The solubility of drugs

2 Factors influencing solubility 141 5.9 Biological activity and partition 

There are many reasons why it is vital to understand the way in which drugs dissolve in solution and the factors that maintain solubility or cause drugs to come out of solution, that is, to precipitate. These include the facts that  

Pharmaceutical solutions might appear to be extremely simple systems, but it is in the solution state that degradation takes place most rapidly, and the solubilisation of poorly soluble compounds is often very difficult. It is ideal if a dmg can be formulated as a simple stable aqueous solution when required for injection, but resort to additives such as water-miscible solvents and surfactants, hydrotropes and cyclodextrins to increase the water solubility of the drug complicates the formulation. Here we deal with simple solutions. Some of the special problems related to peptide and protein solubility are discussed in Chapter 11. 

Aqueous solvents are the most common in pharmaceutical and, of course, in biological systems, so this chapter is concerned mainly with solutions of aqueous and mixed aqueous solvents, such as alcohol-water mixtures. The solution of dmgs in nonaqueous media (such as oils) is also considered because of the many pharmaceutical applications of nonaqueous solutions and formulations such as oil-in-water emulsions, and because of the need to understand the process of the transport of 

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It is poorly soluble in acetone, 2-butanone, ethyl acetate, acetonitrile, and DMF, and insoluble in alcohols, petroleum ether, and diethyl ether. The partition coefficients of a number of solutes between PCL and water have been measured and correlated with octanol-water partition coefficients (Fig. 9) (58,59). The linear correlation (Eq. 2) when combined with the water solubility of the solutes serves as a method of estimating the solubility of drugs in PCL from first principles. ... 

The measurement of the solubility of drugs in polar and non-polar media is very important in the pharmaceutical field. One method proposed to describe this solubility is the partition coefficient between octanol and water. The mathematical calculation of an octanol-water partition coefficient from values for functional groups was first proposed by Hansch et al. as Hansch s n constants,1 and was later developed by Rekker as hydrophobic fragmental constants (logP).2 This method was further improved by the use of molecular connectivities.17 The prediction of logP values can be performed by either a computer program or by manual calculation. For example, approximate partition coefficients (log P) have been calculated by Rekker s method ... 

The main input parameter used to define the highest possible drug concentration in the intestine and to calculate the dissolution rate in the GI tract is the solubility of the dmg in the GI fluids. As described earlier (Sect. 21.2) there are several, both physiological and physicochemical, factors that can affect the solubility in the GI tract and it is therefore important to consider the relevance of the solubility data generated in the early drug discovery phase. A common approach is to use in silico models to predict the solubility of drugs (e.g., [5]). The advantage of this approach is that only the chemical... 

It has been found that the solubility of drug in the polymer is influenced by the temperature of the extrusion process (30). 

Bustamante, P., S. Romero, A. Pena, B. Escalera, and A. Reillo, Enthalpy-entropy compensation for the solubility of drugs in solvent mixtures Paracetamol, acetanilide, and nalidixic acid in dioxane-water , J. Pharrn. Sci., 87, 1590-1596 (1998). 

Jouyban et al. (2004) applied ANN to calculate the solubility of drugs in water-cosolvent mixtures, using 35 experimental datasets. The networks employed were feedforward back-propagation errors with one hidden layer. The topology of neural network was optimized in a 6-5-1 architecture. All data points in each set were used to train the ANN and the solubilities were back-calculated employing the trained networks. The difference between calculated solubilities and experimental... 

Ruelle, R, C. Rey-Mermet, M. Buchmann, H. Nam-Tran, U. W Kesselring, and P. L. Huyskens. 1991. Anew predictive equation for the solubility of drugs based on the thermodynamics of mobile diSttieten. 

For insoluble drugs, the values of Cd can be too low to render adequate and complete drug release. In addition, reduced release is observed often as drug is depleted over time. Similar to matrix systems, developing a reservoir system with pH-independent release is not straightforward unless the solubility of drug molecules is pH independent. 

This equation can be used in conjunction with (6.9) for the estimation of Fa. The microscopic approach points out clearly that the key parameters controlling drug absorption are three dimensionless numbers, namely, absorption number An, dissolution number Dn, and 9. The first two numbers are the determinants of membrane permeation and drug dissolution, respectively, while 9 reflects the ratio of the dose administered to the solubility of drug. 

The solubility of drugs and medicines in either water or fats plays an important part in administering the active components to the sites where they are needed. Water solubility is very important when drugs are taken orally as they usually have to dissolve in gastric fluids before being taken up and transported to the parts of the body where they are needed, for example soluble aspirin. Some drugs, when they reach the site, dissolve in the fluids of the cells and are used by the cells for treatment of the ailment. 

Ionization, pKa, and Aqueous Solubility Most drugs are weak acids or bases. It is important to note the relationship between the pKa of the compound and the absorptive environment. Delivery systems that are dependent on diffusion or dissolution will likewise be dependent on the solubility of drug in the aqueous media. Since drugs must be in solution before they can be absorbed, compounds with very low aqueous solubility usually have the oral bioavailability problems because of limited GI transit time of the undissolved drug particles and they are limited at the absorption site. Unfortunately, for many of the drugs and bioactive compounds, the site of maximum absorption occurs at the site where solubility of these compounds is least. 

Fig. 1 Influence of solvent polarity on the solubility of drugs (A) Polar drug (B) semipolar drug and (C) nonpolar drug. (From Ref. l)...

The advantage of a polyisobutylene adhesives is its chemical inertness thus the stability of drugs in this adhesive is better than that of other adhesives. However, the solubility of drugs is usually lower than those of SIS and acrylic adhesives. 

Both of these two adhesives are basic acrylic adhesives with simple compositions. A full or partial change of 2-ethylhexyl acrylate to n-octyl acrylate or butyl acrylate can modify the stiffness of the adhesive. The addition of vinyl pyrrolidone and/or vinyl acetate monomers can increase the solubility of drugs in the adhesive. Thus various acrylic adhesives can be designed according to the TDS formulation requirements. 

Complexation is the association between two or more molecules to form a nonbonded entity with a well-defined stoichiometry. The two types of complexation that are most useful for increasing the solubility of drugs in aqueous media are stacking and inclusion. Stacking complexes are formed by the overlap of the planar regions of aromatic molecules, while inclusion complexes are formed by the insertion of the nonpolar region of one molecule into the cavity of another molecule (or group of molecules). 

It is well-known that the addition of an organic cosolvent to water can dramatically change the solubility of drugs (Yalkowsky and Roseman, 1981). This fact is important for pharmaceutics because a poor aqueous solubility can often affect the drug efficiency. For this reason, the prediction of the solubility of drugs in aqueous mixed solvents or even a reliable correlation of the available experimental data is of interest to the pharmaceutical science and industry. 

The solubility of drugs in aqueous mixed solvents often exhibits a maximum in the curve solubility versus mixed solvent composition. This enhancement in solubility often greatly exceeds the solubilities not only in water, which is quite natural, but also in nonaqueous cosolvents. Such a dependence could not be explained by simple equations like the log-linear model for the solubility in a mixed solvent (Yalkowsky and Roseman, 1981)... 

Thus, the aim of the present paper is to apply the fluctuation theory for ternary mixtures to the solubility of drugs in aqueous mixed solvents and to suggest on this basis a simple and accurate method for its correlation. 

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