This dissertation is based on the theory and applications of the most commonly used solubilization techniques: pH adjustment, cosolvency, micellization, complexation, and the combinations of pH adjustment with one of the other techniques.Chapter 1 provides an overview for the methods which are available to formulate a poorly water-soluble drug based on its administration route.Chapter 2 applies these commonly used techniques to solubilize two structurally related anticancer drugs. The efficiency of each technique is compared for both drugs side by side. It is observed that each technique is more efficient on the drug which has less polarity. However, the achievable final drug concentration in a formulation depends not only on the efficiency of the applied technique, but also on the drug's water solubility.Chapter 3 emphasizes the overall effectiveness of each technique on drugs which have different physicochemical properties. Solubilization profiles for the above techniques are generated for twelve compounds, eight of which are ionizable and studied under both unionized and ionized conditions. This chapter illustrates that the efficiency of the cosolvency, micellization, and complexation on both unionized and ionized drug species can be predicted from their polarities. Thus, the solubility of an ionizable drug can be estimated by using a given solubilizing excipient at any pH to meet the dose requirement.Chapter 4 studies the effect of cosolvent on complex stability. A series of alcohols were used to illustrate the effect of cosolvent size and polarity on the solubilization of a compound. It is proposed that a ternary drug-ligand-cosolvent complex is formed in these combined systemsThis dissertation provides guidance for the selection of a solubilization technique for a compound based on the physicochemical properties and the dose requirement.

Orientador: Watson Loh / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-19T04:42:09Z (GMT). No. of bitstreams: 1 Brinatti_Cesar_M.pdf: 6269984 bytes, checksum: 65e7cdbf89a7e16102822d62f57e20e9 (MD5) Previous issue date: 2011 / Resumo: As sulfobetaínas (SB) são uma classe de surfatantes zwitteriônicos. A presença de grupos carregados tanto positiva quanto negativamente na mesma molécula concede à sua cabeça polar uma hidrofilicidade intermediária entre surfatantes iônicos e não-iônicos. O estudo termodinâmico de associação da série homóloga de sulfobetaínas, bem como sua interação com polímeros iônicos e não-iônicos, foi feito utilizando a técnica de titulação calorimétrica isotérmica (ITC), em diferentes temperaturas. O aumento da temperatura leva a um valor mais negativo de energia livre de Gibbs de micelização DmicG, o que favorece a micelização. O termo entrópico TDmicS, embora sempre positivo, é o responsável pela micelização em baixas temperaturas. No entanto, com o aumento da temperatura este termo perde sua intensidade, enquanto o termo entálpico DmicHinverte seu sinal, de positivo para negativo, superando em intensidade o termo entrópico, sendo então o responsável pela micelização em temperaturas elevadas. No estudo de interação com polímeros não-iônicos, o poli (ácido acrílico), PAA, induziu a formação de agregados de unímeros de surfatantes em concentrações abaixo de sua cmc, enquanto o poli (óxido de propileno), PPO, foi incorporado às micelas. Em relação aos polímeros iônicos, o polímero catiônico cloreto de poli (dialildimetilamônio), PDADMAC, e o polímero aniônico poli (acrilato de sódio), PAA, não apresentaram interação alguma com a sulfobetaína. Apenas o polímero aniônico poli (4-estireno sulfonato de sódio), PSS, induziu a formação de agregados de unímeros de surfatante em concentrações muito abaixo da cmc. Esta indução deve-se à interação eletrostática entre o grupo sulfonato (-SO3) do PSS e o grupo amônio ( RNMe2X ) da SB, auxiliada pela presença do grupo hidrofóbico estireno do polímero, que é incorporado às micelas / Abstract: Sulfobetaines (SB) are a class of zwitterionic surfactants. The presence of groups both positively and negatively charged in the same molecule renders an intermediate hydrophilicity between ionic and nonionic surfactants. The self-assembly thermodynamic study of a homologous series of sulfobetaines, as well as its interaction with ionic and nonionic polymers, was performed by isothermal titration calorimetry (ITC), in different temperatures. The increase in temperature leads to a more negative value of the Gibbs free energy of micellization DmicG, which favors micellization. The entropic term TDmicS, although always positive, is the responsible for the micellization in lower temperatures. However, with the increase in temperature this term loses its intensity, while the enthalpic term DmicH changes its sign, from positive to negative, overcoming the entropic term in intensity, and therefore being the responsible for the micellization in higer temperatures. In the study of interaction with nonionic polymers, poly (acrylic acid), PAA, induced the formation of aggregates of surfactant monomers in concentrations below its cmc, while poly (propylene oxide), PPO, was incorporated to the micelles. Regarding ionic polymers, the cationic poly(diallyldimethylammonium chloride), PDADMAC, and the anionic polymer poly (sodium acrylate), PAA, didn't show any interaction with the sulfobetaine. Only the anionic polymer poly(sodium 4-styrenesulfonate), PSS, induced the formation of aggregates of surfactant monomers in concentrations well below its cmc. This induction is due to the electrostatic interaction between the sulfonate group (-SO3) from the PSS and the ammonium group (RNMe2X) from the SB, aided by the presence of the hydrophobic group styrene in the polymer, which is incorporated into the micelles / Mestrado / Físico-Química / Mestre em Química

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The properties of a series of well-defined new surfactant oligomers (dimers to tetramers)were examined. From a molecular point of view, these oligomeric surfactants consist of simple monomeric cationic surfactant fragments coupled via the hydrophilic ammonium chloride head groups by spacer groups (different in nature and length). Properties of these cationic surfactant oligomers in aqueous solution such as solubility, micellization and surface activity, micellar size and aggregation number were discussed with respect to the two new molecular variables introduced, i.e. degree of oligomerization and spacer group, in order to establish structure – property relationships. Thus, increasing the degree of oligomerization results in a pronounced decrease of the critical micellization concentration (CMC). Both reduced spacer length and increased spacer hydrophobicity lead to a decrease of the CMC, but to a lesser extent. For these particular compounds, the formed micelles are relatively small and their aggregation number decreases with increasing the degree of oligomerization, increasing spacer length and sterical hindrance. In addition, pseudo-phase diagrams were established for the dimeric surfactants in more complex systems, namely inverse microemulsions, demonstrating again the important influence of the spacer group on the surfactant behaviour. Furthermore, the influence of additives on the property profile of the dimeric compounds was examined, in order to see if the solution properties can be improved while using less material. Strong synergistic effects were observed by adding special organic salts (e.g. sodium salicylate, sodium vinyl benzoate, etc.) to the surfactant dimers in stoichiometric amounts. For such mixtures, the critical aggregation concentration is strongly shifted to lower concentration, the effect being more pronounced for dimers than for analogous monomers. A sharp decrease of the surface tension can also be attained. Many of the organic anions produce viscoelastic solutions when added to the relatively short-chain dimers in aqueous solution, as evidenced by rheological measurements. This behaviour reflects the formation of entangled wormlike micelles due to strong interactions of the anions with the cationic surfactants, decreasing the curvature of the micellar aggregates. It is found that the associative behaviour is enhanced by dimerization. For a given counterion, the spacer group may also induce a stronger viscosifying effect depending on its length and hydrophobicity. Oppositely charged surfactants were combined with the cationic dimers, too. First, some mixtures with the conventional anionic surfactant SDS revealed vesicular aggregates in solution. Also, in view of these catanionic mixtures, a novel anionic dimeric surfactant based on EDTA was synthesized and studied. The synthesis route is relatively simple and the compound exhibits particularly appealing properties such as low CMC and σCMC values, good solubilization capacity of hydrophobic probes and high tolerance to hard water. Noteworthy, mixtures with particular cationic dimers gave rise to viscous solutions, reflecting the micelle growth. / Die Eigenschaften einer Reihe gut definierter neuer oligomerer Tenside (von Dimeren bis zu Tetrameren) wurden untersucht. Strukturell bestehen diese oligomeren Tenside aus einfachen monomeren kationischen Tensidfragmenten, die über die hydrophile Kopfgruppe (Tetraalkyl-Ammoniumchlorid) durch „Spacer“-Gruppen unterschiedlicher Natur und Länge miteinander verbunden/gekoppelt sind. Die Eigenschaften dieser kationischen oligomeren Tenside in wässriger Lösung wie Löslichkeit, kritische Mizellbildungskonzentration und Oberflächenaktivität, Mizellgröße und Aggregationszahl werden in Bezug auf die zwei neuen molekularen Variabeln (d.h. dem Oligomerisationsgrad und der Spacer-Gruppe) untersucht, um Struktur-Eigenschafts-Beziehungen abzuleiten. Die Erhöhung des Oligomerizationsgrads verringert stark die kritische Mizellbildungskonzentration (CMC). Eine kurze Spacer-Länge oder ein erhöhte Hydrophobie des Spacers erniedrigt die CMC ebenfalls, aber in einem geringeren Umfang. Die gebildeten Mizellen sind relativ klein und ihre Aggregationszahl nimmt mit zunehmendem Oligomerisationsgrad ab, genau wie mit zunehmender Spacerlänge oder sterischer Behinderung. Außerdem wurden Pseudo-Phasendiagramme für die Gemini-Tenside in komplexen Systemen, nämlich in inversen Mikroemulsionen untersucht. Auch hier zeigt die Spacer-Gruppe einen großen Einfluß auf das Tensidverhalten. Weiterhin wurde der Einfluss von Zusätzen auf das Eigenschaftsprofil der dimeren Tenside untersucht. Starke Synergien wurden beobachtet, wenn man spezielle organische Anionen (z.B. Natriumsalicylat, Natriumvinylbenzoat, etc.) zu den dimeren Tensiden in stöchiometrischen Mengen hinzugibt. Für solche Mischungen wird die Mizellbildungskonzentration stark zu niedrigen Konzentrationen verschoben, wobei der Effekt für die Dimere ausgeprägter als für die analogen Monomere ist. Eine Verringerung der Oberflächenspannung wird ebenfalls erreicht. Gemini-Tenside mit geeigneten Spacer-Gruppen bilden nach Zugabe ausgewählter organischer Anionen viskoelastische Lösungen, selbst wenn die dimeren Tenside nur über relativ kurz Alkylketten verfügen. Dies wurde mittels rheologischer Messungen gezeigt. Dieses Verhalten resultiert aus der Bildung langer Zylinder-Mizellen aufgrund der starken Wechselwirkung der Anionen mit den kationischen Tensiden, die die Krümmung der mizellaren Strukturen verringern. Es wurde auch festgestellt, dass das assoziative Verhalten durch die Dimerisation erhöht wird. Für ein gegebenes Gegenion kann die Spacer-Gruppe den verdickenden Effekt verstärken, in Abhängichkeit von seiner Länge und Hydrophobie. Als weitere Zusätze wurden entgegengesetzt geladene Tenside wurden mit den kationischen Dimeren kombiniert. Einige Mischungen mit dem käuflichen anionischen Tensid SDS bilden Vesikel in Lösung. Mit Blick auf diese katanionischen Mischungen wurde ein neues anionisches Gemini-Tensid, das auf EDTA basiert ist, synthetisiert und charakterisiert. Der Syntheseweg ist relativ einfach und das Tensid zeigt interessante Eigenschaften wie niedrige CMC- und scmc-Werte, gute Solubilisierungskapazität von hydrophoben Substanzen und hohe Toleranz gegen hartes Wasser. Mischungen dieses anionischen Tensids mit bestimmten kationischen Dimeren bilden visköse Lösungen, was ein starkes Mizell-Wachstum widerspiegelt.

Simple gel formulations may be applied to enhance the systemic and local exposure of potential compounds. The aim of this thesis is the development and characterization of controlled release formulations based on thermo-reversible poloxamer gels, which are suitable for novel drug delivery applications.  In particular co-solvents (DMSO, ethanol), mucoadhesive polymers (chitosan, alginate) and salts (sodium tripolyphosphate, CaCl2) have been used to enhance the applications of poloxamer 407 (P407) formulations in preclinical animal studies. The impact of these additives on the micellization and gelation properties of P407 aqueous solutions was studied by calorimetric methods, nuclear magnetic resonance spectroscopy (NMR) and “tube inversion” experiments. The drug release behavior of hydrophobic and hydrophilic drugs was characterized by using a membrane/membrane-free experimental setup. Finally, preliminary pharmacokinetic studies using a mouse model were conducted for screening of selected inhibitors of bacterial type III secretion and for evaluation of different formulations including P407 gel. All additives, used here, reduced the CMTs (critical micelle temperature) of dilute P407 solutions, with the exception of ethanol. The gelation temperature of concentrated P407 solutions was lowered in the presence of CaCl2, DMSO, TPP and alginate. 1H MAS (Magic Angle Spinning) NMR studies revealed that DMSO influences the hydrophobicity of the PPO segment of P407 polymers. Low concentrations of DMSO did not show any major effect on the drug release from P407 gels and may be used to improve the exposure of lead compounds in poloxamer gels. A newly developed in situ ionotropic gelation of chitosan in combination with TPP in P407 gels showed an enhanced resistance to water and reduced the release rates of model drugs. From preliminary pharmacokinetic studies in mice it was revealed that poloxamer formulations resulted in an increased plasma half-life of the lead compound.

This thesis contains investigations in two different areas, described under six chapters. Chapter 1 contains a broad introduction to the area of foldamers, while Chapters 2, 3, 4, and 5 deal with various novel classes of synthetic polymers which can form folded structures in solution utilizing different non-covalent interactions. Chapter 6 deals with a distinctly different topic, where the objective was to study the effect of phenyl ring location on the micellization properties of a series of isomeric cationic surfactants. Synthetic polymers typically adopt a random coil conformation in solution, which is primarily an entropy driven process. So the generation of well-defined secondary structures in synthetic polymers requires specific intra-chain inter-segment interactions that will give adequate enthalpic contribution to overcome the entropic penalty associated with the formation of well-ordered conformations. During the past decade, various research groups have made significant effort to understand the essential design elements that could enable secondary structure formation in synthetic macromolecules through intra-chain inter-segment interactions, such as hydrogen bonding, solvophobic and solvophilic interaction, acid-base interaction, bond angle constraint, steric interaction, charge-transfer interaction, metal-ion complexation etc.1 Gellman2 first used the term “foldamer” to describe “any polymer with a strong tendency to adopt a specific compact conformation” which was more precisely defined by Moore and coworkers3 as “any oligomer that folds into a conformationally ordered state in solution, the structures of which are stabilized by a collection of non-covalent interactions between nonadjacent monomer units” and where the folded conformation is one of the various possible conformations. Several classes of foldamers have been studied during the past decade; a majority of them are well-defined oligomers that possess relatively restricted conformational degrees of freedom. Relatively fewer studies have explored conformational control in flexible high molecular weight polymers that possess greater conformational freedom.4 A few years ago, Ghosh et al. designed a polymeric system wherein charge-transfer interactions between alternatively placed electron-rich and electron-deficient aromatic units, aided by metal-ion complexation and solvophobic interactions, causes the polymer chain to adopt a specific folded conformation.5 Such charge-transfer induced folding was first studied by Iverson and co-workers6 in well-defined oligomers and was later elaborated by Zhao et al.7 to generate alternate designs to fold oligomeric systems. In all these studies, the C-T interactions served not only to assist the folding process but it also served as a valuable spectroscopic signature to study the folding process. The objectives of the present study are to develop simple synthetic strategies to generate different types of polymers that could be fold in solution using various noncovalent interactions. We have developed a simple synthetic strategy to design a new type of donor (1,5-dialkoxynaphthalene-DAN) containing polymer that carries a tertiary amine unit in the spacer segment, which could interact strongly with a suitably designed acceptor (pyromellitic diimide-PDI) bearing folding agent that carries a carboxylic acid group, as shown in Scheme 1.8 This acid-base interaction, brings the acceptor unit in a suitable position so as to form a C-T complex with the adjacent donors, resulting in the folding of the polymer chain. The folded conformation was studied using UV-vis and NMR spectroscopy and the folding propensities were rationalized using DFT studies. The highest association constant between the folding agent and the polymer was estimated to be around 1200 M-1. Scheme 1. Schematic representation of folding aided by two-point interactions with a folding agent. This value of association constant was not adequate to realize some potentially interesting properties in solid state. In an attempt to develop alternate systems, that could exhibit stronger propensity to fold, we designed a new type of cationic ionene,9 wherein electron-rich (DAN) and electron-deficient (PDI) aromatic units were included within the alkylene segments in an alternating fashion, as shown in Scheme 2.10 The charge-transfer (C-T) interaction between the donor and acceptor units in neighbouring segments of the ionene not only reinforced the transition to the collapsed nano-bundle form but also provides a useful spectroscopic handle to monitor the conformational change. The UV-visible spectra of these novel D-A ionene solutions at a fixed concentration in four different solvents, namely water, methanol, acetonitrile and DMSO, show different extents of charge-transfer interaction. The colour of the solution in water was deep-red, whereas in acetonitrile, it was light-yellow. The conformational transition could also be induced by titrating an acetonitrile solution of the ionene with increasing amounts of water causing a dramatic increase in the intensity of the charge-transfer band, which reflects the extent of collapse to the zig-zag state that brings the donor and acceptor units together. AFM studies confirmed the presence of flat pancake-like aggregates having nearly constant height of about 3-5 nm, which was in accordance with the estimated thickness of the postulated zig-zag structure. Scheme 2. Schematic depiction of folding of D-A ionene (left), AFM micrograph showing pancake-like aggregates of D-A ionenes (right-top), a line scan depicting the heights and diameters of the aggregates along with a schematic depiction of the aggregate (right-bottom). Scheme 3. Schematic representation of folding aided by interactions with a folding agent. In order to explore this concept further, we designed a two component system wherein the solvophobically-driven collapse of a DAN-containing ionene chain in a polar solvent is reinforced by intercalation with a suitably designed electron-deficient acceptor-containing external folding agent. DAN containing ionene polymer chains in polar solvent form an accordion-type zig-zag structure that brings adjacent donor units in close proximity; this provided an ideal hydrophobic pocket for intercalation of suitably designed electron-deficient acceptor molecules, the additional driving motivation for the intercalation being the formation of a C-T complex as shown in Scheme 3.11 Several acceptor-bearing molecules were prepared by the derivatization of pyromellitic dianhydride and naphthalene tetracarboxylic dianhydride with two different oligoethylene glycol monomethyl ether monoamines. UV-vis spectroscopic studies were carried out by using a 1:1 mixture of the DAN-ionenes and different acceptor molecules in water/DMSO solvent mixtures. The intensity of the charge-transfer (C-T) band was seen to increase with the water content in the solvent mixture, thereby suggesting that the intercalation is indeed aided by solvophobic effects. The naphthalene diimide (NDI) bearing acceptor molecules consistently formed significantly stronger C-T complexes when compared to the pyromellitic diimide (PDI) bearing acceptor molecules, which is a reflection of the stronger π-stacking tendency of the former. The highest association constant between the folding agent and the polymer was estimated to be around 4519 M-1, which was a substantial improvement over the earlier reported values.9 With a slight modification in the pendant group, we designed a water-soluble DAN-containing ionene, which can intercalate hydrophobic electron-deficient molecules, like TNT (2,4,6-trinitrotoluene), within the hydrophobic interstices between DAN units (as shown in Scheme 4), causing a depletion in fluorescence from the DAN units; TNT at concentration as low as 30 nM could be detected in this manner. Scheme 4. Schematic representation of folding of water soluble ionene and interactions with an electron-deficient hydrophobic moiety TNT. Scheme 5. Schematic representation of folded D-A allyl ionene. In light of the growing interest in single-chain polymeric nanoparticles, the fully collapsed D-A ionenes in water could be viewed as polymeric nanoparticles that are stitched together by reversible weak noncovalent interactions. In an attempt to transform the folded structure into a polymeric nanoparticle using covalent bonding, we designed D-A ionene that carries potentially polymerizable allyl units on the cationic head group instead of the dimethyl amine head group that was used in previous examples (as shown in Scheme 5). Preliminary studies showed that polymerization does not proceed readily; however, thiol-ene based clicking strategy enabled partial stitching of the folded segments, by the use of a suitably designed dithiol. In the last section of this thesis, we examined the effect of phenyl ring location on the micellization properties of a series of isomeric cationic surfactants, wherein the phenyl ring location was varied from head to tail region (as shown in Scheme 6).12 Thus, cationic surfactants (S1-S5) bearing a long alkyl chain that carries a 1,4phenylene unit and a trimethyl ammonium headgroup was synthesized and their solution properties were examined. Micellization behavior was studied using conductivity, ITC (Isothermal Titration Calorimetry), SANS (Small-Angle Neutron Scattering) and NMR. These present studies demonstrated that the presence of a large rigid ring near the hydrocarbon tail-end of the surfactant leads to a dramatic change in the micelle structure; the driving motivation to form micelles in such systems is greatly reduced and the micelles that are formed are relatively smaller and contain significantly fewer surfactants. NMR studies of micellar solutions of these surfactants indicate that the variation in the phenyl ring location may also help to probe the microenvironment at various depths within the micellar aggregates. Scheme 6. Structures of the various surfactant molecules carrying the 1,4-dioxyphenylene unit at different locations within hydrophobic segment (left), variation of CMC values (right). References (1) Foldamers - structure, properties, and applications, edited by Stefan Hecht and Ivan Huc, Wiley-VCH, 2007. (2) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (3) Hill, D. J.; Mio, M. J.; Prince, R. B.; Huges, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893. (4) (a) Wang, W.; Li, L. S.; Helms, G.; Zhou, H. H.; Li, A. D. Q. J. Am. Chem. Soc. 2003, 125, 1120. (b) Li, A. D. Q.; Wang, W.; Wang, L. Q. Chem. Eur. J. 2003, 9, 4594. (c) Neuteboom, E. E.; Meskers, S. C. J.; Meijer, E. W.; Janssen, R. A. J. Macromol. Chem. Phys. 2004, 205, 217. (d) Balbo Block, M. A.; Hecht, S. Macromolecules 2004, 37, 4761. (5) (a) Ghosh, S.; Ramakrishnan, S. Angew. Chem. Int. Ed. 2004, 43, 3264. (b) Ghosh, S.; Ramakrishnan, S. Angew. Chem. Int. Ed. 2005, 44, 5441. (6) Lokey, R. S.; Iverson, B. L. Nature 1995, 375, 303. (7) Zhao, X.; Jia, M. X. Jiang, X. K.; Wu, L. Z.; Li, Z. T.; Chen. G. J. J. Org. Chem. 2004, 69, 270. (8) De, S.; Koley, D.; Ramakrishnan, S. Macromolecules 2010, 43, 3183. (9) Williams, S. R.; Long, T. E. Prog. Polym. Sci. 2009, 34, 762. (10) De, S.; Ramakrishnan, S. Macromolecules 2009, 42, 8599. (11) De, S.; Ramakrishnan, S. Chem. Asian J. 2011, 6, 149. (12) De, S.; Aswal, V. K.; Ramakrishnan, S. Langmuir 2010, 26, 17882. (For structural formula pl see the abstract file.

La présente étude est une approche holistique axée sur l'étude des effets spécifiques d'ions sur les propriétés d'auto-assemblage de tensioactifs cationiques gemini. Notre objectif principal étant l’étude de l'effet de divers contre-ions sur les caractéristiques d’auto-assemblage de tensioactifs cationiques en solution aqueuse. Afin d'obtenir une vision plus complète de l'effet des interactions ioniques et moléculaires à l’interface sur les propriétés globales, nous avons utilisé des approches différentes. Nous avons combiné une étude expérimentale portant sur les propriétés en solution (concentration micellaire critique, degré d'ionisation, nombre d'agrégation, etc.), avec des approches centrées sur l'étude des propriétés micellaires interfaciales en analysant les concentrations des contre-ions et de l'eau de façon expérimentale (piégeage chimique) et informatique (simulations de dynamique moléculaire). En outre, nous avons étudié l'impact de la nature des contre-ions sur la croissance des micelles géantes par rhéologie. En plus de l'examen des propriétés de tensio-actifs en solution, les effets spécifiques d'ions sur les structures cristallines des agents tensioactifs gémini ont été étudiés.Nous avons trouvé que les effets d'ions spécifiques qui déterminent le comportement des agrégats micellaires de gemini cationiques d'ammonium quaternaire dans des solutions aqueuses dépendent fortement de l'énergie libre d'hydratation des contre-ions, en d'autres termes, sur leur propriétés hydrophile /hydrophobe. Contrairement à la solution aqueuse, dans les cristaux, la taille de l'ion devient le facteur déterminant. La comparaison des résultats obtenus pour un même système en solution aqueuse et à l'état solide a montré l'importance des interactions ion-eau dans les effets spécifiques d'ions. Cependant, il faut noter que les propriétés du substrat (les gemini dans notre cas) doivent être prises en compte non moins soigneusement afin de prédire complétement les effets Hofmeister. / The present study is a holistic approach focused on the investigation of ion specific effects on the self-assembly properties of cationic gemini surfactants. Our main focus was on the effect of various counterions on the self-organization features of cationic surfactants in aqueous solution. In order to obtain amore comprehensive understanding of the effect of interfacial ionic and molecular interactions on aggregate properties we used different approaches. We combined an experimental study focused on the bulk solution properties (critical micelle concentration, ionization degree, aggregation number, etc.), with approaches focused on investigating the interfacial micellar properties by analyzing the interfacial counterion and waterconcentrations, experimentally (chemical trapping) and computationally (molecular dynamic simulations). Moreover, the impact of counterion nature was investigated by studying the growth of wormlike micelles using rheology. Besides the examination of the surfactants properties in solution, the ion specific effects onthe crystalline structures of gemini surfactants were studied.We found that ion specific effects which determine the behavior of micellar aggregates of cationic quaternary ammonium gemini in aqueous solutions strongly depend on the free energy of hydration of the counterions, in others words, on their hydrophilic/hydrophobic properties. Contrarily to aqueous solution, in crystals, the size of the ion becomes the determining factor. Comparison of the results obtained for the same system in aqueous solution and in solid state showed the importance of ion-water interactions in ion specific effects. However, one should note that the properties of substrate (the gemini in our case) should be taken into account not less carefully in order to fully predict Hofmeister effects.

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