray
`diffraction (PXRD) is the most reliable method to determine whether any solid
`state form change has occurred during equilibration. The sample should be
`studied both wet and dry to determine if any hydrate or solvate exists. Thermal
`analysis techniques such as differential scanning calorimetry (DSC) can also be
`used to identify any solid-state transformations, although they may not provide as
`definitive an answer as the PXRD method. Other methods useful in identifying
`any solid-state changes include microscopy, Raman and infrared spectroscopy,
`and solid-state NMR (Brittain, 1999). When changes in solid-state properties are
`identified in solubility studies, it is important to link the new properties to the
`properties of known crystal forms so the solubility result can be associated with
`the appropriate crystal form.
`
`Data Analysis and Interpretation
`Solubility theory based on pH-solubility profiles for weak acids and bases is well
`established (Grant and Higuchi, 1990, Butler, 1998). From a knowledge of the
`intrinsic solubility of the unionized form, the dissociation constant (pKa’) and
`the solubility of a salt, one should be able to construct the pH-solubility profile.
`If multiple solubility data are available, data can be analyzed through the use of
`a non-linear regression model to calculate pKa’. If the solubilities of the various
`salts are also determined, the complete pH-solubility profile can be constructed.
`Deviations from the theoretical pH-solubility profiles may be an indication
`of experimental error. They may also suggest other interactions not predicted by
`the solubility theory. Examples for the causes of such deviations include changes
`in solid-state properties, self-association and micelle formation of the drug in
`solution. Figure 1 shows an example of a compound that forms micelles at a
`pH above 9 (Winnike, 2005). Further addition of sodium hydroxide does not
`increase the pH; rather it enhances solubility through micelle formation. In
`any of these cases, it is important to identify the causes of the deviation so
`that appropriate formulation decisions can be made based on the solubility
`data.
`
`Non-Equilibrium Methods
`
`Any methods that do not contain steps to ensure the establishment of equilib-
`rium can be considered non-equilibrium methods. In the last few years, several
`methods commonly used for solubility measurements in the early discovery set-
`ting have been reported (Lipinski et al., 1997; Pan et al., 2001). These methods
`typically begin with dimethylsulfoxide (DMSO) solutions or with amorphous
`material. Turbidity and ultraviolet detection are commonly used because they
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`141
`
`GSK Anon Ampholyte pH-Solubility at 25C
`
`Calculated Solubility
`Buffered Systems (I = 0.1)
`0.1N HCl
`NaOH (0.0001 - 0.2N)
`
`0.2N NaOH
`
`0.1N NaOH
`
`0.01N NaOH
`
`pKa 1 = 2.89
`pKa 2 = 4.01
`S
` = 0.0000152 mg/mL
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`100
`
`10
`
`1
`
`0.1
`
`0.01
`
`0.001
`
`0.0001
`
`10-5
`
`0
`
`Solubility (mg/mL)
`
`pH
`Figure 1. pH-solubility profile of a compound that forms micelles at high pH values.
`
`easily can be designed into high-throughput instrumentation. A potentiometric
`method has also been reported (Avdeef, 2003).
`The usefulness of the solubility data from these non-equilibrium methods
`often is questionable. Some pharmaceutical companies use these data as a first
`criterion to eliminate poorly soluble compounds. However, because the contri-
`bution of crystallinity to solubility is not controlled in non-equilibrium methods,
`the reliability of the data cannot be guaranteed. If experimental error is mini-
`mized, it is generally safe to assume that solubility can only be less when solid
`crystalline material is later used to determine equilibrium solubility. Therefore,
`the use of these solubility data as a gatekeeper seems to be justified. However,
`it is questionable whether data generated by these methods are any better for
`this purpose than those generated by computational methods. In addition, since
`for highly potent drug candidates the solubility requirement is dose-dependent,
`compounds, whose solubility is in the microgram range, may still be developable.
`Therefore, setting the right criteria to eliminate poorly soluble compounds may
`be challenging. It is the author’s opinion that in order to make informed de-
`cisions, one must understand why these data are needed, and how they will be
`used, prior to initiating solubility studies.
`
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`
`Attention Points in Solubility Determination
`pH-Solubility Profile
`
`For drugs with ionizable functional groups, determining solubility as a function
`of pH is an important preformulation task. pH-solubility profiles define the range
`of opportunities for liquid formulation development, and they provide baseline
`guidance to solubilization strategies for poorly soluble compounds.
`Typically, there are two ways to control pH. One approach is to use buffers.
`Since multiple buffer systems are needed to control the entire pH range, the
`solubility results may be complicated by salt formation with the buffer species
`(Tong and Whitesell, 1998). This can be detected by examining the residual
`solid from solubility determinations.
`Another way to control pH is through the use of a pH-stat, where pH is con-
`trolled by titrating with acidic and/or basic solutions (Todd and Winnike, 1994).
`Ionic equilibrium can be monitored continuously by measuring the solution pH.
`Equilibrium can be considered to have been reached when the pH no longer
`changes over a period of time.
`For poorly soluble compounds, depending on what material is used at the
`starting point for a solubility determination, e.g. the unionized form vs. its salt,
`a different pH-solubility profile may be observed. This may be due to the slower
`dissolution rate of the unionized form, which can cause a delay in reaching true
`equilibrium. Or it may be due to supersaturation of the salt solution because
`of a delay in nucleation of the ionized form. The methods previously described
`for increasing the powder dissolution rate should permit the system to reach
`equilibrium more quickly, thus reducing or eliminating the difference.
`In certain instances, if the ionic form of a drug candidate is used as the
`starting material, the apparent solubility can be different when varying amounts
`of salt are added to the solution. For example, when the excess amount of the
`di-hydrochloride (2·HCl) salt of an experimental compound, E2050, is used
`to determine the pH-solubility profile, the solubility in the pH region where
`the mono-hydrochloride salt controls the solubility is suppressed by the excess
`chloride ion resulting from the conversion of the di-HCl salt to the mono-HCl
`salt (Wang et al., 2002). Figure 2 shows the three pH solubility curves determined
`by using different amounts of di-HCl salt. The difference in salt solubility also
`causes the pHmax to vary.
`
`Solubility of Salts
`
`Solubility determination for pharmaceutical salts using the equilibrium method
`may be challenging for certain compounds such as those with poor intrinsic
`solubility. Theoretically, after an excess amount of solid salt is equilibrated in
`water, the solution concentration at equilibrium should represent the solubility
`of the salt. However, this is only true if the pH of the saturated solution is below
`pHmax. For compounds with low intrinsic solubilities and weak basicity or acidity,
`their salts may convert to the unionized form in the solubility medium. In such
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`
`Figure 2. pH-solubility profiles of a new chemical entity E2050 constructed with
`different amounts of starting material as the Di-HCl salt.
`
`cases the measured solubility is only the solubility of the unionized form at
`those particular pH values. For example, the solubility of the phosphate salt of
`the developmental candidate, GW1818X, was found to be 6.8 mg/mL when the
`solution pH was 5.0 (Tong and Whitesell, 1998). The pHmax is approximately
`4 in this case. Analysis of the residual solid showed that the solution was in
`equilibrium with the free base, indicating that the solubility determined did
`not adequately represent the solubility of the salt. An additional complication
`is that the pH of the solubility sample may vary depending on the lots of drug
`substance used. This is because different lots of material may contain different
`amounts of residual acid, base, or solvent.
`There are several ways to overcome this type of problem. One approach is
`to determine the solubility in a diluted acidic solution using the same acid that
`formed the salt with the base. The concentration of the acid solution needs to
`be such that the solution pH is lower than the pHmax. The solubility can then
`be estimated by correcting for the common ion effect from the acid used in the
`solubility study. A second approach to ensure a lower solution pH than pHmax is
`to use a high ratio of drug to solvent (Pudipeddi, 2002). However, this may not
`be possible for every compound.
`When determining the solubility of salts in simulated gastric fluid, or in pH
`1 or pH 2 hydrochloric acid solutions, the salt may convert to the hydrochloride
`
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`
`salt depending on the relative solubility of the salts. If the simulated gastric fluid
`contains sodium chloride, the common ion effect of the chloride ion may signif-
`icantly depress the solubility of the hydrochloride salt. Therefore, examination
`of the residual solid from these experiments is even more important. A different
`PXRD pattern may be indicative of a different crystal form of the same salt or
`the hydrochloride salt.
`
`In-Situ Salt Screening
`
`For ionizable compounds, pH adjustment is often one of the most important
`ways to improve solubility. Sometimes, solubility data for salts may be needed. For
`example, when developing a solution formulation, the buffer selected should
`not form a less soluble salt with the drug substance. However, the actual salt may
`not be readily available. In these cases, the in-situ salt screening method may be
`useful in estimating the solubility of various salts (Tong and Whitesell, 1998).
`In this method, an accurately known amount of free base is added to a known
`concentration of acid. The acid concentration is chosen so that there is an excess
`amount of acid in the solution to ensure that the pH of the suspension is lower
`than the pHmax. The solubility of the compound is measured by the equilibrium
`method described previously. After correcting for the common ion effect, the
`Ksp and the solubility of the salt formed in-situ can then be calculated.
`Examination of the residual solid is critically important in this case. Some-
`times, the residual solid may not be a perfectly crystalline solid salt. If this is the
`case, it is obvious that the solubility determined only represents the solubility of
`the particular form that is in equilibrium with the saturated solution.
`
`Solubility Determination in Non-Aqueous Solutions
`
`Special precautions are required when determining solubility in non-aqueous
`solvents. Since many non-aqueous systems are viscous, it may be more practical
`to use weight (W/W) instead of volume (W/V) to represent solubility. Since not
`all filters are compatible with non-aqueous solvents, it is essential to choose the
`correct type of filter. Upon dilution of the saturated solution for analysis, it is
`important to ensure that the compound does not precipitate. Precipitation may
`occur in many co-solvent systems because the solubility changes that accompany
`dilution are log-linear.
`Solubility dependence on temperature may be different for different solvent
`compositions. Therefore, it is important to use a statistical factorial design to
`study the effect of composition and temperature simultaneously.
`
`Solubility Determination for Polymorphs and Solvates
`
`The solubility of a solid substance, by definition, is the concentration at which the
`solution phase is in equilibrium with a given solid phase at a stated temperature
`and pressure (Butler, 1998). When a substance exists in more than one crystal
`
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`
`form, only the least soluble form at a given temperature is considered to be the
`most physically stable form, all others are considered to be metastable.
`The thermodynamic activity of each crystalline form, represented by its sol-
`ubility, may change quite differently as a function of temperature. Monotropic
`systems are defined as systems where a single form is always more stable regardless
`of the temperature. Enantiotropic systems are defined as systems where the rela-
`tive stability of the two forms inverts at some transition temperature (Byrn et al.,
`1999).
`Determining the transition temperature of polymorphs is a necessary step
`in understanding the relationship of various forms. The transition temperature
`can be determined by plotting log solubility as a function of inverse temperature
`(Brittain and Grant, 1999; Byrn et al., 1999).
`To determine the solubility of each form, one needs to monitor the solution
`concentration as a function of time more frequently. Enough data points need
`to be collected so the equilibrium concentration of each form can be assessed.
`Theoretically, a single experiment starting with the least stable form should
`generate solubility data for all the other forms. However, since the transition
`temperature is typically unknown initially, it is best to conduct the solubility
`experiment with each form.
`The solubility difference between different polymorphs is independent of
`the solvent used provided the solvent used does not form a solvate with the
`drug substance (Brittain and Grant, 1999). The solvent selected for the solubil-
`ity study should afford reasonable solubility. It should be high enough so the
`solubility can be measured accurately, but low enough so the amount of drug
`substance consumed is minimized. Sometimes, it may be a good idea to use two
`different solvent systems to determine the same transition temperature in order
`to increase one’s confidence in the results.
`If the drug substance can form a hydrate, all polymorphs will eventually con-
`vert to the hydrate(s), since hydrates are typically less soluble in aqueous media
`than anhydrous forms (Grant and Higuchi, 1990). Hydrate formation should be
`detected when the residual solid is characterized as part of the solubility study.
`Care must be taken to make sure that samples are examined both wet and dry
`since some hydrates may readily convert to the anhydrate form upon drying.
`
`Miniaturization, High-Throughput, and Automation
`in Solubility Measurement
`
`Solubility is not only important in preformulation studies. It is also important
`in lead selection and optimization during drug discovery. As discussed earlier,
`the usefulness of the data generated by non-equilibrium methods can be ques-
`tionable, thus, it is desirable to have methods that can determine equilibrium
`solubility with as little compound as possible and with a high enough throughput
`to support the need for lead optimization. A miniaturized shake-flask method
`was reported recently (Glomme et al., 2004) that can provide data on up to
`20 compounds a week with a single set-up. All the steps of the equilibration
`method are included but on a much smaller scale.
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`
`Systems that automate all the steps to measure equilibrium solubility have
`also been developed and are commercial available. The Symyx Discovery Tools
`Solubility and Liquid Formulations Workflow is a good example of such a sys-
`tem (www.symyx.com). This integrated software and instrumentation workflow
`is equipped with automated sample preparation, pH measurement, filtration
`and sample analysis. The manufacturer claims an annual throughput of more
`than 60,000 experiments.
`Analytical techniques such as Raman spectroscopy have been developed for
`examining residual solids from solubility samples. Since the largest difference
`in solubility is observed between crystalline and amorphous materials, it may be
`sufficient to know if the material in equilibrium with the saturated solution is
`crystalline or amorphous.
`
`Typical Solubility Studies to Support
`Formulation Development
`Table 1 summarizes the commonly studied solvents for solubility and the sol-
`ubilization strategies these solubility results support. A combination of various
`
`Solvents
`
`Solution formulation
`
`Solid dosage form
`
`Solubilization strategies
`
`Aqueous solutions of
`various pHs (buffered
`or unbuffered)
`
`pH-adjustment and salt
`formation
`
`Salts
`
`Non-aqueous solvents and
`their mixtures
`
`Co-solvents
`
`Co-solvents, lipid based
`systems in soft or hard
`gelatin capsules
`
`Surfactants and
`phospholipid in
`aqueous and
`non-aqueous media
`
`Micellar solubilization
`Liposome
`
`Lipid based systems in
`capsules
`
`Complexation
`
`Complexation
`
`Aqueous solutions
`containing complexing
`agents such as
`cyclodextrins with or
`without pH adjustment
`Oil, Intralipid r(cid:2)
`or
`pre-made liposomes
`
`Emulsion,
`micro-emulsion, solid
`micro-emulsion in
`capsules
`Table 1. Solubility studies to support various solubilization strategies.
`
`Emulsion
`Liposome
`
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`
`techniques is often required to maximize the solubilization potential. Chemi-
`cal stability studies are typically done in parallel with solubility measurements.
`Solutions from solubility measurements can be used as solution stability samples.
`Other solubility studies often required to support various development ac-
`tivities include:
`◦ solubility studies in physiologically relevant media such as simu-
`lated intestinal fluids for dissolution method development, and
`◦ solubility in organic solvents for analytical method development,
`crystal form screening, and cleaning verification.
`
`Summary
`Solubility determination is an important step in pharmaceutical preformulation.
`Although the experiment seems simple and well known, depending on the prop-
`erties of the drug substance, special care must be taken to ensure the reliability
`of the results. Establishment of equilibrium and identifying what solid material
`is in equilibrium are two of the most important considerations in any solubility
`experiment.
`
`Acknowledgements
`I would like to thank my professor Dr. Keith Guillory of the University of Iowa
`for reviewing and editing this manuscript. He remains to be my endless source
`of advice, suggestions and inspiration.
`
`List of Abbreviations
`MAD......................................................................maximum absorbable dose
`SIWV...................................................................small intestine water volume
`SITT.......................................................................small intestine transit time
`HPLC.........................................high performance liquid chromatography
`PXRD.........................................................................powder x-ray diffraction
`DSC.............................................................differential scanning calorimetry
`DMSO...................................................................................dimethylsulfoxide
`
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