Solubility of polymorphs

Figures 11-13 illustrate the relationship of solubilities of polymorphs to temperature [47],...

At a certain temperature of transition Tt, the two forms will be in equilibrium, AG will be zero, and m = m2. But at other temperatures the two forms will not be in equilibrium, and if ax > a2 then because AG = Z rin (a2/fli), AG will be negative and polymorph 1 will change spontaneously to polymorph 2 and will therefore be considered the less stable form and vice versa. Studies of the two polymorphic forms of methylprednisolone show that significant differences occur in the apparent solubilities of polymorphic forms and that these may be temperature-related. 

The effect of solvent composition on the solubility of polymorphs is illustrated by cimetidine [128], The onset of melting of the two forms is essentially indistinguishable, making it impossible to apply the conventional nomenclature to the labeling of the polymorphs. Form B was found to be less soluble than form A, identifying it as the more stable polymorph at room... 

Examination of the sources of error in the equations suggests the contribution of a number of factors. The purity of dyes, differences in solubilities of polymorphic forms of dyes, tau-tomerization, hydrogen bonding, and polarization all can contribute to the difficulty in accurately measuring the S and Kow. The use of an "average" value of ASf in the presence of variability of a factor of two in the values for rigid structures (e.g., anthraquinone dyes) versus more flexible molecules (e.g., azo dyes) may lead to significant errors in estimation. 

Figure 2-15 Solubility of polymorphs I and III of a reverse transcriptase inhibitor. Below about 80°C, Form in is more soluble than Form I.

In this chapter, the solubility phenomenon will be developed using fundamental theories. The basic thermodynamics of solubility reveals the relation between solubility, and the nature of the solute and the solvent, which facilitates an estimation of solubility using a limited amount of information. Solubility-related issues, such as the solubility of polymorphs, hydrates, solvates, and amorphous materials, are included in this chapter. In addition, dissolution rate phenomena will also be discussed, as these relate to the kinetics of solubility. A discussion of empirical methods for the measurement of solubility is outside the scope of this chapter, but is reviewed elsewhere (Grant and Higuchi, 1990 Grant and Brittain, 1995). 

Systemic absorption of a drug substance from a particulate form takes place after the compound enters the dissolved state. If the dissolution rate of the substance is less than the diffusion rate to the site of absorption and the absorption rate itself, then the dissolution process will be the rate-determining step. This situation is characteristic of drug substances that have low degrees of aqueous solubility, and therefore low dissolution rates, and it has become an established tenet in pharmaceutics that one method to improve the dissolution rate of a relatively insoluble substance is to reduce the particle size of its component particles. As discussed above, the solubilities of polymorphs, solvatomorphs, and amorphous forms are different, and these differences may lead to differences in the dissolution rate, which in turn could lead to differences in bioavailability. 

Where R is the universal gas constant and Sa and Sg are the solubilities of polymorph A and B, respectively. Thus, polymorph B will be more soluble (less stable) than polymorph A below the transition temperature whereas the relative solubilities will be reversed above the transition temperature. 

Figure 3.29 shows the dissolution profile obtained during a solubility experiment for the amorphous form of a development compound. The initial dissolution of the compound is high but falls as the compound crystallizes and the equilibrium reaches that of a crystalline form of the compound. By measuring the solubility of polymorphs, the thermodynamic quantities involved in the transition from a metastable to a stable polymorph can be calculated. Experimentally, the solubilities of the polymorphs are determined at various temperatures, and then the log of the solubility is plotted against the reciprocal of the temperature (the van t Hoff method). A straight line results (the problem of non-linearity has been dealt with by... 

See, for example, the determinations of the solubility of rhombic and mono-clinic sulphur, by J. N. Bronsted, Z. physikal. Chem.y 1906,55, 378 also solubilities of polymorphic phthalylhydrazides (Chattaway and Lambert,/. Chem.Soc.y 1915, 107, 1773). 

B. Studies of the Equilibrium Solubility of Polymorphic and Solvate Systems... 

The solubility of polymorphic solids derived from the anhydrate... 

---