Theme: Halogen derivatives of hydrocarbons, which are used in the medical practice. Some alcohols, aldehydes and ethers as drugs.

 

 

 

Halogenderivatives  of hydrocarbons as drugs

 

Ethyl Chloride

H₃C-CH₂Cl     (C₂H₅Cl)         64.52

Ethyl chloride is chloroethane. It may be prepared by the action of hydrogen chloride on ethanol or on Industrial Methylated Spirit; in the later case it may contain a small variable of methyl chloride.

Characteristics. Gaseous at ambient temperature and pressure, but usually compressed to a colorless, mobile, flammable and very volatile liquid; odour, ethereal. Slightly soluble in water, miscible with ethanol and with ether.

Identification. A. Burns with a luminous flame with the production of hydrogen chloride.

B. Vigorously shake 2 ml with 5M sodium hydroxide and warm on a water bath. Reserve a portion of the solution for test C. To the resulting solution add 2 ml of iodinated potassium iodide solution and warm. Crystals of iodoform are produced.

C. The solution reserved in test B yields the reactions characteristic of chlorides.

Storage. Ethyl chloride should be protected from   ____ and stored at temperature not exceeding 15*C.

INDICATIONS FOR USE  Anaesthetic. For external use only

Ethyl Chloride is a vapocoolant (skin refrigerant) intended for topical application to control pain associated with injections, minor surgical procedures (such as lancing boils, incisions, and drainage of small abscesses) and athletic injuries. It is also intended for the treatment of restricted motion associated with myofascial pain caused by trigger points.

Contents under pressure. Store in a cool place (controlled room temperature). Do not store above 120°C. Do not store on or near high frequency ultrasound equipment.

 

 

 

Chloroform

CHCl₃          119.4

Chloroform is trichloromethane to which ethanol is added. It is colorless, volatile liquid; with characteristic odor.

Slightly soluble in water, miscible with absolute ethanol, ether, with fixed and volatile oils and with most organic solvents.

Identification. A. The infrared absorbtion spectrum.  

         B. Heat with sodium hydroxide solution. Obtained solution yields reactions characteristic of chlorides.

 

Methoxyflurane  (Penthrane)

CHCl₂CF₂–O–CH₃     (2,2-dichloro-1,1-difluoroethyl methyl ether)

Methoxyflurane is a volatile liquid (b.p. 105*C). The agent does not have a high vapor pressure at room temperature: thus concentrations in the inspired are low. This, together with a large                                  blood/gas partition coefficient, produces a slow induction of anesthesia featuring an excitatory phase. Accordingly, induction is usually made with intravenous sodium thiopental. The compound is very soluble in lipids; consequently, recovery is slow. The agent produces exellent analgesia and good muscle relaxation. Methoxiflurane is as much as 70% metabolized. Apparently all labile sites are attackted. Metabolites include dichloroacetic acid, difluoromethoxyacetic acid, oxalic acid and fluoride ions. Fluoride ion especially, and oxalic acid also, are responsible for the renal damage the agent produces when used to produce deep anesthesia over prolonged periods. Accordingly, it has restricted application as an anesthetic.

 

Fluothane (Halothane)

CH(Br)ClCF₃        (2-Bromo-2-chloro-1,1,1-trifluoroethane)

Halotane, a volatile halohenated hydrocarbon (b.p. 50*C), is now taken as a standard inhalation anesthetic agent.

 

 

Iodoform

CHI₃

Iodoform is a yellow crystalline powder (m.p. 116-120*C); odor characteristic; insoluble in water, practically insoluble in alcohol, ether, chloroform.

Identification. Heat in the test tube. The violet vapor of I₂ is produced.

Action and use. Antiseptic (ointment)

 

 

Alcohols and ethers  as drugs

Various alcohols have been used as antiseptics and disinfectants. Antibacterial potencies of primary alcohols increase with molecular weight up to C₈. Beyond this point, water solubility is less than the minimum effective concentration, and the apparent potency decreases with molecular weight. Branching decreases antibacterial potency; hence, the isomeric alcohols follow the order primary > secondary > tertiary. Noneseless, isopropylalcohol is used commercially instead of normal propyl alcohol, because it is cheaper. Isopropyl alcohol is slightly more active than ethyl alcohol against vegetative bacterial growth, but alcohola are largely ineffective against spores.

Alcohol ( C₂H₅OH, ethanol, spiritus vini rectificatus, wine spirit) is a clear, colorless, volatile liquid having a burning taste and characteristic pleasant odour. It is flammable and miscible with water and most organic solvents. The commercial product contains about 95% ethanol by volume because this concentration forms an azeotrope that distills at 78.2*F. Alcohol has been known for centuries as a fermentation product from grain and other carbohydrate sources. It can also be prepared synthetically by the sulphuric acid-catalyzed hydration of ethylene.

Identification. A. Alcohol reacts with acetic acid to form ether.

B. In reaction with iodine (in present of Na₂CO₃) forms iodoform (CHI₃).

C. Complies with the test of Relative density.

D. Mix 0.1 ml with 1 ml of a 10 g/l solution of potassium permanganate R and 0.2 ml of dilute sulphuric acid R in a test-tube. Cover immediately with a filter paper  moistened with a freshly prepared solution containing 0.1 g of sodium nitroprusside R and 0.5 g of piperazine hydrate R in 5 ml of water R. After a few minutes, an intense  blue colour appears on the paper and becomes paler after 10 min to 15 min.

        

MYAMBUTOL (Ethambutol hydrochloride)

Ethambutol ( (+)2,2’-(ethylenediimino)-di-1-butanol dihydrochloride) is a white crystalline powder freely soluble in water and slightly soluble in ethanol

Identification. A. Extract a quantity of the powdered tablets containing 50 mg of Ethambutol hydrochloride with 5 ml of methanol, filter and evaporate the filtrate to dryness. The infrared absorption spectrum of the residue is coccordant with the reference spectrum of ethambutol hydrochloride.

B. Shake a quantity of the powdered tablets containicg 0.1 g of ethambutol hydrochloride with 10 ml of water, filter and add to the filtrate 2 ml of 1% w/v solution of copper(II) sulphate followed by 1 ml of 1M sodium hydroxide. A blue color is produced.

Assay. Dissolve 0.2 g in 10 ml of 2M sodium hydroxide and extract with five successive 25-ml quantities af chloroform. Evaporate the combined extracts to about 25 ml, filter, add 100 ml of anhydrous acetic acid and carry out method for non-aqueous titration, using 1-naphtholbenzein solution as indicator. Each ml of 0.1M perchromic acid is equivalent to 13.86 mg of C₁₀H₂₄N₂O₂,2HCl.

Ethambutol is an oral chemotherapeutic agent which is specifically effective against actively growing microorganisms of the genus Mycobacterium, including M. tuberculosis. MYAMBUTOL is indicated for the treatment of pulmonary tuberculosis. It should not be used as the sole antituberculous drug, but should be used in conjunction with at least one other antituberculous drug. Selection of the companion drug should be based on clinical experience, considerations of comparative safety and appropriate in vitro susceptibility studies. In patients who have not received previous antituberculous therapy, ie, initial treatment, the most frequently used regimens have been the following: MYAMBUTOL plus isoniazid ; MYAMBUTOL plus isoniazid plus streptomycin.

         This compound is remarkably stereospecific. Tests has shown, that although  the toxicities of the dextro, levo and meso isomerc are about equal, their activities vary considerably. The dextro isomer is 16 times as active as the meso isomer. In addition, the length of the alkylene chain, the nature of the branching of the alkyl substituents on the nitrogens, and the extent of N-alkylation all have a pronounced effect on the activity.

        

Ether

C₄H₁₀O  (CH₃-CH₂-O-CH₂-CH₃)                    74.1

         Ether is a diethyl ether to which an appropriate quantity of a suitable non-volatile antioxidant may have been added.

         Characteristics. A clear, colorless, volatile, very mobile liquid; highly flammable; odour, characteristic.

         Identification. Complies with the tests for Distillation range (34.0-35.0*C) and Relative density (0.714-0.716).

         Ether intended for use as  a general anaesthetic. Ether complies with the above requirements with the following modifications.

         Acetone and aldehydes. Shake 10 ml with 1 ml of alkaline potassium tetraiodomercurate solution in a ground-glass-stoppered cylinder for 10 seconds and allow to stand for 5 minutes protected from light. The lower layer shows only a slight opalescence.

         Peroxides. Transfer 8 ml of potassium iodide and starch solution to a ground-stoppered-glass cylinder of about 12 ml capacity and about 1.5 cm in diameter. Fill completely with the substance being examined, shake vigorously and allow to stand protected from light for 30 minutes. No color is produced.   

 

Enflurane (Ethrane)

 HF₂COCF₂CHFCl                

(2-chloro-1,1,2-trifluoroethyldifluoromethyl ether)

         Action and use. General Inhalation anesthetic.

It is a volatile liquid (b.p. 55.5-57.5*C) with a vapor pressure at room temperature about three-fourths that of halotane and a blood/gas partition coefficient also about three-fourth that halotane. The agent is said to be a relatively easy agent with which to work and to have a relatively low frequency of adverse cardiovascular effects. Respiration is depressed, and thus mechanical mentilation and oxygen supplementation are employed.

 

Isoflurane (Forane)

F₃CC(H)ClOCF₃                     (1-chloro-2,2,2-trifluoroethyldifluoromethyl ether)

Isoflurane is a close structural relative of enflurane and shares many properties with it.

 

Glycerol (Glicerin)

Glycerol is propane-1,2,3-triol. It contains not less than 98.0% and not more than 101.0% of C₃H₈O₃, calculated with reference to the anhydrous substance.

It is a clear, colorless or almost colorless, syrupy liquid slippery to the touch; very hydroscopic. Miscible with water and with ethanol (96%); slightly soluble in acetone; practically insoluble in ether and in fixed and volatile oils.

Identification. A. To 5 ml add 1 ml of water and mix carefully. The infrared absorption spectrum of the resulting solution is concordant with the European Pharmacopoeia reference spectrum of glycerol (85%).

B. Mix 1 ml with 0.5 ml of nitric acid and superimpose 0.5 ml of potassium dichromate solution; a blue ring develops at the interface of the two liquids. Allow to stand for 10 minutes; the blue color does not diffuse into lower layer.

C. Heat 1 ml with 2 g of potassium hydrogen sulphate in an evaporating dish. Irritant, lachrymatory vapours are evolved which blacken filter paper moistened with alkaline potassium tetraiodomercurate solution.

D. Complies with the test for Refractive index (1.470-1.475).

Assay. Thoroughly mix 0.1 g with 45 ml of water, add 25 ml of a 2.14% w/v solution of sodium periodate and allow to stand protected from light for 15 minutes. Add 5 ml of a 50% w/v solution of ethane-1,2-diol, allow to stand protected from light for 20 minutes and titrate with 0.1M sodium hydroxide using o.5ml of phenolphthaleine solution as indicator. Repeat the procedure without the substance being examined. The difference between the titrations represents the amount sodium hydroxide required. Each ml of 0.1M sodium hydroxide is equivalent to 9.12 mg of C₃H₈O₃.

Action and use. Lubricant; laxative.

 

Nitroglycerin (Glyceryl trinitrate; Trinitrin tablets)

It is a trinitrate ester of glycerol and is official a tablet form. It is prepared by carefully adding glycerin to a mixture of nitric and fuming sulfuric acids. This reaction is exothermic and the reaction mixture must be cooled between 10* and 20*C. The ester is colorless oil, with a sweet, burning taste. It is only slightly soluble in water, but it is soluble in organic solvents.

Identification. A. Carry out the method for thin-layer chromatography, using silica gel G as the coating substance and toluene as the mobile phase.

B. Extract  quantity of the powdered tablets containing  3mg of glyceryl trinitrate with 5 ml of ether and filter. Evaporate the ether and dissolve the residue in 0.2 ml of sulphuric acid containing a trace of diphenylamine. An intense blue color is produced.

Nitroglycerin has a strong vasodilatating action. It has the action typical of nitrites, but its action is developed more slowly and longer duration. Of all the known coronary vasodilator drugs, nitroglycerin is the only one capable of stimulating the production of coronary collateral circulation and the only one able to prevent experimental myocardial infarction by coronary occlusion.

 

 

 

Aldehydes and ketones as drugs

 

Formaldehyde solution (formaline)

Note: The name Formaline as a synonym for Formaldehyde Solution may be used freely in many countries, including Great Britain and Northern Ireland, but in other countries exclusive proprietary rights in this name are claimed.

CH₂O                30.03

Definition Formaldehyde Solution is an aqueous solution of formaldehyde containing methanol as a stabilizing agent (methanol added to retard polymerization). It contains not less than 34.0% w/w and not more than 38.0 % w/w of CH₂O.

Characteristics A colorless liquid: odor, characteristic, pungent and irritating. A slight white deposit may form during storage. Formaldehyde readily undergoes oxidation and polymerization, leading to formic acid and paraformaldehyde, respectively. It should be preserved in tightly closed containers and stored at temperature above 15*C to prevent the cloudiness that occurs at lower temperatures. Miscible with water and with ethanol (96.6%).

Identification A. Dilute 1 ml with sufficient water to produce 1000 ml. To 10 ml of this solution add 2 ml of a freshly prepared 1% w/v solution of phenylhydrazine hydrochloride, 1 ml of dilute potassium hexacyanoferrate ( ) solution and 5 ml of hydrochloric acid. A brilliant red color is produced.

B. Evaporate on a water bath. A white, amorphous residue is produced.

C. Dissolve salicylic acid in a small amount of H₂SO₄k. Add some drops of formaldehyde solution and heat. A red color is produced.

D. Add some drops of ammonium solution and formaldehyde solution to the silver nitrate solution and heat on the water bath.

Aldehyde reduces silver (I) to silver metal, which deposited as a silver mirror on the side of the test tube.

HCOH + 2[Ag(NH3)₂]NO₃ + H₂O = HCOONH₄ + 2Ag + 2NH₄NO₃ + NH₃

Assay A. To 1 ml of formaldehyde solution add water to obtain 100 ml of solution (solution A). Take 5 ml of solution A and put it into the flask. Add 20 ml of iodine solution and 10 ml of 1M sodium hydroxide solution and allow to stand for 10 minutes. Add 11 ml of 1N H₂SO₄k. Titrate with the Na₂S₂O₃ using the starch as an indicator.

 

B. Add 3 g to a mixture of 25 ml of hydrogen peroxide solution (20 vol) and 50 ml of 1M sodium hydroxide, warm on a water bath until effervescence ceases and titrate the excess of alkali with 1M hydrochloric acid using phenolphthalein solution as indicator. Repeat the operation without the solution being examined. The difference between the titrations represents the amount of sodium hydroxide required to neutralise the formic acid produced by the oxidation of the formaldehyde. Each ml of 1M sodium hydroxide is equivalent to 30.03 mg of CH₂O.

Formaldehyde solution exerts a slow but powerful germicidal action. The mechanism of this effect is believed to involve the direct, nonspecific alkylation of nucleofilic functional groups (amino, hydroxyl, and sulfhydryl) in proteins to form carbinol derivatives. The action of formaldehyde is not confined to microorganisms. The compound is irritating to mucous membranes and causes hardening of the skin. Oral ingestion of the solution leads to severe gastric distress.

Formalin, diluted in water, had been employed to harden the skin, to prevent excessive perspiration, and to disinfect the hands before surgery. The gas has been employed to disinfect rooms, clothing and surgical instruments. A high frequency off allergic reactions associated with formaldehyde and formaldehyde-based products and the designation of formaldehyde as a suspect carcinogen suggest that it should not be used for the indicated foregoing purposes.

 

 

 

Chloral Hydrate or Noctec (trichloracetaldehyde monohydrate, CCl₃CH(OH)₂)

Chloral hydrate is aldehyde hydrate sufficiently stable that it can be isolated. The relative stability of this gem-diol is largely due to unfavorable dipole-dipole repulsion between the trichloromethyl carbon and the carbonyl carbon present in the parent carbonyl compound.

Chloral mixture  is a solution containing 10% w/v of Chloral Hydrate in a suitable vehicle. It is intended to be diluted with water before use.

Extemporaneous preparation It is recently prepared according to the following formula.

Chloral Hydrate 100g, Syrup 200 ml, Water sufficient to produce 1000 ml

Paediatric Chloral Elixir (Paediatric Chloral Oral Solution) is a solution containing 4% of Chloral Hydrate in suitable vehicle with a blackcurrant flavour.

Extemporaneous preparation It is recently prepared according to the following formula.

Chloral Hydrate 40g, Water 20 ml, Blackcurrant Syrup 200 ml, Syrup                          sufficient to produce 1000 ml

Idenification. The compound is unstable under alkaline conditions, undergoing the last step to the haloform reaction to yield chloroform (CHCl₃) and HCOO^–.

To 5 ml add 2 ml of sodium hydroxide and mix. Chloroform separated as liquid, recognizable by its odor.

Assay To 1 g add 2.5g of zinc powder, 15 ml of glacial acetic acid and 30 ml of water, boil under a reflux condenser for 30 minutes, cool, filter through absorbent cotton and wash the residue with water. Combine the filtrate and washings, add 20 ml of 2M nitric acid and 30 ml of 0.1M silver nitrate, shake vigorously, filter, wash the residue with water and titrate the excess of silver nitrate in the combined filtrate and washings with 0.1M ammonium thiocyanate using ammonium iron (III) sulphate solution as a indicator. Each ml of 0.1M silver nitrate  is equivalent to 5.513 mg of C₂H₃Cl₃O_2.

Action and use of chloral hydrate.  Sedative and hypnotic.

In combination with ethanol, chloral hydrate forms the hemiacetal. Whether or not this compound is the basis for the notorious and potentially lethal effect of the combination of ethanol and chloral hydrate can be argued. Synergism between two different CNS depressants also could be involved. Additionally, ethanol, by increasing the concentration of NADH, enhances the reduction of chloral to trichloroethanol, and finally, chloral can inhibit the metabolism of alcohol because it inhibits alcohol dehydrogenase. Although it is suggested that chloral hydrate, per se, may act as a hypnotic, it is also recognized that chloral hydrate is very quickly converted to trichloroethanol and the latter compound is generally assumed to account for almost all of the hypnotic effect.

 

 

Hexamethylenetetramine (urotropine, uritone, urised, prosed)

Definition. It contains not less than 99.0% of hexamethylenetetramine.

It is manufactured by evaporating a solution of formaldehyde to dryness with strong ammonia water.

6(НСНО) + 4NH₃  = (CH₂)₆N₄ + 6Н₂О.

          Characteristics. METHENAMINE (Hexamethylenetetramine) colorless, lustrous crystals or white crystalline powder that sublimes at about 260*C. Its solutions are alkaline to litmus. Freely soluble in water; soluble in alcohol and in chloroform.

Identification. A. (hydrolysis in acid medium) Heat 2 ml of solution 1:10 with 2 ml of dilution sulphuric acid_. The specific odor of formaldehyde is produced.

Add a surplus of sodium hydroxide solution and heat. The odor of ammonia is produced.

B. The solution of hexamethylenetetramine (as all heterocyclic compounds which contain the atom of nitrogen) reacts with:

 a) picrinic acid to form a yellow precipitate;

b) solution of iodine in potassium iodide to form a red-black precipitate;

 c) bromine to form yellow precipitate.

Assay. Dissolve 0.12 g in 10 ml of water, add 50 ml of 0.1N H₂SO₄ and boil during 30 minutes. Cool and add 2 drops of methyl-red solution as indicator. Titrate the surplus of 0.1N H₂SO₄  with 0.1N NaOH antill yellow color is produced.

Action and use.   

It is a combination of antiseptics (Methenamine, Methylene Blue, Phenyl Salicylate, Benzoic Acid) and parasympatholytics (Atropine Sulfate, Hyoscyamine).

Clinical pharmacology. Methenamine itself does not have antiseptic, irritant, or toxic properties in the urine. Methenamine, in acid urine (pH 6 or below), hydrolyzes into formaldehyde within the urinary tract providing mild antiseptic activity. Methenamine is readily absorbed from the gastrointestinal tract and is rapidly excreted almost entirely in the urine. Methylene Blue and Benzoic Acid are mild but effective antiseptics, which contribute to the antiseptic properties of Methenamine. Phenyl Salicylate is a mild analgesic and antipyretic with weak antiseptic activity. All of these compounds are readily absorbed from the gastrointestinal tract and excreted in the urine. Through parasympatholytic action, atropine and hyoscyamine relax smooth muscle spasms resulting from parasympathetic stimulation.

Warnings Methenamine may combine with sulfonamides in the urine to give mutual antagonism and should not be used with sulfonamides. These drugs may precipitate with formaldehyde in the urine increasing the danger of crystalluria.