What Is Fulvestrant?

A poorly soluble drug and a third substance added form a soluble intermolecular complex, association, or double salt in a solvent to increase the solubility of the drug in the solvent. This third substance is called a co-solvent (hydrotropicagent ). Cosolvents are soluble in water, mostly low-molecular compounds, which can increase the solubility of the drug several times or even dozens of times after forming a complex with the drug [1].

Chinese name: Cosolvent
Field: Chemistry

Function: Dissolves poorly soluble drugs
the way: Formation of complexes, associations, etc.

Cosolvent I. Overview

A poorly soluble drug and a third substance added form a soluble intermolecular complex, association or double salt in a solvent to increase the solubility of the drug in the solvent. This third substance is called a co-solvent. Cosolvents are soluble in water, mostly low molecular compounds, and the complexes formed are mostly macromolecules.

The commonly used co-solvents are mainly divided into two categories: one is certain organic acids and their sodium salts, such as: sodium benzoate, sodium salicylate, p-aminobenzoic acid, etc .; the other is amide compounds, such as: urea , Nicotinamide, acetamide and so on.

Due to the complex mechanism of solubilization, many mechanisms are still unclear. Therefore, there is no clear rule on the choice of co-solvent. Generally, only the intermolecular complexes and complexes that can form water-soluble compounds can be selected according to the properties of the drug. Salt or associative substance. It should be noted that it is not a surfactant and therefore distinguishes it from a solubilizer.

Co-solvent II

When a third substance is added to water, a poorly soluble drug can increase its solubility. The mechanism is that the poorly soluble drug forms a soluble complex with a solubilizing agent, an organic molecular complex, an association compound, and generates a soluble salt through a metathesis reaction. Four types.

For example, the solubility of iodine in water is 1: 2950. If an appropriate amount of potassium iodide is added, the solubility of iodine in water can be significantly increased, and it can be formulated into an aqueous solution containing 5% iodine. Potassium iodide is a co-solvent, and the mechanism for increasing the solubility of iodine is that KI forms a complex KI with iodine ^[1] .

Co-solvent III. Advantages of co-solvent

1. Increasing the solubility of poorly soluble drugs is conducive to the preparation and application of the formulation ^[2] ;

2. Co-solvents can also reduce some of the shortcomings of the original drugs, improve the quality of the preparations and develop new preparations;

3. Solubilizer can increase the stability of the preparation, improve physical properties, correct odor and taste, reduce irritation, improve absorption, and increase pharmacological effects;

4. When selecting a co-solvent, the solubility of the poorly soluble drug can be increased at a lower concentration;

5. Does not affect the effect of the main medicine;

6. No irritation and toxicity when used;

7. Its stability does not change during storage and sterilization;

8. Cheap and easy to get.

Cosolvent IV. Determination of the amount of cosolvent

The amount of cosolvent is determined by the following method: It is known that the concentration of cosolvent at a certain temperature and the solubility of poorly soluble drugs in water can have a linear relationship, and then the amount of cosolvent added is determined according to the requirements of the clinical application of the drug ^[3] .

Cosolvent V. Types of Cosolvent

Commonly used co-solvents can be divided into two categories: one is certain organic acids and their salts such as sodium benzoate, sodium salicylate, p-aminobenzoic acid, etc. These are the more commonly used co-solvents in preparations; the other is amides Compounds such as urethane, urea, acetamide and the like. But many other drugs also have better solubilizing effects.

(1) Organic acids and their salts

Sodium benzoate

The molecular formula is C7H5NaO2, also known as sodium benzoate. Usually used for antiseptic and mildew protection of liquid medicaments for oral administration, especially neutral or slightly alkaline medicaments and foods that are not suitable for preserving with benzoic acid. This product is white granules, powder or crystalline powder; it is odorless or slightly scented with benzoin, slightly sweet and salty. Soluble in water, slightly soluble in ethanol.

2. Citric acid

Also known as citric acid (C6H8O7, Citricacid, 2-hydroxypropane 1,2,3-tricarboxylic acid) with a molecular weight of 192.1, this product is a colorless crystal or white crystalline powder. It is mainly used in the food and beverage industries as an acidulant, Flavoring agents, preservatives, and preservatives. It is also used as an antioxidant, plasticizer and detergent in the chemical industry, cosmetics industry and washing industry. When the researchers carried out the preparation of aspirin plus vitamin C effervescent tablets, they studied the prescription and preparation process of aspirin plus vitamin C effervescent tablets. Adjusting the ratio of citric acid to NaHCO3 to 7: 1, aspirin can be quickly dissolved; 30% lactose is used as the diluent and PVP is used as the binder.

3.Calcium lactate

Molecular formula C6H10CaO65H2O, molecular weight 308.3, also known as calcium lactate, is also an organic calcium supplement. In 1909 monvay reported that this product could be used as a soluble calcium agent. China's first pharmaceutical factory in Chengdu in 1951 put into production. This product is calcium hydroxypropionate pentahydrate, which is white or almost white crystalline or granular powder; almost odorless, tasteless, and slightly weathering. Soluble in hot water, soluble in water, almost insoluble in ethanol, chloroform and ether. The researchers used calcium (I) lactate as a co-solvent to investigate the effect of different concentrations of I on the stability of calcium (II) oral solution. The results showed that with the increase of the calcium lactate concentration, the stability of the II oral solution continued to improve. When the calcium lactate concentration was 2% or more, the oral solution had no crystal precipitation and was stable during storage.

(Two) amide compounds

There are urethane, urea, nicotinamide, For acetamide, etc., there is less information about such co-solvents.

(Three) other types of co-solvents

Low molecular compound

EthylAlcohol (CH3CH2OH) is also called alcohol. In the study of the induction of paclitaxel biosynthesis by methyl jasmonate, a mitogen autotrophic Chinese yew cell line was used to study methyl jasmonate during cell suspension (MJ) Induction of Paclitaxel Biosynthesis. The results showed that when ethanol was used as the MJ co-solvent, the induction effect of MJ was best when the dose of 200 mol / L was added at the beginning of subculture. At this time, the yield of paclitaxel increased by 71.2% compared with the control group. The researchers used the 35% ethanol and acetic acid as co-solvents to prepare the dioxazole ear drops in accordance with the law. The dual-wavelength spectrophotometry was used to directly determine the content of the main drug in the dioxazole ear drops. This method is used to observe its stability.

2. Isooctanol

Character is colorless liquid. Miscible with most organic solvents, slightly soluble in water. The refractive index is 1.4300. It has a flash point of 81 degrees and is flammable. Researchers carried out an experimental study on the separation and recovery of oxytetracycline in fermentation waste liquid by alcohol liquid membrane technology. Based on the extraction, they conducted an experimental study on the extraction of oxytetracycline in fermentation waste liquid by emulsion liquid membrane. The composition of the liquid film system is chlorohexadecyl pyridine (PCC) as a carrier, Span-80 is a surfactant, isooctanol is a co-solvent, kerosene is a diluent, and an aqueous hydrochloric acid solution is an inner phase of the film. The effects of factors such as liquid film composition, film internal ratio, surfactant dosage, internal phase HCl concentration, extraction stirring speed, external aqueous phase pH, milk-water ratio, and extraction time on the extraction rate were investigated through experiments. With suitable liquid film composition and extraction conditions, the extraction rate of oxytetracycline in the fermentation waste liquid reached 61.33%.

3. Polymeric co-solvents

There are many types of macromolecular co-solvents. This article only uses Tween as a representative. Tween is a non-ionic surfactant with excellent emulsifying, dispersing and wetting properties. Moreover, it is odorless and tasteless, and is safe and non-toxic to human body. In addition to being a food emulsifier, it is also an ideal industrial emulsifier.

Cosolvent VI. Research Trends of Cosolvent

With the continuous improvement of people's health consciousness and the continuous advancement of science and technology, in the future, good solubilizing products with good solubilizing effects, few toxic and side effects, small stimulating effects, easy absorption, stable properties, and cheap availability will be developed.