Substances have been classified as solids, liquids and gases depending on their molecular mobility and order of molecular packing. Solids are further sub classified as crystalline and amorphous systems. Crystalline solids are characterized by three dimensional short- and long-range order, amorphous solids present only short-range order whereas liquids do not possess any short- or long-range order. Here, short-range order refers to the way that neighbouring molecules are arranged next to each other (molecular coordination) while long-range order refers to the repeating pattern or periodicity between hundreds and thousands of molecular aggregates and then the propagation of this arrangement to longer distance, to form a phase. Liquid crystal phase (LCP) can be said as the fourth state of matter that possesses structural, mechanical and optical properties intermediate to crystalline solids and liquids. These systems form the basis of a new type of a drug delivery system owing to their distinct advantages like thermodynamic stability, high solubilization levels, improved bioavailability, protection against oxidation and controlled release properties.
Figure 1
Figure 1 shows classification of common phases and sub phases of matter; direction of arrow indicate decreasing molecular mobility, intermolecular distance, potential energy and increasing order of packing level from gas to solid; solid refers only to crystalline solid, another type of solid, amorphous, does not possess long-range order observed in mesophases.
Liquids exhibit all large-amplitude motions which include translational, rotational and conformational motions, while in crystalline solids these motions are absent. If the molecular mobility restrictions on crystalline solids are partially lifted, intermediate states are obtained. Liquid crystals are liquids having a certain level of orientational order with partial or complete loss of positional order observed in crystalline solids. Molecules in liquid crystals (LCs) point to a certain direction and they still possess translational freedom. LCs are a condensed state of matter formed by anisotropic organic molecules, interestingly not all anisotropic molecules can form liquid crystals. This type of molecules are called as mesogens and possess either rod-like (prolate) or, less commonly, disc-like (oblate) shape.
Liquid crystal phases
Liquid crystals are classified by their method of generation into the thermotropic and lyotropic phases.
Thermotropic
They are generated by temperature variation in the liquid state. These are usually one compound systems which occur within specific temperature range. At temperatures much higher than the melting point, the system exists as a stable isotropic liquid phase and no directional alignment of molecules can occur due to the high kinetic energy. Upon cooling, the molecular mobility decreases and when temperature falls into a certain range above the melting point, the LC-forming molecules start to reorient themselves and point to a certain direction, liquid crystal is then generated. Upon further cooling to below the melting point, the molecular mobility reduces to the level that the translational movement is not sustainable. As a result, the LC either crystallizes into a fully ordered crystal or a condis crystal or is frozen into an LC glass (obtained when the LC phase vitrifies instead of crystallizing upon cooling) the directional molecular alignment is retained. An example of a compound displaying thermotropic LC behaviour is para-azoxyanisole.
Thermotropic LCs are further classified as calamitic (made up of rod shaped molecules) or discotic (made up of flat or disc shaped molecules). Calamitic LCs are further classified on the basis of anisotropy as nematic and smectic phases.
"Nematic
In nematic phases molecules have no positional order, but they possess long range orientational order. The molecules flow and their centre of mass positions are randomly distributed as in a liquid, but they all point in the same direction (Fig. 2a). Most nematics are uniaxial. They have one axis that is longer and preferred, with the other two being equivalent. Some LCs are biaxial nematics, this means that they have an orientation along a secondary axis along with their orientation in long axis.
" Smectic
The smectic phases form at lower temperatures than the nematics, these are well defined layers that can slide over one another like soap. The smectics are positionally ordered along one direction. In the smectic A phase (Fig. 2b); the molecules are oriented along the layer normal, while in the smectic C phase (Fig. 2c); they are tilted away from the normal layers. Smectic phases are liquid like within the layers. They are characterized by different types and degrees of positional and orientational orders.
(a) (b) (c)
Fig 2: Liquid crystal sub phases. (a) nematic phase; (b) smectic A phase; (c) smectic C phase.
Lyotropic
Lyotropic LCs (LLCs) are generated by dissolving the compound in a solvent, thus, they are always solutions consisting of multiple compounds (i.e., solvent and solute). The lyotropic LCs are often amphiphilic (surface active), in which a hydrophilic head and a hydrophobic tail occupy the two ends of the elongated molecule. When dissolved in water, the molecules align themselves to hide the hydrophobic tails away from the aqueous media and leave the hydrophilic heads in contact with the media. This often results in anti-parallel double layers which lead to smectic LC phases (Fig. 2b and 2c). LLCs have been classified on the basis of increasing order (from micellelar solution to crystalline dispersion or solvate) as lyotropic nematics, lamellar, hexagonal and cubic phase respectively.
Applications in pharma
It has been estimated that approximately 5 per cent of all organic molecules are able to exist as thermotropic LCs. Pharmaceutical compounds have been increasingly characterized by their lyotropic liquid crystalline states with relatively fewer examples of thermotropic LC states. LLCs based delivery systems such as creams, ointments, gels, liposomes, colloidal dispersions and transdermal patches have been used in pharmaceuticals and cosmetics.
Pharma drugs as LCs
Many small molecular pharmaceutical active compounds have been demonstrated to form LC mesophases. Nafoxidine hydrochloride is one such example, this cationic drug has amphiphilic properties and gives rise thermotropic (smectic type) and lyotropic liquid crystalline structures. Palmitolyl propranolol hydrochloride is an amphiphilic derivative of the beta-blocker propranolol hydrochloride which forms smectic type liquid crystalline phase. It has been administered as liquid crystalline dispersion for cardiac problems. Itraconazole hydrochloride is an antifungal drug which forms chiral nematic phases. Some of the other examples of small molecular pharmaceuticals which can form LCs are arsphenamine, fenoprofen sodium, fenoprofen calcium, penbutolol sulphate, nafcillin, methotrexate, folic acid and tobramycin. Large molecular pharmaceutical active compounds are also known to form LCs; some common examples of them are cyclosporine, calcitonin, amylin, nafarelin, detirelix and leuprolide. The recent research has yielded a new investigational LC based anti-tumour drug called Tolecine, a compound which also has antiviral and antibacterial applications. Some of the pharmaceutical excipients such as hydroxypropylcellulose, ethyl cellulose and cellulose acetate have also displayed LC phases. Besides this, examples of naturally occurring LCs are DNA, cholesterol and the biological membranes.
LCs for solubility enhancement
Thermotropic liquid crystalline state of fenoprofen calcium (a class II drug from biopharmaceutical classification system) has demonstrated higher solubility than its crystalline state. Liquid crystalline state of lipids has been used as a model to mimic the biological systems. In various foods, pharmaceutical and biotechnical applications, the liquid crystalline phases formed by surfactants in aqueous medium represent useful host systems for drugs, amino acids, peptides, proteins and vitamins. Various biologically active food additives are soluble in neither aqueous nor oil phase and require environmental protection against hydrolysis or oxidation. Lyotropic liquid crystals meet these requirements mainly due to their high solubilization capacities for hydrophilic, lipophilic and amphiphilic guest molecules. Moreover, recent studies demonstrated controlled and/or sustained release of solubilized molecules form different liquid crystalline matrices.
Colloidal dispersions
The bulk liquid crystalline structure may be dispersed in water in the presence of additional stabilizer/emulsifier to form sub-micrometer soft particles (of 100-500 nm) which retain the internal structure of the liquid crystal bulk phase. In the case of lamellar, hexagonal, and cubic phases, these soft particles have been termed liposomes, hexosomes, and cubosomes, respectively. They have significant advantages in comparison to the bulk phase as these have a high interfacial area (relative to their volume) and low viscosity, thus widening its scope of application.
Smectic nanoparticles
Colloidal smectic nanoparticles are emerging as a carrier system for lipophilic drugs due to their liquid crystalline nature. One such example of this smectic nanoparticulate carrier system is cholesteryl myristate. Colloidal smectic nanoparticles are suitable models to study the crystallization behaviour of pharmaceuticals and determining the influence of various parameters for the development of smectic nanoparticles which are resistant to crystallization upon storage.
Dermal application
Drug molecules and pharmaceutical excipients with amphiphilic character can form lyotropic mesophases, this is particularly for surfactants, which are commonly used as emulsifiers in dermal formulations and associate to form micelles after dissolving in a solvent. With increasing concentration the probability of interaction between the micelles increases and thus liquid crystals form. Liquid crystalline formulations have been used in cosmetics and pharmaceutical controlled release dosage forms. These formulations achieve enhanced penetration of biologically active materials (e.g., vitamin A) into the skin. The delivery systems comprise of cholesteric liquid crystals wherein the active material is retained within the lamellar molecular structure (i.e. between the molecular sheets) of the cholesteric liquid crystal.
Liquid crystals exhibit different molecular arrangements than the liquid and solid states. LCs can be classified as thermotropic and lyotropic crystals. The most common sub phases of LCs are nematics and smectics. Pharmaceutical drugs and excipients have been characterized to show liquid crystalline states which can form the basis for a new class of drug delivery system. The same has found applications in food and dermal products. LC based systems can provide specific advantages of thermodynamic stability, high solubilization levels, improved bioavailability, protection against oxidation and controlled release properties to the pharmaceuticals. Thus material characterization and understanding of the liquid crystalline states of active pharmaceuticals can yield wider options to enhance formulation performance for drug delivery.
(Ganesh Shete is M. Pharm. student in the Dept of Pharmaceutical Technology (Formulations), Vibha Puri is Ph. D. student and Dr. Arvind K Bansal is professor and head in the Dept of Pharmaceutics at National Institute of Pharmaceutical Education and Research, Punjab 160062.)