Aqueous solution Buffers Solubility equilibria

In addition to its impact on the biologically active form, the tautomeric process has profound implications for formulation of drug candidates, as illustrated in some recent further development work on compound 3.62 While it is easy to synthesize and isolate water-soluble salts of the keto-acids, once they are placed in aqueous solution the tautomeric equilibrium determines how much of each form is present. Indeed, if the closed butenolide tautomer is sufficiently water insoluble, it can precipitate out of solution and the equilibrium can drive the complete precipitation of the compound. While 3 has good oral activity, its intravenous use is limited by the insolubility of the closed-form butenolide tautomer without the use of a specific and complex buffered formulation. Thus, in recent work Patt et al.62 developed a series of water-soluble butenolides to overcome this limitation for parenteral uses. This culminated in the development of 4 (Table 2), currently in preclinical evaluation. 

Eary (1992) prepared an amorphous sample of AS2S3 by precipitation of the sulfide from an aqueous solution of NaAs02, buffered at pH 4.0, to which was added an excess of Na2S-9H20. The precipitate was aged 1 to 3 days, and washed with water to remove the buffer. X-ray analysis showed no realgar, orpiment, crystalline sulfur or crystalline arsenic. Eary determined the solubility of this material at 298.15 K, 313.15 K, 333.15 K, and 363.15 K in solutions with the presence and absence of added sulfide. He gave equilibrium constants for the reaction ... 

The solubility measure describes the concentration reached in solution, when a pure phase of the material is allowed to dissolve in the solvent for a defined period of time, at a defined temperature (and pressure). Most often for pharmaceutical purposes, the pure phase is a solid, ideally a crystalline solid, and the liquid is water or a buffered aqueous solution, at a controlled temperature (often 25 or 37 °C) and ambient pressure. The purity of the solid can have a large effect on measured solubility. Solubility can be measured in water or in pH-controlled buffers. In water, the extent of solubility for ionizable compounds will depend upon the p fCa values and the nature of the counterion. In pH-controlled aqueous buffered solution, at equilibrium, the solubility will depend upon the compound s intrinsic solubility, its plQ, and the ionic strength. It may also depend upon the relative solubility of the initial added compound and the solubility of the salt formed by the compound with the buffer salts, with which the solid may equilibrate. In any buffer or solvent system, the measured solubility may depend on the time of sampling, as solubility kinetics... 

Only the unionized form of a drug is extracted into the organic solvent. Therefore acidic drugs, which are unionized imder acidic conditions are extracted from acidified matrices into organic solvents basic drugs are likewise extracted from basified matrices. The optimal pH for acidic species is 1-2 pH units below their pK values, and for basic species it is 1-2 pH units above their pK values. Extraction can be difficult for compoimds which are soluble in water at all pH values, for example water-soluble amphoteric and neutral drugs. In some cases, the addition of buffer salts to the aqueous solution increases its ionic strength and hence its polarity. This tends to decrease the affinity of polar compoimds for the aqueous phase, and thus shifts the partition equilibrium in favor of extraction. 

It is not only the solubility in aqueous solutions that may affect the biopharmaceutical behaviour of an active substance. The solubility in non-polar solvents is of importance too. The solubility in a lipid phase is of relevance to the passive transport of the substance over lipid membranes, a process that plays an important role in the absorption of many drags. In order to quantify the lipophilicity of an active substance in relation to its aqueous solubility the concept of the partition coefficient was developed. The partition coefficient is defined as the quantitative distribution ratio of a dissolved substance over two immiscible liquids at equilibrium. In the pharmaceutical sciences the ratio of the concentrations in an aqueous phase (water or aqueous buffer solutions) and a lipid phase (e.g. n-octanol) is often considered. For this purpose the so called log P value has been defined. The partition coefficient between an aqueous and a lipid phase (log Pq/w value) of non-ionised substances is defined according to (16.1) ... 

The effect of surfactant concentration upon the solubility of cobalt(III) acetylacetonate in buffered aqueous phases at 50 C was also investigated spectroscopically. Saturated solutions were prepared by shaking excess finely-powdered cobalt(III) acetylacetonate with solutions of sodium dodecyl sulphate for approximately one hour at 50 C. It appeared that one hour was sufficient time for the attainment of equilibrium. 

An objective of preformulation scientist is to determine the equilibrium solubility of a drug substance under physiological pH to identify the BCS class of drug candidate for further development. For BCS classification the test conditions are strictly defined by the FDA. The pH solubility profile of the test drug substance should be determined at 37°C in aqueous media with a pH in the range of 1-7.5. Standard buffer solutions described in the USP are considered to be appropriate for use in these studies. A number of pH conditions are used bracketing the pKa value for the respective test substance. For example, for a drug with a Ka of 5, solubility should be determined at... 

Bevan et al. [97] have developed a solubility screen for. small amounts of compounds (10 pi of a 10 mM DMSO solution) on a 96 well plate format by applying reversed-phase HPLC with a fast gradient elution. The DMSO solutions of the compounds are dispensed into a 96 well microtitre plate format at a known concentration (typically 10 mM). Duplicate plates are prepared each containing 10 pi of a 10 mM DMSO solution. For the so-called standard plate the DMSO solution is diluted with known amounts of solvent possibly dissolving the compounds (methanol or DMSO). The wells on the so-called sample plate are diluted with the same known amounts of aqueous buffer used in the enzyme-assay screens. The compounds having poor aqueous solubility will eventually precipitate out in the wells of the sample plates. The precipitation and the equilibrium formation between the saturated solution and the solid can be promoted by applying sonication. Before HPLC analysis of the wells of the standard... 

The equilibrium solubilities of indapamide in aqueous buffer solutions over the pH range of 1 through 10 are shown in Table VI and Figure 12 (12). From the data it can be seen that the aqueous solubility of the compound is 0.1 mg/mL or less at pH values of 8 or below. The rapid increase in solubility beginning at about pH 8 is the result of the formation of the more soluble ionized species. 

In this chapter we will continue the study of acid-base reactions with a discussion of buffer action and titrations. We will also look at another type of aqueous equilibrium—that between slightly soluble compounds and their ions in solution. 

Subarats X, Bosch E, Roses M (2007) Retention of ionizable compounds on high-performance liquid chromatography. XVll. Estimation of the pH variation of aqueous buffers with the change of the methanol fraction ofthe mobile phase. J Chromatogr A 1138 203-215 Siicha E, Kotrly S (1972) Solution Equilibria in Analytical Chemistry. Reinhold, London Butler JN, Cogley DR (1998) Ionic Equilibrium. Solubility and pH Calculations. Wiley, New York... 

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