Barbiturates salt formation

Much of the beneht in solubihty enhancement from salt formation is attributable to the change in solution pH caused by the presence of the counterion. This occurs because the ionization and solubility of acidic drugs (such as barbiturates and non-steroidal anti-inflammatory drugs) increases in basic conditions but decreases in acidic conditions. This behavior is exemplified by derivations of the Henderson-Hasselbalch equations (37.2) and (37.3). The opposite situation occurs for basic drugs such as chlorpromazine, morphine and codeine, which are more soluble in acidic conditions. 

In general, barbiturates—thiopental in particular—change into soluble form on treatment with bases. Therefore, thiopental often appears in the market under the name sodium thiopental. In this case, the formation of a salt occurs due to the sulfur atom in an enethi-olate form. The most common synonyms for thiopental are pentothal, trapanal, farmotal, intraval, and others. 

Interactions are not always visible. The formation of visible precipitates depends to a large extent on the insolubility of the two combining species in the particular mixture and the size to which the precipitated particles grow. One might assume that in an atropine and phenobarbital mixture, a barbiturate-atropine complex may precipitate. Atropine base is soluble to the extent of 1 part in 460 parts of water. There is only 0.6 mg atropine in a 5 cm dose and it is therefore well within its solubility limit. The solubility of phenobarbital is 1 mg cm . The 15 mg of phenobarbital sodium (13.5 mg of phenobarbital) which would result if all the sodium salt were to be precipitated would be in excess of its solubility. Only 0.4 mg of phenobarbital is precipitated by 0.6 mg of atropine sulfate, however, and the phenobarbital therefore remains in solution also. There is thus no precipitation. 

Stxlium salts of the barbiturates are readily prepared and are water soluble. Their aqueous. solutions generate an alkaline pH. A classic incompatibility is the addition of an agent with an acidic pH in solution, which rc.sults in formation and precipitation of the free water-insoluble disubsliluied barbituric acid. Sodium salts of barbiturates in aqueous solution decompose at varying rates by base-catalyzed hydrolysis, generating ring-opened sails of carboxylic acids. 

A large proportion of drug substances, whether neutral molecules, free adds, free bases or salts, are capable of exhibiting polymorphism or pseudopolymorphism (hydrate or solvate formation). It has been reported that 70% of barbiturates, 60% of sulfonamides and 23% of steroids exhibit polymorphism." Polymorphism often influences a range of physicochemical properties such as solubility, dissolution rate, stability and powder properties as well as bioavailability. Usually, it is possible to determine the most stable polymorph and discover recrystallization solvents that uniquely produce this form and improve the physicochemical and physicome-chanical properties and chemical stability of the drug. 

Barbiturate preparations can be determined ) by employing a dropping mercury electrode with 1 X 10 to 1X 10 m solutions in 0 05 M borax. The anodic waves corresponding to the formation of a salt with mercury are recorded. A 100-fold excess of chloride ions did not interfere in this determination. 

In these cases it is usually possible to explain why the color is formed. The reactions can be further classified, on the basis of the type of colored compound formed, into reactions leading to the formation of azo dyes, di- or triphenylmethane dyes, xanthene dyes, polymethine dyes, indophenols, etc. Azo dyes are formed, for example, in the reaction of diazonium salts and phenols (p. 192) or amines (p. 324), azomethines in the reaction of primary aromatic amines with aromatic aldehydes (p. 215), di- and triphenylmethane dyes in the reaction of aromatic aldehydes with aromatic hydrocarbons in concentrated sulfuric acid (p. 213), triphenylmethane dyes in the reaction of phenols with aromatic aldehydes or oxalic acid (p. 196), xanthene dyes in the reaction of anhydrides of dicarboxylic acids with resorcinol (p. 196), polymethine dyes are formed after the cleavage of the pyridine ring in the reaction of the glutaconaldehyde formed and barbituric acid (p. 378), indophenols on reaction of phenols with Gibbs reagent (p. 195), or 4-aminoantipyrine according to Emerson (p. 194), or on the Liebermann reaction (p. 195). 

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