Phospholipid

Background

The appealing characteristics of phospholipids, including their unique interfacial properties, diverse nature, and biocompatibility, make them an attractive option as a pharmaceutical excipient. These amphipathic molecules possess the ability to self-assemble into various structures, and their solubility, chemical and structural properties, surface charge, and packaging parameters are crucial factors in formulation design. Overall, phospholipids serve as versatile excipients for drug delivery, performing multiple functions such as solubilization, emulsification, surfactant action, enhancement of penetration, coating, modification of sustained release, and formation of liposomes. BOC Sciences ensures the quality and purity of its phospholipid products through rigorous quality control measures, with a dedicated team of experts overseeing the production process to meet industry standards and customer requirements.

What is a Phospholipid?

Phospholipids are natural endogenous substances present in all plants, animals and humans. These lipids constitute the main structural and functional components of human cell membranes. They also play various physiological functions in the body. They are present in pulmonary surfactants and are involved in bone formation, apoptosis and blood coagulation. Phospholipids help metabolism by dissolving bile and fatty foods in bile. These lipids can be extracted from various plant and animal sources. The amphiphilicity of these molecules makes them self-assemble into different structures.

Fig. 1. The structure of phospholipid bilayer.

When dispersed in water, phospholipids form layered, micellar, bubbly, cubic and cylindrical nanostructures. The type of structure formed depends on temperature, hydration degree and lipid type. Each of these structures has different applications in the food, cosmetics and pharmaceutical industries. The structure and properties of different phospholipids are directly related to their applications. Phospholipids with monolayer or bilayer structure have the application value as drug carrier systems. They have great potential to stabilize drug emulsions and thus have good emulsifying properties. They can also be used as surfactants to enhance the water solubility of poorly soluble drugs. The unique interface properties, large species diversity and biocompatibility of these molecules make them attractive drug excipients.

Source of Phospholipids

Phospholipids can be natural, semi-synthetic or synthetic. Phospholipids are mainly derived from various plants (vegetable oils extracted from soybeans, sunflowers, corn and cottonseed) and animal sources (animal tissues such as cow brain and egg yolk). Phospholipids of plant and animal origin contain different amounts and types of lipids. Egg yolk phospholipids mainly contain sphingomyelin backbone and long-chain polyunsaturated fatty acids. Compared with soybean phospholipids, egg yolk phospholipids have higher saturation, higher PC content, and better oxidative stability. The oxidative stability of lipids is directly related to the number of double bonds in the fatty acid side chains. Natural phospholipids can be partially or completely modified by chemical or enzymatic methods to produce semi-synthetic phospholipids and synthetic phospholipids with desired properties, respectively. Synthetic or semi-synthetic lipids are expensive compared to natural lipids. Where possible, natural phospholipids should be chosen for formulation development because they can be produced in large quantities at low cost and in a renewable manner. However, synthetic phospholipids produce stable structures compared to natural phospholipids.

Types of Phospholipids

Phospholipids can be classified based on source or structure. Fig. 1 summarizes the different types of phospholipids. The backbone can be glycerol or sphingosine. The polar head attaches to phosphatidic acid to form phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidyl inositol (PI) or phosphatidylglycerol (PG). Sphingomyelins form the sphingomyelin (SM) class. Some fatty acid chains that can be attached are disterol (DS), dipalmitol (DP), dimyristol (DM) and dioleoyl (DO). Fatty acid chains can be saturated or unsaturated.

Fig. 2. Structural characteristics of different types of phospholipids.

Properties of Phospholipids

Solubility of Phospholipids

The solubility of lipids depends on polar head groups and fatty acid side chains. According to solubility, phospholipids are classified as:

• Class 1: Insoluble phospholipids (waxes) that do not absorb water.
• Class 2: Phospholipids with very low solubility, such as PCs, PEs or SM, that swell in water.
• Class 3A: Soluble phospholipids, forming soluble liquid crystals at low water content, such as lysolecithins.
• Class 3B: Soluble phospholipids, forming micelles, such as saponins.

Surface Charge of Phospholipids

The surface charge obtained by the dispersion of phospholipids in water depends on the polar group and the pH value of the medium. At pH 7, phospholipids containing PC and PE head groups have a neutral charge (zwitterionic), while phospholipids containing PS, PI and PG head groups have a negative charge. Due to the negative charge of skin cells, the cationic charge on the phospholipid head promotes the attraction of nanoparticles to the cell membrane and increases the incorporation rate of cells. It has been reported that nanoparticles with neutral charges (provided by PC) exhibit longer circulation time at plasma pH due to less binding to plasma proteins in the blood. Due to the absorption of lung, liver and spleen, charged nanoparticles were cleared faster. In general, surface charge affects the interaction between nanocarriers and cells, macrophage uptake, escape from lysosomes, clearance rate and cytotoxicity.

Phase Transition Temperature of Phospholipids

The temperature at which phospholipids transition from gel (highly ordered) to liquid crystal phase (disordered) is called the phase transition temperature (PTT). It depends on the polar head group, the length of the fatty acid side chain, the degree of saturation of the fatty acid side chain and the purity of the phospholipid. The PTT of the PE headset is higher than that of the PC or PG headset. This is related to stronger headgroup interactions in the former. Phospholipids with longer side chains have a higher PTT than phospholipids with shorter side chains because more energy is required to break bonds. Likewise, saturated phospholipids showed higher PTT. Phospholipids composed of polyunsaturated side chains can show PTT even below 0 °C. In the case of topical formulations, the phospholipid bilayer with higher PTT lipids remains rigid at a skin temperature of 32°C (preferred for topical drug delivery), while the phospholipid bilayer with lower PTT lipids remains in an elastic form. The elastic bilayer is very flexible and can be easily squeezed through keratinocytes into deeper skin layers to provide transdermal delivery. Compared with vesicles formed from phospholipids with higher PTT, vesicles formed from phospholipids with PTT lower than 37°C are more susceptible to destruction by bile salts in the gastrointestinal environment when delivered via the oral route.

Polymorphism of Phospholipids

Phospholipids dispersed in water can exist in various forms, depending on the degree and type of hydration of the phospholipids. They can form two-dimensional lamellar structures or different gel phases. They can exist in three-dimensional spherical, cubic, hexagonal or cylindrical structures. Different polymorphic forms play an important role in modifying the release of the drug and the stability of the formed nanoaggregates. The type of structure formed depends on the size of the polar head group, the saturation of the side chains, the concentration of phospholipids, temperature, ionic strength, pH, and the presence of other molecules such as steroids, oils, or divalent cations such as calcium.

Reference

1. Waghule, T. et al. Tailoring the multi-functional properties of phospholipids for simple to complex self-assemblies. J Control Release. 2022, 349: 460-474.

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