Ways to create new medicines. Principles of searching and creating new medicines

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COURSE WORK

on the topic: “Creation of drugs”

Introduction

1. A little history

2. Sources of pharmaceuticals

3. Creation of medicines

4. Classification of medicinal substances

5. Characteristics of medicinal substances

Conclusion

Bibliography

Introduction

Chemistry has invaded human life since ancient times and continues to provide him with diverse assistance even now. Organic chemistry is especially important, considering organic compounds - saturated, unsaturated cyclic, aromatic and heterocyclic. Thus, on the basis of unsaturated compounds, important types of plastics, chemical fibers, synthetic rubbers, compounds with low molecular weight - ethyl alcohol, acetic acid, glycerin, acetone and others are obtained, many of which are used in medicine.

Nowadays, chemists synthesize a large number of drugs. According to international statistics, chemists must synthesize and subject to rigorous testing from 5 to 10 thousand chemical compounds in order to select one drug that is effective against a particular disease.

Even M.V. Lomonosov said that “a physician cannot be perfect without a good knowledge of chemistry.” He wrote about the importance of chemistry for medicine: “Chemistry alone can hope to correct the shortcomings of medical science.”

Medicinal substances have been known since very ancient times. For example, in Ancient Rus', male fern, poppy and other plants were used as medicine. And until now, 25-30% of various decoctions, tinctures and extracts of plant and animal organisms are used as medicines.

Recently, biology, medical science and practice are increasingly using the achievements of modern chemistry. A huge number of medicinal compounds are supplied by chemists, and new advances have been made in the field of drug chemistry in recent years. Medicine is being enriched with an increasing number of new drugs, more advanced methods of their analysis are being introduced, which make it possible to accurately determine the quality (authenticity) of drugs, the content of acceptable and unacceptable impurities in them.

Each country has legislation on pharmaceuticals, published in a separate book called a pharmacopoeia. The Pharmacopoeia is a collection of national standards and regulations that regulate the quality of medicines. The standards and mandatory norms set out in the pharmacopoeia for medicines, raw materials and preparations are used in the manufacture of dosage forms and are mandatory for the pharmacist, doctor, organizations, institutions that manufacture and use medicines. According to the pharmacopoeia, drugs are analyzed to check their quality.

medicine pharmaceutical drug

1. A little history

The pharmaceutical industry is a relatively young branch of production. Back in the mid-19th century, the production of medicines in the world was concentrated in isolated pharmacies, in which pharmacists prepared drugs according to recipes known only to them, passed down by inheritance. At that time, alternative medicine played a major role.

Pharmaceutical production developed unevenly and depended on a number of circumstances. Thus, the works of Louis Pasteur in the 60s of the 19th century served as the basis for the production of vaccines and serums. The development of industrial synthesis of dyes in Germany in the last quarter of the 19th century led to the production of the drugs phenacetin and antipyrine.

In 1904, the German physician Paul Ehrlich noticed that when certain dyes were introduced into the tissues of experimental animals, these dyes stained bacterial cells better than the animal cells in which these bacteria lived. The conclusion suggested itself: it is possible to find a substance that will “paint over” the bacterium so much that it will die, but at the same time will not touch human tissue. And Ehrlich found a dye that was embedded in trypanosomes that cause sleeping sickness in humans. At the same time for mice. on which the experiment was carried out, the dye was harmless. Ehrlich tested the dye on infected mice; their disease was milder, but still the dye was a weak poison for trypanosomes. Then Ehrlich introduced atoms of arsenic, a powerful poison, into the dye molecule. He hoped that the dye would “drag” all the arsenic into the trypanosome cells, and the mice would get very little of it. And so it happened. By 1909, Ehrlich refined his medicine by synthesizing a substance that selectively affected trypanosomes, but had low toxicity for warm-blooded animals - 3,3"-diamino-4.4"-dihydroxyarsenobenzene. There are two arsenic atoms in its molecule. This is how the chemistry of synthetic drugs began.

Until the 30s of the 20th century, medicinal plants (herbs) occupied the main place in pharmaceutical chemistry. In the mid-30s of the 20th century, the pharmaceutical industry took the path of targeted organic synthesis, which was facilitated by the antibacterial property of the dye - prontosil, discovered by the German biologist G. Domagk (19340), synthesized in 1932. Since 1936, based on this compound, searches for so-called sulfonamide anticoccal drugs.

2. Sources of pharmaceuticals

All medicinal substances can be divided into two large groups: inorganic and organic. Both are obtained from natural raw materials and synthetically.

The raw materials for the production of inorganic preparations are rocks, ores, gases, water from lakes and seas, and chemical waste.

The raw materials for the synthesis of organic drugs are natural gas, oil, coal, shale and wood. Oil and gas are a valuable source of raw materials for the synthesis of hydrocarbons, which are intermediate products in the production of organic substances and medicines. Petroleum jelly, petroleum jelly, and paraffin obtained from petroleum are used in medical practice.

3. Creation of medicines

No matter how many drugs are known, no matter how rich their choice is, there is still a lot to be done in this area. How are new drugs created these days?

First of all, you need to find a biologically active compound that has one or another beneficial effect on the body. There are several principles for such a search.

An empirical approach is very common, which does not require knowledge of either the structure of a substance or the mechanism of its effect on the body. Two directions can be distinguished here. The first is random discoveries. For example, the laxative effect of phenolphthalein (purgen) was accidentally discovered, as well as the hallucinogenic effect of some narcotic substances. Another direction is the so-called “sifting” method, when many chemical compounds are deliberately tested in order to identify a new biologically active drug.

There is also the so-called directed synthesis of medicinal substances. In this case, they operate with an already known medicinal substance and, slightly modifying it, check in experiments with animals how this replacement affects the biological activity of the compound. Sometimes minimal changes in the structure of a substance are enough to sharply enhance or completely remove its biological activity. Example: in the morphine molecule, which has a strong analgesic effect, only one hydrogen atom was replaced with a methyl group and another drug was obtained - codeine. The analgesic effect of codeine is ten times less than that of morphine, but it turned out to be a good cough suppressant. Replaced two hydrogen atoms with methyl in the same morphine - we got thebaine. This substance no longer “works” at all as a pain reliever and does not help with coughing, but causes convulsions.

In very rare cases, the search for drugs based on general theoretical concepts of the mechanism of biochemical processes in health and disease, the analogy of these processes with reactions outside the body, and the factors influencing such reactions is successful.

Often, a natural compound is taken as the basis for a medicinal substance and a new drug is obtained by making small changes in the structure of the molecule. This is exactly how, by chemical modification of natural penicillin, many of its semi-synthetic analogues, for example oxacillin, were obtained.

After a biologically active compound has been selected and its formula and structure have been determined, it is necessary to investigate whether this substance is toxic or whether it has side effects on the body. Biologists and doctors are finding out. And then again it’s the turn of the chemists - they must propose the most optimal way in which this substance will be produced in industry. Sometimes the synthesis of a new compound is so difficult and so expensive that its use as a drug is not possible at this stage.

4. Classification of medicinal substances

Medicinal substances are divided into two classifications: pharmacological and chemical.

The first classification is more convenient for medical practice. According to this classification, medicinal substances are divided into groups depending on their effect on systems and organs. For example: sleeping pills and sedatives (sedatives); cardiovascular; analgesic (painkillers), antipyretic and anti-inflammatory; antimicrobial (antibiotics, sulfonamide drugs, etc.); local anesthetics; antiseptic; diuretic; hormones; vitamins, etc.

Chemical classification is based on the chemical structure and properties of substances, and each chemical group may contain substances with different physiological activities. According to this classification, medicinal substances are divided into inorganic and organic. Inorganic substances are considered according to groups of elements of D. I. Mendeleev’s periodic table and the main classes of inorganic substances (oxides, acids, bases, salts). Organic compounds are divided into derivatives of the aliphatic, alicyclic, aromatic and heterocyclic series. Chemical classification is more convenient for chemists working in the field of synthesis of medicinal substances.

5. HarakTesting of medicinal substances

Local anesthetics

Synthetic anesthetic (painkiller) substances obtained by simplifying the structure of cocaine are of great practical importance. These include anesthesin, novocaine, dicaine. Cocaine is a natural alkaloid obtained from the leaves of the coca plant, native to South America. Cocaine has anesthetic properties, but is addictive, which makes it difficult to use. In the cocaine molecule, the anesthesia group is the methylalkylaminopropyl ester of benzoic acid. Later it was found that para-aminobenzoic acid esters have the best effect. Such compounds include anesthesin and novocaine. They are less toxic than cocaine and do not cause side effects. Novocaine is 10 times less active than cocaine, but approximately 10 times less toxic.

For centuries, the dominant place in the arsenal of painkillers has been occupied by morphine, the main active component of opium. The morphine content in opium averages 10%.

Morphine dissolves easily in caustic alkalis, but worse in ammonia and carbonic alkalis. Here is the most generally accepted formula for morphine.

It was used back in those times to which the first written sources that reached us date back to.

The main disadvantages of morphine are the occurrence of a painful addiction to it and respiratory depression. Well-known morphine derivatives are codeine and heroin.

Sleeping pills

Substances that induce sleep belong to different classes, but the most famous are derivatives of barbituric acid (it is believed that the scientist who obtained this compound named it after his friend Barbara). Barbituric acid is formed by the reaction of urea with malonic acid. Its derivatives are called barbiturates, for example phenobarbital (Luminal), barbital (Veronal), etc.

All barbiturates depress the nervous system. Amytal has a wide range of sedative effects. In some patients, this drug relieves inhibitions associated with painful, deeply buried memories. For some time it was even believed that it could be used as a truth serum.

The human body becomes accustomed to barbiturates through frequent use as sedatives and sleep aids, so people using barbiturates find that they need increasingly larger doses. Self-medication with these drugs can cause significant harm to health.

The combination of barbiturates and alcohol can have tragic consequences. Their combined effect on the nervous system is much stronger than the effect of even higher doses separately.

Diphenhydramine is widely used as a sedative and hypnotic. It is not a barbiturate, but belongs to ethers. The starting product for the production of diphenhydramine in the medical industry is benzaldehyde, which is converted into benzhydrol by the Grignard reaction. When the latter reacts with separately obtained dimethylaminoethyl chloride hydrochloride, diphenhydramine is obtained:

Diphenhydramine is an active antihistamine. It has a local anesthetic effect, but is mainly used in the treatment of allergic diseases.

Psychotropic drugs

All psychotropic substances according to their pharmacological action can be divided into two groups:

1) Tranquilizers are substances that have sedative properties. In turn, tranquilizers are divided into two subgroups:

Major tranquilizers (neuroleptics). These include phenothiazine derivatives. Aminazine is used as an effective remedy in the treatment of mental patients, suppressing their feelings of fear, anxiety, and absent-mindedness.

Minor tranquilizers (ataractics). These include derivatives of propanediol (meprotane, andaxin), diphenylmethane (atarax, amizil) and substances of different chemical nature (diazepam, elenium, phenazepam, seduxen, etc.). Seduxen and Elenium are used for neuroses, to relieve anxiety. Although their toxicity is low, side effects are observed (drowsiness, dizziness, addiction to drugs). They should not be used without a doctor's prescription.

2) Stimulants - substances that have an antidepressant effect (fluoroazicin, indopan, transamine, etc.)

Analgesic, antipyretic and anti-inflammatory drugs

A large group of drugs are derivatives of salicylic acid (ortho-hydroxybenzoic). It can be considered as benzoic acid containing a hydroxyl group in the ortho position, or as a phenol containing a carboxyl group in the ortho position.

Salicylic acid is obtained from phenol, which, under the action of sodium hydroxide solution, turns into sodium phenolate. After evaporation of the solution, carbon dioxide is passed into the dry phenolate under pressure and heating. First, phenyl sodium carbonate is formed, in which, when the temperature rises to 135-140? intramolecular movement occurs and sodium salicylate is formed. The latter is decomposed with sulfuric acid, and technical salicylic acid precipitates:

C Salicylic acid is a strong disinfectant. Its sodium salt is used as an analgesic, anti-inflammatory, antipyretic and in the treatment of rheumatism.

Of the derivatives of salicylic acid, the most famous is its ester - acetylsalicylic acid, or aspirin. Aspirin is an artificially created molecule and does not occur in nature.

When introduced into the body, acetylsalicylic acid does not change in the stomach, but in the intestine, under the influence of an alkaline environment, it disintegrates, forming anions of two acids - salicylic and acetic. Anions enter the blood and are transported by it to various tissues. The active principle responsible for the physiological effect of aspirin is salicylation.

Acetylsalicylic acid has antirheumatic, anti-inflammatory, antipyretic and analgesic effects. It also removes uric acid from the body, and the deposition of its salts in tissues (gout) causes severe pain. When taking aspirin, gastrointestinal bleeding and sometimes allergies may occur.

Medicinal substances were obtained by reacting the carboxyl group of salicylic acid with various reagents. For example, when ammonia acts on salicylic acid methyl ester, the methyl alcohol residue is replaced by an amino group and salicylic acid amide is formed - salicylamide. It is used as an antirheumatic, anti-inflammatory, antipyretic agent. Unlike acetylsalicylic acid, salicylamide undergoes hydrolysis in the body with great difficulty.

Salol - an ester of salicylic acid with phenol (phenyl salicylate) has disinfectant, antiseptic properties and is used for intestinal diseases.

Replacement of one of the hydrogen atoms in the benzene ring of salicylic acid with an amino group leads to para-aminosalicylic acid (PAS), which is used as an anti-tuberculosis drug.

Common antipyretic and analgesic drugs are phenylmethylpyrazolone derivatives - amidopyrine and analgin. Analgin has low toxicity and good therapeutic properties.

Antimicrobial agents

In the 30s of the 20th century, sulfonamide drugs (the name comes from sulfanilic acid amide) became widespread. First of all, it is para-aminobenzenesulfamide, or simply sulfanilamide (white streptocide). This is a fairly simple compound - a benzene derivative with two substituents - a sulfamide group and an amino group. It has high antimicrobial activity. About 10,000 of its different structural modifications have been synthesized, but only about 30 of its derivatives have found practical use in medicine.

A significant disadvantage of white streptocide is its low solubility in water. But its sodium salt was obtained - streptocide, soluble in water and used for injection.

Sulgin is a sulfonamide in which one hydrogen atom of the sulfamide group is replaced by a guanidine residue. It is used to treat intestinal infectious diseases (dysentery).

With the advent of antibiotics, the rapid development of sulfonamide chemistry subsided, but antibiotics failed to completely displace sulfonamides.

The mechanism of action of sulfonamides is known.

For the life of many microorganisms, para-aminobenzoic acid is necessary.

It is part of the vitamin folic acid, which is a growth factor for bacteria. Without folic acid, bacteria cannot reproduce. In its structure and size, sulfanilamide is close to para-aminobenzoic acid, which allows its molecule to take the place of the latter in folic acid. When we introduce sulfanilamide into an organism infected with bacteria, the bacteria, “without understanding,” begin to synthesize folic acid, using streptocide instead of aminobenzoic acid. As a result, “false” folic acid is synthesized, which cannot work as a growth factor and the development of bacteria is suspended. This is how sulfonamides “deceive” microbes.

Antibiotics

Typically, an antibiotic is a substance synthesized by one microorganism and capable of preventing the development of another microorganism. The word “antibiotic” consists of two words: from the Greek. anti - against and Greek. bios - life, that is, a substance that acts against the life of microbes.

In 1929, an accident allowed the English bacteriologist Alexander Fleming to observe the antimicrobial activity of penicillin for the first time. Staphylococcus cultures that were grown in a nutrient medium were accidentally infected with green mold. Fleming noticed that the staphylococcal bacilli found adjacent to the mold were being destroyed. It was later determined that the mold belonged to the species Penicillium notatum.

In 1940, it was possible to isolate the chemical compound that the fungus produced. It was called penicillin. The most studied penicillins have the following structure:

In 1941, penicillin was tested on humans as a drug for the treatment of diseases caused by staphylococci, streptococci, pneumococci and other microorganisms.

Currently, about 2000 antibiotics have been described, but only about 3% of them find practical use, the rest turned out to be toxic. Antibiotics have very high biological activity. They belong to different classes of compounds with small molecular weight.

Antibiotics differ in their chemical structure and mechanism of action on harmful microorganisms. For example, it is known that penicillin prevents bacteria from producing substances from which they build their cell walls.

A damaged or missing cell wall can cause the bacterial cell to rupture and release its contents into the surrounding area. This may also allow antibodies to penetrate the bacteria and destroy it. Penicillin is effective only against gram-positive bacteria. Streptomycin is effective against both gram-positive and gram-negative bacteria. It prevents bacteria from synthesizing special proteins, thus disrupting their life cycle. Streptomycin, instead of RNA, wedges into the ribosome, and all the time confuses the process of reading information with mRNA. A significant disadvantage of streptomycin is that bacteria get used to it extremely quickly; in addition, the drug causes side effects: allergies, dizziness, etc.

Unfortunately, bacteria gradually adapt to antibiotics and therefore microbiologists are constantly faced with the task of creating new antibiotics.

Alkaloids

In 1943, the Swiss chemist A. Hoffmann studied various basic substances isolated from plants - alkaloids (i.e., similar to alkalis). One day, a chemist accidentally took into his mouth a small solution of lysergic acid diethylamide (LSD), isolated from ergot, a fungus that grows on rye. A few minutes later, the researcher showed signs of schizophrenia - hallucinations began, consciousness became clouded, and speech became incoherent. “I felt like I was floating somewhere outside my body,” the chemist later described his condition. “So I decided that I was dead.” So Hoffmann realized that he had discovered a powerful drug, a hallucinogen. It turned out that 0.005 mg of LSD is enough to enter the human brain to cause hallucinations. Many alkaloids belong to poisons and drugs. Since 1806, morphine, isolated from the juice of poppy heads, has been known. This is a good pain reliever, but with prolonged use of morphine, a person develops an addiction to it, and the body requires increasingly larger doses of the drug. The ester of morphine and acetic acid - heroin - has the same effect.

Alkaloids are a very broad class of organic compounds that have very different effects on the human body. Among them are the strongest poisons (strychnine, brucine, nicotine) and useful drugs (pilocarpine - a drug for the treatment of glaucoma, atropine - a drug for dilating pupils, quinine - a drug for the treatment of malaria). Alkaloids also include widely used stimulants - caffeine, theobromine, theophylline. Caffeine is found in coffee beans (0.7 - 2.5%) and tea (1.3 - 3.5%). It determines the tonic effect of tea and coffee. Theobromine is extracted from the husk of cocoa seeds; in small quantities it accompanies caffeine in tea; theophylline is found in tea leaves and coffee beans.

Interestingly, some alkaloids are antidotes to their counterparts. Thus, in 1952, the alkaloid reserpine was isolated from an Indian plant, which makes it possible to treat not only people poisoned by LSD or other hallucinogens, but also patients suffering from schizophrenia.

Conclusion

Modern human society lives and continues to develop, actively using the achievements of science and technology, and it is almost unthinkable to stop on this path or go back, refusing to use the knowledge about the world around us that humanity already possesses.

Currently, there are many scientific centers in the world conducting various chemical and biological research. The leading countries in this area are the USA, European countries: England, France, Germany, Sweden, Denmark, Russia, etc. In our country there are many scientific centers located in Moscow and the Moscow region (Pushchino, Obninsk), St. Petersburg, Novosibirsk, Krasnoyarsk , Vladivostok... Many research institutes of the Russian Academy of Sciences, the Russian Academy of Medical Sciences, the Ministry of Health and Medical Industry continue scientific research.

The mechanisms of transformation of chemical substances in organisms are constantly being studied, and based on the knowledge gained, an ongoing search for medicinal substances is being conducted. A large number of different medicinal substances are currently obtained either biotechnologically (interferon, insulin, antibiotics, medicinal vaccines, etc.), using microorganisms (many of which are the product of genetic engineering), or through chemical synthesis, which has become almost traditional, or using physics. chemical methods of isolation from natural raw materials (parts of plants and animals).

A large number of chemicals are used to make a wide variety of prostheses. Prosthetics of jaws, teeth, kneecaps, and limb joints are produced from various chemical materials, which are successfully used in reconstructive surgery to replace bones, ribs, etc. One of the biological tasks of chemistry is the search for new materials that can replace living tissue needed for prosthetics. Chemistry has given doctors hundreds of different options for new materials.

In addition to many medications, in everyday life people encounter the achievements of physical and chemical biology in various areas of their professional activities and in everyday life. New food products appear or technologies for preserving already known products are improved. New cosmetic preparations are being produced that allow a person to be healthy and beautiful, protecting him from the adverse effects of the environment. In technology, various bioadditives are used for many organic synthesis products. In agriculture, substances are used that can increase yields (growth stimulants, herbicides, etc.) or repel pests (pheromones, insect hormones), cure diseases of plants and animals, and many others...

All of the above successes were achieved using the knowledge and methods of modern chemistry. The introduction of chemical products into medicine opens up endless possibilities for overcoming a number of diseases, primarily viral and cardiovascular.

In modern biology and medicine, chemistry plays one of the leading roles, and the importance of chemical science will only grow every year.

Listlliterature

1. A.M. Radetzky. Organic chemistry and medicine.//Chemistry at school (1995)

2. K.A. Makarov. Chemistry and medicine. M.: Education, 1981

3. A.E. Braunstein. At the intersection of chemistry and biology. M.: Nauka, 1987

4. Biology and medicine. //Sat. works M.: Nauka, 1985

5. M.D. Mashkovsky. Medicines: reference book. M.: Medicine, 1995

6. P.L. Senov. Pharmaceutical chemistry. - Publishing house "Medicine". Moscow, 1971.

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Introduction

Despite the achievements of modern anesthesia, the search continues for less dangerous drugs for anesthesia, the development of various options for multicomponent selective anesthesia, which can significantly reduce their toxicity and negative side effects.

The creation of new medicinal substances includes 6 stages:

Creation of a medicinal substance using computer modeling.

Laboratory synthesis.

Bioscreening and preclinical testing.

Clinical trials.

Industrial production.

Recently, computer modeling has increasingly entered into the technology of creating new synthetic medicinal substances. Pre-conducted computer screening saves time, materials and effort during analogue drug discovery. The local anesthetic drug Dicain was chosen as the object of study, which has a higher level of toxicity among its analogues, but is not replaceable in ophthalmic and otorhinolaryngological practice. To reduce and maintain or enhance the local anesthetic effect, compositions are being developed that additionally contain antihistamines, amino blockers, and adrenaline.

Dicaine belongs to the class of esters P-aminobenzoic acid (β-dimethylaminoethyl ester P-butylaminobenzoic acid hydrochloride). The C -N distance in the 2-aminoethanol group determines the two-point contact of the dicaine molecule with the receptor through dipole-dipole and ionic interactions.

The basis for modifying the dicaine molecule to create new anesthetics is the principle of introducing chemical groups and fragments into the existing anesthesiophore, which enhance the interaction of the substance with the bioreceptor, reduce toxicity and produce metabolites with positive pharmacological effects.

Based on this, we have proposed the following options for new molecular structures:

An “ennobling” carboxyl group was introduced into the benzene ring, and the dimethylamino group was replaced by a more pharmacoactive diethylamino group.

Aliphatic n-butyl radical is replaced by an adrenaline fragment.

Aromatic base P-aminobenzoic acid is replaced by nicotinic acid.

The benzene ring is replaced by a piperidine ring, which is characteristic of the effective anesthetic promedol.

The work carried out computer modeling of all these structures using the HyperChem program. At subsequent stages of computer design, the biological activity of new anesthetics was studied using the PASS program.

1. Literature review

1.1 Medicines

Despite the huge arsenal of available drugs, the problem of finding new highly effective drugs remains relevant. This is due to the lack or insufficient effectiveness of drugs to treat certain diseases; the presence of side effects of certain medications; restrictions on the shelf life of medicines; long shelf life of drugs or their dosage forms.

The creation of each new original medicinal substance is the result of the development of fundamental knowledge and achievements of medical, biological, chemical and other sciences, intensive experimental research, and the investment of large material costs. The successes of modern pharmacotherapy were the result of deep theoretical studies of the primary mechanisms of homeostasis, the molecular basis of pathological processes, the discovery and study of physiologically active compounds (hormones, mediators, prostaglandins, etc.). The development of new chemotherapeutic agents has been facilitated by advances in the study of the primary mechanisms of infectious processes and the biochemistry of microorganisms.

A medicinal product is a single-component or complex composition that has preventive and therapeutic effectiveness. A medicinal substance is an individual chemical compound used as a medicine.

Dosage form is the physical state of a drug that is convenient for use.

A medicinal product is a dosed medicinal product in a dosage form adequate for individual use and in optimal design with an annotation about its properties and use.

Currently, each potential drug substance undergoes 3 stages of study: pharmaceutical, pharmacokinetic and pharmacodynamic.

At the pharmaceutical stage, the beneficial effect of the drug substance is determined, after which it is subjected to preclinical study of other indicators. First of all, acute toxicity is determined, i.e. lethal dose for 50% of experimental animals. Subchronic toxicity is then determined under conditions of long-term (several months) administration of the drug in therapeutic doses. At the same time, possible side effects and pathological changes in all body systems are observed: teratogenicity, effects on reproduction and the immune system, embryotoxicity, mutagenicity, carcinogenicity, allergenicity and other harmful side effects. After this stage, the drug can be admitted to clinical trials.

At the second stage - pharmacokinetic - the fate of the drug in the body is studied: the routes of its administration and absorption, distribution in biofluids, penetration through protective barriers, access to the target organ, pathways and speed of biotransformation, routes of excretion from the body (with urine, feces, sweat and breathing).

At the third - pharmacodynamic - stage, problems of recognition of a drug substance (or its metabolites) by targets and their subsequent interaction are studied. Targets can be organs, tissues, cells, cell membranes, enzymes, nucleic acids, regulatory molecules (hormones, vitamins, neurotransmitters, etc.), as well as bioreceptors. The issues of structural and stereospecific complementarity of interacting structures, functional and chemical correspondence of a drug substance or metabolite to its receptor are considered. The interaction between a drug substance and a receptor or acceptor, leading to activation (stimulation) or deactivation (inhibition) of the biotarget and accompanied by a response from the body as a whole, is mainly ensured by weak bonds - hydrogen, electrostatic, van der Waals, hydrophobic.

1.2 Creation and research of new medicines. Main search direction

The creation of new medicinal substances turned out to be possible on the basis of advances in the field of organic and pharmaceutical chemistry, the use of physicochemical methods, and technological, biotechnological and other studies of synthetic and natural compounds.

The generally accepted foundation for creating a theory of targeted searches for certain groups of drugs is the establishment of connections between pharmacological action and physical characteristics.

Currently, the search for new drugs is carried out in the following main areas.

1. Empirical study of one or another type of pharmacological activity of various substances obtained chemically. This study is based on the “trial and error” method, in which pharmacologists take existing substances and determine, using a set of pharmacological techniques, their belonging to a particular pharmacological group. Then the most active substances are selected from among them and the degree of their pharmacological activity and toxicity is determined in comparison with existing drugs that are used as a standard.

2. The second direction is to select compounds with one specific type of pharmacological activity. This direction is called directed drug discovery.

The advantage of this system is the faster selection of pharmacologically active substances, but the disadvantage is the lack of identification of other, possibly very valuable types of pharmacological activity.

3. The next direction of search is modification of the structures of existing drugs. This route to finding new drugs is now very common. Synthetic chemists replace one radical with another in an existing compound, introduce other chemical elements into the composition of the original molecule, or make other modifications. This route allows you to increase the activity of the drug, make its action more selective, and also reduce the undesirable aspects of the action and its toxicity.

Targeted synthesis of medicinal substances means the search for substances with predetermined pharmacological properties. The synthesis of new structures with putative activity is most often carried out in the class of chemical compounds in which substances have already been found that have a specific effect on a given organ or tissue.

For the basic skeleton of the desired substance, those classes of chemical compounds that include natural substances involved in the performance of body functions can also be selected. Targeted synthesis of pharmacological substances is more difficult to carry out in new chemical classes of compounds due to the lack of necessary initial information about the relationship between pharmacological activity and the structure of the substance. In this case, data on the benefits of the substance or element are required.

Next, various radicals are added to the selected basic skeleton of the substance, which will promote the dissolution of the substance in lipids and water. It is advisable to make the synthesized structure soluble in both water and fats so that it can be absorbed into the blood, pass from it through the blood-tissue barriers into tissues and cells and then come into contact with cell membranes or penetrate through them into the cell and connect with molecules of the nucleus and cytosol.

Targeted synthesis of medicinal substances becomes successful when it is possible to find a structure that, in size, shape, spatial position, electron-proton properties and a number of other physicochemical parameters, will correspond to the living structure to be regulated.

Targeted synthesis of substances pursues not only a practical goal - obtaining new medicinal substances with the desired pharmacological and biological properties, but is also one of the methods for understanding the general and particular patterns of life processes. To build theoretical generalizations, it is necessary to further study all the physicochemical characteristics of the molecule and clarify the decisive changes in its structure that determine the transition from one type of activity to another.

The formulation of combination drugs is one of the most effective ways to find new drugs. The principles on the basis of which multicomponent drugs are formulated can be different and change along with the methodology of pharmacology. Basic principles and rules for the preparation of combined products have been developed.

Most often, combination drugs include medicinal substances that affect the etiology of the disease and the main links in the pathogenesis of the disease. A combination drug usually includes medicinal substances in small or medium doses if there are phenomena of mutual enhancement of action between them (potentiation or summation).

Combined remedies, formulated taking into account these rational principles, are distinguished by the fact that they cause a significant therapeutic effect in the absence or minimum of negative effects. Their last property is due to the introduction of small doses of individual ingredients. A significant advantage of small doses is that they do not disrupt the body’s natural protective or compensatory mechanisms.

Combined preparations are also formulated on the principle of including additional ingredients that eliminate the negative effects of the main substance.

Combined preparations are formulated with the inclusion of various corrective agents that eliminate the undesirable properties of the main medicinal substances (smell, taste, irritation) or regulate the rate of release of the medicinal substance from the dosage form or the rate of its absorption into the blood.

Rational formulation of combined drugs allows one to purposefully increase the pharmacotherapeutic effect and eliminate or reduce possible negative aspects of the effect of drugs on the body.

When combining drugs, the individual components must be compatible with each other in physicochemical, pharmacodynamic and pharmacokinetic terms.

Ways to create new medicines I. Chemical synthesis of drugs; directed synthesis; empirical path. II. Obtaining drugs from medicinal raw materials and isolating individual substances: of animal origin; of plant origin; from minerals. III. Isolation of medicinal substances that are products of the vital activity of microorganisms and fungi. Biotechnology.

Chemical synthesis of drugs directed synthesis Reproduction of nutrients Adrenaline, norepinephrine, γ-aminobutyric acid, hormones, prostaglandins and other physiologically active compounds. Creation of antimetabolites Synthesis of structural analogues of natural metabolites with opposite effects. For example, antibacterial agents sulfonamides are similar in structure to para-aminobenzoic acid, which is necessary for the life of microorganisms, and are its antimetabolites:

Chemical synthesis of drugs directed synthesis Chemical modification of compounds with known activity The main task is to create new drugs that compare favorably with already known ones (more active, less toxic). 1. Based on hydrocortisone produced by the adrenal cortex, many much more active glucocorticoids have been synthesized, which have a lesser effect on water-salt metabolism. 2. Hundreds of synthesized sulfonamides are known, only a few of which have been introduced into medical practice. The study of a series of compounds is aimed at elucidating the relationship between their structure, physicochemical properties and biological activity. The establishment of such patterns allows for more targeted synthesis of new drugs. At the same time, it becomes clear which chemical groups and structural features determine the main effects of the substances.

Chemical modification of compounds with known activity: modification of substances of plant origin Tubocurarine (curare poison) and its synthetic analogues Relax skeletal muscles. What matters is the distance between two cationic centers (N+ - N+).

Chemical synthesis of drugs directed synthesis Study of the structure of the substrate with which the drug interacts. The basis is not the biologically active substance, but the substrate with which it interacts: receptor, enzyme, nucleic acid. The implementation of this approach is based on data on the three-dimensional structure of macromolecules that are the targets of the drug. A modern approach using computer modeling; X-ray diffraction analysis; spectroscopy based on nuclear magnetic resonance; statistical methods; genetic engineering.

Chemical synthesis of drugs; directed synthesis. Synthesis based on the study of chemical transformations of a substance in the body. Prodrugs. 1. Complexes “carrier substance - active substance” Provide directed transport to target cells and selectivity of action. The active substance is released at the site of action under the influence of enzymes. The function of carriers can be performed by proteins, peptides and other molecules. Carriers can facilitate the passage of biological barriers: Ampicillin is poorly absorbed in the intestine (~ 40%). The prodrug bacampicillin is inactive but is 9899% absorbed. In serum, under the influence of esterases, active ampicillin is cleaved.

Chemical synthesis of drugs; directed synthesis. Synthesis based on the study of chemical transformations of a substance in the body. Prodrugs. 2. Bioprecursors They are individual chemical substances that are inactive by themselves. In the body, other substances are formed from them - metabolites, which exhibit biological activity: prontosil - L-DOPA sulfonamide - dopamine

Chemical synthesis of drugs; directed synthesis. Synthesis based on the study of chemical transformations of a substance in the body. Agents affecting biotransformation. Based on knowledge of enzymatic processes that ensure the metabolism of substances, it allows the creation of drugs that change the activity of enzymes. Acetylcholinesterase inhibitors (prozerin) enhance and prolong the action of the natural mediator acetylcholine. Inducers of the synthesis of enzymes involved in the detoxification processes of chemical compounds (phenobarbital).

Chemical synthesis of drugs empirical way Random findings. The decrease in blood sugar levels found with the use of sulfonamides led to the creation of their derivatives with pronounced hypoglycemic properties (butamide). They are widely used for diabetes. The effect of teturam (antabuse), which is used in the production of rubber, was accidentally discovered. Used in the treatment of alcoholism. Screening. Testing chemical compounds for all types of biological activity. A labor-intensive and ineffective way. However, it is inevitable when studying a new class of chemical substances whose properties are difficult to predict based on their structure.

Preparations and individual substances from medicinal raw materials Various extracts, tinctures, and more or less purified preparations are used. For example, laudanum is a tincture of raw opium.

Preparations and individual substances from medicinal raw materials Individual substances: Digoxin - cardiac glycoside from foxglove Atropine - M-anticholinergic agent from belladonna Salicylic acid - anti-inflammatory substance from willow Colchicine - alkaloid of crocus, used in the treatment of gout.

Stages of drug development Preparation of the drug Testing on animals Natural sources Efficacy Selectivity Mechanisms of action Metabolism Safety assessment ~ 2 years Drug substance (active compound) Chemical synthesis ~ 2 years Clinical trials Phase 1 is the medicine safe? Phase 2: Is the medicine effective? Phase 3: Is the drug effective in double-blind conditions? Metabolism Safety assessment ~ 4 years Marketing INTRODUCTION OF MEDICINES 1 year Phase 4 post-marketing surveillance Appearance of Genetics 17 years after approval for use Patent expiration

The development of new medicines is carried out jointly by many branches of science, with the main role played by specialists in the field of chemistry, pharmacology, and pharmacy. The creation of a new drug is a series of successive stages, each of which must meet certain provisions and standards approved by government agencies - the Pharmacopoeial Committee, the Pharmacological Committee, the Department of the Ministry of Health of the Russian Federation for the Introduction of New Medicines.
The process of creating new medicines is carried out in accordance with international standards - GLP (Good Laboratory Practice), GMP (Good Manufacturing Practice - Quality

industrial practice) and GCP (Good Clinical Practice).
A sign of compliance of a new drug being developed with these standards is the official approval of the process of further research - IND (Investigation New Drug).
The production of a new active substance (active substance or complex of substances) proceeds in three main directions.
Chemical synthesis of medicinal substances

• Empirical path: screening, incidental findings;
• Directed synthesis: reproduction of the structure of endogenous substances, chemical modification of known molecules;
• Targeted synthesis (rational design of a chemical compound), based on an understanding of the “chemical structure - pharmacological action” relationship.

The empirical way (from the Greek empeiria - experience) of creating medicinal substances is based on the “trial and error” method, in which pharmacologists take a number of chemical compounds and determine using a set of biological tests (at the molecular, cellular, organ levels and on the whole animal) the presence or their lack of certain pharmacological activity. Thus, the presence of antimicrobial activity is determined on microorganisms; antispasmodic activity - on isolated smooth muscle organs (ex vivo); hypoglycemic activity - by the ability to lower blood sugar levels in test animals (in vivo). Then, among the chemical compounds being studied, the most active ones are selected and the degree of their pharmacological activity and toxicity is compared with existing drugs, which are used as a standard. This method of selecting active substances is called drug screening (from English, screen - to sift out, sort). A number of drugs were introduced into medical practice as a result of accidental discoveries. Thus, the antimicrobial effect of an azo dye with a sulfonamide side chain (red streptocide) was revealed, as a result of which a whole group of chemotherapeutic agents appeared - sulfonamides.
Another way to create medicinal substances is to obtain compounds with a certain type of pharmacological activity. It is called the directed synthesis of medicinal substances. The first stage of such synthesis is the reproduction of substances formed in living organisms. This is how adrenaline, norepinephrine, a number of hormones, prostaglandins, and vitamins were synthesized.
Chemical modification of known molecules makes it possible to create medicinal substances that have a more pronounced pharmacological effect and fewer side effects. Thus, a change in the chemical structure of carbonic anhydrase inhibitors led to the creation of thiazide diuretics, which have a stronger diuretic effect.
The introduction of additional radicals and fluorine into the nalidixic acid molecule made it possible to obtain a new group of antimicrobial agents - fluoroquinolones with an extended spectrum of antimicrobial action.
Targeted synthesis of medicinal substances involves the creation of substances with predetermined pharmacological properties. The synthesis of new structures with putative activity is most often carried out in that class of chemical compounds where substances with a certain direction of action have already been found. An example is the creation of H2-histamine receptor blockers. It was known that histamine is a powerful stimulator of hydrochloric acid secretion in the stomach and that antihistamines (used for allergic reactions) do not eliminate this effect. On this basis, it was concluded that there are subtypes of histami - new receptors that perform different functions, and these receptor subtypes are blocked by substances of different chemical structures. It was hypothesized that modification of the histamine molecule could lead to the creation of selective antagonists of gastric histamine receptors. As a result of the rational design of the histamine molecule, the antiulcer drug cimetidine, the first H2-histamine receptor blocker, appeared in the mid-70s of the 20th century.
Isolation of medicinal substances from tissues and organs of animals, plants and minerals
In this way, medicinal substances or complexes of substances are isolated: hormones; galenic, novogalenic preparations, organopreparations and mineral substances.
Isolation of medicinal substances that are products of the vital activity of fungi and microorganisms using biotechnology methods (cellular and genetic engineering)
Biotechnology deals with the isolation of medicinal substances that are products of the vital activity of fungi and microorganisms.
Biotechnology uses biological systems and biological processes on an industrial scale. Microorganisms, cell cultures, plant and animal tissue cultures are commonly used.
Semi-synthetic antibiotics are obtained using biotechnological methods. Of great interest is the production of human insulin on an industrial scale using genetic engineering. Biotechnological methods have been developed for the production of somatostatin, follicle-stimulating hormone, thyroxine, and steroid hormones.
After obtaining a new active substance and determining its basic pharmacological properties, it undergoes a series of preclinical studies.
Preclinical trials
In addition to studying specific activity, during preclinical testing in animal experiments, the resulting substance is examined for acute and chronic toxicity; its effect on reproductive function is also being studied; the substance is tested for embryotoxicity and teratogenicity; kaizenogenicity; mutagenicity. These studies are conducted on animals in accordance with GLP standards. During these studies, the average effective dose (ED50 - the dose that causes an effect in 50% of animals) and the average lethal dose (BD50 - the dose that causes the death of 50% of animals) are determined.
Clinical trials
Clinical trials are planned and conducted by clinical pharmacologists, clinicians, and statisticians. These tests are carried out on the basis of the GCP system of international regulations. In Russian
Based on the GCP rules, the Federation has developed and applied the industry standard “Rules for Conducting High-Quality Clinical Trials.”
GCP rules are a set of provisions in accordance with which clinical trials are planned and conducted, and their results are analyzed and summarized. When following these rules, the results obtained truly reflect reality, and patients are not exposed to unreasonable risks, their rights and the confidentiality of personal information are respected. In other words, GCP explains how to obtain reliable scientific evidence while protecting the well-being of medical research participants.
Clinical trials are conducted in 4 phases.

1. the clinical trial phase is carried out with the participation of a small number of volunteers (from 4 to 24 people). Each study is carried out in one center and lasts from several days to several weeks.

Typically, phase I studies include pharmacodynamic and pharmacokinetic studies. Phase I trials examine:

• pharmacodynamics and pharmacokinetics of a single dose and multiple doses under different routes of administration;
• bioavailability;
• metabolism of the active substance;
• the influence of age, gender, food, liver and kidney function on the pharmacokinetics and pharmacodynamics of the active substance;
• interaction of the active substance with other drugs.

During phase I, preliminary data on the safety of the drug are obtained and
provide the first description of its pharmacokinetics and pharmacodynamics in humans.

1. The clinical trial phase is intended to evaluate the effectiveness of the active substance (medicinal substance) in patients with a profile disease, as well as to identify negative side effects associated with the use of the drug. Phase II studies are carried out under very strict control and observation on patients in a group of 100-200 people.
2. the clinical trial phase is a multicenter extension study. They are carried out after receiving preliminary results indicating the effectiveness of the drug substance, and their main task is to obtain additional information on the effectiveness and safety of various dosage forms of the drug, which are necessary to assess the overall balance of benefits and risks from its use, as well as to obtain additional information for preparation of medical labeling. A comparison is made with other drugs in this group. These studies usually involve several hundred to several thousand people (average 1000-3000). Recently, the term “mega-studies” has emerged, in which more than 10,000 patients can participate. During phase III, optimal doses and administration regimens are determined, the nature of the most common adverse reactions, clinically significant drug interactions, the influence of age, concomitant conditions, etc. are studied. The research conditions are as close as possible to the real conditions of use of the drug. Such studies are initially conducted using an open method (the doctor and the patient know which drug is being used - new, control or placebo). Further studies are carried out using a single-blind method (the patient does not know which drug is being used - new, control or placebo), double-blind (double-blind) method, in which neither the doctor nor

the patient does not know which drug is being used - a new one, control or placebo, and a triple-blind method, when neither the doctor, nor the patient, nor the organizers and statisticians know the prescribed therapy for a particular patient. This phase is recommended to be carried out in specialized clinical centers.
Data obtained in phase III clinical trials are the basis for creating instructions for the use of the drug and an important factor for official decision-making on its registration and the possibility of medical use.
Bioequivalence studies of drugs
Assessing the bioequivalence of medicinal products is the main type of quality control of reproduced (generic) drugs - medicinal products containing the same medicinal substance in the same dose and dosage form as the original medicinal product.
Two drugs (in the same dosage form) are bioequivalent if they provide the same bioavailability of the drug substance and the same rate of achievement of the maximum concentration of the substance in the blood.
Bioequivalence studies allow one to make informed conclusions about the quality of the drugs being compared using a relatively smaller amount of primary information and in a shorter period of time than during clinical trials. In the Russian Federation, bioequivalence studies are regulated by “Methodological recommendations for conducting high-quality clinical studies of bioequivalence of medicinal products.”
Registration of a medicinal product
The data obtained during the research is formalized in the form of appropriate documents, which are sent to government organizations that register the drug and give permission for its medical use. In the Russian Federation, registration of medicinal products is carried out by the Ministry of Health of the Russian Federation.
Post-marketing testing
Registration of a drug does not mean that research into its pharmacological properties has been stopped. There is phase IV clinical trials, which is called “post-marketing studies,” i.e. Phase IV clinical trials are carried out after the start of drug sales in order to obtain more detailed information about the safety and effectiveness of the drug in various dosage forms and doses, with long-term use in various groups of patients, which allows for a more complete assessment of the strategy for using the drug and identifying long-term treatment results. The studies involve a large number of patients, which makes it possible to identify previously unknown and rarely encountered adverse effects. Phase IV studies are also aimed at assessing the comparative effectiveness and safety of the drug. The data obtained is compiled in the form of a report, which is sent to the organization that has given permission for the release and use of the drug.
If, after registration of a drug, clinical trials are conducted, the purpose of which is to study new, unregistered properties, indications, methods of use or combinations of medicinal substances, then such clinical trials are considered as tests of a new medicinal product, i.e. are considered early phase studies.

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STATE EDUCATIONAL INSTITUTION

HIGHER PROFESSIONAL EDUCATION

NOVOSIBIRSK STATE MEDICAL UNIVERSITY

FEDERAL HEALTH AGENCY

AND SOCIAL DEVELOPMENT OF THE RUSSIAN FEDERATION

(GOU VPO NSMU ROSZDRAVA)

Department of Pharmaceutical Chemistry

TOURSOVMY JOB

in pharmaceutical chemistry

on the topic: “Creation and testing of new drugs”

Completed by: 4th year correspondence student

departments of the Faculty of Pharmacy

(shortened form of training based on VChO)

Kundenko Diana Alexandrovna

Checked by: Pashkova L.V.

Novosibirsk 2012

1. Stages of the process of creating a new drug. Stability and shelf life of medicines

2. Clinical trials of medicinal products (GCP). GCP Stages

3. Quantitative analysis of mixtures without preliminary separation of components by physical and chemical methods

4. Quality control system in chemical and pharmaceutical plants and factories

5. Main tasks and features of biopharmaceutical analysis

6. Types of state standards. Requirements of general standards for dosage forms

7. Hydrochloric acid: physical properties, authenticity, quantitative determination, application, storage

8. Oxygen: physical properties, authenticity, quality, quantification, application, storage

9. Bismuth nitrate basic: physical properties, authenticity testing, quantitative determination, application, storage

10. Preparations of magnesium compounds used in medical practice: physical properties, authenticity, quantitative determination, use, storage

11. Preparations of iron and its compounds: physical properties, authenticity, quantitative determination, application, storage

12. Pharmacopoeial radioactive drugs: authenticity, establishment of radiochemical composition, specific activity

1. Stages of the process of creating a new drug. Stability and shelf life of medicines

The creation of medicines is a long process, including several main stages - from forecasting to sale in pharmacies.

The creation of a new drug is a series of successive stages, each of which must meet certain provisions and standards approved by government agencies, the Pharmacopoeial Committee, the Pharmacological Committee, and the Department of the Ministry of Health of the Russian Federation for the Introduction of New Medicines.

The development of a new drug includes the following stages:

1) The idea of ​​​​creating a new drug. It usually arises as a result of the joint work of scientists of two specialties: pharmacologists and synthetic chemists. Already at this stage, a preliminary selection of synthesized compounds is carried out, which, according to experts, may be potentially biologically active substances.

2) Synthesis of pre-selected structures. At this stage, selection is also carried out, as a result of which substances, etc., are not subjected to further research.

3) Pharmacological screening and preclinical testing. The main stage, during which unpromising substances synthesized at the previous stage are eliminated.

4) Clinical testing. It is performed only for promising biologically active substances that have passed all stages of pharmacological screening.

5) Development of technology for the production of a new drug and a more rational dosage form.

6) Preparation of regulatory documentation, including methods for quality control of both the drug itself and its dosage form.

7) Introduction of drugs into industrial production and testing of all stages of production in the factory.

The production of a new active substance (active substance or complex of substances) proceeds in three main directions.

Empirical path: screening, incidental findings;

Directed synthesis: reproduction of the structure of endogenous substances, chemical modification of known molecules;

Targeted synthesis (rational design of a chemical compound), based on an understanding of the “chemical structure-pharmacological action” relationship.

The empirical way (from the Greek empeiria - experience) of creating medicinal substances is based on the “trial and error” method, in which pharmacologists take a number of chemical compounds and determine using a set of biological tests (at the molecular, cellular, organ levels and on the whole animal) the presence or their lack of certain pharmacological activity. Thus, the presence of antimicrobial activity is determined on microorganisms; antispasmodic activity - on isolated smooth muscle organs (ex vivo); hypoglycemic activity based on the ability to lower blood sugar levels in test animals (in vivo). Then, among the chemical compounds being studied, the most active ones are selected and the degree of their pharmacological activity and toxicity is compared with existing drugs that are used as a standard. This method of selecting active substances is called drug screening (from the English screen - sift out, sort). A number of drugs were introduced into medical practice as a result of accidental discoveries. Thus, the antimicrobial effect of an azo dye with a sulfonamide side chain (red streptocide) was revealed, as a result of which a whole group of chemotherapeutic agents, sulfonamides, appeared.

Another way to create medicinal substances is to obtain compounds with a certain type of pharmacological activity. It is called the directed synthesis of medicinal substances.

The first stage of such synthesis is the reproduction of substances formed in living organisms. This is how adrenaline, norepinephrine, a number of hormones, prostaglandins, and vitamins were synthesized.

Chemical modification of known molecules makes it possible to create medicinal substances that have a more pronounced pharmacological effect and fewer side effects. Thus, a change in the chemical structure of carbonic anhydrase inhibitors led to the creation of thiazide diuretics, which have a stronger diuretic effect.

The introduction of additional radicals and fluorine into the nalidixic acid molecule made it possible to obtain a new group of antimicrobial agents, fluoroquinolones, with an extended spectrum of antimicrobial action.

Targeted synthesis of medicinal substances involves the creation of substances with predetermined pharmacological properties. The synthesis of new structures with putative activity is most often carried out in that class of chemical compounds where substances with a certain direction of action have already been found. An example is the creation of H2 histamine receptor blockers. It was known that histamine is a powerful stimulator of hydrochloric acid secretion in the stomach and that antihistamines (used for allergic reactions) do not eliminate this effect. On this basis, it was concluded that there are subtypes of histamine receptors that perform different functions, and these receptor subtypes are blocked by substances of different chemical structures. It was hypothesized that modification of the histamine molecule could lead to the creation of selective antagonists of gastric histamine receptors. As a result of the rational design of the histamine molecule, the antiulcer drug cimetidine, the first H2 histamine receptor blocker, appeared in the mid-70s of the 20th century. Isolation of medicinal substances from tissues and organs of animals, plants and minerals

In this way, medicinal substances or complexes of substances are isolated: hormones; galenic, novogalenic preparations, organopreparations and mineral substances. Isolation of medicinal substances that are products of the vital activity of fungi and microorganisms using biotechnology methods (cellular and genetic engineering). Biotechnology deals with the isolation of medicinal substances that are products of the vital activity of fungi and microorganisms.

Biotechnology uses biological systems and biological processes on an industrial scale. Microorganisms, cell cultures, plant and animal tissue cultures are commonly used.

Semi-synthetic antibiotics are obtained using biotechnological methods. Of great interest is the production of human insulin on an industrial scale using genetic engineering. Biotechnological methods have been developed for the production of somatostatin, follicle-stimulating hormone, thyroxine, and steroid hormones. After obtaining a new active substance and determining its basic pharmacological properties, it undergoes a series of preclinical studies.

Different drugs have different expiration dates. The shelf life is the period during which the medicinal product must fully meet all the requirements of the relevant State quality standard. The stability (stability) of a medicinal substance (DS) and its quality are closely related. The criterion for stability is the preservation of drug quality. A decrease in the quantitative content of a pharmacologically active substance in a drug confirms its instability. This process is characterized by a drug decomposition rate constant. A decrease in quantitative content should not be accompanied by the formation of toxic products or changes in the physicochemical properties of the drug. As a rule, a decrease in the amount of drugs by 10% should not occur within 3-4 years in finished dosage forms and within 3 months in drugs prepared in a pharmacy.

The shelf life of drugs is understood as the period of time during which they must fully retain their therapeutic activity, harmlessness and, in terms of qualitative and quantitative characteristics, comply with the requirements of the State Fund or the Federal Pharmacopoeia, in accordance with which they were released and stored under the conditions provided for in these articles.

After the expiration date, the drug cannot be used without re-control of quality and a corresponding change in the established expiration date.

Processes that occur during storage of drugs can lead to changes in their chemical composition or physical properties (formation of sediment, change in color or state of aggregation). These processes lead to a gradual loss of pharmacological activity or to the formation of impurities that change the direction of the pharmacological action.

The shelf life of drugs depends on the physical, chemical and biological processes occurring in them. These processes are greatly influenced by temperature, humidity, light, pH, air composition and other factors.

The physical processes that occur during drug storage include: absorption and loss of water; change in phase state, for example melting, evaporation or sublimation, delamination, enlargement of particles of the dispersed phase, etc. Thus, during storage of highly volatile substances (ammonia solution, bromine camphor, iodine, iodoform, essential oils), the content of drugs in the dosage form may change.

Chemical processes occur in the form of reactions of hydrolysis, oxidation-reduction, racemization, and the formation of high-molecular compounds. Biological processes cause changes in drugs under the influence of the vital activity of microorganisms, which leads to a decrease in the stability of drugs and human infection.

Medicines are most often contaminated by saprophytes, which are widespread in the environment. Saprophytes are capable of decomposing organic substances: proteins, lipids, carbohydrates. Yeast and filamentous fungi destroy alkaloids, antipyrine, glycosides, glucose, and various vitamins.

The shelf life of a drug can be sharply reduced due to poor quality packaging. For example, when storing injection solutions in bottles or ampoules made of low-quality glass, sodium and potassium silicate transfer from the glass into the solution. This leads to an increase in the pH value of the medium and the formation of so-called “spangles” (particles of broken glass). When pH increases, salts of alkaloids and synthetic nitrogen-containing bases decompose with a decrease or loss of therapeutic effect and the formation of toxic products. Alkaline solutions catalyze the oxidation of ascorbic acid, aminazine, ergotal, vikasol, vitamins, antibiotics, and glycosides. In addition, the alkalinity of glass also promotes the development of microflora.

The shelf life of drugs can be increased by stabilization.

Two methods of drug stabilization are used - physical and chemical.

Physical stabilization methods are usually based on protecting medicinal substances from adverse environmental influences. In recent years, a number of physical methods have been proposed to increase the stability of drugs during their preparation and storage. For example, freeze drying of thermolabile substances is used. Thus, an aqueous solution of benzylpenicillin retains its activity for 1 - 2 days, while the dehydrated drug is active for 2 - 3 years. Ampulation of solutions can be carried out in a flow of inert gases. It is possible to apply protective coatings to solid heterogeneous systems (tablets, dragees, granules), as well as microencapsulation.

However, physical stabilization methods are not always effective. Therefore, chemical stabilization methods are more often used, based on the introduction of special auxiliary substances - stabilizers - into drugs. Stabilizers ensure the stability of the physicochemical, microbiological properties, and biological activity of drugs over a certain period of storage. Chemical stabilization is of particular importance for drugs subjected to various types of sterilization, especially thermal. Thus, stabilization of drugs is a complex problem, including the study of the resistance of drugs in the form of true solutions or dispersed systems to chemical transformations and microbial contamination.

2. Clinical trials of medicinal products (GCP). GCP Stages

The process of creating new medicines is carried out in accordance with the international standards of GLP (Good Laboratory Practice), GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice).

Clinical drug trials involve the systematic study of an investigational drug in humans to test its therapeutic effect or detect an adverse reaction, and the study of absorption, distribution, metabolism and excretion from the body to determine its effectiveness and safety.

Clinical trials of a drug are a necessary stage in the development of any new drug, or the expansion of indications for the use of a drug already known to doctors. At the initial stages of drug development, chemical, physical, biological, microbiological, pharmacological, toxicological and other studies are carried out on tissues (in vitro) or on laboratory animals. These are so-called preclinical studies, the purpose of which is to obtain scientific estimates and evidence of the effectiveness and safety of drugs. However, these studies cannot provide reliable information about how the drugs being studied will act in humans, since the organism of laboratory animals differs from humans both in pharmacokinetic characteristics and in the response of organs and systems to drugs. Therefore, clinical trials of drugs in humans are necessary.

Clinical study (test) of a medicinal product - is a systemic study of a drug through its use in humans (patient or healthy volunteer) in order to assess its safety and effectiveness, as well as identify or confirm its clinical, pharmacological, pharmacodynamic properties, assess absorption, distribution, metabolism, excretion and interaction with other drugs means. The decision to initiate a clinical trial is made by the customer, who is responsible for organizing, monitoring and financing the trial. Responsibility for the practical conduct of the research rests with the researcher. As a rule, the sponsor is a pharmaceutical company that develops drugs, but a researcher can also act as a sponsor if the study was initiated on his initiative and he bears full responsibility for its conduct.

Clinical trials must be conducted in accordance with the fundamental ethical principles of the Declaration of Helsinki, GСP (Good Clinical Practice) and applicable regulatory requirements. Before the start of a clinical trial, an assessment must be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. The principle of priority of the rights, safety and health of the subject over the interests of science and society is put at the forefront. The subject can be included in the study only on the basis of voluntary informed consent (IS), obtained after a detailed review of the study materials. Patients (volunteers) participating in testing a new drug must receive information about the essence and possible consequences of the tests, the expected effectiveness of the drug, the degree of risk, enter into a life and health insurance agreement in the manner prescribed by law, and during the tests be under constant supervision of qualified personnel. In the event of a threat to the health or life of the patient, as well as at the request of the patient or his legal representative, the head of the clinical trial is obliged to suspend the trial. In addition, clinical trials are suspended if a drug is unavailable or insufficiently effective, or if ethical standards are violated.

The first stage of clinical trials of the drug is carried out on 30 - 50 volunteers. The next stage is expanded trials on the basis of 2 - 5 clinics involving a large number (several thousand) of patients. At the same time, individual patient cards are filled out with a detailed description of the results of various studies - blood tests, urine tests, ultrasound, etc.

Each drug undergoes 4 phases (stages) of clinical trials.

Phase I. First experience of using a new active substance in humans. Most often, studies begin with volunteers (healthy adult men). The main goal of the research is to decide whether to continue working on a new drug and, if possible, to establish the doses that will be used in patients during phase II clinical trials. During this phase, researchers obtain preliminary data on the safety of the new drug and describe its pharmacokinetics and pharmacodynamics in humans for the first time. Sometimes it is impossible to conduct phase I studies in healthy volunteers due to the toxicity of this drug (treatment of cancer, AIDS). In this case, non-therapeutic studies are carried out with the participation of patients with this pathology in specialized institutions.

Phase II. This is usually the first experience of use in patients with the disease for which the drug is intended to be used. The second phase is divided into IIa and IIb. Phase IIa are therapeutic pilot studies because the results obtained from them provide optimal planning for subsequent studies. Phase IIb studies are larger studies in patients with the disease that is the primary indication for the new drug. The main goal is to prove the effectiveness and safety of the drug. The results of these studies (pivotal trial) serve as the basis for planning phase III studies.

Phase III. Multicentre trials involving large (and, if possible, diverse) patient groups (average 1000-3000 people). The main goal is to obtain additional data on the safety and effectiveness of various forms of the drug, the nature of the most common adverse reactions, etc. Most often, clinical studies of this phase are double-blind, controlled, randomized, and the research conditions are as close as possible to normal real routine medical practice. Data obtained in phase III clinical trials are the basis for creating instructions for the use of the drug and for deciding on its registration by the Pharmacological Committee. A recommendation for clinical use in medical practice is considered justified if the new drug:

More effective than known drugs of similar action;

It is better tolerated than known drugs (with the same effectiveness);

Effective in cases where treatment with known drugs is unsuccessful;

It is more economically beneficial, has a simpler treatment method or a more convenient dosage form;

In combination therapy, it increases the effectiveness of existing drugs without increasing their toxicity.

Phase IV. Studies are conducted after the drug is marketed in order to obtain more detailed information about long-term use in various patient groups and with various risk factors, etc. and thus more fully evaluate the drug strategy. The study involves a large number of patients, which makes it possible to identify previously unknown and rare adverse events.

If a drug is going to be used for a new indication that has not yet been registered, then additional studies are conducted, starting with phase II. Most often in practice, an open study is carried out, in which the doctor and the patient know the method of treatment (the study drug or a comparison drug).

When testing with a single-blind method, the patient does not know which drug he is taking (it may be a placebo), and when using a double-blind method, neither the patient nor the doctor is aware of this, but only the leader of the trial (in a modern clinical trial of a new drug, four parties: the sponsor of the study (most often this is a pharmaceutical manufacturing company), the monitor - a contract research organization, a doctor-researcher, a patient). In addition, triple-blind studies are possible, when neither the doctor, nor the patient, nor those who organize the study and process its data know the assigned treatment for a particular patient.

If doctors know which patient is being treated with which drug, they may spontaneously evaluate treatment based on their preferences or explanations. The use of blind methods increases the reliability of the results of a clinical trial, eliminating the influence of subjective factors. If the patient knows that he is receiving a promising new drug, the effect of treatment may be associated with his reassurance, satisfaction that the most desired treatment possible has been achieved.

Placebo (Latin placere - to like, to appreciate) means a drug that obviously does not have any healing properties. The Large Encyclopedic Dictionary defines placebo as “a dosage form containing neutral substances. Used to study the role of suggestion in the therapeutic effect of any medicinal substance, as a control when studying the effectiveness of new drugs.” quality medicine pharmaceutical

Negative placebo effects are called nocebo. If the patient knows what side effects the drug has, then in 77% of cases they occur when he takes a placebo. Belief in a particular effect can cause side effects to occur. According to the commentary of the World Medical Association on Article 29 of the Declaration of Helsinki , “...the use of placebo is justified if it does not lead to an increased risk of causing serious or irreversible damage to health...”, that is, if the patient is not left without effective treatment.

There is a term for “completely blinded studies” when all parties to the study are blinded to the type of treatment being given to a particular patient until the results are analyzed.

Randomized controlled trials serve as the standard of quality for scientific research into the effectiveness of treatments. The study first selects patients from a large population of people with the condition being studied. These patients are then randomly divided into two groups matched according to the main prognostic features. Groups are formed randomly (randomization) using tables of random numbers in which each digit or each combination of digits has an equal probability of selection. This means that patients in one group will, on average, have the same characteristics as patients in another. In addition, before randomization, it should be ensured that disease characteristics known to have a strong influence on outcome occur at equal frequencies in the treatment and control groups. To do this, you must first distribute patients into subgroups with the same prognosis and only then randomize them separately in each subgroup - stratified randomization. The experimental group (treatment group) receives an intervention that is expected to be beneficial. The control group (comparison group) is in exactly the same conditions as the first group, except that its patients are not exposed to the intervention being studied.

3. Quantitative analysis of mixtures without preliminary separation of components by physical and chemical methods

Physicochemical methods are becoming increasingly important for the purpose of objective identification and quantification of medicinal substances. Photometric methods are most accessible for use in pharmaceutical analysis, in particular spectrophotometry in the IR and UV regions, photometry in the visible region of the spectrum and their various modifications. These methods are included in the State Pharmacopoeia, the International Pharmacopoeia and the national pharmacopoeias of many countries, as well as in other regulatory documents. Pharmacopoeial monographs, which are state standards containing a list of indicators and methods used to control the quality of a medicinal product.

Physicochemical methods of analysis have a number of advantages over classical chemical methods. They are based on the use of both physical and chemical properties of substances and in most cases are characterized by rapidity, selectivity, high sensitivity, and the possibility of unification and automation.

The inclusion of the developed methods in regulatory documents is preceded by extensive research in the field of pharmaceutical analysis. The number of completed and published works on the use of photometric methods is enormous.

To establish the authenticity of medicinal substances, pharmacopoeias use, along with other physical and chemical methods, IR spectroscopy - a method that provides the most objective identification. The IR spectra of the tested medicinal substances are compared either with the spectrum of a standard sample obtained under the same conditions, or with the attached spectrum taken previously for this medicinal substance.

Along with IR spectroscopy, various options for UV spectrophotometry of organic compounds are used in the analysis of medicinal substances. The first works in this direction summarized the state of the art and outlined the prospects for using this method. Approaches to the use of UV spectrophotometry in drug standardization have been formulated, and various methods of performing analysis have been developed. In the authenticity testing methods presented in pharmacopoeias and other regulatory documentation, identification is usually carried out according to generally accepted parameters of UV spectra - the wavelength of the maximum and minimum light absorption and the specific absorption index. For this purpose, parameters such as the position and half-width of the absorption band, asymmetry factor, integral intensity, and oscillator strength can also be used. When controlling for these parameters, the specificity of qualitative analysis increases.

In some cases, the visible region of the spectrum is used for the photometric determination of medicinal substances. The analysis is based on carrying out color reactions followed by measuring optical density using spectrophotometers and photocolorimeters.

In pharmaceutical analysis, UV-visible spectrophotometry is often combined with separation methods (thin layer and other types of chromatography).

As is known, differential methods of photometric measurements carried out using a reference solution containing a certain amount of a standard sample of the test substance have increased accuracy. This technique leads to an expansion of the working area of ​​the instrument scale, allows you to increase the concentration of the analyzed solutions and, ultimately, increases the accuracy of the determination.

4. Quality control system in chemical and pharmaceutical plants and factories

The manufacturer of medicinal products must organize production in such a way that the medicinal products are guaranteed to meet their intended purpose and requirements and do not pose a risk to consumers due to violations of safety, quality or effectiveness. Managers and all employees of the enterprise are responsible for fulfilling these requirements.

To achieve this goal, the manufacturing enterprise must create a quality assurance system, including the organization of work according to GMP, quality control and a risk analysis system.

Quality control includes sampling, testing (analysis) and preparation of relevant documentation.

The purpose of quality control is to prevent materials or products that do not meet quality requirements from being used or sold. Quality control activities are not limited only to laboratory work, but also include conducting research, inspections and participating in any decisions regarding product quality. The fundamental principle of quality control is its independence from production departments.

Basic requirements for quality control:

Availability of the necessary premises and equipment, trained personnel, approved methods for sampling, inspection and testing of starting and packaging materials, intermediate, packaged and finished products;

Conducting tests using certified methods;

Drawing up records confirming that all necessary sampling, inspection and testing have actually been carried out, as well as recording any deviations and investigations in full;

Maintain sufficient samples of raw materials and products for possible inspection if necessary. Product samples should be stored in their final packaging, with the exception of large packages.

Each manufacturing enterprise must have a quality control department, independent from other departments.

For medicinal products, proper microbiological purity is regulated. Microbial contamination can occur at various stages of production. Therefore, tests for microbiological purity are carried out at all stages of drug production. The main sources of microbial contamination are raw materials, water, equipment, air in production premises, packaging of finished products, and personnel. To quantify the content of microorganisms in the air, various sampling methods are used: filtration, deposition in liquids, deposition on solid media. To assess microbiological purity, sterility tests are performed.

When determining the sterility of drugs that have a pronounced antibacterial effect, bacteriostatic, fungistatic properties, as well as drugs containing preservatives or bottled in containers larger than 100 ml, the membrane filtration method is used.

When monitoring the sterility of dosage forms of β-lactam antibiotics, it is possible to use direct inoculation using the penicillinase enzyme in an amount sufficient to completely inactivate the test antibiotic as an alternative method.

The use of the membrane filtration method is based on passing drugs through a polymer membrane. In this case, microorganisms remain on the surface of the membrane. Next, the membrane is placed in an appropriate nutrient medium and the formation of colonies during incubation is observed.

Cellulose ether membranes (nitrocellulose, cellulose acetolate, and mixed cellulose ethers) with a pore size of 0.45 μm are commonly used to count viable microorganisms.

The technique for testing the microbiological purity of medicinal products using the membrane filtration method is given in the addition to the FS “Test for microbiological purity” dated December 28, 1995.

The quality of medicinal products can be confidently guaranteed if at all stages of the life cycle of medicinal products all rules of circulation are strictly observed, in particular the conduct of preclinical and clinical studies, production, wholesale and retail sales of pharmaceutical products.

5. Main tasks and features of biopharmaceutical analysis

Biopharmaceutical analysis is a new promising direction in pharmaceutical chemistry. The objective of biopharmaceutical analysis is to develop methods for the isolation, purification, identification and quantification of drugs and their metabolites in biological fluids such as urine, saliva, blood, plasma or serum, etc. Only on the basis of the use of such methods can biopharmaceutical research be performed, i.e. .e. study issues of absorption, transport and excretion of medicinal substances, its bioavailability, metabolic processes. All this makes it possible to prevent possible toxic effects of drugs, develop optimal pharmacotherapy regimens and monitor the treatment process. It is especially important to determine the concentration of a drug substance in biological fluids when, along with the therapeutic effect, they exhibit toxicity. It is also necessary to monitor the content of medicinal substances in the biological fluids of patients suffering from gastrointestinal diseases and diseases of the liver and kidneys. With such diseases, absorption processes change, metabolic processes are disrupted, and the removal of drugs from the body slows down.

Biological fluids are very difficult objects to analyze. They are multicomponent mixtures, including a large number of inorganic and organic compounds of various chemical structures: trace elements, amino acids, polypeptides, proteins, enzymes, etc. Their concentration ranges from 10 mg/ml to several nanograms. Even in such a relatively simple physiological fluid as urine, several hundred organic compounds have been identified. Any biological object is a very dynamic system. Its condition and chemical composition depend on the individual characteristics of the body, the influence of environmental factors (food composition, physical and mental stress, etc.). All this further complicates the performance of biopharmaceutical analysis, since against the background of such a large number of organic substances with a complex chemical structure, it is often necessary to determine very small concentrations of drugs. Drugs introduced into biological fluids during the process of biological transformation form metabolites, the number of which often amounts to several dozen. Isolating these substances from complex mixtures, separating them into individual components and establishing their chemical composition is an extremely difficult task.

Thus, the following features of biopharmaceutical analysis can be distinguished:

1. The objects of study are multicomponent mixtures of compounds.

2. The quantities of the substances being determined are usually calculated in micrograms and even nanograms.

3. The studied medicinal substances and their metabolites are located in an environment consisting of a large number of natural compounds (proteins, enzymes, etc.).

4. The conditions for isolation, purification and analysis of the substances under study depend on the type of biological fluid being studied.

In addition to the theoretical significance that research in the field of biopharmaceutical analysis has for the study of newly created medicinal substances, the practical role of this branch of knowledge is also undoubted.

Therefore, biopharmaceutical analysis is a unique tool necessary for conducting not only biopharmaceutical, but also pharmacokinetic studies.

6. Types of state standards. Requirements of general standards for dosage forms

Product quality standardization refers to the process of establishing and applying standards. A standard is a standard or sample taken as the initial one for comparison of other similar objects with it. A standard as a normative document establishes a set of norms or requirements for the object of standardization. The application of standards helps to improve product quality.

In the Russian Federation, the following categories of regulatory documents have been established: State standards (GOST), industry standards (OST), republican standards (RS.T) and technical conditions (TU). The standards for drugs are FS, technical specifications that regulate their quality, as well as production regulations that normalize their technology. FS - regulatory documents defining a set of quality standards and methods for their determination. These documents ensure the same effectiveness and safety of drugs, as well as the consistency and uniformity of their production, regardless of the series. The main document regulating the quality of drugs produced in our country is the State Pharmacopoeia (SP). Regulatory documents reflecting additional technical requirements for the production, control, storage, labeling, packaging, and transportation of drugs are industry standards (OST).

Since June 2000, the industry standard “Rules for organizing production and quality control of drugs” has been put into effect in Russia. This is a standard identical to the international GMP rules.

In addition to the specified standard, which ensures the production of high-quality drugs, a standard has been introduced that normalizes the quality of drugs, regulating the procedure for creating new and improving existing regulatory documentation for drugs. It was approved by the Ministry of Health of the Russian Federation on November 1, 2001 (order No. 388), registered by the Ministry of Justice of the Russian Federation on November 16, 2001 and is an industry standard OST 91500.05.001-00 “Quality Standards for Medicines. Basic provisions". The previously existing standard OST 42-506-96 has lost its force. The purpose of creating an industry standard is to establish categories and a unified procedure for the development, presentation, execution, examination, coordination, designation and approval of drug quality standards. The requirements of this standard are mandatory for development organizations, drug manufacturing enterprises, organizations and institutions that carry out examination of quality standards of domestic drugs, regardless of departmental affiliation, legal status and forms of ownership.

In the newly approved OST, the categories of drug quality standards have been changed. A medicinal product quality standard is a normative document (ND) containing a list of standardized indicators and methods for drug quality control. It must ensure the development of effective and safe drugs.

The new OST provides for two categories of quality standards:

State quality standards for medicines (GSKLS), which include: general pharmacopoeial monograph (GPM) and pharmacopoeial monograph (PS);

Quality Standard (SKLS); pharmacopoeial monograph of the enterprise (FSP).

The General Pharmacopoeia Monograph contains the basic general requirements for the dosage form or a description of standard methods for drug control. The General Pharmacopoeia Monograph includes a list of standardized indicators and test methods for a specific drug or a description of drug analysis methods, requirements for reagents, titrated solutions, and indicators.

The FS contains a mandatory list of indicators and methods for quality control of a medicinal product (taking into account its DF), which meet the requirements of leading foreign pharmacopoeias.

Drug treatment is inextricably linked with the dosage form. Due to the fact that the effectiveness of treatment depends on the dosage form, the following general requirements are imposed on it:

Compliance with the therapeutic purpose, bioavailability of the drug substance in this dosage form and corresponding pharmacokinetics;

Uniformity of distribution of medicinal substances in the mass of auxiliary ingredients and hence dosing accuracy;

Stability during shelf life;

Compliance with microbial contamination standards, if necessary, preservation;

Ease of administration, possibility of correcting unpleasant taste;

Compactness.

The General Pharmacopoeia Monograph and the FS are developed and revised after 5 years by the Scientific Center for Expertise and State Control of Medicines, and for immunobiological drugs - by the National MIBP Control Authority.

OFS and FS constitute the State Pharmacopoeia (SP), which is published by the Ministry of Health of the Russian Federation and is subject to reissue every 5 years. The State Pharmacopoeia is a collection of state drug quality standards that has a legislative nature.

7. Hydrochloric acid: physical properties, authenticity, quantitative determination, application, storage

Diluted hydrochloric acid (Acidum hydrochloridum dilutum) is a colorless transparent liquid of an acidic reaction. density, solution density 1.038-1.039 g/cm3, volume fraction 8.2-8.4%

Hydrochloric acid (Acidum hydrochloridum) is a colorless, transparent, volatile liquid with a peculiar odor. Density 1.122-1.124 g/cm3, volume fraction 24.8-25.2%.

Medicinal preparations of hydrochloric acid are mixed with water and ethanol in all proportions. They differ only in the content of hydrogen chloride and, accordingly, in density.

Chloride ion can be detected with the help of silver nitrate by the formation of a silver chloride precipitate, insoluble in water and in nitric acid solution, but soluble in ammonia solution:

HCl+H2O->AgClv+HNO3

AgCl+2NH3*H2O->2Cl+2H2O

Another method for detecting chloride ion is based on the release of free chlorine when heating drugs from manganese dioxide:

4HCl+MnO2->Cl2?+MnCl2+2H2O

Chlorine is detected by smell.

The content of hydrogen chloride in medicinal preparations of hydrochloric acid is determined by the acid-base titration method, titrating with a solution of sodium hydroxide in the presence of the methyl orange indicator:

HCl+NaOH->NaCl+H2O

Purity tests. Hydrochloric acid may contain impurities of heavy metals, mainly in the form of iron (II) and iron (III) salts. These impurities can enter the drug from the material of the apparatus in which the acid is produced. The presence of iron salts can be detected by the following reactions:

FeCl3 + K4>KFeFe(CN)6v + 3KCl

FeCl2 + K3>KFeFe(CN)6v + 2KCl

From the last two reactions it is clear that the composition of the resulting sediments is identical. This was established relatively recently. Previously, it was believed that two individual compounds were formed - Prussian blue and Turnbull blue.

If hydrogen chloride is produced by the reaction between hydrogen and chlorine, then chlorine may be detected as an impurity. Its determination in solution is carried out by adding potassium iodide in the presence of chloroform, which acquires a purple color as a result of concentrating the released iodine in it:

Cl2 + 2KI > I2 + 2 KCl

When producing hydrogen chloride by the reaction:

2NaCl(TS) + H2SO4(END) > Na2SO4(TS) + 2 HCl^

The drug may contain impurities of sulfites and sulfates. An admixture of sulfurous acid can be detected by adding iodine and starch solution. In this case, iodine is reduced: H2SO3 + I2 + H2O > H2SO4 + 2HI and the blue color of the starch iodine complex disappears.

When barium chloride solution is added, a white precipitate of barium sulfate is formed:

H2SO4 + BaCl2 > BaSO4 + HCl

If hydrochloric acid was produced using sulfuric acid, arsenic may also be present as a very undesirable impurity.

Quantitation. The concentration of hydrochloric acid can be determined by two methods:

1). neutralization method (titration with alkali using methyl orange - pharmacopoeial method):

HCl + NaOH > NaCl + H2O

2) argentometric method for chloride ion:

HCl + AgNO3> AgClv + HNO3

Hydrochloric acid was previously used as a medicine for insufficient acidity of gastric juice. Prescribed orally 2-4 times a day during meals, 10-15 drops (per? -1/2 glass of water).

Titrated solutions of hydrochloric acid with a molar concentration of 0.01 - 1 mol/l are used in pharmaceutical analysis. Storage: in closed containers made of glass or other inert material at temperatures below 30 °C.

Use diluted hydrochloric acid when gastric juice is insufficiently acidic. Prescribed orally 2-4 times a day during meals, 10-15 drops (per? -1/2 glass of water). If it is prescribed without indicating the concentration, diluted hydrochloric acid is always dispensed; A 6% acid solution is used in the treatment of scabies according to Demyanovich.

Storage conditions:

List B. In a dry place. In bottles with ground stoppers. For medical purposes, diluted hydrochloric acid is used.

8. Oxygen: physical properties, authenticity, quality, quantification, application, storage

Oxygen - Oxygenium. The simple substance oxygen consists of non-polar O2 molecules (dioxygen) with a y, p-bond, a stable allotropic form of the element existing in a free form.

A colorless gas, in the liquid state it is light blue, in the solid state it is blue.

Component of air: 20.94% by volume, 23.13% by mass. Oxygen boils away from liquid air after nitrogen N2.

Supports combustion in air

Slightly soluble in water (31 ml/1 l H2O at 20 °C), but somewhat better than N2.

The authenticity of oxygen is determined by introducing a smoldering splinter into the gas stream, which flares up and burns with a bright flame.

It is necessary to occasionally bring a smoldering splinter to the hole of the gas outlet tube, and as soon as it begins to flare up, you should lift the tube, then lower it into the crystallizer with water and bring it under the cylinder. Incoming oxygen fills the cylinder, displacing water.

A smoldering splinter is brought into one of the cylinders with N2O, it flares up and burns with a bright flame.

To distinguish oxygen from another gaseous drug - nitrous oxide (dianitrogen oxide), equal volumes of oxygen and nitric oxide are mixed. The mixture of gases turns orange-red due to the formation of nitrogen dioxide: 2NO+O2-> 2NO2

Nitrous oxide does not give the indicated reaction. During industrial production, oxygen can become contaminated with impurities of other gases.

Purity assessment: In all purity tests, the admixture of other gases is determined by passing a certain amount of oxygen (at a rate of 4 l/h) through 100 ml of a reagent solution.

Oxygen must be neutral. The presence of gaseous impurities of an acidic and basic nature is determined by the colorimetric method (change in color of the methyl red indicator solution)

The admixture of carbon (II) is detected by the passage of oxygen through an ammonia solution of silver nitrate. Darkening indicates the reduction of silver to carbon monoxide:

CO+2[ Ag(NH3)2]NO3+2H2O -> 2Agv+(NH4)CO3+2NH4NO3

The presence of carbon dioxide impurities is determined by the formation of opalescence when oxygen is passed through a solution of barium hydroxide:

CO2+Ba(OH)2 -> BaCO3v+H2O

The absence of ozone and other oxidizing substances is determined by passing oxygen through a solution of potassium iodide, to which a solution of starch and a drop of glacial acetic acid have been added. The solution should remain colorless. The appearance of a blue color indicates the presence of ozone impurities:

2KI+O3+H2O -> I2+2KOH+O2 ?

Quantitation. All methods for the quantitative determination of oxygen are based on interaction with easily oxidized substances. Copper can be used for this. Oxygen is passed through a solution containing a mixture of ammonium chloride and ammonia solutions (ammonia buffer solution, pH = 9.25 ± 1). Pieces of copper wire with a diameter of about 1 mm are also placed there. Copper is oxidized by oxygen:

The resulting copper(II) oxide reacts with ammonia to form bright blue copper(II) ammonia:

CuO + 2 NH3 + 2 NH4CI > Cl2 + H2O

Application. In medicine, oxygen is used to prepare oxygen water and air baths, and “medical gas” is used for inhalation by patients. For general anesthesia in the form of inhalation anesthesia, a mixture of oxygen and low-toxic cyclopropane is used.

Oxygen is used for diseases accompanied by oxygen deficiency (hypoxia). Oxygen inhalations are used for diseases of the respiratory system (pneumonia, pulmonary edema), cardiovascular system (heart failure, coronary insufficiency), poisoning with carbon monoxide (II), hydrocyanic acid, asphyxiants (chlorine C12, phosgene COC12). A mixture of 40-60% oxygen and air is prescribed for inhalation at a rate of 4-5 l/min. Carbogen is also used - a mixture of 95% oxygen and 5% carbon dioxide.

In hyperbaric oxygenation, oxygen is used at a pressure of 1.2-2 atm in special pressure chambers. This method has been established to be highly effective in surgery, intensive care of severe diseases, and in cases of poisoning. This improves oxygen saturation of tissues and hemodynamics. Usually one session is performed a day (40-60 minutes), the duration of treatment is 8 - 10 sessions.

The method of enteral oxygen therapy is also used by introducing oxygen foam into the stomach, used in the form of an oxygen cocktail. The cocktail is prepared by passing oxygen under low pressure through the white of a chicken egg, to which is added rosehip infusion, glucose, vitamins B and C, and infusions of medicinal plants. Fruit juices and bread kvass concentrate can be used as a foaming agent. The cocktail is used to improve metabolic processes in the complex therapy of cardiovascular diseases.

Storage. In pharmacies, oxygen is stored in blue cylinders with a volume of 27-50 liters, containing 4-7.5 m3 of gas under a pressure of 100-150 atm. The threads of the cylinder reducer must not be lubricated with grease or organic oils (spontaneous combustion is possible). Only talc (“soapstone” is a mineral belonging to layered silicates) serves as a lubricant. Oxygen is dispensed from pharmacies in special pillows equipped with a funnel-shaped mouthpiece for inhalation.

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