`This article is protected by copyright and is provided by the University or Wisconsin-
`
`Madison under license from iehri wi'iey a Sons. All rigms reserved.
`
`
`
`J. Pharm. Pharmacol., 1964, 16, 3237331
`
`Received October 14, 1963
`
`The solubilisation and inactivation of preservatives
`
`by non-ionic detergents*
`
`W. P. EVANS
`
`A novel potentiometric method, which depends on the pH changes which occur
`when an acidic material is solubilised, has been used to determine the solubilisation
`of the weakly acidic preservative, p-hydroxybenzoic acid, in a non—ionic detergent.
`From the pH changes observed, the partition coefficient, Km, for the distribution of
`the un-ionised acid between the micellar and the aqueous phase has been calculated
`and found to be 2‘8 x 103.
`Specific interaction between the acid and the detergent.
`to form a complex is shown not to be important.
`It is suggested that the arguments
`.against specific interaction apply generally to other preservatives and non-ionic
`detergents.
`
`ON-IONIC detergents are used to an increasing extent as solubilising
`and emulsifying agents in cosmetic and pharmaceutical systems. They
`'
`have some disadvantages, the main one being the inactivation of preserva-
`tives such as p-hydroxybenzoic acid and benzoic acid or their esters,
`which are commonly employed in such systems (de Navarre, 1953, 1956).
`The cause of the inactivation has not been established, although
`complex formation between the preservative and the non-ionic detergent
`is often postulated. Higuchi & Lach (1954) state that Carbowax, a
`polyethylene glycol, forms complexes with benzoic, salicylic and p-hydroxy-
`benzoic acid by reaction of the phenolic or carboxylic hydrogen with the
`ether oxygen of the glycol. Several authors have suggested that similar
`interactions also occur with non-ionic surface-active agents. The following
`formula has been proposed, but no quantitative data have been given, for
`a complex between phenol and a non-ionic detergent.
`
`a—:-—
`
`——
`
`H
`
`ii
`
`—
`
`RO'(CH2CH26)3 (CH.CH,O)bi—i
`
`C.H,o
`
`__ a
`
`Protonation of the ether oxygen is, however, extremely improbable at
`the non-ionic detergent concentration and pH values of most cosmetic
`preparations; this is proved by the results described in this paper. Further-
`more, it is unlikely that such interaction is the whole or even part of the
`inactivation, since inactivation may occur with preservatives of widely
`different types (Wedderburn, 1958). A more probable explanation is
`solubilisation of the preservative in the non-ionic micelles. Solubilisation
`of phenolic bactericides by micellar soap solutions is well known and it
`has been shown by many investigators that solubilisation results in a
`decrease of bactericidal activity (Alexander, 1946, 1949).
`From the Unilever Research Laboratory, Unilever Ltd., Port Sunlight, Cheshire.
`* Part of a paper presented at a conference of “Group Rech. Prod. Superf. Actf.
`5° COIL”, in Paris, 1959.
`
`323
`
`UCB Biopharma SPRL (IPR2019—00400)
`Exhibit 2014 Page 1
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 1
`
`

`

`W. P. EVANS
`
`The normal method of estimating the amount solubilised by anionic
`and cationic detergents is to add increasing amounts of the solubilisate
`to the detergent solution and to equilibrate. When excess solubilisate is
`present the solutions are turbid and the amount solubilised can then
`readily be determined. Unfortunately, it is impossible in many cases to-
`determine solubilisation by non-ionic detergents by this method because
`their cloud points are depressed by many solubilisates;
`the observed
`turbidity in such cases is not due to excess solubilisate but to “salted out”
`detergent or coacervate.
`Apart from being inapplicable to many non-ionic detergents the equili—
`bration solubilisation method is generally unsatisfactory even with anionic
`and cationic detergents since the results are difficult to interpret because
`measurements, apart from one or two exceptions (McBain, 1940), have
`always been made in saturated systems. The present paper describes a
`simple titration method which overcomes this difficulty, and which allows
`determination of solubilisation in unsaturated systems;
`it can be used
`with solubilisates containing a weak acidic group and depends on pH
`changes which result from preferential solubilisation of the un-ionised
`acid.
`It has been used in the present study to determine the solubilisation
`of p-hydroxybenzoic acid (a common cosmetic preservative) by the-
`non-ionic detergent octyl phenol condensed with 8-5 moles of ethylene
`oxide.
`
`TITRATIONS
`
`Experimental
`
`p-Hydroxybenzoic acid solutions (100 m1, either 0-01 or 003 M) con'
`taining varying concentrations of the non-ionic detergent (from 0-03 to
`020 M) were titrated potentiometrically with 01 N sodium hydroxide
`using calomel and glass electrodes. Preliminary titrations with acetic
`and hydrochloric acids showed that the titration curves of the two acids
`were unaffected by the detergent, proving that it did not affect the potentials
`of the electrodes.
`
`CLOUD POINTS
`
`Cloud points were determined by the usual method of heating a 1%
`solution of the detergent alone or with additive until a faint turbidity
`appeared. The temperatures at which turbidity first appeared were taken
`as the cloud point of the detergent. These were reproducible to i0-2".
`
`Results and discussion
`
`Fig. 1 shows a plot of the apparent “solubility” at 25° of p-hydroxy-
`benzoic acid in varying concentrations of the detergent determined by
`the conventional turbidity method.
`Up to a detergent concentration of about 36% (w/v), the apparent
`solubility of the acid in the detergent solution is less than its solubility
`in pure water. That the turbidity is due, not to excess solubilisate, but
`to a salted-out mixture of detergent plus solubilisate was confirmed by
`324
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 2
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 2
`
`

`

`INACTIVATION OF PRESERVATIVES BY NON-IONIC DETERGENTS
`
`‘d(molar)
`
`Apparentsolubilityofp-hydroxybenzoicacu
`
`
`
`
`
`
`
`B
`6
`lo
`'2
`ll
`Conc. non-ionic detergent (% w/v)
`FIG. 1. Apparent solubility of p-hydroxybenzoic acid (molar) at 25° in varying
`concentrations of octyl phenol/86 moles ethylene oxide.
`
`10
`
`allowing the solutions to stand for some time, when two layers separate
`out, one layer being detergent rich, the other being water rich, but both
`layers containing the solubilisate. The separation of non-ionic detergents
`in this way is related to the cloud point phenomenon; a solution of the
`
`°C
`
`Cloudpoints
`
`[no
`0.05
`2”
`Conc. p-hydroxybenzoic acid (moles/litre)
`
`FIG. 2: Cloud points of various concentrations of octyl phenol/S-S moles ethylene
`oxide in presence of p-hydroxybenzoic acid. 0 10% (w/v) octyl phenol/86 moles
`ethylene oxide. A 5% (w/v) octyl phenol/8-5 moles ethylene oxide.
`El 1% (w/v)
`octyl phenol/8'5 moles ethylene oxide. V 01% (w/v) octyl phenol/8-5 moles
`ethylene oxide.
`
`325
`
`UCB Biopharma SPRL (lPR2019-00400)
`Exhibit 2014 Page 3
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 3
`
`

`

`W. P. EVANS
`
`detergent becomes cloudy when heated above a certain temperature—
`“the cloud point”. The effect of p-hydroxybenzoic acid on the cloud
`point of different concentrations of the detergent is shown in Fig. 2.
`It is often stated that addition of organic additives such as phenol or
`hydroxybenzoic acid, results in precipitation of a complex of the non-
`ionic detergent and its additive. This is unlikely, however, since pre-
`cipitation also occurs with additives such as benzene or sodium sulphate.
`with which it is difficult to visualise the formation of such a complex.
`The precipitate which separates in these instances is not a detergent-
`additive complex, but the separation of a detergent-rich layer containing-
`the dissolved additive,
`i.e.. a coacervate. For example, a 20% (w/v)-
`solution of octyl phenol/85 mole ethylene oxide saturated with p-hydroxy-
`benzoic acid separates into two layers at 250. The analysis of the two
`layers is as follows:
`
` Cloud point Surface tension 1 Acid in each
`
`‘’C
`‘ dynes/cm at 25° ‘
`layer %
`>98
`36-0
`‘
`0-68
`Aqueous layer
`
`
`7* . ~..Non-ionic layer 19-0
`
`
`
`
`
`
`
`
`The aqueous phase contains virtually no detergent as shown by the-
`high “cloud point” and only 068% (w/v) of acid, while the detergent
`phase contains 190% (w/v) of the acid.
`[The solubility of the acid in
`pure water is 0-63% (w/V) and in the anhydrous detergent 26% (w/v]).
`
`10
`
`
`
`[I
`
`l.
`
`8
`ml O-IN NaOH
`
`12
`
`16
`
`20
`
`FIG. 3. Titration of 100 ml of 0-01 M p-hydroxybenzoic acid containing varying
`concentrations of octyl phenol/8-5 moles ethylene oxide with 0le NaOH. V Acid
`alone.
`[3 Acid containing 5% (w/v) ethanol.
`>< Acid containing 0~03M octyl
`phenol/8'5 moles ethylene oxide. 0 Acid containing 0-10M octyl phenol/8'5 moles
`ethylene oxide. A Acid containing O-ZOM octyl phenol/8'5 moles ethylene oxide_
`326
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 4
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 4
`
`

`

`INACTIVATION OF PRESERVATIVES BY NON-IONIC DETERGENTS
`
`With sodium sulphate as the additive, separation into two phases again
`occurs, with the sodium sulphate dissolved in both phases, but, unlike
`the p-hydroxybenzoic acid,
`it
`is preferentially soluble in the aqueous
`phase. Further unpublished results confirm that with most additives
`the detergent-additive precipitate is not a definite chemical complex but
`a coacervate of varying stoichiometry.
`Typical titration curves of p-hydroxybenzoic acid in the presence of a
`non-ionic detergent (below the cloud point) are given in Fig. 3.
`The titration curves given in Fig. 3 show a pH shift to higher values
`in the presence of the detergent, therefore either the free concentration of
`the un-ionised acid has decreased as a result of some interaction with the
`
`detergent, or the detergent has changed the dielectric constant of the
`solution or the electrode potentials because it has been adsorbed on the
`glass electrode.* The titration curves of acetic acid and hydrochloric
`acid. however, were not affected by the presence of the detergent, so that
`the pH changes observed are not due to dielectric changes or to changes
`in the electrode potentials, but must be due to a decrease in the concen-
`tration of un-ionised acid. Furthermore,
`the normal
`titration results
`observed with acetic and hydrochloric acids show that protonation of the
`ether oxygen of the detergent as suggested by various authors does not
`take place, or, at least, the extent of protonation is too small to be detected
`by pH changes.
`The titration results of p-hydroxybenzoic acid can be interpreted by
`assuming a decrease in the concentration of the un—ionised acid due either
`to complex formation of the type suggested by Higuchi & Lach (1954)-
`or to solubilisation of the un-ionised acid; the results have therefore been
`used to calculate constants (Kc and Km), assuming:
`
`(1) Formation of a 1:1 complex between non-micellar detergent (i.e.,.
`single molecules) and the un-ionised acid (Kc).
`
`(2) Solubilisation of the un-ionised acid in the detergent micelles (Km)-
`The equilibria considered here are:
`HAwater Fl H+ ‘i‘ A—
`Jr
`HAmtcelles
`
`The constants obtained are given in Table 1, from which it is evident.
`that the “constant”, Kc, for a 1:1 complex shows considerable drift;
`interaction of the acid with monomeric detergent molecules is therefore
`unlikely.
`Furthermore, any such interaction should, at constant acid concen-
`tration, result
`in pH shifts which are independent of total detergent
`concentration provided this is above the critical micelle concentration
`(about l~7 X 10—4 M for the detergent used here) since the concentration of
`the monomeric detergent molecules is constant above the CMC. Further
`evidence against complex formation was obtained by titrating aqueous
`
`* Since this work was completed (Paris, 1959), Donbrow & Rhodes (1963) have
`published titration curves showing similar pH shifts, but no quantitative treatment
`was given.
`
`327
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 5
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 5
`
`

`

`W. P. EVANS
`
`solutions of p-hydroxybenzoic acid containing polyethylene glycol 400,
`a polymer of 9 ethylene oxide units, identical with the hydrophilic part
`of the non-ionic detergent, but, unlike the latter, not aggregating to form
`micelles; no pH shifts were observed.
`
`TABLE 1.
`
`THE pH, CONCENTRATION OF THE VARIOUS SPECIES, AND SOLUBILISATION
`AND COMPLEXING CONSTANTS (Kch) FOR VARIOUS CONCENTRATIONS 0F
`p-HYDROXYBENZOIC ACID AND OCTYL PHENOL/S-S MOLES ETHYLENE OXIDE
`
`
`[HA];
`[Detergent]
`[A']
`[HA]aq
`[HA]m
`Kc X 10"“ 1 Km X 10’3
`
`
`-
`0001056
`0003557
`0005289
`002970
`0009902
`1-2
`X
`2-8
`
`
`
`
`01869
`5-73
`0006269
`0009346
`0000330
`0002747
`021
`‘
`25
`0029 l 3
`4-48
`0002824
`0009710
`0002803
`0004083
`12
`‘
`28
`
`
`
`002678
`4-59
`001030
`002670
`0007101
`0009300
`1-3
`x
`2-7
`
`
`002577
`0-1724
`5-44
`001322
`0001248
`001130
`019
`1
`29
`
`
`0009524
`009524
`5-20
`0004568
`0000836
`0004120
`035
`l
`29
`
`
`
`002770
`01852
`4-96
`0007109
`0002175
`001842
`020
`L
`2-6
`
`
`0009616
`009616
`5-05
`0003695
`0000970
`0004951
`03
`1
`2-9
`
`
`
`
`
`
`
`
`002670
`0-1786
`5-22
`001028
`0001666
`001475
`019
`.
`2-8
`0009854
`002957
`414
`0001488
`0003 342
`0005024
`H
`l
`2-8
`002718
`01818
`512
`0008718
`0001807
`001666
`019
`:
`2-8
`
`
`
`
`
`= Concentration acid anion H0 - </—\ - COO’ (moles/litre).
`[A']
`[HA]: = Total concentration of acid in system (moles/litre).
`
`[HAlaq = Concentration un-ionised acid HO - \/ > - COOH in water phase (moles/litre).
`[HAJm = Concentration un-ionised acid H0 ~ <_>’\\ - COOH in micelle (moles/litre).
`[Detergent] = Concentration of detergent (moles/litre).
`‘Calculations assuming 1:2 or 1:3 complexes also gave unsatisfactory constants, Kc.
`
`The results can, however, be interpreted satisfactorily by assuming
`solubilisation of the p-hydroxybenzoic acid in the detergent micelles,
`without postulating any specific interaction. McBain & Hutchinson
`(1955) point out that many instances of solubilisation can be quantitatively
`described as a partition of solute between two immiscible phases. When
`the solubilisate carries a polar group, as in the present study,
`it may
`orient itself on the surface of the micelle instead of passing into the
`hydrocarbon interior, but even in this case the solubilisation may be
`approximately characterised by a simple distribution coeflicient.
`In the
`present work the solubilisation is also treated as a distribution phenomena
`of the un-ionised acid between the aqueous phase and the micellar phase
`and a distribution constant, Km, calculated. The distribution constant
`is defined as:
`
`K _
`_ [HAanelle mole acid/mole detergent
`[HAlwater
`mole acid/mole water
`m
`
`That solubilisation and not complex formation is the correct inter-
`pretation of the pH shifts is further supported by the fact that pH shifts
`are also observed when long-chain fatty acids are titrated in the presence
`of anionic detergents (e.g., lauric acid in the presence of sodium dodecyl
`sulphate). Again there is no evidence of specific interaction to form
`complexes but from the results (to be published) similar partition coeffi-
`cients for solubilisation can be calculated.
`(From the data on page 326
`328
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 6
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 6
`
`

`

`INACTIVATION OF PRESERVATIVES BY NON-IONIC DETERGENTS
`
`a partition coefficient was also calculated and found to be 2-3 x 103, in
`good agreement with that calculated from the potentiometric data).
`The anions of the acid would not be expected to be solubilised to the
`same extent, and this is proved by the fact that there are no pH shifts
`when the phenolic group of the p-hydroxybenzoic acid is titrated. A
`number of authors (e.g., Maclay, 1956) have stated that solubilisation
`results in a decrease in the hydrophilic character of the non-ionic micelles,
`and any solubilised material would therefore decrease the cloud point
`whereas the mono-sodium salt, which is not solubilised,
`increases the
`cloud point (Fig. 4).
`
`Cloudpoints°C
`
`‘5
`
`3D
`
`20
`
`0-05
`
`0.10
`
`Conc. additives (moles/litre)
`
`FIG. 4. Cloud points of 1% (w/v) octyl phenol/8‘5 moles ethylene oxide in presence
`of various additives. A p-hydroxybenzoic acid, I] mono sodium salt of p-hydroxy-
`benzoic acid, 0 benzoic acid, V sodium benzoate,
`>< phenol, 0 sodium phenate.
`
`The value of the distribution constant, Km, obtained in this work
`(Km = 2-8 x 103)
`is constant over
`the whole concentration range
`examined, and is of the same order as those values reported in the literature
`for solubilisation by anionic and cationic detergents (McBain & Hut-
`chinson, 1955). Few data are available for solubilisation by non-ionic
`detergents; Moore & Bell’s results (1957) on the solubilities of phenyl
`ethyl alcohol and benzaldehyde in hexadecyI/l4 moles ethylene oxide and
`in hexadecyl/24 moles ethylene oxide respectively as determined by the
`conventional turbidity method are given in Table 2 (in Moore and Bell’s
`study, saturation of the solution by the solubilisate was apparently reached
`before the cloud point was reduced sufficiently to precipitate the deter-
`gents).
`
`329
`
`UCB Biopharma SPRL (IPR2019—00400)
`Exhibit 2014 Page 7
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 7
`
`

`

`W. P. EVANS
`
`Moore and Bell’s results have been used to calculate the relevant
`distribution constants, Km, which are of the same order as those obtained
`in the present study.
`
`TABLE 2.
`
`SOLUBILITY (g/lOO m1) 0F PHENYLETHYL ALCOHOL AND BENZALDEHYDE
`IN HEXADECYL/24 MOLEs ETHYLENE OXIDE AND HEXADECYL/l4 MOLES
`ETHYLENE OXIDE RESPECTIVELY AT 25° (Moore & Bell, 1957)
`
`Solubility of benzaldehyde
`Solubility of phenylethyl
`in hexadecyl/l4
`alcohol in hexadecyl/24
`
`moles ethylene oxide
`moles ethylene oxide
`!
`
`Concentration of detergent %
`
`
`
`__
`_._
`___[—_
`5-0
`2-5
`5-0
`10-0
`2-5
`|
`10-0
`
`Total wt solubilised (g) .
`.
`3-24
`5-04
`8-28
`-38
`4-13
`160
`160
`~
`Wt in aqueous phase (g)
`['60
`033
`
`3-44
`6-68
`Wt in micellar phase (g)
`1-64
`3-8
`
`2-9
`2-8
`Km X 10'3
`._
`2-7
`5-4
`
`
`
`..
`.
`.
`
`_.
`
`Apart from the exception noted (McBain, 1940), all previously reported
`solubilisation data have been obtained by examination of systems con-
`taining excess insoluble phases, where both the micellar phase and the
`aqueous phase are saturated with the solubilisate. By subtracting the
`solubility of the solubilisate in pure water from its solubility in the deter-
`gent solution, the amount Of solubilisate dissolved in the micelles can be
`obtained. This type of calculation, however, assumes that the concentra-
`tion of the solubilisate in the aqueous phase in a saturated detergent
`solution is the same as its solubility in pure water; this may not always
`be true, e.g., potassium laurate even below the CMC increases the water
`solubility of phenol five times. Furthermore, due to deviation from ideal
`behaviour, the distribution constant of a solute between two immiscible
`phases changes as the two phases become saturated. That the results
`obtained in the present paper are of the same order as those calculated
`from Moore and Bell’s work must therefore be regarded as somewhat
`fortuitous.
`
`TABLE 3. MOLAR CONCENTRATION OF UN-IONISED p-HYDROXYBENZOIC ACID IN THE
`WATER PHASE IN THE PRESENCE AND ABSENCE OF 58% (w/v) DETERGENT
`AT VARIOUS pH’s USING 01% (w/v) TOTAL CONCENTRATION OF p-HYDROXY-
`BENZOIC ACID
`
`[HAhmfl in
`Total (7,) (w/v) acid required in presence of
`presence of
`5-8 7. (w/v) detergent to be equivalent to
`pH
`[HAMMH
`5-8 % detergent
`O-l % (w/v) acid in pure water
`
`3-5
`0-00662
`000118
`0.56
`4-0
`000559
`000114
`0-49
`4-5
`0-00376
`000104
`036
`5-0
`000220
`0000805
`
`0-27
`
`All the results Obtained in this study can be adequately explained by
`solubilisation of the un-ionised p-hydroxybenzoic acid in the non-ionic-
`micelles, without postulating specific interaction or formation of com-
`plexes as has been done by most authors. Since the un-ionised acid
`(Simon, 1952), is generally regarded as being the active preservative, and
`330
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 8
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 8
`
`

`

`lNACTIVATION OF PRESERVATIVES BY NON-IONIC DETERGENTS
`
`since only the acid in the aqueous phase is effective, it is reasonable to
`assume, at least in the case of p-hydroxybenzoic acid and the detergent
`used, that solubilisation and not complex formation is the cause of the
`inactivation by non-ionic detergents. Knowing the total concentration
`of p-hydroxybenzoic acid,
`its dissociation constant, Kc, (2-95 x 10—5),
`the concentration of the detergent, and the partitition coefficient, Km, it
`is easy to calculate the amounts of the acid dissolved in the aqueous
`and the micellar phases at varying pH, detergent, and total acid concen—
`tration. The results of such a calculation, assuming a total concentration
`of 01% (w/v) p-hydroxybenzoic acid and 58% (w/v) detergent are given
`in Table 3.
`
`Thus if 01% (w/v) is the optimum total concentration of acid needed
`to give the required preservative elTect in water at pH 4-0, the concen—
`tration of the un-ionised acid (the ‘active’ species) is 000559 M. Addition
`of 58% of the detergent reduces this concentration of un-ionised acid
`to 000114 M (Column 3, Table 3), and Column 4 ShOWS that at pH 4-0,
`049% (w/v) of acid would be required in presence of 58% (w/v) of the
`detergent to give the optimum molar concentration of the un-ionised acid
`in the water phase—Le, five times as much acid would be required to give
`the same concentration of the un-ionised acid in the aqueous phase in
`the presence of the detergent as in the absence of the non-ionic detergent.
`Acknowledgements. The author wishes to acknowledge many valuable
`discussions with Dr. T. G. Jones of this Department.
`
`References
`
`Trans. For. $00., 45, 528—536.
`Agar, A. & Alexander, A. E. (1949).
`Alexander, A. E. & Trim, A. R. (1946). Proc. Roy. Soc. (Lond.), B, 133, 200—234.
`Donbrow, M. & Rhodes, C. T. (1963).
`J. Pharm. Pharmacol., 15, 233—238.
`Higuchi, T. & Lach, J. L. (1954).
`J. Amer. pharm. Ass. Sci. Ed., 43, 465—470.
`Kushner, L. N., Hubbard, W. D. & Dean, A. S. (1957).
`J. phys. Chem., 61, 371—373.
`Maclay, W. N. (1956).
`J. Coll. Sci., 11, 273—285.
`McBain, J. W. & O’Connor, J. J. (1940).
`J. Amer. chem. Soc., 62, 2855—2859.
`McBain, M. E. L. & Hutchinson, E. (1955). Solubilisotion and Related Phenomena,
`lst ed., New York: Academic Press.
`Moore, C. D. & Bell, M. (1957). Soap, Perfum. Cosm., 30, 69—76.
`Navarre de, M. G. (1954).
`1st World Congress on Surface Active Agents, Vol. 2,
`pp. 741—742. Paris: Chambre Syndicate Tramagras.
`Navarre de, M. G. (1956).
`J. Soc. cos. Chem, 7, 427—430.
`Simon, E. W. (1952). New Phytol., 51—2, 163—197.
`Wedderburn, D. L. (1958).
`J. Soc. cos. Chem, 9, 210—228.
`
`331
`
`UCB Biopharma SPRL (IPR2019—00400)
`Exhibit 2014 Page 9
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2014 Page 9
`
`