Organogel: A Propitious Carman in Drug Delivery System

Abstract

A gel is a semi-solid formulation having an external solvent phase that is either apolar (organogels) or polar (hydrogels) that is immobilized inside the voids contained in a three-dimensional networked structure. Organogels are bi-continuous systems composed of apolar solvents and gelators. When used at a concentration of around 15%, the gelators form self-assembled fibrous structures that become entangled with one another, resulting in the formation of a three-dimensional networked structure. The resulting three-dimensional networked structure blocks the flow of the external apolar phase. Sterol, sorbitan monostearate, lecithin, and cholesteryl anthraquinone derivatives are examples of gelators. The unique characteristics such as thermo-reversibility, viscoelasticity, and versatility impart a longer shelf-life, prolonged drug release, and patient compliance. These characteristics can easily be adjusted by simple formulation modifications, resulting in highly-structured architectures. Organogels are more likely to be used in various types of delivery systems because of their ability to entrap both hydrophilic and hydrophobic molecules inside their structure. Their combination with other materials allows for tailoring their potential as dosage forms. Organogels have potential applicability in numerous ways; hence this article discusses the various aspects of it.

1. Introduction

Gels are defined as semisolid, cross-linked systems containing condensed solid particles interpenetrated by a liquid [1]. Gels can be referred to as hydrogels or organogels, which can be distinguished on the basis of polarity comprised by the gel, that is, if the liquid phase in the gel is water then it is referred to as a hydrogel, whereas if the liquid phase in the gel is an apolar solvent, then it is referred as an organogel. Organogels are the carriers used for delivering the medicament at its desired site [2]. Organogels are formed by gelators, which are foundational building blocks. Gelators are often certain low-molecular-mass substances (e.g., sorbitan derivatives, lecithin, fatty acid derivatives, bis-urea compounds) [3, 4, 5]. The gelators help in the formation of a 3D structure of a mesh network due to the entanglement of self-assembled fibrous structures, which are formed due to some physical or chemical interactions of gelators when used in the concentration of <15% (approx.) [6, 7]. Gelators are hence responsible for immobilizing the apolar solvent phase. The gels formed by the physical interactions are termed physical gels (held by physical forces such as Van der Waals and hydrogen bonds) whereas the gels formed by chemical bonding are termed chemical gels (held by covalent bonds) [7]. The gelators elevate the surface tension which predominantly prevents the flow of the solvent phase. Gelators immobilize organic solvents by the establishment of non-covalent intermolecular interactions forces (H-bonds, electrostatic interactions, metal coordination, p–p stacking, and London dispersion forces), resulting in the formation of various entangled structures like wrinkles, lamellar, and fibers [8, 9, 10, 11]. The thermo-reversible property, non-irritating nature, and biocompatibility of the organogels have generated much interest in their potential application as a drug delivery system. Wide formulations can be developed for the administration of drugs via various routes using organogels as they can incorporate hydrophilic and hydrophobic bioactive agents within their gel structure. The rate-limiting step in the bioavailability of drugs from organogels is its characteristic features, that is, high permeability, and low aqueous solubility, which affect the rate of drug release from drug delivery systems. They have no confined application as they can be used for topical application or for the release of drugs into systemic circulation by cutaneous delivery and percutaneous absorption [7, 12].

2. Types of organogel

2.1 Lecithin organogels (LOs)

Since LOs have the desirable physicochemical characteristics ideal for topical formulations, these are employed most frequently for topical application. These are useful for the delivery of a wide variety of hydrophilic as well as lipophilic drugs through the skin. Lecithin is a constituent of natural origin which can be isolated from various animal and plant sources (except egg yolk) and hence biocompatible, safe and stable [7, 13, 14]. It is a potential vehicle for a number of bioactive agents. Lecithin is chemically a phosphatidylcholine, a constituent of the class phospholipids. It has been observed that lecithin is unable to form a gel if its phosphatidyl content is less than 95% [7, 15]. The concept of designing organogels with lecithin was first mentioned by Luisi and Scartazzini in the year 1988 [16]. Lecithin can only produce gelation if it is used in its pure form (e.g., the hydrogenated form of soya-lecithin failed to induce gelation). The unsaturated fatty acids present in naturally occurring lecithin are hence important [15].

2.2 Pluronic lecithin organogels (PLOs)

High-purity lecithin is costly and difficult to procure in significant quantities. Due to the convenience of synthetic polymers such as pluronics, which serve as co-surfactant and stabilizers, they have been widely studied in combination with lecithin to formulate lecithin micro-emulsion-based organogels [17]. It was prepared in 1990 in the US by a compounding pharmacist to use as a topical carrier system [15]. The primary benefit of employing PLs in organogels is their capacity to self-assemble into micelles at approximate physiological temperatures [11]. Pluronic F-127 is a copolymer which causes gelation when used in a concentration of 15–30% w/v [18]. It is formed by adding the Pluronic F-127 to the LOs. It is majorly used for transdermal as well as topical drug delivery systems and also for oral and mucosal drug delivery systems to some extent [15]. It forms a non-transparent yellow gel [19]. After topical administration, PLOs rupture the lipid layer of the stratum corneum and deliver the drug into the systemic circulation with minimal irritation to the skin [7, 18]. Additionally, in order to have a synergistic effect, it has also been demonstrated to be a useful transporter for combinations of drugs [20]. It works best when combined with medications whose molecular weight is less than 500 Da [21].

2.3 Limonene GP1/PG organogels

Limonene is a terpenoid with magnificent penetration power and is used in transdermal drug delivery systems as it can enhance the bioavailability of drugs [22]. This organogel is prepared by mixing a suitable amount of GP1 (dibutyllauroylbutamide) amino acid type of organogelator with limonene and PG (propylene glycol), followed by its incubation at 120°C. After cooling down to an appropriate temperature, it forms a gel that appears white in color. It has been observed that the co-existence of limonene with GP1 and PG influences its rheological behavior to some extent, whereas their chemical characteristics are not significantly affected [7, 15, 19, 23]. The GP1/PG organogels tend to have increased gel moduli due to the incorporation of limonene, which gives an indication of increased gel physical stability [24]. Other terpenoids such as cineole and linalool, have also been successfully mixed with GP1 and PG to obtain an effective organogel with improved penetration power [18].

2.4 Micro-emulsion-based organogels (MBG) stabilized by gelatin

Micro-emulsions offer good bioavailability of drugs when introduced via topical or systemic routes of the drug delivery systems. Micro-emulsions are known to deliver a greater amount of drug than other gel systems [15]. The micro-emulsion system can undergo gelation when gelatin is dissolved in the water microphase, and the resultant gel will consist of more than 80% hydrocarbon solvent [25]. The basic mechanism involved in the formation of MBG is that a solution of gelatin in water is added to the parent micro-emulsion after it has been incubated at 50°C in the incubation chamber. In order to obtain an optically transparent single-phase gel, the resulting liquid is forcefully mixed and then allowed to cool to ambient temperature [26]. Gelatin is a protein that has the ability to form gels. It can undergo gelation when its concentrated solution is heated beyond 45°C and is then cooled down below 35°C and increases thermostability. When gelatin is added to w/o micro-emulsions, a transparent gel of the complete micellar solution is obtained [7, 15, 19, 27, 28].

2.5 Sorbitan organogels derived from fatty acids

Sorbitan monopalmitate (span 40) and Sorbitan monostearate (span 60) are the gelators of this class. They are non-ionic, hydrophobic in nature, and possess surfactant properties. They form a solid-fiber matrix when heated with the apolar solvent and then cooled down to a relatively lower temperature. A gel of toroidal reverse micelle is formed due to a drop in the temperature, which is followed by self-assembly leading to its transformation into rod-shaped tubules. The gel so obtained is white, opaque, semisolid, and thermostable at room temperature. These organogels are used as vehicles for hydrophilic vaccines [29, 30, 31].

2.6 Polyethylene organogels

Low molecular-weight polyethylene is solubilized in mineral oil at a high temperature of more than 130°C, yielding a colorless organogel. This causes intermolecular interaction within the polyethylene, which leads to the precipitation of its molecules, which forms a solid-fiber matrix to form a gel [16]. They are generally used as a base for ointment preparations [19]. A study conducted in the 1950s concluded that the patches of polyethylene organogel were found to be non-irritating along with low sensitizing properties [15].

2.7 Eudragit organogels

Eudragit organogels are formed by the mixture of polyhydric alcohols (propylene glycol and glycerol), a high concentration (30–40%) of Eudragit (L or S), and liquid PEG. To prepare a formulated Eudragit organogel, the drug is first dissolved in the PEG, and this solution is then added to the Eudragit powder. This mixture is further triturated with the help of a mortar and pestle for approximately 1 minute. The concentration of Eudragit and the amount of drug are found to directly influence the consistency of the gel. The gel viscosity is enhanced with a high concentration of Eudragit, whereas it decreases with an increasing amount of the drug. In low concentrations of drugs, the gel has high rigidity as well as stability [7, 15].

2.8 Supramolecular organogels

These organogels are made of gelators of low molecular mass. The molecules of different gelators of this class differ immensely in their structural characteristics. Hence, they have offered a scope of interest to develop different gels with technological application. For example, having sensitivity toward external stimuli like light. Remarkable thermoreversibility and mechanical capabilities are displayed by supramolecular organogel systems with controlled self-assembled structures. These organogels can offer controlled drug delivery. They can be used as carriers for multiple purposes [15, 32].

2.9 L-alanine-derived organogels

LAM (N-lauroyl-L-alanine methylester) undergoes gelation with organic solvents such as triglycerides and soya-bean oil. It is not as extensively used as other organogels. At room temperature, it remains in a gel state [7, 15, 18]. In a biphasic mixture of water and apolar solvent, a fatty acid derivative of L-alanine aids the gelling of the solvent-specific portion of the mixture without gelling the aqueous portion [33]. This characteristic makes it considerably more appealing to use in organogel. It can be used as an implant for sustained release system. Currently, it is used as a vehicle for the drugs like leuprolide, rivastigmine [7, 18].

3. Importance of organogels

For the conveyance of medications in the body/target site, numerous procedures and frameworks have been analyzed. Out of the effective applications accessible, organogels are getting greater fame on account of the simplicity of utilization, better ingestion through the skin layers, etc. Amongst the existing dosage forms, organogels are the easiest to prepare and have also been proven to be cost-effective [7, 34, 35]. They offer a better stability profile than that of other gels. The characteristic features of organogels not only make it easier for the manufacturer to process but also provide an easy handling and utilization method for the consumers, hence making it of commercial importance. The organogels can deliver the drugs more effectively than other dosage forms. This has been validated through a study which was conducted by I.M. Shaikh et al., where it was observed that the penetration efficiency of organogel (LO) was greater than that of hydrogels when applied over skin [35, 36]. As it offers a controlled drug delivery system, many chronic diseases could be cured if the organogels are loaded with appropriate drugs and then implanted at the target site. This characteristic also eliminates the obligation of frequent dosing. They have an extended application as they lend opportunities to incorporate various constituents having wide-ranging characteristics. Organogels can be used as an alternative to UV-treatment methods. Hence, it will eliminate the chances of cancer caused by exposure to UV rays [37, 38]. Organogel can reduce/control the dissemination rate of medication, hence making it liable for designing an appropriate formulation for an appropriate purpose to deliver the drug as required. As it comprises both hydrophilic and lipophilic parts, both lipophilic and hydrophilic bioactive agents could be consolidated within it [15, 38]. Therefore, wide-ranging drugs could be incorporated into them.

4. Advantages of organogels

It is an easy formulation to prepare and has a longer life span. Bioactive agents of distinct characteristics can be incorporated [37, 38]. Their physical form remains unaffected by the factor of time owing to structural cohesion. It is cost-effective as it requires a lower number of components [37, 38, 39]. They have simple handling and usage requirements. It also provides improved patient compliance [34]. It has various applications for topical delivery systems. It has thermal stability [38]. A few chemical modifications can lead to the release of drugs in the desired manner and at the desired place [34]. It bypasses first-pass metabolism, ensuring that medicines have the highest possible bioavailability. They are relatively safe as bio-compatible constituents are used. Hence, it can be used to deliver various drugs. It is non-invasive and is better tolerated by the patients. It is a thermodynamically stable system. As it can be used for an extended period of time, the need for dosing is less frequent. It has both hydrophobic and hydrophilic units. Therefore, bioactive agents of either nature can be incorporated into it. There is no risk of microbial contamination as they are insensitive to moisture [34, 38].

5. Limitations

It accounts for low thermostability. It has a greasy texture [2]. For the drugs that are intended to be penetrated through the skin, they must possess an appropriate partition coefficient. It holds good chances for the occurrence of swelling (uptake of liquid resulting in an increase in its volume) or syneresis (natural shrinkage if allowed to be at rest for a period of time) [15, 40]. Organogels intended for topical application might irritate the local skin. Topical organogels cannot comprise bioactive agents with molecular weights of more than 500 Dalton, since skin can be permeated by drugs with molecular weights under 500 Dalton [18]. The purity of the constituents present is important, or else there might be no gel formation. Few organogelators are not available on a large scale, hence causing expense elevation for formulation, for example, lecithin organogelator. The purity of the constituents present is important, or else there might be no gel formation. Precise control of process variables (pH, temperature, etc.) is mandatory. Skin permeation enhancers and non-polar solvents are added in order to achieve deep penetration through skin, which may produce toxicity. Because of the gelator and the necessary solvent used, it is difficult to determine whether the gelation process will be successful [41].

6. Properties of organogel

A few characteristic attributes that organogels possess include non-invasiveness, non-toxicity, etc. But its substantial physicochemical properties, which frame it as a significant and essential system, are as follows.

6.1 Viscoelasticity

The term “viscoelasticity” is related to the materials that possess the two properties, that is, viscosity and elasticity. The viscoelastic property of organogels has also been authenticated by stress relaxation studies [6, 42]. They act as solids at lower shear stress (elasticity) and as a flowing fluid at escalated shear stress [15, 38]. At low shear rates, there is no pressure acting over them; hence they behave like solids with an intact structure, but at higher shear stress, as the pressure increases, the 3D-mesh network within the structure starts rupturing, permitting it to flow. It is observed that the organogels appear to follow the Maxwell model of viscoelasticity. It is observed that they retain plastic-flow behavior. “Organogels” are similar to other gel systems; the gelling agent creates an ongoing, three-dimensional network in the solvent, obstructing the flow of liquid. The rheological behavior of the gelator solution and its interaction with the solvent can greatly influence the flow property of the organogels [6, 15].

6.2 Thermostability

The nature of the organogels makes them innately thermostable. The capability of the gelators to undergo self-assembly under suitable conditions to produce organogels may be responsible for the stability of the organogels. The overall free energy of the system decreases when the gelators undergo self-assembly, yielding a low-energy thermostable organogel. At elevated temperatures, the molecules within the organogels acquire some kinetic energy to reduce any loss in their structure, and low temperatures, they resume their original structure. This innate property of the organogel is responsible for its longer shelf-life, thereby making it ideal for the delivery of bioactive agents [15, 16, 19].

6.3 Thermoreversibility

The matrix structure of the organogel is distorted when it is heated at a temperature that is extended from its critical temperature and hence it starts flowing. This added thermal energy causes interaction amongst the molecules of the organogel, causing disruption in the structure. But as the temperature decelerates, the interaction of the molecules also retards, which results in the reverting back of the organogel to its original configuration. This whole phenomenon is called thermoreversibility property of the organogels. For example, PLOs, when heated above 25°C (critical temperature), lost solid-matrix configuration, and after cooling, and returned to a stable configuration. The fluid matrix systems (Fluid matrix organogels) are thermoreversible [7, 16].

6.4 Non-birefringence

Birefringence is the optical property of a material that allows propagation of light when polarized light passes through it. The organogels are non-birefringent, that is, they do not allow the propagation of light when polarized light passes through their matrix. As a result, when organogels are observed under polarized light, these appear as dark matrix. This can be attributed to the isotropic property of the organogels [16, 19, 29, 43].

6.5 Optical clarity

The transparency or opacity of the organogels will depend on the chemical makeup they possess. For example, sorbitan monostearate organogels and PLOs are opaque, whereas the lecithin organogels are transparent in nature [30, 44].

6.6 Chirality effect

It has been observed that the stability and growth of the solid-fiber networks are both impacted by the presence of chirality in LMW (Low-Molecular Weight) gelators. Additionally, the thermoreversibility of the gels produced as a result of the self-assembled solid-fiber network is related to chirality. A competent solid-fiber gelator has been shown to be generally effective in possessing a chiral center, but fluid-fiber gels are unaffected by chirality. The gelators inclusive of chiral centers aid in the production of a tight molecular packing, hence impart kinetic and thermodynamic stability to organogels. The Crown ether phthalocyanine organogel is a good chiral organogel example [7, 45].

6.7 Biocompatibility

Previously, the organogels were formulated by using several non-biocompatible components, which resulted in non-biocompatible organogels. Currently, research on organogels involving different biocompatible constituents such as vegetable oil and cocoa butter has increased their potential for extended use in biomedical field [15, 19, 38, 40].

7. Organogelators

Organogelators are the gelling agents that have the capability to transform a preparation into a semisolid mass, that is, gel. They are used to impart the desired consistency in organogels. Hence, they are an integral component in the formulation of organogels. The solubility of the organogelator in the solvent generates a few forces, which is the reason for the stability of the thermodynamic and kinetic characteristics of the gel [7]. Organogelators have the property of changing their physical state depending upon the temperature. They remain as a solid matrix at room temperature but transform into liquid at relatively lower temperatures. The structure of organogels mainly depends upon the constructing ability of the organogelator [9]. The degree of cooperative self-assembly in an organogel is also regulated by the gelator structure and solubility [46]. The most manageable type of organogelators are n-alkanes and are useful in gelling the other proportionally short-chained alkanes [2]. It precipitates out as fibers form a 3D-structure. It is mainly responsible for the design/structure of organogels. They produce bond formation within the molecules of organogels, leading to their interaction and bonding amongst each other and an increase in the thickness of the preparation. Depending upon the type of bond they form, organogelators can be regarded as-hydrogen bond forming organogelators, viz., amino acids, amides, carbohydrates, etc., or as non-hydrogen bond forming organogelators, viz., anthraquinone, steroidal moieties, anthracene, etc. [9, 19, 38]. The ongoing research on organogelators has formed a branch for other novel types of gelators, including sugar-based organogelators and green organogelators, etc. [47, 48]. These new types of gelators each have their own concepts that should be studied comprehensively for a better understanding of the widespread availability of organogelators from a variety of sources.

7.1 Types of organogelators

7.1.1 Aryl cyclohexanol derivatives

These are 4-Tertiary Butyl-1-aryl cyclohexanols derivatives. Their characteristic features, which they impart in the gel, may differ depending upon the nature of the apolar solvent involved in the organogel. They possess low solubility in apolar solvents and hence they might appear as a turbid or transparent preparation, depending on the nature of apolar solvent involved. Their physical state is solid at room temperature. They can produce gelation only if the phenyl group in their structure lies in the axial configuration. The derivatives possessing phenyl groups in the equatorial configuration are unable to form the gel. They help in obtaining the organogels with the desired property of thermo-reversibility. A few common examples of this class are CCl4, benzene, cyclohexane, etc.

7.1.2 Polymer organogels

These are long chain-containing gelling agents. These are the gelators that possess a high capability of inducing gelation. They have a molecular size of more than 2 kilo Dalton. They can impart gel formation even if used in very low concentrations. They can appear in different shapes (straight, branched, etc.). Their efficiency of imparting gelation can be modified if their chemical structure is somewhat altered. They can be further divided into physical or chemical organogelators. If they form chemical bonds within the network of organogel, then they are regarded as physical organogelators which result in a cross-linked network, and if they form non-covalent bonds, then they are regarded as chemical organogelators which result in an entangled chain-linked network. The transition temperature for the transformation of the gel state to a sol state is also very low. They have relatively higher gel-strength than other LMOGs. They mostly include L-lysine derivatives and the other conventional examples are polyethylene, polycarbonate, polymethylmethacrylate, polyester, etc. [18, 19, 34, 38, 40].

7.1.3 Gemini organogelator

“Gemini” means “twins”. This word has been derived from Latin language. The first Gemini organogelator of L-lysine was synthesized by Suzuki et al. [49]. It had two chains of L-lysine of different chain lengths, linked together by an amide bond. This chain length is inversely proportional to the gelation ability of the gelator. They possess good gelation properties. They have a high ability to immobilize various kinds of apolar solvents. A good example of this class is Bis (N-lauroyl-L-lysine ethyl ester) oxylamide which can immobilize solvents like ketones, alcohols, etc. [9, 18, 19, 38].

7.1.4 Boc-Ala(1)-Aib(2)-β-Ala(3)-OMe organogelators

It is a synthetic tripeptide gelator of synthetic origin. It is capable of undergoing self-CB (1, 2-dichlorobenzene), 1-chlorobenzene, etc.

7.1.5 Low-molecular-weight organogelators (LMWOs)

These are the gelling agents that possess a small molecular weight (≤3000 Dalton) [9, 50]. Assembly which is the contributor of its gel-formation ability. They form thermoreversible and transparent gels. The apolar solvents, to which they can immobilize include benzene. These are most widely used organogelators. They contain a high capability of immobilizing the aqueous phase, even if used in small concentrations (<2%). The length of the alkyl chain in LMWO directly influences its gelling ability [51]. They mostly form solid-fiber matrices or can form fluid-fiber matrices based on the intermolecular interaction they perform. A solid-fiber matrix can be obtained if the organogelator is cooled down beyond the solubility range of the gelator, which is then followed by a rapid, incomplete precipitation, in the organic solvent, which leads to physical intermolecular interactions. For forming a fluid matrix, a polar solvent should be added to the solution of surfactant, leading to the re-arrangement of molecules to form a clump, hence immobilizing the aqueous phase. This also results in a difference in the kinetic-stability between both the matrices, which can be used as a distinguishing factor. Solid-fiber matrix offers an enhanced mechanical property compared to that of fluid-fiber matrix. This is because a solid-fiber matrix contains a highly arranged molecular structure compared to a fluid-fiber matrix. LMOGs have been further categorized into steroidal organogelators, ALS organogelators, etc., depending on the chemical backbone they possess [7, 19, 34, 38, 52].

8. Mechanism of organogelation

Organogelation is generally induced by the incorporation of a polar solvent into the organogel. If lecithin is present in it, then, it forms reverse spherical micelles at a ~ 0.01 mM concentration. This is induced by the addition of a small quantity of polar additives which bind to the hydrophilic head of the lecithin. This creates linear networks. If the amount of polar additive is further increased, then it leads to the formation of long tubular flexible micelles. After overlapping with each other sufficiently, they entangle themselves and build up a transient 3D network (Figure 1).

Figure 1.

Mechanism of Organogelation.

In the case of PLOs, the mechanism of gelling and the structural network may be related to the synergistic contribution of both phospholipids and polymeric co-surfactant molecules in their respective hydrated states. In this case, solvent molecules and lecithin phosphate groups can be arranged in such a way that a hydrogen-bonded network will be formed [15, 34, 52].

9. Mechanism of gel permeation into skin

Human skin is made up of different types of tissue layers. The outermost layer, Stratum corneum is the rate limiting barrier for the permeation of gel into the skin [35]. It has been observed that lipid based formulations enhance penetration through the skin; however, they modify the hydration state of the skin, causing dermatitis. Aqueous formulations maintain the skin intact and bioactive, but have less penetration [18]. In the case of Pluronic Lecithin organogels, penetration and permeation are enhanced due to lecithin, which alters the skin structure and transiently opens the skin pores. It is believed that this happens due to the interaction between the lecithin’s phospholipid and skin lipids. Hence, there occurs the formation of a cylindrical network which results in an increase in the area of the lecithin polar region, and non-polar solvent acts as a penetration enhancer and then penetration occurs by forming a thin film on the skin surface (Figure 2) [16, 18, 35].

Figure 2.

Pathways for permeation of organogel into skin.

10. Method for preparation of organogels

At 60°C, the oil-surfactant mixture is heated to produce a transparent solution that, when cooled, transforms into organogels. Lecithin solutions are made by first dissolving lecithin in organic solvents using a magnetic stirrer, according to the phase diagrams that have been constructed. Organogels are created by adding water with the use of a micropipette syringe. Heat may be used occasionally to completely dissolve drugs. Lecithin and an organic solvent are combined to create the oil phase, which is then let to stand overnight to guarantee full breakdown. When preparing the aqueous (polar) phase, pluronic is added to ice-cold water and stirred to ensure thorough dissolve. The produced PLO is blended with the Pluronic’s aqueous phase using a high-shear mixing technique by a magnetic stirrer. Fatty-acid gelators can also be used to create organogels by first dissolving them at a higher temperature in a water-in-oil emulsion, then lowering the temperature. The solubility of the gelator decreases as a result of the drop in temperature, which leads to precipitation and self-assembly of the gelators into a network of tubules that become entangled to create a gelled structure [2, 19].

10.1 Fluid-filled fiber method

It is a well-known technique for making organogels, where in reverse micelles are produced by dissolving surfactants and co-surfactants in an apolar solvent. Reverse micelles are then transformed to tubular reverse micelles after the addition of water. The elongated reverse micelle becomes entangled to create a 3-dimensional network, which immobilizes apolar solvent [53].

10.2 Solid fiber method

In the Solid fiber method, an apolar solvent and solid organogelator are heated together at an apolar solution of the solid organogelator is produced. Then cool it at room temperature, the organogelator precipitates out as fibers that interact physically with one another to form a three-dimensional network structure that immobilizes apolar solvent [15, 38].

10.3 Hydration method

In this technique the inorganic chemical is directly hydrated to form the dispersed phase of the dispersion, which is then used to create gel. Other substances such as propylene glycol, propyl gallate, and hydroxypropyl cellulose may be employed in addition to water as a carrier to improve gel formation [53].

10.4 Novel methods

Conventional methods of preparing organogels usually require longer heating times and neutralizing agents. Evren et al. prepared organogels employing a new technique, high-speed homogenization which was followed by microwave heating. Evren et al. prepared Triclosan organogel employing Carbopol 974 NF in PEG 400. Carbopol in varying concentrations (2–4%) was dispersed in PEG 400. The resulting dispersion was homogenized at 24,000 rpm.. The dispersion was heated using two methods. The first involved heating at 80°C, stirring mechanically at 200 rpm. In the second method, the dispersion was subjected to micro-irradiation (1200 W/1 h) for 2 min. The results demonstrated that microwave heating was suitable for preparing carbopol organogels. Owing to significant reduction in time and energy, the method holds good promise for industrial applicability [54] (Table 1).

Types	Administration Route	Study carried out	Model Drugs	Reference
Sorbitan; monostearate	Nasal; Oral Subcutaneous &; intramuscular	In vitro release; In vivo efficacy	Propranolol; Cyclosporin A	[55]; [56]
Lecithin	Transdermal	Clinical studies; Skin permeation and effectiveness in vivo; Skin permeation in vitro; Skin release in vitro	Metoprolol; Aceclofenac; Indomethacin; Diclofenac; Bioactive agents	[57]; [13, 58, 59]
Eudragit; organogels	Rectal; Buccal	In vivo efficacy	Salicylic acid; BSA	[44, 60]

Table 1.

Formulations of organogels used in drug delivery.

11. Factors affecting organogels

11.1 pH

A pH change stimulates the reversible transition of an organogel from a gel state to a sol state [61]. Hence, pH can influence the physical state of gels.

11.2 Temperature

Organogels are often less stable with increasing temperatures, causing disruption of the 3D mesh-network structure. Temperature also affects viscosity. As the temperature increases, the viscosity decreases [4]. Hence, the temperature range during their storage should be closely controlled [5, 18, 19].

11.3 Organogelator

The type of organogelator used for the preparation has the capability to influence the mechanical and rheological properties of the organogel [40].

11.4 Adjuvants

1. Surfactants: Characteristics of gel can be varied depending upon the surfactant.

2. Salts: The addition of salt to the organogel may result in salting-out (formation of more secondary bonds amongst the molecules) [15, 38].

3. Organic solvent: The structure of an organogel depends upon the nature of the solvent (polar/non-polar).

4. Organogelator: The rate of drug release from the organogel is affected by/depends upon the concentration of the gelator used [62].

5. Skin permeation enhancers: These chemical entities might also possess additional characteristics, which may interact and alter the properties of the organogel.

Terpenes operate as chemical penetration enhancers and also act as rheology modifiers, which may result in any alteration in the flow property and deformation characteristics of an organogel [63].

11.5 Moisture

Organogels swell when exposed to moisture as they absorb water molecules from it This may aid in the instability of the organogels [38].

11.6 Purity

The constituents used in an organogel should be in its pure form. Any impurity in the components may lead to instability in the network of the matrix, for example, lecithin is unable to induce gelation if not used in its pure form [2, 40].

12. Application of organogels

12.1 Pharmaceutical industry

1. Topical drug delivery system.

The skin, being the largest tissue in the body, provides good bioavailability of drugs, as the drugs meant to enter the systemic circulation via permeation through the skin bypass the first-pass metabolism. Pluronic lecithin organogels (PLOs) contain isopropyl myristate/isopropyl palmitate as an apolar organic solvent used as a vector for the release of NSAIDs (ketoprofen, flurbiprofen, diclofenac sodium), used as an analgesic. Reverse micellar MBGs possess soya-lecithin/iso-octane/water as a solvent phase for the delivery of propranolol. Organogels can be regarded as potential matrices for the controlled release of topical antimicrobials. Organogels loaded with Piroxicam are used for the treatment of rheumatoid arthritis. In-situ forming organogel of L-alanine injectable can be used for the release of labile macromolecular drugs. Various studies on formulation of transdermal organogels, such as development of PLO with mometasone furoate for psoriasis and fluconazole-loaded organogels based on olive oil for fungal infections, have exhibited positive results [9, 42, 64].

1. Oral and trans-mucosal drug delivery system.

The drugs can be delivered through oral cavity with the help of implantation of bio-adhesive organogels, that is, the drugs will be administered as implants. The drug can be dissolved within the organic solvent and then mixed with the muco-adhesive polymer. An organogel of 12-HSA-soyabean oil was used for the delivery of ibuprofen [15]. An in-vivo study conducted in rats depicted that the organogels can be employed as a vector for controlled release of lipophilic drugs [38]. Sorbitan monoleate based organogel, incorporated with cyclosporine A is given orally. An oral organogel can be prepared by incorporating an NSAID (ibuprofen) to achieve desired therapeutic results [65].

1. Parenteral drug delivery system.

Parenteral routes are the preferential choice for the administration of drugs, as it avoids first-pass metabolism, provides quicker onset of action, etc. An in-situ forming organogel prepared for sustain delivery of leuprolide (used in prostate cancer) from the L-alanine derivatives in safflower oil and was injected by SC route. It was observed that the gel degraded slowly for drug release over a span of 14–25 days [7, 15]. Sorbitan monostearate organogel preparation have been developed and given by SC and IM route for the release of propranolol/ cyclosporine A/ BSA and HA [7]. A study depicted that, safflower oil-based N-methyl pyrrolidone (NMP) injections were introduced into rats subcutaneously, which was well-tolerated by the surrounding tissues over a period of 8 weeks [66]. The injection of an in-situ organogel forming implant based on SAM (N-stearoyl-L-alanine methyl ester) demonstrated significant promise for safe and suitable delivery method for therapeutic medications that require regulated release [67]. A successful evaluation was conducted for the purpose of using parenteral organogel in schizophrenia therapy [68]. The micro-emulsion based organogels and niosomes containing organogels have been formulated for delivery of vaccines. After administration of these gels via intramuscular route, a depot effect was observed (Table 2) [15].

Parameters	Description
Gelation Studies	A straightforward visual test to establish whether gelation has been established and includes: inverting the reaction vessel, pouring with organogel; if the sample does not flow, gelation has occurred [40]
Rheological Behavior	An indication of the structural organization of the organogel is obtained by its rheological behavior. The viscosity the usually determined with the help of a Brookfield viscometer [69]
Structural features	Utilizing NMR spectroscopy, the molecular design of organogels has been evaluated, and FTIR spectroscopy has demonstrated hydrogen bonding. Optical microscopy, freeze fracture electron microscopy, transmission electron microscopy and X-ray diffraction have been used to learn about the molecular packing within the organogel network [29, 38]
Phase transition Temperature	It is the determination of the temperature at which the organogel transforms from gel state to sol state. It provides details on the types of the microstructures that make up the cross-linked gelling network. The presence of uniform microstructures within the gel is indicated by a restricted PTT range (3–5°C). Hot stage microscopy (HST) and high sensitivity DCS are employed to determine it. Basically, the organogels are placed in glass tubes which are subjected to incrementing temperature. The transition is analyzed by inverting the tubes and this temperature is then noted [59]
pH	A digital pH meter is used to assess the pH of the formulation. A suitable amount of organogel is dissolved in a solvent. The pH meter electrode is submerged in this mixture, which then display the value of pH [42]
Water Content	Evaporation of water can cause viscosity to drop, which can impair the stability of the gel. The use of NIR spectroscopy (NIR, 1800–2200) to measure water content [59]
Stability study	The stability of organogels can be determined at different temperature and relative humidity conditions as per ICH guidelines.; 25°C ± 2°C at 75 ± 5% RH; 40°C ± 2°C at 75 ± 5% RH
In vitro studies	Through a dialysis membrane, the formulation is subjected to in vitro diffusion. A Franz diffusion cell can be employed to determine the drug release [2]
In vivo studies	Various animals, such as rats, are employed as models for several evaluation such as skin irritation tests and compatibility tests
Physical examination	It is a preliminary assessment in which, the prepared organogel is evaluated for its color, texture, appearance, odor, etc. [29]

Table 2.

Evaluation of organogels.

1. Ophthalmic drug delivery system.

Ophthalmic solutions are generally used for administering drugs in the eye, but due to its consistency, frequent dosing is required as the drug may not be properly absorbed in the target site. Hence thicker preparations like gels are desired to increase the contact time to facilitate the maximum absorption of drugs from the formulation. Methazolamide is incorporated into carbomer and poloxamer gels for the treatment of glaucoma which was ineffective when formulated as ophthalmic solution [38]. Organogelators are employed with drugs such as Eudragit L and S for ophthalmic preparation for sustained delivery [50].

12.2 Food industry

Organogels are primarily employed in the food industry owing to their ability to reduce oil mobility in food items, particularly those containing multiple ingredients. Organogels can be used as replacer for Trans and saturated fat in processed foods to install a specific texture. Wax-based organogels provide good oxidative stability, and also influence the firmness and spreadability and thus can be used in spreadable food product [18, 64, 70].

12.3 Cosmetics industry

Low molecular weight organogelators (LMOGs) such as DBS and 12-HSA are used for preparation of lipsticks [71]. 12-HSA organogelator is used in sunscreens to block UVB rays [41]. It is possible to improve the properties of organogels developed for cosmetic applications by using organic solvents like Amazonian oils, which already possess moisturizing and nourishing effects [72]. Various dermatological cosmetics such as lip-gels, skin, and hair protectants can be prepared in the form of organogels [18, 38]. Other cosmetic preparations such as shampoo, dentifrices, and perfumes are prepared in the form of organogels [15].

13. Conclusion

Organogels are a visco-elastic substance primarily made by gelling the organic solvent with a bioactive agent. It has captivated a section of curiosity to explore all the aspects of their application, as these can potentially eliminate or replace many components, techniques as well as limitations being faced normally for different types of formulations, due to unique properties. The organogels have a huge area for application, although possess few drawbacks and limitations. Though these can be administered to the body via various drug delivery routes, the major site is topical route considering ease of application and many more reasons. A stable organogel designed with all the bio-compatible components might attract the commercial market in future as they can potentially become the preferential choice of formulators and consumers.

Acronyms and abbreviations

LOs

lecithin organogels

PLs

pluronics

PLOs

pluronic lecithin organogels

GP1

dibutyllauroylbutamide

PG

propylene glycol

MBG

micro-emulsion based organogels

w/o

water in oil

span 40

sorbitan monopalmitate

span 60

sorbitan stearate

PEG

poly ethylene glycol

LAM

N-lauroyl-L-alanine methylester

CCl₄

carbon tetrachloride

LMWO

low-molecular-weight organogelators

3D

3 dimensional

NSAIDs

non-steroidal anti-inflammatory drugs

HST

hot stage microscopy

PTT

phase transition temperature

NIR

near infra-red

NMP

N-methyl pyrrolidone

SC

subcutaneous

IM

intramuscular

SAM

N-stearoyl-L-alanine methyl ester

BSA

bovine serum albumin

HA

hemagglutinin