Vitamins № 8

1. Vitamins №8 Vitamins of the heterocyclic row: pyrimidinetiazol, isoalloxazine, corrine. Properties, quality requirements, storage, application. Multivitamin drugs. prepared as. Medvid I.I., as.Kozachok S.S.

2. Heterocyclic row vitamins Chromane derivatives • Heterocyclic vitamins, chromane derivatives (vitamins of Е group - tocopherols), are in (Corn, cotton, flax, peanuts, sea buckthorn, etc.) oils, and in the green parts of plants, especially in the young shoots of cereals. They are also available in small quantities in milk, butter, egg yolks, meat, fats.Source of tocopherols extraction is wheat germ oil, or corn.In industry, the vitamin E extracted from natural sources or by synthesis.

3. The basis of the structure of E vitamin group is a tocol molecule - 6-oxy-2-methyl-2 (4 ', 8', 12'-trimethyltridecyl) chromane: • Different tocopherols by the number of methyl groups in the core of chromane, there are seven natural vitamins of E group. The most active-α-tocopherol. In clinical practice using tocopherol acetate.

4. Obtaining of α-tocopherol Tocopherol acetate is synthetically extracted by the condensation of trimethylhydroquiinone with phythilbromide and subsequent acetylation of α-tocopherol:         Phythilbromide is extracted from phytol containing in the nettles. From 1 ton of nettles get about 3 kg of phytol.

5. Tocopherol acetate(Tocopheroli acetas)Vitamin Е (±)-2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-acetoxichromane • CHARACTERS.Light yellow, transparent, thick, oily liquid with low odor. Practically insoluble in water, soluble in 95% alcohol and very easily soluble in ether, acetone, chloroform, and oils. Under the influence of light tocopherol acetate is oxidized and darkened.

6. Identificationof Tocopherol acetate • Oxidation of the fuming nitric acid, at the heating in a water bathe – appearance a red-orange color (o-tocopherylquinone). If we continue the condensation of o-tocopherylquinone with o-phenylenediamine, then forming a phenazine dye of red-orange color with a yellow-green fluorescence

7. Tocopherol acetate is hydrolyzed by a solution of potassium hydroxide in absolute alcohol (at the heating), then to add the concentrated sulfuric acid – feeling the smell of ethyl acetate. • At the oxidation of tocopherol by a potassium ferricyanide in an alkaline medium there is formed colored di-α-tocopherol:

8. Assay • Cerimetry. Direct titrationafter hydrolysis, indicator – diphenilamine. Е = ½ М.m. Firstly tocopherol is hydrolyzed by boiling with H2SO4, and then extracted tocopherol is titrated with cerium (IV) sulfate to the blue-violet color. • Photocolorimetry • Liquid chromatography • Spectrophotometry. Storage • Store protected from light in a cold place.

10. Application • An important antioxidant. It participates in the biosynthesis of proteins and other important metabolic processes in cells. At its insufficient amount appearance the degenerative changes in nerve cells, skeletal muscle, cardiac muscle, increased fragility and permeability of capillaries.  Apply for nervous diseases, muscular dystrophy, sclerosis, menstrual irregularities and the threat of termination of pregnancy, dysfunctionof the sexual men glands, to improve vision, with radiation sickness, etc. Using 50-100 mg / day (sometimes up to 400 mg) as oil solutions of 5%, 10%, 30% α-tocopherol; intra/muscular - 5%, 10%, 30% oil solutions; inside - Capsules 100 , 200, 400 mg.

11. Heterocyclic vitamins Phenylchromane derivatives (flavan) Flavans derivatives are naturally in a free state, or in conjunction with sugars (glycosides) - flavonoids. Flavonoids are a group of Vitamins P. They are able to reduce the fragility and permeability of capillaries, take part in the ox-red processes and have specific antioxidant properties. They are in green tea, rose hips, citrus fruit, unripe walnuts, mountain ash. How drugs they are used as - quercetin, rutin, and their natural (katergen) and semisynthetic (troxevasin) analogues.

12. Rutin (Rutinum) 3-Rutinoside quercetinor 3-ramnoglycosyl-3,5,7,3',4'-pentaoxiflavone • Belongs to a glycosides class: quercetin aglycone is 3,5,7,3 ', 4'-pentaoxiflavon; sugar molecule part - rutenoza is a disaccharide consisting of D-glucose and L-rhamnose.Rutin is found in the leaves and fragrant flowers of rue (Ruta graveolens), buckwheat (Fagopyrum esculentum).

13. CHARACTERS Greenish-yellow finely crystalline powder, odorless and tasteless. Practically insoluble in water, slightly soluble in alcohol, it is difficult to dissolve in boiling alcohol, practically insoluble in acid solution, ether, chloroform, acetone and benzene, soluble in dilute alkali. Identification The reaction wth iron (III) chloride - there is a dark green color (the presence of phenolic groups). Mineral acids at the heating hydrolyze rutin with the formation of quercetin, glucose and rhamnose. Quercetin + H2SO4 → oxonium salt is bright yellow color with a green fluorescence. Glucose residue is detected after acidic hydrolysis by the reaction with copper-tartrate reagent (Feling).

14. When dissolved a substance in a sodium hydroxide solution appears yellow-orange color. According to the reaction flavonoid becomes into halcon: • The presence of two absorption maxima in the UV spectrum at 259 and 362.5 nm. • Reactions on the keto group (formation of oxime, phenylhydrazone, semicarbazone).

15. Rutin is reduced by hydrogen in an acidic medium, and forming the perylene salts, which have red colors (cyanine reaction). For occurring of this reaction to the alcohol solution of substance to add concentrated chloric acid and magnesium powder: Assay UV-spectrophotometry

16. Storage Store protected from light Application Vitamin P regulates vascular permeability, enhances the action of ascorbic acid. Used for the prevention and treatment of hypo-and avitaminosis of P vitamin, and for the treatment of diseases associated with the violation of vascular permeability and capillary lesions. Produced in powder and tablets on 20 mg. Included in the Table. "Ascorutin" (along with ascorbic acid and glucose) and vikalin (bismuth nitrate basic, basic magnesium carbonate, sodium bicarbonate, powders of sweet flag (calamus) root and buckthorn bark, rutin and Kelin).

17. Heterocyclic vitamins Pyridine derivatives • the nicotinic acid, its amide (vitamin PP) and oximethylpyridine vitamins (group В6 )belong to the vitamins of pyridine derivatives. • Nicotinic or β-pyridinecarboxylic acid was firstly synthetically obtained by Huber in 1867-1870. Its vitamin properties were found in 1937-1938. In the natural materials nicotinic acid themselves does not occur but nicotinamide occures, which is a part of many enzymes. Thus, nicotinic acid is a pro-vitamin of nicotinamide. • Nicotinic acid is obtained only synthetically.

18. Nicotinic acid obtaining The main source of the obtaining of nicotinic acid - an nicotine alkaloid, which is a by-product of the tobacco production and the anabasine alkaloid it is contained in anabazis - wild growing plant in Central Asia. These alkaloids are easily oxidized by various oxidants to nicotinic acid:

19. Nicotinic acid (Acidum nicotinicum), Vitamin РР, Vitamin В5, Niacyn (ДФУ) Pyridine-3-carboxylic acid CHARACTERS. Crystalline white powder. Soluble in boiling water and boiling 96% alcohol, moderately soluble in water, practically insoluble in ether. Dissolves in dilute solutions of hydroxides and carbonates of alkali metals.

20. Identification • Substance at the interaction with the cyanobromide (cyanochloride) solution and aniline solution forms a yellow color:

21. Melting point, ІR-spectroscopy. • Un pharmacopoeia reaction : а) Reaction of pyridine cycle with 2,4-dinitrochlorbenzene(Cink reaction)

22. b) formation of copper nicotinate blue color: c) With copper sulfate and ammonium thiocyanide solutions - green color:

23. d) At the heating of the substance with anhydrous sodium carbonate, there is a smell of pyridine: Assay • Alkalimetry, direct titration, the indicator - phenolphthalein. Parallel to conduct a blind test. Е = М.м

24. In the injection solutions (except nicotinic acid there is sodium bicarbonate), the quantitative content of the drug is determined by a coppermetry. In this case, to the solution of nicotinic acid to add a solution of Copper sulfate, the precipitate is filtered and in the filtrate there is determined the excess of CuSO4 by iodometric. Indicator - starch. Parallel to conduct the control test. Е = 2 М.м 3. UV-spectrophotometry in the injection solution. Storage Store protected from light.

25. Application • Antipellagric medicine. Nicotinic acid has vasodilator and hypocholesterolemic action, so it is prescribed for liver disease, vascular spasm in the limbs, kidneys and brain, at the infectious diseases. • Side effects: flushing, feeling a rush of blood to the head. • H.d. – 0,1 g; h.d.d. – 0,5 g. • Producing: tablets оn 0,05 g №50; amp. 1% - 1,0 №10. • It is in the complex tablets “Nicoshpan”

26. Nicotinamide (Nicotinamidum) (UP) Pyridine-3-carboxamide CHARACTERS. Crystalline white powder or colorless crystals. Easily soluble in water and ethanol. It has basic properties. It is obtained by the interaction of ammonia and ethylnicotinate.

27. Identification • Melting point. • IR-spectroscopy. • Ammonia evolving at the heating of the substance with a sodium hydroxide solution: • Reaction of the formation of Schiff bases at the interaction with cyanobromide reagent and aniline (see nicotinic acid).

28. Un pharmacopoeia reaction. а) At the heating with crystallineNa2CO3– appearance pyridine small: b) With CuSO4 andNH4SCNsolutions appearance emerald-green color. c) With 2,4-dinitrochlorbenzene and NaOH solution –red-violetcolor (on the pyridine cycle). d) Dragendorff’s reagent (on the heterocyclic nitrogen atom).

29. Assay • Acidimetryin nonaqueous medium of the mixture of anhydrous acetic acid and acetic anhydride, a direct titrationat the present of mercury(II) acetate, the indicator -crystal violet(Е=М.м).Parallel to conduct a blind test. • Modified Kjeldahl method (determination of ammonia after alkaline hydrolysis. Storage Store protected from light.

30. Application • Antipellagric medicine. • It is included in the kodegidraz enzymes that transfer hydrogen, take part in ox-red reactions in the body. Daily requirement -   15 mg. • Assign at pellagra, liver disease, gastritis with low acidity, chronic colitis. Nicotinamide has no vasodilatory action. • producing: tab. оn 15 mg; amp. 1% - 1,0 №10. • It is in polyvitamins.

31. Oxymethylpyridine vitamins (vitamins of В6group) Vitamins of В6group are represented by the related substances: pyridoxol (pyridoxine), pyridoxal and pyridoxamine, consistently converted into each other:

32. Pyridoxinehydrochloride (UP) (Pyridoxini hydrochloridum) viyamin В6 (5-hydroxy-6-methylpyridine-3,4-diyl)-dimethanolh/ch оr 3,4-di (oximethyl)-5-oxi-6-methylpyridineh/ch CHARACTERS. Crystalline powder of white or nearly white color. Easily soluble in water, slightly soluble in 96% alcohol. Melts at about 205 ° C with decomposition.

33. Storage Store in tightly closed container of a dark glasses, in a cool place. Obtaining of Pyridoxinehydrochloride Contained in the raw grain cereals, vegetables, meat, fish, cod liver oil and cattle, yeast, egg yolk, etc.             Now pyridoxine is obtained only by a synthetic way. Precursor for the synthesis of pyridoxine by the method of M.A. Preobragensky is monochloracetate acid.

35. Identification • According to the physico-chemical constants: IR and UV spectroscopy, TLC (as a developer using 2,6-dichlorquinonechlorimide): • It giver reaction of chlorides. • Un pharmacopoeia reaction : а) With silicontungstenic and phosphorustungstenic acids it is formed sediments (on the presence of pyridine bases).

36. b)At the interaction with FeCl3 solution it is formed a red coloration, which disappears when you add sulfuric acid (reaction to a phenolic hydroxyl group): c)Pyridoxine takes part in the azoconnection reacts with diazonium salts. Formed the azo dyes yield colored complexes with salts of heavy metals, particularly zinc:

37. Assay • Acidimetry in non-aqueous medium in a mixture of formic acid and acetic anhydride. Equivalence point is determined by potentiometric method. E = М.м. Conduct a blind test. (UP, addition 1)

38. Alkalimetry, direct titration in a mixture of 0.01 M hydrochloric acid solution and 96% alcohol. Equivalence point is determined by potentiometric method. (UP). Е = М.м. • Alkalimetry, direct titration. Indicator - bromothymol blue. E = A.m. Cl. Calculations are carried out on the chlorine content, which in terms of dry matter should be 17,1-17,35%.

39. Acidimetryin nonaqueous medium, a direct titrationat the present of mercury(II) acetate, the indicator -crystal violet(Е=М.м).

40. Purity test • Specific impurity: methyl ether of pyridoxine. It is determined by the using of a 2,4-dichlorquinonechlorimide - after binding of pyridoxine by a boric acid to a complex, which does not give the reaction of the dye: • An the presence of impurities appears a blue color layer of butyl alcohol.

41. Application • Pyridoxine is in codecarboxilase. Daily requirement for healthy humans is 2 mg. When hypo-and avitaminosis there is observed characteristic dermatosis (erythredema), swelling, degenerative changes in the nervous system, etc. • Applied in various forms of Parkinson's disease, chorea, acute and chronic hepatitis, toxicosis during pregnancy, anemia, radiculitis, neuritis, neuralgia and other nervous diseases. • producing: tab оn 0,01 g №10; аmp 1% - 1,0 №10; 2,5%-1,0 №10; 5% - 1,2 №10. • You can not mix in the same syringe В1and В12. • Included in the medicines of B vitamins: magne-B6, Neyrorubin, Neurobex, Neurovitan, neuron, multi-tabs B-complex.

42. Antivitamins • Investigation of the relationship between chemical structure and vitamin activity allowed to establish for each vitamin, one or more antivitamin. They tend to differ from vitamins structure of a single functional group.In some antivitamin structure differs significantly from the vitamins. For example, antivitamin naphthoquinones (neodicoumarin, phenyline).Antivitamin in biocatalytic reactions behave as competitive inhibitors. The essence of their actions that they form a kind of psevdoenzymes that suppress the action of these enzymes or displace vitamins from enzymatic systems. This leads to the using of antivitamin as drugs for the treatment of many diseases.

44. Derivatives of pyrimidine and thiazole Molecule of pyrimidine-thiazol vitamins (vitamins B1 - thiamines) consists of two heterocycles - pyrimidine (A) and thiazole (B) connected by a methylene group: In medical practice used thiamine hydrobromide, thiamine hydrochloride, diphosphate ester of thiamine hydrochloride (cocarboxylase).

45. Preparations of vitaminВ1 Thiamine hydrobromide (Thiamini hydrobromidum)(SPhU) 3-[(4-Amino-2-methyl- pyrimidine-5-yl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolebromidehydrobromide Thiamine hydrochloride (Thiamini hydrochloridum) (SPhU) 3-[(4-Amino-2-methyl- pyrimidine-5-yl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolechloridehydrochloride

46. VitaminВ1is the first vitamin, which pioneered the opening of vitaminology science. For the first time it was identified from the rice bran(Funk in1912 y.). This substance in small doses cured polyneuritis of pigeons and because its structure contains sulfur atom, called thiamine. Most contained in the cereal (grain) plants, yeast, egg yolks, ox liver.Extraction from natural sources is difficult with low output (from 1 t of yeast - 0,25 g of vitamin В1). For the medical purpose it is received synthetically, at the first pyrimidine and thiazole compounds should be extracted separately, then they are condensed. Thiamine belongs to the aminoalcohol of heterocyclic series (availability of carbonyl and amino-groups).

47. Properties of thiamines Thiaminehydrobromide The crystalline powder of white or white with yellowish tint with a specific smell. Easily soluble in water, little soluble in 96% alcohol, practically insoluble in ether. Thiaminehydrochloride The crystalline powder of white or almost white or colorless crystals. Easily soluble in water, soluble in glycerin, slightly soluble in 96% alcohol. Hygroscopic. This compounds are stable only in acidic environmentIn the neutral and alkaline environments decompose with rupture of thiazole cycle and formation of mercaptogroup.

48. Identification of thiamines Thiaminehydrobromide IR-spectrophotometry. Thiochrometest. Reactions on bromides. Thiamine hydrochloride ІЧ-spectrophotometry. Thiochrome test. Reactions on chlorides. Unpharmacopoeialreactions а) With solutions ofFeCl3 andK3[Fe(CN)6] a bluecolorationofBerlinblueformed. b) At the meltingwith crystallineNaOHormetallic sodium sulfide ions formed, which can be detected by the reaction with sodium nitroprusside(red-purple coloration). c) Thiamine can be quantitatively precipitated from the solutionsby the usage of some general alkaloid reagents (Dragendorff, Bertran, Sheibler, picric acid, p-aminoacetophenone,Reinecke salt).

49. Thiochrometest Thiamineis oxidizedby the alkali solution of potassiumferricyanidewith the thiochrome formation (bright yellow substance), which is extracted by isoamyl or butyl alcohol - alcohol layer gives blue fluorescence in UV light (λ = 365 nm):

50. Quantitative determination of thiamine hydrochloride and hydrobromide Thiamineh/br. (SPhU). Acidimetry innon-aqueous environmentin the presence of mercury (II) acetate. Equivalent point is determined by potentiometric method: Е = ½ М.m.(C12H18Br2N4OS)