Dicaine quantitative determination. Authenticity reactions and methods for quantitative determination of drugs anesthesin and dicaine hydrochloride. Composition and release forms

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Course work

Topic: 2.4 "Authenticity reactions and methods for quantitative determination of drugs anesthesin and dicaine hydrochloride"

Introduction

1. Justification of authenticity reactions and methods of quantitative determination based on their properties of the aromatic amino group for organic compounds

2. Identification and quantification of anesthesin (benzocaine)

2.1 Authenticity reaction equations

2.2 Methods of quantitative determination. Content calculation

3. Identification and quantification of dicaine hydrochloride (tetracaine hydrochloride)

3.1Authenticity reaction equations

3.2 Methods of quantitative determination. Content calculation

Conclusion

Bibliography

Introduction

The course work is aimed at considering authenticity reactions and methods of quantitative determination in proposed medicines based on the properties of functional groups.

The purpose of the work is to consider theoretical issues of methods for determining the authenticity and quantitative determination of individual drugs containing an aromatic amino group on the basis of regulatory documentation, GF X and GF XII, FS.

Qualitative and quantitative analysis of organic drugs consists of reactions to the corresponding functional groups present in the compound. The course work presents the main qualitative reactions to functional groups, as well as methods for the quantitative determination of substances, determining numerical indicators for calculating quantitative content.

Performing a pharmacopoeial analysis makes it possible to establish the authenticity of the drug, its purity, and determine the quantitative content of the pharmacologically active substance or ingredients included in the dosage form. Although each of these stages has its own specific purpose, they cannot be considered in isolation. They are interconnected and mutually complement each other.

1. RationalereactionsauthenticityAndmethodsquantitativedefinitionsbased ontheirpropertiesaromaticamino groupsFororganicconnections

2. DefinitionauthenticityAndquantitativedefinitionsanesthesin (benzocaine)

2.1 Equationsreactionsauthenticity

aromatic amino group anesthesin benzocaine

A) General reactions of n-aminobenzoic acid esters having an unsubstituted primary aromatic amino group

Reaction of formation of azo dye. The diazotization reaction occurs under the influence of sodium nitrite in an acidic environment. As a result, unstable diazonium salts are formed. With the subsequent addition of an alkaline solution of any phenol (β-naphthol, resorcinol, etc.), a cherry, red or orange-red azo dye is formed.

WhereR-WITH 2 N 5

Anestesin forms a Schiff base when it reacts with aldehydes, for example with n-dimethylaminobenzaldehyde in the presence of concentrated sulfuric acid, a yellow or orange color appears:

WhereR-WITH 2 N 5

When interacting with hydroxylamine in an alkaline environment, benzocaine forms hydroxamic acid, since it is an ester:

WhereR-WITH 2 N 5

When acidified with hydrochloric acid and adding a solution of iron (III) chloride, iron hydroxamate is formed, which has a red-brown color:

When performing this reaction, it is necessary to strictly follow the procedure, since the results are noticeable at a certain pH value.

Primary aromatic amines enter into condensation reactions with 2, 4 - dinitrochlorobenzene, forming zwitterion compounds with a quinoid structure. A yellow-orange color appears after adding the reagent, sodium hydroxide solution and heating. The colored compound is extracted with chloroform after acidification with acetic acid.

WhereR-WITH 2 N 5

Under the influence of chloroform and an alcohol solution of sodium hydroxide, isonitriles are formed, which have a nauseating odor:

WhereR-WITH 2 N 5

The condensation products with hexamethylenetetramine in the presence of concentrated sulfuric acid exhibit weak violet fluorescence.

Can be identified by precipitation (general alkaloid) reagents (picric, phosphotungstic, phosphomolybdic acids, mercury (II) chloride and others.

Benzocaine forms dibromo or diiodo derivatives.

When exposed to a 5% solution of chloramine in an acidic environment, a red-orange colored product is formed.

With nitric acid in concentrated sulfuric acid, a yellow-green color appears, turning to red with the addition of water and sodium hydroxide.

When benzocaine is mixed in glacial acetic acid with lead (IV) oxide, a red color appears.

B) Partial reaction to benzocaine - hydrolysis in a solution of sodium hydroxide, the resulting ethyl alcohol can be detected by the reaction producing iodoform, a yellow precipitate with a characteristic odor:

The presence of an ethoxyl radical in benzocaine can be determined by the action of acetic and concentrated sulfuric acids - by the characteristic fruity odor:

2.2 Methodsquantitativedefinitions.Calculationcontent

A) For the quantitative determination of anesthesin FS, a nitritometric method is recommended, based on the formation of diazonium salt:

1) potentiometrically;

Iodine-starch paper is porous, ashless filter paper soaked in a solution of starch with potassium iodide and dried in a dark place. Titration is carried out until a drop of the titrated solution taken 1 minute after the equivalence point

addition of titrant will not immediately cause a blue color on a strip of starch iodine paper:

2 KI+ 2 NaNABOUT 2 + 4 HCl= I 2 + 2 NO+ 2 KCl+ 2 NaCl+ 2 H 2 O

I 2 + starch= bluecoloring

K stech =Z =1

Mm. =165.19 g

M(1/Z) = 165.19 g/mol

Formula for calculating quantitative content taking into account the control experiment:

B) Bromide-bromometric method, based on the formation of dibromo derivatives:

Excess bromine is determined iodometrically, the indicator is starch, titrate until it turns blue:

Br 2 + 2 KI= I 2 +2 KBr

I 2 + Na 2 S 2 O 3 = 2 NaI+ Na 2 S 4 O 6

K stoich =1/Z =1/4 (based on the number of bromine atoms participating in the reaction)

Mm. =165.19 g

M(1/Z) = 41.3 g/mol

Formula for calculating quantitative content:

3. DefinitionauthenticityAndquantitativedefinitionsdicainehydrochloride(tetracainehydrochloride)

3.1 Equationsreactionsauthenticity

A) General reactions of n-aminobenzoic acid esters having a substituted primary aromatic amino group

Secondary amines under the influence of sodium nitrite form nitroso compounds:

An azo dye can also be obtained by adding a weakly acidic solution of an aromatic amine to a diazonium salt.

These reactions form the basis of the nitritometric method for the analysis of aromatic amines.

Condensation reactions. Aromatic amines enter into condensation reactions with 2, 4-dinitrochlorobenzene, aldehydes and other substances. As a result of the interaction of amines with aldehydes, Schiff bases are formed - compounds colored yellow or orange-yellow.

WhereR-WITH 4 N 9

Halogenation reactions. Substitution occurs in the ortho and para positions relative to the amino group. As a result of the bromination reaction, white or yellow precipitates are formed and bromine water becomes discolored.

Oxidation reactions. Under the influence of various oxidizing agents, aromatic amines form indophenol dyes

Reaction to an aromatic nitro group.

When an alkali acts on a compound containing a nitro group, the color intensifies to yellow, yellow-orange or red as a result of the formation of an aci salt.

Tetracaine hydrochloride from solutions is precipitated by potassium iodide in the form of hydrogen iodide salt

Under the influence of ammonium isothiocyanate, tetracaine isothiocyanate precipitates, the melting point of which is 130-132 ° C

Tetracaine hydrochloride, when interacting with potassium iodate in a phosphoric acid medium upon heating, forms a violet-colored oxidation product with a light absorption maximum at 552 nm. The reaction is specific for qualitative and quantitative determination.

B) Particular reactions to tetracaine hydrochloride:

Tetracaine hydrochloride, after heating with concentrated nitric acid and adding to the remainder of the potassium hydroxide solution, acquires a blood-red color. The reaction is based on its nitration and the subsequent formation of a potassium soliorthoquinoid compound:

For alkaline hydrolysis products:

Upon acidification, a white precipitate of p-butylaminobenzoic acid precipitates, which dissolves in excess hydrochloric acid:

From p-butylaminobenzoic acid, under the action of sodium nitrite, a precipitate of the N-nitroso compound of this acid precipitates:

Chloride ion detection reaction:

3.2 Methodsquantitativedefinitions.Calculationcontent

1. Nitritometry.

The method is based on the reaction of diazotization of primary and secondary aromatic amines with sodium nitrite, which is used as a titrant. Titration is carried out in an acidic environment (hydrochloric acid), at a low temperature, to prevent the decomposition of nitrous acid and diazonium salt; Potassium bromide is used as a catalyst. The diazotization reaction takes place over time, so titration is carried out slowly.

The equivalence point can be fixed in three ways:

1) potentiometrically;

2) using internal indicators - tropeolin 00 (color transition from red to yellow), tropeolin 00 mixed with methylene blue (color transition from red-violet to blue), neutral red (color transition from red-violet to blue);

3) using external indicators, for example, iodine-starch paper.

Iodine-starch paper is porous, ashless filter paper soaked in a solution of starch with potassium iodide and dried in a dark place. Titration is carried out until a drop of the titrated solution, taken 1 minute after adding the titrant, immediately causes a blue color on a strip of starch iodine paper.

Secondary aromatic amines form nitroso compounds with sodium nitrite:

K stech =Z =1

Mm. = 300.83 g

M(1/Z) = 300.83 g/mol

Formula for calculating quantitative content:

Tetracaine hydrochloride can be determined by the amount of bound hydrochloric acid by alkalimetry; titration is carried out in the presence of chloroform, which extracts the released base:

Chloride ion argentometry method:

Conclusion

The primary or secondary aromatic amino group is contained in derivatives of p-aminobenzoic acid (novocaine, anesthesin, dicain, sodium diclofenac and others).

The mutual influence of atoms in a molecule affects the properties of aromatic amines. The lone electron pair of the nitrogen atom of the primary aromatic amino group is involved in conjugation with the p-electron system of the benzene ring. As a result, a shift in electron density occurs, which leads to activation of the ortho and para positions in the aromatic ring and a decrease in the basicity of the nitrogen atom in the amino group. Thus, aromatic amines are weak bases.

Aromatic amines are characterized by reactions of azo dye formation, condensation, halogenation, and oxidation.

Listliterature

1. Belikov, V. G. Pharmaceutical chemistry: a textbook for pharmaceuticals. Universities. - M.: Higher School, 2003. - 697 p.

2. Pharmaceutical chemistry: Textbook / ed. A.P. Arzamastseva.-2nd ed., revised.- M.: GEOTAR - Medicine, 2008.- 640 p.

3. State Pharmacopoeia of the USSR: X edition. 1968

4. State Pharmacopoeia of the USSR: X1 edition. Issue 1.- M.: Medicine, 1987.-336 p.

5. State Pharmacopoeia of the USSR: X1 edition. Issue 2. M.: Medicine, 1986.-368 p.

6. Dudko, V.V., Tikhonova, L.A. Analysis of medicinal substances by functional groups: textbook / ed. E. A. Krasnova, M. S. Yusubova. - Tomsk: NTL, 2004. - 140 p.

7. Guide to laboratory classes in pharmaceutical chemistry: textbook / ed. A. P. Arzamastseva. - M.: Medicine, 2004. - 384 p.

8. Pharmaceutical chemistry: textbook for universities / ed. A. P. Arzamastseva. - M.: GEOTAR-Media, 2006. - 640 p.

9. Chekryshkina L.A. et al. Analysis of drugs by functional groups. Perm. 2012

10. Chekryshkina L.A. et al. Methods of titritometric analysis. Permian. 2012

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White crystalline powder, odorless. Easily soluble in water and alcohol, difficult in chloroform, insoluble in ether.

Receipt.

Similar to novocaine: anesthesin is converted by esterification into β-dimethylaminoethyl ether

n-aminobenzoic acid and then alkylated.

Authenticity.

1. Alkaline hydrolysis reaction.

When acidified, a precipitate of n-butylaminobenzoic acid precipitates, which dissolves in excess hydrochloric acid.

2. Reaction with concentrated nitric acid, after heating the drug with HNO 3 (conc.), add a few drops of an alcohol solution of potassium hydroxide, a blood-red color appears.

3. R-I with ammonium thiocyanate - dicaine thiocyanate precipitates, which after recrystallization and drying is checked for its melting point.

Quantitation.

1. Nitritometry after acid saponification (SA).

2. Neutralization with hydrochloric acid in the presence of chloroform.

Application.

The activity of dicaine is 8-10 times stronger than cocaine, but it is used in significantly lower doses than cocaine. Used for superficial anesthesia in ophthalmic and otorhinolaryngological practice.

Storage.

According to list A. In a well-closed orange glass container.

Sulfonamides.

Streptocidum. Steptocid.

White crystalline powder, odorless. Slightly soluble in water, easily in boiling water, soluble in diluted hydrochloric acid, alkali solutions and acetone.

Drugs in this group were discovered as the most powerful antibacterial agents. The mechanism of the antimicrobial action of sulfonamides is based on the theory of competitive antagonism. Its essence: to maintain the vital activity of many pathogenic microorganisms, growth factors containing purine bases are necessary. Their biosynthesis is carried out by microorganisms based on para-aminobenzoic acid, which is found in the tissues of the human body. Sulfonamides are not only structurally, but also spherically similar to p-minobenzoic acid. Therefore, when sulfonamides enter the body tissues (when taking the drug), they replace para-aminobenzoic acid. Biosynthesis occurs of substances that, due to differences in chemical structure, have a bacteriostatic effect against microorganisms. The theory of competitive antagonism made it possible to substantiate the optimal doses of sulfonamides. Initial (loading) doses should be twice as high as subsequent single doses, and no breaks in administration should be allowed.

Authenticity.

1. General reaction – formation of an azo dye:

2. Reaction with hydrogen peroxide in the presence of iron (III) chloride - streptocide forms a purple color.

3. Pyrolysis - streptocide forms a blue-violet melt, and aniline and ammonia are released.

4. Determination of sulfamide sulfur.

To detect sulfamide sulfur, the substance is mineralized by boiling with concentrated nitric acid.

Molecular formula. Ci5H24N202-HC1.

Relative molecular weight. 300.8.

Structural formula.

CH3(CHg)3NH-Q-COOCH2CH2N(CH3)2

Chemical name. 2-(dimethylamino)ethyl p-(butylamino)ibenzoate monohydrochloride; 2-(dimethylamino)ethyl 4-(butylamino) benzoate monohydrochloride; per.

CAS No. 136-47-0.

Synonyms. Amethocaine hydrochloride; Dicaine

Description. White crystalline powder, odorless.

Solubility. Soluble in about 8 parts water; soluble in ethanol (- 750 g/l) TS; sparingly soluble in chloroform R; practically insoluble in ether R.

Storage. Tetracaine hydrochloride should be stored in a tightly closed container, protected from light.

Additional Information. Tetracaine hydrochloride is hygroscopic; it has a slightly bitter taste and causes local numbness of the tongue. Even in the dark, it gradually decomposes in a humid atmosphere, and the destruction accelerates as the temperature rises.

Tetracaine hydrochloride melts at about 148°C or can occur in one of two polymorphic forms, one of which melts at 134°C and the other at 139°C. Mixtures of these forms melt in the range of 134-147 °C.

REQUIREMENTS

General requirement. Tetracaine hydrochloride contains at least

98.0 and not more than 101.0% Si5H24^02-HC1 in terms of the dried substance.

Authenticity

A. Dissolve 0.2 g of the test substance in 10 ml of water and add 1 ml of ammonium thiocyanate (75 g/l) TS. Collect the precipitate on a filter, recrystallize from water and dry for 2 hours at 80 °C; melting point is about 131 °C.

B. A solution of the test substance at a concentration of 20 mg/ml gives the characteristic reaction A for chlorides, described in the section “General tests for authenticity” (vol. 1, p. 129).

Transparency and color of the solution. A solution of 0.20 g of the test substance in 10 ml of carbon dioxide-free water R is clear and colorless.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105 °C; loss no more than 10 mg/g.

pH of the solution. The pH of a solution of the test substance in carbon dioxide-free water P with a concentration of 10 mg/ml is 4.5-6.0.

Foreign impurities. Carry out the test as described in the section “Thin layer chromatography” (vol. 1, p. 92), using silica gel R4 as the sorbent, and a mixture of 80 volumes of dibutyl ether R, 16 volumes of hexane R and 4 volumes of glacial acetic acid as the mobile phase. acid R. Place the plate in the chromatographic chamber, immersing it 5 mm in the liquid. After the solvent front reaches a height of about 12 cm, remove the plate from the chamber and dry it for several minutes in a stream of warm air. Allow the plate to cool and apply separately 5 µl of each of 2 solutions containing (A) 0.10 g of the test substance in 1 ml and (B) 0.050 mg of 4-aminobenzoic acid R in 1 ml. Allow the solvent front to rise 10 cm above the application line. After removal from the chromatographic chamber, dry the plate for 10 minutes at 105 °C and evaluate the chromatogram in ultraviolet light (254 nm). Any stain produced by Solution A, other than the main stain, should not be more intense than the stain produced by Solution B. The main stain remains on the line of application.

Quantitation. Carry out the test as described in the section “Nitritometry” (vol. 1, p. 153), using about 0.5 g of the test substance (accurately weighed) dissolved in a mixture of 50 ml of water and 5 ml of hydrochloric acid (-420 g / l ) TS, and titrate with sodium nitrite (0.1 mol/l) VS. Each milliliter of sodium nitrite solution (0.1 mol/l) VS corresponds to 30.08 mg of Ci5H24N202-HC1.

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