Pharmaceutical salts solid state properties

Unfortunately, our understanding of the physics and chemistry of salt formation is not yet at a stage where we can predict a priori the physicochemical properties of a proposed salt. A particular problem in this regard is the formation of a range of salt polymorphs and/or solvates. While qualitative/semiempi-rical guidelines have been developed, the selection process is still largely experiment based. It is to be hoped that developments in computational methods will soon lead to the more accurate prediction of bio-pharmaceutically relevant solid-state properties that will ultimately simplify the task of appropriate salt selection. 

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... 

Compounds of pharmaceutical interest can exist in different solid forms. Broadly, they can be classified as being in the amorphous or in the crystalline state. In crystalline pharmaceuticals, solvates are formed when the solvent molecule is incorporated, either stoichiometrically or non-stoichiometrically, in the crystalline lattice. Hydrates are a subclass of solvates, wherein the incorporated solvent is water. Because of regulatory considerations, non-aqueous solvates find limited use as pharmaceuticals. Our dis-cu.ssions will, therefore, be restricted to hydrates. If the solvent is non-volatile, co-crystals are obtained, and this is an emerging field in solid-state pharmaceutics. In case of weakly acidic and basic compounds, salt forms are prepared with the goal of obtaining the desired biopharmaceutical properties. Figure 3 is a schematic representation of the various types of solid forms of interest in pharmaceuticals (6). 

Multicomponent crystalline pharmaceutical solids, as for example, ionic complexes or salts, are usually developed to improve the pharmaceutical profile of a single organic molecule in terms of solubility, stability, bioavailability and organoleptic properties. A better understanding of the solid-state interactions in these complexes may lead to a rational design of crystalline APIs to rapidly advance a drug candidate through development to the launch of a product. 

Salts, and more recently co-crystals, have attracted much interest in the pharmaceutical industry for their promise in tailoring the physical properties of an active pharmaceutical ingredient (API) to meet the needs of the drug product and ultimately the patient.Salt forms, produced by add (A)-base (B) reactions in the solid state, are multi-component solids comprising minimally an A B pair they may be crystalline or amorphous. The term co-crystal, on the other hand, refers specifically to crystalline molecular complexes, which may include an A B pair among the different components and by definition necessarily include solvates (hydrates), inclusion compounds, clathrates and solid solutions. 

---