Solubility Expressions and Mechanisms of Solute Solvent Interactions

As a quantitative property, the solubility of a substance is determined by its concentration in a saturated solution at a particular temperature, and as a qualitative property, it is regarded as the inevitable interaction between molecules to produce a homogeneous molecular dispersion. Dissolution is an extrinsic property affecting a wide range of chemical, physical and crystallographic factors including complexation, particle size, surface properties, and modifications to the solid-state or formulation strategies that improve solubility. A compound's solubility depends on several factors, including moisture content, temperature, pressure, pH, and other chemical and physical properties.

The body of the drug's crystalline form that is most stable at equilibrium can dissolve in a given volume of a solvent at a given temperature and under a given pressure. When the system reaches the state with the lowest energy, the system is in thermodynamic equilibrium. A solid's equilibrium solubility is dependent only on the balance between the forces acting between its solution and its lowest energy crystal form.

Solubility expressions

Solubility can be measured in a variety of different ways. As defined by the United States Pharmacopeia (USP), the solubility of drugs is expressed as the amount of solvent needed per unit of solute. Additionally, solubility is quantified by the molality, molarity, and percentage of the solvent. As shown in the Table, solubility is categorized into seven groups. Six categories are provided by the European Pharmacopoeia (rather than the practically insoluble division).

Solvent solute interactions

As pharmacists know, water is an excellent solvent for salts, sugars, and similar compounds, whereas petroleum is often used to dissolve substances like those that are barely soluble in water. "Like dissolves like," summarizes these empirical findings.

Polar solvents

A drug's solubility depends hugely on the polarity of the solvent with which it is dissolved, i.e., its dipole moment. Solvents with polar properties dissolve ionic solutes and other polar materials. Accordingly, water dissolves sugars and other polyhydroxy compounds in all proportions with alcohol but dipole moments alone are insufficient to explain why polar substances dissolve in water. An acidic or basic constituent also contributes to specific interactions in solutions from the Lewis electron donor-acceptor point of view. In contrast to the dipole moment, hydrogen bonds are a more important aspect of the solute than polarity.

As a liquid, water can dissolve alcohols, aldehydes, ketones, amines, and other nitrogen-and oxygen-containing compounds that can form hydrogen bonds with the liquid. Solubility is determined, as we have already mentioned, by the relative proportion of nonpolar to polar groups in a substance's molecules. In aliphatic alcohols, as a nonpolar chain's length increases, a compound's solubility in water decreases. More than four or five carbons in a monohydroxy alcohol, aldehyde, ketone, or acid cannot penetrate the hydrogen bonding structure of water. As polar groups are added to water-soluble molecules, such as in propylene glycol, glycerine, or tartaric acid, the solubility is greatly increased. A carbon chain divided allows the nonpolar effect to be reduced, which leads to increased water solubility. n-Butyl alcohol, however, dissolves in water at a rate of approximately 8 g/100 mL of water at 20°C, whereas tertiary butyl alcohol dissolves at any ratio.

Nonpolar solvents

A nonpolar solvent like hydrocarbons differs from a polar solvent because of its molecular structure. Low dielectric constants of nonpolar solvents prevent them from reducing the attraction between ions in both strong and weak electrolytes. Since the solvents belong to the group of aprotic solvents, they cannot ionize weak electrolytes nor can they break covalent bonds. They cannot form hydrogen bridges with non-electrolytes. Nonpolar solvents don't dissolve ionic or polar solutes, or only slightly dissolve them. Through induced dipole interactions, nonpolar compounds in essence dissolve nonpolar compounds with similar pressures. Molecular repulsion forces stop the solute molecules from escaping into the solution. All these solvents can dissolve oils and fats, including carbon tetrachloride, benzene, and mineral oil. Nonpolar solvents are also suitable for dissolving alkaloidal bases and fatty acids.

Semi polar solvents

In nonpolar solvent molecules, such as benzene, semipolar solvents can give the molecules some degree of polarity, so that they become soluble in semipolar solvent molecules, such as ketones and alcohols. In general, semipolar compounds serve as intermediate solvents, eliminating polarity from nonpolar liquids and bringing them into miscibility. In this way, acetone facilitates ether's solubility in water. Water–castor oil mixtures were studied by Loran and Guth as intermediate solvents. The combination of peppermint oil and propylene glycol has been shown to enhance the mutual solubility of the two. The same investigation was conducted with benzyl benzoate and water.

Solubility of liquids in liquids

A pharmaceutical solution typically takes two or more liquids to achieve its desired characteristics. Example - Various alcoholic solutions can be made by mixing water and alcohol; volatile oils can be placed in water to produce aromatic waters; alcohol and volatile oils can be combined to create spirits and elixirs; and several fixed oils are blended into lotions, sprays, and medicated oils. A liquid-liquid system can be divided into two categories, depending on their solubility with one another: complete miscibility and partial miscibility. Liquid-liquid systems fit into the miscible category when both components are soluble in each other.

Complete miscibility

Solvents regarded as fully miscible, such as water and alcohol, glycerine and alcohol, and alcohol and acetone, are considered polar and semipolar because they mix in any proportion. In addition to benzene and carbon tetrachloride, they are both nonpolar solvents that are perfectly miscible.

Partial miscibility

A mixture of certain amounts of liquids forms two liquid layers if ether or phenol are also added. A portion of the other liquid is present throughout each layer in the form of dissolved molecules. Reiterating here that partially miscible liquids' mutual solubilities are affected by temperature is adequate. As soon as phenol and water reach their critical solution temperature (or solid solution temperature), they will have identical mutual solubilises, the temperature at which normal phase separation is formed is called the homogeneous temperature.

We know that the solubility in some liquid pairs may increase as temperatures decrease. In the system, the temperatures under which two components are soluble in all proportions will be below and above which two distinct layers will exist. The other type of trajectory involves other mixtures of liquids such as nicotine and water, with an equilibrium temperature in the lower and upper ranges as well as an intermediate-range in which the liquid is only partially miscible. The final type of solution does not have a critical solution temperature. For example, ethyl ether and water are insoluble at both an upper and a lower solution temperature. When the mixture exists at all temperatures, only a small portion of the mixture is soluble.

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