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Thread: [Medicinal Chemistry] Water Solubility of Drug

  1. #1

    Default [Medicinal Chemistry] Water Solubility of Drug

    The solubility of a drug molecule in water greatly affects the routes of administration that are available, as well as its absorption, distribution, and elimination.

    Two key concepts to keep in mind when considering the water (or fat) solubility of a molecule are the potential for hydrogen bond formation and ionization of one or more functional groups within the molecule.

    Hydrogen Bonds

    Each functional group capable of donating or accepting a hydrogen bond contributes to the overall water solubility of the compound and increases the hydrophilic (water-loving) nature of the molecule. Conversely, functional groups that cannot form hydrogen bounds do not enhance hydrophilicity and will contribute to the hydrophobic (water-fearing) nature of the molecule.

    For a hydrogen bonding interaction to occur, at least one functional group must contain a dipole with an electropositive hydrogen. The hydrogen atom must be covalently bound to an electronegative atom, such as oxygen (O), nitrogen (N), etc.

    Even though the energy associated with each hydrogen bond is small, it is the additive nature of multiple hydrogen bonds that contributes to the overall water solubility of a given drug molecule. As a general rule, the more hydrogen bonds that are possible between a drug molecule and water, the greater the water solubility of the molecule.

    [Medicinal Chemistry] Water Solubility of Drug-screen-shot-2016-04-23-at-2-43-32-pm-png

    Ionization

    In addition to the hydrogen-bonding capacity of a molecule, another type of interaction plays an important role in determining water solubility: the ion-dipole interaction. This type of interaction can occur with organic salts. Ion-dipole interactions occur between either a cation and the partially negatively charged atom found in a permanent dipole or an anion and the partially positively charged atom found in a permanent dipole.

    Organic salts are composed of a drug molecule in its ionized form and an oppositely charged countering. For example, the salt of a carboxylic acid is composed of the carboxylate anion (ionized form of the functional group) and a positively charged ion (e.g., Na+) and the salt of a secondary amine is composed of the ammonium cation (ionized form of the functional group and a negatively charged ion; e.g., Cl-).

    Not all organic salts are very water soluble, the salt must be highly dissociable; in other words, the cation and anion must be able to separate and interact independently with water molecules. Highly dissociable salts are those formed from strong acids with strong bases (e.g., sodium chloride), weak acids with strong bases (e.g., sodium phenobarbital), or strong acids with weak bases (e.g., atropin sulfate).

    The salt formed by a carboxylic acid with an alkylamine is the salt of a weak acid and weak base, respectively. This salt does not dissociate appreciably and cannot significantly contribute to the overall water solubility of a given drug molecule. In general, low molecular weight salts are water soluble, and high molecular weight salts are water insoluble.

    The extent to which ionized molecules are soluble in water is also dependent on the presence of intramolecular ionic interactions. Molecules with ionizable functional groups of opposite charges have the potential to interact with each other rather than with water molecules. When this occurs, these molecules often become water insoluble.
    Last edited by Janis.Y.Chen; Sat 23rd April '16 at 4:34pm.
    Clinical Pharmacy Specialist - Infectious Diseases

  2. #2

    Default Predicting Water Solubility: The Empirical Approach

    Lemke (10) developed an empiric approach to predicting the water solubility of molecules based on the carbon-solubilizing potential of several functional groups. In this approach, if the solubilizing potential of the functional groups exceeds the total number of carbon atoms present, then the molecule is considered to be water soluble. Otherwise, it is considered to be water insoluble. Participation in intramolecular hydrogen bonding or ionic interactions decreases the solubilizing potential of a given functional group. It is difficult to quantitate how much such interactions will decrease a molecule's overall water solubility.

    [Medicinal Chemistry] Water Solubility of Drug-screen-shot-2016-04-23-at-3-49-27-pm-png
    Last edited by Janis.Y.Chen; Sat 23rd April '16 at 4:56pm.
    Clinical Pharmacy Specialist - Infectious Diseases

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