SURFACTANT SYSTEMS
`
`Their clzcrni.m'y. phurrnuc_y and biology
`
`PAGE 1 OF 98
`
`SENJU EXHJBIT 2043
`
`LUPIN V SENJU
`
`IPR2015—0l105
`
`

`
`SURFACTANT SYSTEMS
`
`Their chemistry, pharmacy and biology
`
`D. Attwood
`Depahhment of Pharmacy A
`University of Manchester
`
`A. T. Florence
`
`Department of Pharmacy
`University of Strathclyde
`
`LONDON
`
`NEW YORK
`
`CHAPMAN AND HALL
`
`PAGE 2 OF 98
`
`

`
`
`7 F974
`74
`
`First published 1983 by
`Chapman and Hall Ltd
`11 New Fetter Ixme, London EC4P 4EE
`Published in the USA by
`Chapman and Hall
`
`7
`
`/
`
`733 Third Avenue, New York NY 10017
`
`(C) 1983 D. Attwood and A. T. Florence
`
`Printed in Great Britain by
`J. W Arrowsmilh Ltd, Bristol
`
`ISBN 0 412 14840 4
`
`All rights reserved. No part of this book may be reprinted, or
`reproduced or utilized in any form by any electronic, mechan-
`ical or other means, now known or hereafter invented, includ-
`ing photocopying and recording, or in any information storage
`and retrieval system, without permission in writing from the
`Publisher.
`
`
`
`British Library Cataloguing in Publication Data
`
`Attwood, D.
`Surfactant systems.
`1. Surface active agents
`
`ll. Florence, A. T.
`1. Title
`TP994
`668’.l
`ISBN 0-412-14840-4
`
`R! R
`(
`(J '\\‘.
`’] \ \
`
`PAGE 3 OF 98
`
`

`
`6 Pharmaceutical aspects of
`solubilization
`
`6.1 Introduction
`
`Solubilization in surfactant solutions above the critical micelle concentration
`offers one approach to the formulation of poorly soluble drugs in solution form
`1
`.
`‘
`
`[ Jfhe objective ofthis chapterand ofChapter 7 is to review the state ofthe art of
`
`solubilization in surfactant systems with emphasis on the consequences of a
`surfactant presence in pharmaceutical formulations. In particular, emphasis will
`be‘ placed on the effect of surfactants on bioavailability and the toxicity of
`formulations for neglect of these topics will, on the one hand, prevent the
`realization of the potential of surfactant systems and, on the other, might lead to
`the unwise use of surfactants in formulations. Some attempt will be made to place
`the topic in perspective and to answer the question as to the real value of
`surfactant solubilization in pharmaceutical formulation.
`It is perhaps true that micellar solubilization has not made much impact on
`drug formulation. There are relatively few marketed products which could be
`considered to be isotropic solutions of drug and surfactant in either the UK or the
`USA, although surfactants are present in many formulations as minor adjuvants
`and to that extent their presence and influence is perhaps hidden.
`- The limiting factors in the use of solubilizers as effective formulation aids are (i)
`the finite capacity of the micelles for the drug, (ii) the possible short- or long-term
`adverse effects of the surfactant on the body, and (iii)
`the concomitant
`solubilization of other ingredients such as preservatives, flavouring and colouring
`matter in the formulation with consequent alterations in stability and effective-
`ness. Nonetheless,-thcrc is scope for development simply because there is a need
`for agents to increase the solubility of poorly soluble drugs even if only at the
`stageiof vpharmaoological evaluation where, indeed, surfactants are used often
`without due regard to the implications. The use of co-solvents and surfactants to
`'solve 1-problems of low solubility has the advantage that the drug entity can be
`used without chemical modification and hence toxicological data do not have to
`r berepeated as would be the case when alternative approaches are used to produce
`-more soluble compounds. Some caution has, however, to be adopted in the
`
`293
`
`PAGE 4 OF 98
`
`

`
`294
`
`‘ Surfactant systems
`
`interpretation of animal pharmacology and toxicology on formulations which
`differ from the final marketed product, especially if the final preparation contains
`surfactant but early test formulations do not or vice versa. Surfactants. as we will
`see in Chapter 7, are not inert substances some having distinctive pharmaco-
`logical actions. There is a demonstrable need for the development of less toxic
`surfactants; the polyoxyethylene—polyoxypropylene block co-polymers which
`will be discussed later seem to have fewer side effects than conventional
`surfactants and seem to be worthy of further investigation.
`With the development ofnew dosage form technology in which control ofdrug
`release is achieved, it is conceivable that micellar systems will find some place
`because of the ability of the micellar phase to alter the transport properties of
`solubilized drug molecules. One can envisage the deliberate addition of
`surfactants to drug reservoirs to control the exit rate of drugs from polymeric
`devices. This will be explained in Chapter 7.
`This chapter is restricted mainly to aqueous systems and the solubilization of
`water-insoluble and poorly soluble drug entities and pharmaceutical additives,
`and, because of the lesser toxicity of non-ionic surfactants, it will concentrate on
`non-ionic surfactant systems. Wherever possible cited work refers to systems
`which have potential utility in pharmacy as there is a danger that all our
`knowledge is gained on model systems (of toxic ionic surfactants which are used
`because they are available in a pure state. benzene or similar well-defined solutes,
`and other unacceptable additives such as propanol) while we remain blissfully
`unaware of how to solve the real problems that arise [1].
`As we have seen in Chapter 1, the range of available surfactants is wide, and so,
`too, are the mechanisms of solubilization and the effects the surfactants have on
`
`the solubilized material. Examples are known of enhanced drug activity and of
`inactivation, of increased stability. and instability;
`the interactions of the
`surfactants with components of the body must also be considered. In the case of
`insoluble drugs, the presence of micelles may enhance their activity through
`solubilization and transport to the site of action, a process which otherwise might
`have been a slow one. This has, of course, dire consequences in the ease of
`carcinogens: normally insoluble carcinogenic substances which may be ingested
`may become very active in combination with surfactants, and, as the latter are
`taken in increasing amounts in food (non-ionics in bread is one example), this isa
`problem which warrants further study. Drugs which are meant to act on the
`intestinal mucosa, such as sulphaguanidine, might be inadvertently solubilized.
`There is the problem. especially with non-ionic surfactants. of interactions with
`preservatives in pharmaceuticals and consequent loss-of biological action."
`.Some drugs themselves are surface-active and form micelles. While surface
`activity may. not, in all cases, be the cause of their biological activity-, «it mustin
`some way influence it and modify their interaction with the _components.of
`dosage forms or the components of the body. Surface-active drugs and-surfactant
`molecules will interactto form mixed micelles at sufficiently high concentrations,
`a phenomenon which has implications for the thermodynamic activity and
`possibly the biological activity of the drug molecule.
`
`PAGE 5 OF 98
`
`

`
`Pharmaceutical aspects of so/ubilization
`
`-
`
`295
`
`Since 1964 there have been several comprehensive reviews of solubilization in
`surfactant systems, notably those by Swarbrick [2], Mulley [3], Sjoblom [4],
`Droseler and Voight [5], Elworthy et al. [6], and Florence
`These reviews
`together cite over a thousand sources primarily concerned with pharmaceutical
`applications. Other major publications which deal with micellar systems
`implicating solubilized species include Cordes [7], Fendler and Fendler [8] and
`the collections of papers edited by Mittal contain several contributions on the
`topic [9].
`In this chapter the solubilization of a number of classes of drugs and
`pharmaceutical products will be dealt with; in some cases the division into
`sections has had to be somewhat arbitrary, but, as far as possible, compounds
`with similar structures, such as the steroids, have been dealt with as a group.
`
`6.2 Solubilization of drugs
`
`6.2.1 Antibacterial compounds
`
`(A) PHENOLIC COMPOUNDS
`Solutions of cresol with soap were early pharmaceutical examples of solubilized
`systems. Phenol itself is soluble in water to the extent of 7.7% (w/v), but it has
`disadvantages; the alternatives, cresol, chlorocrcsol, chloroxylenol, and thymol,
`are much less soluble in water, and their use as disinfectants has led to the need for
`
`fprmulation in surfactant solutions.
`Solution of cresol with soap (lysol) is a saponaceous solution containirrg 50%
`v/v cresol. Its monograph specifies no particular soap, although activity of the
`preparation depends to a large extent on the type of soap employed. Although
`still used, the absence of strict standards for lysol, the widely varying phenol
`fractions used in its preparation, and the varying properties of the soaps make it
`an unsatisfactory solution. The high toxicity of phenol and the cresols has
`mitigated against their more widespread use. Emphasis is now being placed on
`their chlorinated derivatives, chloroxylenol and chlorocresol. Chloroxylenol is a
`potent, non-irritant bactericide of low toxicity. It has, however. a low solubility in
`water, 0.031 gml' ‘ at 20°C [10];
`the oflicial preparation, Solution of
`Chloroxylenol B.P., contains 5 "/0 v/v chloroxylenol with terpineol in an alcoholic
`soap solution. A modification of this, claimed to be less alkaline, has been
`described by Lloyd and Clegg [1 1]. There are numerous commercial formu-
`lations with a wide spread of Rideal—Walker coeflicients.
`Mulley and Metcalf [12] have carried out detailed investigations of the phase
`behaviour of non-ionic detergent systems containing chloroxylenol (4-cl1loro-
`3,5-xylenol). Two of their phase diagrams are reproduced in Fig. 6.1. The
`surfactant C611, ,(OCH2CH2)6OH is an efficient solubilizer above its CMC,
`which is approximately 3% w/w, but high concentrations are required to form
`isotropic
`liquids
`containing
`reasonable
`quantities
`of
`chloroxylenol.
`C51-l,3(OCH;CH2)2OH requires concentrations above 50% w/w to achieve an
`isotropic solution, and this compound probably acts more as a hydrotrope than
`
`in ‘ PAGE 6 OF 98
`
`

`
`296
`
`-
`
`Surfactant systems
`
`as a micellar solubilizer in this concentration region. The former detergent forms
`only small aggregates ofabout 13 monomers in aqueous solution [13]. To obtain
`systems suitable for use it
`is essential
`to increase the alkyl chain length;
`C,0H2 1 (OCHzCH,)6OH has a low CMC and its micelles are reasonably large,
`containing 73 monomers at 25°C [14]. Isotropic micellar systems are formed at
`lower concentrations of detergent than for the shorter alkyl-chain homologues,
`However, there is a concomitant increase in the complexity of the phase diagram
`with the formation of liquid crystalline phases (Fig. 6.1).
`There is apparently no evidence from these phase diagrams for the existence of
`simple phenol—glycol chain complexes: the liquid which separates at a solubility
`limit is a solution of variable composition. Ultraviolet spectroscopy shows that a
`hydrogen-bonded complex between the phenolic hydroxyl group and the other
`oxygens of cetomacrogol 1000 (C,5H,3(OCH,CH,),3_.,,,OH) is formed when
`chloroxylenol
`is solubilized by this commercial non-ionic surfactant. The
`
`C§H‘3iOCHzCHz)x OH
`
`Water
`
`Chloroxylenol
`
`Figure 6.1 The upper phase diagram (after Mulley and Mctcalf [l2]) illustrates the
`phases existent in the system C,H, _, (OCH, CH,), OH: 4—chloro-3,5-xylenol: water at
`20° C.The dotted line represents the behaviour when x = Zand thesolid lines where x = 6.
`The lower diagram shows the much more complex behaviour
`in the system:
`C“, H,, (0CH,CH,)6OH: chloroxylenol: water.
`I1. = isotropic liquid; LC = liquid
`crystalline; S = solid 2L = two liquids (immiscible.)
`
`PAGE 7 OF 98
`
`

`
`7-—:—-—-——
`
`Pharmaceutical aspects of solubilization
`
`-
`
`297
`
`to the surfactant
`is directly proportional
`solubility of the chloroxylenol
`concentration, above the CMC [l5]. However, rough determinations of the
`solubilities of resorcinol and phenol
`in cetomacrogol solutions. varying in
`concentration from I to 20 "/,,,showed these compounds to be less soluble than in
`water, although their solubility was proportional to detergent concentration
`16]-
`
`[ Solutions ofphenols in ionic systems exhibit similar behaviour. An initial fall in
`
`in potassium laurate
`the solubility of 2-hydroxyphenol and 4-benzylphenol
`solutions was noted below the CMC of the soap [17]. Few workers have
`commented on this ‘insolubilization‘; compounds with very low water solubility
`possibly do not show this property. That it is not restricted to phenols is shown by
`the results of Heller and Klevcns [18] for ethyl benzene in potassium laurate.
`Ethyl benzene has a solubility in water similar to that of 4-benzylphenol.
`The binding of series of phenols, cresols and xylenols to the non-ionic
`surfactant cetomacrogol 1000 can be described by a Langmuir adsorption
`isotherm [19]
`
`X = KlK2C“1
`
`where x is the solute bound (mmol g" micelle), c is the concentration of free
`unionized solute (mmol), K 1 is the binding constant (1 mmol ‘ ‘) and K 2 the solute
`bound at hypothetical saturation (mmol g’ ‘ micelle). The combined parameter
`K 1 K2 is specific for each system and may be defined as the distribution coefficient
`of the solubilizate at infinitely dilute solubilizate concentration (Po), Azaz and
`Donbrow [19] assert. Its value characterizes ideal behaviour both in the aqueous
`and mieellar phases hence strictly would be subject
`to activity corrections.
`Binding capacity is inversely related to the water solubility of the phenoL cresol
`and xylenol, as can be seen in Table 6.1.
`Values of P0 in 0.1 M NaCl are also shown for a few compounds in this Table. A
`log——log plot of binding capacity and aqueous solubility yields a straight line. A722
`
`Table 6.1 Aqueous solubility and distribution coefficient at infinite dilution (Po) between
`cetomacrogol and water of phenols at 25° C
`
`Compound
`
`Phenol
`a~Cresol °'
`p-Cresol
`m-Cresol
`2,4-Xylenol
`2,6-Xylenol
`3,5-Xylenol
`3.4-Xylenol
`2,3-Xylenol
`2.5-Xylenol
`
`Solubility in water
`(mol l‘ ‘ x 10’)
`
`P0 in water‘
`
`Solubility in 0.1 M P0 in 0.1 M
`NaCl3 (mol|"
`NaCl‘
`x 10 )
`
`233
`I 88
`I 33
`
`117
`80.6
`
`1000
`240
`199
`142
`SLO
`49.5
`40.0
`39.0
`37.4
`29.0
`
`42.0
`79.5
`76.4
`85.1
`125
`1 14
`132
`151
`169
`197
`
`° PMS! (1/8) X 10’ = 1/1000s or dimensionless units assuming density of cetomacrogol is unity at
`25 C. Measured in 2% cetomacrogol. From Azaz and Donbrow [19].
`
`PAGE 8 OF 98
`
`

`
`298
`
`-
`
`Surfactant systems
`
`and Donbrow’s work has supported earlier work [20—23] which demonstrated
`that in unsaturated systems the binding ‘constants’ of solubilizates to surfactants
`are concentration-dependent and not, in fact, constant as some authors have
`assumed (e.g. [24—26] ). This variation may have important practical implications
`in formulation.
`
`A wider range of 34 benzoic acid derivatives has been studied in detail by
`Tomida et al. [27]. Using a solubility method these workers obtained saturation
`solubilities of the benzoic acid derivatives in Brij 35 (a polyoxyethylene lauryl
`ether) over a range of concentrations. Solubility ratios, calculated as the solubility
`in the surfactant solution/solubility in HC1, were a linear function of surfactant
`concentration allowing the calculation of a partition coetficient Pm which can b_c
`defined as
`
`Cm
`P = —,
`..
`Ca
`
`6.
`
`(
`
`1)
`
`where Cm and C, are the concentrations in the miocllar and aqueous phases,
`respectively. Pm is obtained from the solubility data as
`
`St
`
`S.
`
`= (Pm — 1)rC, +1
`
`(6.2)
`
`where S. is the total solubility of solubilimte in the presence of surfactant at
`concentration C.,S. is the solubility in the absence of surfactant and 5 is the
`partial molar volume of the surfactant. Some of the extensive data is reproduced
`in Table 6.2 for the ortho, para and meta substituents. The data are consistent
`with the findings of Azaz and Donbrow: the order of aqueous solubilities ‘is
`always ortho > meta > para and the order of Pm is the opposite except for the
`hydroxybenzoic acids for which the ortho compound was solubilized most,
`followed by para and meta compounds. Patel and Foss [21] obtained the
`
`Table 6.2 Aqueous solubilities. S.. and partition coefficients of benzoic acids. P.,,hetwee_n
`aqueous and micellar phases obtained from solubility method‘
`_.
`.
`~_
`
`Substituent
`
`ortho
`
`meta
`
`para
`
`S,(moll“)
`
`Pm
`
`S,(rnoll“)
`
`Pm
`
`S,(mo1l")
`
`Pm
`
`57.4
`2.61 x 10"
`H
`94.6
`4.98 X10"
`91.2
`1.65 X10"
`F
`446
`3.48 X 10"
`346
`1.92 X 10‘3
`Cl
`634
`1.42 X 10"‘
`505
`1.36 X 10"
`B1’
`908
`9.16 X10-6
`1150
`2.74 X10-‘
`1
`I63
`2.23-x 10"
`166
`6.13 X10"
`CH,
`109
`1.30 X 10"
`72.8
`1.18 X 10’;
`OCH,
`42.2
`4.17 x 10"
`38.3
`5.71 X 10-3
`CH
`117
`1.01 X 10"’
`96.8
`1.57 X 10"
`NO;
`CN
`2.35 x 10"
`50.1
`5.60 x 10" 3
`57.0
`COOH
`2.57 X 10"
`22.4
`4.42 X 10"
`155
`6.50 x 10"
`69.8
`
`
`c
`
`4.05 X10”
`8.66 X 10"
`5.29 X104
`1.75 X10"
`6.55 X 10"’
`2.50 x 10"
`1.08 X10"
`2.53 X10-2
`
`43.1
`99.8
`150
`271
`120
`32.0
`116
`47.5
`
`‘ From [27].
`
`PACE 5 OF 98
`
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`
`'-1';-———-——
`
`Pharrnaceuzical aspects ojsoluhilizariori
`
`-
`
`299
`
`magnitude of interaction of hydroxy-, chloro- and aminobenzoic acids in
`polysorbate 80 and eetomacrogol 1000; hydroxy and amino derivatives showed
`the order of interaction to be ortho > para > meta. Substitution of a hydroxy
`group in the ortho position results in more alfinity for any surfactant than para
`and meta substituents. This can be explained by the fact that the intramolecular
`hydrogen bonding increases the proton-donating nature ofthe carboxylic group.
`The greater the dissociation constant of the acid group the greater the hydrogen
`bonding to the oxyethylene groups in the micelle.
`Plots of log Pm versus log P,.c._,,,(,. for the 34 compounds studied produced three
`groupings of results [27] to which the following equations applied.
`n
`r
`5
`
`log Pm = 0.921 log P.,..,,,,.,. + 0.112 21
`
`0.986
`
`0.080
`
`log Pm = 0.881 log P.,c..,,.,. +0392 5
`
`0.999
`
`0.014
`
`log Pm = 0.968 log Poctanol + 0.600
`
`3
`
`0.999
`
`0.036
`
`(6.3)
`
`(6.4)
`
`(6.5)
`
`where n is the number of points used in the regression, r is the correlation
`coefficient, and sis the standard deviation. Equation 6.3 applies to the majority of
`the compounds studied; Equation 6.4 to the nitro and cyano derivatives and the
`last equation to the compounds with diearboxylic groups. The intercept values of
`the three groups are quite different; it is believed that the magnitude of the
`intercept is a reflection of the site of solubilization in the micelle. The closer the
`environment is to the nature of oetanol used in the partitioning studies to obtain
`Pm, the closer the intercept should be to zero. A negative intercept (for salicylic
`acid derivatives) has been identified with solubilization in the hydrocarbon core.
`The site of solubilization while of little practical importance in the design of
`pharmaceutical formulations is of more than academic interest as the position of
`the solubilizate in the micelle may determine its stability and reactivity towards
`attacking species in the continuous phase (see Chapter 11).
`To obviate the problem of the different affinities of ionized and unionized
`species for micelle, Tomida er al. [27] carried out their investigations at a pH such
`that ionization was suppressed. pH is rarely as low as that in this work and its
`influence on solubilization must be considered. Although the hydrogen ion
`V concentration can influence the solution properties of non—ionic surfactants [28],
`the principal influence on uptake is exercised through the effect of pH on the
`equilibrium between ionized and unionized drug or solute species. This effect has
`been studied in most detail by Collett and [(00 [29]. Increasing pH leads to a
`decrease in the micellar uptake of organic acids because of increasing solute
`solubility in the aqueous phase through increased ionization. This effect is clearly
`seen in Fig. 6.2 when the results of uptake of 4-chlorobenzoic acid between pH 3
`and 4.40 are plotted as a ratio of its solubility in water of the appropriate pH, i.e.
`as the solubility ratio R. Considering the micellar species to form a phase or
`pseudophase allows a simple quantitative measure of the interaction between
`solubilizate and micelle. The concentration of solubilizate in the micelle is related
`
`to its concentration in the aqueous phase by a partition coeificient as defined in
`Equation 6.1.
`
`PAGE10oF9s
`
`

`
`300
`
`-
`
`Surfactant systems
`
`on
`
`3.0
`
`3.4
`
`3.62
`
`4.0
`4.15
`
`4.4
`
`I2
`
`e
`
`is
`
`1
`
`E
`
`2
`
`E3
`
`33I
`
`D
`
`
`
`1
`
`3
`2
`Polysorbore concn
`
`a x 1o"<mou 1")
`
`Figure 6.2 The influence of polysorbate 20 concentration and pi! on the solubility ratio,
`R, of 4-chlorobenzoic acid. From Collett and Koo [29].
`
`Curved Scatchard plots for the interaction of propyl p-hydroxybenzoale
`(propyl paraben) with four polyoxyethylene dodecyl ethers are shown in Fig. 6.3
`[31]. The primary class of binding sites exhibited a high affinity and a low
`capacity for the preservative while the secondary sites had a low affinity and large
`binding capacity. This
`-
`
`"1 K ID!
`(555?
`V -W + MK: [Prl
`Analysis of these has allowed ‘n , , n,, K , and K 1 to be’ estimated and related to the
`nature of the binding ‘process in the micelles, especially in respect of the
`interaction with the hydrophilic polyoxyeth'ylene lay'er"j[32].
`Qf great practical'i'rnporta'nce are t-he effects of additives on the binding of
`preservative molecules 'to- surfactant micelles. ‘Blanchard et al., [33] have
`confirmed the negligible effect of sorbitol on the interaction of phenolic
`preservatives with polysorbate 80 using a Scatchard approach. The sorbitol is
`probably too hydrophilic to interact with the micelle and thus does not compete
`for binding sites. Similar conclusions were reached by Shimamoto and Mirna [34]
`studying-the effects of glycerol, propylene glycol and 1,3-butylene glycol on
`paraben-Anon-ionic surfactant interactions. These polymers had little effect on the
`binding of preservatives to the primary binding sites located at the core/PEG
`boundary of the micelle but they were ‘thought to decrease binding at the
`secondary sites,
`l,3—butylene glycol" being most effective in displacing the
`preservatives: These secondary sites are reckoned to be non-specific and located
`in the PEG layer. As materials such as 1,3-butylene glycol may penetratethe PEG
`region they would probably displace solubilizate molecules. It would seem that
`displacement from the primary site would require much greater structural
`specificity (see discussion on interaction of preservative mixtures with micelles‘,
`
`-
`
`n
`
`PLACE; 1l1mOll7 98 _
`
`

`
`Pharmaceutical aspects of solubilizalion
`
`-
`
`301
`
`Figure 6.3 Scatchard plots for the interaction of propyl paraben with polyoxyethylene
`dodecyl ethers, n being the number of oxyethylene units.
`On=l5;On=20;An=30;An=50
`From [31] with permission.
`
`below). Any displacement of preservative from the micelle is likely to increase the
`preservative activity of the formulation.
`The effects of added electrolytes on solubilized systems are discussed in
`Chapter 5. In Table 6.1 it can be seen that‘the addition of sodium chloride to a
`non-ionic system increases the Pm of the solubilizate. An electrolyte can have a
`dual effect, first on the properties of the surfactant and secondly on the
`solubilizate. If the electrolyte salts out the solubilizate Pm will increase, an effect
`observed with non-ionic surfactant systems whose micelles would-be increased in
`size by such electrolytes. In ionic surfactant systems the effect can be more
`complex. The addition of electrolyte to an ionic surfactant results in a decrease in
`CMC, increase in micellar size and a decrease in effective charge per monomer,
`probably leading to a greater concentration of head groups and a more rigid
`micellar interior [35] which might result in decreased uptake of solubilizate into
`the micellar core. Uptake ofmethyl and ethyl paraben is increased by the addition
`of 10 mM NaCl to sodium lauryl sulphate [36] (see Table 6.3} As both electrolyte
`and the presence of paraben lowers the surfactant CMC, analysis of the results
`produced the unexpected conclusion that for all three compounds the partition
`coefficient to the micellar phase is reduced on addition of electrolyte. This is a
`problem which occurs and recurs in detailed studies of mechanisms of
`solubilization, being clearest when pH effects are studied. Generally the
`formulator is interested in total solubility which includes solubility in the aqueous
`and micellar phases. While the partitioning of a species to the micellar phase
`might be reduced, its increased solubility in the aqueous phase may compensate
`for this. ln spite of the partition coefficient of the methyl, ethyl and butyl paraben
`
`PAGE 12 OF 98
`
`

`
`302
`
`~
`
`Surfactant systems
`
`Table 6.3 Solubilization of alkylparabens in water and in 40 mm sodium
`lauryl sulphate solution at 27° C‘.
`
`Alkylparaben
`
`Solubility (mmol l ' ’) in
`
`Water
`
`:10mM NaLS
`
`2
`
`40mM NaLS and
`so mM NaCl
`
`Methylparaben
`Ethylparaben
`Butylparaben
`
`l4.5
`5.4
`1.1
`
`‘ From [36, 38].
`
`33.9
`22.7
`24.3
`
`31.6
`2 l .9
`26.7
`
`increasing towards the micellar phase from 1.2 through 3.2 to 21, respectively, in
`40 mM sodium lauryl sulphate (NaLS) the total solubility is still highest for
`methyl paraben with a solubility limit of 33.9 mM. Ethyl paraben has the lowest
`solubility (22.7 mM)and butyl paraben has a solubility of 24.3 mM in 40 mM NaLS
`[38]. In a series such as the alkyl parabens their different locations in the micelle
`may be another factor complicating a ready understanding of the observation; the
`effect of the paraben on CMC which follows the order butyl > ethyl
`> methylparaben is of little importance when the total surfactant concentration
`is 40 mM as in the investigations in question but would obviously be important at
`surfactant concentrations close to the concentration (Fig. 6.4 shows this elfect).
`Uptake ofsolubilizate into surfactant micelles changes the physical state of the
`micelle (see Section 5.5). Sometimes the change in shape may result in drastic
`changes in the physical properties of the system as a whole — this may influence its
`use. The effect of additive on the cloud point of non-ionic surfactants
`
`I 9X o2U
`
`4
`
`6 3
`[0,] x lo M
`
`B
`
`‘IO
`
`12
`
`Figure 6.4 The CMCs of sodium lauryl sulphate solutions in the presence of alkyl
`parabens. O, methylparaben; O, ethylparaben; x, butylparaben. From Goto and Endo
`[37] with permission.
`
`

`
`Pharmaceutical aspects of solubilization
`
`-
`
`303
`
`60
`
`0
`
`
`
`Cloudpoinr(°C) 8on
`
`Figure 6.5 Relation between the cloud point and P, values for phenol and its homologues
`at concentrations of 0.05 mol l" in 2%. cetomacrogol 1000. From Donbrow and Azaz
`[43]. Values of P0 from Table 6.1.
`
`[3942] is of some practical importance as the cloud point may be lowered
`below room temperature. Fig. 6.5 shows the eifect of a range of phenols on
`the cloud point of cetomacrogol solutions (cetornacrogol 1000 B.P.
`is
`C,5H,3(OCH,CH,),,_ 1.011) where the relation between cloud point and the
`distribution coefficient of phenols, cresols and xylenols between micelles and
`water is demonstrated. The effect of a phenol on the cloud point is inversely
`related to its hydrophilicity. As the cloud point is thought to be due to the growth
`of the non-ionic micelles with increasing temperature, the binding of solute to the
`rnicellar structure could explain the lowering of the cloud point if the surfactant
`monomer—solute complex is more hydrophobic than the surfactant monomer
`itself.
`
`Phenol—water systems display critical solution temperatures (CST). Addition
`of fatty acid soaps generally causes a lowering of CST. 3 "/0 sodium oleate lowers
`the CST of the phenol—water mixture from ~ 65 to 0° C [45]. 17,, lowers it to
`43°C and 1% sodium stearate lowers it
`to 49.l° C [46]. Prins [44]
`in
`investigations on cetyltrimethylammonium bromide (CTAB)—phenol—watet
`mixtures, found striking effects caused by the detergent on the CST of the
`phenol—water system. Table 6.4 gives the concentrations of CTAB and phenol
`which have in admixture with water a CST of 20° C. The figures were obtained
`from a study of the phase diagram of the system.
`
`Table 6.4 Concentrations of Cl"AB and phenol
`having a critical solution temperature of 20° C‘
`
`CTAB (% w/w)
`
`Phenol ("/o w/w)
`
`8.0
`17.5
`28.0
`34.0
`40.5
`41.5
`40.0
`
`‘ From Prins
`
`I 1.0
`16.8
`25.2
`31.7
`35.6
`41.0
`45.1
`
`PAGE 14 OF 98
`
`

`
`304
`
`'
`
`Surfactant systems
`
`Cetyltrimethylammonium bromide has a more complicated action than the fatty
`acid soaps. Although it generally enhances the mutual solubility of phenol and
`water, at some levels it has been shown to decrease the mutual solubility. Addition
`ofmore CTABcauses the mutual solubility to increase again until at 48 ‘Z, CTAB,
`complete miscibility is attained. Prins has gone some way to explaining this
`behaviour. When phenol is added to an aqueous solution of CTAB consisting of
`spherical micelles the phenol induces the formation of rod-shaped aggregates (see
`simplified phase diagrams in Fig. 6.6).
`
`CYAB
`
`Spherical micelles
`:2 Rod-shaped micelles
`
`'3 Molecular dispersion
`
`PHENOL
`
`cetyltrimcthylammonium
`the
`of
`reprcsenta_tion
`6.6 A diagrammatic
`Figure
`bromide—phenol—water system. (After Prins [44]). Horizontal arrow shows increasing
`phenol concentrations and passage from solutions containing spherical micelles, through
`solutions containing asymmetric micelles to a molecular dispersion on breakdown of the
`micelles.
`
`The rod-shaped micelles can solubilizc large quantities of phenol, but they
`reach a point (b) where they disintegrate, forming a molecular dispersion which
`results in a loss of mutual solubility. All systems containing more than 48 ‘)1,
`CTAB are completely miscible. Examination of the interfacial tension curve of
`the co-existent phases in the water—phenol—CTAB system (phenolzwater 40: 60 by
`weight) shows that the curve mimics the solubility behaviour. A minimum at
`about 4 "/0 is followed by an increase in interfacial tension, which falls again after
`15 ‘X, concentration, falling to 0 mN in “ at about 40 %.
`
`INTERACTION OF PRESERVATIVE MIXTURES WITH SURFACTANTS.
`(B)
`In many formulations more than one solute will be a potential solubilizate
`whether or not this is desired. As discussed in Chapter 5, the effect, if any, of one
`solute on the solubilization of another will depend on the mechanisms of
`solubilization. If solubiliuition of one solute occurs at specific ‘sites’ within the
`micelles then molecules with similar binding affinities might compete for the
`available sites leading to a decreased solubilization of each. In some cases one
`solute might induce a reorganization of the micelle structure and allow increased
`uptake; both mechanisms might operate such that maxima and minima are seen
`in the plots of solubility versus the concentration of second solubilizatc [47] (see
`Fig. 5.23). Bcnzoic acid, for example, increases the solubility of methyl paraben in
`
`PAGE 15 OF 98
`
`

`
`Pharmaceutical aspects of solubilization
`
`-
`
`305
`
`cctomacrogol solutions, but dichlorophenol decreases its solubilization [47].
`Chloroxylenol reduces the solubility of methylparaben and methylparaben
`reduces the solubility of chloroxylenol in cetomacrogol, there being no effect on
`mutual solubilities in the absence of surfactant.
`The distribution of a solubilizate between micelles and the aqueous phase does
`not obey necessarily a simple partition law when a second solubilizate is present
`[48]. A non-linear increase in solubilization with increasing surfactant concen-
`tration has been found with a second solubili7ate present. Fig. 6.7 shows the
`change in micellar partition coefficient of o-hydroxybenzoic acid in the presence
`of increasing levels ofbenzoic acid when polysorbate 80 is the solubilizer [48]. At
`1 "/0 surfactant there is a marked decrease in partition coefficient, but at 3 ‘X, there
`is little change. Nalidixic acid does not alter the micellar distribution coefficient of
`0-hydroxybcnzoic acid but chloramphenicol reduces the distribution. Nalidixic
`acid has no detectable effects on the cloud point of the polysorbate solutions,
`suggesting that it does not alter micellar structure. Alhaique et at. [48] conclude
`that if the added compound does not induce significant changes in micellar
`structure it will not alter the distribution into the micelle of another solubilizate;
`this problem requires further and more detailed examination, primarily because
`of its importance in pharmaceutical systems and because of the potential
`importance of the phenomenon in altering drug bioavailability from micellar
`systems. Preliminary work on permeation through polymer membranes [48] has
`shown that the reduction in permeation caused by solubilization of a solute can
`
`0O
`
`8
`
`A
`EV
`..
`r:
`_o
`.9
`3.‘tv
`0L’
`
`:o
`
`'2
`'2I-
`0Q
`
`L 3
`
`.’o
`3i
`
`2T
`
`i
`L’
`2
`
`‘
`2
`1
`Added species (Mx‘lO )
`
`3
`
`Figure 6.7 Changes in micelle/water apparent partition coefficie