Codeine salts

Levopropoxyphene [2338-37-6] (42), the optical antipode of the dextrorotatory analgetic propoxyphene, is an antitussive without analgetic activity. The 2-naphthalenesulfonate salt has a less unpleasant taste than the hydrochloride salt, and is widely used. Clinical effectiveness has been demonstrated against pathological and artificially induced cough, but the potency is somewhat less than codeine. The compound is reported not to cause addiction. Levopropoxyphene can be prepared (62) by first resolving [ -dimethylamino-CX-methylpropiophenone with dibenzoyl-(+)-tartaric acid. The resolved... 

The citrate salt of isoaminile [77-51-0] (50) is a nitrile used as an antitussive in numerous European countries. In clinical trials it was shown to be as effective as codeine or chlophedianol, with few mild side effects. Isoaminile citrate is longer acting than chlophedianol and does not cause the respiratory depression of codeine (68). 

Non-aqueous titration with acetous perchloric acid is used in the pharmacopoeial assays of adrenaline, metronidazole, codeine, chlorhexidine acetate, chlorpromazine.HCl, amitriptyline.HCl, propranolol.HCl, lignocaine.HCl and quaternary amine salts such as neostigmine bromide and pancuronium bromide. 

Dosages and routes of administration Codeine is used orally in single doses of 30 to 60 mg up to a total dose of 240 mg per day for pain relief. Codeine is used in the form of different salts such as hydrochloride, phosphate and sulfate. To increase the duration of action, slow-release preparations have been developed. Codeine is often combined with other analgesics e.g. acetyl salicylic acid or paracetamol. For cough inhibition lower doses are sufficient. 

The salt obtained in this manner is a double one, free from narcotic. It is dissolved in water, boiled, and treated with ammonia, which precipitates the morphin. This is filtered off, washed with a little cold water, and dried. From the filtrate codein is obtained. 

Codein is a very powerful base it turns red litmus paper blue, and precipitates the oxides of lead, iron, cobalt, and nickel from their solutions. It is precipi. tated from the solutions of its salts by potassa and by ammonia in the latter case, however, It does not fall immediately, but is slowly deposited as small transparent crystals. ... 

Opium alkaloids such as codeine, thebaine, papaverine, and noscapine exhibit high solubility (0.09-0.9 mg/g) in supercritical fluids including CO N,0, CHF, [37]. However, in spite of their high solubilities, they were not extracted from plant material by pure CO, to the degree expected [29], possibly because these alkaloids exist as their salt forms in plant tissue. In this chapter, the examples that show the difference of the solubilities between alkaloidal free bases and salts are presented. For this comparison, the solubilities of the free bases of hyoscyamine (1), scopolamine (2), pseudoephedrine (6) were measured and compared with those of their hydrochloride salts (Figures 3 and 4). 

Codeine Phosphate The presence of aspirin along with codeine, even at a low moisture level, leads to acetylation of codeine phosphate in solid dose forms and is incompatible.36 Codeine sulfate solutions are more stable than phosphate salts.37 Drug dependence and withdrawal resemble that of opioid analgesics. Overdose causes acute intoxication in children, as accidental or deliberate ingestion of cough preparations containing codeine.38... 

The acetylation of morphine and of codeine by aspirin202 and the enzymatic hydrolysis of heroin203 and the reduction of codeinone204 have been studied. Dihydronorcodeine and dihydromorphine have been isolated from urine as metabolites of dihydrocodeine.205 Patents have been published covering the preparation of -(cyclopropylmethyOnormorphine,206 the conversion of thebaine into codeinone,207 and the preparation of nalorphine 6-sulphate.208 Salts of codeine and ethylmorphine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one have been prepared.209 The circular dichroism210,211 and fluorescence characteristics212 of morphine and related bases have been studied. 

In the same way, organic bases such as amines can be dissolved by lowering the pH. Codeine (7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol) is a commonly used painkiller. Codeine itself is not very soluble in water but it does contain a basic nitrogen atom that can be proto-nated to give a more soluble salt. It is usually encountered as a phosphate salt. The structure is com-... 

Medical treatments of IBS are limited. Laxatives (particularly dietary fibre and bulking laxatives such as ispaghula) and antidiarrhoeals (loperamide and sometimes codeine) are prescribed to manage the symptoms of altered bowel habit. Colestyramine is of use in those with diarrhoea caused by bile salt... 

Q4 Constipation can be a troublesome side effect of opiates used for pain relief, for example morphine and codeine. It is also a side effect of some calcium channel blocking agents, antacids containing aluminium compounds and iron salts used in the treatment of anaemia. 

Morphine has been found to couple with the diazonium salt of 4-aminoacetophenone(l68) to give a single product substituted at C-2. Codeine, on the other hand, gave a mixture of C-2 and C-8 substituted products. 

Codeine, dihydrocodeinone, and 14-hydroxydihydrocodeinone couple with the diazonium salt of 4-aminoacetophenone at C-8, giving the corresponding azo adduct.(168)... 

The structure of (—)-morphine was established conclusively 10 by X-ray crystallography from two projections of the hydroiodide dihydrate salt and confirmed for codeine and morphine by an X-ray study of their hydrochloride trihydrate salts/111 The piperidine ring was shown to adopt a chair conformation with the N-Me equatorial. The absolute stereochemistry of morphine was also confirmed by X-ray studies/415"417 ... 

Codeine (2, R = CH3) occurs in the opium poppy along with morphine (2, R = H) but usually in much lower concentration. Because it is less toxic than morphine and because its side effects (including depression, etc) are less marked, it has found widespread use in the treatment of minor pain and much of the morphine found in crude opium is converted to codeine. The commercial conversion of morphine to codeine makes use of a variety of methylating agents, among which the most common are trimetliylphenylammonium salts. In excess of two hundred tons of codeine are consumed annually from production facilities scattered around the world. 

To prepare the diamorphine hydrochloride, ethanol, diethyl ether and concentrated HCl are used. The base is dissolved in ethanol and the acid is added. Once all of the drug has been converted to the hydrochloride salt, further alcohol and ether are added. After a few minutes, crystals of heroin hydrochloride form. Further ether is added and the whole system allowed to stand. The solid diamorphine hydrochloride is then ready for packing and shipping. A consequence of all of these processes is that the opiates which may be contained within a heroin sample include diamorphine, 6-0-monoacetylmorphine (7), morphine, codeine and acetylcodeine (8). 

Many other drugs, such as codeine and quinine, are amines, but they are rarely used in their pure amine forms. Instead, they are treated with an acid to become acid salts. An example of an acid salt is ammonium chloride, obtained by the reaction... 

Cobeine is the methyl-phenyl ether with the hydroxyl hydrogen in position 3 replaced by methyl. Both morphine and codeine are crystalline compounds reacting as tertiary mono-acid bases. Morphine is slightly soluble in water, codeine being more so, the former being more bitter in taste than the latter. The salts are soluble and in this form the alkaloids are used in medicine though codeine is also used as the free base. 

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