The use of natural and synthetic phospholipids as pharmaceutical excipients

Abstract

In pharmaceutical formulations, phospholipids obtained from plant or animal sources and synthetic phospholipids are used. Natural phospholipids are purified from, e.g., soybeans or egg yolk using non-toxic solvent extraction and chromatographic procedures with low consumption of energy and minimum possible waste. Because of the use of validated purification procedures and sourcing of raw materials with consistent quality, the resulting products differing in phosphatidylcholine content possess an excellent batch to batch reproducibility with respect to phospholipid and fatty acid composition. The natural phospholipids are described in pharmacopeias and relevant regulatory guidance documentation of the Food and Drug Administration (FDA) and European Medicines Agency (EMA). Synthetic phospholipids with specific polar head group, fatty acid composition can be manufactured using various synthesis routes. Synthetic phospholipids with the natural stereochemical configuration are preferably synthesized from glycerophosphocholine (GPC), which is obtained from natural phospholipids, using acylation and enzyme catalyzed reactions. Synthetic phospholipids play compared to natural phospholipid (including hydrogenated phospholipids), as derived from the number of drug products containing synthetic phospholipids, a minor role. Only in a few pharmaceutical products synthetic phospholipids are used. Natural phospholipids are used in oral, dermal, and parenteral products including liposomes. Natural phospholipids instead of synthetic phospholipids should be selected as phospholipid excipients for formulation development, whenever possible, because natural phospholipids are derived from renewable sources and produced with more ecologically friendly processes and are available in larger scale at relatively low costs compared to synthetic phospholipids. Practical applications: For selection of phospholipid excipients for pharmaceutical formulations, natural phospholipids are preferred compared to synthetic phospholipids because they are available at large scale with reproducible quality at lower costs of goods. They are well accepted by regulatory authorities and are produced using less chemicals and solvents at higher yields. In order to avoid scale up problems during pharmaceutical development and production, natural phospholipid excipients instead of synthetic phospholipids should be selected whenever possible.

Keywords: Emulsifier; Lecithin; Liposomes; Natural phospholipids; Phosphatidylcholine; Solubilizer; Synthetic phospholipids.

Figure 1

Flow sheet of a lecithin producing unit. Crude soybean oil is heated in the preheater, (1) to 80°C, mixed with 2% water in the proportion control unit, (2) and intensively agitated in (3). The mixture goes to a dwelling container, (4), and is then centrifuged after a residence time of 2–5 min. The degummed oil flows without further drying to the storage tanks. The lecithin sludge is dried in the thin-film evaporator, (6), at 100°C and 6 kPa (60 mbar) for 1–2 min and is discharged after cooling to 50–60°C in the cooler, (8). (9) and (10) are the condenser and vacuum pump, respectively .

Figure 2

(A) Flow chart of the isolation process steps of soybean phosphatidylcholine from crude soybean oil. (B) Visual aspect of soybean lecithin fractions with varying PC content.

Figure 3

HPLC (normal phase chromatography)-ELSD chromatograms of soybean lecithin extraction and chromatography fractions differing in PC content. Peak numbers reference 1: N-acyl-PE, 2:PA, 3:PE, 4:PC, 5: PI, 6: LPC .

Figure 4

HPLC (normal phase chromatography)-ELSD chromatograms of egg lecithin extraction and chromatography fractions differing in PC content. Peak numbers reference 1: PE, 2: PC, 3: SM, 4: LPC .

Figure 5

Enzymatic conversion possibilities of phosphatidylcholine .

Figure 6

Conversion of d-mannitol to mixed (fatty acid) chain and identical (fatty acid) chain phospholipids (first steps) ,.

Figure 7

Conversion of d-mannitol to mixed (fatty acid) chain and identical (fatty acid) chain phospholipids (continued).

Figure 8

Synthetic preparation of mixed fatty acid chain phosphatidylcholines. Tr = triphenylmethyl .

Figure 9

Synthesis of mixed fatty acid chain phospholipids and polar head group modification (X), starting from phosphatidylcholine and using enzymatic procedures.