PSol determination

Other methods employ a microplate format followed by fast HPLC. Some researchers approach the determination from a different perspective. For example, an alternative method for ionizable substances is the pSol determination based on an acid-base titration.25 26 Kinetic solubility determinations involve determining the concentration of the compound in the buffer of interest when an induced precipitate first appears. 

Logarithm of intrinsic solubility (mol L ) experimentally determined (pSOL) also logSexp Melting point Molecular weight... 

McFarland et al. recently [1] published the results of studies carried out on 22 crystalline compounds. Their water solubilities were determined using pSOL [21], an automated instrument employing the pH-metric method described by Avdeef and coworkers [22]. This technique assures that it is the thermodynamic equilibrium solubility that is measured. While only ionizable compounds can be determined by this method, their solubilities are expressed as the molarity of the unionized molecular species, the intrinsic solubility, SQ. This avoids confusion about a compound s overall solubility dependence on pH. Thus, S0, is analogous to P, the octanol/water partition coefficient in both situations, the ionized species are implicitly factored out. In order to use pSOL, one must have knowledge of the various pKas involved therefore, in principle, one can compute the total solubility of a compound over an entire pH range. However, the intrinsic solubility will be our focus here. There was one zwitterionic compound in this dataset. To obtain best results, this compound was formulated as the zwitterion rather than the neutral form in the HYBOT [23] calculations. 

With only 22 compounds available, there was only enough information to support a three-term correlation equation. Since this work was published, the solubilities of an additional 36 compounds have been reported to us. Many of these were determined [27] in the same laboratories as those cited in [1], but 21 were determined in the laboratory of Artursson [28], and six in the laboratories of Faller and Wohnsland [29]. While this introduced some inter-laboratory variability, we believe that this is minimal because the same automated method on comparable, commercial pSOL instruments was employed. This new dataset now contains six zwitterionic compounds as before, their structures were entered in their zwitter-ionic forms to do the HYBOT calculations. When they were entered in their neutral forms, poorer results were obtained in the subsequent MLR analysis. 

The solubility should be measured at all of these pH values with a suitable, validated method such as shake-flask or pSol (2) at 37°C to determine whether the (envisaged) dose of the drug can be completely dissolved at all points of interest in the GI tract (see Chapter 11 for more discussion of solubility determination). Typically, this would be the upper GI pH (stomach and proximal small intestine) for immediate release (IR) products, the pH in the small intestine for enteric-coated products and, additionally for MR dosage forms intended to release over a period of six hours or more, the pH in the proximal colon. 

With the potentiometric approach, determination of intrinsic solubility is based upon the measurement of the pH shift caused by compound precipitation during acid-base titration of ionizable compounds. Two commercial potentiometric methods currently available are pSol [30, 39] and Cheqsol [40-42], In the pSol method developed by Avdeef, a minimum of three titrations in the direction of dissolution are performed. Normal pH versus volume titration plots are reexpressed as Bjerrum plots, that is, average number of bound protons versus pH. The Bjermm plots enable the shift in compound pKa to be more readily observed and are used to determine intrinsic solubility (S0) via Equation 2.5 ... 

As compound supply is Ukely to be limited, only a few solvent systems can be investigated during initial solubility studies. Typically, the solubility of the com-potmds in water, 0.9% w/v saline, 0.1 M HCl and 0.1 M NaOH will be determined. If there is sufficient compotmd, then the solubility in other systems may be considered (e.g., co-solvents, such as PEG400 and propylene glycol). In addition, the solubility in oils and surfactants systems (e.g.. Tween 80) may be considered. Automated instruments allow ready measure of solubility, such as by using the pION s pSOL (5) whereas as little as 0.1 mg of the compound is sufficient to establish a complete solubility profile. 

Recently, an instrument for determining intrinsic solubility and pH-solubility profiles has been introduced. Known as pSOL , it claims that with as little as 0.1 mg a complete solubility profile can be derived (Avdeef et al. 2000). 

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