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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 challenges 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 of 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 accumulation concentrations when taken in the blood and tissues), therapeutic equivalence (equal effectiveness and safety when administered under 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 the State Register in 1996 (in the amount of 1192 monopreparations). Subsequently, this nomenclature expanded and now includes, in addition to 1192 monomedicines, 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 biotechnology industries in the form of extracts, tinctures, balms, powders, dry and liquid concentrates, syrups, tablets, capsules and other forms. Dietary supplements are sold in 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 directions 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. It is extremely important to identify new pharmacophores and targeted synthesis of generations of drugs based on previously unexplored aromatic and heterocyclic compounds related to the biological systems of the body.
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, physicochemical 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 have been 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 will retain their importance, 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 liquids 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 of 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' teaching 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 of various metals (mercury, lead, copper, iron, antimony, arsenic, etc.), as well as herbal medicines.
Paracelsus conducted a study of the effects of many substances of mineral and plant origin on the body. 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 of 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; here the genuine craft of making medicines immediately began to develop. 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 Moscow in 1706. 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 numerous works, two books published in 1800 are of greatest importance for pharmacy: “A Method for Testing the Purity and Innocence of Medicinal Chemical Products” and “A Method for Testing 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 drug research. The procedure and plan for studying medicinal substances proposed by V.M. Severgin has changed little and is now used in the compilation of State Pharmacopoeias. V.M. Severgin created the scientific basis of not only pharmaceutical, but also 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, there was 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 converting 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 the Periodic Table of 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 his multifaceted scientific activities, D.I. Mendeleev 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 institutes 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, drugs such as Shostakovsky's balm, phenamine, and later promedol, polyvinylpyrrolidone, etc. were created here. Research conducted 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 reactions for the synthesis of pyridine derivatives formed the basis for new ways to obtain 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 is especially important, which provides 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 the theoretical foundations for the 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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Pharmaceutical chemistry as a science. History of development. Modern scientific problems
Modern scientific problems of pharmaceutical chemistry is an elective discipline and belongs to the variable part of the professional cycle of the Federal State Educational Standard.
The study of the discipline ends with current control in the 9th semester - undifferentiated credit.
The goal of mastering an elective discipline is for students to acquire in-depth knowledge on the main research problems of pharmaceutical chemistry:
creation of new medicines;
development of new and improvement of existing methods for quality control of medicines.
Pharmaceutical chemistry is an applied science that, based on the general laws of chemical sciences, studies:
chemical nature of the drug;
methods of obtaining drugs;
drug structure;
physical and chemical properties of drugs;
methods of drug analysis;
the connection between the chemical structure of a drug and its effect on the body;
changes that occur during drug storage;
application and forms of release of drugs.
History of the development of pharmaceutical chemistry
I. Period of iatrochemistry (XVI-XVII centuries)
Iatrochemistry, outdated. iatrochemistry (from ancient Greek ἰ ατρός - doctor) is a rational direction of alchemy of the 16th–17th centuries, which sought to put chemistry at the service of medicine and set as its main goal the preparation of medicines.
Explained the origin of diseases by chemical processes in the human body.
The origin and development of iatrochemistry, which is most widespread in Germany and the Netherlands, is associated with the activities of a number of researchers.
Jan Baptist van Helmont(1580-1644) - Dutch naturalist, physician. Van Helmont was one of the first to use silver nitrate (lapis) to cauterize wounds, inflammations and warts. He believed that gastric acid plays a decisive role in digestion, and therefore proposed treating diseases caused by excess acids in the stomach with alkalis. He introduced the term “gas” into chemistry.
Francis Silvius, aka Francois Dubois, France de la Boe
(1614-1672) - Dutch physician, physiologist, anatomist and chemist. counted
“caustics” of an acidic or alkaline nature and prescribed alkalis for one type of disease, and acids for another. I learned to obtain silver nitrate (lapis) and use it to cauterize wounds, inflammations and warts. Opened the first chemical laboratory for analysis at Leiden University.
(real name Philip Aureolus Theophrastus Bombast von Hohenheim, 1493-1541) - famous alchemist and physician of Swiss-German origin, one of the founders of iatrochemistry. He believed that “chemistry should serve not the extraction of gold, but the protection of health.”
The essence of Paracelsus' teaching 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 of various metals (mercury, lead, copper, iron, antimony, arsenic, etc.), as well as extracts from plants. Paracelsus conducted a study of the effects of many substances of mineral and plant origin on the body. 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 – the period of the birth of pharmaceutical chemistry.
Pharmacies in the XVI-XVII 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.
II. 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 iatrochemistry. 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” - 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.
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, but addition
(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.
The French pharmacist L. Vauquelin (1763-1829) discovered new elements - chromium, beryllium.
The French chemist 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 quinine, strychnine, brucine and other alkaloids from plant materials.
The pharmacist Karl Friedrich Mohr (1806-1879), a German chemist and pharmacist, did a lot for the development of pharmaceutical analysis. He was the first to use burettes, pipettes, and pharmaceutical scales, which bear his name.
Development of pharmaceutical chemistry in Russia
The emergence of pharmacy in Russia is associated with the widespread development of traditional medicine and witchcraft. The first cells of the pharmacy business in Rus' were herbal shops (XIII-XV centuries), in which “herbalists” sold various herbs and medicines prepared from them.
The emergence of pharmaceutical analysis should be attributed to the same period (XIII-XV centuries), as there was a need to check the quality of drugs. Russian pharmacies in the XVI-XVII centuries. were unique laboratories for the production of not only drugs, but also acids (sulfuric and nitric), alum, vitriol, sulfur purification, etc. Consequently, pharmacies were the birthplace of pharmaceutical chemistry. The training of pharmacists was carried out by the first medical school opened in Moscow in 1706. 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 Mikhail Vasilyevich Lomonosov (1711–1765). On the initiative of M.V. Lomonosov in 1748, the first scientific chemical laboratory was created, and in 1755 the first Russian university was opened. Together with the Academy of Sciences, these were centers of Russian science, including chemical and pharmaceutical science.
One of the many successors of M.V. Lomonosov was a pharmacy student, and then a major Russian scientist, Toviy Yegorovich Lovitz (1757-1804). He first discovered the adsorption capacity of coal and
used it to purify water, alcohol, tartaric acid; developed methods for producing absolute alcohol, acetic acid, and grape sugar. Among the numerous works of T.E. Lowitz's development of a microcrystalscopic method of analysis (1798) is directly related to pharmaceutical chemistry.
A worthy successor to M.V. Lomonosov was the largest Russian chemist Vasily Mikhailovich Severgin (1765-1826). Of greatest importance for pharmacy are his two books, published in 1800: “A Method for Testing the Purity and Innocence of Medicinal Chemical Products” and “A Method for Testing Mineral Waters.” V.M. Severgin created the scientific basis of not only pharmaceutical, but also chemical analysis in our country.
The “Encyclopedia of Pharmaceutical Knowledge” refers to the works of the Russian scientist Alexander Petrovich Nelyubin (1785-1858). 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.
The founders of the first Russian chemical schools in Russia were
A.A. Voskresensky (1809-1880) and H.H. Zinin (1812-1880).
A.A. Voskresensky and H.H. Zinin played an important role in personnel training,
V the creation of laboratories had a great influence on the development of chemical sciences, including pharmaceutical chemistry. A.A. Voskresensky carried out a number of studies with his students that were directly related to pharmacy. They isolated the alkaloid theobromine and conducted studies of the chemical structure of quinine. The outstanding discovery of H.H. Zinina was a classic reaction for the conversion of aromatic nitro compounds into amino compounds.
DI. Mendeleev (1834-1907) is the creator of the Periodic Law and the Periodic Table of Elements. DI. Mendeleev also paid attention to pharmacy. Back in 1892, he wrote about the need for “a device
V Russia of factories and laboratories for the production of pharmaceutical and hygienic preparations” in order to be exempt from imports.
hexamethylenetetramine, discovered quinoline, studying the structure of quinine, synthesized sugary substances from formaldehyde. A.M. brought world fame. Butlerov created (1861) the theory of the structure of organic compounds.
Periodic table of elements D.I. Mendeleev and the theory of the structure of organic compounds A.M. Butlerov had a decisive influence on the development of chemical science and its connection with production.
At the end of the 19th century. In Russia, extensive research has been carried out on natural substances. Back in 1880, long before the work of the Polish scientist Funk
Russian doctor N.I. Lunin suggested that in addition to protein, fat, and sugar, food contains “substances essential for nutrition.” 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.
At the turn of the 20th century. Chemotherapy arose 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.L. Romanovsky. He formulated in 1891 and confirmed experimentally 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.
Based on the one developed at the end of the 19th century. German scientist P. Ehrlich theory, called the principle of chemical variation, many, including Russian scientists (O.Yu. Magidson, M.Ya. Kraft, M.V. Rubtsov, A.M. Grigorovsky) created a large number of chemotherapeutic agents 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, 1930). The discovery of Prontosil was a confirmation of the continuity of scientific research - from dyes to sulfonamides.
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 cultural liquid when growing green mold (Pénicillium glaucum). 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 production of new effective drugs in subsequent years.
Development of pharmaceutical chemistry in the USSR
Formation and development of pharmaceutical chemistry in the USSR
occurred 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.
Large schools:
organic chemists A.E. Favorsky and N.D. Zelinsky;
terpene chemistry researcher S.S. Nametkina;
creator of synthetic rubber C.B. Lebedeva;
researcher in the field physical and chemical research methods N.S. Kurnakova and others.
The center of science in the country is the USSR Academy of Sciences (now the Russian Academy of Sciences - RAS).
Pharmaceutical chemistry developed on the basis of fundamental theoretical research, which was carried out in chemical and biomedical research institutes of the USSR Academy of Sciences (RAN) and the USSR Academy of Medical Sciences (now RAMS). Scientists from academic institutes were directly involved in the creation of new medicines.
A.E. Chichibabin (1871-1945) – the first research in the field of chemistry of natural biologically active substances (BAS).
I.L. Knunyants (1906-1990), O.Yu. Magidson (1890-1971) – development of technology for the production of the domestic antimalarial drug akriquin.
H.A. Preobrazhensky (1896-1968) - new methods for obtaining vitamins A, E, PP were developed and introduced into production, the synthesis of pilocarpine was carried out, studies of coenzymes, lipids and other biologically active substances were carried out.
V.M. Rodionov (1878-1954) - contributed to the development of research in the field of chemistry of heterocyclic compounds and amino acids, one of the founders of the domestic fine organic synthesis industry
And chemical-pharmaceutical industry.
A.P. Orekhov (1881-1939) - development of methods for isolating, purifying and determining the chemical structure of many alkaloids, which were then used as drugs.
MM. Shemyakin (1908-1970) - the Institute of Chemistry of Natural Compounds was created. Fundamental research has been carried out 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.
A.N. Nesmeyanov, A.E. Arbuzov, B.A. Arbuzov, M.I. Kabachnik, I.L. Knunyants – research in the field of organoelement compounds.
Development of a theoretical basis for the creation of new drugs that are organic element compounds.
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 domestic drugs.
Creation of pharmaceutical research institutes in the USSR
1920 - Research Chemical and Pharmaceutical Institute (NIHFI), in 1937 - renamed VNIHFI named after. S. Ordzhonikidze.
1920 – NIHFI in Kharkov.
1930 – NIHFI in Leningrad.
1932 – NIHFI in Tbilisi.
70s - NIHFI in Novokuznetsk to provide scientific and technical assistance to chemical and pharmaceutical enterprises in Siberia.
VNIHFI research
The iodine problem in our country was solved (O.Yu. Magidson, A.G. Baychikov, etc.). Methods have been developed for obtaining original antimalarial drugs, sulfonamides (O.Yu. Magidson, M.V. Rubtsov, etc.), antituberculosis drugs (S.I. Sergievskaya), organoarsenic drugs (G.A. Kirchhoff, M.Ya. Kraft and 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 (CHLS). The center carries out research work and produces pharmaceutical substances.
TsHLS-VNIHFI today
Main mission:
development, preclinical research and introduction into industrial production of original medicines for the prevention and treatment of widespread diseases;
reproduction of expensive synthetic drugs used in world medical practice, with the aim of making them accessible to patients in Russia;
development of original and reproduced medicines (antihistamines, hormonal, ophthalmic, anti-inflammatory, antiviral, antimicrobial, psychotropic, cardiovascular, antispasmodic, cytostatic and other drugs);
preclinical research of synthetic drugs (clause
28 Roszdravnadzor letter dated July 14, 2009 No. 04I-389/09);
leading organization implementing scientific and technical examination of draft regulatory and technological documentation for the production of synthetic medicines, single- and multi-component finished dosage forms in accordance with paragraph
4.9 and Appendix A to OST 64-02-003-2002;
manufacturer of pharmaceutical substances, intermediates and placebos (Roszdravnadzor license No. FS-99-04-000667 dated 02/06/2009);
more than 170 generics have been reproduced, widely used in world medical practice: Akrikhin, Aminazin, Diphenhydramine, Ibuprofen, Imipramine, Clonidine, Lidocaine, Nitrazepam, Ortofen, Piracetam, Sinaflan, Tropindol, Cyclodol, Cisplatin, etc.;
About 80 original domestic medicines have been developed, including such well-known ones as Azafen (Pipofezin), Arbidol, Galantamine, Dioxidine, Metacin, Metronidazole hemisuccinate, Pyrazidol (Pirlindol), Platiphylline, Proxodolol, Promedol, Riodoxol, Salazopyridazine (Mesalazine), Tetraxoline (Oxolin) , Fenkarol (Hifenadine), Ftivazid, Emoxipine;
preclinical studies of drugs are being carried out:
pharmacological studies, including studying the mechanism of action of drugs and studying the effectiveness of the drug in comparison with analogues;
biological studies, including primary studies of in vitro and in vivo activity of compounds;
toxicological studies;
analysis of acute, chronic toxicity and pyrogenicity of drugs;
pharmacokinetic studies.
The Industrial Technology Department of the Center for the Chemistry of Medicines produces the following pharmaceutical substances:
Benzethonium chloride is an antimicrobial agent;
Collargol is an antiseptic;
Methylethylpyridinol hydrochloride (emoxipine) is an antioxidant;
Mycosidine is an antifungal agent;
Proxodolol - alpha and beta blocker;
Protargol (silver proteinate) is an anti-inflammatory agent for topical use;
Tropindole (tropisetron) is an antiemetic.
VILAR - All-Russian Research Institute of Medicinal and Aromatic Plants (established in 1931)
Based on the study of plant raw materials, more than 100 drugs were developed at the institute: individual drugs or a sum of substances,
medicinal preparations, individual plants with different types of action:
cardiovascular;
neurotropic;
antiviral;
anti-inflammatory;
antibacterial;
wound healing;
bronchodilator;
regulating the functions of the gastrointestinal tract and genitourinary tract;
immunomodulatory.
Dietary supplements have been created based on plant raw materials (general strengthening and mild tonic effect).
VILAR structure
Plant Science Center;
Center for Chemistry and Pharmaceutical Technology;
Medicine Center;
Research and educational and methodological center of biomedical technologies;
Center for the Development and Support of Scientific Research, etc. Main Goals of the Institute:
fundamental and priority applied scientific research in the field of life sciences on molecular, cellular, tissue
And organismal levels;
development and creation of promising technologies for living systems and medications aimed at improving the quality and life expectancy of the population;
introduction of scientific achievements and best practices in the field of agro-industrial complex, ensuring its innovative technological, economic and social development;
development and modernization of our own research and production
GNIISKLS
The State Research Institute for Standardization and Control of Medicines (GNIISKLS) was created in 1976 to improve quality control of medicines. The Institute carried out fundamental and applied research on the problem of “Standardization of Medicines”, including the development of reference materials (RM) and regulatory documentation (ND) for drugs, the development of quality control methods and the study of physicochemical and biological properties of drugs.
In 1999, GNIISKLS was reorganized into two research institutes: the Institute for Quality Control of Medicines and the Institute for Standardization
medicines. Both of them became part of the State Scientific Center for Expertise and Control of Medicines.
History of the Department of Pharmaceutical Chemistry of the OOO
In 1918, the Soviet government issued a decree on the opening of a pharmaceutical department at Perm State University. Classes in the pharmaceutical chemistry course were held at the university. The founder of the Department of Pharmaceutical Chemistry is Professor Nikolai Ivanovich Kromer.
1931 - the beginning of the formation of the department. The department operated in the building of the Medical Institute (K. Marx Street) from 1931 to 1937.
The Department of Pharmaceutical Chemistry was established as an independent structural unit in 1937 after a series of transformations and the separation of the pharmaceutical department into the Perm Pharmaceutical Institute. In a building on the street. Lenin, 48, the department operated from 1941 to 1965.
Main problems of pharmaceutical chemistry
I. Creation of new medicines.
II. Development of new and improvement of existing methods for quality control of medicines.
The problem of creating and researching new drugs in Russia is being addressed by:
universities;
chemical-technological institutions;
research institutions;
educational establishments;
research institutions of the Russian Academy of Medical Sciences, etc.
I. Creation of new medicines
Empirical search is a method of random discoveries. Variety – general screening (screening). A large number of obtained substances are subjected to pharmacological tests on animals and substances with biological activity are identified.
Directed synthesis involves obtaining drugs with expected biological activity.
Main types of directed synthesis
1. Reproduction of biogenic physiologically active substances (vitamins, hormones, enzymes, biogenic amines, etc.).
2. Identification of physiologically active metabolites and creation of new drugs based on metabolites and antimetabolites.
Department of Pharmacy
Organic medicines.
Aromatic compounds.
Brief lecture notes.
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 are considered, 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.
Complexation reaction with iron ions.
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.
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).
5.1. Halogenation reaction (bromination and iodination).
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 similarly, 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) 
5.2. Condensation reactions
5.2.1. With aldehydes.
5.2.2. The reaction of phenols with chloroform (CHCl 3) to form aurine dyes.
Aurines are colored:
phenol – yellow color;
thymol – yellow color turning to purple;
resorcinol – red-violet color.
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.
5.3. Nitration reaction
5.4. The reaction of azo coupling of phenols with diazonium salt in an alkaline medium.
In the case of phenol
Ministry of Agriculture of the Russian Federation
Federal State Budgetary Educational Institution
higher education
"Saratov State Agrarian University
named after N.I. Vavilov"
PHARMACEUTICAL CHEMISTRY
short course
lectures
for students 3
course
Speciality
36.05.01
Veterinary
Graduate qualification (degree)
Specialist
Standard training period
5
years
Form of study
Full-time
Saratov 201
6
UDC 615.1:54(075.8)
BBK 52.58
REVIEWER:
Candidate of Medical Sciences, Associate Professor of the Department of Faculty Surgery and Oncology
GBOU "Saratov State Medical University named after. S.V. Razumovsky"
V.L. Meshcheryakov
Pharmaceutical chemistry
: a short course of lectures for 3rd year students of the specialty
36.05.01
Veterinary medicine (specialization:
“Veterinary Pharmacy”) / Comp.: L.G. Lovtsova // Federal State Budgetary Educational Institution of Higher Education "Saratov State Agrarian University". – Saratov,
2016. – 57
With.
A short course of lectures on the discipline “Pharmaceutical Chemistry” is compiled in accordance with the work program of the discipline and is intended for students of the specialty 36.05.01 “Veterinary Medicine”, specialization “Veterinary Pharmacy”.
A short course of lectures contains theoretical material on the main issues of this discipline, in particular the following are considered: sources of medicinal substances, ways and methods of their synthesis; classification and main characteristics of medicines; pharmacokinetics and pharmacodynamics; fundamentals of pharmaceutical analysis of drugs of inorganic, organic nature and biologically active substances; basic provisions and documents regulating pharmaceutical products, as well as the control and licensing system for the quality of medicines and forms.
In general, the course is aimed at developing students’ knowledge of the basic methods of pharmaceutical analysis for drug quality control and their use in professional activities.
UDC 615.1:54(075.8)
BBK 52.58
©Lovtsova L.G., 2016
© Federal State Budgetary Educational Institution of Higher Education "Saratov State Agrarian University", 2016
3
Introduction
A veterinary pharmacist needs knowledge with which to control the quality of medicinal substances (forms), determine their authenticity, storage conditions, and information about methods for obtaining new drugs from natural resources.
Pharmaceutical chemistry occupies a central place in the complex of pharmaceutical sciences - this is the science of the chemical properties and transformations of medicinal substances, methods of their development and production, qualitative and quantitative analysis.
A short course of lectures on this discipline reveals the main methods of preparation, structure, physicochemical properties and classification of medicinal substances; the relationship between the structure of their molecules and the effect on the body; methods for quality control of drugs of inorganic, organic nature, biologically active substances and changes that occur in them during storage, as well as the main provisions and documents regulating pharmaceutical products.
Ultimate goal of training: to form in students theoretical thinking, professional habits, abilities and skills necessary for the activities of a pharmacist in the field of organizing and conducting quality control of medicines, including:
- establishing a connection between the structure of medicinal substances and their properties
(pharmacological, physicochemical);
- forecasting the stability of medicines;
- principles and requirements that determine the quality of medicines;
- selection of methods for assessing the quality of medicines, both industrial production and those manufactured in a pharmacy;
- analysis of the quality of medicines in accordance with the requirements
State Pharmacopoeia and other NTD.
4
Lecture 1
MAIN DIRECTIONS AND PROSPECTS OF CREATION
MEDICINES
1.1. The subject and content of pharmaceutical chemistry, its connection with others
sciences
A veterinary pharmacist needs knowledge with which to control the quality of medicinal substances (DS), determine their authenticity, storage conditions, and know how to obtain new drugs from natural resources.
Pharmacy
(from the Greek pharmakeia - use of drugs) - a complex of sciences and practical knowledge, including issues of research, research, storage, manufacture and dispensing of medicinal and therapeutic and prophylactic drugs.
Pharmaceutical chemistry
(PH) occupies a central place in the complex of pharmaceutical sciences - this is the science of the chemical properties and transformations of drugs, methods of their development and production, qualitative and quantitative analysis.
The creation and development of pharmaceutical chemistry is closely related to the history of pharmacy, which originated in ancient times. They are distinguished: the period of alchemy (IV-XVI centuries,
“philosopher’s stone”), the Renaissance (XVI-XVII centuries - iatrochemistry, from other Greek ἰατρός - doctor) and the period of the emergence of the first chemical theories (XVII-XIX centuries).
The origin of pharmacy in Russia is associated with traditional medicine and witchcraft (XVI-
XVII centuries).
Task discipline is to study the composition and structure of drugs, their physical and chemical properties; in the development of production methods (synthesis); the influence of the structural features of the drug on the nature of the pharmacological action; quality control, storage and dispensing of drugs and dosage forms (DF).
To dispense medicine to a patient, it is necessary to check: authenticity; goodness; quantitative content of drugs in the preparation. Based on these data, the question of the suitability of the medicine for use is decided.
Pharmaceutical chemistry is based on knowledge chemical disciplines(inorganic, organic, analytical, physical, colloidal and biochemistry) and medical
biological(biology, physiology, anatomy, pharmacology, microbiology, etc.). In addition, it serves as a necessary basis for studying related
pharmaceutical
disciplines
(drug technology, pharmacognosy, toxicological chemistry, economics and organization of pharmaceutical business). Pharmaceutical and chemical disciplines study the chemistry and technology of medicines, and biomedical disciplines study the effect of medicinal substances on the body, the transformation of substances in the body.
So, a close relationship with all of these disciplines provides a solution 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.
5
1.2. Sources of medicinal substances, routes and methods of synthesis
Medicinal substances by nature are divided into inorganic and organic, which can be obtained from natural sources and synthetically.
For getting inorganic Medicines use mineral raw materials: rocks, ore, gases, water from lakes and seas. So, to prepare sodium chloride
(Natrii chloridum) NaCl natural solutions are used: waters of lakes and seas.
Synthetic organic Medicines are obtained from products of processing of coal, oil, natural gas, wood, and minerals. The individual organic compounds isolated in this case are reagents in the organic synthesis of drugs.
Natural source of receipt organic drugs is a plant medicinal raw material from which alkaloids, terpenes, glycosides, vitamins, essential and fatty oils, resins, milky juices, proteins, carbohydrates are obtained, and is also used to obtain herbal preparations.
Hormonal preparations are prepared from raw materials of animal origin: thyroidin - from the thyroid gland, adrenaline - from the adrenal medulla.
Animal organisms are used for the biosynthesis of antibiotics
– microorganisms. Semi-synthetic antibiotics are known, which are synthesized from biologically active products of natural origin: penicillins and cephalosporins. The semi-synthetic method is also used to obtain alkaloids, vitamins, hormones, and anabolic steroid drugs.
In the 20th century the first ones appeared synthetic Medicines: antimicrobial serums, preventive vaccines and antidotes; antitumor, cardiovascular, sulfonamide and other drugs. With development genetic engineering learned to synthesize: insulin producer, somatotropin and interferon.
In other words, the range of drugs is growing every year. The State Register of Medicines of Russia “Encyclopedia of Medicines” 2004 already includes several thousand different dosage forms.
1.3. Classification of medicinal substances
Currently, there are several classifications of dosage forms:
- by state of aggregation (solid; liquid; soft; gaseous);
- by dosage (dosed and undosed);
- by route of administration: enteral and parenteral ;
- by chemical structure: acids, salts, alkalis, alcohols, etc.
For pharmaceutical chemistry, the following classifications are important:
1. Chemical classification
Drugs based on the commonality of their chemical structure and properties:
- inorganic medicines. They are divided in accordance with the position in the Periodic Table of Elements of D.I. Mendeleev (s-, p- and d-elements of the first, second, third, etc. groups) and the main classes (oxides, acids, salts, complex compounds and etc.);
- organic medicines. They are divided according to two characteristics: a) According to the structure of the carbon chain or cycle: aliphatic and cyclic
(heterocyclic
and carbocyclic compounds).
6 b) Based on the nature of the functional group, aliphatic and aromatic hydrocarbons are divided into halogen derivatives, alcohols, phenols, ethers and esters, aldehydes and their derivatives, ketones, carboxylic acids and their derivatives, etc. c) Depending on the method of production: natural, synthetic, semi-synthetic.
The disadvantage of this classification is that in some cases substances that are similar in chemical structure have different physiological effects.
2. Pharmacological classification
– it reflects the principles of the predominant action of the drug on one or another physiological system
(cardiovascular, central nervous system, gastrointestinal tract). In each of these groups, drugs are classified according to their chemical structure.
3. Pharmacotherapeutic classification
– Medicines are grouped depending on their use for the treatment of a specific disease. Chemical classification is carried out inside it.
Pharmacological and pharmacotherapeutic classifications are combined. Their disadvantage is that substances with different chemical compositions are combined into one group.
Since each type of classification has its own disadvantages, many authors use mixed classifications, which take into account many features.
1.4. General and special terms of pharmaceutical chemistry
In pharmaceutical chemistry, general (used in other chemical disciplines) and special (pharmaceutical) terms are used. Let's look at some of the most important terms for the PH course in accordance with GOST
91500.05.001-2000 “Quality standards for medicines. Basic provisions”, which implements the provisions of the Federal Law “On Medicines” dated June 22, 1998 No. 86-FZ (as amended on December 30, 2001).
Bioavailability- the completeness and speed of absorption of a medicinal substance, which are characterized by its amount entering the body after administration of the medicinal product.
Bioequivalence- equality of bioavailability within acceptable limits for the same medicinal products prepared by different manufacturers.
Validation- assessment and documentary confirmation of compliance of the production process and product quality with the approved requirements.
Quality of the drug- a set of properties that give the medicinal product the ability to meet its intended purpose and meet the requirements established by the standard.
Medicines- substances used for the prevention, diagnosis and treatment of disease, obtained from blood, blood plasma, as well as organs, human or animal tissues, plants, microorganisms, minerals by synthesis methods or using biological technologies. This term corresponds to the term Pharmacological agent is a substance or mixture of substances with established pharmacological activity that is the subject of a clinical trial.
Medicinal substance (DS)– a medicine that is an individual chemical compound or biological substance.
7
Excipient- a relatively chemically and biologically indifferent substance approved for medical use in order to obtain a dosage form, impart or maintain certain properties of a medicinal product.
Medicinal (pharmaceutical) raw materials- medicines, medicinal plant materials, excipients approved for medical use for the production of medicines or other pharmaceutical products, or semi-finished products. In fact, the concept of “raw materials” includes all initial materials entering production for processing in order to obtain a finished product or semi-finished product.
Dosage form (DF)- a state imparted to a medicinal product or medicinal plant material, convenient for use, providing the necessary therapeutic effect.
Medicinal product (LP)- dosed medicinal product in a specific dosage form and ready for use.
In turn, the drug is distinguished:
Poisonous agent- a medicine with very high biological activity, the prescription, dispensing, storage and recording of which is carried out according to special rules established by the Russian Ministry of Health. Included in "list A".
Potent drug-
a medicine with high biological activity, the prescription, dispensing, storage and recording of which is carried out according to special rules established by the Ministry of Health of Russia. Included in
"list B".
Narcotic drug- a poisonous or potent drug that requires limited use and is classified as a narcotic in accordance with the law. Narcotic drugs are sold according to special rules established by the Russian Ministry of Health.
Radioactive agent- a drug used in medical practice due to its ability to produce ionizing radiation.
In foreign literature the term “ pharmaceutical (or
medicinal) products" This is due to the fact that about 95% of drugs are industrially produced dosage forms. Thus, it is possible to distinguish ready-made industrial forms from medicinal substances and drugs manufactured in pharmacies.
In addition, each medicinal product has:
Certificate- written evidence (guarantee) that the quality of the medicine
(efficiency, safety) meets the established requirements of specifications, and the production process meets the rules of GMP (Good Manufacturing
Practice - good manufacturing practice (rules for organizing production and quality control of drugs)).
Certification- a procedure by which a third party provides written assurance that a product, process, or service meets specified requirements.
Best before date- shelf life of the medicinal product approved by the legislative body based on the results of special studies
(drug), during which it retains its physicochemical, microbiological and therapeutic properties without changes or within the limits established for them, subject to storage conditions.
8
Stability- the ability of a medicinal product (drug) to maintain its physicochemical and microbiological properties for a certain time from the moment of its release.
Questions for self-control
1) What does pharmaceutical chemistry study? Name its goals, objectives and history of formation.
2) What disciplines is pharmaceutical chemistry based on? Provide a list of disciplines indicating the sections (topics) the mastery of which is necessary for its study.
3) Name the sources of medicinal substances, routes and methods of synthesis.
4) Give classifications of medicinal substances. Their features and disadvantages.
5) Define the basic terms (general and special) that are used in pharmaceutical chemistry.
BIBLIOGRAPHY
Main
1. Aksenova, E.N.. Pharmaceutical chemistry / E.N. Aksenova, O.P. Andrianova, A.P.
Arzamastsev. - Tutorial. - Publishing house: GEOTAR-Media. – 2008. - 640 pp., ISBN 978-5-9704-
0744-8 2. Belikov, V.G.. Pharmaceutical chemistry. At 2 o'clock: Part 1. General pharmaceutical chemistry;
Part 2. Special pharmaceutical chemistry: textbook./V.G.Belikov – M.: MEDpress inform. – 2009. – 616 pp., ISBN 5-98322-585-5 3. GOST 91500.05.001-2000“Quality standards for medicines. Basic provisions". Federal Law: “On Medicines” dated June 22, 1998 No. 86-FZ (as amended on December 30, 2001).
4. Chupak-Belousov, V.V.. Pharmaceutical chemistry. Course of lectures./V.V. Chupak-Belousov. Book one. – 3rd year - M.: Publishing house. BINOM, 2012. – 335 pp., ISBN 978-5-9518-0479-2
Additional
1. Mashkovsky, M.D.. Medicines./M.D. Mashkovsky - 15th ed. - M.: New
Wave, 2005. – 1200 p. – ISBN 5-7864-0203-7 2. Certification system medicinal certification systems GOST R dated 04/16/98. - M.:
Medicine - 1998.- 28 p., ISBN 5-225-04067-5 3. Sokolov, V.D. Veterinary pharmacy / V.D. Sokolov, N.L. Andreeva, G.A. Nozdrin et al.
– M.: Kolos S, 2003. – 496 p., ISBN 5-02-029288-5 4. Tyukavkina, N.A. Bioorganic chemistry: textbook for universities / N.A. Tyukavkina, Yu.I.
Baukov – 4th ed., stereotype. – M.: Bustard, 2005. – 542 p., ISBN 5-7107-8994-1 5.
Electronic scientific Internet library. lib.e-science.ru › book/?c=11&p=2 6. www.ximuk.ru
9
Lecture 2
RESEARCH AND METHODS OF ANALYSIS OF MEDICINAL SUBSTANCES
2.1.
The relationship between the structure of a substance and its effect on the body
The concept “structure-activity” refers to a complex of physicochemical properties determined by the structure of the molecule of the compound being studied. To date, it has been possible to establish only a few patterns that provide only approximate ideas about how the effect of a substance on the body can change. Thus, it has been established that:
1) Unsaturated compounds are more pharmacologically active than saturated ones.
2) The chain length of the aliphatic radical introduced into the molecule affects the activity and toxicity of the substances. An increase in biological activity occurs when the chain lengthens to six carbon atoms, then a “breaking point” is reached and higher homologues turn out to be ineffective.
3) The introduction of halogens into the molecule enhances the pharmacoactivity of the compounds, and the activity and toxicity depend on the number of halogen atoms and their location.
Halogens introduced into the aromatic cycle (Ar) increase toxicity. Chlorine and bromine derivatives enhance the narcotic effect and lower blood pressure.
Iodine derivatives are less active, but have a pronounced antiseptic effect.
4) The influence of oxygen depends on the functional group of which it is included: the introduction of –OH into the molecule increases absorption and solubility, and the pharmacoactivity increases from primary to tertiary alcohols. In aromatic compounds, the introduction of hydroxyl and carbonyl groups also enhances pharmacoactivity. The carboxyl group reduces pharmacoactivity and toxicity, but improves solubility.
5) Introducing a nitro group into the molecule does not reduce the toxicity of benzene; it increases with the introduction of a halogen. Halogen derivatives of benzene exhibit antimicrobial activity. The reduction of nitrobenzene leads to the formation of aniline, which has a toxic effect on the central nervous system, but at the same time exhibits antipyretic and analgesic effects. The toxicity of aniline is reduced with the introduction of phenolic hydroxyl.
6) Properties of the nitrogen atom: in the NH series
3
> -NH
2
- > -NH- > -N= activity increases and a ganglion-blocking effect appears, and -
N=: enhances the effect of substances on various parts of the central nervous system; -NH
2
: increase toxicity; N.H.
3
: irritates nerve centers and smooth muscles, causing spasms and convulsions.
7) The activity of the drug is also influenced by: crystal structure, solubility, spatial structure (cis- and trans-isomers, optical activity and direction of rotation).
The above examples show that when creating a new drug, a pharmaceutical chemist has certain prerequisites when choosing certain compounds and functional groups, but these will only be indicative outlines, which do not always coincide with the goal.
10
2.2. Dependence of the pharmacological action of drugs on pharmacokinetic
properties
It is important that the drug can be transported to the site of action and placed under the conditions necessary for interaction with the biological substrate.
To do this, it is necessary that it have a certain set of physicochemical properties that ensure its distribution in the body, since the body’s biological response to a given substance depends on many factors: penetration of the substance through the lipid layer, transport, adsorption, ionization, complex formation, metabolism.
Solubility determines the distribution of the substance in the body, determines the pharmacological properties of the drugs, since it significantly affects the penetration of the drug from the intestine into the blood, ensuring its bioavailability. When synthesizing drugs, it is necessary to take into account the effects of various radicals
(atomic groups) on the hydrophilicity or hydrophobicity of a substance. It was found that the affinity for water decreases with the introduction of radicals (functional groups) in the following sequence:
Hydrophilic groups: -COOH > -OH > -CHO > -CO- > -NH
2
> -CONH
2
;
Hydrophobic radicals:-CH
3
> -CH
2
-> -C
2
H
5
> -C
3
H
7
>...Alk > -C
6
H
5
Many body systems operate in an aqueous environment or include water, and this environment presents certain requirements for the structure of drugs, the molecules of which must have hydrophilic-hydrophobic properties, this determines the possibility of their distribution between water and lipids and, consequently, interaction with enzymes and receptors.
The hydrophobicity parameter is logarithm of distribution coefficients Drug in the octanol-water system (lgP). The range of variation in the lgP value depends on the type of action of the drug and has an average value for antimalarial drugs - 4.5; sleeping pills -
1.33; analgesics - 0.83; antibiotics - 0.27; sulfonamides - 0.13, etc.
Consequently, antimalarials are extremely hydrophobic substances, while hypnotics are highly hydrophobic. All known pharmacological groups can be systematized in a similar way.
Lipophilicity (hydrophobicity) and the coefficient of its distribution between water and lipids. This factor determines the penetration of drugs through membranes to tissue cells. In this case, the penetration of the substance into the cell occurs in two ways:
1.
Penetration of molecules of water-soluble substances and ions through submicroscopic (0.7-1 nm in diameter) water-filled pores that penetrate protoplasm;
2. Dissolution of drugs in lipids, which are part of the protoplasm. This route is used to transport drugs that are insoluble in water but soluble in lipids.
The rate of drug absorption is affected by pH of the environment. Hydrogen and hydroxyl ions practically cannot penetrate into cells, because They are highly reactive and interact with terminal chemical groups localized on the cell surface. Based on this, by changing the pH of the environment during oral administration of drugs, it is possible to increase or decrease the number of undissociated molecules and thus enhance or weaken the process of penetration of drugs into the cell.
Affects drug activity
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Phys. and chem. Saints, as well as methods of qualities and quantities, analysis. Basic pharmaceutical problems: obtaining biologically active substances and their research; identifying patterns between structure and. chem. conn.; improvement of medical quality assessment. Wed to ensure their max, therapeutic. efficiency and safety; research and development of methods for analyzing lek. in-in in. objects for toxicological and eco-pharmaceutical. monitoring.
F pharmaceutical is closely related to specialties. disciplines such as lek technology. forms, pharmacognosy (studies of medicinal raw materials of plant and animal origin), organization and economics of pharmacy, and is part of a complex of disciplines that form basic pharmaceuticals. education.
Application of chemical B-B as a lec. sr-v was carried out already in ancient and medieval medicine (Hippocrates, Galen, Avicenna). The emergence of pharmaceuticals is usually associated with the name of Paracelsus (who contributed to the introduction of chemical drugs into medicine) and the subsequent discoveries of the therapeutic effect of MH. chem. conn. and elements (K. Scheele, L. Vauquelin, B. Courtois), as well as with the works of M. V. Lomonosov and his school on methods of obtaining and methods for studying the quality of drugs. Wed. The formation of pharmaceutical science is attributed to the 2nd half. 19th century The 90s should be considered milestone periods in the development of pharmaceuticals. 19th century (preparation, ), 1935-37 (use of sulfonamides), 1940-42 (discovery), 1950 (psychotropic drugs of the phenothiazine group), 1955-60 (semi-synthetic and later cephalosporins), 1958 (b-blockers) and 80s (antibacterial drugs of the fluoroquinolone group).
Prerequisites for searching for lek. Weds usually serve as data about . in-va, the similarity of its structure with biogenic physiologically active substances (for example, diff.,). Sometimes lek. Wed can be obtained by modifying biogenic compounds. (eg animals) or due to the study of substances foreign to humans (eg derivatives and benzodiazepines).
Synthetic substances are obtained through org. synthesis or apply methods using achievements.
Methods for studying the content of lek are important in the pharmaceutical industry. substances in the preparation, its purity and other factors that serve as the basis for quality indicators. Analysis of lec. Wed, or pharmaceutical. analysis aims to identify and quantify the basic. component (or components) in a medicine. Pharmaceutical analysis depending on pharmacological action of the drug (purpose, dosage, route of administration) · provides for the determination of impurities, auxiliary. and accompanying medications. forms. Lek. Weds are assessed comprehensively, according to all indicators. Therefore, the expression “pharmacopoeial quality” means the suitability of the drug for use in medicine.
Compliance with lek. The average required level of quality is established using standard methods of analysis, usually specified in the pharmacopoeia. For lek. in-in along with group chemicals. r-tions use and. For the analysis of multicomponent lek. formsusually used. Purity tests are designed to confirm the absence (within the limits of the method used) of individual impurities, and in some cases to assess their content. For this purpose, chromatography is used. methods, often in combination with optical ones.
Pharmacokinetic characteristics of lek. Wed (the effect of the drug and its distribution in time) represent extremely important and mandatory information that ensures the rational and effective use of drugs, allows us to expand knowledge regarding