INTRODUCTION:

“Ionic liquids are the salts with melting point below 100^ºC which are solely composed of large organic cations and small inorganic anions; many of them are liquid at room temperature hence called as room temperature ionic liquids.” The low melting point of ionic liquids are due to crystalline network formation which is caused by the geometric characteristics of both ions and their charge diffuse nature.¹ The thermodynamic properties and reaction kinetics of various reactions carried out in ionic liquids are different from those in conventional reaction media. This creates new opportunities for catalytic reactions, separation techniques because ionic liquids do not vomit volatile organic carbon and has negligible vapour pressure thus helps in clean manufacturing and hence proved to be the “green solvents”.^2,28 Ionic liquids has various fascinating properties such as negligible vapour pressure, good thermal stability, tunable viscosity, good miscibility with water and organic solvents, good extractability, non flammability, etc.

These are also called to be the ‘designer solvents’ as the design of liquid salt is carried out with some improved properties like viscosity, hydrophilicity, and many other chemical and physical properties; because of this tunable nature ionic liquids have many applications in drug delivery.³ With this primary focus a door is open to the design of active pharmaceutical ingredients in the form of ionic liquids, this helps to overcome many problems currently encountered by the APIs like polymorphic changes, stability related problems, etc. as well as it offers new drug delivery options.¹ A liquid phase of given active compound is usefully different form of active compound because it avoids problems related to polymorphism. The development of liquid drugs are carried out eutectic mixtures to avoid various issues associated with crystalline salt form of drug but this tends to introduce a substantial quantity of inactive ballast in the formulation.⁴ In case of the ionic liquids the liquid phase is present at temperature lower than room temperature. The low melting points are induced due to stress produced by packing of asymmetric cations as well as more diffuse charge on both the ions.⁵ The combination of cations and anions with little chance for intermolecular interactions in an “anti-crystal engineering” approach decreases the crystallization and provides an elegant access to pharmaceutically active ionic liquids.⁶ The huge interest of ionic liquids has led to an extensive and diverse range of ions to support ILs formation. There are equally diverse range of applications has emerged, such as in separation process⁵, catalytic reactions¹⁰, in organic synthesis, electrochemical cells, chromatographic extraction, nanomaterial synthesis, microemulsion formulation^8,9, in formulation of transdermal patches and novel use as ‘drug ionic liquid’ such as local anaesthetic, antibacterial, antimicrobial, antitumour agent⁷; because of its green nature and various fascinating properties.

First ionic liquid; Ethanol ammonium nitrate was synthesized by Gabriel, which has melting point 52-55ºC; in 1888. Then in 1914 first room temperature ionic liquid was synthesized named ethyl ammonium nitrate which has melting point only 12^ºC. Development of ionic liquid with chloralluminate ions was carried out by Hurley and Wier in 1948 at Rice institute at Texas. Ionic liquids based on 1,3 dialkylimmidazolium or alkylpyridinium halides or trihalogenaluminates were synthesized in 1970. First publication on ionic liquids as catalyst in organic synthesis and reaction media was observed in 1980’s. Synthesis of weakly co-ordinating anions [PF₆],[BF₃], triflate[CF₃SO₃], bistriflimide[(CF₃SO₂)₂N] containing ionic liquids was carried out by Wilkes and Zawarotko in 1992. When ionic liquids were first studied and some articles published in 1990 and onwards, this important thing, triggered huge interest and excitement in pharma world and within short period of time this received more attention by industrial communities.^10-12

Properties of ionic liquids:

The various fascinating properties of ionic liquids that set ionic liquids apart from other solvents are as follows:

i. Ionic liquids are present in molten state, in many cases below room temperature so that called to be the room temperature ionic liquids.

ii. These are highly polar solvents; miscible with water and other organic solvents which depends upon side chain length of cation and choice of anion; for example- 1-alkyl-3-methyl immidazolium tetrafluoroborate salts are miscible with water when the alkyl chain length is less than 6 carbon atoms but when more than 6 carbon atoms are present, they forms a separate phase with water.

iii. An ionic liquid has negligible vapour pressure; hence these are noninflammable, non explosive and so that their distribution in air cannot be possible; because of this ionic liquids are known as green solvents.

iv. Ionic liquids have high thermal stability as well as electrical stability.

v. They have good electrical conductivity.

vi. They have amazing dissolution properties e.g.- can dissolve wood, cellulose, polyamides, etc.

vii. These can act as acids, bases and ligands.

viii. They reduces the related cost, disposal requirements and hazards associated with volatile organic solvents and allows simple recycling and reuse of ionic liquids.

ix. Ionic liquids are the environmental friendly alternative to other organic solvents for various reactions like catalysis, separation process, analytical chemistry, electrochemistry, etc.^2-5

Ions used in ionic liquid preparation: ^2,4,12-14

Cations

Anions

Quaternary ammonium,

Imidazolium,

Pyrrolidium,

Pyridinium,

Tetraalkylphosphonium,

Thiazolium,

Pyrazolium,

Triazolium,

Oxazolium.

Inorganics

BF4-

PF6-

Cl-

Br-

[SbF6]-

[AlCl4]

[AuCl4]-

Organics

Sulfonate: -O-(SO2R),

Imide: -N-(SO2R)2,

Methide: -C-(SO2R)3

Methods of synthesis of ionic liquids:

The synthesis of ionic liquids is not such a difficult task. Now a day’s ionic liquid are prepared by using active pharmaceutical ingredients; commonly known as drug ionic liquids. This is the third age of ionic liquids, which provides ILs with specific biological activity. The first generation ionic liquids were synthesized for the purpose of improving various physical and chemical properties, like solubility, viscosity, density, stability, etc. The second generation ionic liquids mainly focus on the synthesis of ‘task specific ionic liquids’ which has special applications as reaction media, for separation, extraction, etc only because of its green nature.⁷ However the various applications of ILs varies with generation of ILs but their methods of preparation generally involves two basic methods which are metathesis reactions and neutralisation reactions; which are described as follows:

1. Metathesis reaction:

Metathesis reaction is the rearrangement of bonds between two reacting species. In ionic liquid synthesis metathesis of halide salt is carried out with silver salt/ammonium salt/phosphonium salt. This is two step reaction in first step quarternisation of halide salt is takes place with one of the silver, ammonium or phosphonium salt. And in the second step anion can be modified in different ways. The reaction is shown as follows:

Fig. 1. Synthesis of ionic liquids

An ionic liquid [emim][BF₄] i.e. 1-ethyl, 3-methyl immidazolium tetrafluoro borate can be synthesized by using [emim]I and Ag[BF₄] in methanol which has melting point 12⁰C. [emim][PF₆] can be synthesized by using [emim]Cl and [HPF₆], which has melting point 60⁰C. The preparation of pyridinium and immidazolium halides can be carried out similarly. Preparation of ionic liquids involving volatile haloalkanes requires sealed tubes.^15,16

2. Neutralization reaction:

This reaction involves simple acid-base neutralization. For example tetra alkyl ammonium sulphonates have been prepared by using equimolar concentrations of sulphonic acid and tetra alkyl ammonium hydroxide; excess of water can be removed by using vacuum. Purification of ionic liquids can be carried out by dissolving it in acetonitrile or tetrahydrofuran and then treated with activated charcoal for 24 hrs, and remaining organic solvent will be removed by using vacuum.¹⁰ In 1914 Walden reported neutralized ethylamine with nitric acid to prepare an ionic liquid with melting point 12⁰C. This was found to be the first ionic liquid prepared by neutralization reaction.^15,16

Modified ionic liquids:

1. Room temperature ionic liquids:

“Room temperature ionic liquids are salts which are present in a liquid state over wide temperature range, including room temperature.”

Physical properties of ionic liquids like, melting point, viscosity, density, water solubility are depends upon choice of cation and anion. Cations are typically bulky, asymmetric which helps in reduction of melting point, for example- 1-alkyl-3-methylimidazolium, 1-alkylpyridinium, N-methyl-N-alkylpyrrolidium, ammonium, etc. and anions including halides and many organic and inorganic anions like, tetrafluoroborate, hexafluorophosphate, triflate, bistriflimide, etc. are important for determining the air water solubility.

E.g.- alkylimmidazolium hexafluorophosphate [RMIM] [PF6].^15-18

2. Task specific ionic liquid:

“TSILs are new type of ionic liquids in which functional group is incorporated as cation or anion; such functional group can take part in particular reactivity pattern, enhancing its capacity for interaction with the specific solute and dissolved molecules, such type of ionic liquids are called as task specific ionic liquids.”¹⁰

Inclusion of functional group in IL is to instil the salt with a capacity to covalently bind to or catalytically activate a dissolved molecule. ILs having large aromatic functional groups show enhanced activity for the extraction of aromatics in aqueous biphasic systems. Functional groups such as thioether, urea, thiourea to immidazolium cations produce task specific ionic liquids.¹⁹

Applications of ionic liquids in drug delivery:

1. Active pharmaceutical ingredients as ionic liquids:

Out of the three generations of ionic liquids, the most recent third generation specially involves active pharmaceutical ingredients (API). This is aimed at the production of ionic liquids with specific biological activity and known to be ‘drug ionic liquid’.⁷ APIs can be easily converted into the ionic liquid form which helps to avoid many problems related to solid salts of APIs, that is such type of liquid salts have various improved properties such as solubility, thermodynamical stability, and do not under go polymorphism and hence proved to be the best alternative to the phase control.²⁰ The design of active pharmaceutical ingredient in the form of ionic liquid can be achieved by pairing known API with its counterion which are able to produce low melting ionic liquid. With this approach side effects of any drug can be encountered. For example local anaesthetic lidocane was proved to have enhanced solubility, and long lasting effect on rats when applied as an ionic liquid that is lidocanium docusate as compared to its hydrochloride salt.¹ Now a days by using this approach ionic liquids are synthesized containing both active compounds, which gives it dual functionality.^21,22

2. Formulation of dual functional painkillers of aspirin: Ionic liquids are synthesized containing two active ions which are responsible to provide it dual functional nature as one counteract side effects of another API or both the ions are pharmacologically independent or both ions act synergistically rather than giving additive results.²⁰ An oral administration of aspirin can suffer from problems such as poor solubility, bitter taste and large dose requirement. An ionic liquid form may overcome these issues. The novel ionic liquid was prepared by using ion exchange reactions between active ions like acetyl salicylate or salicylic acid and another pharmacologically active ion that is ammonium that is aspirinate ionic liquid. An ammonium ion added to provide second function to the drug ionic liquid such as antibacterial or antimalerial activity. This work shows that pharmaceutical ionic liquids provide important means in drug development. In future any combination of two or more drugs having opposite and active ionic forms able to synthesize drug ionic liquid.^21,22 There are number of possible combinations of active cations and anions to be formulated in the form of drug ionic liquid or dual functional ionic liquid.²⁰

Active cation(+)

Active anion(-)

Local anaesthetics & analgesics NSAIDS

Antibacterials/antiparasitics Vitamins

Antiemetics Emollients

Stimulants/appetite suppressants Sweeteners

Antiarrythmics UV protectors

Vitamins Penetration enhancers

Antipsychotics Antibiotics

Chemotherapeutics

Pesticides

3. Microemulsions using an ionic liquid as surface active agent:

“Microemulsions are thermodynamically stable, isotropic transparent mixtures of hydrophilic, hydrophobic or amphiphilic component, commonly using water as polar phase.

”To increase the stability of microemulsion ionic liquids are used as surfactant and room temperature ionic liquid is used as polar phase. Ionic surfactants like, sodium dodecylsulfate or dodecyltrimethyl ammonium bromide are generally used as these are strongly hydrophilic and do not form large micelles. Also critical solution temperature is not observed for such type of surfactants as well as size of the micelles does not change with temperature.^23,24

4. Nanotechnological applications of ionic liquids:Ionic liquids are used in the formulation of nanoparticles, as stability protective agent and efficient drug delivery agent.

i. Gold nanoparticles are prepared by using ligand based immidazolium salts which act as nanoparticles stabilizer and transfer agent in organic media. Gold nanoparticles are used for diagnosis purpose in medical therapy.

ii. Thiol functionalized ionic liquids are used for the synthesis of gold and platinum ionic liquids which act as stabilizing agent. It is known that uniform size and distribution of nanoparticles depends upon the number and position of thiol groups in the ionic liquids when the characterization of nanoparticles were carried out by using NMR spectroscopy, transition electron microscopy, and electron diffraction.²⁵

iii. Silver nanoparticles were prepared by using mono and dihydroxylated ionic liquids in aqueous systems which act as protective and reducing agent. By changing the anion of the hydroxyl functionalized ionic liquid, the particle size and uniform dispersibility of nanoparticles can be controlled. These silver nanoparticles were found to be environmentally friendly antimicrobial agents.²⁶

iv. The dispersion of titanium dioxide nanoparticles prepared by using room temperature ionic liquid. And characterization was carried out by using X-ray diffraction analysis, nitrogen adsorption, Brunauer- Emmett-Teller (BET) analysis and FTIR spectroscopy.²⁷

v. The transition metal nanoparticles have good solubility in ionic liquids hence catalytic reactions were studied in ionic liquids.²⁸

5. Novel ionic liquid method in the treatment of Parkinson’s disease:

Dutch researchers were developed low cost levodopa production for treatment of Parkinson’s disease. They used ionic liquid method which is inexpensive as compared to general dosage forms. They dissolved levodopa as raw material in ionic liquid and applied carbon dioxide with high pressure and force so that to act as gas and liquid and to mix contents uniformly. Then separation was carried out by lowering the pressure and evaporating gas mixture, end product obtained in solid form, it may be obtained in liquid form also. In this process carbon dioxide was used as compared to conventional process in which methanol was used in that case energy required for evaporation of methanol is more than that of carbon dioxide, so that this ionic liquid method was found to be inexpensive one.²⁹

6. Ionic liquids in transdermal drug delivery system:

Ionic liquids are used in transdermal drug delivery of acyclovir, which is insoluble or sparingly soluble in water and other organic solvents. In this method non aqueous microemulsion was prepared by using ionic liquid which is stabilized by two surface active agents like Tween-80 and Span-20 and further used for transdermal delivery of drug.³⁰

Toxicology of ionic liquids:

1. The toxicological effects of ionic liquids are due to the structure of compounds, so that various trends might occur in test systems of different biological complexity for e.g. enzymes, microorganisms.

2. Ionic liquids consisting of halogen containing anions with poor stability in water are toxic and corrosive species such as HF and HCl might be liberated, to overcome this use of halogen free and relatively hydrolysis stable anions such as octylsulfate compounds can be done.

3. Higher loss of cell viability with increasing chain length of alkylimmidazolium ionic liquids has been observed using mammalian cells.

4. Experiments with soil nematodes (caenorhabditis elegans) shows that lethality of these organisms increases in presence of alkylimmidazolium salts of chloride with increasing alkyl chain length.

5. Acute toxicity is reported for [3-hexyloxymethyl-1-methylimidazolium] [BF4] for male and female rats respectively.

6. Ionic liquids impact on aquatic ecosystem-

- The impact of ionic liquid on aquatic ecosystem is particularly important; due to their non-volatile nature and mild to high solubility of some of them.

- Daphnia are a common fresh water crustaceans, they are at the base of aquatic food chain, their responses to ionic liquids are crucial for assessing how these new solvents will impact on environmental ecosystem.

- The ionic liquids are toxic to daphnia as like benzene and are more toxic than acetone.

- The following LC50 values were obtained for 1-n-butyl-3-methylimidazolium cations with different anions

a. [bmim][PF6]- 250 to 300,

b. [bmim] [BF4]- 225 to 275

c. Acetone- 30642.

- To overcome this, attention must be paid to the purity of ionic liquids used.^1,10,16,31

CONCLUSION:

Ionic liquids are promising class of new materials with bright technological future. They have many fascinating properties which makes them different from conventional solvents so that ionic liquids are called to be ‘Designer solvents’. Ionic liquids are proved to be the ‘green solvents’ because of negligible vapour pressure and simple recycling and reuse. With the help of such a versatile properties ionic liquids hence proved as a good drug delivery option than common solid salts.

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Received on 14.08.2013 Modified on 10.09.2013

Research J. Pharm. and Tech. 6(11): November 2013; Page 1274-1278