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Introduction of Pharmaceutical Impurities
2021-08-23
Impurities of drugs refer to substances that have no therapeutic effect or affect the stability and efficacy of drugs, and are even harmful to human health. In the research, production, storage and clinical application of drugs, it is necessary to maintain the purity of the drugs and reduce the impurities of the drugs, so as to ensure the effectiveness and safety of the drugs. Generally, the structure, appearance properties, physical and chemical constants, impurity inspection and content determination of the drug can be regarded as an interrelated whole to evaluate the purity of the drug. The impurities contained in the drug are the main factors affecting the purity of the drug. For example, if the drug contains impurities that exceed the limit, it may change the physical and chemical constants, change the appearance properties, and affect the stability of the drug; the increase in impurities will inevitably increase the content of the drug. Low or reduced activity, significantly increased side effects. Therefore, drug impurity inspection is a very important link to control drug purity and improve drug quality.
Purity of the drug:
The purity of the medicine is the purity of the medicine, and it is an important indicator reflecting the quality of the medicine.
Human understanding of drug purity is accumulated in the practice of disease prevention and treatment, and with the improvement of separation and detection technology, new impurities in the drug are further discovered, thereby continuously increasing the requirements for drug purity. Meperidine hydrochloride is a typical example. As early as 1948, pethidine hydrochloride has been included in the British Pharmacopoeia and widely used. It was not until 1970 that it was separated and identified by gas chromatography, and it was discovered that there were two ineffective isomers (II) and (III). These two impurities are caused by improper control of process conditions during production, and their content is sometimes even as high as 20% to 30%. At present, the Chinese Pharmacopoeia, the British Pharmacopoeia, and the United States Pharmacopoeia all control the amount of these impurities. In short, the requirements for drug purity are not static, but should be continuously improved with the development of clinical application practice and analytical testing technology to make it more perfect.
Medicinal substances should not be confused with reagents, industrial substances, etc. For example, potassium chloride for reagents cannot be used instead of medicinal potassium chloride. Because the purity of the drug mainly considers the physiological effects of impurities, while for substances for other purposes, only the impact of impurities on chemical reactions and material stability is considered. For example, the content of industrial alcohol may be higher than that of medical alcohol, but the content of methanol and lead is also relatively high.
Source of the impurities:
There are two main sources of impurities in drugs: on the one hand, they are introduced during the production process of the drug; on the other hand, they are caused by changes in the physical and chemical properties of the drug due to the influence of external conditions during the storage process. Of course, contaminated drugs can also introduce impurities.
Impurities introduced in the production process of drugs are often due to impure raw materials or incomplete reactions, as well as the existence of intermediate products and reaction by-products, which cannot be removed according to the required standards during refining. In addition, heavy metals and arsenic salts will be introduced to varying degrees in contact with production vessels. For example, when salicylic acid is used as a raw material to synthesize aspirin, the impurity of salicylic acid may be introduced due to the incomplete reaction.
Extracting and separating drugs from plant raw materials, because plants often contain substances that are similar or dissimilar to the chemical structure and properties of the product, the separation is incomplete during the extraction process and introduced into the product. For example, when morphine is extracted from opium, other alkaloids may be introduced from the raw material.
It is often necessary to add reagents, solvents or catalysts in the production process of drugs. Due to solubility, adsorption, occlusion, co-precipitation, mixed crystal formation and other reasons, it is impossible to completely remove them, resulting in related impurities in the product. If acidic or alkaline reagents are used for treatment, the product may contain acidic or alkaline impurities; after extraction or refining with organic solvents, there may be residual organic solvents in the product. The Chinese Pharmacopoeia stipulates that the residual amount of harmful organic solvents (such as benzene, chloroform, 1,4-dioxane, methylene chloride, pyridine, etc.) introduced in the production process of drugs must be checked.
New impurities may also be generated during the production of pharmaceutical preparations. For example, procaine hydrochloride injections may be hydrolyzed into p-aminobenzoic acid and diethylaminoethanol during high temperature sterilization. Therefore, procaine hydrochloride raw materials in the Chinese Pharmacopoeia do not check for p-aminobenzoic acid, but injections need to check this Impurities.
During the storage process, the drug is affected by external conditions and produces related impurities. For example, under the influence and action of temperature, humidity, microorganisms, time and other factors, the drug will undergo hydrolysis, oxidation, decomposition, isomerization, moldy and other changes. Related impurities are produced in the drug. The hydrolysis reaction is the most prone to deterioration reaction of drugs. Drugs with glycosides, halocarbons, esters, ureas, hydrazides, and amides are easily hydrolyzed in the presence of water. Drugs with phenolic hydroxyl groups, sulfhydryl groups, aromatic first amine groups, hydrazine groups, aldehyde groups, and long-chain conjugated double bonds are easily oxidized in the air to introduce impurities and make these drugs ineffective or ineffective, or even toxic. For example, anesthetic ether is easily oxidized and decomposed into aldehydes and toxic peroxides under the action of sunlight, air and humidity. The Pharmacopoeia stipulates that it should be used within 24 hours after unsealing. Under the influence of temperature, light and other factors, some drugs can also produce isomerization reactions. Under suitable moisture and temperature conditions, microorganisms can spoil certain drugs.
Purity of the drug:
The purity of the medicine is the purity of the medicine, and it is an important indicator reflecting the quality of the medicine.
Human understanding of drug purity is accumulated in the practice of disease prevention and treatment, and with the improvement of separation and detection technology, new impurities in the drug are further discovered, thereby continuously increasing the requirements for drug purity. Meperidine hydrochloride is a typical example. As early as 1948, pethidine hydrochloride has been included in the British Pharmacopoeia and widely used. It was not until 1970 that it was separated and identified by gas chromatography, and it was discovered that there were two ineffective isomers (II) and (III). These two impurities are caused by improper control of process conditions during production, and their content is sometimes even as high as 20% to 30%. At present, the Chinese Pharmacopoeia, the British Pharmacopoeia, and the United States Pharmacopoeia all control the amount of these impurities. In short, the requirements for drug purity are not static, but should be continuously improved with the development of clinical application practice and analytical testing technology to make it more perfect.
Medicinal substances should not be confused with reagents, industrial substances, etc. For example, potassium chloride for reagents cannot be used instead of medicinal potassium chloride. Because the purity of the drug mainly considers the physiological effects of impurities, while for substances for other purposes, only the impact of impurities on chemical reactions and material stability is considered. For example, the content of industrial alcohol may be higher than that of medical alcohol, but the content of methanol and lead is also relatively high.
Source of the impurities:
There are two main sources of impurities in drugs: on the one hand, they are introduced during the production process of the drug; on the other hand, they are caused by changes in the physical and chemical properties of the drug due to the influence of external conditions during the storage process. Of course, contaminated drugs can also introduce impurities.
Impurities introduced in the production process of drugs are often due to impure raw materials or incomplete reactions, as well as the existence of intermediate products and reaction by-products, which cannot be removed according to the required standards during refining. In addition, heavy metals and arsenic salts will be introduced to varying degrees in contact with production vessels. For example, when salicylic acid is used as a raw material to synthesize aspirin, the impurity of salicylic acid may be introduced due to the incomplete reaction.
Extracting and separating drugs from plant raw materials, because plants often contain substances that are similar or dissimilar to the chemical structure and properties of the product, the separation is incomplete during the extraction process and introduced into the product. For example, when morphine is extracted from opium, other alkaloids may be introduced from the raw material.
It is often necessary to add reagents, solvents or catalysts in the production process of drugs. Due to solubility, adsorption, occlusion, co-precipitation, mixed crystal formation and other reasons, it is impossible to completely remove them, resulting in related impurities in the product. If acidic or alkaline reagents are used for treatment, the product may contain acidic or alkaline impurities; after extraction or refining with organic solvents, there may be residual organic solvents in the product. The Chinese Pharmacopoeia stipulates that the residual amount of harmful organic solvents (such as benzene, chloroform, 1,4-dioxane, methylene chloride, pyridine, etc.) introduced in the production process of drugs must be checked.
New impurities may also be generated during the production of pharmaceutical preparations. For example, procaine hydrochloride injections may be hydrolyzed into p-aminobenzoic acid and diethylaminoethanol during high temperature sterilization. Therefore, procaine hydrochloride raw materials in the Chinese Pharmacopoeia do not check for p-aminobenzoic acid, but injections need to check this Impurities.
During the storage process, the drug is affected by external conditions and produces related impurities. For example, under the influence and action of temperature, humidity, microorganisms, time and other factors, the drug will undergo hydrolysis, oxidation, decomposition, isomerization, moldy and other changes. Related impurities are produced in the drug. The hydrolysis reaction is the most prone to deterioration reaction of drugs. Drugs with glycosides, halocarbons, esters, ureas, hydrazides, and amides are easily hydrolyzed in the presence of water. Drugs with phenolic hydroxyl groups, sulfhydryl groups, aromatic first amine groups, hydrazine groups, aldehyde groups, and long-chain conjugated double bonds are easily oxidized in the air to introduce impurities and make these drugs ineffective or ineffective, or even toxic. For example, anesthetic ether is easily oxidized and decomposed into aldehydes and toxic peroxides under the action of sunlight, air and humidity. The Pharmacopoeia stipulates that it should be used within 24 hours after unsealing. Under the influence of temperature, light and other factors, some drugs can also produce isomerization reactions. Under suitable moisture and temperature conditions, microorganisms can spoil certain drugs.
