Solubility and Dissolution

The concept of maximum absorbable dose (MAD) relates drug absorption to solubility via [27, 28]  

Each cellular membrane can be considered as a combination of physicochemical and biological barriers to drug transport. Poor physicochemical properties may some- 

Often during drug development, the terms dissolution , dissolution rate , intrinsic dissolution rate (IDR) and solubility are used interchangeably. 

This is incorrect as there are significant differences between the phenomenon they refer to. On many occasions however, their effects and/or alterations are related and this is responsible for the subtlety in their difference. 

The incorporation of an ionizable center, such as an amine or similar function, into a template can bring a number of benefits, including water solubility. A key step in the discovery of the protease inhibitor, indinavir was the incorporation of a basic amine (and a pyridine) into the backbone of hydroxyethylene transition state mimic compounds L-685,434 to enhance solubility (and potency) (Fig. 1.2) [17]. 

SIWV = small intestinal water volume (mL), assumed to be c. 250 mL SITT = small intestinal transit time (min), assumed to be 4.5 h = 270 min. 

High-throughput solubility measurements have been developed which can be used in early discovery [9, 20-22]. 

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G. L. Amidon. Dissolution and solubility behavior of fenofibrate in sodium lauryl sulfate solutions potential in vivo performance implications (Unpublished). 

Tab. 21.1. Summary of physiological gastrointestinal characteristics in fasted and fed state of importance for drug dissolution and solubility.

For highly permeable, poorly soluble drugs given in lower doses, the dissolution rate rather than the saturation solubility is the limiting factor. An increase in dissolution rate due to in vivo solubilization mediated by food intake could theoretically be obtained, but this situation is not always found in vivo. For example, food does not affect the rate and extent of bioavailability for candesartan cilexitil, a very poorly soluble compound [78], An in vitro dissolution and solubility study of this compound in simulated intestinal media provided a potential explanation it was revealed that the solubility was increased as a function of bile concentration as expected, whereas the dissolution rate was not increased by the higher bile concentrations being representative for the fed state (see Fig. 21.14). Thus, although... 

This volume gives an overview of the current status and an outlook to future more reliable predictive approaches. It is subdivided in five sections dealing with studies of membrane permeability and oral absorption, drug dissolution and solubility, the role of transporters and metabolism in oral absorption, computational approaches to drug absorption and bioavailability, and finally with certain drug development issues. 

From the above equation, the dissolution rate is proportional to solubility at the early stage of dissolution. However, there is an important distinction between dissolution and solubility solubility implies that the process of dissolution has reached equilibrium and the solution is saturated. 

Avdeef A., Voloboy D. and Forman, A. (2006) Dissolution and solubility, in Comprehensive Medicinal Chemistry II,... 

The crystal structure of the cocrystal formed by celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide) with nicotinamide has been solved from powder X-ray diffraction data [54], The dissolution and solubility of the cocrystal product were found to depend on the medium involved, and a number of the observed phenomena were shown to originate from differences in conversion of the cocrystal celecoxib polymorphic forms I and III. However, through the judicious use of choice excipients, a formulation was developed that took advantage of the crystalline conversion to be up to fourfold more bioavailable than the celecoxib Form-Ill marketed product. 

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