Several main types of phospholipid reagents

Phospholipids are an important component of cell membranes and the main component of lipoprotein particles. They play an important role in the endogenous transport of lipids and contribute to physiological functions such as blood coagulation and bone formation. In addition, phospholipids can be found in the bile of the gastrointestinal tract and are therefore essential for the digestion and absorption of lipophilic compounds. In addition, phospholipids are a major source of essential nutrients such as choline and polyunsaturated fatty acids, as well as second messenger molecules such as diacylglycerol and inositol triphosphate.

Based on their unique physicochemical properties, phospholipids are versatile excipients for a variety of pharmaceutical applications. In relation to their physiological functions, they are biocompatible, biodegradable, and safe for any route of administration. Phospholipids have a long history as essential excipients for many globally marketed pharmaceuticals.

Therefore, based on these unique properties, phospholipids are ideal excipients for a class of innovative drug delivery systems.

Figure 1 General structure of phospholipids

The molecular structure of phospholipids consists of a glycerol backbone esterified with fatty acids and phosphoric acid. For example, the systematic name for phosphatidic acid (PA) is 1,2-diacyl-sn-glycero-3-phosphate. The phosphate group of PA can be further esterified under the catalysis of phospholipase D: esterify with choline to generate phosphatidylcholine (PC); esterify with ethanolamine to obtain phosphatidylethanolamine (PE); esterify with glycerol to obtain phosphatidylcholine Glycerol (PG); esterification with serine to obtain phosphatidylserine (PS); esterification with inositol to obtain phosphatidylinositol (PI).

Figure 2 Neutral (amphoteric) phospholipids and anionic phospholipids

Phospholipids can be zwitterionic (neutral) or anionic, depending on the structure of the polar region and the pH of the medium. PC and PE are zwitterionic and have no charge at physiological pH. PA, PG, PS, and PI are anionic phospholipids that exhibit anionic state at physiological pH. Natural cationic phospholipids do not exist, but phospholipid compounds with a positive net charge can be obtained synthetically. For example, by derivatizing phosphatidylcholine (PC), a new type of cationic phosphatidylcholine can be obtained.

Figure 3 Synthesis of cationic phospholipids

In addition, phospholipids can contain one or two fatty acids, which can be either saturated or unsaturated. The length of the fatty acid chain as well as the degree of unsaturation of the fatty acid can significantly affect the physicochemical properties of phospholipids, such as phase transition temperature, formation of mesophase (e.g. micelles, reverse micelles, liposomes), appearance, solubility and miscibility. Combining the many different phospholipid headgroups and fatty acid tails, there is a huge number of phospholipid compounds.

Phospholipids are generally less soluble in acetonitrile and acetone, and more soluble in chloroform and dichloromethane. Sometimes adding a small amount of methanol to chloroform or dichloromethane can increase the solubility of phospholipids. For phospholipids of the same fatty acid, the solubility of phosphatidylcholine (PC) is relatively large, while other types of phospholipids are less soluble. For phospholipids of different fatty acids, the solubility of phospholipids of saturated fatty acids is significantly less than that of unsaturated fatty acids. For example, DSPC and DOPC are both octadecyl fatty acid chains, but DSPC is saturated stearic acid, while DOPC is unsaturated oil acid. The two differ greatly in appearance and solubility, with DSPC being a fine white powder and DOPC being a waxy solid. The solubility of DOPC in organic solvents is also significantly greater than that of DSPC. In addition, phospholipids with longer fatty acids are generally less soluble than phospholipids with shorter fatty acids. For example, DSPC of octadecanoic acid is less soluble than DMPC of myristic acid. Therefore, when doing NMR of phospholipid compounds, deuterated chloroform or a mixed solvent of deuterated chloroform and deuterated methanol is generally used for NMR. For phospholipids with poor solubility, it is usually necessary to heat and dissolve them with a hair dryer before doing NMR. For lysophospholipids, deuterated methanol can be used as a solvent.

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