Ind. Eng. Chem. Res. 1993, 32, 1471-1481
`
`1471
`
`Solubility of Naproxen in Supercritical Carbon Dioxide with and
`
`without Cosolvents
`
`Simon S. T. Ting, Stuart J. Macnaughton, David L. Tomasko,* and Neil R. Foster‘
`
`School of Chemical Engineering and Industrial Chemistry, University of New South Wales, P.0. Box 1,
`Kensington, N.S. W. 2033, Australia
`
`The solubility of naproxen ((S)-6-methoxy-a-methyl-2-naphthaleneacetic acid) in supercritical CO2
`was determined at 313.1, 323.1, and 333.1 K. The influence of six polar cosolvents, ethyl acetate,
`acetone, methanol, ethanol, 1-propanol, and 2-propanol, was studied at concentrations of 1.75, 3.5,
`and 5.25 mol % . The solubility enhancement with these cosolvents is considerable, and the cosolvent
`effect increases in the order ethyl acetate, acetone, methanol, ethanol, 2-propanol, 1-propanol. A
`nonlinear increase in solubility is observed with an increase in cosolvent concentration. The use
`of the Peng-Robinson and Soave-Redlich-Kwong equations of state to correlate these ternary
`systems requires the use of negative binary interaction parameters indicating strong interactions
`between naproxen and the cosolvents. The cosolvent effects cannot be explained by any one physical
`property of the cosolvents but appear to be influenced by hydrogen bonding ability as determined
`from solvatochromic parameters as well as the relative distance from the CO2-cosolvent binary
`critical point.
`
`Introduction
`
`In recent years, a great deal of research has been carried
`out in the field of supercritical fluid (SCF) technology.
`The interest in using this technology for selective extrac-
`tion or reaction is due to the superior properties that are
`inherent to this class of fluid, including the ability to vary
`solvent density and to effect a change in solvent properties
`by changing either the pressure or temperature. The
`viscosity of a SCF is much lower than a liquid, and
`diffusivities can vary between gaslike and liquidlike values.
`As a result, extraction processes can be carried out more
`rapidly. Another advantage of using SCF’s in separation
`processes is the relative ease of solvent recovery and the
`separation of the desirable product(s).
`For most high molecular weight, nonvolatile organic
`compounds, the solubility in SCF’s is low requiring high
`temperatures and pressures for substantial loadings. Thus
`the capital cost for commercial-scale processes can be
`prohibitive, and this has been one of the major hindrances
`to the advance of SCF technology. Carbon dioxide is one
`of the most common gases used as a SCF mainly because
`it is an easy gas to handle, it is inert and nontoxic, it is
`nonflammable, and it has a convenient critical temper-
`ature. Although CO2 is the most common SCF being used,
`it does have limitations as a result of its lack of polarity
`and associated lack of capacity for specific solvent-solute
`interactions which would lead to high loading and/ or
`selectivity for polar organic compounds. Pure SCF’s
`exhibit polarization behavior that is primarily related to
`the density and SC CO2 at 308 K and 200 bar only has a
`solubility parameter approaching that of liquid isopentane
`(6.5 (cal/cm3)1/2); thus there is a great incentive to improve
`its polarity. It has been found that the addition of a small
`amount of cosolvent to a SCF can have dramatic effects
`on its solvent power.
`In recent years, progress has been made toward un-
`derstanding the interactions involved in dilute supercritical
`mixtures. It has been shown that near the critical point
`of a SCF solution, the solvent molecules “cluster” around
`
`* To whom correspondence should be addressed.
`* Present address: Department of Chemical Engineering, The
`Ohio State University, Columbus, OH 43210-1180.
`
`the relatively large solute molecule to form a local density
`higher than the bulk density (Eckert et al., 1986; Kajimoto
`et al., 1988; Cochran and Lee, 1989; Debenedetti, 1987;
`Debenedetti et al., 1989; Petsche and Debenedetti, 1989,
`1991; Brennecke et al., 1990; Morita and Kajimoto, 1990).
`When a cosolvent
`is added,
`the situation is further
`complicated by the differences in local and bulk compo-
`sitions (Kim and Johnston, 1987a; Yonker and Smith,
`1988). Frye et al.
`(1987) also indicated a change in
`composition ofthe cybotactic region (a region in the vicinity
`of the solute) in a cosolvent-modified SCF.
`The increase in solubility due to the addition of cosolvent
`is the result of additional interactions between the solute
`and the cosolvent. Considering the interactions possible,
`these cosolvent effects could be the result of several
`mechanisms. The addition of a cosolvent will generally
`increase the mixture density which will contribute to the
`overall solubility enhancement as will physical interactions
`like dipole—dipole, dipole—induced dipole, and induced
`dipole-induced dipole interactions. However, when using
`a polar cosolvent for polar solutes, the largest increase in
`solubility would be expected to be a result of specific
`chemical interactions like hydrogen bonding or charge
`transfer complex formation.
`There are relatively few reported studies of solid—SCF
`cosolvent solubility to date (Dobbs et al., 1986; Schmitt
`and Reid, 1986; Wong and Johnston, 1986; Van Alsten,
`1986; Larson and King, 1986; Dobbs et al., 1987; Schaeffer
`et al., 1988; Lemert and Johnston, 1989, 1991; Tavana et
`al., 1989; Cygnarowizc et al., 1990; Hollar and Ehrlich,
`1990; Smith and Wormald, 1990; Gurdial et al., 1993; Ekart
`et al., 1992). Overall, only two SCF’s have been used,
`ethane and CO2--whereas a multitude of cosolvents have
`been used ranging from nonpolar gases to polar liquids.
`In this work, the flow technique coupled with gravimetric
`analysis was used to measure the solubility of naproxen,
`(S)-6-methoxy-a-methyl-2-naphthaleneacetic acid (a non-
`steroidal antiinflammatory drug), in pure SC CO2 and also
`in various SC C02—cosolvent mixtures. The cosolvents
`chosen were all polar and could either exhibit self-
`association (alcohols) or not (ketone and ester). For all
`the cosolvents studied, three concentrations ranging from
`1.75 to 5.25 mol % were investigated at 333.1 K. This was
`to enable the study of the effect of concentration together
`
`0888-5885/93/2632-1471$04.00/0
`
`© 1993 American Chemical Society
`
`|nnoPharma Exhibit 1110.0001
`
`

`

`1472
`
`Ind. Eng. Chem. Res., Vol. 32, No. 7, 1993
`
`Table I. Source and Purity of Materials
`
`source
`Sigma Chemicals 99+ %
`Liquid Air
`liquid withdraw grade, 99.8+ %
`
`purity
`
`compound
`naproxen
`carbon
`dioxide
`BDH
`acetone
`ethyl acetate Aldrich
`methanol
`BDH
`ethanol
`BDH
`1-propanol BDH
`2-propanol BDH
`
`HiPerSolv grade, 99.8% by HPLC
`99.9+ % by GLC
`HiPerSolv grade, 99.8% by GLC
`AnalaR grade. 99.7 % v/ v
`HiPerSolv grade, 99.8% by GLC
`HiPerSolv grade, 99.8% by GLC
`
`with the functionality of the cosolvent. Experiments were
`also carried out at 323.1 and 318.1 K with acetone cosolvent
`and 323.1 K with methanol, ethanol, and 2-propanol
`cosolvents.
`
`Materials
`
`The sources and purities of the various compounds used
`are given in Table I. These materials were used without
`further purification.
`
`Experimental Section
`
`Binary System. A schematic diagram of the equipment
`used is shown in Figure 1. The syringe pump used was an
`Isco Model 260D, with constant pressure operating ca-
`pability, equipped with an external jacket for heating or
`cooling purposes. In the study of the solubility of naproxen
`in pure SC CO2, the equilibrium cells consisted of two
`6-in. by 0.5-in. o.d. stainless steel tubes and a Jerguson
`sight gauge. For the cosolvent studies a slight modification
`was made to the overall equipment setup used for solubility
`measurements in pure CO2. Because of the anticipated
`higher solubility involved, the equilibrium cells were
`replaced with a 300-mL bomb half-filled with naproxen.
`The system temperature was monitored by a platinum
`resistance thermometer accurate to $0.1 K, and the system
`pressure was measured by a Druck pressure transducer
`(Model TJE), with an accuracy of :l:5 psi, located just
`after the sight gauge. The equilibrium cells and sight gauge
`were placed in a water bath which was regulated to :l:0.1
`K.
`
`The equilibrium cells were packed with naproxen, and
`each end was plugged with glass wool to prevent the fine
`naproxen powder from plugging the smaller 1/8-in. o.d.
`interconnecting stainless steel tubing. Similarly, the sight
`gauge was three-quarters filled with naproxen and also
`plugged loosely with glass wool to prevent entrainment.
`The sight gauge provided a means of determining the
`physical state of the mixture (i.e., to detect potential
`melting of the solid). A 7-um Nupro inline filter, F1, was
`placed after the pressure transducer to prevent any further
`entrainment of solid particles of naproxen. The pressure
`drop through the saturators was less than 0.5 bar.
`The method used in this study is similar to that used
`by Gurdial and Foster (1991). Initially, the system was
`purged with carbon dioxide at low pressure and then
`brought up to the required system pressure and temper-
`ature. After equilibrating for several hours, the system
`was purged with SC CO2 equivalent to 520 cm?‘ or two
`syringes of liquid CO2 at room temperature and system
`pressure which corresponded to at least three complete
`system volumes. For operation, the metering valve, V5
`(Whitey 32RS4 with lubricant removed), was first closed
`and V4 was slowly opened and the system was allowed to
`equilibrate further at system pressure and temperature
`for 15-30 min. The experiment was then started by
`opening valve V5, which was heated by a 100-W lamp.
`
`The flow rate was normally maintained to within 10 dm3/ h
`CO2 at ambient conditions. Consistent results could still
`be obtained when this flow rate was halved indicating that
`equilibrium was achieved. The solute which precipitated
`on expansion through valve V5 was collected in a 0.5-pm
`Nupro inline filter, F2. The total volume of CO2 at ambient
`conditions, after passing through a water saturator, was
`measured by a wet test meter (Type DM3A, Alexander
`Wright & Co.).
`At the end of each run, V4 was closed and the section
`between V4 and V5 was allowed to depressurize through
`V5. The valve V4 was located outside the constant-
`temperature water bath so that V5 together with the
`section of tubing connecting to V4 could be disconnected.
`As V4 was located outside the water bath, its temperature
`was controlled with a heating tape to that of the bath
`temperature. The solute collected in the valve and the
`connecting tubing was flushed with high-purity acetone
`(99% or better) into a Petri dish. The acetone was then
`evaporated until a constant mass was obtained. The Petri
`dish and the filter were then weighed and the mass
`difference was recorded. The reproducibility and uncer-
`tainty of the solubility data obtained using this method
`were within :l:5%.
`
`Ternary Systems. To ensure that the solvent—cosol-
`vent mixtures were supercritical at the chosen operating
`conditions, the critical locus for each system was deter-
`mined for the concentration range of interest. A rigorous
`technique to determine the critical locus is via a vapor-
`liquid equilibrium (VLE) experiment. However,
`the
`method proposed by Gurdial et al. (1991a,b) provides a
`quick technique for the determination of critical loci of
`binary mixtures. The critical loci for COg—acetone, CO2-
`methanol, CO2—1-propanol, and CO2—2-propanol have been
`established using this technique (Gurdial, 1991a,b). As
`no CO2—ethyl acetate critical locus data in the concen-
`tration range of interest were available, the critical locus
`was determined using the above method. The data
`obtained are shown in Figure 2. As expected with these
`dilute systems, the variations of critical temperatures and
`pressures are linear with composition. It can be seen that
`for the ethyl acetate—C02 system, at 5.25 mol % ethyl
`acetate, the critical temperature and pressure are ap-
`proximately 330 K and 97 bar, respectively, and thus all
`work done at this concentration was carried out above
`these conditions.
`
`To prepare the cosolvent mixtures, the barrel of the
`syringe pump was used as a mixing bomb. The syringe
`volume was calibrated with N2 at ambient temperature
`and at various pressures and was found to be 265 :1: 5 cm3.
`The maximum volume readout on the pump was found to
`be reliable and was close to the calibrated volume. The
`mixture was prepared by raising the head of the piston as
`far up as possible and then purging with C02. The required
`amount of cosolvent was injected directly into the pump
`via T1 as shown in Figure 1. The barrel of the pump was
`then cooled by circulating chilled water through the water
`jacket. The three-way valve, V2, was switched to the liquid
`CO2 cylinder, and at the same time the piston was drawn
`down. The temperature was set at 274 K primarily because
`at this temperature and around 50-60 bar (CO2 cylinder
`pressure) C02 exists only as a liquid. A secondary
`consideration was that, at this temperature, the density
`of liquid CO2 is not too sensitive to small variations in
`pressure (:|:5 bar). With these parameters set, the required
`amount of CO2 to be added could be determined by setting
`the pressure. No account was made for excess volume of
`mixing. When the desired pressure (e.g., 52 bar) was
`
`|nnoPharma Exhibit 1110.0002
`
`

`

`Ind. Eng. Chem. Res., Vol. 32, No. 7, 1993
`
`1:173
`
`_ _ _ _ _ _.
`
`W¢RGa$
`
`‘L
`192
`® vi
`j- on of:
`
`Q imam
`V3; M
`C
`>4
`
`- H H II
`F1
`:13:
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`:-
`
`7
`~
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`Tempmbxe Comroned Waier Bath
`
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`.
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`Wwfsmffliw‘
`
`Figure 1. Flow apparatus for solubility measurements in pure and cosolvent modified SC‘F's.
`3513 «m——————-——
`10%
`
`E“
`
`so:
`
`33o§-
`i
`
`3193
`
`
`
`mo
`
`Figure 3. Stxuoture of naproxen.
`
`95
`
`90 g
`as E
`
`G
`
`1
`
`4
`3
`2
`MOLE ‘ifs ETHYL ACETJQTE
`
`5
`
`6
`
`Figure 2. Binary critical locus for the ethyl acot:ate-COg ayatem.
`
`reached, V1 was oloaod and warm water (313-.l-323.1 K)
`was circulated through the outside water jacket to provide
`thermal mixing of the solvent mixture. The mixture was
`allowed to equilihrate for about 15 min and then cooled
`and reheated to enhance the mixing pro-3&3.
`The homogeneity of the {3(}g—a<:oi:one mixture was
`checked by using an UV detector equipped with a high
`pressure flow cell. The aolsront mixture was prepared as
`described above, and the whole syringe was pumped
`through the UV detoctor to check for the consistency of
`the baseline. 01:: results showed a reasonably stable
`baseline with respect to the volume of the solvent mixture
`passed through, indicating a homogeneous solvent mixture
`along the length of the syringe. This woo further confinzood
`by the reproducihlity of the solubility data.
`Prior to each change in cosolvent concentration and
`each change over to an entirely new cosolvent, the whole
`system was purged with at least two syringes of the
`cosolvent mixtures at the required conditions to ensure
`consistent results.
`The procedure was similar to that stated earlier.
`However, more com was taken to ensure any collected
`oosolvent was removed from the filter, F2. This was done
`by placing the filter and the Petri dish containing the
`aolute, oooolvent, and acetone in a vacuum oven. Although
`the ooluto was not analyzed, no change in appearance was
`observed afoot doprossorization which implies that none
`of the oosolvents chemically reacted with naproxen. For
`these ternary systems, the reproduoibilities. were slightly
`better than with the pure studies because of the higher
`solubilitios involved.
`
`Choice of Cosolvents
`
`The ohoioe of cosolvents used was based on availability
`in high purity, toxicology, and physical and chemical
`
`characteristics. The functionality of the ooonlventa was
`chosen such that they might interact differently with
`naproxen, whose structure is shown in Figure 3. As
`naproxon has an acid group, it was expected that inter-
`actions with cosolvents via hydrogen bonding might play
`an important role in solubility enhancement. Thus all
`the oosolvents chosen in this study how hydrogen bond
`accepting capability.
`Various workers have provided methods for cosolvent
`selection. Sunol at al. (1985) divided solvents into various
`classes according to their potential to form hydrogen bonds.
`These workers also listed the likelihood of hydrogen bond
`formation when two aeparaie classes of solvent were mixed,
`and oosohrent was chosen basocl on this. Walsh at al. (1982
`1989) used a similar concept for choosing cosolvonts for
`SCF systems. Tavana at :11. (1£*89} used the ability of the
`oosolvent to reduce retention time of the solute in packed
`GC columns as a method for scanning potential cooolvents.
`In this work, the Kamlot—Tal‘t solvato-chromic solvent scale
`of acidity {us}, boaioity (33), and polorit:;fpo1arizal>ility{w*)
`{Kam1et and Taft, 19‘?€»a,b; Kamlet oi: al., 19?}, 1983) was
`one tool used as a measure ofhydrogon bonding capability.
`Perhaps a more quantitative measure of solvent: power is
`the I-Iilderbrand solubility parameter (Hildebrand and
`Scott, 1950). This parameter can be partitioned into a
`dispersion (Ed), polar (tip), and hydrogen bonding (51,)
`components (Hanson, 1967a.i:», 1969; Hanson and Bear-
`bower, 1971) which again provides a convenient tool for
`classifying solvent strength. The Kamlot—Taft «:2, 3, and
`1* along with the Hansen 5,, for the oosolvonts used are
`given in Table II.
`The dipole moment for the various cosolvents are also
`included in Table II. The dipole moment largely deter-
`mines the orientation of a solvent around an organic solute
`molecule (Keosom forces) in the absence ofspecific solute-
`aoivent interactions. In turn, the dissolving power of a
`solvent also depends on the effectiveness of this elect:-o«
`atatio solvation.
`
`The polarizahility o:* of neighboring molecules is fun-
`damental in accounting for the strength of both Debye
`and London forces between them. The at* values for all
`the cooolvents and naproxen wore estimated and are listed
`in Table II. However, the effectiveness of these attraction
`foroes also depends on molecular size as suggested by Grant
`
`|nnoPharma Exhibit 11100003
`
`

`

`1474
`
`Ind. Eng. Chem. Res., Vol. 32, No. 7, 1993
`
`Table II. Solvatochrornic and Solubility Parameters for All Compounds
`6‘ (MPa1/2)
`
`cosolvent
`1r* "
`a“
`)3“
`M’ (D)
`a“ (cm3 X 1025)
`oz‘/D
`v (cm3/mol)
`5,1
`6,,
`6;,
`5,0,.)
`acetone
`0.71
`0.06
`0.48
`2.9
`64.1
`0.0525
`74.0
`15.5
`10.4
`7.0
`20.0
`ethyl acetate
`0.55
`0.00
`0.45
`1.9
`88.3
`0.0543
`98.5
`15.8
`5.3
`7.2
`18.1
`methanol
`0.60
`0.93
`0.62
`1.7
`32.3
`0.0485
`40.7
`15.1
`12.3
`22.3
`29.6
`ethanol
`0.54
`0.83
`0.77
`1.7
`51.2
`0.0528
`58.5
`15.8
`8.8
`19.4
`26.5
`1-propanol
`0.52
`0.78
`1.7
`69.5
`0.0559
`75.2
`16.0
`6.8
`17.4
`24.5
`2-propanol
`0.48
`0.76
`1.7
`69.9
`0.0550
`76.8
`15.8
`6.1
`16.4
`23.5
`naproxen
`252.5
`0.0850
`178.3”
`10.0’
`6.95
`20.0”
`23.4‘
`C02
`27.4
`
`0.95
`
`0
`
`“ Kamlet et al. (1983). 5 Reid et al. (1988). ° Estimated using eq 2.132-3, Grant and Higuchi (1990). 4 Barton (1983). 9 Fedors group contribution
`method (Fedors, 1974). f Koenhen and Smolders (1975). I Group molar attraction constants (Hay, 1970). " 61, = (6.2 - 6,12 — 6,,2)1/2 (Hansen, 1971).
`
`Table III. Solubility of Naproxen in Pure SC C02
`
`mole fraction naproxen X 105
`313.1 K
`323.1 K
`333.1 K
`0.20
`
`0.83
`
`1.29
`
`1.72
`
`2.08
`
`2.43
`
`0.19
`0.43
`
`1.20
`
`1.77
`
`2.32
`
`2.91
`
`0.70
`
`1.08
`
`1.56
`2.33
`
`2.71
`3.18
`
`press. (bar)
`89.6
`100.0
`110.3
`124.1
`131.0
`137.9
`144.8
`151.7
`165.5
`172.4
`179.3
`193.1
`
`0.005
`
`0.003
`
`0.002
`
`0.001
`
`MOLE%NAPROXEN 0.0003 0.0002
`
`0.0005
`
`Table IV. Solubility of Naproxen in SC CO; with Acetone
`Cosolvent
`
`mole fraction naproxen X 105
`
`press. (bar)
`89.6
`96.5
`110.3
`124.1
`137.9
`151.7
`165.5
`179.3
`193.1
`
`1.75“
`
`333-1 K
`3.5“
`
`0.67
`1.49
`2.67
`3.91
`5.05
`6.09
`5.75
`
`2.03
`3.42
`5.37
`6.96
`8.55
`10.8
`
`5.25“
`
`4.55
`7.88
`10.68
`13.14
`15.07
`16.97
`
`323.1 K
`3.5“
`
`3.25
`4.78
`5.84
`7.05
`7.91
`8.98
`
`318.1 K
`3.5“
`2.45
`3.17
`4.66
`5.22
`6.05
`6.79
`7.18
`7.63
`
`“ Cosolvent composition in mol % (solute free).
`
`Table V. Solubility of Naproxen in SC CO; with Ethyl
`Acetate Cosolvent at 333.1 K
`
`mole fraction naproxen x 105
`
`press. (bar)
`110.3
`124.1
`137.9
`151.7
`165.5
`179.3
`
`1.75“
`0.64
`1.32
`2.36
`3.26
`4.15
`5.26
`
`3.5“
`2.10
`3.43
`5.27
`6.55
`7.18
`9.75
`
`0 Cosolvent composition in mol % (solute free).
`
`5.25“
`5.32
`7.38
`9.64
`11.60
`13.11
`14.33
`
`0.0001
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`Results and Discussion
`
`DENSITY (MOL/L)
`
`Figure 4. Solubility ofnaproxen in pure supercritical carbon dioxide.
`Solid line represents line of best fit.
`
`and Higuchi (1990). A useful measure of the relative
`potential of these kind of interactions would be to divide
`the polarizability a* by the mean volume 0 of the molecule.
`The oz*/0 ratios for all the cosolvents and naproxen are
`listed in Table II. The molar volume, u, was used instead
`of the mean molecular volume. The units used were such
`that this ratio remains a dimensionless entity.
`
`Acetone and ethyl acetate do not self-associate and are
`solely hydrogen bond acceptors. However, they vary
`greatly in terms of dipole moment, dielectric constant,
`molecular size, and critical properties. Alcohols on the
`other hand are able to be both hydrogen bond donors and
`acceptors. They also tend to self-associate even in SCF’s
`(Fulton et al., 1991a,b). Because of the similarities in the
`chemical and physical behavior of compounds in a
`homologous series, their use as cosolvents could contribute
`to a further understanding of their contributions to
`solubility enhancement. The alcohols used are methanol,
`ethanol, 1-propanol, and 2-propanol. The reason for
`including 2-propanol was to study possible steric effects.
`
`Pure Component Solubility. The solubility of naprox-
`en in pure SC CO2 was obtained at 313.1, 323.1, and 333.1
`K and is shown in Table III. As indicated by Figure 4, the
`logarithm of the experimental solubility data gave a good
`linear correlation with respect to pure CO2 density. This
`was expected as shown by various workers (Chrastil, 1982;
`Kumar and Johnston, 1988; Gurdial et al., 1989; Wells et
`al., 1990; Gurdial and Foster, 1991) and provides a check
`on the internal consistency of the data.
`Cosolvent Effect. The introduction of cosolvents
`resulted in a marked increase in solubility for all the
`cosolvents used in this study. These solubility data are
`given in Tables IV-IX. The shapes of the isotherms were
`similar to those obtained with pure CO2, with each
`concentration offset by almost a constant distance from
`the previous one. The solubility isotherms are also linear
`on a log solubility—mixture density plot as represented in
`Figure 5 for the CO2—methanol system. Mixture densities
`were determined as described in the Effect of Density
`section. Thus the solubility behavior in SC CO2-cosolvent
`mixtures is similar to that in pure CO2 under the conditions
`studied. Some workers have observed a significant shift
`of the crossover pressure (Gurdial, 1992; Dobbs et al., 1986)
`when cosolvents were added, however this shift is not
`significant with naproxen and the cosolvents studied.
`
`|nnoPharma Exhibit 1110.0004
`
`

`

`Table VI. Solubility of Naproxen in SC CO; with
`Methanol Cosolvent
`
`mole fraction naproxen X 105
`333.1 K
`
`press. (bar)
`110.3
`124.1
`137.9
`151.7
`165.5
`179.3
`193.1
`
`1.75“
`0.87
`1.95
`3.53
`5.64
`7.76
`9.53
`
`3.5“
`3.29
`7.27
`12.22
`16.54
`20.39
`23.56
`28.54
`
`5.25“
`8.11
`15.63
`22.99
`30.25
`35.90
`41.61
`
`‘' Cosolvent composition in mol % (solute free).
`
`323.1 K
`3.5“
`8.69
`11.37
`14.75
`16.31
`19.52
`22.46
`24.05
`
`Table VII. Solubility of Naproxen in SC CO; with Ethanol
`Cosolvent
`
`mole fraction naproxen X 105
`333.1 K
`
`press. (bar)
`110.3
`124.1
`137.9
`151.7
`165.5
`179.3
`
`1.75“
`1.26
`2.69
`4.42
`6.26
`8.09
`9.55
`
`3.5“
`4.76
`9.62
`14.17
`18.16
`22.19
`25.61
`
`5.25“
`12.78
`21.47
`29.87
`36.43
`42.58
`47.78
`
`“ Cosolvent composition in mol % (solute free).
`
`323.1 K
`3.5“
`8.13
`11.42
`14.21
`15.24
`16.82
`19.18
`
`Table VIII. Solubility of Naproxen in SC CO; with
`I-Propanol Cosolvent at 333.1 K
`
`mole fraction naproxen X 105
`
`press. (bar)
`110.3
`124.1
`137.9
`151.7
`179.3
`
`1.75“
`2.23
`3.86
`5.88
`7.35
`11.20
`
`3.5“
`8.66
`14.34
`19.30
`23.18
`31.58
`
`5.25“
`25.17
`34.65
`42.34
`50.40
`61.82
`
`‘' Cosolvent composition in mol % (solute free).
`
`Table IX. Solubility of Naproxen in SC CO; with
`2-Propanol Cosolvent
`
`press. (bar)
`110.3
`124.1
`137.9
`151.7
`165.5
`179.3
`
`1.75“
`1.37
`3.20
`5.32
`7.22
`8.91
`10.84
`
`mole fraction naproxen X 105
`333.1 K
`323.1 K
`3.5“
`9.54
`13.80
`15.85
`18.31
`21.64
`22.00
`
`3.5“
`7.01
`11.80
`16.83
`21.67
`
`28.11
`
`5.25“
`19.71
`28.09
`36.33
`43.82
`
`56.60
`
`“ Cosolvent composition in mol % (solute free).
`
`In order to illustrate the enhancement as the result of
`the introduction of cosolvent more clearly, the cosolvent
`effect is defined as the ratio of the solubility obtained
`with cosolvent to that obtained without cosolvent. The
`cosolvent effects as a function of cosolvent composition
`on a solute-free basis at 333.1 K and 179.3 bar for all the
`cosolvent systems are shown in Figure 6. Ekart et al. (1992)
`observed that the cosolvent effect for most of the systems
`they studied varied almost linearly with cosolvent com-
`positions. They studied the cosolvent effects of a wide
`selection of cosolvents on a variety of organic compounds
`in SC ethane using SCF chromatography. However, as
`can be seen in Figure 6, the naproxen solubility varied
`nonlinearly with composition and the cosolvent effect
`increases more rapidly at higher concentration. This may
`be indicative of higher order interactions between the
`solute and the cosolvent.
`
`Ind. Eng. Chem. Res., Vol. 32, No. 7, 1993
`
`1475
`
`0.1
`
`0.05
`
`0.02
`
`0.01
`
`0.005
`
`0.002
`
`0.001
`
`0.0005
`
`8
`
`MOLE%NAPHOXEN
`
`
`
`10
`
`12
`
`14
`
`16
`
`18
`
`MIXTURE DENSITY (MOUL)
`
`Figure 5. Solubility of naproxen in supercritical carbon dioxide-
`methanol mixtures at 333.1 K. Solid line represents line of best fit.
`25
`
`1-PROPMDL
`—I-
`2-VHOPANOL
`_._
`ETHANOL
`_‘__
`MEMANOL
`_E_
`AOETONE
`_e...
`ETHVL
`ACETATE
`
`99
`
`loa
`
`.s U!
`
`.a 0
`
`0|
`
`
`
`COSOLVENTEFFECT
`
`0 0
`
`1
`
`4
`3
`2
`MOLE PERCENT COSOLVENT
`
`5
`
`6
`
`Figure 6. Cosolvent effect as a function of cosolvent concentration
`at 333.1 K and 179.3 bar.
`
`Effect of Density. The addition of a cosolvent
`generally increases the bulk density of the fluid mixture
`which would contribute to solubility enhancement. A large
`variation in density would be anticipated close to the
`critical point where the isothermal compressibility is
`largest. However, at pressures and temperatures further
`away from this region, where the fluid is less compressible,
`the increase in bulk density is not expected to be very
`significant and should be within a few percent (0-3 % for
`P > 180 bar) for the cosolvent concentration range between
`1 and 5 mol %.
`The magnitude of the density contribution to the
`cosolvent effect was estimated using the Peng—Robinson
`equation of state (PR EOS). In order to obtain a reasonable
`estimate of the mixture density, the following procedure
`was used. First, the ratio of the calculated mixture density
`to the calculated pure SC CO2 density was obtained using
`the PR EOS. This ratio was then multiplied by the actual
`CO2 density (Wells, 1991) to give the estimated density.
`This procedure will help the density curves fit the shape
`of pure CO2 isotherms. The binary interaction parameters
`necessary were obtained by fitting the EOS to binary
`vapor—liquid equilibrium data as described later. This
`procedure gives binary cosolvent—CO2 density estimates
`accurate to within 20 % and will in general overpredict the
`correct value based on the limited density data available
`(Dobbs et al., 1987; Tilly, 1992).
`On the basis of the calculated mixture densities, the
`density contribution to the overall enhancement was
`estimated by determining the increase in naproxen sol-
`ubility in pure SC CO2 at the same temperature and density
`as the CO2-cosolvent mixture. The contribution of the
`bulk density increase to the overall cosolvent effect for
`the methanol system at 333.1 K is shown in Figure 7. At
`
`|nnoPharma Exhibit 1110.0005
`
`

`

`l4?6 Ind. Eng. Chem. Res., Vol. 32, No. '7, 1993
`25
`
`
`
`
`H
`
`20
`
`1-
`0
`Lu
`|.|,.
`
`3
`
`E 15
`2
`_.I
`g
`:9
`0 1o --
`
`
`1.25 as 5.25
`
`_
`
`137.9
`but
`
`..
`
`151.?
`bl!
`
`wave
`
`265.5
`bar
`
`‘
`%
`
`$T9.3n
`bar
`
`g
`s
`:
`
`
`
`.
`I
`_
`..
`
`1.15 3.5 5.25 ms 35 5.25
`1.75 ea 3.25
`MOLE PERCENT COSOLVENT
`
`.
`
`us 3.5 5.25
`
`120
`
`no
`
`no
`
`see
`use
`esessuse (size)
`
`no
`
`138'
`
`190
`
`EFFECT
`
`1-FHOPIWDL
`_.....
`2-FRCWAMDL
`
`ETHANOL
`
`ASETATE
`. Q... .
`ACETGHE
`..;.g .
`
`GOSGLVENT
`
`Figure '2’. Contribution to the cosolvent effect from the increased
`bulk density as 3 result ofcosolvent addition. System shown is carbon
`dioxide-methanol at 333.1 K.
`
`1.75% co-solvent, the density increase is responsible for
`30-70% of the total cosolvent effect at all pressures. This
`is clearly significant and shows that the density increase
`must he considered when interpreting these effects. It
`can be seen that at higher cosolvent concentrations these
`contributions do not seem as significant when compared
`to the total solubility enhancement observed. This result
`is consistent both with an operating condition removed
`from the high compressibility region and with strong
`specific interactions between the cosolvents and naprosen.
`These observations suggest that accurate density data are
`needed for SCFw~cosolve:ot mixtures so that density effects
`may be more clearly separated from specific interactions
`in systems where both are present.
`Effect of Pressure. The addition of cosolvent to a
`binary SCF-solid system can cause the phase behavior to
`change in three significant ways (Lemert end Johnston,
`1989}. The cosolvent lowers the melting temperature of
`the solid at a given pressure. This can be as much as 70
`°C as shown by the 2~naphthol-meti1anol-CD»; system.
`The shape of the temperature-pressure projection of the
`solid-liqui€l—g'ss melting point curve can also change.
`Finally, the presence of cosolyent lowers the upper critical
`end point (UCEP} pressure significantly. At a critical
`end point {LCEP or UCEP), the solubility, yg, is very
`sensitive to pressure and dyg/8P is large (Kim et al., 1985;
`Lemert and Johnston, 1990) when compared to that
`obtained in the pure SCF. Although ayg/6P values for all
`the coeolvent systems are higher than those in pure 003,
`there were no abrupt rises in solubility (usually observed
`near a CEP) for the range of temperatures and pressures
`studied, indicating that CEP’s were not approached in
`this study.
`The effect of pressure on the cosolvont effect changes
`with cosolvent concentration (see Figure 7). For the system
`CO3-niethanol-nsproxen the total cosolvent effect is
`essentially constant (within experimental uncertainty) at
`1.75 92 methanol. It goes through a clear maximum at 138
`bar for 3.5 % methanol and then monotonically decreases
`with pressure for 5.25% methanol. All the cosolvent
`systems exhibited a decreasing cosolvent effect with
`increasing pressure at 5.25 ii cosolvent as shown in Figure
`8. Various workers have investigated the nature of the
`solute-cosolvent interactions under these conditions (Kim
`and Johnston, 198'7a,b; Yonlrer and Smith, 1988, 1989}. It.
`was shown that the region within the first few solvent
`shells around the solute molecule is enriched with the
`cosolrent and the local concentration can be several times
`that of the bulk composition. The significance of this
`local ordering of the cosolvent molecules decreases with
`
`Figure 8. Cosclvent effect as a function of pressure at 333.1 K and
`a cosolvent concentration of 5.25 mol %.
`
`increasing pressure, and at high enough pressures, the
`concentration of the cosolvent around the solute will
`ultimately approach the bulk concentration {Yonker and
`Smith, 1988). An important point to realize is that while
`the local composition enhancement decreases, the absolute
`local concentration of cosolvent around the solute will
`always increase with increasing pressure due to the increase
`in density. In the present case, it appears that the cosolvent
`effect at low cosolvent concentrations depends predom-
`inantly on the absolute concentration ofcosolvent around
`the solute as no distinct pressure dependence was observed.
`As the cosolvent concentration is increased, the effect of
`local composition enhancement becomes apparent. Since
`the local composition enhancement is maximized in the
`region of high compressibility, it seems plausible that the
`decrease in the difference between bulk and local cosolvent
`concentration with pressure would lead to the observed
`decrease in cosolvent effect with pressure. This could be
`confirmed with information on the compressibility of the
`cosolvent mixtures.
`Effect of Mixture Critical Point. As an aid to the
`interpretation of the effect of alcohol chain length and
`nonspecific interactions, we compare the relative distance
`of the operating conditions from the critical state of each
`binary CO;x-cosolvent system. This comparison is possible
`because the critical locus data for all the Cflrcosolvent
`binary mixtures need in this study are