Department of Pharmacy
Organic medicines.

Aromatic compounds.
Brief summary lectures.

Nizhny Novgorod

UDC 615.014.479

Organic medicines. Aromatic compounds. Brief lecture notes - Nizhny Novgorod: Publishing House of the Nizhny Novgorod State Medical Academy, 2004.

Brief lecture notes on pharmaceutical chemistry have been compiled for foreign students and third-year correspondence students.

The properties of aromatic organic substances used as medicines, methods for obtaining, identifying and quantifying these substances are presented.
Compiled in accordance with the approximate program for pharmaceutical chemistry and order of the Ministry of Health of the Russian Federation No. 93 dated March 31, 1997 “On the phased introduction since 1997 of the final state certification of graduates of higher medical and pharmaceutical universities.”
Recommended for publication by the council of the Nizhny Novgorod State Medical Academy.
Compiled by: Melnikova N.B., Kononova S.V., Pegova I.A., Popova T.N., Ryzhova E.S., Kulikov M.V. .
Reviewers: Professor of the Department of Biotechnology, Physical and Analytical Chemistry, Nizhny Novgorod State Technical University, Doctor of Chemical Sciences. Arbatsky A.P..; Chief Technologist of Nizhpharm OJSC, Ph.D. Zheng F.H.

© N.B. Melnikova,

S.V. Kononova,

I.A. Pegova,

T.N. Popova,

E.S. Ryzhova,

M.V. Kulikov, 2004.

	Aromatic compounds (arenes), general characteristics.	4
	Phenols, quinones and their derivatives.	6
	Derivatives of naphthoquinones (vitamins of group K).	24
	Para-aminophenol derivatives (paracetamol).	31
	Aromatic acids and their derivatives. Salicylic acid esters. Salicylic acid amides.
	Para-, ortho-aminobenzoic acids and their derivatives.	51
	Arylalkylamines, hydroxyphenylalkylamines and their derivatives.	70
	Benzenesulfonamides and their derivatives.	92
	Literature	103

Aromatic compounds (arenes).

General characteristics.

Arenas– compounds with a planar cyclic aromatic system, in which all atoms of the ring participate in the formation of a single conjugated system, including, according to Hückel’s rule (4n+2) π-electrons.

Arenas are classified according to functional groups, because they allow the analysis of drugs and determine the physiological effect.
Relationship between structure and physiological activity.

resorcinol – violet-black, turning into violet;

hexestrol (sinestrol) – red-violet, turning into cherry.

1. 
   Complexation reaction with iron ions.

Depending on the amount of phenolic hydroxyls, the presence of other functional groups in the molecule, their relative position, the pH of the environment, and temperature, complex compounds of various compositions and colors are formed (with the exception of thymol).
4.1.

Complexes are colored:

phenol – blue color;

resorcinol – blue-violet color;

salicylic acid – blue-violet or red-violet color;

osalmid (oxaphenamide) – red-violet color;

sodium para-aminosalicylate – red-violet color;

quinosol – bluish-green color.

The reaction is pharmacopoeial for most phenolic compounds.

1. 
   Electrophilic substitution reactions – S E of a hydrogen atom in the aromatic ring (bromination, condensation with aldehydes, combination with diazonium salts, nitration, nitrosation, iodination, etc.). The ability of phenols to enter into electrophilic substitution reactions is explained by the interaction of the lone electron pair of the oxygen atom with the π-electrons of the benzene ring. The electron density shifts towards the aromatic ring. The greatest excess of electron density is observed at carbon atoms in O- And n- positions relative to the phenolic hydroxyl (type I orientant).

1. 
   5.1. Halogenation reaction (bromination and iodination).

5.1.1. When interacting with bromine water, white or yellow precipitates of bromine derivatives are formed.

When there is an excess of bromine, oxidation occurs:

The bromination reaction of phenols depends on the nature and position of the substituents.

Iodization occurs in a similar way, for example:

5.1.2. If there are substituents in O- And n- positions of the aromatic ring, unsubstituted hydrogen atoms of the aromatic ring react.

5.1.3. If in O- And n- positions in relation to the phenolic hydroxyl there is a carboxyl group, then under the action of excess bromine decarboxylation occurs:


5.1.4. If a compound contains two phenolic hydroxyls in m- position, then under the action of bromine tribromo derivatives are formed (consistent orientation):


5.1.5. If two hydroxyl groups are located relative to each other in O- or n- positions, then the bromination reaction does not occur (inconsistent orientation)

1. 
   5.2. Condensation reactions
   1. 
      5.2.1. With aldehydes.

An example of the condensation of phenols with aldehydes is the reaction with Marquis reagent. When phenols are heated with a solution of formaldehyde in the presence of concentrated H 2 SO 4, colorless condensation products are formed, the oxidation of which produces intensely colored compounds of a quinoid structure. Sulfuric acid plays the role of a dehydrating, condensing agent and oxidizing agent in this reaction.

1. 
   5.2.2. The reaction of phenols with chloroform (CHCl 3) to form aurine dyes.

When phenols are heated with CHCl 3 in an alkaline environment, aurines– triphenylmethane dyes:

Aurines are colored:

phenol – yellow;

thymol – yellow color turning to purple;

resorcinol – red-violet color.

1. 
   5.2.3. With acid anhydrides.

A. The reaction of fluorescein formation (condensation of resorcinol with phthalic anhydride).


yellow-red solution with green fluorescence (pharmacopoeial reaction to resorcinol)

B. Reaction of formation of phenolphthalein (condensation of phenol with phthalic anhydride).

With a large excess of alkali, a trisubstituted sodium salt is formed.

The condensation of thymol with phthalic anhydride proceeds similarly to the reaction of the formation of phenolphthalein; thymolphthalein is formed, which has a blue color in an alkaline medium.

1. 
   5.3. Nitration reaction

Phenols react with dilute nitric acid(HNO 3) and form ortho- and para-nitro derivatives. The addition of sodium hydroxide solution enhances the color due to the formation of a well-dissociated salt.

1. 
   5.4. The reaction of azo coupling of phenols with diazonium salt in an alkaline medium.

When phenols react with diazonium salt at pH 9-10, azo dyes are formed, colored yellow-orange or red. The azo coupling reaction occurs in the ortho and para positions relative to the phenolic hydroxyl. Diazotized sulfanilic acid is usually used as a diazo reagent.


In the case of phenol

PHARMACY (Greek: φαρμακεία use of drugs) a complex of sciences and practical knowledge, including issues of research, extraction, research, storage, manufacture and dispensing of medicinal and therapeutic and prophylactic drugs. PHARMACY “Pharmaceutical chemistry” V.V. Chupak-Belousov is a complex of scientific and practical disciplines that study the problems of creation, safety, research, storage, PHARMACEUTICAL CHEMISTRY TOXICOLOGICAL CHEMISTRY of manufacturing, dispensing and marketing of medicines, as well as the search for natural sources of medicinal substances. TECHNOLOGY OF DOSAGE FORMS PHARMACOGNOSY Wikipedia ECONOMICS AND ORGANIZATION OF PHARMACEUTICAL BUSINESS 3

Toxicological chemistry is a science that studies methods for isolating toxic substances from various objects, as well as methods for detecting and quantifying these substances. Pharmacognosy is a science that studies medicinal plant materials and the possibilities of creating new medicinal substances from them. Technology of dosage forms (pharmaceutical technology) is a field of knowledge that studies methods of preparing medicines. Economics and organization of pharmaceutical business is a field of knowledge that deals with solving problems of storing medicines, as well as organizing control and analytical services. 4

Pharmaceutical chemistry is a science that, based on general laws chemical sciences, explores methods of production, structure, physical and chemical properties medicinal substances, the relationship between their chemical structure and effect on the body, quality control methods and changes that occur during storage. “Pharmaceutical chemistry” by V. G. Belikov is the science of the chemical properties and transformations of medicinal substances, methods of their development and production, qualitative and quantitative analysis. Wikipedia 5

Objects of pharmaceutical chemistry Medicinal substances (DS) – (substances) individual substances of plant, animal, microbial or synthetic origin that have pharmacological activity. Substances are intended for the production of medicines. Medicines (medicines) are inorganic or organic compounds with pharmacological activity, obtained by synthesis from plant materials, minerals, blood, blood plasma, organs, human or animal tissues, as well as using biological technologies. Dosage form (DF) is a state given to a drug that is convenient for use, in which the required healing effect. Medicinal products (MPs) are dosed drugs in a specific dosage form, ready for use. “Pharmaceutical chemistry” V. G. Belikov 6

The relationship of pharmaceutical chemistry with other chemical disciplines PHARMACEUTICAL CHEMISTRY Methods of development and methods of obtaining drugs Inorganic chemistry Ensuring the quality of drugs Properties of drugs Organic chemistry Physical chemistry Analytical chemistry Biochemistry 7

Name of drug Commission on international names WHO, in order to streamline and (2 RS, 3 S, 4 S, 5 R)-5 -amino-2 -(aminomethyl)-6 unify drug names in all countries of the world, has developed -((2 R, 3 S, 4 R, 5 S)-5 -((1 R, 2 R, 5 R, 6 R)-3, 5 international classification, based on diamino-2 -((2 R, 3 S, 4 R, 5 S)-3 - amino-6 which contains (aminomethyl)-4, 5 -dihydroxytetrahydro-2 H a certain system for the formation of drug terminology. The principle of this -pyran-2 -yloxy)-6 -hydroxycyclohexyloxy)-4 system INN - INN (International Nonproprietary Names - International hydroxy -2 -(hydroxymethyl)tetrahydrofuran Generic Names) consists in -3 -yloxy)tetrahydro-2 H-pyran-3, 4 -diol in that the name of the drug approximately indicates its group affiliation. This is achieved through the IUPAC name by including in the name parts of words corresponding to the pharmacotherapeutic group to which the drug belongs. WHO members are required to recognize the names of substances recommended by WHO as INNs and prohibit their registration as trademarks or trade names of Neomycin. INN name 8

Classification of drugs Pharmacological classification - all drugs are divided into groups depending on their effect on systems, processes and executive organs (for example, heart, brain, intestines, etc.). In accordance with this, drugs are grouped into the groups of narcotic drugs, hypnotics and sedatives, local anesthetics, analgesics, diuretics, etc. Chemical classification - drugs are grouped according to their common chemical structure and chemical properties. Moreover, each chemical group of drugs may contain substances with different physiological activities. 9

Contemporary issues pharmaceutical chemistry Creation and research of new drugs Despite the huge arsenal of drugs, the problem of finding new highly effective drugs. The main directions of searching for new and modernizing existing drugs remains relevant. The role of drugs is continuously growing in modern medicine, which is due to a number of reasons: Synthesis of bioregulators and metabolites of energy and plastic exchange A number of serious diseases cannot yet be cured by drugs Identification of potential drugs during screening of new chemical products Long-term use of a number of drugs creates tolerant pathologies, to combat the synthesis of which new drugs with a different mechanism of action are needed Synthesis of compounds with programmable properties (modified Processes in known series of drugs, lead to the emergence of new structures of the evolution of microorganisms, resynthesis of natural phytosubstances, diseases, for treatment, computer search for biologically active substances) which require effective drugs. Some of the drugs used cause side effects, in which Stereoselective synthesis of eutomers (an enantiomer of a chiral drug, which requires pharmacological activity) and the most active conformations of the greatest to create safer drugs of socially significant drugs 10

Modern problems of pharmaceutical chemistry Development of methods for pharmaceutical and biopharmaceutical analysis Promising directions of search in this only Solution of this important problem possible areas based on fundamental theoretical studies of the physical and chemical properties of drugs. Work to improve the accuracy of analysis, its specificity, sensitivity and with the widespread use of modern chemical and physicochemical methods. expressness, as well as automation of individual stages or the entire analysis. The use of these methods should cover the entire process from the creation of new drugs to quality control and increasing the cost-effectiveness of analysis methods. Reducing the labor intensity of the final production product. It is also necessary to develop new and improved regulatory documentation for drugs and dosage forms. It is promising to develop quality and provide for the analysis of groups of drugs, reflecting the requirements for their unified methods of standardization. united by the affinity of the chemical structure based on the use of physicochemical methods 11

Raw materials base of pharmaceutical chemistry Plant raw materials (leaves, flowers, seeds, fruits, bark, plant roots) and products of their processing (fatty and essential oils, juices, gums, resins); Animal raw materials (organs, tissues, glands of slaughter cattle); Fossil organic raw materials (oil and its distillation products, distillation products coal; products of basic and fine organic synthesis); Inorganic minerals (mineral rocks and products of their processing by the chemical industry and metallurgy); 12

History of pharmaceutical chemistry The emergence of pharmacy is lost in the depths of the primitive era. Primitive man was completely dependent on the outside world. In search of relief from illness and suffering, he used various remedies from his environment, the first of which appeared during the gathering period and were of plant origin: belladonna, poppy, tobacco, wormwood, henbane. With the development of agriculture, the domestication of animals and the transition to cattle breeding, new plants with healing properties: hellebore, centaury and many others. The production of tools and household items from native metals and the development of pottery production led to the production of utensils that made it possible to prepare medicinal potions. During this period, medicines of mineral origin were introduced into the practice of healing, which they learned to extract from rocks, oil, and coal. 13

History of pharmaceutical chemistry With the advent of writing, the first medical texts appeared containing descriptions of medicines, methods of their preparation and use. Currently, more than 10 ancient Egyptian papyri are known, in one way or another dedicated to medicine. The most famous of these is the Ebers Papyrus (“Book of Preparation of Medicines for All Parts of the Body”). This is the largest of the papyri and dates back to 1550 BC. e. and contains about 900 recipes for the treatment of diseases of the gastrointestinal tract, lungs, eyes, ears, teeth, and joints. 14

History of Pharmaceutical Chemistry Theophrastus - Father of Botany Theophrastus (c. 300 BC), one of the greatest early Greek philosophers and naturalists, is often referred to as the "father of botany." His observations and writings regarding the medicinal qualities and characteristics of herbs are extremely accurate, even in the light of modern knowledge. In his hands he holds a branch of belladonna. 15

History of Pharmaceutical Chemistry Dioscorides In the evolution of all successful and enduring systems of knowledge, there comes a point when a body of observation and intensive research transcends the level of craft or profession and acquires the status of science. Dioscorides (first century AD), greatly influenced this transition in pharmacy. He carefully described the rules for collecting medicines, storing and using them. During the Renaissance, scholars again turn to his texts. 16

History of Pharmaceutical Chemistry During the Middle Ages in Western civilization, remnants of knowledge about pharmacy and medicine were preserved in monasteries. The monks collected herbs in the vicinity of the monasteries and transferred them to their own herbal gardens. They prepared medicines for the sick and wounded. Many manuscripts have been preserved in reprints or translations in monastery libraries. Such gardens can still be found in monasteries in many countries. 17

History of pharmaceutical chemistry Avicenna (Ibn Sina) 980 - 1037 The most prominent representative of the philosophers of the Arabian period. He made significant contributions to pharmacy and medicine. Avicenna's pharmaceutical teachings were accepted as an authority in the West until the 17th century. The treatise “The Canon of Medicine” is an encyclopedic work in which the prescriptions of ancient physicians are interpreted and revised in accordance with the achievements of Arab medicine. In the Canon, Ibn Sina suggested that diseases could be caused by some tiny creatures. He was the first to draw attention to the contagiousness of smallpox, determined the difference between cholera and plague, described leprosy, separating it from other diseases, and studied a number of other diseases. Ibn Sina also pays no attention to the description of medicinal raw materials, medicines, methods of their manufacture and use. 18

History of pharmaceutical chemistry The period of iatrochemistry (XVI-XVII centuries) The founder of iatrochemistry is considered to be the German physician and alchemist Philip Aureolus Theophrastus Bombastus von Hohenheim (1493-1541), who went down in history under the pseudonym Paracelsus and shared the ancient Greek doctrine of the four elements. Paracelsus' medicine was based on the mercury-sulfur theory. He taught that living organisms consist of the same mercury, sulfur, salts and a number of other substances that form all other bodies of nature; when a person is healthy, these substances are in balance with each other; disease means the predominance or, conversely, deficiency of one of them. To restore balance, Paracelsus used in medical practice many medicines of mineral origin - compounds of arsenic, antimony, lead, mercury, etc. - in addition to traditional herbal preparations. Paracelsus argued that the task of alchemy is the production of medicines: “Chemistry is one of the pillars on which medical science should rest. The task of chemistry is not at all to make gold and silver, but to prepare medicines.” 19

History of pharmaceutical chemistry The period of origin of the first chemical theories (XVII-XIX centuries) centuries. p. XVII century – phlogiston theory (I. Becher, G. Stahl) c. p. XVIII century – refutation of the phlogiston theory. Oxygen theory (M.V. Lomonosov, A. Lavoisier) 1804 - German pharmacologist Friedrich Sertürner isolated the first alkaloid (Morphine) from opium 1818 -1820. – Pelletier and Caventon isolate strychnine, brucine, develop methods for separating quinine and cinchonine isolated from the bark of the cinchona tree XIX – American and European pharmaceutical associations are formed 20

History of Pharmaceutical Chemistry One of the successful researchers in the development of new chemical compounds specifically created to combat pathogens was the French pharmacist, Ernest Forugneux (1872 -1949 In his early works, he proposed the use of bismuth and arsenic compounds for the treatment of syphilis. His research “paved the way” for sulfonamide compounds and chemicals with antihistamine properties. In 1894, Behring and Roux announced the effectiveness of antibodies against diphtheria. Pharmaceutical scientists in Europe and the USA immediately began to put the new discovery into production. The serum became available in 1895 (!). , and the lives of thousands of children were saved. Vaccination of horses with diphtheria was the first of many steps in the production of antidotes. The development of a vaccine against polio in 1955 was a kind of culmination in this area.

History of pharmaceutical chemistry Modern period The second quarter of the 20th century marked the heyday of the era of antibiotics. Penicillin is the first antibiotic, which was isolated in 1928 by Alexander Fleming from a strain of the fungus Penicillium notatum. In 1940-1941, H. W. Flory (bacteriologist), E. Chain (biochemist) and N. W. Heatley (biochemist) worked on the isolation and industrial production of penicillin, and also used it for the first time to treat bacterial infections. In 1945, Fleming, Florey and Chain were awarded the Nobel Prize in Physiology or Medicine "for their discovery of penicillin and its beneficial effects in various infectious diseases." Using the latest technical advances in each branch of science, pharmaceutical chemistry develops and produces the newest and best medicines. Today, for this purpose, pharmaceutical production uses methods and highly qualified personnel from every branch of science. 22

Literature "Pharmaceutical Chemistry" ed. V. G. Belikova “Pharmaceutical chemistry. Course of lectures”, ed. V. V. Chupak-Belousova “Fundamentals of Medical Chemistry” V. G. Granik “Synthesis of Basic Medicines” R. S. Vartanyan “Medical Chemistry” V. D. Orlov, V. V. Lipson, V. V. Ivanov “ Medicines" M. D. Mashkovsky https: //vk. com/nspu_pc 23

Information on specialty

The Department of Organic Chemistry of the Faculty of Chemical Technology prepares certified specialists in the specialty 04.05.01 “Fundamental and Applied Chemistry”, specializations “Organic Chemistry” and “Pharmaceutical Chemistry”. The department's staff consists of highly qualified teachers and researchers: 5 doctors of science and 12 candidates of chemical sciences.

Professional activities of graduates

Graduates prepare for the following types professional activities: research, scientific and production, pedagogical, design and organizational and managerial. A chemist specializing in “Fundamental and Applied Chemistry” will be ready to solve the following professional tasks: planning and setting up work, which includes studying the composition, structure and properties of substances and chemical processes, creating and developing new promising materials and chemical technologies, solving fundamental and applied problems in the field of chemistry and chemical technology; preparation of reports and scientific publications; scientific and pedagogical activities at a university, a secondary specialized educational institution, and a secondary school. Successful students engaged in scientific work can undergo an internship, take part in scientific conferences, olympiads and competitions at various levels, and also present their results scientific work for publication in Russian and foreign scientific journals. Students have at their disposal chemical laboratories equipped with modern equipment and a computer class with necessary literature and access to full-text electronic databases.

Specialists will:

• possess the skills of chemical experimentation, basic synthetic and analytical methods for obtaining and studying chemical substances and reactions;
• present the basic chemical, physical and technical aspects of chemical industrial production, taking into account raw materials and energy costs;
• have the skills to operate modern educational and scientific equipment when conducting chemical experiments;
• have experience working with commercial equipment used in analytical and physicochemical studies (gas-liquid chromatography, infrared and ultraviolet spectroscopy);
• own methods of recording and processing the results of chemical experiments.
• Possess the skills of planning, setting up and conducting chemical experiments in the field of fine organic synthesis to obtain substances with specified beneficial properties

Students acquire knowledge in the fundamentals of inorganic chemistry, organic chemistry, physical and colloidal chemistry, analytical chemistry, planning of organic synthesis, chemistry of alicyclic and framework compounds, catalysis in organic synthesis, chemistry of organoelement compounds, pharmaceutical chemistry, modern methods of analysis and quality control of drugs , fundamentals of medicinal chemistry, fundamentals of pharmaceutical technology, fundamentals of pharmaceutical analysis. During practical classes, students gain skills in working in a modern chemical laboratory and master methods for preparing and analyzing new compounds. Students have the skills to operate a gas-liquid chromatograph, infrared spectrophotometer, and ultraviolet spectrophotometer. Students undergo in-depth study of a foreign language (for 3 years).

During the training process, students master methods of working on analytical equipment of the Department of Organic Chemistry:

Finnigan Trace DSQ chromatography-mass spectrometer

NMR spectrometer JEOL JNM ECX-400 (400 MHz)

HPLC/MS with high-resolution time-of-flight mass spectrometer with ESI and DART ionization source, with diode array and fluorimetric detectors

Preparative flash chromatography system with UV and ELSD detectors Reveleris X2

Fourier transform infrared spectrometer Shimadzu IRAffinity-1

Waters liquid chromatograph with UV and refractometric detectors

Differential scanning calorimeter TA Instruments DSC-Q20

Automatic C,H,N,S analyzer EuroVector EA-3000

Varian Cary Eclipse scanning spectrofluorimeter

Automatic polarimeter AUTOPOL V PLUS

Automatic melting point tester OptiMelt

High performance computing station

The training process includes introductory and chemical-technological practice in the laboratories of enterprises:

• CJSC "All-Russian Scientific Research Institute of Organic Synthesis of NK";
• OJSC "Srednevolzhsky Research Institute for Oil Refining" NK Rosneft;
• CJSC "TARKETT";
• Samara Thermal Power Plant;
• OJSC "Syzran Refinery" NK Rosneft;
• OJSC Giprovostokneft;
• OJSC "Aircraft Bearings Plant";
• LLC Novokuybyshevsk Oil and Additives Plant of Rosneft Oil Company;
• JSC "Neftekhimiya"
• LLC "Pranafarm"
• Ozon LLC
• JSC "Electroshield"
• FSUE SNPRKTs
• "TSSKB-Progress"
• JSC "Baltika"
• PJSC SIBUR Holding, Tolyatti

Successful students engaged in scientific work can undergo internships, take part in scientific conferences, olympiads and competitions at various levels, and also present the results of scientific work for publication in Russian and foreign scientific journals. Specialists trained in “Fundamental and Applied Chemistry” are in demand in the laboratories of state research centers and private companies, in research and analytical laboratories of various industries (chemical, food, metallurgical, pharmaceutical, petrochemical and gas production), in forensic laboratories; in customs laboratories; diagnostic centers; sanitary and epidemiological stations; environmental control organizations; certification testing centers; enterprises chemical industry, ferrous and non-ferrous metallurgy; in educational institutions of the secondary vocational education system; departments of labor protection and industrial sanitation; weather stations.

The qualification “Chemist” is awarded. Chemistry teacher" with a specialization in "Organic Chemistry" or "Pharmaceutical Chemistry". Enrollment by Unified State Exam results: chemistry, mathematics and Russian language. Duration of study: 5 years (full-time). Possibility of admission to graduate school.

General pharmaceutical chemistry.

Subject and tasks of pharmaceutical chemistry.

Pharmaceutical chemistry (PC) is a science that studies methods of obtaining,

structures, physical and chemical properties of medicinal substances; the relationship between their chemical structure and effect on the body; methods of quality control of drugs and changes that occur during their storage. The problems facing it are solved with the help of physical, chemical and physicochemical research methods, used both for the synthesis and analysis of medicinal substances. Physics is based on the theory and laws of related chemical sciences: inorganic, organic, analytical, physical and biological chemistry. It is closely related to pharmacology, biomedical and clinical disciplines.

Terminology in FX

The object of study of PCs are pharmacological and medicinal products. The first of these is a substance or mixture of substances with established pharmacological activity, which is the object of clinical trials. After conducting clinical trials and obtaining positive results, the drug is approved for use by the Pharmacological and Pharmacopoeial Committees and is given the name of the drug. A medicinal substance is a substance that is an individual chemical compound or biological substance. A dosage form is a convenient state for use given to a drug in which the desired therapeutic effect is achieved. It includes powders, tablets, solutions, ointments, suppositories. A dosage form manufactured by a specific company and given a brand name is called a drug.

Sources of medicines

Medicinal substances by their nature are divided into inorganic and organic. They can be obtained from natural sources and synthetically. Raw materials for obtaining inorganic substances there may be rocks, gases, sea water, industrial waste, etc. Organic medicinal substances are obtained from oil, coal, oil shale, gases, plant tissues, animals, microorganisms and other sources. In recent decades, the number of drugs obtained synthetically has increased sharply.

Often, the complete chemical synthesis of many compounds (alkaloids, antibiotics, glycosides, etc.) is technically complex and new methods for obtaining drugs are used: semi-synthesis, biosynthesis, genetic engineering, tissue culture, etc. Using semi-synthesis, drugs are obtained from intermediate products natural origin, for example, semisynthetic penicillins, cephalosporins, etc. Biosynthesis is the natural synthesis of the final product by living organisms based on natural intermediates.

The essence of genetic engineering is to change the genetic programs of microorganisms by introducing into their DNA genes encoding the biosynthesis of certain drugs, such as insulin. Tissue culture is the reproduction in artificial conditions of animal or plant cells, which become raw materials for the production of drugs. To produce the latter, hydrobionts, plant and animal organisms of the seas and oceans are also used.

Classification of medicinal substances.

There are two types of classification of a large number of used medicinal substances: pharmacological and chemical. The first of them divides medicinal substances into groups depending on the mechanism of action on individual organs and systems of the body (central nervous, cardiovascular, digestive, etc.). This classification is convenient for use in medical practice. Its disadvantage is that substances with different chemical structures may appear in the same group, which complicates the unification of methods for their analysis.

According to chemical classification medicinal substances are divided into groups based on the commonality of their chemical structure and chemical properties, regardless of their pharmacological action. For example, pyridine derivatives have different effects on the body: nicotinamide is a vitamin PP, nicotinic acid diethylamide (cordiamin) stimulates the central nervous system, etc. Chemical classification is convenient because it allows us to identify the relationship between the structure and mechanism of action of medicinal substances, and also allows us to unify the methods of their analysis. In some cases, a mixed classification is used to take advantage of the pharmacological and chemical classification of drugs.

Requirements for medicines.

The quality of a medicinal product is determined by appearance, solubility, identification of its authenticity, degree of purity and quantitative determination of the content of pure substance in the drug. The complex of these indicators constitutes the essence of pharmaceutical analysis, the results of which must comply with the requirements of the State Pharmacopoeia (SP).

The authenticity of a medicinal substance (confirmation of its identity) is established using chemical, physical and physicochemical research methods. Chemical methods include reactions to functional groups included in the structure of the drug that are characteristic of a given substance: These, according to the Global Fund, are reactions to aromatic primary amines, ammonium, acetates, benzoates, bromide, bismuth, ferrous and oxide iron, iodides, potassium, calcium, carbonates (bicarbonates), magnesium, arsenic, sodium, nitrates, nitrites, mercury oxide, salicylates, sulfates, sulfites, tartrates, phosphates, chlorides, zinc and citrates.

Physical methods for establishing the authenticity of a drug include determining its: 1) physical properties: state of aggregation, color, smell, taste, crystal shape or type of amorphous substance, hygroscopicity or degree of weathering in air, volatility, mobility and flammability and 2) physical constants: temperatures melting (decomposition) and solidification, density, viscosity, solubility in water and other solvents, transparency and degree of turbidity, color, ash, insoluble in hydrochloric acid and sulfate and volatile substances and water.

Physico-chemical methods for studying authenticity involve the use of instruments for chemical analysis: spectrophotometers, fluorometers, flame photometers, chromatography equipment, etc.

Impurities in medicines and their sources.

Many medicines contain certain impurities of foreign substances. Exceeding their level may cause undesirable effects. The reasons for the ingress of impurities into medicinal substances may be insufficient purification of the starting materials, synthesis by-products, mechanical impurities, impurities in the materials from which the equipment is made, and violation of storage conditions.

GF requires either the complete absence of impurities, or allows a maximum permissible limit for a given drug, which does not affect the quality and therapeutic effect of the drug. To determine the permissible limit of GF impurities, standard solutions are provided. The result of a reaction to a particular impurity is compared with the result of a reaction carried out with the same reagents and in the same volume with a reference, standard solution containing an acceptable amount of the impurity. Determining the degree of purity of a medicinal product includes testing for: chlorides, sulfates, ammonium salts, calcium, iron, zinc, heavy metals and arsenic.

region. State Pharmacopoeia of the USSR (SF USSR)

State Fund of the USSR - a collection of mandatory national standards and regulations regulating the quality of medicinal substances. It is based on the principles of Soviet healthcare and reflects modern achievements in the field of pharmacy, medicine, chemistry and other related sciences. The Soviet Pharmacopoeia is a national document; it reflects the social essence of Soviet healthcare, the level of science and culture of the population of our country. The State Pharmacopoeia of the USSR is of a legislative nature. Its requirements for medicines are mandatory for all enterprises and institutions of the Soviet Union that manufacture, store, control the quality and use medicines.

The first edition of the Soviet Pharmacopoeia, called the VII edition of the State Pharmacopoeia of the USSR (GF VII), was put into effect in July 1926. To create it, a special pharmacopoeial commission was formed in the People's Commissariat of Health of the RSFSR in 1923, chaired by prof. A. E. Chichibabina. The first Soviet Pharmacopoeia differed from previous editions by its increased scientific level and the desire for the possible replacement of medicines made from imported raw materials with domestically produced medicines. In Global Fund VII, higher requirements were imposed not only on medicinal products, but also on the products used for their manufacture.

Based on these principles, GF VII included 116 articles on new drugs and excluded 112 articles. Significant changes have been made to the requirements for drug quality control. A number of new methods for chemical and biological standardization of drugs were provided, 30 general articles were included in the form of appendices, descriptions were given of some common reactions used to determine the quality of drugs, etc. Organoleptic control of many drugs was for the first time replaced by more objective physicochemical methods, and biological control methods were introduced.

Thus, in GF VII, priority was given to improving the quality control of medicines. This principle has found its way further development in subsequent editions of pharmacopoeias.

In 1949, the VIII edition was published, and in October 1961, the IX edition of the State Pharmacopoeia of the USSR was published. By this time, new groups of highly effective drugs (sulfonamides, antibiotics, psychotropic, hormonal and other drugs) had been created, which required the development of new methods of pharmaceutical analysis.

The X edition of the State Pharmacopoeia (SP X) came into force on July 1, 1969. It reflected the new successes of domestic pharmaceutical and medical science and industry.

The fundamental difference between GF IX and GF X is the transition to new international terminology for drugs, as well as a significant update of both the nomenclature and methods of drug quality control.

In GF X, the requirements for the quality of medicinal products have been significantly increased, methods of pharmacopoeial analysis have been improved, and the scope of application of physicochemical methods has been expanded. Numerous general articles, reference tables and other materials included in the Global Fund X reflected the requirements necessary to assess the qualitative and quantitative characteristics of medicines.

The State Pharmacopoeia of the USSR X edition includes 4 parts: “Introductory part”; “Medicines” (private and group articles); “General methods of physicochemical, chemical and biological research”; "Applications".

The “Introductory Part” outlines the general principles of construction and the procedure for using GF X, indicates the compilers, changes that distinguish GF X from GF IX, list A and list B of medicinal substances.

GF X contains 707 articles on medicinal substances (in GF IX there were 754) and 31 group articles (in GF IX there were 27). The nomenclature was updated by 30% due to the exclusion of discontinued drugs and those with limited use. The quality of the latter is established in accordance with the requirements of Global Fund IX.

Compared to GF IX, the number of individual (synthetic and natural) drugs increased from 273 to 303, from 10 to 22 antibiotic drugs, and for the first time radioactive drugs were included in GF X. Among the drugs included in the Global Fund X are new cardiovascular, psychotropic, ganglion-blocking, antimalarial, anti-tuberculosis drugs, drugs for the treatment of malignant neoplasms, fungal diseases, new anesthesia drugs, hormonal drugs, and vitamins. Most of them were obtained for the first time in our country.

“Drugs” is the main part of GF X (p. 39-740). 707 articles set out the requirements for the quality of medicines (quality standards). Each drug, in accordance with the requirements of the pharmacopoeia, is subjected to physical properties testing, authenticity testing, purity testing and determination of the quantitative content of the drug. In GF X, the structure of articles reflecting the sequence of control is detailed. The "Properties" section has been replaced by two sections: "Description" and "Solubility". Descriptions of authenticity reactions for 25 ions and functional groups are summarized in one general article, and links are provided in specific articles.

The order of the articles has been changed. For the first time in Global Fund X, articles on finished dosage forms are located after articles on the corresponding medicinal product. Most articles of the Global Fund X contain a section indicating the pharmacological action of the drug. Information on higher doses of drugs for in various ways introduction.

The third part of the State Fund X “General methods of physicochemical, chemical and biological research” provides a brief description of the methods used for pharmacopoeial analysis, and provides information on reagents, titrated solutions and indicators.

“Appendices” to the State Pharmacopoeia X contain reference tables of atomic masses, densities, constants (solvents, acids, bases) and other quality indicators of medicinal products. It also includes tables of the highest single and daily doses of poisonous and potent drugs for adults, children, and also for animals.

After the publication of the X edition of the State Pharmacopoeia, the Ministry of Health of the USSR approved a number of new highly effective medicines for use in medical practice. Many of them were first developed by scientists in our country. At the same time, ineffective drugs were excluded, which were replaced by more modern drugs. Therefore, there is a need to create a new XI edition of the State Pharmacopoeia of the USSR, which is currently being prepared. Scientific institutions and enterprises of the USSR Ministry of Health, the Ministry of Medical Industry and other departments are involved in this work. The new State Pharmacopoeia will reflect modern achievements in the field of pharmaceutical analysis and improving the quality of medicines.

National and regional pharmacopoeias

Such large capitalist states as the USA, Great Britain, France, Germany, Japan, Italy, Switzerland and some others systematically release national pharmacopoeias every 5-8 years. Published in 1924-1946. the pharmacopoeias of Greece, Chile, Paraguay, Portugal, and Venezuela have already lost their significance.

Along with pharmacopoeias, some countries periodically publish collections of official requirements for drugs such as the US National Formulary and the British Pharmaceutical Code. They standardize the quality of new drugs that are not included in pharmacopoeias or were included in earlier editions of pharmacopoeias.

The first experience in creating a regional pharmacopoeia was carried out by the Scandinavian countries (Norway, Finland, Denmark and Sweden). The published Scandinavian Pharmacopoeia since 1965 has acquired a legislative character for these countries.

Eight Western European countries (Great Britain, Germany, France, Italy, Belgium, Luxembourg, the Netherlands and Switzerland), members of the EEC (European Economic Community), created a pharmacopoeial commission in 1964. She prepared and published in 1969 the first and in 1971 the second volume of the EEC Pharmacopoeia (a supplement to these publications was published in 1973). In 1976, the EEC Pharmacopoeia was recognized by the Scandinavian countries, Iceland and Ireland. The EEC Pharmacopoeia has a legislative nature, but does not replace the national pharmacopoeias of these countries.

Regional pharmacopoeias contribute to the unification of nomenclature and quality requirements for medicines obtained in different countries

Quality control of drugs in pharmacies

In-pharmacy drug quality control includes not only analytical control, but also a system of measures that ensure proper storage, preparation and dispensing of drugs. It is based on strict adherence to the pharmaceutical and sanitary regime in the pharmacy. Particular care must be taken to follow the rules for storing medications and the technology for preparing injection solutions, concentrates and eye drops.

For in-pharmacy quality control of drugs, pharmacies must have analytical rooms or analytical tables equipped with the necessary instruments, reagents, reference and specialized literature. In-pharmacy control is carried out by pharmacist-analysts who are part of the staff of large pharmacies, as well as pharmacist-technologists, whose responsibilities include checking the quality of drugs. They have equipped workplace on or near the assistant's table. The head of the pharmacy and his deputies manage the quality control of medicines. They must master all types of intra-pharmacy control, and in small pharmacies they themselves must perform the functions of a pharmacist-analyst or pharmacist-technologist.

Direct analytical control in a pharmacy includes three main areas: quality control of medicinal substances coming from industry, quality control of distilled water and various types of quality control of dosage forms manufactured in a pharmacy.

Medicinal substances supplied to pharmacies from industry, regardless of the presence of a Quality Control Department stamp, are controlled for identity. Drugs that change rapidly during storage are sent for testing to control and analytical laboratories at least once a quarter.

Systematic control over the quality of distilled water in a pharmacy ensures the quality of preparation of all liquid dosage forms. Therefore, distilled water in each cylinder is monitored for the absence of chlorides, sulfates and calcium salts. Even higher demands are placed on water used for the preparation of injection solutions. It is checked for the absence of reducing substances, ammonia, and carbon dioxide. At least once a quarter, the pharmacy sends distilled water for complete analysis to the control and analytical laboratory, and twice a year to the sanitary and bacteriological laboratory to check the absence of microflora contamination.

All dosage forms manufactured in pharmacies are subject to internal pharmacy control. There are several types of control: written, organoleptic, survey, physical and chemical. Written, organoleptic, survey and physical control is carried out, as a rule, by a pharmacist-technologist after the pharmacist has prepared at least 5 drugs, and chemical control is carried out by a pharmacist-analyst.

All medications manufactured in any pharmacy are subject to written control. The essence of written control is that after preparing the medicine, the pharmacist writes down from memory on a special form the name and total weight of each ingredient or indicates the content of each concentrate taken. Then the form along with the recipe is handed over to the pharmacist-technologist for verification. Completed forms are stored in the pharmacy for 12 days.

Organoleptic control includes checking the appearance (color, uniformity of mixing), smell and taste of drugs, and the absence of mechanical impurities. All medicines prepared for internal use by children and selectively prepared for adults (excluding medicines containing List A ingredients) are taste tested.

Survey control is carried out by a pharmacist-technologist. He names the ingredient, and in complex medicines the content of the first ingredient. After this, the pharmacist names all other ingredients and their quantities. If concentrates were used to make the medicine, the pharmacist lists them indicating the percentage. Questionnaire control is carried out immediately after the manufacture of medicines, if they are intended for injection or if they contain drugs from list A. If there is doubt about the quality of the manufactured medicine, survey control is an additional type of control.

Physical control consists of checking the total volume (mass) of the prepared drug or the mass of its individual doses. 5-10% of the number of doses prescribed in the prescription is controlled, but not less than three doses. Physical control is carried out selectively, periodically throughout the working day. Along with physical control, accuracy checks are carried out to check the correctness of the formulation of the medicines and the compliance of the packaging with the physicochemical properties of the ingredients included in the dosage form.

Chemical control includes qualitative and quantitative chemical analysis of drugs prepared in a pharmacy. All injection solutions are subjected to qualitative chemical analysis (before they are sterilized); eye drops; each series of concentrates, semi-finished products and in-pharmacy preparations; medicines coming from the supplies department to the assistant's departments; children's dosage forms; medicines containing drugs from list A. Medicines manufactured according to individual impurities are selectively monitored.

To perform qualitative analysis, the drop method is mainly used, using tables of the most characteristic reactions.

This practical work requires studying the fundamentals of general pharmaceutical chemistry and methods for studying the qualitative and quantitative study of substances most often encountered in veterinary practice.

The list of drugs subject to quantitative analysis depends on the availability of a pharmacist-analyst in the pharmacy. If the pharmacy has one on staff, then all injectable medications are subjected to quantitative analysis (before sterilization); eye drops (containing silver nitrate, atropine sulfate, dicaine, ethylmorphine pilocarpine hydrochloride); atropine sulfate solutions for internal use; all concentrates, semi-finished products and in-pharmacy preparations. The remaining drugs are analyzed selectively, but daily by each pharmacist. First of all, drugs used in pediatric and ophthalmic practice are monitored, as well as those containing drugs from List A. Perishable drugs (solutions of hydrogen peroxide, ammonia and formaldehyde, lime water, ammonia-anise drops) are analyzed at least once a quarter.

If there is no pharmacist-analyst, but the pharmacy staff has two or more pharmacists, then injection solutions (before sterilization) containing novocaine, atropine sulfate, calcium chloride, sodium chloride, glucose are subjected to quantitative analysis; eye drops containing silver nitrate, atropine sulfate, pilocarpine hydrochloride; all concentrates; hydrochloric acid solutions. Perishable medicines from these pharmacies are sent for testing to control and analytical laboratories.

Injection solutions containing novocaine and sodium chloride are subject to qualitative and quantitative analysis in pharmacies of category VI with one pharmacist on staff and in pharmacies of the first group; eye drops containing atropine sulfate and silver nitrate.

The procedure for assessing the quality of drugs manufactured in pharmacies and the norms of permissible deviations in the manufacture of drugs are established by order of the USSR Ministry of Health No. 382 dated September 2, 1961. To assess the quality of manufactured drugs, the terms are used: “satisfies” or “does not satisfy” the requirements of the State Fund of the USSR, FS , VFS or instructions of the USSR Ministry of Health.

Features of pharmaceutical analysis.

Pharmaceutical analysis is one of the main branches of pharmaceutical chemistry. It has its own specific features that distinguish it from other types of analysis. They consist in the fact that substances of various chemical natures are subjected to research: inorganic, organic, radioactive, organic compounds from simple aliphatic to complex natural biologically active substances. The range of concentrations of the analyzed substances is extremely wide. The objects of pharmaceutical research are not only individual medicinal substances, but also mixtures containing different numbers of components. The number of drugs used is increasing every year. This leads to the need to both develop new methods of analysis and unify already known ones.

Continuously increasing requirements for the quality of medicines dictate the need for continuous improvement of pharmaceutical analysis. Moreover, the requirements for both the good quality of medicinal substances and the quantitative content are growing. This necessitates the widespread use of not only chemical, but also more sensitive physicochemical methods to assess the quality of drugs.

There are high demands on pharmaceutical analysis. It must be quite specific and sensitive, accurate in relation to the standards stipulated by the State Fund of the USSR, VFS, FS and other scientific and technical documentation, carried out in short periods of time using minimal quantities of tested drugs and reagents.

Pharmaceutical analysis, depending on the objectives, includes various shapes drug quality control: pharmacopoeial analysis, step-by-step control of drug production, analysis of individually manufactured dosage forms, express analysis in a pharmacy and biopharmaceutical analysis.

An integral part of pharmaceutical analysis is pharmacopoeial analysis. It is a set of methods for studying drugs and dosage forms set out in the State Pharmacopoeia or other regulatory and technical documentation (VFS, FS). Based on the results obtained during the pharmacopoeial analysis, a conclusion is made about the compliance of the medicinal product with the requirements of the USSR State Fund or other regulatory and technical documentation. If you deviate from these requirements, the medicine is not allowed for use.

Performing a pharmacopoeial analysis makes it possible to establish the authenticity of the drug, its good quality, and determine the quantitative content of the pharmacologically active substance or ingredients included in the dosage form. Although each of these stages has its own specific goal, they cannot be considered in isolation. They are interconnected and mutually complement each other. For example, melting point, solubility, pH of an aqueous solution, etc. are criteria for both the authenticity and good quality of a medicinal substance.

The State Pharmacopoeia X describes the methods of relevant tests in relation to a particular pharmacopoeial drug. Many of these techniques are identical. To summarize a large amount of private information on pharmacopoeial analysis, the main criteria for pharmaceutical analysis and the general principles of testing for authenticity, goodness and quantitative determination of medicinal substances will be considered. Separate sections discuss the state and prospects for the use of physicochemical and biological methods in the analysis of drugs.

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Pharmaceutical Chemistry and Pharmaceutical Analysis

Introduction

1. Characteristics of pharmaceutical chemistry as a science

1.1 Subject and objectives of pharmaceutical chemistry

1.2 Relationship between pharmaceutical chemistry and other sciences

1.3 Pharmaceutical chemistry objects

1.4 Modern problems of pharmaceutical chemistry

2. History of the development of pharmaceutical chemistry

2.1 Main stages of development of pharmacy

2.2 Development of pharmaceutical chemistry in Russia

2 .3 Development of pharmaceutical chemistry in the USSR

3. Pharmaceutical analysis

3.1 Basic principles of pharmaceutical and pharmacopoeial analysis

3.2 Pharmaceutical Analysis Criteria

3.3 Errors possible during pharmaceutical analysis

3.4 General principles for testing the authenticity of medicinal substances

3.5 Sources and causes of poor quality of medicinal substances

3.6 General requirements for purity tests

3.7 Methods for studying the quality of medicines

3.8 Validation of analytical methods

Conclusions

List of used literature

Introduction

Among the tasks of pharmaceutical chemistry - such as modeling new drugs and their synthesis, studying pharmacokinetics, etc., a special place is occupied by the analysis of the quality of drugs. The State Pharmacopoeia is a collection of mandatory national standards and regulations regulating the quality of drugs.

Pharmacopoeial analysis of medicines includes quality assessment based on many indicators. In particular, the authenticity of the drug is established, its purity is analyzed, and quantitative determination is carried out. Initially, exclusively chemical methods were used for such analysis; authenticity reactions, impurity reactions and titrations for quantitative determination.

Over time, not only the level of technical development of the pharmaceutical industry has increased, but also the requirements for the quality of medicines have changed. IN recent years There has been a tendency towards a transition to the expanded use of physical and physicochemical methods of analysis. In particular, spectral methods such as infrared and ultraviolet spectrophotometry, nuclear magnetic resonance spectroscopy, etc. are widely used. Chromatography methods (high-performance liquid, gas-liquid, thin-layer), electrophoresis, etc. are widely used.

The study of all these methods and their improvement is one of the most important tasks of pharmaceutical chemistry today.

1. Characteristics of pharmaceutical chemistry as a science

1.1 Subject and tasks of pharmaceutical chemistry

Pharmaceutical chemistry is a science that, based on the general laws of chemical sciences, studies methods of production, structure, physical and chemical properties of medicinal substances, the relationship between their chemical structure and effect on the body, methods of quality control and changes that occur during storage.

The main methods for studying medicinal substances in pharmaceutical chemistry are analysis and synthesis - dialectically closely related processes that complement each other. Analysis and synthesis are powerful means of understanding the essence of phenomena occurring in nature.

The problems facing pharmaceutical chemistry are solved using classical physical, chemical and physicochemical methods, which are used both for the synthesis and analysis of medicinal substances.

To learn pharmaceutical chemistry, the future pharmacist must have deep knowledge in the field of general theoretical chemical and biomedical disciplines, physics, and mathematics. A solid knowledge of philosophy is also required, because pharmaceutical chemistry, like other chemical sciences, deals with the study of the chemical form of the movement of matter.

1.2 Relationship of pharmaceutical chemistry with other sciences

Pharmaceutical chemistry is an important branch of chemical science and is closely related to its individual disciplines (Fig. 1). Using the achievements of basic chemical disciplines, pharmaceutical chemistry solves the problem of targeted search for new drugs.

For example, modern computer methods make it possible to predict the pharmacological action (therapeutic effect) of a drug. A separate direction has been formed in chemistry associated with the search for one-to-one correspondence between the structure of a chemical compound, its properties and activity (QSAR or QSAR method - quantitative correlation of structure - activity).

The structure-property relationship can be detected, for example, by comparing the values ​​of the topological index (an indicator reflecting the structure of the drug substance) and the therapeutic index (the ratio of the lethal vine to the effective dose LD50/ED50).

Pharmaceutical chemistry is also related to other non-chemical disciplines (Fig. 2).

Thus, knowledge of mathematics allows, in particular, to apply metrological assessment of the results of drug analysis, computer science ensures timely receipt of information about drugs, physics - the use of fundamental laws of nature and the use of modern equipment in analysis and research.

The relationship between pharmaceutical chemistry and specialized disciplines is obvious. The development of pharmacognosy is impossible without the isolation and analysis of biologically active substances plant origin. Pharmaceutical analysis accompanies individual stages of technological processes for drug production. Pharmacoeconomics and pharmacy management come into contact with pharmaceutical chemistry when organizing a system of standardization and quality control of medicines. Determination of the content of drugs and their metabolites in biological media in equilibrium (pharmacodynamics and toxicodynamics) and over time (pharmacokinetics and toxicokinetics) demonstrates the possibilities of using pharmaceutical chemistry to solve problems of pharmacology and toxicological chemistry.

A number of biomedical disciplines (biology and microbiology, physiology and pathophysiology) provide a theoretical basis for the study of pharmaceutical chemistry.

The close relationship with all of these disciplines provides solutions to modern problems in pharmaceutical chemistry.

Ultimately, these problems come down to the creation of new, more effective and safe drugs and the development of methods for pharmaceutical analysis.

1.3 Pharmaceutical chemistry objects

Objects of pharmaceutical chemistry are extremely diverse in chemical structure, pharmacological action, mass, number of components in mixtures, presence of impurities and related substances. Such objects include:

Medicinal substances (MS) - (substances) individual substances of plant, animal, microbial or synthetic origin that have pharmacological activity. Substances are intended for the production of medicines.

Medicines (medicines) are inorganic or organic compounds with pharmacological activity, obtained by synthesis from plant materials, minerals, blood, blood plasma, organs, human or animal tissues, as well as using biological technologies. Drugs also include biologically active substances (BAS) of synthetic, plant or animal origin, intended for the production or manufacture of medicines. Dosage form (DF) is a condition given to a drug or drug that is convenient for use, in which the necessary therapeutic effect is achieved.

Medicinal products (MPs) are dosed drugs in a specific dosage form, ready for use.

All of the indicated drugs, medicinal products, dosage forms and medicinal products can be of both domestic and foreign origin, approved for use in the Russian Federation. The given terms and their abbreviations are official. They are included in OSTs and are intended for use in pharmaceutical practice.

The objects of pharmaceutical chemistry also include the starting products used to obtain drugs, intermediate and by-products of synthesis, residual solvents, auxiliary and other substances. In addition to patented drugs, the objects of pharmaceutical analysis are generics (generic drugs). The pharmaceutical manufacturing company receives a patent for the developed original drug, which confirms that it is the property of the company for a certain period (usually 20 years). A patent provides the exclusive right to sell it without competition from other manufacturers. After the expiration of the patent, free production and sale of this drug is allowed to all other companies. It becomes a generic drug, or generic, but must be absolutely identical to the original one. The only difference is the difference in the name given by the manufacturing company. A comparative assessment of the generic and the original drug is carried out on the basis of pharmaceutical equivalence (equal content of the active ingredient), bioequivalence (equal concentrations of accumulation when taken in the blood and tissues), therapeutic equivalence (equal effectiveness and safety when administered intravenously). equal conditions and doses). The advantages of generics are a significant reduction in costs compared to the creation of an original drug. However, their quality is assessed in the same way as the corresponding original drugs.

The objects of pharmaceutical chemistry are also various ready-made medicinal products (FMD) and pharmaceutical dosage forms (MF), medicinal plant raw materials (MPR). These include tablets, granules, capsules, powders, suppositories, tinctures, extracts, aerosols, ointments, patches, eye drops, various injectable dosage forms, and ophthalmic medicinal films (OMFs). The content of these and other terms and concepts is given in the terminological dictionary of this textbook.

Homeopathic medicines are single- or multicomponent drugs containing, as a rule, microdoses of active compounds produced using special technology and intended for oral, injection or topical use in the form of various dosage forms.

An essential feature of the homeopathic method of treatment is the use of small and ultra-low doses of drugs prepared by stepwise sequential dilution. This determines the specific features of technology and quality control of homeopathic medicines.

The range of homeopathic medicines consists of two categories: monocomponent and complex. For the first time, homeopathic medicines were included in State Register in 1996 (in the amount of 1192 single-drug products). Subsequently, this nomenclature expanded and now includes, in addition to 1192 monopreparations, 185 domestic and 261 names of foreign homeopathic drugs. These include 154 matrix tincture substances, as well as various dosage forms: granules, sublingual tablets, suppositories, ointments, creams, gels, drops, injection solutions, lozenges, oral solutions, patches.

Such a large range of homeopathic medications requires high requirements for their quality. Therefore, their registration is carried out in strict accordance with the requirements of the control and licensing system, as well as for allopathic drugs with subsequent registration with the Ministry of Health. This provides a reliable guarantee of the effectiveness and safety of homeopathic medicines.

Biologically active additives (BAA) to food (nutraceuticals and parapharmaceuticals) are concentrates of natural or identical biologically active substances intended for direct intake or introduction into food products in order to enrich the human diet. Dietary supplements are obtained from plant, animal or mineral raw materials, as well as by chemical and biotechnological methods. Dietary supplements include bacterial and enzyme preparations that regulate the microflora of the gastrointestinal tract. Dietary supplements are produced at food, pharmaceutical and biotechnological industries in the form of extracts, tinctures, balms, powders, dry and liquid concentrates, syrups, tablets, capsules and other forms. Dietary supplements are sold by pharmacies and health food stores. They should not contain potent, narcotic or toxic substances, as well as MPs not used in medicine or used in food. Expert assessment and hygienic certification of dietary supplements is carried out in strict accordance with the regulations approved by Order No. 117 of April 15, 1997 “On the procedure for examination and hygienic certification of biologically active food additives.”

Dietary supplements first appeared in medical practice in the United States in the 60s. XX century At first they were complexes consisting of vitamins and minerals. Then their composition began to include various components of plant and animal origin, extracts and powders, incl. exotic natural products.

When compiling dietary supplements, the chemical composition and dosage of components, especially metal salts, are not always taken into account. Many of them can cause complications. Their effectiveness and safety are not always sufficiently studied. Therefore, in some cases, dietary supplements can cause harm instead of benefit, because their interaction with each other, dosages, side effects, and sometimes even narcotic effects are not taken into account. In the USA, from 1993 to 1998, 2621 reports of adverse reactions of dietary supplements were registered, incl. 101 fatal. Therefore, the WHO decided to tighten control over dietary supplements and impose requirements for their effectiveness and safety that are similar to the quality criteria for medicines.

1.4 Modern problems of pharmaceutical chemistry

The main problems of pharmaceutical chemistry are:

* creation and research of new medicines;

* development of methods for pharmaceutical and biopharmaceutical analysis.

Creation and research of new drugs. Despite the huge arsenal of available drugs, the problem of finding new highly effective drugs remains relevant.

The role of drugs is continuously growing in modern medicine. This is caused by a number of reasons, the main ones being:

* a number of serious diseases cannot yet be cured by drugs;

* long-term use of a number of drugs creates tolerant pathologies, to combat which new drugs with a different mechanism of action are needed;

* the processes of evolution of microorganisms lead to the emergence of new diseases, the treatment of which requires effective drugs;

* Some of the drugs used cause side effects, and therefore it is necessary to create safer drugs.

The creation of each new original drug 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. The creation of new drugs turned out to be possible on the basis of advances in the field of organic and pharmaceutical chemistry, the use of a complex of physicochemical methods, and conducting technological, biotechnological, biopharmaceutical and other studies of synthetic and natural compounds.

The future of pharmaceutical chemistry is connected with the demands of medicine and the further progress of research in all these areas. This will create the prerequisites for the discovery of new areas of pharmacotherapy, obtaining more physiological, harmless drugs using both chemical or microbiological synthesis and by isolating biologically active substances from plant or animal raw materials. Priority is given to developments in the production of insulin, growth hormones, drugs for the treatment of AIDS, alcoholism, and production of monoclonal bodies. Active research is being conducted in the field of creating other cardiovascular, anti-inflammatory, diuretic, neuroleptic, antiallergic drugs, immunomodulators, as well as semisynthetic antibiotics, cephalosporins and hybrid antibiotics. The most promising is the creation of drugs based on the study of natural peptides, polymers, polysaccharides, hormones, enzymes and other biologically active substances. The identification of new pharmacophores and the targeted synthesis of generations of drugs based on previously unexplored aromatic and heterocyclic compounds related to the biological systems of the body are extremely important.

The production of new synthetic drugs is practically limitless, since the number of synthesized compounds increases with their molecular weight. For example, the number of even the simplest compounds of carbon and hydrogen with a relative molecular weight of 412 exceeds 4 billion substances.

In recent years, the approach to the process of creating and researching synthetic drugs has changed. From the purely empirical method of “trial and error”, researchers are increasingly moving to the use of mathematical methods for planning and processing experimental results, and the use of modern physical and chemical methods. This approach opens up broad opportunities for predicting the likely types of biological activity of synthesized substances and reducing the time required to create new drugs. In the future, the creation and accumulation of data banks for computers, as well as the use of computers to establish the relationship between the chemical structure and pharmacological action of synthesized substances, will become increasingly important. Ultimately, these works should lead to the creation of a general theory of targeted design of effective drugs related to the systems of the human body.

The creation of new drugs of plant and animal origin consists of such basic factors as the search for new species of higher plants, the study of organs and tissues of animals or other organisms, and the establishment of the biological activity of the chemical substances they contain.

The study of new sources of drug production and the widespread use of waste from chemical, food, woodworking and other industries for their production are also important. This direction has a direct connection with the economics of the chemical and pharmaceutical industry and will help reduce the cost of drugs. Particularly promising is the use of modern methods of biotechnology and genetic engineering to create drugs, which are increasingly used in the chemical and pharmaceutical industry.

Thus, the modern nomenclature of drugs in various pharmacotherapeutic groups requires further expansion. New drugs being created are only promising if they are superior to existing ones in their effectiveness and safety, and meet world requirements in quality. In solving this problem, an important role belongs to specialists in the field of pharmaceutical chemistry, which reflects the social and medical significance of this science. Most widely, with the participation of chemists, biotechnologists, pharmacologists and clinicians, comprehensive research in the field of creating new highly effective drugs is carried out within the framework of subprogram 071 “Creation of new drugs by methods of chemical and biological synthesis.”

Along with traditional work on screening biologically active substances, the need for continuation of which is obvious, research on the targeted synthesis of new drugs is becoming increasingly important. Such work is based on studying the mechanism of pharmacokinetics and metabolism of drugs; identifying the role of endogenous compounds in biochemical processes that determine one or another type of physiological activity; research of possible ways of inhibition or activation of enzyme systems. The most important basis for the creation of new drugs is the modification of molecules of known drugs or natural biologically active substances, as well as endogenous compounds, taking into account their structural features and, in particular, the introduction of “pharmacophore” groups and the development of prodrugs. When developing drugs, it is necessary to increase bioavailability and selectivity, regulate the duration of action by creating transport systems in the body. For targeted synthesis, it is necessary to identify the correlation between the chemical structure, physical and chemical properties and biological activity of compounds, using computer technology to design drugs.

In recent years, the structure of diseases and the epidemiological situation have changed significantly; in highly developed countries, the average life expectancy of the population has increased, and the incidence rate among older people has increased. These factors have determined new directions for the search for drugs. There is a need to expand the range of drugs for the treatment of various types of psychoneurological diseases (parkinsonism, depression, sleep disorders), cardiovascular diseases (atherosclerosis, arterial hypertension, coronary artery disease, heart rhythm disorders), diseases of the musculoskeletal system (arthritis, spinal diseases), lung diseases (bronchitis, bronchial asthma). Effective drugs for the treatment of these diseases can significantly affect the quality of life and significantly extend the active period of people’s lives, incl. elderly. Moreover, the main approach in this direction is the search for mild drugs that do not cause sudden changes in the basic functions of the body and exhibit a therapeutic effect due to their influence on the metabolic links of the pathogenesis of the disease.

The main directions of searching for new and modernizing existing vital drugs are:

* synthesis of bioregulators and metabolites of energy and plastic metabolism;

* identification of potential drugs during screening of new products of chemical synthesis;

* synthesis of compounds with programmable properties (modification of structure in known series of drugs, resynthesis of natural phytosubstances, computer search for biologically active substances);

* stereoselective synthesis of eutomers and the most active conformations of socially significant drugs.

Development of methods for pharmaceutical and biopharmaceutical analysis. The solution to this important problem is possible only on the basis of fundamental theoretical studies of the physical and chemical properties of drugs with the widespread use of modern chemical and physicochemical methods. The use of these methods should cover the entire process from the creation of new drugs to quality control of the final production product. It is also necessary to develop new and improved regulatory documentation for drugs and dosage forms, reflecting the requirements for their quality and ensuring standardization.

Based on scientific analysis Using the method of expert assessments, the most promising areas of research in the field of pharmaceutical analysis were identified. An important place in these studies will be occupied by work to improve the accuracy of the analysis, its specificity and sensitivity, the desire to analyze very small quantities of drugs, including in a single dose, and also to perform the analysis automatically and in a short time. Reducing labor intensity and increasing the efficiency of analysis methods is of undoubted importance. It is promising to develop unified methods for analyzing groups of drugs united by related chemical structure based on the use of physicochemical methods. Unification creates great opportunities to increase the productivity of an analytical chemist.

In the coming years, chemical titrimetric methods, which have a number of positive aspects, in particular, high accuracy of determinations. It is also necessary to introduce new titrimetric methods into pharmaceutical analysis, such as burette-less and indicator-less titration, dielectrometric, biamperometric and other types of titration in combination with potentiometry, including in two-phase and three-phase systems.

In recent years, in chemical analysis, fiber-optic sensors (without indicators, fluorescent, chemiluminescent, biosensors) have been used. They make it possible to remotely study processes, make it possible to determine the concentration without disturbing the state of the sample, and their cost is relatively low. Kinetic methods, which are characterized by high sensitivity both in testing purity and in quantitative determination, will be further developed in pharmaceutical analysis.

The complexity and low accuracy of biological testing methods necessitate their replacement with faster and more sensitive physicochemical methods. Studying the adequacy of biological and physicochemical methods for analyzing drugs containing enzymes, proteins, amino acids, hormones, glycosides, and antibiotics is a necessary way to improve pharmaceutical analysis. In the coming 20-30 years, optical, electrochemical and especially modern chromatographic methods will take a leading role as they most fully meet the requirements of pharmaceutical analysis. Various modifications of these methods will be developed, for example, difference spectroscopy such as differential and derivative spectrophotometry. In the field of chromatography, along with gas-liquid chromatography (GLC), high-performance liquid chromatography (HPLC) is gaining increasing priority.

The good quality of the resulting drugs depends on the degree of purity of the starting products, compliance with the technological regime, etc. Therefore, an important area of ​​research in the field of pharmaceutical analysis is the development of methods for quality control of initial and intermediate products for drug production (step-by-step production control). This direction follows from the requirements that the OMR rules impose on the production of drugs. Automatic analysis methods will be developed in factory control and analytical laboratories. Significant opportunities in this regard are offered by the use of automated flow injection systems for step-by-step control, as well as GLC and HPLC for serial control of drug products. A new step has been taken towards complete automation of all analysis operations, which is based on the use of laboratory robots. Robotics has already found wide use in foreign laboratories, especially for sampling and other auxiliary operations.

Further improvement will require methods for analyzing ready-made, including multicomponent dosage forms, including aerosols, eye films, multilayer tablets, spansuls. For this purpose, hybrid methods based on a combination of chromatography with optical, electrochemical and other methods will be widely used. Express analysis of individually manufactured dosage forms will not lose its importance, but here chemical methods will increasingly be replaced by physicochemical ones. The introduction of simple and fairly accurate methods of refractometric, interferometric, polarimetric, luminescent, photocolorimetric analysis and other methods makes it possible to increase objectivity and speed up the assessment of the quality of dosage forms manufactured in pharmacies. The development of such methods is becoming increasingly relevant in connection with the problem of combating drug counterfeiting that has arisen in recent years. Along with legislative and legal norms, it is absolutely necessary to strengthen control over the quality of drugs of domestic and foreign production, incl. express methods.

An extremely important area is the use of various methods of pharmaceutical analysis to study the chemical processes occurring during the storage of drugs. Knowledge of these processes makes it possible to solve such pressing problems as stabilization of drugs and dosage forms, development of scientifically based storage conditions for drugs. The practical feasibility of such studies is confirmed by their economic significance.

The task of biopharmaceutical analysis includes the development of methods for determining not only drugs, but also their metabolites in biological fluids and body tissues. To solve the problems of biopharmaceuticals and pharmacokinetics, accurate and sensitive physicochemical methods for analyzing drugs in biological tissues and fluids are needed. The development of such methods is among the tasks of specialists working in the field of pharmaceutical and toxicological analysis.

The further development of pharmaceutical and biopharmaceutical analysis is closely related to the use of mathematical methods to optimize methods for drug quality control. In various fields of pharmacy, information theory is already used, as well as mathematical methods such as simplex optimization, linear, nonlinear, numerical programming, multifactor experiment, pattern recognition theory, and various expert systems.

Mathematical methods for planning an experiment make it possible to formalize the procedure for studying a particular system and ultimately obtain its mathematical model in the form of a regression equation that includes all the most significant factors. As a result, optimization of the entire process is achieved and the most probable mechanism of its functioning is established.

Increasingly, modern analysis methods are combined with the use of electronic computing technology. This led to the emergence of a new science at the intersection of analytical chemistry and mathematics - chemometrics. It is based on the widespread use of methods mathematical statistics and information theory, the use of computers at various stages of choosing an analysis method, its optimization, processing and interpretation of results.

A very revealing characteristic of the state of research in the field of pharmaceutical analysis is the relative frequency of application of various methods. As of 2000, there was a downward trend in the use of chemical methods (7.7%, including thermochemistry). The same percentage of use of IR spectroscopy and UV spectrophotometry methods. The largest number of studies (54%) were performed using chromatographic methods, especially HPLC (33%). Other methods account for 23% of the work completed. Consequently, there is a stable trend towards expanding the use of chromatographic (especially HPLC) and absorption methods to improve and unify drug analysis methods.

2. History of the development of pharmaceutical chemistry

2.1 Main stages of development of pharmacy

The creation and development of pharmaceutical chemistry is closely related to the history of pharmacy. Pharmacy originated in ancient times and had a huge influence on the formation of medicine, chemistry and other sciences.

The history of pharmacy is an independent discipline that is studied separately. To understand how and why pharmaceutical chemistry originated in the depths of pharmacy, how the process of its formation into an independent science took place, let us briefly consider the individual stages of the development of pharmacy, starting from the period of iatrochemistry.

The period of iatrochemistry (XVI - XVII centuries). During the Renaissance, alchemy was replaced by iatrochemistry (medicinal chemistry). Its founder Paracelsus (1493 - 1541) believed that “chemistry should serve not the extraction of gold, but the protection of health.” The essence of Paracelsus's teachings was based on the fact that the human body is a collection of chemical substances and the lack of any of them can cause disease. Therefore, for healing, Paracelsus used chemical compounds various metals (mercury, lead, copper, iron, antimony, arsenic, etc.), as well as herbal medicines.

Paracelsus conducted a study of the effects on the body of many substances of mineral and plant origin. He improved a number of instruments and apparatus for performing analysis. That is why Paracelsus is rightfully considered one of the founders of pharmaceutical analysis, and iatrochemistry as the period of the birth of pharmaceutical chemistry.

Pharmacies in the 16th - 17th centuries. were original centers for the study of chemical substances. In them, substances of mineral, plant and animal origin were obtained and studied. A number of new compounds were discovered here, and the properties and transformations of various metals were studied. This allowed us to accumulate valuable chemical knowledge and improve chemical experiments. Over 100 years of development of atrochemistry, science has been enriched with more facts than alchemy in 1000 years.

The period of origin of the first chemical theories (XVII - XIX centuries). To develop industrial production during this period, it was necessary to expand the scope of chemical research beyond the boundaries of atrochemistry. This led to the creation of the first chemical production facilities and the formation of chemical science.

Second half of the 17th century. - the period of the birth of the first chemical theory - the theory of phlogiston. With its help, they tried to prove that the processes of combustion and oxidation are accompanied by the release of a special substance - “phlogiston”. The theory of phlogiston was created by I. Becher (1635-1682) and G. Stahl (1660-1734). Despite some erroneous provisions, it was undoubtedly progressive and contributed to the development of chemical science.

In the struggle with supporters of the phlogiston theory, the oxygen theory arose, which was a powerful impetus in the development of chemical thought. Our great compatriot M.V. Lomonosov (1711 - 1765) was one of the first scientists in the world to prove the inconsistency of the phlogiston theory. Despite the fact that oxygen was not yet known, M.V. Lomonosov experimentally showed in 1756 that in the process of combustion and oxidation, it is not decomposition that occurs, but the addition of air “particles” by the substance. Similar results were obtained 18 years later in 1774 by the French scientist A. Lavoisier.

Oxygen was first isolated by the Swedish scientist - pharmacist K. Scheele (1742 - 1786), whose merit was also the discovery of chlorine, glycerin, a number of organic acids and other substances.

Second half of the 18th century. was a period of rapid development of chemistry. Pharmacists made a great contribution to the progress of chemical science, who made a number of remarkable discoveries that are important for both pharmacy and chemistry. Thus, the French pharmacist L. Vauquelin (1763 - 1829) discovered new elements - chromium, beryllium. Pharmacist B. Courtois (1777 -- 1836) discovered iodine in seaweed. In 1807, the French pharmacist Seguin isolated morphine from opium, and his compatriots Peltier and Caventou were the first to obtain strychnine, brucine and other alkaloids from plant materials.

The pharmacist More (1806 - 1879) did a lot for the development of pharmaceutical analysis. He was the first to use burettes, pipettes, and pharmaceutical scales, which bear his name.

Thus, pharmaceutical chemistry, which originated during the period of iatrochemistry in the 16th century, received its further development in the 17th - 18th centuries.

2.2 Development of pharmaceutical chemistry in Russia

The origins of Russian pharmacy. The emergence of pharmacy in Russia is associated with the widespread development traditional medicine and witchcraft. Handwritten “healing books” and “herbal books” have survived to this day. They contain information about numerous medicinal products of the plant and animal world. The first cells of the pharmacy business in Rus' were herbal shops (XIII - XV centuries). The emergence of pharmaceutical analysis should be attributed to the same period, as there was a need to check the quality of drugs. Russian pharmacies in the 16th - 17th centuries. were unique laboratories for the production of not only medicines, but also acids (sulfuric and nitric), alum, vitriol, sulfur purification, etc. Consequently, pharmacies were the birthplace of pharmaceutical chemistry.

The ideas of alchemists were alien to Russia; a genuine craft for making medicines immediately began to develop here. Alchemists were involved in the preparation and quality control of medicines in pharmacies (the term “alchemist” has nothing to do with alchemy).

The training of pharmacists was carried out by the first medical school opened in 1706 in Moscow. One of the special disciplines in it was pharmaceutical chemistry. Many Russian chemists were educated at this school.

The true development of chemical and pharmaceutical science in Russia is associated with the name of M.V. Lomonosov. On the initiative of M.V. Lomonosov, the first scientific chemical laboratory was created in 1748, and the first Russian university was opened in 1755. Together with the Academy of Sciences, these were centers of Russian science, including chemical and pharmaceutical science. M.V. Lomonosov has wonderful words about the relationship between chemistry and medicine: “...A physician cannot be perfect without a sufficient knowledge of chemistry, and all the shortcomings, all the excesses and the tendencies that arise from them in medical science; additions, aversions and corrections from one almost chemistry should rely."

One of the many successors of M.V. Lomonosov was a pharmacy student and then a major Russian scientist T.E. Lovitz (1757 - 1804). He first discovered the adsorption capacity of coal and used it to purify water, alcohol, and tartaric acid; developed methods for producing absolute alcohol, acetic acid, and grape sugar. Among the numerous works of T.E. Lovitz, the development of a microcrystalloscopic method of analysis (1798) is directly related to pharmaceutical chemistry.

A worthy successor to M.V. Lomonosov was the largest Russian chemist V.M. Severgin (1765 - 1826). Among his many works highest value for pharmacy there are two books published in 1800: “A way to test the purity and integrity of medicinal chemical products” and “A way to test mineral waters". Both books are the first domestic manuals in the field of research and analysis of medicinal substances. Continuing the thought of M.V. Lomonosov, V.M. Severgin emphasizes the importance of chemistry in assessing the quality of drugs: “Without knowledge in chemistry, drug testing cannot be undertaken.” The author deeply scientifically selects only the most accurate and accessible methods of analysis for the study of drugs. The procedure and plan for the study of medicinal substances proposed by V.M. Severgin has changed little and is now used in the compilation of State Pharmacopoeias. V.M. Severgin has created a scientific basis not only for pharmaceuticals, but also for pharmaceuticals. chemical analysis in our country.

The works of the Russian scientist A.P. Nelyubin (1785 - 1858) are rightly called the "Encyclopedia of Pharmaceutical Knowledge". He was the first to formulate the scientific foundations of pharmacy and carried out a number of applied research in the field of pharmaceutical chemistry; improved methods for obtaining quinine salts, created instruments for obtaining ether and for testing arsenic. A.P. Nelyubin conducted extensive chemical studies of Caucasian mineral waters.

Until the 40s of the 19th century. In Russia there were many chemist scientists who made a great contribution to the development of pharmaceutical chemistry with their works. However, they worked separately; there were almost no chemical laboratories, no equipment and no scientific chemical schools.

The first chemical schools and the creation of new chemical theories in Russia. The first Russian chemical schools, the founders of which were A.A. Voskresensky (1809-1880) and N.N. Zinin (1812-1880), played an important role in training personnel, in the creation of laboratories, and had a great influence on the development of chemical sciences, in including pharmaceutical chemistry. A.A. Voskresensky carried out a number of studies with his students that are directly related to pharmacy. They isolated the alkaloid theobromine and conducted studies of the chemical structure of quinine. N.N. Zinin’s outstanding discovery was the classical reaction of the transformation of aromatic nitro compounds into amino compounds.

D.I. Mendeleev wrote that A.A. Voskresensky and N.N. Zinin are “the founders of the independent development of chemical knowledge in Russia.” Their worthy successors D.I. Mendeleev and A.M. Butlerov brought world fame to Russia.

D.I.Mendeleev (1834 -- 1907) is the creator of the Periodic Law and Periodic table elements. The enormous importance of the Periodic Law for all chemical sciences is well known, but it also contains a deep philosophical meaning, since it shows that all elements form a single system connected by a general pattern. In its multifaceted scientific activity D.I. Mendeleev also paid attention to pharmacy. Back in 1892, he wrote about the need to “establish factories and laboratories in Russia for the production of pharmaceutical and hygienic preparations” in order to be free from imports.

The works of A.M. Butlerov also contributed to the development of pharmaceutical chemistry. A.M. Butlerov (1828 - 1886) received urotropine in 1859; While studying the structure of quinine, he discovered quinoline. He synthesized sugary substances from formaldehyde. However, his creation (1861) of the theory of the structure of organic compounds brought him worldwide fame.

The periodic table of elements by D.I. Mendeleev and the theory of the structure of organic compounds by A.M. Butlerov had a decisive influence on the development of chemical science and its connection with production.

Research in the field of chemotherapy and chemistry of natural substances. At the end of the 19th century, new studies of natural substances were carried out in Russia. Back in 1880, long before the work of the Polish scientist Funk, the Russian doctor N.I. Lunin suggested that in addition to protein, fat, sugar, “substances essential for nutrition” are present in food. He experimentally proved the existence of these substances, which were later called vitamins.

In 1890, E. Shatsky’s book “The Doctrine of Plant Alkaloids, Glucosides and Ptomaines” was published in Kazan. It examines the alkaloids known at that time according to their classification according to their producing plants. Methods for extracting alkaloids from plant materials are described, including the apparatus proposed by E. Shatsky.

In 1897, K. Ryabinin’s monograph “Alkaloids (Chemical and Physiological Essays)” was published in St. Petersburg. In the introduction, the author points out the urgent need “to have in Russian such an essay on alkaloids, which, in a small volume, would give an accurate, significant and comprehensive understanding of their properties.” The monograph has a short introduction describing general information about the chemical properties of alkaloids, as well as sections that provide summary formulas, physical and chemical properties, reagents used for identification, as well as information on the use of 28 alkaloids.

Chemotherapy emerged at the turn of the 20th century. in connection with the rapid development of medicine, biology and chemistry. Both domestic and foreign scientists contributed to its development. One of the creators of chemotherapy is the Russian doctor D. JI. Romanovsky. He formulated in 1891 and experimentally confirmed the foundations of this science, indicating that it is necessary to look for a “substance” that, when introduced into a diseased organism, will cause the least harm to the latter and cause the greatest destructive effect in the pathogenic agent. This definition has retained its meaning to this day.

Extensive research in the field of the use of dyes and organoelement compounds as medicinal substances was carried out by the German scientist P. Ehrlich (1854 - 1915) at the end of the 19th century. He was the first to propose the term “chemotherapy”. Based on the theory developed by P. Erlich, called the principle of chemical variation, many scientists, including Russians (O.Yu. Magidson, M.Ya. Kraft, M.V. Rubtsov, A.M. Grigorovsky), created a large number of chemotherapeutic drugs with antimalarial effects.

The creation of sulfonamide drugs, which marked the beginning of a new era in the development of chemotherapy, is associated with the study of the azo dye prontosil, discovered in the search for drugs for the treatment of bacterial infections (G. Domagk). The discovery of Prontosil confirmed the continuity of scientific research - from dyes to sulfonamides.

Modern chemotherapy has a huge arsenal of drugs, among which antibiotics occupy the most important place. The antibiotic penicillin, first discovered in 1928 by the Englishman A. Fleming, was the ancestor of new chemotherapeutic agents effective against pathogens of many diseases. A. Fleming's work was preceded by research by Russian scientists. In 1872, V.A. Manassein established the absence of bacteria in the culture liquid when growing green mold (Pйnicillium glaucum). A.G. Polotebnov experimentally proved that cleaning of pus and healing of a wound occurs faster if mold is applied to it. The antibiotic effect of mold was confirmed in 1904 by veterinarian M.G. Tartakovsky in experiments with the causative agent of chicken plague.

The research and production of antibiotics led to the creation of an entire branch of science and industry and revolutionized the field of drug therapy for many diseases.

Thus, carried out by Russian scientists at the end of the 19th century. Research in the field of chemotherapy and the chemistry of natural substances laid the foundation for the development of new effective drugs in subsequent years.

2.3 Development of pharmaceutical chemistry in the USSR

The formation and development of pharmaceutical chemistry in the USSR took place in the first years of Soviet power in close connection with chemical science and production. The domestic schools of chemists created in Russia, which had a huge influence on the development of pharmaceutical chemistry, have been preserved. It is enough to name the large schools of organic chemists A.E. Favorsky and N.D. Zelinsky, researcher of terpene chemistry S.S. Nametkin, creator of synthetic rubber S.V. Lebedev, V.I. Vernadsky and A.E. Fersman - in the field geochemistry, N.S. Kurnakov - in the field of physical and chemical research methods. The center of science in the country is the USSR Academy of Sciences (now NAS).

Like other applied sciences, pharmaceutical chemistry can only develop on the basis of fundamental theoretical research, which was conducted in chemical and biomedical research institutes of the USSR Academy of Sciences (NAS) and the USSR Academy of Medical Sciences (now AMS). Scientists from academic institutions are also directly involved in the creation of new drugs.

Back in the 30s, the first research in the field of chemistry of natural biologically active substances was carried out in the laboratories of A.E. Chichibabin. These studies were further developed in the works of I.L. Knunyants. He, together with O.Yu. Magidson, was the creator of the technology for the production of the domestic antimalarial drug Akrikhin, which made it possible to free our country from the import of antimalarial drugs.

An important contribution to the development of the chemistry of drugs with a heterocyclic structure was made by N.A. Preobrazhensky. Together with his colleagues, he developed and introduced into production new methods for obtaining vitamins A, E, PP, carried out the synthesis of pilocarpine, and conducted research on coenzymes, lipids and other natural substances.

V. M. Rodionov had a great influence on the development of research in the field of chemistry of heterocyclic compounds and amino acids. He was one of the founders of the domestic fine organic synthesis and chemical-pharmaceutical industries.

The research of A.P. Orekhov’s school in the field of alkaloid chemistry had a great influence on the development of pharmaceutical chemistry. Under his leadership, methods for isolating, purifying and determining the chemical structure of many alkaloids were developed, which then found use as medicines.

On the initiative of M.M. Shemyakin, the Institute of Chemistry of Natural Compounds was created. Fundamental research is conducted here in the field of chemistry of antibiotics, peptides, proteins, nucleotides, lipids, enzymes, carbohydrates, and steroid hormones. New drugs have been created on this basis. The institute laid the theoretical foundations of a new science - bioorganic chemistry.

Research conducted by G.V. Samsonov at the Institute of Macromolecular Compounds made a great contribution to solving the problems of purifying biologically active compounds from accompanying substances.

The Institute of Organic Chemistry has close ties with research in the field of pharmaceutical chemistry. During the Great Patriotic War here drugs such as Shostakovsky's balm, phenamine, and later promedol, polyvinylpyrrolidone, etc. were created. Research carried out at the institute in the field of acetylene chemistry made it possible to develop new methods for the synthesis of vitamins A and E, and the reactions of the synthesis of pyridine derivatives formed the basis of new ways obtaining vitamin Be and its analogues. Work has been carried out in the field of synthesis of anti-tuberculosis antibiotics and studying the mechanism of their action.

Research in the field of organoelement compounds, carried out in the laboratories of A.N. Nesmeyanov, A.E. Arbuzov and B.A. Arbuzov, M.I. Kabachnik, I.L. Knunyants, has received widespread development. These studies provided the theoretical basis for the creation of new drugs that are organoelement compounds of fluorine, phosphorus, iron and other elements.

At the Institute of Chemical Physics, N.M. Emanuel first expressed the idea of ​​the role of free radicals in suppressing the function of a tumor cell. This made it possible to create new antitumor drugs.

The development of pharmaceutical chemistry was also greatly facilitated by the achievements of domestic medical and biological sciences. The work of the school of the great Russian physiologist I.P. Pavlov, the work of A.N. Bach and A.V. Palladin in the field of biological chemistry, etc. had a huge influence.

At the Institute of Biochemistry named after. A.N. Bach, under the leadership of V.N. Bukin, developed methods for the industrial microbiological synthesis of vitamins B12, B15, etc.

Fundamental research in the field of chemistry and biology carried out at the institutes of the National Academy of Sciences creates a theoretical basis for the development of targeted synthesis of medicinal substances. Research in the field of molecular biology, which gives a chemical interpretation of the mechanism of biological processes occurring in the body, including under the influence of medicinal substances.

Research institutes of the Academy of Medical Sciences make a great contribution to the creation of new drugs. Extensive synthetic and pharmacological research is carried out by the institutes of the National Academy of Sciences together with the Institute of Pharmacology of the Academy of Medical Sciences. This collaboration made it possible to develop theoretical foundations targeted synthesis of a number of drugs. Scientists: synthetic chemists (N.V. Khromov-Borisov, N.K. Kochetkov), microbiologists (Z.V. Ermolyeva, G.F. Gause, etc.), pharmacologists (S.V. Anichkov, V.V. Zakusov, M.D. Mashkovsky, G.N. Pershin, etc.) created original medicinal substances.

Based on fundamental research in the field of chemical and biomedical sciences, pharmaceutical chemistry developed in our country and became an independent industry. Already in the first years of Soviet power, pharmaceutical research institutes were created.

In 1920, the Scientific Research Chemical and Pharmaceutical Institute was opened in Moscow, which in 1937 was renamed VNIHFI named after. S. Ordzhonikidze. Somewhat later, such institutes (NIHFI) were created in Kharkov (1920), Tbilisi (1932), Leningrad (1930) (in 1951 LenNIHFI was merged with the Chemical and Pharmaceutical Educational Institute). In the post-war years, NIHFI was formed in Novokuznetsk.

VNIHFI is one of the largest scientific centers in the field of creating new medicines. The scientists of this institute solved the iodine problem in our country (O.Yu. Magidson, A.G. Baychikov, etc.), and developed methods for producing antimalarial drugs, sulfonamides (O.Yu. Magidson, M.V. Rubtsov, etc. ), anti-tuberculosis drugs (S.I. Sergievskaya), organoarsenic drugs (G.A. Kirchhoff, M.Ya. Kraft, etc.), steroid hormonal drugs (V.I. Maksimov, N.N. Suvorov, etc.) , major research was carried out in the field of alkaloid chemistry (A.P. Orekhov). Now this institute is called the "Center for the Chemistry of Medicines" - VNIHFI named after. S. Ordzhonikidze. Scientific personnel are concentrated here, coordinating activities to create and introduce new medicinal substances into the practice of chemical and pharmaceutical enterprises.

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