INTRODUCTION:

The discovery of liquid crystals (LCs) is assumed to have occurred almost 150 years ago, but its significance was not fully understood until more than a century later. Around the middle of the last century, Virchow, Mettenheimer, and Valentin discovered that the nerve fibers they were studying formed a fluid substance when immersed in water, which exhibited odd behavior when observed under polarized light. They were not aware that this was a separate phase, yet they are credited with the first observation of LCs. Otto Lehmann studied the phase transitions of several substances using a polarizing microscope with a heated stage in 1877. He discovered that one chemical transformed from a clear liquid to a hazy liquid before crystallizing, but he assumed that this was due to an imperfect phase transition from liquid to crystal. Friedrich Reinitzer, an Austrian botanist, initiated the study of liquid crystals in 1888.Substances that display a phase of matter with characteristics halfway between those of a typical liquid and a solid crystal are known as liquid crystals. It is frequently referred to as a state of matter, or mesomorphic state. Between the lack of long-range order present in isotropic liquids, gases, and amorphous solids and the flawless three-dimensional, long-range positional and orientational order present in solid crystals, the degree of molecular order in mesomorphic states is in the middle. Another name for it is meso intermediate. The liquid's molecules are orientated and/or arranged like crystals. Based on their many optical characteristics, such as birefrigrance, the several varieties of LC phases can be identified. Various liquid crystal phases will appear to have different textures when seen under a microscope with a polarized light source. There are two types of liquid crystals: thermotropic and lyotropic. Thermotropic LCs change phase when temperature changes, while lyotropic LCs change phase based on the concentration of the mesogen in a solvent (usually water) and temperature¹. The liquid crystalline state is distinguished by molecules (mesogens) aligning along a common axis known as the director. Molecules in the liquid phase lack intrinsic order. Molecules in the solid state are highly organized with limited translational freedom1.The orientational order of the liquid crystal state falls between the traditional. The term "mesogenic state" refers to the presence of both solid and liquid phases.

Classification of Liquid Crystals:

LCs are classified based on their positional order (randomly placed molecules in a lattice) and orientational order (most molecules facing the same direction). Order can be short-range (between nearby molecules) or long-range (to bigger, occasionally macroscopic) in nature. LCs are classed as lyotropic or thermotropic based on their manufacturing process ^2,3,4.

Lyotropic Liquid Crystals:

Lyotropic liquid crystalline systems consist of rod-like micelles that exhibit long-range orientational order along their symmetry axis but lack long-range positional order. There are three types of LLCs: lamellar, hexagonal, and 2. Lamellar LCs cubic.⁵

Lamellar LCs:

Lamellar LCs often have a bilayered structure and exhibit long-range positional and orientational order within the layer. They are also known as multilayer packing of indefinitely stretched disc-like micelles ^[6-8].

Hexagonal LCs:

Hexagonal LCs exhibit long-range positional order in two dimensions. Polarized light microscopy can identify lamellar and hexagonal LCs based on their characteristic textures. They are also referred to as the middle phase.^9,5

Cubic LCs:

Cubic LCs exhibit long-range order in three dimensions. Polarized light microscopy cannot identify these LCs, which often have cubic micelles. Compared to lamellar and hexagonal LCs, they exhibit a higher viscosity and pour-flowing properties^10-12

Thermotropic Liquid Crystals:

Thermotropic mesophases are generated by heating a single crystalline solid, unlike lyotropic mesophases, which require a solvent to develop. The thermotropic liquid crystalline form of a medication is considered a unique polymorphic form^5,13,14 The three thermotropic liquid crystalline phases are nematic, smectic, and cholesteric. These are based on G. Friedel's proposed system from 1922.

Smectic LCs:

The term "smectic" comes from the Greek word for "grease" or "clay." In a smectic state, all molecules in a layer have long axes that are parallel to each other and perpendicular to the plane of the layers, allowing them to slip and pass over each other. The state is viscous, fluid, and orderly².

Nematic LC:

Nematic is taken from Greek, which means thread-like. Nematic LCs can be seen as thread-like structures under polarized light microscopy. In the nematic state, molecules are not as highly ordered as in the smectic state, but still exhibit parallel order. Electronic displays generally use nematic liquid crystals (LCs). Nematic LCs exhibit anisotropic physical properties due to their specific molecular alignment. Measurements of refractive index, dielectric constant, permeability, electrical conductivity, and viscosity in the long axis direction differ from those in the normal plane^2,
15

Cholesteric LCs:

Cholesteric organization combines nematic and smectic phases, with nematic layers and smectic layer forms¹³,¹⁶. The molecules in cholesteric LCs are organized in layers. Molecules in each layer align in parallel, akin to nematic LCs. Cholesteric LCs have thin molecular layers with long axes that align with the plane.¹⁷

Methods for the Characterization of Liquid Crystals:

1. Transmission Electron Microscopy (TEM)

2. X-Ray Scattering

3. Differential Scanning Calorimetry (DSC)

4. Polarized Light Microscopy

Ideal Characteristics of Liquid Crystal:

1. There are two types of liquid crystals: lyotropic and thermotropic liquid crystal

2. Because of the transition phase, liquid crystals can flow like liquids.

3. Discotic phases are flat and contain disc-like molecules with cores close to aromatic rings.

4. Many chemical substances can form liquid crystals.

5. Liquid crystal phases seem murky, scattering light similarly to colloids.

Controlled Release of Bioactive Materials:

Diffusion frequently regulates the release of the active ingredient from liquid crystal delivery systems, while certain systems use the liquid crystals' photoinduced or thermal phase shift to release bioactive materials¹⁸.

Drug Loading:

The medicine can be added in both the aqueous and oil phases, depending on its composition. The solubility of the active ingredients and how they are distributed among the phases that are already present determine loading completely.

Advantage of Liquid Crystals in Pharmaceutical:

1. Increased stability

2. Controlled drug delivery

3. Prolonged hydration.

Stability:

The multilayers surrounding the emulsion stability of the oil droplets prevent coalescence. The emulsion breaks when oil droplets mix. This coalescence barrier contributes to the emulsion’s increased stability.

Controlled Drug Delivery:

Liquid crystals prevent the medication dissolved in an emulsion’s oil phase from releasing rapidly. This is because the lamellar liquid crystalline multilayer reduces the drug’s interfacial transit while it dissolves in the oil droplets. Microscopic investigations under polarized light show the incredibly thick liquid crystalline lamellar layer surrounding the oil droplets¹⁹.

Prolonged Hydration:

Water layers are present in lamellar liquid crystalline and gel networks, indicating that these structures can bind half of the water in the oil in an o/w emulsion. When administered topically, this kind of water is less likely to evaporate, providing a longer-lasting moisturizing and hydrating effect that is crucial for medication absorption.

Applications:

Ointments and Creams:

Compared to surfactant gels, ointments and creams usually contain a significantly smaller amount of surfactant. Creams are made by adding water to ointments, which are nonaqueous treatments. As long as amphiphilic molecules create a liquid crystalline network or matrix, liquid crystals may make up the microstructure of both ointments and creams. A liquid crystalline matrix makes it simpler for shear to distort the system. On shear, these compositions exhibit thixotropic and plastic flow characteristics. Although shear frequently causes irreversible damage to the crystalline matrix, a liquid crystalline matrix exhibits a brief time of sheared matrix regeneration. To develop a liquid crystalline matrix, amphiphilic surfactants that form lyotropic liquid crystals at room temperature must be selected. Lamellar liquid crystals that can dissolve large amounts of components and distribute throughout the entire formulation as a network-forming cross-linked matrix are preferred. On the other hand, at room temperature, ointments that include long-chain fatty alcohols, like cetyl and/or stearyl alcohol, have a crystalline structure²⁰.

Transdermal Patches:

A pharmaceutical component must have a high potency for the low dose to be administered and a high permeability through the stratum corneum and the underlying living tissue in order for percutaneous penetration to produce a systemic impact. Controlled release transdermal devices are a good choice in cases where the biological half-life is short. Transdermal patches are cutting-edge medical devices with zero-order kinetics, or controlled release of the therapeutic ingredient from a reservoir. A matrix or membrane is one kind of control element. Membrane-controlled patches were the first available on the market. However, these patches have the disadvantage of “dose-dumping” if the membrane is damaged during handling. To ensure the desired drug control, even liquid crystalline polymers have been investigated for their possible use in membrane-controlled transdermal patches²¹. The only useful part of the matrix-controlled transdermal patch is the porous polymer matrix, which controls medication release and serves as an adhesive element and drug reservoir. Transdermal patches that include nicotine, fentanyl, clonidine, scopolamine, testosterone, estradiol, and glycerol triturate are sold all over the world. The patch must remain in place on the body for no more than a week. In this case, the reservoir contains a sizable quantity of medication. Due to their superior solubilization capabilities, liquid crystalline vesicles with a lamellar microstructure are recommended for use as transdermal patch reservoirs.²²However, the high surfactant content of the lamellar liquid crystal may cause skin irritation. By avoiding direct skin contact with the liquid crystalline vehicle, the membrane-controlled patch avoids skin irritation.

Ophthalmic Delivery:

Is a further topic of interest where LLC NPs are being researched as possible therapeutic possibilities? According to recent research by Gan et al., cubosomes can be employed as nanocarriers for ocular drugs to provide advantages such improved preocular retention, reduced ocular irritancy, and enhanced bioavailability. Trans-corneal permeability is enhanced when flurbiprofen and dexamethasone (DEX) are prepared as cubosomes. Actually, because the drug-loaded cubosomes remain in the pre-ocular area longer than comparable solutions administered through eye drops, their ocular bioavailability is enhanced. Moreover, the DEX-cubosome formulation has been shown to have no impact on the structure or tissue integrity of the cornea. Flurbiprofen’s inherent irritancy is reduced by the cubosome composition^23-26.

Liquid Crystals in Cosmetics:

In cosmetics, liquid crystals are mostly used as ornamental features. Cholesterol liquid crystals are commonly utilized in lipsticks, nail polish, and eye shadow because to their unique iridescent tint. Thermotropic liquid crystals undergo structural changes in response to body temperature, resulting in the desired color. These liquid crystals, which are dispersed in a hydrogel, are thermotropic cholesteric and have lately been used in body care products. The iridescent liquid crystalline particles are distributed statistically in the gel (Este Lauder Time Zone Moisture Recharging Complex) or concentrated locally (Vichy Re structure Contour des Yeux) to achieve the desired appearance, depending on whether stirring or spraying is required. Currently, no published tests have evaluated the cosmetic efficacy of liquid crystalline components²⁷.

Solubility Enhancement of Poorly Soluble Drugs:

Lyotropic liquid crystals allow a wide spectrum of chemicals to dissolve more efficiently. Hydrocortisone is one such example. Although commonly used topically, the maximum concentration is only 1%, limiting its use. As soon as hydrocortisone levels hit 4%. Liquid crystals may eventually take the lead as the primary solvent for topical applications.^28,29

Stability of Drug:

Lyotropic liquid crystals were used to create a stable hydrocarbon foam. Producing hydrocarbon foams has historically been hard due to their low surface tension, which prevents adsorption by oil-soluble surfactants. In the absence of adsorption, hydrocarbons behave like liquids. The surfactant can interact with water but not dissolve in it. Instead, it can dissolve in hydrocarbons ^28,23.

Biological and Chemical Sensing:

It has been proven that LCs can detect and analyze a wide range of bacteria and viruses. Non-toxic lipophilic chemicals (LCs) have been used to stimulate mammalian cell proliferation and understand the interaction between cells and proteins. Polyelectrolyte-coated LC droplets can identify charged macromolecules in a solution. Adsorption of positively charged dendrimers onto negatively charged polyelectrolyte-coated droplets causes bipolar-to-radial ordering transitions. The size and amount of droplets in the solution play a key role in these transitions^17,30.

Temperature Modulated:

Drug penetration occurs through cellulose membranes covered with liquid crystals. Sensitivity-sensitive membranes act as "permeability valves" or "on-off switches," causing pulsing release patterns that are controlled by external inputs. We developed thermoresponsive cellulose nitrate (CN) and cellulose acetate (CA) monolayer membranes with thermotropic liquid crystals (LC) to prevent drug penetration To limit drug permeability, nheptyl-cyano bi phenyl, a low molecular thermotropic liquid crystal with a 41.5°C nematic-isotropic phase transition, was utilized. Cellulose membranes without liquid crystals were found to be insensitive to temperature changes in drug permeation. However, membranes with liquid crystal entrapment showed a clear increase in permeability when temperatures were raised above the drug's liquid crystal transition temperature^31,32.

Topical Treatment:

The highly organized stratum corneum, the skin's outermost layer, acts as a barrier, limiting the amount of medicine that may permeate the skin during transdermal distribution of active molecules. Several strategies for increasing skin permeability have been proposed, including iontophoresis, the use of a skin permeation enhancer, and the chemical alteration of the active molecule. When employing topical medicines, the active ingredient's thermodynamic activity must be increased in the vehicle and decreased in the skin. This reduces the function of the skin's barrier while improving the molecule's partition from the vehicle to the skin^20,21.

Cubosomes, or liquid crystals, have been identified as promising topical delivery systems due to their ability to modify permeability. Silver sulfadiazine is a highly successful topical treatment for burns, but it requires a delivery mechanism. Cubosomes stabilized with F127 and polyvinyl alcohol were synthesized from monoolein, loaded with silver sulfadiazine, and then incorporated to hydrogels (cubogels) as a potential burn treatment. An in vivo study found that the cubic nano-structured vehicle was more effective in treating deep second-degree burns than the currently available product. This could result in more patient compliance, better healing outcomes, and fewer adverse effects^28,33.

Vaccines:

In addition to their role in cancer treatments, cubosomes are essential components of vaccines. Cubosomes can be loaded using antigens, adjuvants, and/or the correct distribution of immunostimulants, such as polysaccharides, into the membrane. In a study, inactivated viruses were given subcutaneously together with phytantriol cubosomes containing polysaccharides. Cubosomes containing polysaccharides have been found to enhance the immune effects of immunostimulants by increasing antigen transport into lymph nodes and improving the immunological response^28,34.

Latest Development in Pharmaceutical:

Kent State University, Summa Health System, and IC-MedTech have created a new approach to drug discovery using the pharmacologic features of Liquid Crystal Pharmaceuticals (LCP). LCPs, a type of lyotropic liquid crystal, provide potential as medication candidates for treating many disorders. The researchers have applied for two new patents: one for Tolecine™, an anti-tumor medication based on LCPs, and another for a combination of Tolecine and Apatone.

Olecine is a novel pre-clinical anti-tumor LCP with antiviral and antibacterial properties. It selectively targets tumor cells and has high anti-neoplastic effect, inhibiting aberrant cell proliferation in tissues and organs. Furthermore, it has proven to be more effective than existing herpes treatment methods.

Apatone is a clinically investigated novel medication for late-stage prostate cancer. Clinical trials are being conducted for prospective applications, including augmentation of chemotherapy to reduce hazardous doses of commonly used drugs. Apatone is composed of two non-toxic chemicals, a liquid crystal and a sugar, which selectively bio-concentrate within cancer cells and generate free radicals. The formation of powerful, short-lived free radicals is a concentration-driven intracellular response that occurs primarily in cells with high sugar concentrations, such as cancer cells. The response causes oxidative stress, weakening the targeted cells from within. The process occurs swiftly within cancer cells and does not produce harmful byproducts that could harm healthy cells.

CONCLUSION:

The article concludes that liquid crystal cream is a promising vehicle for topical drug administration due to its superior stability, biocompatibility, and diversity in formulation. More research and clinical trials are needed to properly understand its efficacy and safety in various therapeutic applications, opening the road for its adoption into mainstream pharmaceutical practice.

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Received on 27.03.2025 Revised on 17.04.2025

Accepted on 28.04.2025 Published on 10.05.2025

Available online from May 14, 2025

Res. J. Pharmacognosy and Phytochem. 2025; 17(2):179-184.

DOI: 10.52711/0975-4385.2025.00029

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