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L ECTURE № 1

L ECTURE № 1 Theme: Course introduction and importance of Pharmaceutical Chemistry for pharmaceutical analysis. Introduction about Pharmacopoeia and methods of drug analysis. Inorganic drugs from group of halogenides of alkaline metals. Associate prof. Mosula L.M. The plan

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L ECTURE № 1

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  1. LECTURE № 1 Theme: Course introduction and importance of Pharmaceutical Chemistry for pharmaceutical analysis. Introduction about Pharmacopoeia and methods of drug analysis. Inorganic drugs from group of halogenides of alkaline metals. Associate prof. Mosula L.M.

  2. The plan 1. A subject and the contents of pharmaceutical chemistry, its interrelation with chemical, medical and biologic and pharmaceutical disciplines. 2. The State Pharmacopoeia of Ukraine (SPU), the International (Ph. Int.), Europian (Ph. Eur.) and British Pharmacopoeias (BP), and other analytical normative documentation (AND), which regulates high quality of pharmaceutical preparations. 4. Classification of drugs. 5. Inorganic drugs from group of halogenides of alkaline metals: obtaining, properties (appearance and solubility), identification, tests, assay, storage, action and use of preparations of: Fluorine (sodium fluoride); Chlorine (sodium and potassium chlorides); Bromine (sodium and potassium bromides); Iodine (sodium and potassium iodides).

  3. Pharmaceutical chemistry is a highly interdisciplinary science combining organic chemistry with biochemistry, inorganic chemistry, analytical chemistry, pharmacology, pharmacognosy, molecular biology and physical chemistry. Pharmaceutical chemistry is the chemistry of drugs and pharmaceutical products. The aim of pharmaceutical chemistry is the discovery and development of new therapeutic agents. The mission of the Pharmaceutical Chemistry course is to introduce the structure, properties, and analysis (both qualitative and quantitative) of pharmaceutical agents as well as the fundamental techniques used for near patient testing in clinical laboratories to the students. Topics include some of the basic concepts in pharmaceutical chemistry as well as methods of pharmaceutical analysis such as 1) the drug synthesis, 2) review of organic functional groups found in drug molecules as well as cations and anions of the inorganic drugs, 3) physicochemical properties related to drug action, 4) physicochemical and chemical analysis of drugs, 5) methods of identification of pharmaceutical agents, 6) the storage conditions and use of drugs.

  4. Pharmaceutical Chemistry is a multifaceted discipline that encompasses synthetic organic chemistry, inorganic, analytical, physical, colloidal, biological chemistry and some disciplines of medical and biological profile: biology, normal and pathological physiology, microbiology. The pharmaceutical chemistry is closely connected with other profile disciplines: pharmacognosy, technology of medicines, the organisation and pharmacy economy, pharmacotherapy. Pharmaceutical chemistry is a discipline at the intersection of chemistry and pharmacology involved with designing, synthesizing and developing pharmaceuticaldrugs. Compounds used as medicines are overwhelmingly organic compounds including small organic molecules and biopolymers. However, inorganic compounds and metal-containing compounds have been found to be useful as drugs.

  5. Drugs are prepared from Pharmaceutical Substances. Pharmaceutical Substances is designed to be a complete reference guide to every pharmaceutical compound of significance. It provides a compendium of some 2400 active pharmaceutical ingredients (API's) of interest to the chemical and pharmaceutical industries. Pharmaceutical Substances is an invaluable resource for anybody involved in the design, discovery, development, and evaluation of drugs.

  6. Pharmacopoeiain its modern technical sense, is a book containing directions for the identification of samples and the preparation of compound medicines, and published by the authority of a government or a medical or pharmaceutical society. The word derives from Ancient Greekφαρμακοποιεια (pharmakopoieia), from φαρμακο- (pharmako-) 'drug', followed by the verb-stem ποιε- (poie-) 'make' and finally the abstract noun ending -ια (-ia). These three elements together can be rendered as 'drug-mak-ing'. The aim of theInternational Pharmacopoeia (Ph. Int.), which is issued by the World Health Organization as a recommendation, is to achieve a wide global uniformity of quality specifications for selected pharmaceutical products, excipients, and dosage forms. The information published in the International Pharmacopoeia is collated via a consultative procedure and is based on international experience, the monographs being established in an independent manner. Priority is given to medicines that are widely used throughout the world. High priority is accorded to medicines that are important to WHO health programs, and which may not appear in any other pharmacopoeias.

  7. The European Pharmacopoeia (Ph. Eur.) of the Council of Europe is a pharmacopoeia, listing a wide range of active substances and excipients used to prepare pharmaceutical products in Europe[citation needed]. The 2005 edition includes 1800 specific and general monographs, including various chemical substances, antibiotics, biological substances. The European Pharmacopoeia is developed by the European Directorate for the Quality of Medicines (EDQM) and is a part of the Council of Europe, Strasbourg, France. It has been created by the Convention on the elaboration of a European Pharmacopoeia from 1964. The British Pharmacopoeia(BP) is an annual published collection of quality standards for UKmedicinal substances. It is used by individuals and organizations involved in pharmaceutical research, development, manufacture and testing. Pharmacopoeial standards are publicly available and legally enforceable standards of quality for medicinal products and their constituents. The Pharmacopoeia is an important statutory component in the control of medicines which complements and assists the licensing and inspection processes of the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom. Pharmacopoeial standards are compliance requirements; that is, they provide the means for an independent judgment as to the overall quality of an article and apply throughout the shelf-life of a product. Inclusion of a substance in a pharmacopoeia does not indicate that it is either safe or effective for the treatment of any disease.

  8. The State Pharmacopoeia of Ukraine (SPU) is a legal document which contains the general requirements to pharmaceutical preparations, monographies (pharmaceutical articles) as well as techniques of quality assurance of medical products. The first edition of SPU was published in 2001. It has legislative character and its requirements are obligatory for all enterprises and establishments, independently on a form of property which develop, keep, supervise, realize and apply medical products. Quality assurance of drugs in Ukraine at the state level is carried out by Ministry of Public Health. It supervises the service of medical products and products of medical appointment, the State Enterprise „Scientific and Expert Pharmacopoeial Centre”, the State Pharmacological Centre, the State Drugs inspection (its structure includes the Central laboratory of quality assurance of medical products), territorial inspections of quality assurance of medical products.

  9. Impurities are substances inside a confined amount of liquid, gas, or solid, which differ from the chemical composition of the material or compound. Impurities are either naturally occurring or added during synthesis of a chemical or commercial product. During production, impurities may be purposely, accidentally, inevitably, or incidentally added into the substance. The level of impurities in a material are generally defined in relative terms. Standards have been established by various organizations that attempt to define the permitted levels of various impurities in a manufactured product. Strictly speaking, then, a material's level of purity can only be stated as being more or less pure than some other material.

  10. Destructive impurities Impurities can be destructive when they obstruct the working nature of the material. Examples include ash and debris in metals and leaf pieces in blank white papers. The removal of impurities is usually done chemically. For example, in the manufacturing of iron, calcium carbonate is added to the blast furnace to remove silicon dioxide from the iron ore. Zone refining is an economically important method for the purification of semiconductors. However, some kinds of impurities can be removed by physical means. A mixture of water and salt can be separated by distillation, with water as the distillate and salt as the solid residue. Impurities are usually physically removed from liquids and gases. Removal of sand particles from metal ore is one example with solids. No matter what method is used, it is usually impossible to separate an impurity completely from a material. What technicians can do is to increase the purity of a material to as near 100% as possible or economically feasible.

  11. There are two types of impurities: generaland specific. The sources of general impurities are equipment, solvents, auxiliary materials, and of specific ones – by-products, semiproducts of synthesis of substances of medicinal forms and compounds which are formed in medical products at their wrong storage. The State Pharmacopoeia of Ukraine, other Analytical Normative Documentation (AND) on the basis of experimental researches regulate specific impurities and their quantity for each preparation. For revealing the impurities in the medical products and their approximate quantitative estimation use standard solutions (standards). Standard solution is a chemical term which describes a solution of known concentration of testing impurity. The concentration of the solution is normally expressed in unit of ppm (parts-per-million, ppm = 10–6) (One part per million (ppm) denotes one part per 1,000,000 parts, one part in 106, and a value of 1 × 10–6.). For standards (standard solutions) preparation use chemically pure initial substances (mother substances). Presence of impurities defines by means of such methods:nephelometry and colorimetry. At the revealing same impurities use instrumental methods of analysis(atomic absorption spectroscopy, spectrophotometry, chromatography, etc.).

  12. The proposed program will you prepare to fully and confidently participate in health and biomedical careers. Pharmaceutical companies need employees with strong skills in modern chemical techniques as well as a good understanding of biomedical issues such as drug action, drug design and drug development. Students are increasingly careeroriented and are motivated by early exposure to applications of their studies. Pharmacists are health professionals who practice the science of pharmacy. It is very important propfession.

  13. Browse: British Pharmacopoeia 2009 SPU, add. 1 Sodium Chloride General Notices (Ph Eur monograph 0193) NaCl 58.44 DEFINITION Content 99.0 per cent to 100.5 per cent (dried substance). CHARACTERS Appearance White or almost white, crystalline powder or colourless crystals or white or almost white pearls. Solubility Freely soluble in water, practically insoluble in anhydrous ethanol.

  14. OBTAINING: • From water of lakes and the seas by evaporation. • 2. Clarification of technical mineral salt NaCl from impurity, which carry out consistently. Addition of a solution barium chloride ВаCl2 is precipitates by sulphates and phosphates: • Precipitate filter off, and to filtrate add excess of Na2CO3 for precipitation of impurities of Mg, Ca, Ba salts. • For deleting of exess of Na2CO3 to filtrate add HCl: • Na2CO3 + 2HCl = 2NaCl + H2O + CO2

  15. IDENTIFICATION A. It gives the reactions of chlorides(2.3.1). Chlorides: A. (BrPh, SPU, add. 1). Reaction with solution of AgNO3 in the nitric-acid medium. Dissolve in 2 ml of water R a quantity of the substance to be examined equivalent to about 2 mg of chloride (Cl–) or use 2 ml of the prescribed solution. Acidify with dilute nitric acid R and add 0.4 ml of silver nitrate solution R1. Shake and allow to stand. A curdled, white precipitate is formed. Centrifuge and wash the precipitate with three quantities, each of 1 ml, of water R. Carry out this operation rapidly in subdued light, disregarding the fact that the supernatant solution may not become perfectly clear. Suspend the precipitate in 2 ml of water R and add 1.5 ml of ammonia R. The precipitate dissolves easily with the possible exception of a few large particles which dissolve slowly. NaCl + AgNO3 → AgCl↓ + NaNO3; Cl– + Ag+ → AgCl↓ curdled, white precipitate AgCl↓ + 2NH4OH → [Ag(NH3)2]Cl + 2H2O

  16. B. (BrPh, SPU, add. 1).Reaction with oxidizers in the acid medium with the next identification of toxic gas – Cl2. Introduce into a test-tube a quantity of the substance to be examined equivalent to about 15 mg of chloride (Cl–) or the prescribed quantity. Add 0.2 g of potassium dichromate R and 1 ml of sulphuric acid R. Place a filter-paper strip impregnated with 0.1 ml of diphenylcarbazide solution R over the opening of the test-tube. The paper turns violet-red. The impregnated paper must not come into contact with the potassium dichromate. 6NaCl + K2Cr2O7 + 7H2SO4 = 3Cl2 + Cr2(SO4)3 + K2SO4 + 3Na2SO4 + 7H2O Cr2O72– + 14H+ + 6е  2Cr3+ + 7Н2О 2Cl– – 2е  Cl2 diphenylcarbazide diphenylcarbazonediphenylcarbadiazone (colourless) (orange-yellow) (violet-red)

  17. B. It gives the reactions of sodium(2.3.1). Sodium and Sodium Salts: A. (BrPh, SPU, add. 1).Reaction with potassium pyroantimonate solution. Dissolve 0.1 g of the substance to be examined in 2 ml of water R or use 2 ml of the prescribed solution. Add 2 ml of a 150 g/l solution of potassium carbonate R and heat to boiling. No precipitate is formed. Add 4 ml of potassium pyroantimonate solution R and heat to boiling. Allow to cool in iced water and if necessary rub the inside of the test-tube with a glass rod. A dense white precipitate is formed. NaCl + K[Sb(OH)6] → Na[Sb(OH)6]↓ + KCl Na+ + [Sb(OH)6]– Na[Sb(OH)6] dense white precipitate

  18. B. Reaction with methoxyphenylacetic reagent. Dissolve a quantity of the substance to be examined equivalent to about 2 mg of sodium (Na+) in 0.5 ml of water R or use 0.5 ml of the prescribed solution. Add 1.5 ml of methoxyphenylacetic reagent R (it is solution of methoxyphenylacetic acid in the tetramethylammonium hydroxide solution and ethanol) and cool in ice-water for 30 min. A voluminous, white, crystalline precipitate is formed. Place in water at 20 °C and stir for 5 min. The precipitate does not disappear. Add 1 ml of dilute ammonia R1. The precipitate dissolves completely. Add 1 ml of ammonium carbonate solution R. No precipitate is formed. white, crystalline precipitate Other reaction: SPU, N. Pyrochemical reaction.Sodium salt, wetted with hydrochloric acid and brought in a colourless flame, paints its in yellow colour: Na+ + hν → *Na+ → Na+ + hν1.

  19. TESTS If the substance is in the form of pearls crush before use. Solution S Dissolve 20.0 g in carbon dioxide-free water R prepared from distilled water R and dilute to 100.0 ml with the same solvent. Ferrocyanides - inadmissible impurity. Dissolve 2.0 g in 6 ml of water R. Add 0.5 ml of a mixture of 5 ml of a 10 g/l solution of ferric ammonium sulphate R in a 2.5 g/l solution of sulphuric acid R and 95 ml of a 10 g/l solution of ferrous sulphate R. No blue colour develops within 10 min. 4Fe3+ + 3[Fe(CN)6]4–  Fe4[Fe(CN)6]3 3Fe2+ + 2[Fe(CN)6]3–  Fe3[Fe(CN)6]2 Iodides - inadmissible impurity. Moisten 5 g by the dropwise addition of a freshly prepared mixture of 0.15 ml of sodium nitrite solution R, 2 ml of 0.5 M sulphuric acid , 25 ml of iodide-free starch solution R and 25 ml of water R. After 5 min, examine in daylight. The mixture shows no blue colour. 2I– + 2NO2– + 4H+ I2 + 2NO + 2H2O Barium - inadmissible impurity. To 5 ml of solution S add 5 ml of distilled water R and 2 ml of dilute sulphuric acid R. After 2h, any opalescence in the solution is not more intense than that in a mixture of 5 ml of solution S and 7 ml of distilled water R. Ва2+ + SO42–  ВаSO4 

  20. ASSAY (BrPh, SPU, add. 1). Argentometry, direct titration with potentiometric fixation of end-point. Dissolve 50.0 mg in water R and dilute to 50 ml with the same solvent. Titrate with 0.1 M silver nitrate determining the end-point potentiometrically (2.2.20). 1 ml of 0.1 M silver nitrate is equivalent to 5.844 mg of NaCl. NaCl + AgNO3 = AgCl↓ + NaNO3 Еm(NaCl) = M. m. Other methods: 1.SPU, add. 1. Thiocyanatometry. 2. SP X. Argentometry, direct titration (Morh method). Indicator – K2CrO4. 3. Argentometry, back titration (Volhard method) (see thiocyanatometry). To investigated solution add double excess of standart solution of AgNO3. NaCl + AgNO3 = AgCl + NaNO3 AgNO3 + NH4SCN = AgSCN + NH4NO3 3NH4SCN + (NH4)Fe(SO4)2 = Fe(SCN)3 + 2(NH4)2SO4 Еm(NaCl) = M. м.

  21. Argentometry, direct titration (Fajance method). Indicator – fluoresceine. 5. Mercurymetry, direct titration. Indicator – diphenylcarbazone. To titrate until changing of colouring solution from yellow-red to dark blue colour. In the equivalence point excess drop of titrant Нg(NO3)2 interaction with indicator of diphenylcarbazone and formation of dark blue complex.

  22. Leybeling — where applicable, that the substance is suitable for use in the manufacture of parenteral dosage forms; — where applicable, that the substance is suitable for use in the manufacture of peritoneal dialysis solutions, haemodialysis solutions or haemofiltration solutions. Action and use Used in treatment of electrolyte deficiency. Plasma substitute. Ions Na + are basic extracellular Ions. It is the basic component of all salt solutions, which are applied as plasma substitutes. Isotonic (0,9 %) a solution of sodium chloride (Solutіo Natrіі chlorіdііsotonіca pro іnjectіonіbus) apply hypodermically, intravenously (more often drop method) and in clyster as antitoxic means and at organism dehydration, at bleedings, a shock (sometimes - to 3 L). Introduction of great volumes of this solution can lead chloride acidisis, hyperhydrations, strengthening of conclusion of Potassium from an organism. Preparations Compound Glucose, Sodium Chloride and Sodium Citrate Oral Solution Oral Rehydration Salts Potassium Chloride and Sodium Chloride Intravenous Infusion Potassium Chloride, Sodium Chloride and Glucose Intravenous Infusion Sodium Chloride Eye Drops Sodium Chloride Eye Lotion Sodium Chloride Intravenous Infusion Sodium Chloride and Glucose Intravenous Infusion Sodium Chloride Irrigation Solution Compound Sodium Chloride Mouthwash Sodium Chloride Oral Solution Sodium Chloride Solution Sodium Chloride Tablets Ph Eur

  23. Browse: British Pharmacopoeia 2009 SPU, add. 1 Potassium chloride Kalіі chlorіdum KCl 74.6 DEFINITION Content 99.0 per cent to 100.5 per cent of KCl (dried substance). CHARACTERS Appearance White or almost white, crystalline powder or colourless crystals. Solubility Freely soluble in water, practically insoluble in anhydrous ethanol. OBTAINING: 1.Clarification of Potassiumnatural salt from impurities(analogical to NaCl).

  24. Identification A. It gives the reactions of chlorides(2.3.1). Chlorides A. (BrPh, SPU, add. 1) Reaction with solution of AgNO3 in the nitricacid medium. Dissolve in 2 ml of water R a quantity of the substance to be examined equivalent to about 2 mg of chloride (Cl–) or use 2 ml of the prescribed solution. Acidify with dilute nitric acid R and add 0.4 ml of silver nitrate solution R1. Shake and allow to stand. A curdled, white precipitate is formed. Centrifuge and wash the precipitate with three quantities, each of 1 ml, of water R. Carry out this operation rapidly in subdued light, disregarding the fact that the supernatant solution may not become perfectly clear. Suspend the precipitate in 2 ml of water R and add 1.5 ml of ammonia R. The precipitate dissolves easily with the possible exception of a few large particles which dissolve slowly.

  25. B. SPU. Reaction with oxidizers in the acid medium with the next identification of toxic gas – Cl2. Introduce into a test-tube a quantity of the substance to be examined equivalent to about 15 mg of chloride (Cl–) or the prescribed quantity. Add 0.2 g of potassium dichromate R and 1 ml of sulphuric acid R. Place a filter-paper strip impregnated with 0.1 ml of diphenylcarbazide solution R over the opening of the test-tube. The paper turns violet-red. The impregnated paper must not come into contact with the potassium dichromate. diphenylcarbazide diphenylcarbazonediphenylcarbadiazone (colourless) (orange-yellow) (violet-red)

  26. B. Solution S (see Tests) gives the reactions of potassium(2.3.1). Potassium and Potassium Salts: A. (BrPh).Reaction with tartaric acid. Dissolve 0.1 g of the substance to be examined in 2 ml of water R or use 2 ml of the prescribed solution. Add 1 ml of sodium carbonate solution R and heat. No precipitate is formed. Add to the hot solution 0.05 ml of sodium sulphide solution R. No precipitate is formed. Cool in iced water and add 2 ml of a 150 g/l solution of tartaric acid R. Allow to stand. A white crystalline precipitate is formed. white crystalline precipitate

  27. B. (BrPh).Reaction with sodium cobaltinitrite. Dissolve about 40 mg of the substance to be examined in 1 ml of water R or use 1 ml of the prescribed solution. Add 1 ml of dilute acetic acid R and 1 ml of a freshly prepared 100 g/l solution of sodium cobaltinitrite R. A yellow or orange-yellow precipitate is formed immediately. orange-yellow precipitate Other reaction: SPU, N. Pyrochemical reaction. Potassium Salt, wetted with hydrochloric acid and brought in a colourless flame, paints its in violet colour:

  28. TESTS Solution S Dissolve 10.0 g in carbon dioxide-free water R prepared from distilled water R and dilute to 100 ml with the same solvent. Iodides–inadmissible impurity. Moisten 5 g by the dropwise addition of a freshly prepared mixture of 0.15 ml of sodium nitrite solution R, 2 ml of 0.5 M sulphuric acid , 25 ml of iodide-free starch solution R and 25 ml of water R. After 5 min, examine in daylight. The substance shows no blue colour. 2I– + 2NO2– + 4H+ I2 + 2NO + 2H2O Barium–inadmissible impurity. To 5 ml of solution S add 5 ml of distilled water R and 1 ml of dilute sulphuric acid R. After 15 min, any opalescence in the solution is not more intense than that in a mixture of 5 ml of solution S and 6 ml of distilled water R. Ва2+ + SO42–  ВаSO4  Sodium–inadmissible impurity. Maximum 0.10 per cent, if intended for use in the manufacture of parenteral preparations or haemodialysis solutions. Atomic emission spectrometry (2.2.22, Method I).

  29. ASSAY (BrPh, SPU, add. 1). Argentometry, back titration (thiocyanatometry). Dissolve 1.300 g in water R and dilute to 100.0 ml with the same solvent. To 10.0 ml of the solution add 50 ml of water R, 5 ml of dilute nitric acid R, 25.0 ml of 0.1 M silver nitrate and 2 ml of dibutyl phthalate R. Shake. Titrate with 0.1 M ammonium thiocyanate, using 2 ml of ferric ammonium sulphate solution R2 as indicator and shaking vigorously towards the endpoint. 1 ml of 0.1 M silver nitrate is equivalent to 7.46 mg of KCl.

  30. Other methods: 1. Argentometry (Моrh method) (see NaCl) Еm(КCl) = M. m. 3. Argentometry (Fajance method) (see NaCl) Еm(КCl) = M. m. 4. Mercurymetry (see NaCl) Еm(КCl) = M. m. LABELLING The label states:э э— where applicable, that the substance is suitable for use in the manufacture of parenteral preparations; э— where applicable, that the substance is suitable for use in the manufacture of haemodialysis solutions. Ph Eur

  31. Action and use Used in prevention and treatment of potassium deficiency and electrolyte imbalance. A source of ions of Potassium, antiarrhytmic agent. Release forms: a powder, tablets - 0,5 g and 1 g, 4 % a solution for injections; 10 % a solution for oral using. Preparations Bumetanide and Prolonged-release Potassium Tablets Oral Rehydration Salts Sterile Potassium Chloride Concentrate Potassium Chloride and Glucose Intravenous Infusion Potassium Chloride and Sodium Chloride Intravenous Infusion Potassium Chloride, Sodium Chloride and Glucose Intravenous Infusion Potassium Chloride Oral Solution Prolonged-release Potassium Chloride Tablets Ph Eur

  32. Sodium Bromide General Notices (Ph Eur monograph 0190) NaBr 102.9 DEFINITION Content 98.0 per cent to 100.5 per cent (dried substance). CHARACTERS Appearance White or almost white, granular powder or small, colourless, transparent or opaque crystals, slightly hygroscopic. Solubility Freely soluble in water, soluble in alcohol. Browse: British Pharmacopoeia 2009 SPU, add. 1

  33. Obtaining: Processing of iron scraps by means of bromine: 3Fe + 4Br2 = Fe3Br8 Received of solution of iron (II) bromide and iron (III) bromides to heat with solution of sodium carbonate Na2CO3 or potassium carbonate К2CO3:

  34. IDENTIFICATION A. It gives reaction (a) of bromides (2.3.1). Bromides: A. (BrPh).Reaction with silver nitrate in the nitric acid medium. Dissolve in 2 ml of water R a quantity of the substance to be examined equivalent to about 3 mg of bromide (Br–) or use 2 ml of the prescribed solution. Acidify with dilute nitric acid R and add 0.4 ml of silver nitrate solution R1. Shake and allow to stand. A curdled, pale yellow precipitate is formed. Centrifuge and wash the precipitate with three quantities, each of 1 ml, of water R. Carry out this operation rapidly in subdued light disregarding the fact that the supernatant solution may not become perfectly clear. Suspend the precipitate obtained in 2 ml of water R and add 1.5 ml of ammonia R. The precipitate dissolves with difficulty.

  35. Other reactions: B.(BrPh). Introduce into a small test-tube a quantity of the substance to be examined equivalent to about 5 mg of bromide (Br–) or the prescribed quantity. Add 0.25 ml of water R, about 75 mg of lead dioxide R, 0.25 ml of acetic acid R and shake gently. Dry the inside of the upper part of the test-tube with a piece of filter paper and allow to stand for 5 min. Prepare a strip of suitable filter paper of appropriate size. Impregnate it by capillarity, by dipping the tip in a drop of decolorised fuchsin solution R and introduce the impregnated part immediately into the tube. Starting from the tip, a violet colour appears within 10 s that is clearly distinguishable from the red colour of fuchsin, which may be visible on a small area at the top of the impregnated part of the paper strip. 2NaBr + PbО2 + 4CH3COOH = Br2 + Pb(CH3COO)2 + 2CH3COONa + 2H2O PbО2 + 4H+ + 2е  Pb2+ + 2Н2О 2Br– – 2е  Br2 Bromine Br2, which allocated, react with decolorised fuchsin solution R in the indicator paper and,as oxidizing agent, reduce again structure offuchsin:

  36. B. Solution S (see Tests) gives the reactions of sodium(2.3.1). Sodium and Sodium Salts: A. (BrPh, SPU). Reaction with potassium pyroantimonate solution. B. (BrPh, SPU). Reaction with methoxyphenylacetic reagent. Other reaction: SPU, N. Pyrochemical reaction. TESTS Solution S Dissolve 10.0 g in carbon dioxide-free water R prepared from distilled water R and dilute to 100 ml with the same solvent. Bromates –inadmissible impurity. To 10 ml of solution S add 1 ml of starch solution R, 0.1 ml of a 100 g/l solution of potassium iodide R and 0.25 ml of 0.5 M sulphuric acid and allow to stand protected from light for 5 min. No blue or violet colour develops. 5Br– + BrО3– + 6H+ = 3Br2 + 3H2O Br2 + KI = 2KBr + I2 Iodides –inadmissible impurity. To 5 ml of solution S add 0.15 ml of ferric chloride solution R1 and 2 ml of methylene chlorideR. Shake and allow to separate. The lower layer is colourless(2.2.2, Method I). This reaction is not presents: 2I– + 2Fe3+ I2 + 2Fe2+

  37. ASSAY (BrPh, and SPU, add. 1).Thiocyanatometry. Dissolve 2.000 g in water R and dilute to 100.0 ml with the same solvent. To 10.0 ml of the solution add 50 ml of water R, 5 ml of dilute nitric acid R, 25.0 ml of 0.1 M silver nitrate and 2ml of dibutyl phthalate R. Shake. Titrate with 0.1 M ammonium thiocyanate, using 2 ml of ferric ammonium sulphate solution R2 as indicator and shaking vigorously towards the endpoint. 1 ml of 0.1 M silver nitrate is equivalent to 10.29 mg of NaBr. NaBr + AgNO3 = AgBr + NaNO3 AgNO3 + NH4SCN = AgSCN + NH4NO3 3NH4SCN + (NH4)Fe(SO4)2 = Fe(SCN)3 + 2(NH4)2SO4 Еm(NaBr) = M. m. Calculate the percentage content of NaBr from the expression: A – 2.902 b a=percentage content of NaBr and NaCl obtained in the assay and calculated as NaBr, b=percentage content of Cl in the test for chlorides.

  38. Other methods of assay: 1. Argentometry (Мorh method) (see NaCl) Еm(NaBr) = M. m. 2. Argentometry, back titration (Volhard method) (see NaCl) Еm(NaBr) = M.m. 3. Mercurymetry (to see NaCl) Еm(NaBr) = M.m. 4. Ion-exchange chromatography The fixed volume of an investigated solution of bromide through a column with cation exchanger KatН + with speed of 20-25 drops for a minute; wash out water (50-70 ml) to neutral reaction behind the methyl orange. The filtrate and washing waters collect in a flask and the received solution титруют 0,1 M of solution NaOH in the presence of methyl orange to transition of colouring from pink to the yellow: Kat Н+ + NaBr = Kat Na+ + HBr HBr + NaOH = NaBr + H2O Еm(NaBr) = M. m.

  39. STORAGE In an airtight container . Action and use Sedative. Bromides - demulcents. They can restore balance between processes of excitation and braking, especially at raised activation of CNS. Bromides use at treatment of a neurasthenia, neurosises, a hysteria, the raised irritability, an epilepsy, a trochee, etc. Release forms: a powder, tablets - 0,5 g.

  40. Browse:British Pharmacopoeia 2009 SPU, add. 1 Potassium Bromide General Notices (Ph Eur monograph 0184) KBr 119.0 DEFINITION Content 98.0 per cent to 100.5 per cent (dried substance). CHARACTERS Appearance White or almost white, crystalline powder or colourless crystals. Solubility Freely soluble in water and in glycerol, slightly soluble in alcohol. OBTAINING (see NaBr)

  41. IDENTIFICATION A. It gives reaction (a) of bromides (2.3.1). (see NaBr) Bromides: A. (BrPh, SPU, add. 1). Reaction with silver nitrate in the nitric acid medium. Other reactions: B. (BrPh). Reaction with lead dioxide, acetic acid and decolorised fuchsin solution. B. Solution S (see Tests) gives the reactions of potassium(2.3.1). (see KCl) Potassium and Potassium Salts: A. (BrPh). Reaction with tartaric acid. B. (BrPh). Reaction with sodium cobaltinitrite. Other reaction: SPU, N. Pyrochemical reaction.

  42. TESTS Solution S Dissolve 10.0 g in carbon dioxide-free water R prepared from distilled water R and dilute to 100 ml with the same solvent. Bromates –inadmissible impurity. To 10 ml of solution S add 1 ml of starch solution R, 0.1 ml of a 100 g/l solution of potassium iodide R and 0.25 ml of 0.5 M sulphuric acid and allow to stand protected from light for 5 min. No blue or violet colour develops. 5Br– + BrО3– + 6H+ = 3Br2 + 3H2O Br2 + KI = 2KBr + I2 Iodides –inadmissible impurity. To 5 ml of solution S add 0.15 ml of ferric chloride solution R1 and 2 ml of methylene chlorideR. Shake and allow to separate. The lower layer is colourless (2.2.2, Method I). This reaction is not presents: 2I– + 2Fe3+ I2 + 2Fe2+

  43. ASSAY (BrPh, and SPU, add. 1).Thiocyanatometry. Dissolve 2.000 g in water R and dilute to 100.0 ml with the same solvent. To 10.0 ml of the solution add 50 ml of water R, 5 ml of dilute nitric acid R, 25.0 ml of 0.1 M silver nitrate and 2ml of dibutyl phthalate R. Shake. Titrate with 0.1 M ammonium thiocyanate, using 2 ml of ferric ammonium sulphate solution R2 as indicator and shaking vigorously towards the endpoint. 1 ml of 0.1 M silver nitrate is equivalent to 11.90 mg of KBr. KBr + AgNO3 = AgBr + KNO3 AgNO3 + NH4SCN = AgSCN + NH4NO3 3NH4SCN + (NH4)Fe(SO4)2 = Fe(SCN)3 + 2(NH4)2SO4 Еm(KBr) = M. m. Calculate the percentage content of KBr from the expression: a – 3.357 b a=percentage content of KBr and KCl obtained in the assay and calculated as KBr, b=percentage content of Cl in the test for chlorides. Ph Eur Action and use Sedative.

  44. Browse: British Pharmacopoeia 2009 SPU, add. 1 Sodium Iodide General Notices (Ph Eur monograph 0196) NaI 149.9 DEFINITION Content 99.0 per cent to 100.5 per cent (dried substance). CHARACTERS Appearance White or almost white, crystalline powder or colourless crystals, hygroscopic. Solubility Very soluble in water, freely soluble in ethanol (96 per cent). OBTAINING Analogical to NaBr – from chemical industrial waste – iron(II) iodide and iron(III) iodide, which heat with Na2CO3: 3Fe + 4I2 = Fe3I8 (FeI2 • 2FeI3) Fe3I8 + 4Na2CO3 + 4H2O = 8NaІ + Fe(OH)2 + 2Fe(OH)3 + 4CO2

  45. IDENTIFICATION A. Solution S (see Tests) gives the reactions ofiodides(2.3.1). Iodides: A. Reaction with silver nitrate solution in the nitric-acid medium. Dissolve a quantity of the substance to be examined equivalent to about 4 mg of iodide (I–) in 2 ml of water R or use 2 ml of the prescribed solution. Acidify with dilute nitric acid R and add 0.4 ml of silver nitrate solution R1. Shake and allow to stand. A curdled, pale-yellow precipitate is formed. Centrifuge and wash with three quantities, each of 1 ml, of water R. Carry out this operation rapidly in subdued light disregarding the fact that the supernatant solution may not become perfectly clear. Suspend the precipitate in 2 ml of water R and add 1.5 ml of ammonia R. The precipitate does not dissolve. NaI + AgNO3 → AgI↓ + NaNO3. curdled, pale-yellow precipitate AgI↓ + NH4OH

  46. B. Reaction with potassium dichromate solution in the presence of dilute sulphuric acid and chloroform. To 0.2 ml of a solution of the substance to be examined containing about 5 mg of iodide (I–) per millilitre, or to 0.2 ml of the prescribed solution, add 0.5 ml of dilute sulphuric acid R, 0.1 ml of potassium dichromate solution R, 2 ml of water R and 2 ml of chloroform R. Shake for a few seconds and allow to stand. The chloroform layer is coloured violet or violet-red. 6NaI + K2Cr2O7 + 7H2SO4 → 3I2 + Cr2(SO4)3 + 4Na2SO4 + 7H2O. Cr2O72– + 14H+ + 6е  2Cr3+ + 7Н2О 2I– – 2е  I2 B. Solution S gives the reactions of sodium(2.3.1). (see NaCl) Sodium and Sodium Salts: A. (BrPh, SPU). Reaction with potassium pyroantimonate solution. B. (BrPh, SPU). Reaction with methoxyphenylacetic reagent. Other reaction: SPU, N.Pyrochemical reaction. TESTS Solution S Dissolve 10.0 g in carbon dioxide-free water R prepared from distilled water R and dilute to100 ml with the same solvent. Iodatesand Thiosulphates are inadmissible impurities.

  47. ASSAY (BrPh, SPU, add. 1). Iodatometry, direct titration. Dissolve 1.300 g in water R and dilute to 100.0 ml with the same solvent. To 20.0 ml of the solution add 40 ml of hydrochloric acid R and titrate with 0.05 M potassium iodateuntil the colour changes from red to yellow.Add 5 ml of chloroform R and continue the titration, shaking vigorously, until the chloroform layer is decolorised. 1 ml of 0.05 M potassium iodate is equivalent to 14.99 mg of NaI. Indicators of this method: 1. Starch solution. or 2. Chloroform СНСl3 or tetrachlormethane (phenoxin) CCl4. IO3– + 6H+ + 6e  I– + 3H2O E0 = 1,08 В 2IO3– + 12H+ + 10e  I2 + 6H2O E0 = 1,195 В 5KI + KIO3 + 6HCl = 3I2 + 3H2O red 2I2 + KIO3 + 6HCl = 5ICl + KCl + 3H2O yellow General reaction: 2NaI + KIO3 + 6HCl = 3ICl + KCl + 2NaCl + 3H2O IO3– + 6H+ + 4e  I+ + 3H2O I– – 2e  I+ IO3– + 2I– + 6H+  3I+ + 3H2O Em(NaI) = М. m./2; k (KIO3) = 4

  48. Other methods: • 1. SP Х. Argentometry (Fajance-Khodacov method), direct titration. • Em = М. m. • 2. Argentometry (Volhard method), back titration. • Em = М. m. • 3. Mercurymetry. • Em = М.m. • 4. Ion-exchange chromatography. • Em = М. m. • STORAGE • Protected from light. • Ph Eur • Action and use • Thireoid agent (Iodine drug) • Preparation • Sodium Iodide Injection • Ph Eur

  49. Browse: British Pharmacopoeia 2009 SPU, add. 1 • Potassium Iodide • General Notices • (Ph Eur monograph 0186) • KI • 166.0 • DEFINITION • Content • 99.0 per cent to 100.5 per cent (dried substance). • CHARACTERS • Appearance • White or almost white powder or colourless crystals. • Solubility • Very soluble in water, freely soluble in glycerol, soluble in ethanol (96 per cent).

  50. OBTAINING • Analogical to NaBr – from chemical industrial waste – iron(II) iodide and iron(III) iodide, which heat with K2CO3: • 3Fe + 4I2 = Fe3I8 (FeI2 • 2FeI3) • Fe3I8 + 4К2CO3 + 4H2O = 8КI + Fe(OH)2 + 2Fe(OH)3 + 4CO2 • IDENTIFICATION • A.Solution S (see Tests) gives the reactions of iodides (2.3.1). • B. Solution S gives the reactions of potassium (2.3.1). • STORAGE • Protected from light. • Action and use • Antithyroid. • Ph Eur

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