Acidic drugs salts solubility

For an acidic and basic drug, the solubility over the GI pH range varies depending on the intrinsic solubility (SD) of the compound (i.e., solubility of unionized or nonprotonated species), pfCa, and the solubility of the salt form.71 72... 

It is common practice in pharmaceutical industry to generate salt forms of a drug substance to improve solid-state properties and solubility. CE has proven its ability to analyze reliably organic acids (direct, indirect detection) and alkaline/earth alkaline metals and basic amino acids. For basic drugs, a non-toxic organic acid or inorganic acid is chosen as counterion. Acidic drug substances will usually be deprotonated by alkaline and earth alkaline... 

Murti, S. K. 1993. On the preparation and characterization of water-soluble choline salts of carboxylic acid drugs, Ph.D. Dissertation, University of Missouri-Kansas City, Kansas City, MO. 

Analytical Procedure Microscopic Examination Place a small amount of a crushed tablet or capsule contents on a slide, mix with a drop of water, and cover carefully with a cover-slip avoiding trapped air bubbles. Observe under low-power magnification. Effervescence will be obvious. If crystalline material is visible, note if it is water-soluble. Check the pH of the solution. An alkaline reaction may indicate the presence of a sodium salt of an acidic drug. Introduce a small drop of silver nitrate solution along one edge of the cover-slip a visible precipitate indicates the possible presence of a hydrochloride salt of a basic drug. 

Barbiturates in either the free acid or salt forms are readily soluble in methanol and thus this is the solvent of choice for extraction in qualitative analysis. A known mass of the dose form is dissolved in a volume of methanol to provide the drug component at a working concentration of between 1 and 20 mgml The extract should be filtered or centrifuged prior to analysis in order to remove any unwanted particulate materials. For quantitative analysis, ethyl acetate can be used as the extraction solvent - if the drug is in the free acid form - with the extract treated in the same way as described above. If the original material is in the salt form, then the drug can be converted to the free acid form and extracted if required. 

Solubility is a key determinant of bioavailability, and alteration of solubility by salt formation may be used to improve biopharmaceutical performance. Typical counterions, cations, and anions, used to prepare salts of acidic drugs and basic drugs, are summarized... 

The stability, both chemical and physical, of a drug may be enhanced or retarded by salt formation. For example, solid dosage forms of diclofenac contain salt forms rather than the less stable free acid. Although salt formation may result in improved dissolution rate and bioavailability of a poorly water-soluble compound, the preparation of stable salt forms for some drugs may not be feasible and the free acid or base forms may be preferred. For example, the base form of a-pentyl-3-(2-quinolinylmethoxy)benzenemethanol was selected for dosage form design because of the physical instability of its hydrochloride salt. ... 

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. 

Where it is necessary to incorporate the drug into the oil phase of a dispersed o/w system, a hydrophobic drug is required. The drug substance should have a low aqueous solubility and it may be necessary to select a more lipophilic, low melting salt (e.g. a fatty acid ester salt such as stearate or an amine salt such as diethanolamine) or... 

Many synthetic substances to be used in solid dosage form are too limited in solubility to be therapeutically effective. The desirable solubility for an oral solid is suggested to be more than 1 mg/ml (0.1%). To increase solubility, a weak basic drug such as an amine may react with respective mineral acids to form salts, that is, hydrochloride (more than 40% of the salt marketed), sulfate, or phosphate. For an amine with two functional groups, a mono- or dihydrochloride salt may be formed, depending on the condition and amount of hydrochloric acid added. For an organic acid, a salt with sodium or potassium can easily be formed. Because a molecule of salt is polar, it should be freely soluble in water, reaching a therapeutic solubility level. The other types of acids commonly used for salt formation with a weak base are sulfonic acids and carboxylic acids. 

Many drug substances fall in the category of slightly soluble weak acids, or slightly soluble weak bases, whose salt forms are much more soluble in water. Upon addition of acid to an aqueous solution of a soluble salt of a weak acid, or upon addition of alkali to an aqueous solution of a soluble salt of a weak base, crystals often result. These crystals may be different from those obtained by solvent crystallization of the weak acid or weak base. Nucleation does not necessarily commence as soon as the reactants are mixed, unless the level of supersaturation is high, and the mixing stage may be followed by an appreciable time lag before the first crystals can be detected. Well-formed crystals are more likely to result in these instances than when rapid precipitation occurs. 

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