Application of PEG in Formulation and Chemical Synthesis


1. Introduction to PEG
PEG is an ethylene glycol polymer with a relative molecular weight of 200 to 8000 or more than 8000, which is polymerized by ethylene oxide. It is composed of repeated oxyethylene groups. It not only has good water solubility, but also dissolves in DCM. , DMF, benzene, acetonitrile and ethanol and other organic solvents. PEG has 2 terminal hydroxyl groups and has a linear (relative molecular mass of 5000 to 30000) or branched (relative molecular mass of 40000 to 60000) chain structure. The molecular formula of linear PEG is H-(O-CH2-CH2) n-OH. Commonly used PEGs are PEG200, PEG300, PEG400, PEG600, PEG1000, PEG2000, PEG4000, PEG6000, PEG10000, etc. PEGs with a relative molecular weight of 200 to 600 at room temperature are liquid, and those with a relative molecular weight of 1000 and above are solids.

2. The use of PEG in formulations
PEG has been used as a pharmaceutical excipient for hundreds of years. Due to its low toxicity and good water solubility, PEG has been favored by the majority of pharmacists for a long time and has been widely used in various pharmaceutical dosage forms such as injections, topical preparations, ophthalmic preparations, oral and rectal preparations. PEG has good solubility in water and good compatibility with drugs and other solvents. Liquid PEG with small relative molecular weight can be used as a solvent in preparations. Solid PEG with large relative molecular weight can be made with insoluble drugs. Solid dispersions to facilitate drug dissolution.

PEG200, PEG300, PEG400 and PEG600 are colorless, slightly odorous viscous liquids with stable chemical properties, safety and low toxicity, so they are often used as solvents for drugs. PEG4000 and PEG6000 are the typical representatives of water-soluble lubricants in tablets. The disintegration and dissolution of tablets made by PEG are not affected, which can improve the solubility of the main drug in the stomach and ultimately help increase bioavailability. Spend. In addition to being used as a lubricant, PEG can also be used as a binder. Among them, PEG4000 is the most commonly used, especially for heat-labile drugs. If PEG4000 is used as a binder, the powder can be directly compressed in a dry state, and the effect is relatively low. ideal.

In addition, PEG can also be used as a plasticizer to change the physical and mechanical properties of the polymer, making it more flexible and plastic; as a pore-forming agent for membrane-controlled slow-release drugs; Solvation, occupying the hydrogen bonding site of protein, reducing the binding between drug and tissue, increasing the distribution of other penetration enhancers in the stratum corneum, etc.

3. The use of PEG in synthesis
The application of PEG in chemical synthesis also has a long history and has been widely used in combinatorial chemistry and organic chemistry. It can provide homogeneous reaction conditions and has the advantages of easy purification and easy analysis. Therefore, PEG is used as a solvent, catalyst It is increasingly used in laboratory research and industrial production.

As a solvent, researches in recent years tend to be “green” of PEG. With its viscosity at room temperature and high temperature, low toxicity, thermal stability, low price, non-volatile, biodegradable, and environmental friendliness, its It has received increasing attention in synthetic chemistry and heterogeneous catalysis, such as Heck reaction, Suzuki coupling reaction, oxidation reaction, reduction reaction, addition reaction and asymmetric aldo reaction, etc. And PEG has different solubility at different temperatures, and can be miscible with water, dichloromethane, alcohol, acetone and other solvents. However, PEG is insoluble in diethyl ether, n-hexane and other solvents, so it can be used to precipitate PEG, so that PEG and solute can be separated. At present, a large number of articles have reported that PEG is a reusable solvent.

In terms of catalysis, since the chain structure of PEG can be folded into holes of different sizes, the chain link can be folded into a helical and freely sliding chain, forming a shape similar to a crown ether, so it can complex with metal ions of different sizes. combined to carry out the phase transfer catalytic reaction. Although the reaction effect in liquid-liquid phase is not good, it has a good catalytic effect on the reactions involving sodium, potassium and other metal salts. For the reactions involving different salts, PEG400-1000 is a commonly used catalyst. Studies have shown that PEG400, due to its moderate molecular weight, especially the high relative proportion of two polar terminal hydroxyl groups, is more suitable for catalyzing Na+ and K+ salts. Reaction; Due to the strong water solubility, the catalyst and salt by-products can be washed away with water after the reaction is completed, which greatly simplifies the treatment process of the product. Using PEG400 as a phase transfer catalyst has been widely used in many liquid-liquid, gas-liquid, gas- Solid, solid-liquid two-phase organic chemical reactions. Especially in the solid-liquid reaction under solvent-free conditions, PEG400 shows the superiority that other PTCs cannot match.

4. The connection of PEG and drug molecules
In the 1970s, Davis et al. reported the modification of proteins with PEG, and then successively carried out many studies on the covalent binding of PEG to proteins and small molecule drugs. The PEG modification of drugs, namely PEGylation, is to chemically couple activated PEG to proteins, polypeptides, small molecular organic drugs and liposomes. The PEG modification of drugs can be divided into two stages. The modification technology of the first stage is limited to the application of monomethoxy PEG with low relative molecular mass (<20000). Commonly used modifiers are monomethoxy polyethylene glycol succinimidyl succinimide, monomethoxy polyethylene glycol succinimide carbonate, etc., which couple PEG to drug molecules through ester bonds or triazine rings. This non-specific and unstable linking way makes one drug molecule often link several PEG molecules. For example, monomethoxy polyethylene glycol succinimidyl succinimide is coupled to the ε-amino group of the side chain of the Lys residue, because there are generally multiple Lys residues on the surface of the protein molecule, plus the reaction of each ε-amino group Due to different activities, the modified products are often mixtures of products with different degrees of modification and different modification sites. These mixtures are generally difficult to separate and difficult to separate. Therefore, the first-generation PEG-modified drugs usually show instability, greater toxicity and immunogenicity, and the biological activity and pharmacokinetic properties are not substantially changed from those of the original drug.

The second-stage modification technology, which is characterized by the application of high molecular weight (>20000) PEG modifiers, has the characteristics of stable connection, site-specific modification, and controlled release. Therefore, the modified drug has higher biological activity, better physical and thermal stability, higher product homogeneity and purity. This stage of PEG modification technology has not only been successfully applied to the research of protein and peptide drugs, but also made breakthroughs in the field of organic small molecule drugs and liposome research.

The connection methods of PEG and drug molecules are roughly divided into *bonding and non-*bonding. The former is that PEG is stably combined with drug molecules through chemical bonds, and the drug molecules can still effectively exert their efficacy; the latter is that PEG forms unstable bonds with drug molecules through chemical bonds, and this type of complex often needs to be at a certain pH value or a certain Under the conditions of the presence of these specific enzymes, the free drug can only be effectively exerted after hydrolysis to release the free drug. Small molecule drugs are generally less directly connected to PEG, but are connected through various linking arms. Selecting the appropriate linker type can also achieve the purpose of slow release, targeted release and increased drug loading. Generally, there are four main types of tethers, pH-sensitive tethers, enzyme-sensitive tethers, ortho-promoting tethers and N-Mannich base tethers.

Compared with unmodified drugs, modified drugs often have the following outstanding advantages: (1) stronger biological activity; (2) liposomes have stronger passive targeting effect on tumors; (3) longer half-life; (4) lower maximum blood drug concentration; (5) less fluctuation of blood drug concentration; (6) less enzymatic degradation; (7) less immunogenicity and antigenicity; (8) Less toxicity; (9) better solubility; (10) reduced frequency of medication; (11) improved patient compliance, improved quality of life, and reduced treatment costs.

5. Key technical points of PEG modification
Relative molecular weight selection of PEG
The choice of molecular weight should comprehensively consider the factors of biological activity and pharmacokinetics. Studies have shown that the action time of modified protein drugs in vivo is directly proportional to the number and relative molecular weight of the conjugated PEG, and the biological activity in vitro is inversely proportional to the number and relative molecular weight of the conjugated PEG. The choice of specific PEG molecular weight during modification To be determined according to experiments, PEG with a molecular weight in the range of 40,000 to 60,000 is generally selected as the modifier.

Selection of modification sites
During protein PEG modification, protein surface residues that are not bound to receptors should be selected as modification sites according to the analysis of protein structure-activity relationship, so that the modified protein can retain higher biological activity. The modification sites of organic small molecule drugs have nothing to do with biological activity. The ideal PEG modification technology is to select the appropriate PEG according to the site to be modified to obtain a homogeneous product.