SU730276A3 - Method of preparing aqueous iron-containing preparate - Google Patents

Abstract

1411266 Polyesters ASTRA LAKEMEDEL AB 5 Oct 1972 [6 Oct 1971 (2)] 46074/72 Heading C3R [Also in Division A5] A water swellable or soluble polymer capable of forming a complex with a polyvalent metal cation is derived from (a) a hydroxy carboxylic acid component which is arabonic acid, gluconic acid or glucoheptonic acid or a salt or lactone thereof, (b) a polyhydric alcohol component which is glycerol, a polyglycerol, tetritol, pentitol, hexitol, heptitol or a partially etherified derivative of one of these alcohols with an alkyl or hydroxyalkyl group containing from 1 to 5 carbon atoms, and (c) epichlorohydrin. The metal cation is preferably ferric iron. The examples describe polymers derived from the following compounds:- (a) gluconic acid lactone, sodium gluconate, potassium arabonate or glucoheptonic acid lactone, (b) sorbitol, hydroxypropyl sorbitol, pentaerythritol, glycerol, dulcitol or mannitol, and (c) epichlorohydrin, the polymers being converted into a ferric iron complex by reaction with, e.g. ferric chloride.

Description

0.15, 30 and 45 minutes after starting the reaction, 50 ml of epichlorohydrin is added over about 7 minutes. The temperature is increased during 30 minutes to 60 ° C, at which the subsequent condensation is carried out. After 60 minutes from the start of the reaction, 5.0 g of NaOH is added over 2 minutes. After 90, 120, 150, 165 and 180 minutes after the start of the reaction, 10.0 g of NaOH are introduced. After 180 minutes from the start of the reaction, 50 ml of epichlorohydrin are also added within 7 minutes. After 195, 210 and 225 minutes after the start of the reaction, 10 g of NaOH are introduced, after 240 and 255 minutes, 14, 0 ml of 50% NaOH and after 270 minutes, 40.0 ml of epichlorohydrin. After 285, 300 and 315 minutes after the start of the reaction, 14.0 ml of 50% NaOH are added. The reaction is continued for 415 minutes at, after which the temperature is lowered to and 50 ml of 4 N are added. With constant cooling, 160 ml of a 6 M solution of NSB are introduced into the reaction mixture, giving it a pH value of 0.65. The reaction mixture is filtered to remove precipitated NaCC, which is washed with 100 ml of 50% ethanol. The filtrate and industrial liquid are combined, and then they are mixed with 2220 ml of 95% ethanol and 65 ml of water, and then the polymer and alcohol phases are left to stand overnight to separate. The next day, the ethanol phase is filtered off with suction and the polymer phase is filtered off to remove precipitated NaC, which is washed with 100 ml of 70% ethanol. The polymer phase is mixed with 1550 ml of 95% ethanol and 10 ml of absolute ethanol. For the purpose of separation, the phases are incubated for 1 hour, then the alcohol phase is sucked off and the polymer phase is mixed with 1550 ml of 95% eta. iola and 10 ml of absolute ethanol. For the purpose of separation, the phases are incubated for 1 hour, then the alcohol phase is sucked off and the polymer phase is mixed with 316 ml of 95% ethanol and 100 ml of water. After a one-hour separation, the alcohol phase is sucked off and the polymer phase is washed twice with 316 ml of 95% ethanol and then 300 ml of acetone 5 times. After adding the last portion of acetone, the mixture is kept overnight. The next day, the acetone is decanted and the polymer is dried in a vacuum dryer for 45 minutes at. The content of chlorine in the product is 6.0.% By weight, sodium 4.0% by weight. Content of dry organic matter 346.1 g. Example 2. Preparation of dry iron-containing composition, in 113 ml of distilled water, 154 g of polymer (desired product) obtained from sorbitol, gluconic acid lactone and zichlorohydrin are dissolved by the method of Example 1, and 45 ml of lactic acid. A separate solution is prepared, a solution of 144 g of NaOH in 600 ml of distilled water, 75 ml of which is added to a mixture of polymer and lactic acid. After heating the mixture thus obtained, nine portions of 45 ml of NaOH solution are added with stirring in a 2-liter round-bottomed flask equipped with a baffle plate. At the end of each additive, 30 ml of a 1.88 M solution of FeC (Ill) are added. Additives are added dropwise over 1 minute to the NaOH solution and over 2 minutes to solution (III), with the intervals between the additions of the NaOH solution and FeCSj being 2 minutes. After the addition of the ninth portion of the FeCC (III) solution, 83 ml of addition NaOH are added. The reaction mixture is stirred for 35 minutes at, then cooled to 25 ° C. The solution is then diluted to a volume of 1125 ml. To the diluted solution, 2550 ml of 95% ethanol are added over 20 minutes with stirring. Stirring is continued for 10 minutes. After 60 minutes, the mother liquor is sucked off from sediment and the precipitate is washed with 450 ml of 63% ethanol. Then, the precipitate is dissolved in a 6 liter flask with 675 ml of distilled water having a temperature of 40 ° C. The temperature is controlled for 30 minutes and at this temperature the mixture is stirred for 30 minutes. The solution is cooled to 25 ° C and the pH is adjusted to 6.8 with 6 N HC. Then, an insoluble precipitate formed during the reaction was separated by centrifugation for 2 minutes (in a dry state, this residue weighs 30 g). After that, the solution is filtered through a Seitz filter 3/1250. The filtrate is diluted with distilled water to a volume of 1050 ml and 2300 ml of 95% ethanol are added dropwise over 20 minutes with stirring, then stirring is continued for 2 minutes. The precipitate obtained is allowed to stand for 15 hours, after which the mother solution is sucked off from the deposited precipitate and the precipitate is washed 3 times with 450 ml of 63% ethanol and 3 times with 450 ml of 95% ethanol. The precipitate is dried under vacuum at 40c, and 72.8 g of a dry preparation with an iron content of 24.3% by weight per preparation is obtained. Example 3: Preparation of injection solution. In a closed round-bottomed flask with stirring for 15 m n. To 170 fvui g-Stylized NOLA, having a temperature, 41.2 of the dry preparation prepared according to Example 2 was added in portions. The temperature was maintained for a further 50 minutes, then the solution was cooled to . The solution is diluted to a volume of 200 ml. After filtration through a Seitz W 3/1250 filter and through a 0.65 micron membrane filter, the solution is poured into 10 ml ampoules for injection, which are sterilized for 20 minutes at 1200 s. The iron-containing solution has a total iron content of 48.8 mg / ml , iron (II) content 0.70 mg / ml, viscosity 5.4 cP and pH value 7.47. After the administration of 20 mg of iron per 1 kg of body weight, the absorption of iron by the body of rabbits is 63% and after 7 days - 88%. At the end of the day, 16% of the iron is released.

Example 4. Obtaining polymer from sorbitol, sucrose and epichlorohydrin.

In a round bottom flask with a capacity of 5 l equipped with a stirrer, an addition funnel, a thermometer and a refrigerator, 150 ml of distilled water, 34 g of NaOH, 300 g of sorbitol and 150 g of sucrose are fed; 200 ml of epichlorohydrin is continuously added over 55 min. For 20 min, starting with the addition of epichlorohydrin, the temperature is raised to 75 ° C. At this temperature, polymerization is carried out with vigorous stirring, as the reaction mixture becomes very viscous at the end of the synthesis. 85 g of NaOH in solid form, 20 g of NaOH dissolved in water to a volume of 28 ml, and 55 epichlorohydrin are added in portions to the above products in portions. 250 ml of benzene and 200 ml of distilled water are also added due to the increased viscosity of the reaction mixture during the reaction. After 285 minutes, the reaction mixture is cooled while adding 50 ml of 4 M HC. Then 100 ml of BM are added, and the polymer forms a highly mobile suspension of benzene and water. After 305 minutes, the temperature of the reaction mixture is 5b-C, after 330 minutes the cooling is suspended at 30 ° C. 70 ml of NaOH are added. After 15 minutes, the pH is O. The reaction mixture is filtered through a double filter. Since filtration takes a lot of time, it is carried out overnight.

Example 5. Obtaining polymer by the reaction between the product of example 4 and potassium cyanide. Source products:

1, 273 g of the polymer obtained in example 4, containing products corresponding to 18 g of glucose, 500 ml of distilled alcohol:: ps13 uHKOfi water, 0.5 -. - L 251% NHqOH, 2. A solution of 15 g of KCN, corresponding to a double equivalent of the amount of glucose plus 10% of glucose in excess from a solution of 18 g of glucose, in 50 ml of distilled water.

Solution 1 is fed into a round-bottom flask equipped with a magnetic stirrer with a dropper, a funnel, a thermometer and a cooler with a receiver. The solution is added to solution 1 at room temperature and held for

d 30 min Then the temperature is raised to and maintained at it for 120 minutes. After that, the rag-creator is cooled and kept at room temperature for 3 days. Within 90 minutes, the temperature is raised to 70 ° C and simultaneously a stream of air is passed through the solution. After 15 minutes, the heating is interrupted and the temperature is lowered to 30. With vigorous stirring, a 2 M PCH solution is slowly added until the pH reaches about 6. Then the solution is simultaneously heated to approximately approx.

five

After reheating and. blowing air, which lasts 60 minutes, the solution is cooled to room temperature and the pH is set to about 1 using 2 M

0 solution NS. The bribed solution is kept for the next day and then heated for 30 minutes. After cooling, the solutions are examined for the presence of cyanide ions. The experiment did not detect any cyanide ions. The solution is evaporated in vacuo to about half of its volume and then the pH is adjusted to 5 with NaHCO. With stirring, 10 g of activated carbon is added. After 15 minutes the mixture is filtered through a Seitz W Ko2 filter plate. The filter plate is washed with distilled water. Wash water is mixed with

5 the filtrate and the resulting mixture is evaporated in vacuo to approximately 250 ml. Add 2 vol. including 99.5% ethanol and the mixture is kept for 30 minutes.

0

Example 6. Getting a dry iron-containing drug.

The amount of the polymer of Example 5, corresponding to 60 g of dry organic matter, is dissolved in 300 m

5 distilled water at room temperature. At room temperature, a solution of 60 g of FeCtj-in 100 ml of distilled water is added to the polymer solution. To received

With the stirring, 1000 ml of 1 M NaOH are added. After a 70-minute morning reagent at room temperature, the temperature of the mixture is raised to 80 ° C. The mixture is maintained at this temperature for 20 minutes, then it is cooled.

Claims (1)

5 are brought to room temperature and filtered through a Seitz Ko2 filter plate. The filtrate is diluted with distilled water to a volume of 1900 ml and, with vigorous stirring, 3800 ml of 99.5% ethanol are added. After 20 minutes, the precipitate obtained is filtered off and dissolved in a mixture of 600 ml of distilled water, 15 g of polymer, based on dry organic matter, and 20 ml of 1 M NaOH, the temperature is raised to and maintained at 25 minutes, then the solution cooled to room temperature. Under intensive stirring, 1 M HC1 is added to the cooled solution to pH 6.7. The solution is filtered through a Seitz Ko2 filter plate and washed with distilled water mixed with filtrate. The pH value of the mixture from 7.7 was adjusted to 7.3, using 1 M solution of HC, then the volume of the mixture with distilled water was adjusted to 1000 ml. With vigorous stirring, 2000 ml of 99.5% ethanol is added. After 30 minutes, the precipitate obtained is filtered and washed with 100 ml of ethanol, diluted to a concentration of the mother liquor, and 100 ml of ethanol, diluted to 75% and, finally, three times with 150 ml of 99.5% ethanol. The washed precipitate is dried in vacuo at. Yield 74 g. Total Fe 22.8 based on the initial sample. Example 7: Preparation of injection solution. A 500 ml round bottom flask equipped with a stirrer, a thermometer and a refrigerator is fed 130 m of distilled water, which is heated to 80 ° C. With stirring, 32.9 g of a dry iron-containing preparation is added to the water with stirring (see Example 7). The mixture is kept for 70 min (calculated from the beginning of the addition of a dry iron-containing preparation). The resulting solution was cooled to room temperature and the pH value was adjusted to 7.6, using 1 M HC solution, then the volume of the solution was adjusted to 150 ml with distilled water. After that, the solution is filtered through a Seitz Ko2 filter plate and a Pyrex glass filter. The filtrate is poured into ampoules which are kept in an autoclave for 2Q min at l2 (. The total amount of Fe is 50.5 mg / ml, the amount of Fe is 0.98 mg / ml, the viscosity is 10.7 cP, the pH value is 7.7. Iron absorption by the muscles of rabbits after 7 days is 86%, iron release during the first days is 2%. Formula of the invention A method of obtaining an aqueous iron-containing preparation by the interaction of iron compounds and soluble polymers capable of forming complexes with ferric iron, when heated, characterized in in order to reduce toxicity and better the body uses as a polymer the compounds obtained by reacting in an aqueous solution of hydroxycarboxylic acid selected from the arabon, gluconic and glucoheptonic acid groups, or their derivatives, in particular salts and lactones, of a polyhydric alcohol selected from the group: glycerin, polyglucserin, tetrite, pentrite, hexitol, heptitol or their derivatives, obtained by partial esterification with mono- or dihydric alcohols of 1 to 5 carbon atoms, and an epoxy-containing component taken from the group: di galoidhydrin and epihalohydrin, their diepoxy derivatives or their mixtures, or products obtained by the interaction of Cs1haroza, these polyhydric alcohols and epoxy compounds, in the subsequent treatment in the latter case of the reaction product with cyanide and hydrolysis of the cyanohydrin compound.