What should be considered when choosing a phospholipid?
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phase transition temperature

The phase transition temperature is defined as the temperature required to induce a change in the physical state of lipids from an ordered gel phase to a disordered liquid crystal phase, where the hydrocarbon chains are fully extended and tightly packed, where the hydrocarbon chains are randomly oriented and mobile [1 ,2]. Several factors directly affect the phase transition temperature, including hydrocarbon chain length, degree of unsaturation, charge, and headgroup species. As the hydrocarbon chain length increases, the van der Waals interactions become stronger, requiring more energy to break the ordered packing, and thus the phase transition temperature increases. Likewise, the introduction of a double bond in the acyl group causes the chain to kink, resulting in an ordered packing arrangement at lower temperatures.

Controlling the transition temperature of lipids may be useful when developing new products, processes or methods. If you choose a lipid with a high phase transition temperature, the lipid vesicles are always in the gel phase and will not leak. On the contrary, when the phase transition temperature of the lipid is between the start temperature and the end temperature of the system, the vesicles become easily leaky when the lipid undergoes a phase transition, and the encapsulated substances can be released. In addition, how the transition temperature of the lipid affects the processing steps should also be considered. When filtration is required, the use of lipids with a high phase transition temperature may pose some technical problems.

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The long-term stability or shelf life of lipid-containing drugs can be significantly affected by the type of lipid in the formulation. Generally, the higher the degree of unsaturation of the compound, the more susceptible the product is to oxidation and the shorter the shelf life of the product. Lipids of biological origin (e.g., eggs, cattle, or soybeans) typically contain high amounts of polyunsaturated fatty acids, which are less intrinsically stable than saturated fatty acids. While saturated lipids are more stable against oxidation, they also have a much higher phase transition temperature, leading to additional difficulties in formulation. If fatty acid unsaturation is necessary, use lower unsaturated fatty acids whenever possible. In most cases, oleic acid (18:1, cis D9) is sufficient for unsaturation and, since oleic acid is monounsaturated, is much more stable than polyunsaturated fatty acids.

Stability issues due to hydrolytic degradation are a common problem with lipid products. Aqueous formulations of pharmaceutical products are often less stable because the presence of large amounts of water can lead to rapid hydrolytic degradation of lipid formulations [3,4,5]. This hydrolysis depends on several factors, including pH [3], temperature [3,5], buffer substances [5], ionic strength, acyl chain length, phospholipid headgroups [4], and state of aggregation [4]. The discussion and summary of these factors can also refer to other literature [6]. It has been shown that this hydrolysis may be due to the penetration of water into the membrane. Simon and McIntosh [7] determined the penetration depth of water in membranes constructed of phosphatidylethanolamine (PE) and phosphatidylethanolamine (PE)/cholesterol by X-ray diffraction and specific capacitance measurements. In PE membranes, water permeates deeper near the carbonyls, whereas in cholesterol-containing PE membranes, water permeates only to the glycerol backbone. This suggests that cholesterol can play a role in stabilizing lipid membrane hydrolysis.

Keeping membranes stable has been the subject of research for many years. The main objective of this study was to stabilize intact liposomes in dry powder form so that they retain their captured contents when reconstituted. More recently, lipid formulations have been stabilized with carbohydrates [8,9]. A possible reason for the stabilizing effect of carbohydrates on lipid membranes is that carbohydrates can insert into the head region near the membrane/water interface and expel water from this region. In dry lipid formulations, this will help maintain the "hydrated" lipid film and maintain the integrity of the liposomal structure. If this is true, then in an aqueous environment carbohydrates can still enter this area and displace water. This will tend to stabilize the membrane against its hydrolysis.

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The surface of many biological membranes has a net negative charge, usually imparted by anionic phospholipids. The main natural anionic phospholipids are phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidic acid (PA) and cardiolipin. Some bacteria also contain phosphatidylglycerol (PG). Charges can provide membranes with specific functions. For example, several steps of the coagulation cascade require lipid membranes. Assembly of protein aggregates on platelet surfaces requires a negatively charged membrane surface. For the conversion of prothrombin to thrombin, it not only requires a negatively charged surface, but also has certain specific requirements for lipids, limited to phosphatidylserine (PS) and phosphatidic acid (PA) [10]. Although the coagulation protein binds as tightly to PG or PI as it does to PS or PA, the activity is much lower. Therefore, in some systems, not only the charge requirements must be met, but also specific lipids must be required.

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lipid mixture

In many cases, a single type of lipid does not produce the physicochemical properties required for a particular system, or does not adequately mimic the natural system it is intended to replace or replicate. For these questions, consider complex lipid mixtures composed of two or more lipids designed to generate or reproduce specific charge ratios, degrees of unsaturation, phase transition temperatures, or biological functions. In order to reproduce the function of natural brain tissue extracts, it was found that the synthetic lipid PE:PS:PC ratio of 5:3:2 (wt%) can achieve satisfactory results [11] - this result also Exhibits a common phospholipid composition in most brain tissues. Furthermore, many commercially available coagulation reagents that used to contain crude brain extracts are being replaced by synthetic lipid mixtures. This alternative mixture has several advantages: improved stability due to the absence of polyunsaturated fatty acids in biological extracts; additionally, the reproducibility of lipid mixtures is also improved. The mixing of various types of lipids also does not require much effort during sample preparation. If the amount of lipid reagent is sufficient, the lipid supplier premixes according to the user's specification and provides a ready-to-use product.

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Cholesterol is a membrane component widely present in biological systems and has a unique role in regulating membrane fluidity, elasticity, and permeability. When the protein is embedded in the membrane, it actually fills in the gaps created by the imperfect assembly of other lipid species. Cholesterol plays essentially the same role in model membranes. Unfortunately, cholesterol can present certain problems when used in human medicine. Sources of high-purity cholesterol suitable for clinical use are not widely available. Most commercially available cholesterol is derived from eggs or lanolin (of sheep origin). These animal sources may not be suitable for use in human medicine due to potential viral contamination. In addition, cholesterol is easily oxidized, which poses stability issues for lipid-based drug products [12]. Some of these oxidation byproducts tend to be quite toxic in biological systems. Oxidation products are 25-hydroxycholesterol, 7-carbonylcholesterol, 7a- and 7β-hydroxycholesterol, cholestane-3β, 5a, 6β-triols, and 5- and 7-hydroperoxides [13]. This suggests that the results of atherosclerosis studies may be ambiguous due to the likely presence of high amounts of oxidized sterols.

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Phospholipids come from two basic sources: chemical synthesis and animal tissue extraction. Phospholipids derived from animal tissues are usually derived from eggs or bovine. For clinical applications, such animal-derived phospholipids are not suitable due to stability issues and the possibility of viral or protein contamination. The US Food and Drug Administration issued a bulletin restricting the source of bovine tissue to countries and animals that have been certified free of "mad cow disease" (BSE, bovine spongiform encephalopathy). U.S. cattle have not been certified BSE-free and cannot be used to produce pharmaceuticals. Egg sources are currently unrestricted, but pharmaceutical products may require additional testing for viral contamination. Regardless of the regulatory issues, phospholipids derived from animal tissue have lost their edge over synthetic phospholipids. Moreover, they are inherently less stable due to the presence of polyunsaturated fatty acids. In addition, in most cases, the production cost of synthetic phospholipids is not much different from that of animal tissue-derived phospholipids, or even lower.

In addition, synthetic lipids are not necessarily completely equal due to different sources of raw materials. Synthetic lipids can be prepared from glycerol or from glycerol-3-phosphocholine (GPC). In the latter case, GPCs are sometimes referred to as semi-synthetic phospholipids because they are derived from plants or animals. Glycerol-derived phospholipids require synthetic chiral centers, which can lead to chiral isomeric impurities in the final product. Lipids prepared using animal-derived GPC can suffer from the same viral and protein contamination issues as above, although a typical plant source of GPC is soybean lecithin, which can of course also be chemically synthesized.


1. Small, DM, Handbook of Lipid Research: The Physical Chemistry of Lipids, From Alkanes to Phospholipids, Vol. 4, Plenum Press, New York, 1986.

2. Ellens, H., Bentz, J., and Szoka, FC, Destabilization of phosphatidylethanolamine liposomes at the hexagonal phase transition temperature, Biochemistry, 25, 285, 1986.

3. Frrkjaer, S., Hjorth, EL, and Wrrts, O., Stability and storage of liposomes, in Optimization of Drug Delivery, Bundgaard, H., Bagger Hansen, A., and Kofod, H., Eds., Munksgaard , Copenhagen, 1982, 384.

4. Kensil, CR and Dennis, EA, Alkaline hydrolysis of phospholipids in model membranes and the dependence on their state of aggregation, Biochemistry, 20, 6079, 1981.

5. Grit, M., de Smidt, JH, Struijke, A., and Crommelin, DJA, Hydrolysis of phosphatidylcholine in aqueous liposome dispersions, Int. J. Pharm., 50, 1, 1989.

6. Grit, M., Zuidam, NJ, and Crommelin, DJA, Analysis and hydrolysis kinetics of phospholipids in aqueous liposome dispersions, in Liposome Technology: Liposome Preparation and Related Techniques, Vol. 1, 2nd edn, Gregoriadis, G., Ed ., CRC Press, Ann Arbor, 1993, 527.

7. Simon, SA and McIntosh, TJ, Depth of water penetration into lipid bilayers, Meth. Enzymol., 127, 511, 1986.

8. Crowe, JH and Crowe, LM, Factors affecting the stability of dry liposomes, Biochim. Biophys. Acta, 939, 327, 1988.

9. Crowe, JH, Crowe, LM, Carpenter, JF, and Aurell Winstrom, C., Stabilization of dry phospholipid bilayers and proteins by sugars, Biochem. J., 242, 1 1987.

10. Jones, ME, Lentz, BR, Dombrose, FA, and Sandberg, H., Comparison of the abilities of synthetic and platelet-derived membranes to enhance thrombin formation, Thromb. Res., 39, 711, 1985.

11. van den Besselaar, AMHP, Neuteboom, J., and Bertina, RM, Effect of synthetic phospholipids on the response of the activated partial thromboplastin time to heparin, Blood Coag. Fibrinol., 4, 895, 1993.

12. Smith, LL, Cholesterol Autoxidation, Plenum Press, New York, 1981.

13. Taylor, CB, Peng, SK, Werthesen, NT, Than, P., and Lee, KT, Spontaneously occurring angiotoxic derivatives of cholesterol, Am. J. Clin. Nutri., 32, 40, 1979.

This article is translated from Burgess, SW, Moore, JD, and Shaw, WA, Handbook of Nonmedical Applications of Liposome: From Design to Microreactors, Vol. 3, Y. Barenholz & D. Lasic, Eds., CRC Press, Ann Arbor, 1996 , 5.

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