Pharmaceutical salts bioavailability

It is estimated that half of all pharmaceuticals are formulated as salts, to achieve increased stability and bioavailability [13]. Predictive solubility methods are very limited for this area, and the development of new models to address this category is very important. The NRTL-SAC model has recently been extended by C.-C. Chen, and Y. Song to represent such electrolytic solutes, that partly dissociate to ions in solution. This extension has been achieved by the addition of one new segment type into the preceding NRTL-SAC model. NRTL-SAC thus becomes a limiting case of the eNRTL-SAC formulation [27]. 

This method of crystallization has become increasingly common in the pharmaceutical industry because organic molecules often have poor water solubility and must be converted to a salt form to improve water solubility and enhance bioavailability. Reactive... 

A variety of factors need to be considered when selecting the optimum chemical form of a new drug candidate. These include all physicochemical properties which would influence physical and chemical stability, processability under manufacturing conditions, dissolution rate, and bioavailability. Such selection of chemical form must be done at the initial stages of development, when material and time are limited. Often the medicinal and process chemists select salt forms based on a practical basis, such as previous experience with the salt type, ease of synthesis, reaction yield, etc. Pharmaceutical considerations such as stability, handleability, hygroscopicity, and suitability for a specific dosage form may be secondary considerations. 

Once the kilogram bulk has been produced in its preferred polymorphic form, or salt form, or solvate form, it will proceed to the pharmaceutics department, where it will be mixed with excipients, exposed to processing conditions, and converted to a marketable dosage form. The pharmaceutical scientist must formulate this material into a dosage form that is homogeneous, scalable, stable, and bioavailable. Since... 

To determine the behavior of a product, it must be stored at known conditions for a period of time and its properties measured. In the case of oxidation, for example, some method must be available to determine the amount of reaction with oxygen that the product has undergone. This is often done by measuring peroxide values for oil-containing products, or hexanal values for products that have hexanal as the end degradation product for oxidation. For moisture sorption, the product can be stored over a saturated salt solution until moisture uptake is at equilibrium. Then taste or texture is often the measured parameter to determine the end-point of shelf life. For pharmaceuticals, the true end-point is determined by the bioavailability of the drug. 

Experimental measurements of solubility are influenced by many different factors, including the purity of the solute and solvent, presence of cosolvents, presence of salts, temperature, physical form of the undissolved solute, ionization state, and solution pH [18]. Consequently many different definitions of solubility are in common use in the published literature. Here we discuss the intrinsic aqueous solubility, Sg, which is defined as the concentration of the neutral form of the molecule in saturated aqueous solution at thermodynamic equilibrium at a given tanperature [18-20]. Intrinsic aqueous solubility is used to calculate dissolution rate and pH-dependent solubility in models such as the Noyes-Whimey equation [21] and the Henderson-Hasselbalch equation [22, 23], respectively. Prediction of the intrinsic aqueous solubility of bioactive molecules is of great importance in the biochemical sciences because it is a key determinant in the bioavailability of novel pharmaceuticals [1, 3, 24-26] and the environmental fate of potential pollutants [27, 28],... 

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. 

A major reason for the popularity of pharmaceutical co-crystals in industry is that they lend themselves well to patent protection. They admirably satisfy the three criteria of patentability, namely novelty, non-obviousness and utility. A co-crystal almost always satisfies the novelty criterion because it is a new composition of matter. Non-obviousness is provided by the fact that the identification of the co-former is hardly ever routine, unlike say salt formation wherein an acid is obviously required to make a salt from a base. Utility is generally the only criterion that must be established but it is often easy to demonstrate—usually it is the lack of a particular attribute (solubility, bioavailability, dissolution profile, good shelf life) that has led to the identification of a pharmaceutical co-crystal. With respect to patentability, co-erystals offer opportunities vis-d-vis polymorphs. They are clearly new substances, problems of inherent anticipation are not likely to arise so often and more of them can be made for any given API, expanding the pharmaceutical space around it and consequently the types of advantageous properties that may be accessed. 

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