Hexamethylenetetramine was synthesized by A.M. Butlerov from paraformaldehyde and ammonia in 1860, but found medical use only in 1895. It is a condensation product of formaldehyde and ammonia. According to its chemical structure, hexamethylenetetramine can be classified as a heterocyclic compound derived from 1,3,5-triazine. Its test methods and pharmacological action are based on hydrolysis reactions accompanied by the formation of formaldehyde. Therefore, hexamethylenetetramine is considered together with other aldehydes. In the modern drug nomenclature, it is known as methenamine.

The source of methenamine (hexamethylenetetramine) is a formaldehyde solution. It is mixed with an excess of 25% ammonia solution and evaporated in vacuum at 40-50 ° C:

6 + 4NH 3 ¾® (CH 2) 6 N 4 + 6H 2 O

Methenamine synthesis consists of two stages. First, three molecules of formaldehyde and three molecules of ammonia condense to form a triimino derivative (hydrogenated 1,3,5-triazine). The latter is then condensed with three formaldehyde molecules and one ammonia molecule:

To free it from the impurities of methenamine used in medicine (Table 22.2), it is subjected to additional purification with activated carbon, crystallized by evaporation from an aqueous solution, and recrystallized from ethanol.

22.2. Methenamine (Hexamethylenetetramine) Properties

Methenamine is readily soluble in water, soluble in ethanol and chloroform, but very slightly soluble in ether. Its characteristic property is the ability to sublimate without melting. It is flammable and is used as "dry alcohol".

To confirm the authenticity, compare the IR absorption spectra of the tested methenamine in the 4000-400 cm –1 region with the spectrum pattern attached to the PS.

Like most heterocyclic nitrogen-containing compounds, methenamine is precipitated from solutions with picric acid (yellow precipitate); iodine solution in potassium iodide solution (red-brown precipitate); bromine water (orange-yellow precipitate). These reactions are used to identify it. Methenamine precipitates iron (III), aluminum, chromium (III), titanium (IV) ions from solutions.

Methenamine is resistant to the action of alkalis, and its solutions in water quite easily (especially when heated) hydrolyze to form the initial synthesis products:

(CH 2) 6 N 4 + 6H 2 O ⇄ + 4NH 3

The hydrolysis reaction is accelerated in an acidic environment. The resulting formaldehyde can be detected by various reagents (for example, salicylic acid, chromotropic acid, etc.). The FS recommends the hydrolysis reaction in an acidic medium for authenticity testing:

(CH 2) 6 N 4 + 2H 2 SO 4 + 6H 2 O ¾® + 2 (NH 4) 2 SO 4

Methenamine is identified by the smell of formaldehyde released when heated with diluted sulfuric acid. If you then add an excess of alkali and reheat it, you get the smell of ammonia:

(NH 4) 2 SO 4 + 2NaOH ¾® 2NH 3 + Na 2 SO 4 + 2H 2 O

The process of hydrolysis in an acidic medium proceeds quantitatively; therefore, this reaction is recommended by the FS for the determination of methenamine. For this purpose, a portion of methenamine is boiled with an excess of 0.1 M sulfuric acid solution. Excess acid is titrated with 0.1 M alkali solution (methyl red indicator).

Methenamine, due to the presence of four nitrogen atoms in its molecule, has an alkaline reaction in aqueous solutions. Therefore, quantitative determination can also be performed by acid-base titration, without hydrolysis reaction. Unstable salts are formed:

(CH 2) 6 N 4 + HCl ¾® (CH 2) 6 N 4 × HCl

A mixture of methyl orange and methylene blue is used as an indicator.

Methenamine can be quantitatively determined by the iodometric method, since it forms a poorly soluble polyiodide (CH 2) 6 N 4 × 2I 2 with iodine. However, it is partially soluble in potassium iodide solution. This limits the application of this method, since it requires the preparation of a titrant with a lower iodide content.

More widely applicable is the iodochlorometric method based on the formation of a water-insoluble complex compound of methenamine with iodine monochloride:

(CH 2) 6 N 4 + 2ICl ¾® (CH 2) 6 N 4 × 2ICl¯

Determination is performed by reverse iodine chlorometric method. After filtering off the formed complex, the excess of monochloride iodine is titrated in the presence of potassium iodide:

ICl + KI ¾® I 2 + KCl

I 2 + 2Na 2 S 2 O 3 ¾® 2NaI + Na 2 S 4 O 6

Methenamine is stored in a well-closed container at a temperature not exceeding 20 ° C, given its ability to sublimate. Since it is easily hydrolyzed in solutions, they cannot be sterilized.

Methenamine is used as an antiseptic inside 0.5-1.0 g and intravenously in 5-10 ml of a 40% solution.

Hexamethylenetetramine (Urotropine)

Obtaining hexamethylenetetramine

Hexamethylenetetramine is a product of the interaction of a formaldehyde solution with ammonia. It was first obtained by A.M.Butlerov (1860), but only 35 years after its discovery, it began to be used in medicine.

The raw material for the production of hexamethylenetetramine is a 40% formaldehyde solution in water and ammonia water. 25% ammonia water is added to the formaldehyde solution, the mixture is stirred and the temperature is maintained within 40-50 ° C.

After the end of the reaction, the medium of the reaction mixture should “be alkaline and smell of ammonia should be felt. Activated carbon is added to the mixture, it is filtered, the filtrate is evaporated in vacuum to a mushy mass. On cooling, crystals of hexamethylenetetramine crystallize out. They are sucked off, washed and dried at a temperature of 30-35 ° C. The obtained hexamethylenetetramine is recrystallized from alcohol.

Hexamethylenetetramine is a white crystalline powder, highly hygroscopic. Has no smell. The taste is pungent, at first sweet, then bitter. The drug is readily soluble in water and alcohol, soluble in chloroform, almost insoluble in ether. Aqueous solutions of hexamethylenetetramine have a slightly alkaline reaction. When heated, they volatilize without melting.

Pharmacological properties of hexamethylenetetramine

Synonyms:

Urotropine, Aminoform, Cystamine, Cystogen, Formamin, Hexamethylentetramin, Hexamina, Methenamine, Metramine, Urisol, Urotropinum, etc.

Colorless crystals or white crystalline powder, hot and sweet, and then bitter taste, odorless. Easily soluble in water (1: 1.5) and alcohol (1:10). When heated, it evaporates without melting. Burns with a pale flame. Aqueous solutions are alkaline (40% solution pH 7.8 - 8.2).

For intravenous administration, the solution is prepared aseptically.

Pharmacological properties:

The production of hexamethylenetetramine was the first experiment (1899) in the creation of a drug that is now called a prodrug (Phenyl salicylate). With the decomposition of hexamethylenetetramine in the body (in an acidic environment), formaldehyde is released, which, when excreted in the urine, has an antiseptic property.

Hexamethylenetetramine is used as an antiseptic for infectious processes in the urinary tract (cystitis, pyelitis). With an alkaline reaction of urine, formaldehyde is not cleaved and no therapeutic effect is observed. In these cases, substances are prescribed that shift the reaction of urine to the acidic side (Ammonium chloride). To prevent the breakdown of hexamethylenetetramine in the stomach, it is prescribed on an empty stomach. If necessary, a solution of hexamethylenetetramine is administered intravenously.

Indications for the use of hexamethylenetetramine are also cholecystitis and cholangitis, allergic skin diseases (urticaria, polymorphic erythema, etc.), eye diseases (iridocyclitis, keratitis, etc.). The drug is also used for meningitis, encephalitis, arachnoiditis.

Currently, due to the availability of more effective agents, hexamethylenetetramine is not widely used.

Application:

Assign inside in tablets and solutions for adults, 0.5 - 1.0 g per dose, children - 0.1 - 0.5 g; take several times a day. 5-10 ml of a 40% solution is injected into a vein.

Side effects: Hexamethylenetetramine can irritate the renal parenchyma and, in some cases, contribute to the spread of the painful process in pyelitis. If signs of kidney irritation are found, the drug is discontinued.

Method of production: powder; tablets of 0.25 and 0.5 g; 40% solution in ampoules of 5 and 10 ml.

Storage: in a well-closed container; solutions - at a temperature not higher than +20 C.

Hexamethylenetetramine is an integral part of the combined tablets "Calceks" and "Urobesal". Previously released tablets "Urosal", containing 0.3 g of hexamethylenetetramine and phenyl salicylate, are excluded from the range of drugs.

328. Hexamethylentetraminum

Hexamethylenetetramine

Urotropinum Urotropin Methenaminum *

C 6 H 12 N 4 M. c. 140.19

Description. Colorless crystals or white crystalline powder-shock, odorless, burning and sweet, and then bitter taste. When heated, it evaporates without melting.

Solubility. We will easily dissolve in water and alcohol, we will dissolve in chlorine form, we will dissolve very little in ether.

Authenticity. 2 mlsolution of the drug (1: 10) is heated with 2 mldiluted sulfuric acid; a formaldehyde odor appears. Then add 2 ml30% caustic soda solution and heated again; the smell of ammonia appears.

Acidity or alkalinity. Solution 4 rdrug in 10 mlwater should be alkaline to litmus and not give an alkaline reaction to phenolphthalein.

Ammonium and paraform salts. C 10 ml5 drops of Nessler's reagent are added to a freshly prepared solution of the drug (1: 20) and heated in a water bath at 50 ° for 5 minutes. There should be no yellow coloration and cloudiness of the solution.

Note. To prepare a solution of the drug (1:20), distilled water that meets the requirements of the State Pharmacopoeia is additionally boiled (up to about 1/3 of the volume) until a negative reaction with Nessler's reagent is obtained. The test is carried out as follows: 10 mlwater is heated with 5 drops of Nessler's reagent in a water bath at 50 ° for 10 minutes. There should be no yellow discoloration or cloudiness.

Nessler's reagent is used with a shelf life of no more than one month. Organic impurities. In a test tube pre-rinsed with concentrated sulfuric acid, pour 2 mlconcentrated sulfuric acid, gradually add 0.1 rpreparation and shake. The solution should not be stained.

Chlorides. 1.5 rthe drug is dissolved in 30 mlwater. ten mlthe resulting solution must withstand the chloride test (no more than 0.004% in the preparation).

Sulphates. ten mlof the same solution must withstand the sulfate test (no more than 0.02% in the preparation).

Heavy metals. Solution 2 rdrug in 10 mlwater must withstand the test for heavy metals (no more than 0.00025% in the preparation).

Sulphated ash. 0.5 rthe preparation is placed in a weighed crucible and carefully burned. After cooling the crucible, the residue is moistened with 0.5 mlconcentrated sulfuric acid, heated and calcined to constant weight. Sulphated ash should be weightless.

Quantitation. About 0.12 g of the drug (accurately weighed) is dissolved in a conical flask in 10 mlwater, pour 50 ml0.1 n. sulfuric acid solution, the mixture is boiled over low heat for 30 minutes and cooled. 2 drops of methyl red solution are added to the cooled liquid, and the excess sulfuric acid is titrated with 0.1 N. sodium hydroxide solution until yellow.

A control experiment is carried out in parallel.

1 ml 0.1n. sulfuric acid solution corresponds to 0.003505 rC 6 H 12 N 4, which must be at least 99.0% in the preparation.

Storage. In a well-sealed container.

Antiseptic, used internally and intravenously.

Note. Hexamethylenetetramine Injection must additionally pass the following tests.

Amines. 2 rthe drug is dissolved in 5 mlwater, add 0.5 mlacetone and 10 drops of freshly prepared sodium nitroprusside; no pink-violet color should appear after 10 minutes.

Ammonium and paraform salts. Solution 2 rdrug in 10 mlwater must withstand the test for ammonium salts and paraforms.

Physicochemical characteristicsHexamethylenetetramine is a product of the interaction of a formaldehyde solution with ammonia. It was first received by A.M. Butlerov (1860), but only 35 years after its discovery, it began to be used in medicine.

Hexamethylenetetramine is a white crystalline powder, highly hygroscopic. Has no smell. The taste is pungent, at first sweet, then bitter. The drug is readily soluble in water and alcohol, soluble in chloroform, almost insoluble in ether. Aqueous solutions of hexamethylenetetramine have a slightly alkaline reaction. When heated, they volatilize without melting. When heated aqueous solutions of hexamethylenetetramine, it is hydrolyzed to form formaldehyde and ammonia.

Hexamethylenetetramine is a one-acid base, tertiary nitrogen gives it basic properties, therefore it forms double salts with acids, for example, hexamethylenetetramine hydrochloride. The presence of tertiary nitrogen, as in alkaloids, also causes the formation of picrates (yellow precipitate), tetraiodides (CH 2) in ^ -14 and other reaction products. Hexamethylenetetramine has the ability to give complex compounds with silver, calcium and phosgene salts.

Methods for the analysis of Urotropin

Identify Urotropine in an acidic medium hexamethylenetetramine decomposes with the release of formaldehyde. When an alkali solution is added to the reaction mixture, the smell of ammonia is felt.

The quantitative content of the drug can be determined by the neutralization method. A sample of the preparation is heated with a certain amount of a titrated solution of sulfuric acid, after cooling the mixture, the excess acid is titrated with alkali using methyl red. A control experiment (pharmacopoeial method) is carried out in parallel under the same conditions.

5 ml of 10% solution is placed in a volumetric flask with a capacity of 50 ml and the volume of the solution is brought to the mark with water. To 2 ml of the diluted solution add 2 ml of water, 2 drops of methyl orange solution, 1 drop of methyl new blue solution and titrate with 0.1 N. solution of hydrochloric acid until violet.

1 ml 0.1 N. solution of hydrochloric acid corresponds to 0.0140 g of hexamethylenetetramine.

To analyze a 2% solution, take 1 ml of a solution of hexamethylenetetramine, add 2 drops of a solution of methyl orange, 1 drop of a solution of methylene blue and titrate with 0.1 N. solution of hydrochloric acid until violet.

The quantitative content of hexamethylenetetramine (x,%) in a 10% solution is calculated by the formula:

and -the volume of hexamethylenetetramine solution taken for determination, ml (5 ml);

V1 -the volume of the drug solution after the first dilution, ml (50 ml);

V2 -the volume of the aliquot part of the dilution taken for titration, ml (2 ml);

V -titrant volume (HCl) used for titration;

K -correction factor for the concentration of the titrant solution;

T -titer of the titrant for the substance to be determined.

1. Refractometric method.

A weighed portion of 0.06 g of powder is shaken with 1 ml of water, filtered. Determine the refractive index of the aqueous filtrate (sodium bicarbonate).

Another weighed portion of 0.1 g powder is shaken with 1 ml of ethanol, filtered. Determine the refractive index of the resulting alcohol solution (phenyl salicylate). In parallel, under the same conditions, the refractive indices of solvents - water and alcohol - are determined.

The amount of each component is calculated individually using the formula

2. Titrimetric method.

Sodium bicarbonate. A weighed portion of 0.05 g of powder is shaken with 2-3 ml of water, filtered. The filtrate is titrated with 0.1 N HC1 solution in the presence of methyl orange indicator.

Phenyl salicylate.

1. The residue on the filter is dissolved in 5 ml of 0.1 N sodium hydroxide solution, boiled for about 30 minutes, the excess of alkali is titrated with 0.1 N HC1 solution in the presence of phenolphthalein indicator until it becomes discolored. E \u003d M.m.

2. The residue on the filter is dissolved in 5 ml of 10% sodium hydroxide solution, boiled for 10-15 minutes, neutralized with div. HCl, add an excess of 0.1 N solution of potassium bromate, potassium bromide, acidify with sulfuric acid, stir, leave for 10-15 minutes, then add a 10% solution of potassium iodide to the mixture, shake, leave for 5 minutes. The released iodine is titrated with 0.1 N sodium thiosulfate solution (starch indicator). E \u003d M.m. / 12

7. PHENYL SALICYLATE

HEXAMETHYLENETHETHRAMINE 0.3

Authenticity:

To 0.1 g of powder add 3-4 drops of conc. sulfuric acid, heated - a pink coloration of the auric dye appears, in the formation of which both phenyl salicylate and formaldehyde are involved, released during acid hydrolysis of hexamethylenetetramine (urotropine).

quantitation

1. Refractometric method.

A sample of 0.08 g of powder is dissolved in 1 ml of alcohol and the refractive index of the resulting alcohol solution is determined.

Another weighed portion of 0.08 g is treated with 1 ml of water, filtered and the refractive index of the aqueous filtrate (hexamethylenetetramine) is determined.

Calculation of the amount of hexamethylenetetramine is carried out according to the formula (No. 1), phenyl salicylate according to the formula (No. 2) above.

2. Titrimetric method.

Hexamethylenetetramine. After extraction with water, it is determined by the method of neutralization (titration with HCl solution in the presence of methyl orange indicator or a mixed indicator).

Phenyl salicylate. The residue on the filter is determined by the method of neutralization or bromatometry (the methods are described in detail for dosage form No. 4).

Factors of the increase in the refractive indices of aqueous and alcoholic solutions
Concentration in%	Hexamethylenetetramine	Sodium bicarbonate	Phenyl salicylate
	water	alcohol	water	alcohol
	0,00166	0,00150	0,00136	0,00190
	0,00165	0,00149	0,00135	0,00189
	0,00164	0,00148	0,00134	0,00188
	0,00163	0,00147	0,00133	0,00187
	0,00162	0,00146	0,00132	0,00186
	0,00161	0,00145	0,00131	0,00185
	0,00160	0,00144	0,00130	0,00184
	0,00159	0,00143	0,00129	0,00183
	0,00158	0,00142	0,00128	0,00182
	0,00157	0,00141	0,00127	0,00181

TOPIC: APPLICATION OF REFRACTOMETRY TO DETERMINE