(6) E. R. Garrett and P. B. Chemburkar, J. Pharm. Sci., 57,
`944(1968).
`(7) Ibid., 57,949(1%8).
`(8) Ibid., $7, 1401(1968).
`(9) M. Nakano and N. K. Patel. J. Pharm. Sci., 59, 79(1970).
`(10) J. Haleblian, R. Runkel, N. Mueller, J. Christopherson, and
`K. Ng, ibid., 60, 541(1971).
`(11) C. F. Most, J. Appl. Polym. Sci., 14, 1019(1970).
`(12) G. L. Flynn and T. J. Roseman, J. Pharm. Sci., 60, 1788
`(1971).
`(13) G. L. Flynn and R. W. Smith, ibid., 61,61(1972).
`(14) T. J. Roseman and W. I. Higuchi, ibid., 59, 353(1970).
`(15) T. J. Roseman, ibid., 61,46(1972).
`(16) T. Higuchi, ibid., 52, 1145(1963).
`(17) B. J. Zwolinski, H. Eyring, and C. E. Reese, J. Phys. Chem.,
`53, 1426(1949).
`(18) R. E. Beck and J. S. Schultz, Science, 170, 1302(1970).
`(19) J. Dainty and C. R. House, J. Physiol., 182,66(1966).
`(20) A. W. Cuthbert and Y. Dunant, Brit. J. Phormacol., 40,
`508( 1970).
`(21) G. L. Flynn and E. W. Smith, J. Pharm. Sci., 60, 1713
`(1971).
`(22) H. C. Brill, J. Amer. Chem. SOC., 43, 132q1921).
`(23) G. L. Flynn, J. Phurm. Sci., 60, 345(1971).
`(24) T. Higuchi and S . S. Davis, ibid.. 59,1376(1970).
`(25) G. Saracco and E. S . Marchetti, Ann. Chim., 48, 1357(1958).
`(26) H. A. Daynes, Proc. Roy. Soc., Ser. A, 97, 28q1920).
`(27) R. M. Barrer, Truns. Faradoy Soc.. 35, 628(1939).
`(28) K. F. Finger, A. P. Lemberger, T. Higuchi, L. W. Busse, and
`D. E. Wurster, J. Amer. Pharm. Ass., Sci. Ed, 49, 569(1960).
`(29) W. I. Higuchi and T. Higuchi, ihid., 49, 598(1960).
`(30) G. L. Flynn, 0. S. Carpenter, and S. H. Yalkowsky, J .
`Pharm. Sci.. 61, 312(1972).
`(31) S. H. Yalkowsky, G. L. Flynn, and T. G. Slunick, ihid., 61,
`852( 1972).
`(32) 1. D. Robb, Ausfr. J . Chem., 19, 2281(1966).
`(33) J. J. Kipling, “Adsorption from Solutions of Nonelectro-
`lytes,” Academic, New York, N. Y., 1965, pp. 179-187.
`(34) E. G. Klarmann, V. A. Shternov, and W. L. Gates, J. Lab.
`Clin. Med., 20, 40(1934).
`
`(35) J. B. Niederl, V. Niederl, S. Shapiro, and M. E. McGreal,
`J. Amer. Chem. Soc., 59, 1 1 13( 1937).
`(36) R. R. Read and E. Miller, ibid., 54, 1195(1932).
`(37) W. 1. Higuchi,J.Pharm. Sci., 56, 31x1967).
`(38) R. Adams, E. K. Rideal, W. B. Burnett, R. L. Jenkins, and
`E. E. Dreger, J. Amer. Chem. SOC., 48, 1758(1926).
`(39) K. Kakemi, T. Arita, R . Hori, and R. Konishi, Chem.
`Pharm. Bull., 15, 1883(1967).
`(40) K. Kakemi, T. Arita, R. Hoii, R. Konishi, and K.
`Nishimura, ibid., 17, 248(1969).
`(41) R. Zahradnik, Arch. In/. Pharmacodyn. Ther., 135, 311
`(1962).
`(42) K. Kakemi, T. Arita, S. Kitazawa, M. Kawamura, and H.
`Takenaka, Chem. Pharm. Bull., 15, 1819(1967).
`(43) K. Kakemi, T. Arita, R. Hori, and R. Konishi, ibid., 15,
`1 5 34( 1 967).
`(44) “The Merck Index,” 7th ed., Merck & Co., Rahway, N. J.,
`1960, p. 119.
`(45) M. Mayerson and M. Gibaldi, J. Pharm. Sci., 58,1429(1969).
`(46) Ibid., 60, 22y1971).
`
`ACKNOWLEDGMENTS AND ADDRESSES
`
`Received October 29, 1971, from the Pharmacy Research Uirir,
`The Upjohn Company, Kalumuzoo, MI 49001
`Accepted for publication February 2, 1972.
`The authors express their indebtedness t o Mr. R. W. Smith for
`technical assistance and Dr. M. A. Reberistorf who performed the
`hydrogenations converting nitro compounds to amines. Dr. W.
`Morozowich and Dr. R. G. Stehle’s constructive criticisms and
`comments are acknowledged, as is the critical review of the manu-
`script by Mr. E. L. Rowe. Thanks are ;dso extended to Mr. 0.
`S. Carpenter for assisting in the computer analyses.
`(All men-
`tioned are personnel of The Upjohn Co.) The authors would also
`like to thank the reviewer for his very conscientious efforts on their
`behalf.
`A To whom inquiries should be directed.
`
`Importance of Chain Length on Physicochemical and
`Crystalline Properties of Organic Homologs
`
`S. H. YALKOWSKY., G . L. FLY“,
`
`and T. G . SLWICK
`
`Abstract 0 It has been observed that certain physical properties of
`normal alkyl paminobenzoates (i.e., their melting behavior and their
`solubilities in water, silicone oil, and hexane) exhibit an unusual
`dependency upon chain length. Each property is characterized by a
`definite break in the chain length profile about the butyl ester.
`However, the silicone oil-water and hexane-water partition co-
`efficients of these esters shou a regular increase with chain length
`extending over many orders of magnitude. The overall behavior of
`these homologs is attributed to basic difference in the crystal lattices
`of short ( s f o u r carbons) and long (>four carbons) homologs.
`X-ray patterns and thermal data were obtained and are supportive
`of this conclusion. As an additional veriflcation, the hexane solu-
`bility of each compound was calculated by Scatchard-Hildebrand
`theory using the thermal data and empirically estimated solubility
`
`parameters. Agreement between calculated and experimental
`values is excellent. Because of relationships drawn for the influenct
`of chain length on solubility and relative solubility (partition co-
`efficients), these experiments also indicate a convenient method of
`estimating congeneric solubilities in other solvents.
`Keyphrases 0 Alkyl p-aminobenzoates-ffect
`of chain length on
`melting point, solubilities, partition coefficients, crystalline proper-
`ties Homologous alkyl series, p-aminoknzoates-effect of chain
`length on melting point, solubilities, partition coefficients, crystal-
`line properties 0 Chain length effect- melting point, solubilities,
`partition coefficients, and crystalline properties of alkyl pamino-
`benzoates 0 Structure-activity relationships -effect of alkyl chain
`length on physicochemical and crystalline properties, pamino-
`benzoate esters
`
`The importance of a drug’s physical-chemical proper-
`ties in determining its biological and pharmaceutical
`characteristics has long been recognized. Of particular
`
`importance are the aqueous solubili.ty and the partition
`coefficient which are the major determinants of a drug’s
`dissolution, distribution, and availability. An under-
`
`852 0 Journal of Pharmaceutical Sciences
`
`NOVARTIS EXHIBIT 2219
`Par v. Novartis, IPR 2016-00084
`Page 1 of 6
`
`

`
`Table I-Melting Points of Alkyl pAminobenzoates
`-~
`Hot Stage
`
`Ester
`
`~~~~~
`
`~
`
`~~~
`
`~
`
`DSC
`
`Literature (8)
`
`Methyl
`Ethyl
`ROPY 1
`Butyl
`Pentyl
`Hexyl
`Heptyl
`octyl
`Nonyl
`Dodecyl
`Hexadecyl
`4 Endotherm :it 49" is not present in cooling curve or in remelting
`curvc. * Shoulder on major endotherm.
`
`112"
`89 '
`74"
`56"
`52 O
`61 '
`75"
`71 =
`69"
`82
`87 '
`
`112"
`90"
`73"
`56"
`53
`61 a
`49", 76""
`70", 7Zob
`68"
`82'
`79", 850b
`
`112-1 14"
`90-91 O
`74-91 O
`58-59'
`53-54"
`62-64 '
`75-77"
`70-72 '
`-
`-
`-
`
`~~~~~~~~~~~~~~~
`
`~~
`
`standing of the manner in which these and other proper-
`ties change within a homologous series, i.e., with in-
`cremental additions of methylene units, can be of use
`in choosing a derivative having optimum properties.
`In this regard, the physical-chemical properties of a
`homologous series of alkyl p-aminobenzoates were in-
`vestigated. This series was chosen because: (a) its bio-
`logical activity was studied previously by a number of
`workers (1-.5), giving baseline data for possible cor-
`relations, and (b) the needed compounds were previously
`synthesized for another study (I). Because they are bio-
`logically active, have an ionizable amine function and
`a strong U V chromophore, and cover a wide range of
`hydrophobicity, these compounds are well suited as a
`model series for structure-activity studies.
`The relative solubilities of the members of the n-alkyl
`p-aminobenzoates are atypical of a homologous series.
`However, it will be shown that the solubility data can
`be correlated with the anomolous melting, crystallo-
`graphic, and thermal properties of the respective con-
`geners.
`
`EXPERIMENTAL
`
`Materials-pAininobenzoic acid', methyl paminobenzoatel, and
`ethyl paminobenzoatel were used as received. All other esters u x d
`in this study were synthesized from the appropriate alcoholz and
`pnitrobenroyl chlorideJ. as described previously (I). In the solu-
`bility studies, reagent grade hexanel and a silicone oil' (20 cSt.
`viscosity grade) were used.
`Melting Points--The melting points of all of the esters prepared
`were determined hy the following two independent methods: (u)
`controlled heating on a Mettler hot stage with digital readout, and
`(6) differential scanning calorimetry with the melting point deter-
`mined as the temprrature at which melting begins by extrapolating
`the initial segment of the endotherm to the baseline. The values de-
`termined by these two methods and the available literature values,
`for comparative purposes. are shown in Table 1.
`Aqueous Solubiliyy--The aqueous solubilities of these esters were
`determined at 37:., as described in Rejference I, by either UV spec-
`trophotometric or GC assay.
`Silicone Oil and Hexane Solubility-The hexane and silicone oil
`solubilities were ohtained by equilibrating an excess of pamino-
`benzoic acid ester in the solvent for 3 days at 37". The saturated
`solutions were then diluted with hexane, and the absorbance at 293
`nm. was determined against a similarly prepared blank using a
`UV spectrophotometerl. l h e molar absorptivities at 293 nm. were
`determined in standurd hexane solutions.
`
`120'
`
`c
`5
`0
`n.
`80'
`c) z
`5
`w f
`
`40"
`
`I
`
`2
`
`4
`10
`6
`8
`N U M B E R OF CARBONS
`Figure 1- Melring points of olkyl p-ominobnrzoorrs.
`
`12
`
`14
`
`16
`
`X-Ray Diffraction-The X-ray diffraction patterns of powdered
`samples of each ester were determined on an X-ray spectropho-
`tometer*. The d spacings were calculated from the diffraction angle,.
`8, and the Kal wavelength for a copper target ( A = 1.540% A).
`Differential Scanning Calorimetry (DSC) -The heat of fusion.
`AH,. and the entropy of fusion, AS,, were determined on a DSC
`cell' connected to a differential thermal analyzer console' equipped
`with an X- Y recorder.
`An accurately weighed sample (between 400 and 800 mg.) was
`placed on the sample thermocouple and maintained in a nitrogen
`atmosphere throughout the experiment. All samples were heated at
`lO"/min. The heating curves were recorded at IO"/in. (2.54 cm.) and
`an instrument sensitivity of 1.0. The molar heats of fusion were
`calculated by multiplying the area of the melting endotherm by 160,
`the previously determined heat transfer coefficient of the cell. and
`then dividing by the number of moles of sample used. The entropy
`of fusion of each compound was determined by dividing the heat
`of fusion by the absolute temperature of melting, T,.
`
`RESULTS
`
`Melting Point-The melting points of the p-aminobenzoic acid
`esters determined by DSC are shown in Fig. I . As chain length i\
`increased, the melting point decreases alniost linearly to the butyl
`ester and then increases gradually and irregularly. Thus, a change
`
`10 - 1
`
`10 -'
`
`t'
`2 10-1
`rn
`
`10 -7
`
`10 - 1
`
`1
`
`2
`
`5 6 7
`1 0 1 1 1 2
`4
`8
`9
`N U M B E R OF CARBONS
`iir worer 01 37 '.
`Figure 2-Solubility of alkyl p-c~mbiobenroo~es
`
` 3
`
`1 Eastman.
`2 Eastman or Aldrich.
`* Matheson.
`4 Dow Corning 360 Medical Oil.
`Cary 11.
`
`8 General Electric SRDS.
`1 Dupont Pressure.
`8 Dupont 900.
`
`Yo/. 61. No. 6. Jutre 1972 0 853
`
`NOVARTIS EXHIBIT 2219
`Par v. Novartis, IPR 2016-00084
`Page 2 of 6
`
`

`
`1
`
`2
`
`3
`
`I
`
`I
`
`I 1 I
`
`II
`
`I
`
`I
`
`1
`
`
`
`1
`
`I
`
`I
`
`1
`
`I
`I
`
`.
`
`
`
`\
`
`I
`
`I
`
`.
`
` I
`
`I
`
`1
`
`,
`
`I
`
`I
`
`t
`
`
`
` , I
`
`I I
`
`m 4
`z
`: 5
`u
`0 b 6
`P : I
`-
`: 1
`z
`3 z
`8
`
` I
`
` I
`
`'
`
`
`I l l II
`
`J '
`
`ul
`
`I
`I
`I 1 I
`
`. I
`
`I
`
`9
`
`12
`
`I
`
`I
`
`I 1
`
`I
`
`I 1
`
`I 1
`
`I
`
`I I
`
`I
`
`25"
`
`20"
`
`1'9
`
`10" 9" 8" 7' 6"
`28
`Figure 5- X-ray dijractiotl patterns for olkyl paminobenzoates.
`
`5"
`
`4"
`
`3"
`
`organic phases. However, the variation in water is over a million-
`fold.
`X-Ray Diffraction and Thermal Analysis--Each of the four sets
`of data presented show a change in the chain length dependency at
`four carbons. Since it was presumed that the observed behavior
`was due to a fundamental change in thc crystal properties, X-ray
`diffraction and thermal analyses were performed on the crystalline
`materials to get information on their dimensions and thermo-
`dynamic properties. The major spots of the X-ray diffraction pat-
`terns are summarized in Fig. 5. The angles reported for 20 are
`plotted logarithmically to facilitate the detection of angle multiples.
`The intensities indicated are rough approximations of the true
`values.
`The heat of fusion, AH,, and the entropy of fusion, AS,, of each
`ester are listed in Table 11. Although there is considerable scatter
`in the data, plots of entropy and enthalpy of fusion indicate an
`essentially linear increase with chain length. The change in AS,
`per methylene unit is 2.9 em. This increase is close to the value of
`2.7 f 0.1 e.u. characteristic of monoclinic crystals (6). (By contrast,
`the value for orthorhombic crystals is 2.3 f 0.1 e.u. per methylene
`addition.)
`
`DISCUSSION
`
`Melting Point, Solubility, and Partition Coefficient-Silicone oil
`was used as a solvent in this study became of its chemical similarity
`to the more highly polymerized silicone rubber, which is a solid and
`
`Table 11-Thermal Properties of Alkyl pAminobenzoates
`
`Ester
`
`T,, "K.
`
`~
`
`~
`
`~~~~~
`
`A H i ,
`kcal.!mole
`
`AS,, e.u.
`
`Methyl
`Ethyl
`ROPY1
`Butyl
`Pentyl
`Hexyl
`Heptyl
`octyl
`Nonyl
`Dodecyl
`Hexadecyl
`
`385
`363
`346
`3 29
`326
`334
`349
`345
`341
`355
`358
`
`5850
`4720
`5070
`5870
`5820
`8450
`6350
`9750
`I0800
`14700
`19900
`
`15. 1
`13.1
`14.6
`17.8
`17.8
`25.2
`18.1
`28.3
`31.4
`41.5
`55.5
`
`i
`
`A
`
`t
`
`\
`\
`\
`\
`\ --I
`
`\
`\
`\
`\
`
`\ b
`
`2
`
`.,
`
`10
` 6
`8
`4
`N U M B E R OF CARBONS
`calues calculuted by a. 4 .
`Figure 3-Solubility of alkyl p-aminobenzoatcs in hexane at 37".
`Key: e, experimental oalues; and
`
`12
`
`in melting behavior relative to increasing chain length at the butyl
`ester is clearly evident. These trends are emphasized by the arbi-
`trarily drawn lines in Fig. I.
`Wubility Studies---The logarithms of the 37" aqueous solubilities
`of the eyters studied are plotted cersus chain length in Fig. 2. The
`data appear to fall on two straight lines; p-aminobenzoic acid and its
`methyl, ethyl, propyl, and butyl esters fall on a line having a slope
`of -0.349, which corresponds to a 2.24-fold decrease in solubility
`per methylene unit. The solubility values for butyl and the remaining
`paminobenzoic acid esters describe a line having a slope of -0.625.
`The latter represents a 4.22-fold solubility decrease per methylene
`unit.
`The sdlubilities of these esters were also studied at 37" in two
`organic solvents: dimethylpolysiloxane (silicone) oil and hexane.
`The semilogarithmic solubility profiles of the esters in these two
`solvents are given in Figs. 3 and 4. Unlike the aqueous solubilities,
`the organic phase solubilities of these esters increase linearly with
`chain length for shortchain esters and reach a maximum at about
`the butyl derivative. Thereafter, the solubilities in each of these
`solvents decrease irregularly. The positive slopes of the lines drawn
`through the solubility data for the short-chain esters are 0.19 and
`0.31 for silicone oil and hexane, respectively. There is a definite
`odd-euen alteration in the solubilities of the higher esters, with the
`average decrease in solubility per methylene unit being a factor of
`about 1.3 in silicone oil and 0.6 in hexane. There is roughly only a
`10-fold variation in solubility from one carbon to 12 carbons in the
`
`lo-"
`
`,
`2
`
`,
`,
`,
`,
` 6
`4
`0
`1
`8
`N U M B E R OF CARBONS
`&Solubility of alkyl paminohenzoaies in silicone oil at 37".
`
`,
`
`1
`
`2
`
`
`
`Figure
`
`854
`
`Journal of Pharmaceutical Sciences
`
`NOVARTIS EXHIBIT 2219
`Par v. Novartis, IPR 2016-00084
`Page 3 of 6
`
`

`
`Table 111-Solubilities and Partition Coefficients of Alkyl pAminobenzoates
`
`Silicone Oil
`
`Ester
`
`Methyl
`Ethyl
`ROPY1
`Butyl
`Pentyl
`Hexyl
`Heptyl
`o c t y l
`Nonyl
`Dodecyl
`Hexadecyl
`
`Water
`Solubility,
`moles/l.
`2.53 X 10-'
`1.02 x 10-2
`4.70 x 10-3
`1.72 X
`4.50 x lo-'
`1.07 x lo-'
`2.50 x lo-&
`4.00 x 10-6
`1.00 x 10-6
`1.60 x
`-
`
`r
`
`Solubility,
`moles/l.
`
`5.25 X lW3
`8.33 x 10-3
`1.29 X 1W2
`1.78 X I@'
`1.78 X
`1.12 x 10-2
`1.00 x 10-2
`5.95 x 10-3
`5.34 x 10-3
`1.31 X lW3
`-
`
`Oil-Water
`Partition
`Coefficient
`2.08 x 10-l
`8.17 X lo-'
`2.74 X 100
`1.03 X 10'
`3.95 x 10'
`1.05 X lop
`4 . m x 10'
`1.48 X lo3
`5.34 x 103
`8 . 2 0 ~ 104
`-
`
`-.
`
`r
`
`-Hexan-
`
`Solubility,
`moles/l.
`5.67 x 10-3
`1.28 X
`2.47 x 10-2
`4.60 x 10-2
`6.30 x 10-2
`3.98 X lo-'
`3.81 X 1 0 - 2
`2.46 x 10-3
`2.57 x 10-2
`7.40 x 10-3
`7 . 2 0 ~ 10-3
`
`Oil-Water
`Partition
`Coefficient
`2.24 x 10-1
`1.25 X loo
`5.25 X loo
`2.68 X 10'
`1.40 X lo2
`3.72 X lo2
`1.52 x 103
`6.15 x 103
`2.57 X 10'
`4.64 X 106
`-
`
`not well suited for partition coefficient studies. Dimethylpoly-
`siloxane membranes (silicone rubber) have been used by the authors
`(1, 7, 8) and others (9-12) for theoretical studies on membrane
`transport. A second organic solvent, hexane, was used to demon-
`strate the generality of the solubility profile and to provide assurance
`that the silicone ciil data are not artifactual.
`The solubilities of each ester studied in water, silicone oil, and
`hexane are given in Table 111. These values provide estimates of the
`partition coefficients of each homolog between the immiscible
`phases. Although the solubilities of the esters cannot be described
`by a single exponential function of chain length in any of the three
`solvents, the logarithm of the partition coefficient (as estimated
`by the solubility ratio) IS linearly dependent on chain length. Figure
`6 shows this linearity and the absence of an inflection point at
`four carbons for both the silicone oil-water and the hexane-water
`partition coefficients. The data of Buchi el a/. (5) for these esters
`indicate that the logarithms of the oleyl alcohol-water and amyl
`acetate--water partition coefficients also have a linear dependency
`on chain length through this range.
`The change in log [partition coefficient] with chain length, i.e.,
`the slope of the lines of Fig. 6, is commonly designated as x . The
`T values for silicone oil and hexane are 0.54 and 0.66, respectively.
`If the negative slopes of the segment above four carbons (which are
`typical of most homologous series) of the logarithms of the aqueous
`and organic solvent solubilities are designated as - 6 and - t, respec-
`tively, it can be seen that x = ( - t ) - (-6) = 6 - c. The value of
`6 is 0.625 for the alkyl paminobenzoates. Most homologous series
`have 6 values very close to this value. The T values vary only slightly
`from series to serics and even from nonpolar solvent to nonpolar
`solvent. Thus, it can be seen that the major contribution to the T
`value of a series is the change in aqueous solubility with chain
`
`101
`
`c,
`I- 3
`
`IZ:
`
`10'
`
`100
`
`10 -1
`
` 3
`
`1
`
`2
`
`4
`9
`6
`7
`1 0 1 1 1 2
`5
`8
`NUMBER OF CARBONS
`Figure 6-Purtitiori
`coeficienls of alkyl p-aminobenzoates.
`silicone oil-water; and m, hexane-wuter.
`
`length. Furthermore, the T value is usually around 0.5 for most
`nonpolar solvents.
`The curves in Figs. 1-4 all show a sharp change in slope at the
`butyl derivative. Because melting points and solubilities of crystal-
`line materials are heavily dependent upon crystal energies, it is
`proposed that the nonlinearity of these curves is due to a change in
`crystal structure with chain length. The crystal structure of the
`lower homologs is probably determined primarily by the aromatic
`ring and the dipolar nature of the p-aminobenzoic acid moiety. I f
`chain length is increased beyond four carbons, the linear aliphatic
`chains begin to exert a dominating effect. The odd-even alteration
`seen in the melting point and organic solvent solubility, which is
`characteristic of longchain compounds, supports this contention.
`The fact that no alteration is observed in the aqueous solubility
`data cannot be regarded as significant, since the error in solubility
`measurement is of sufficient magnitude to mask the expected odd--
`even alterations. The linearity (i.e., lack of change in slope) of the
`data in Fig. 6 also supports this hypothesis, because the partition
`coefficient is a property of the solute and therefore is not de-
`pendent on crystal structure. Since the solubility in any solvent is
`dependent upon the sum of the energy required to disrupt the crystal
`and the intermolecular interactions between like and unlike species
`in solution, the solubility ratios are independent of the crystal dis-
`ruption term which appears in the numerator and denominator (see
`section on DSC). Therefore, the partition coefficient is only de-
`pendent upon the interactions occurring in solution.
`These facts provide the basis of the following convenient method
`for determining the aqueous solubility of very insoluble members of
`any homologous series, even if some or all of the congeners are
`crystalline. In a solvent for which the A value of a methylene unit is
`known, the solubility ratio of a shortchain derivative is deter-
`mined. The solubility of the longchain derivative is determined in
`the same solvent. This is usually possible because, as shown in the
`Results section, the solubility does not decrease greatly with chain
`length for most organic solvents. The logarithm of the solubility
`ratio plus Am, where rn is the difference in the carbons between the
`short- and longchain compounds, is equal to the logarithm of the
`solubility ratio of the insoluble congener. The aqueous solubility is
`then determined from the solubility ratio and the organic solvent
`solubility. This method can be used to predict the solubility profile
`of a series in one solvent from its solubility profile in another sol-
`vent and one solubility ratio.
`
`Table IV-Group Contributions to Molar Volume
`and Molar Attraction Constants
`
`Group
`
`Volume,
`cm.3/mole
`
`(EzV?)'/?,
`cal.'/lcrn.'/?/mole
`
`NHz
`CaHd
`_ _ _
`coo
`CHa
`CHz
`Ethyl p-aminobenzoate
`
`7.7
`64
`15.9
`32.4
`16.2
`144.2
`
`423a
`658*
`3 lob
`214b
`133b
`173&
`
`Key: 0 ,
`
`a Determined by subtracting values of other components from 1738.
`b Small's values (22). 5 Determined from solubility in hexane.
`Vol. 61, No. 6, June 1972 0 855
`
`NOVARTIS EXHIBIT 2219
`Par v. Novartis, IPR 2016-00084
`Page 4 of 6
`
`

`
`Table V-Estimation of Solubility Parameters
`for Alkyl pAminobenzoates
`
`Methyl
`Ethyl
`PrOPYl
`Butyl
`Pentyl
`Hexyl
`Heptyl
`Octyl
`Nonyl
`Dodecyl
`Hexadecyl
`
`128.0
`144.2
`160.4
`176.6
`192.8
`209.0
`225.2
`241.4
`257.6
`306.2
`371.4
`
`1605
`1738
`1871
`2004
`2137
`2270
`2403
`2536
`2669
`3068
`3600
`
`12.53
`12.05
`11.69
`11.53
`11.07
`10.86
`10.68
`10.50
`10.39
`10.01
`9.71
`
`explore further the influences of the
`XRay Diffraction-To
`crystal structure, X-ray diffraction patterns were obtained for each
`ester. The patterns of Fig. 5 suggest a similarity in structure for the
`higher homologs. Based on the diffraction patterns, the lower deriva-
`tives are clearly distinctly ditferent from the higher ones and from
`each other.
`The easiest feature of each pattern to detect and interpret is the
`angle of least diffraction, i.e., the spot or spike on the profile farthest
`to the right. This angle is related to the longest d spacing (the dis-
`tance between adjacent molecular planes of the unit cell) of the
`crystal by:
`
`aX
`d = -
`2 sin 8
`where a is a positive integer, X is the wavelength of the X-irradiation,
`and 8 is half the angle between the incident and diffracted rays.
`The d spacings increase linearly with chain length above four car-
`bons, as can be seen from Fig. 7. The slope of the line (1.25 &
`methylene unit) is almost exFctly what would be expected for a
`linear aliphatic chain (1.26 A/rnethylene unit), assuming a tetra-
`hedral angle of 109", 28' and an interatomic distanceof 1.54 A(13).
`Furthermore, the values of these d spacings correspond almost
`exactly to the distance between the amine proton and the end
`methyl protons of a fully extended-scale molecular model of each
`higher homolog. The higher homologs all have a second d spacing
`of 4.1 A which is common for aliphatic hydrocarbons. The longest
`d spacing of the lower homologs is less than the fully extended di-
`mensions of the molecules. Methyl paminobenzoate has a length
`that would not allow the methyl group to be any farther from the
`amine g o u p than the ester oxygen, suggesting Structure I. This
`structure would allow overlap of aromatic orbitals and also maxi-
`
`25
`
`-=a
`
`10
`6
`8
`N U M B E R OF CARBONS
`Figure 7-Crystal spacings of alkyl p-aminobenzoates. Key: @, long-
`est spacing: and m, spacings along a second axis.
`
`12
`
`14
`
`16
`
`2
`
`4
`
`856 IJ Journal of Pharmaceutical Sciences
`
`I
`planar structure of methyl paminobenzoate
`
`mum dipole-dipole interactions between adjacent molecules. This
`would account for its high melting point and large energy and en-
`tropy of melting.
`the change observed in the dependence of
`Thermal Analysis-If
`solubility upon chain length is related to crystal structure, it should
`be possible to correlate mathematically the solubility with the
`melting temperature, the heat of fusion, and the solubility parame-
`ter of each ester by the theory of regular solution (14-16). The mole
`fractional solubility, X I , of a solid in an ideal solution is:
`
`(Eq. 2)
`where T, and T are absolute melting point and temperature, re-
`spectively, and AC, is the difference in heat capacity of the solid
`and the liquid form of the solute.
`In a regular solution (14-16) (one in which heat is absorbed on
`mixing without any entropy change, other than the entropy of
`mixing, taking place), Eq. 2 must be modified to account for the
`intermolecular interactions which occur, diving:
`
`where VZ is the solute molar volume; ti1 and 6% are the solubility
`parameters of the solvent and solute, respectively; and I$1 is the
`volume fraction of solvent. Normally, A(:, is small (14) and the
`last term of Eq. 3 is ignored. Also, for materials of reasonably low
`solubility, @ I may be taken as unity. Thus, Eq. 3 becomes:
`v2 (a1 - 6 1 ) ~ (Eq. 4)
`4.575( TmT ) 4.575T
`log x2 = -I m - -_
`A H T - T
`Since the heat of fusion for each homolog has already been deter-
`mined (Table 11) and the solubility parameters of hexane and water
`are known to be 7.3 and 23.4, respectively (17), only Vt and 8% must
`be known to calculate xp.
`The molecular volume of each ester can be calculated from its
`structure by the summation of group and atomic volumes (18-21).
`The molar volumes of the component groups of the alkyl p-amino-
`benzoates, taken from Yalkowsky (19) and Yalkowsky and Zograli
`(21), are given in Table IV. From these values it can be seen that the
`molar volume of the ethyl ester of p-amiaobenzoic acid is 144.2
`cm.' and changes by 16.2 cm.3 per methylene group.
`The solubility parameter of the solute, Sz, which is defined as:
`
`6 2 = ($)''2
`
`(Eq. 5 )
`
`can be calculated by dividing the molar attraction constant (EsVI)'/Z
`by V2. The additivity of (EI & ) ' I 2
`is well established for hydrocarbons
`(22), but, unfortunately, there is no conclusive evidence for the
`additivity of (EIVz)'/z for polar groups (22). However, if a
`value of the molar attraction constant for one of the alkyl p-amino-
`benzoates can be determined, the values of (EIV2)'/2 for the other
`esters can be estimated by adding 133 cal.'/r cm.*/2 per methylene
`unit. The value of ethylp-aminobenzoate was determined from its
`hexane solubility, molar volume, melting point, and molar heat of
`fusion and Eq. 4 to be 12.05. The value of ( E ? V I ) ~ / ~
`for ethyl p-ami-
`nobenzoate was obtained by dividing bZ by V2. The values of V,,
`(E2V2)'/2, and 6, derived from the values for the ethyl ester are
`shown in Table V. These values, along with the parameters already
`discussed, can now be incorporated into Eq. 4 to predict the hexane
`solubility of each ester. As can be seen from Table VI and Fig. 3,
`
`NOVARTIS EXHIBIT 2219
`Par v. Novartis, IPR 2016-00084
`Page 5 of 6
`
`

`
`Table VI-Estimation of Hexane Solubility of Alkyl pAminobenzoates
`-AH/(Tm - T )
`- Vd6, - 61)’
`_
`_
`_
`4.575TmT
`4.575T
`
`~
`
`
`-log (XI)
`
`Ester
`
`(XI)
`
`5 . 1 2 x 1 0 - 4
`1.64 X 1 0 - 8
`3 . 0 6 X 1 0 - 3
`5.49 x 10-3
`7.51 X 1 0 - 8
`4.85 X 1 0 - 8
`4 80 X 1 0 - 8
`3.63 X 1 0 - 3
`3.95 x lo-’
`1 . 0 0 x 10-3
`4.39 x 10-4
`
`-Molar
`Calculated
`3.94 x 1 0 - 3
`1.27 X 10-1
`,. .
`2.36 X 1 0 - 2
`4.23 x 10-2
`5.80 X 10-*
`3.73 x 1 0 - 2
`3.69 X 1 0 - 2
`_
`
`- .. _
`2.80 x 10-1
`3.07 X lo-’
`7.70 x lo-’
`3.38 X 10-*
`
`~
`
`Solubility--
`Experimental
`5.67 x
`1.28 x lo-’
`2.47 X 10-2
`4.60 x i o - 2
`6.30 x 10-2
`3.98 X 10-’
`3.81 X 1 0 - 2
`2 . 4 6 X 10-2
`2.57 X io-2
`7.40 x 10-3
`7.20 X 1W3
`
`Methyl
`Ethyl
`PrOPYI
`Butyl
`Pentyl
`Hexyl
`Heptyl
`Octyl
`Nonyl
`Dodecyl
`Hexadecyl
`
`2.490
`2.295
`~~ 2.143
`2.022
`1.923
`1.889
`1.819
`1.760
`1.709
`1.564
`1.478
`
`0.80
`0.490
`0.371
`0.239
`0.201
`0.426
`0.500
`0.680
`0.690
`1.438
`1.880
`
`3.290
`2.785
`2.514
`2.261
`2.124
`2.315
`2.319
`2.440
`2.399
`3.002
`3.358
`
`the agreement between the theoretical and experimental solubility is
`excellent.
`Attempts to use Q. 4 and the solubility parameter of water to
`predict the aqueous solubility of the alkyl paminobenzoates were
`unsuccessful. This is not surprising since the theory of regular
`solutions is not valid for polar solvents or when 6, - 61 is large as
`it is in this case. This theory is also not valid if solute inter- or intra-
`molecular interactions are present.
`
`CONCLUSION
`
`The type of behavior described hereforthealkylpaminobenzoates
`would be expected for other homologous series containing either a
`polar and/or aromatic moiety, the so-called “loading group” of
`Ubbelohde (23). All that is required is that the loading group be
`property determining until the polymethylene unit is large enough
`to dominate the crystal structure. Breusch (24) showed that 0-
`hydroxy-, 0-phenyl-, and 0-alkyl propionic acids show a maximum
`in solubility at about five carbons in ethyl acetate, benzene, and
`hexane. These compounds show a regular odd-even alteration in
`solubilities and in melting points above five carbons. The melting
`points of the pnitrobenzoate esters (25) show the same type of
`behavior as the paminobenzoates, with a break in the curve at six
`carbons and odd-even alteration above six carbons. Other ho-
`mologous series (24)with smaller loading groups show breaks in their
`melting-point curves at lower chain lengths. In general, large groups
`such as a- or 0-naphthyl or anilino (23), or groups that can interact
`strongly by hydrogen-bond formation or dipolar interactions such
`as amides, require more methylene units to offset their effects on
`crystal packing (23).
`This change in crystal structure as a function of chain length is
`somewhat analogous to micelle formation within a homologous
`series. The lower members of a surfactant series exist only as mono-
`mers whose properties are primarily determined by the polar
`group. They are, of course, without appreciable surface activity.
`As chain length is increased, the increasingly amphiphilic character
`provides for orientation of the molecules into a particular structure,
`the micelle. Further increases in chain length serve to increase the
`stability of these structures relative to the monomeric state. Based
`on the solubility and thermodynamic data presented here, the same
`descriptive analysis could easily be applied to changes in crystal
`structure with chain length.
`
`REFERENCES
`(1) G. L. Flynn and S. H. Yalkowsky, J. Pharm. Sci., 61, 838
`(1972).
`(2) R. Zahradnik, Arch. Inf. Pharmacodyn. Ther., 135, 311
`(1962).
`
`(3) R. Adams, E. K. Rideal, W. B. Burnett, R. L. Jenkins, and
`E. E. Dreger, J. Amer. Chem. SOC., 48, 1758(1926).
`(4) H. C. Brill, ibid., 43, 1320(1921).
`( 5 ) J. Buchi, X. Perlia, and A. Strassle, Arzm+n.-Forsch., 16,
`1657( 1966).
`(6) A. Bondi, Chem. Reu., 67,565(1967).
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`( 1971 ).
`(8) G. L. Flynn and R. W. Smith, ibid., 61,61(1972).
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`1401 ( 1968).
`(10) M. Nakano and N. K. Patel, ibid., 59,79(1970).
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`(12) T. J. Roseman and W. 1. Higuchi, J. Phorm. Sci., 59,
`353( 1970).
`(13) A. W. Ralston, “Fatty Acids and Their Derivatives,” Wiley,
`New York, N. Y., 1948. p. 338.
`(14) J. H. Hildebrand and R. L. Scott, “The Solubility of Non-
`electrolytes,’’ Reinhold, New York, N. Y., 1950, chap. 12.
`(15) A. N. Martin, J. Swarbrick, and A. Carnmarata, “Physical
`Pharmacy,” Lea & Febiger, Philadelphia, P