yes pH palys a vital role in solubilities of diferrent substances including drugs.stomach pH is usaully 2.while blood has nearly Neutral pH.
Drug solubility is widely accepted as important in the candidate selection process. Solubility is essential if an orally administered drug is to be absorbed across the intestinal walls and enter the portal vein. Absorption is to be distinguished from bioavailability: the latter is less because first pass metabolism, protein binding, hydrolysis, and other degradative pathways reduce the systemic concentration from that observed in the portal vein.
Most drugs are ionizable in water, having either proton acceptor groups (bases), proton donor groups (acids), or both (amphoterics). The principles will be illustrated with reference to bases, but the behavior of acids and amphoterics will be analogous.
At high pH (at least 2 pH units above the pKa), bases will be fully un-ionized and their solubility will be a minimum, the intrinsic solubility. As the pH is gradually lowered, increasingly more base will be protonated and the solubility will begin to rise. When the pH equals the pKa, half the molecules are protonated, and the solubility rises to double the intrinsic solubility. Further reduction in the pH causes progressively more protonation, and the solubility rises steeply according to an equation that follows the degree of ionization as described by the Henderson-Hasselbalch equation:
(1)
CS is the observed solubility at the given pH, and COB is the intrinsic solubility of the base. The equation predicts that the solubility will rise indefinitely at even lower pHs, although in practice a limit is reached at the salt solubility. This salt solubility depends on the salt itself (the acid used to lower the pH in the experiment) and on the ionic strength.11 The salt form of the base likewise varies in solubility, becoming progressively more soluble as the pH is raised. This solubility also obeys the Henderson-Hasselbalch equation expressed in the reverse form:
(2)
CS remains the observed solubility of the salt form at the given pH; COA represents the intrinsic solubility of the salt form, the limiting value at the lowest pHs.12 The 2 intersecting concentration curves, the base solubility curve and the salt solubility curve, are combined such that the minimum at any one pH is taken to be the solubility.
In practice then, the result is a composite curve for base solubility as a function of pH comprising 2 parts separated by a sharp discontinuity. It can be shown by combination of Equations 1 and 2 that the intersection occurs at a pH given by
(3)
where the ratio COA/COB is referred to as the acid solubility factor. In titrating from low to high pH, a nearly constant solubility is predicted until the pH of the discontinuity (the intersection), the solubility of the salt form. Beyond the pH of the intersection, the base solubility curve, the solubility is predicted to be sensitively dependent on the pH and on the drug pKa. It is important to note that if any point on this base solubility curve is known (solubility and the pH at which it was measured) then the whole curve, base and salt solubility, can be calculated provided the pKa and the acid solubility factor are also available. GastroPlus prompts the user for these 4 parameters in order to construct the composite curve.
In the drug discovery setting, large numbers of molecules are synthesized in small quantities for biological and physicochemical screening. Initially, physicochemical properties may be predicted from structure by proprietary software packages, giving in silico estimates of log D, pKa, solubility, permeability, and diffusivity. Indeed, these estimates do not even require that the molecule be synthesized. Recently, much effort has been put into the in silico prediction of solubility with the purpose of making the discovery process manageable and productive. Jorgensen and Duffy13 reviewed the prediction of solubility from structure, while Parshad et al14 studied 22 salts within a narrow structural class. Their solubilities were measured and correlated with measured parameters and molecular descriptors. Bergstrom et al15 also combined small-scale in-house solubility measurements of 17 compounds with correlations based on lipophilicity and molecular surface areas. Gao et al16 used 930 compounds in their Quantitative Structure Property Relationship (QSPR) approach and claimed an estimation error of just 0.39 of the log solubility value in their test set. On the experimental side, Avdeef et al17 have described a pH-metric titration method for determining not just the intrinsic solubility but the whole solubility-pH profile and have compared the results favorably with the shake-flask method.
However, a fraction of synthesized molecules will have their in silico properties refined by in vitro experiments, including solubility. The number of candidates needing in vitro solubilities is such that traditional equilibrium "stirred beaker" experiments are impracticable. They require more drug than is available and take too long. A trade-off is appropriate between accuracy on one hand and speed and scale on the other. Various high-throughput screening methods are currently used in the industry, based upon examination of very small quantities of material and upon automation. The methods used will not be described here, but it is worth emphasizing that they are screens and are approximate. The aim is a solubility estimate at a known pH, and received wisdom suggests a pH close to that of the intestine is most appropriate, typically around 6 or 7. It was shown above that provided the pKa is known (whether by prediction or by experiment) then the whole of the solubility/pH relationship for the base solubility curve is known, and additionally if the acid solubility factor is known then the salt solubility curve is also known. In general, salt solubilities (pH sufficiently low that it is below the pH of the intersection, Equation 3) appear not to be measured, perhaps because they are considered irrelevant to the areas of the GIT where absorption is likely to take place. However, the change in solubility due to ionization is a critical factor for the accurate simulation of drug dissolution. A more extensive determination of solubility factors for a chemically diverse set of drug molecules might lead to additional in silico models that allow us to accurately represent the complete pH versus solubility profile. The question of whether low pH solubilities as defined above are relevant to absorption predictions is one significant part of the present investigation. The question of what solubility value is required of a candidate to ensure it will not fail on that account is the other.
http://www.aapspharmsci.org/view.asp?art=ps050104
http://www.pharmacy.wsu.edu/courses/PharS531/Solubility%20II.3.htm
http://pharmlabs.unc.edu/solubility/text.htm
http://www.nyu.edu/classes/tuckerman/honors.chem/lectures/lecture_24/node3.html
2007-04-11 17:21:33
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answer #1
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answered by Anonymous
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