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L ECTURE № 4

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  1. LECTURE № 4 Theme: Inorganic metal-containing compounds of Calcium, Magnesium, Zinc, Copper and Bismuth as drugs Associate prof. Mosula L.M.

  2. The plan 1. Inorganic drugs of Calcium. 2. Inorganic drugs of Magnesium. 3. Inorganic drugs of Zinc. 4. Inorganic drugs of Copper. 5. Inorganic drugs of Bismuth.

  3. Inorganic drugs of Calcium Biological action and medical application Ions Са2 + – formation of bone and tooth tissue; strengthen ability to live of cages; promote reduction of skeletal muscles and heart muscles; curlings of blood necessary for improvement.

  4. Calcium preparations 1. Calcium oxide(Calcii oxydum) CaО – for preparation of limy water (Aqua calcis). 2. Plaster medicinal (Calcii sulfas) 2СаSО4Н2O – for surgery. 3. Calcium a carbonate precipitated (Calcii carbonas praecipitatus) СаСО3-at the raised acidity of gastric juice. 4. Calcium chloride crystal (we will consider in more details). 5. Organic preparations of Calcium (calcium lactate, calcium gluconate, calcium glycerophosphate) will be considered in following lectures.

  5. CALCIUM CHLORIDE HEXAHYDRATE SPU, addition 1 Calcii chloridum hexahydricum CaCl26H2O Calcium chloratum

  6. CALCIUM CHLORIDE DIHYDRATE SPU, addition 1 Calcii chloridum dihydricum CaCl22H2O Calcium chloratum Not less than 97,0 % and no more than 103,0 % of corresponding substances.

  7. Obtaining 1. Marble processing by chloride acid: CaCO3 + 2HCl = CaCl2 + CO2 + H2O The received solution concentrate and clear calcium chloride CaCl2 of impurity (Fe2 + and Mg2 +) action of chloride acid HCl (FeCl2 and MgCl2) Elimination: a solution sate with chlorine Cl2: FeCl2  FeCl3 Precipitation FeCl3 and MgCl2 by hydrated lime Ca (OH) 2: 2FeCl3 + 3Ca (OH) 2 = Fe (OH) 3 + 3CaCl2

  8. MgCl2 + Ca (OH) 2 = Mg (OH) 2 + CaCl2 Filter The solution is enriched CaCl2. Excess of hydrated lime Ca (OH) 2 delete action of chloride acid HCl: Ca (OH) 2 + 2HCl = CaCl2 + 2H2O Calcium chloride hexahydricum CaCl26H2O is crystallize out. 2. From solutions which are formed as a waste at soda reception on Solve method (CaCl2 – a unique by-product in this method).

  9. Properties (SPU, addition 1) The description CaCl26H2O. Crystal weight of white colour or colourless crystals. CaCl22H2O. A crystal powder of white colour. Hygroscopic.

  10. Solubility CaCl26H2O. Very soluble in water R, freely soluble in 96 % R. (Freezes at temperature nearby 29). CaCl2H2O. Freely soluble in water Р, soluble in 96 % R.

  11. Because of the big hygroscopicity in drugstores prepare 50 % a solution (Calcium chloratum solutum 50 %), and from this concentrate prepare necessary drugs which contain calcium chloride.

  12. Identification 1. Reactions for Calcium-ions Са2 + (see lime chloride, lecture 1): a) SPU. Interaction with a alcoholic solution of glyoxalhydroxyanil in the alkaline medium in the presence of chloroform; chloroformiclayer is painted in red colour at the expense of formation of intracomplex compound with Calcium, which extract by chloroform: b) SPU. Interaction solution of a preparation in acetic acid with potassium ferrocyanide (II) К4 [Fe (CN) 6] at presence of ammonium chloride NH4Cl; the white crystal precipitate of ammonium-potassium-calcium ferrocyanide (II), insoluble in acetic acid СН3СООН is formed: Ca2 ++ K + + [Fe (CN) 6] 4- + NH4 + KNH4Ca [Fe (CN) 6].

  13. c) SPU, N. Reaction with ammonium oxalate (NH4) 2C2O4; the white precipitate, insoluble in dissolved acetic acid СН3СООН and a solution of ammonia R, soluble in the dissolved mineral acids is formed: Ca2 + + C2O42 - CaС2O4. d) SPU, N: Pirochemical reaction. The salt of Calcium wetted with chloride acid R and brought in a colourless flame, paints it in orange-red colour. Са2 + + h *Са2 + Са2 + + h1

  14. 2. Reactions for chlorides-ions Cl - (acid chloride see, lecture 1) a) SPU. Reaction with a solution silver nitrate in the presence of nitric acid; the white curdled precipitate is formed СaCl2 + 2AgNO3 =2 AgCl + Сa (NO3) 2 CL - + Ag + A AgCl + 2NH4OH = [Ag (NH3) 2] Cl + 2H2O [Ag (NH3) 2] Cl + HNO3 = AgCl + 2NH4NO3 b) Action of oxidizers (К2Cr2O7 (SPU)), in the presence of sulphatic acid; gas chlorine Cl2 is allocated (to smell it is impossible – toxicant gas!):

  15. b) Action of oxidizers (К2Cr2O7 (SPU)), in the presence of sulphatic acid; gas chlorine Cl2 is allocated (to smell it is impossible – toxicant gas!): 3СаCl2 + K2Cr2O7 + 7H2SO4 = 3Cl2 + Cr2 (SO4) 3 + 3СаSO4 + К2SO4 + 7H2O Cr2O72 - + 14H + + 6е 2Cr3 + + 7Н2О 2Cl - – 2е Cl2 Cr2O72– + 6Cl– + 14H+  2Cr3+ + 3Cl2 + 7Н2О diphenylcarbazidediphenylcarbazone diphenylcarbadiazone (Colourless) (orange-yellow) (violet-red)

  16. Tests • Aluminium (an inadmissible impurity). • To solution S add a solution of ammonium chloride R, • solution of ammonia dissolved R1 and heat up to boiling; • the solution should not cloud and the precipitate should not be formed: • Al3+ + 3NH4OH  Al(OH)3+ 3NH4+ • 2. Barium (an inadmissible impurity). • To solution S add a solution calcium of sulphate R; • opalescence the received solution is not more intense • than that in a mix of solution S and water: • Ва2 + + SO42 -  ВaSO4

  17. ASSAY 1. SPU. Chelatometry, direct titration Titrant – a standard solution of sodium EDTA (ethylenediaminetetraacetate acid) (Na2–EDTA) Medium– the concentrated solution of sodium hydroxide NаOH Indicator – indicator mix of calconcarbonic acid Titrate test solution before change of colouring with violet to dark blue.

  18. Chemism: At addition to test solution of calcium chloride of indicator mix of calconcarbonic acid H2Ind (dark blue colouring) the complex metal-indicator CaInd (red-violet colour) is formed: CaCl2 + H2Ind= CaInd + 2HCl dark blue violet. At titration of such solution by standard solution Na-edetate in the environment of the concentrated solution sodium hydroxide NаOH (рН 7) is formed very strongcolourless soluble in water a complex of ions Са2 + with Na-edetate under the scheme:

  19. Superfluous drop Na2-EDTA destroys complex CaInd, forming complex Ca-edetat and free indicator H2Ind of dark blue colour. Violet dark blue Em (CaCl26H2O) = М m.

  20. Chelatomerty in the pharmaceutical analysis (SPU) Titrant – sodium EDTA (sodium salt of ethylenediaminetetraacetate acid) (Na2-EDТА)

  21. 2. Argentometry (Моrh method), direct titration Titrant – a standard solution of silver nitrate AgNO3; Medium – neutral (!) Indicator – a solution of potassium chromate K2CrО4. Titrate before occurrence of orange-red colour of precipitate 1СаCl2 + 2AgNO3 = 2AgCl + Сa (NO3) 2 The superfluous drop of AgNO3 co-operates with the indicator with formation of precipitate of orange-red colour Ag2CrО4: 2AgNO3 + K2CrО4 = Ag2CrО4 + 2KNO3 Em (CaCl26H2O) = М m./2

  22. 3. Oxalic method It is based on such processes: Quantitativeprecipitation of Calcium-ions: Са2 + + С2О42–СCаС2О4 Precipitate dissolution in dissolved sulphatic acid H2SO4 СаС2О4 + 2Н+ Са2+ + Н2С2О4;

  23. Titration oxalate acid Н2С2О4, which was formed (its quantity is equivalent to an investigated preparation of Calcium), by standard solutionof potassium permanganate KMnO4 2KMnО4 + 5Н2С2О4 + 3H2SO4 = 2MnSO4 + 10CO2 + K2SO4 + 8H2O MnО4–+ 8H + + 5 e Mn2 + + 4H2O | 5 | 2 H2С2O4 – 2e 2СО2 + 2H + | 2 | 5 5H2С2O4 + 2MnО4– + 6H+  2Mn2+ + 10СО2 + 8H2O Em (CaCl26H2O) = Мm./2

  24. Storage. In the air-tight container. Store in a dry place, in the glasswares which stoppers fill in with paraffin, considering high hygroscopicity. Therefore in drugstores prepare a concentrate – 50 % a solution (Calcium chloratum solutum 50 %) which cultivation receive solutions of a preparation of necessary concentration. Marks. In necessary cases mark: the substance is suitable for manufacture of solutions for a dialysis. Application, Anti-inflammatory, antiallergic, hemostatic means. Accept oral or enter intravenously on 5–15 ml of 10 % of a solution (contains СаCl26H2O – 100 ml, waters for injections – to 1L). At introduction hypodermically or intramuscularly causes necrosis tissue (!).

  25. Inorganic drugs of Magnesium MAGNESIUM OXYDE, HEAVY SPU Magnesii oxydum ponderosum MAGNESIUM OXYDE, LIGHT SPU Magnesii oxydum leve MAGNESIUM OXYDE Magnesii oxydum MgО Маgnеsіuм oxydatum Маgnеsіаusta Not less than 98,0 % and no more than 100,5 % MgО, in recalculation on the fried substance.

  26. Obtaining 1. Thermal processing of magnesium carbonate basic: 3MgCO3Mg (OH)23H2O 4 MgО + 3CO2 + 4H2O t 250–300 C. 2. From a brine (pickle) at processing of potash salts which contain MgCl2 a) To a brine add limy milk Ca (OH)2 for sedimentation of impurity Fe2 + and Fe3 +: Fe2 + + 2ON -  Fe (OH)2 Fe2 + + 3ON -  Fe (OH)3 And sulphatic acid H2SO4 for binding (linkage) of Calcium-cations Ca2 +: SO42 - + Ca2 + C aSO4

  27. b) Excess of limy milk Ca (OH) 2 binding of magnesium chloride MgCl2 in a kind magnesium hydroxide Mg (OH)2:, MgCl2 + Ca (OH) 2 = Mg (OH) 2 + CaCl2 c) Calcination of magnesium hydroxide (500) C) to magnesium oxide MgО: Mg (OH) 2 M gO + H2O 3. Processing of magnesium chloride superheated water steam: MgCl2 + H2О = MgО + 2НCl

  28. Properties The description (SPU) Magnesium oxide heavy is fine powder of white colour. Magnesium oxide light – finel amorphous powder of white colour. Solubility. Are practically insoluble in water R, in which find out alkaline reaction with phenolphthalein. (Are soluble in the dissolved acids.)

  29. Identification • Reactions for Magnesium-ions Mg2 + (after dissolution substance • in nitric acid dissolved R HNO3 • and neutralisations by a solution sodium гидроксида dissolved Р NаOH). • MgО + 2HNO3 = Mg (NO3) 2 + H2O • SPU. Reaction with sodium hydrogenphosphate in the • presence of ammonia solution and ammonium chloride Mg2 + + HPO42 - + NH4ОН NH4MgPO4 + Н2О white precipitate b) Reaction with 8-oxyquinoline in the medium of an ammoniac buffer solution; the yellow- green crystal precipitate of magnesium 8-oxyquinoline is formed:

  30. Tests 1. Inadmissible specific impurity are not present. ASSAY Shot of magnesium oxide preliminary dissolve in chloride acid dissolved R and dilute by water R: MgO + 2HCl = MgCl2 + H2O 1. SPU. Chelatometry, direct titration (see the table) Em (MgО) = М m. 2. The acid-base titration, back titration In the presence of methyl orange colouring before transition from pink to the yellow. 1MgО + 2HCl = MgCl2 + H2O excess 2HCl + 2NaOH = 2NaCl + 2H2O 1 mol MgО 2 mol (2 equivalent) HCl 2 mol (2 equiv.) NaOH Therefore Em(MgO) = М m./2

  31. Storage. In densely corked container. Application. Antiacid agent. MgO neutralizes chloride acid of gastric juice, magnesium oxide turns in magnesium chloride MgO + 2HCl = MgCl2 + H2O which finds out laxative effect. The release form: a powder and tablets for 0,5 g. Is a part of preparations of “Almagel”, “Gastal”, and also an antidote at a poisoning with acids.

  32. MAGNESIUM CARBONATE, HEAVY SPU, add. 1 Magnesii subcarbonas ponderosus MAGNESIUM CARBONATE, LIGHT SPU, add. 1 Magnesii subcarbonas levis MAGNESIUM CARBONATE ALKALINE (BASIC) N Magnesii subcarbonas Magnesia alba Magnesium subcarbonicum 3MgCO3Mg (OH)23H2O

  33. Obtaining • Interaction of solutions of magnesium sulphate and sodium carbonate (70-80): 4MgSO4 + 4Na2CO3 + 4H2O 3 MgCO3Mg (OH)23H2O + 4Na2SO4 + CO2 2. Thermal decomposition of magnesium hydrogencarbonate: 4Mg (HCO3) 2 3 MgCO3Mg(OH)23H2O + 5CO2

  34. Properties The description SPU, add. 1. A powder of white colour. Solubility SPU, add. 1. It is practically insoluble in water R. (It is dissolved in the dissolved acids with rough allocation of bubles of gas) 3MgCO3Mg (OH) 23H2O + 8HCl = 4MgCl2 + 3CO2 + 8H2O It is much easier dissolved in water which contains CO2, forming magnesium hydrogencarbonate: 3MgCO3Mg (OH) 23H2O + 5CO2 = 4Mg (HCO3) 2 It is possible to express this process to such simplified equations: MgCO3 + H2O + CO2 = Mg (HCO3)2 Therefore magnesium hydrogencarbonate is a component of many mineral waters. At standing a transparent solution magnesium hydrogencarbonate again cloud as a result of decomposition reaction: Mg(HCO3)2 MgCO3 + H2O + CO2

  35. Identification 1. SPU, add. 1. Bulk volume 15 g substances of magnesium carbonate heavy are occupied with volume about 30 ml. 15 g substances of magnesium carbonate light are occupied with volume about 180 ml. Test for identity of magnesium carbonate of the core spend: 3MgCO3Mg (OH) 23H2O + 8HCl = 4MgCl2 + 3CO2 + 8H2O 2. Reactions for Magnesium-ions Mg2 + (after preliminary dissolution in the dissolved acids) (see magnesium oxide).

  36. 3. Reactions for carbonate-anions СО32–: • SPU, interaction with mineral acids (SPU – acetic acid • dissolved R СН3СООН): • СО32– + 2СН3СООН = 2СН3СОО– + Н2О + СО2 • Gas, which is allocated (without colour and a smell), • pass through a solution barium hydroxide R Ва (OH)2; • the white precipitate, which is dissolved a lot of chloride acid R1 HCl is formed. • СО2 + Ва (OH) 2 = ВаСО3 + Н2О • ВаСО3 + 2HCl = BaCl2 • b) SPU, N. Reaction with the sated solution of magnesium sulphate • At addition to a water solution of a substance, which contains anions of СО32–, • sated solution of magnesium sulphate R MgSO4 at room temperature • is formed white precipitate MgCO3 (difference hydrogencarbonate, • which form a precipitate only at boiling): • CO32 - + Mg2 + = MgCO3

  37. Tests • 1. N. An inadmissible impurity – Barium. • Ва2 + + SO42 -  B aSO4 • ASSAY • Shot of test substance dissolve in chloride acid хлоридной diluted R HCl • 3MgCO3Mg (OH) 23H2O + 8HCl = 4MgCl2 + 3CO2 + 8H2O • soluble with water R and spend quantitative definition (MgCl2) • similarly magnesium oxide (see above). • SPU. Chelatometry, direct titration • (see magnesium oxide) • As the preparation structure is not constant, • recalculation do on the maintenance magnesium oxide MgО. • Em (MgО) =М. M. • 2. The acid-base titration, back titration • (similarly magnesium oxide). • Em(MgО) = М m./2

  38. 3. Gravimetric (weight) method Shot of magnesium carbonate alkaline 3MgCO3Mg (OH)23H2Odry up , calcinate to constant weight and weigh (weight or gravimetric form – MgО): 3MgCO3Mg (OH)23H2O = 4MgО + 3СО2 + 4Н2О Calculate the maintenance of magnesium oxide MgО in a preparation under the formula: , Where F – gravimetric factor, which calculate under the formula: Maintenance МgO should be less than 40,0 % and no more than 45 %.

  39. Storage. In densely corked container. Application. Antiacid agent. Release forms: a powder and tablets which contain magnesium carbonate alkaline (0,5 g) and sodium a hydrocarbonate (0,5 g). Is a part of tablets “Vicalinum”, “Vicairum”.

  40. MAGNESIUM SULPHATE HEPTAHYDRATE SPU, add. 1 Magnesii sulfas heptahydricus MAGNESIUM SULPHATE Magnesii sulfas Magnesium sulfuricum Sal amarum Bitter salt Epson salt MgSO47H2O Not less than 99,0 % and no more than 100,5 % MgSO4 (М m. = 120,4 g/mol)

  41. Obtaining • Dissolution of magnesite MgCO3 a lot of hot dissolved • sulphatic acid H2SO4: • MgCO3 + H2SO4 = MgSO4 + CO2 + H2O • Solution filter, evaporate before crystallisation; • thus receive epsom salt • – MgSO47H2O. The filtered crystals recrystallization from water. • Properties • The description. SPU, add. 1. A crystal powder of white colour • or brilliant colourless crystals. • Solubility.SPU, add. 1. Freely soluble in water R, • very soluble in boiling water R, it is practically • insoluble in 96 % alcohol R.

  42. Properties • The description. SPU, add. 1. A crystal powder of • white colour or brilliant colourless crystals. • Solubility.SPU, add. 1. Freely soluble in water R, • very soluble in boiling water R, it is practically • insoluble in 96 % alcohol R. • Identification • 1. Reactions for Magnesium-ions Mg2 + (see magnesium oxide): • 2. Reactions for sulphate-anions SO42 – • (see sodium sulphate, lecture 2): • SPU. Reaction with solution of barium chloride • ВаCl2 in chloride-acid medium HCl; • white precipitate ВаSO4 is formed: • MgSO4 + BaCl2 = BaSO4 + MgCl2 • white • SO42 - + Ва2 + ВаSO4 • The white precipitate is insoluble in mineral acids and alkalis.

  43. SPU. To the suspension, received in reaction a), • add a solution of iodine I2; yellow colouring does not disappear • (difference from sulphites SO32 - and dithionites S2O32–), • but becomes colourless at addition by dropsof solution • tin (ІІ) chloride SnCl2 (difference from iodates IO3–). • A mix boil; the deposit does not become colourless • (difference from selenates and wolframates): • MgSO4 + I2 (iodine does not become colourless). • I2 + SnCl2 + 4HCl = 2HI + H2 [SnCl6] (iodine becomes colourless). • Tests • As magnesium sulphate MgSO47H2O apply • for parenteral introductions, and also inside and in • considerable quantities therefore especial requirements • to its cleanliness are put. • Solution S. The substance solution in water R • should be clearand colourless. • 2. Acidity or alkalinity.

  44. ASSAY SPU. Chelatometry (see magnesium oxide) Em (MgSO4) = М m. Storage. In hermetically corked container because easily disappears.

  45. Application Magnesium sulphate has versatile influence on an organism. 1. At intake as a laxative. 2. At parenteral introduction - restful action on the central nervous system. 3. In the form of 25 % of a solutionenter hypodermically as antispasmodic. 4. Apply to a labour pain relief, as anticonvulsant intramuscularly on5–20 ml of 25 %of a solution. In case of redispensing of magnesium sulphate enter intravenously 10 % a solution of calcium chloride (antagonists). Release forms: a powder, 20 % or 25 % a solution in ampoules 5, 10 or 20 ml.

  46. MAGNESIUM CHLORIDE HEXAHYDRATE SPU, add. 1 Magnesii chloridum hexahydricum MgCl26H2O Not less than 99,0 % and no more than 100,5 % MgCl26H2O. Properties The description. Colourless crystals. Hygroscopic. Solubility. Very soluble in water R, freely soluble in 96 % alcohol R.

  47. Identification 1. Definition of water by semimicromethod (Fisher's method). Iodometric definition of a moisture. The maintenance of water from 51,0 % to 55,0 %.Fisher's reagent is a solution of sulphur dioxide SO2, iodine I2 and pyridine C5H5N in a methanol. At the heart of a method oxidation SO2by means of iodine I2 in the presence of water lays: SO2 + I2 + 2Н2О  H2SO4 + 2HI Reaction needs to be spent at presence pyridine, which as the mild base ,connects (binds) HI and SO2 in nonvolatile compounds: The titration end define visually on change of colouring fromellow to red-brown or by means of potentiometry.

  48. 2. Reactions for Magnesium-ions Mg2 + (see magnesium oxide): • 3. Reactions for chlorides-ions Cl- (see calcium chloride): • SPU. Reaction with a solution of silver nitrate in the presence • of nitric acid; the white curdled precipitateis formed; • b) SPU. Action of potassium dichromate К2Cr2O7 • in the sulphatic-acid medium; • gas chlorine Cl2 which paints the filtering paper • moistened of diphenylcarbazide, in violet-red colour is allocated.

  49. Tests • Solution S prepared by dissolution test substance in water, • free from СО2, R, should be clear and colourless. • 2. Acidity or alkalinity. • 4. Potassium. (not more than 500 ppm). • 5. Aluminium. (not more than 1 ppm). • 6. N. An inadmissible impurity – Barium: • Ва2 + + SO42 -  BaSO4 • white precipitate • ASSAY • SPU. Chelatometry (see magnesium sulphate). • Em (MgCl26H2O) = М m. • Storage • In the air-tight container. • Marks • In necessary cases mark: • The substance is suitable for manufacture of solutions for • perenteral dialysis, a hemodialysis or a haemofiltration; • The substance is suitable for manufacture of drugs • for parenteral applications.