Solubility solid-state properties

QSPRs in which solubilities and vapor pressures are correlated against molecular structure are done exclusively using the liquid state property. This avoids the complication introduced by the effect of fugacity ratio or melting point on the solid state property. 

The solubility behavior of enantiomers and racemates has been reviewed by Jacques et al. [141]. Other solid state properties of chiral drugs have been reviewed by Brittain [142]. 

As shown in Fig. 2 [37], and also in the work of Barraclough and Hall [34], moisture uptake onto sodium chloride as a function of relative humidity is reversible as long as RH0 is not attained. This is evidence that actual dissolution of water-soluble crystalline substances does not occur below RH0. This is consistent with thermodynamic rationale that dissolution below RHo would require a supersaturated solution (i.e., an increased number of species in solution would be necessary to induce dissolution at a relative humidity below that of the saturated solution, RH0). In this regard, one should only need to consider the solid state properties of a purely crystalline material below RH0. As will be described, other considerations are warranted for a substance that contains amorphous material. 

It is common practice in pharmaceutical industry to generate salt forms of a drug substance to improve solid-state properties and solubility. CE has proven its ability to analyze reliably organic acids (direct, indirect detection) and alkaline/earth alkaline metals and basic amino acids. For basic drugs, a non-toxic organic acid or inorganic acid is chosen as counterion. Acidic drug substances will usually be deprotonated by alkaline and earth alkaline... 

The ability of mPEs to form a compact, folded conformation in solution [23,25] led researchers to look at the solid-state properties. Unfortunately, the Tg side chains needed to impart solubility in organic solvents make the oligomers... 

Rubino, J.T. and Thomas, E.Jnence of solvent composition on the solubilities and solid-state properties of the sodium salts of some drUgfe, J. Pharm., 65, 141-145, 1990. 

The Side Groups. The side groups linked to phosphorus play an equally important role, as shown schematically in Figure 2. They influence not only chemical properties and solubility but solid-state properties as well. 

Altering the substituents on the Cp rings also has radical effects on a variety of physical properties, including solid-state geometries, solubility, stability to hydrolysis, oxidation, and ligand extrusion, and others. 

Permeability and solubility/dissolution are two major determinants of gastrointestinal drug absorption. The prediction of solubility of molecules is more difficult than for lipophilicity. Solubility critically depends on the solid-state properties of compounds. The same compound can exist in amorphous or in several crystalline states and this can result in very different solubility of molecules. The prediction of crystalline properties, represented, for example, by the melting point, is one of the most difficult problems of physical chemistry. Like the octanol-water partition coefficient, water solubility critically depends on the pH and ionization state of molecules. 

Among other things, it became established that the nature of the structure adopted by a given compound on crystallization would then exert a profound effect on the solid-state properties of that system. For a given material, the heat capacity, conductivity, volume, density, viscosity, surface tension, diffusivity, crystal hardness, crystal shape and color, refractive index, electrolytic conductivity, melting or sublimation properties, latent heat of fusion, heat of solution, solubility, dissolution rate, enthalpy of transitions, phase diagrams, stability, hygroscopicity, and rates of reactions were all affected by the nature of the crystal structure. 

Subsequently, workers in pharmaceutically related fields realized that the solid-state property differences derived from the existence of alternate crystal forms could translate into measurable differences in properties of pharmaceutical importance. For instance, it was found that various polymorphs could exhibit different solubilities and dissolution rates, and these differences sometimes led to the existence of nonequivalent bioavailabilities for the different forms. Since then, it has become recognized that an evaluation of the possible polymorphism available to a drug substance must be thoroughly investigated early during the stages of development. In various compilations, it has been reported that polymorphic species are known for most drug substances and that one should be surprised to encounter a compound for which only one structural type can be formed. 

Solid-state properties Physical/molecular Powder flow, tabletabilily, solubility, dissolution rate, stability... 

Wassvik, C.M., Holmen, A.G., Bergstrom, C.A.S., Zamora, I. and Artursson, P. (2006) Contribution of solid-state properties to the aqueous solubility of drugs. European Journal of Pharmaceutical Sciences, 29, 294-305. 

The solubility is most often experimentally determined from the dmg concentration in the liquid phase after adding excessive amounts of a solid dmg substance to the test medium. This apparent solubility is affected by the solid-state properties of the dmg, for example, polymorphs, solvates, impurities, and amorphous content. An equilibrium with the thermodynamically most stable solid-state form, being the least... 

Examination of the residual solid from solubility samples is one of the most important but often overlooked steps in solubility determinations. Powder X-ray diffraction (PXRD) is the most reliable method to determine whether any solid state form change has occurred during equilibration. The sample should be studied both wet and dry to determine if any hydrate or solvate exists. Thermal analysis techniques such as differential scanning calorimetry (DSC) can also be used to identify any solid-state transformations, although they may not provide as definitive an answer as the PXRD method. Other methods useful in identifying any solid-state changes include microscopy, Raman and infrared spectroscopy, and solid-state NMR (Brittain, 1999). When changes in solid-state properties are identified in solubility studies, it is important to link the new properties to the properties of known crystal forms so the solubility result can be associated with the appropriate crystal form. 

Deviations from the theoretical pH-solubility profiles may be an indication of experimental error. They may also suggest other interactions not predicted by the solubility theory. Examples for the causes of such deviations include changes in solid-state properties, self-association and micelle formation of the drug in solution. Figure 1 shows an example of a compound that forms micelles at a pH above 9 (Winnike, 2005). Further addition of sodium hydroxide does not increase the pH rather it enhances solubility through micelle formation. In any of these cases, it is important to identify the causes of the deviation so that appropriate formulation decisions can be made based on the solubility data. 

It is surprising that the confusion over fundamental solid state properties such as phase composition and cationic oxidation states should have remained unclarified for so long, and it is disturbing that so many contradictory results and interpretations have been reported from supposedly similar materials. The lack of unanimity over the extent of antimony solubility in tin(IV) oxide is particularly surprising since many workers 9-11, 23, 25) have suggested that the formation of a solid solution is an important factor in the catalytic character of these materials. Hence, it is clear from these early studies that the extent and conditions for solid solution formation are completely uncertain. 

It may be added here, that, as extensions to these computational predictors of solubility, initial information has been published recently on the search for models for the prediction of drug solubility and permeability, bioavailability and for the determination of the influence of some solid-state properties (melting point, enthalpy of melting and entropy of melting) on the intrinsic solubility of drugs. °... 

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