Physicochemical Determinants of Drug Action
The polarity and acid–base property of a drug are two primary physiochemical characteristics of drugs.
Polarity of drugs
It is a measure of their lipid and water solubility and is generally expressed as the partition coefficient.
1. Partition coefficient (P) of a drug is the ratio of the solubility of the agent in an organic lipophilic solvent (usually n-octanol) to its solubility in water or aqueous buffer. The partition coefficient is often expressed as the logarithmic value, log P.
2. Water solubility or hydrophilicity of a drug is dependent on two major factors: its ionic and hydrogen-bonding capacity. The presence of oxygen- and nitrogen-containing functional groups generally enhances water solubility, which is required for:
- drug dissolution in the gastrointestinal (GI) tract,
- preparation of parenteral drug solutions, and
- ophthalmic drug solutions.
3. Lipid solubility or lipophilicity is increased by the presence of nonionizable functional groupsm (hydrocarbon chains or ring systems) and is important in:
- drug absorption from the GI tract,
- penetration of drug through biological membranes (e.g., cell membranes, blood–brain barrier),
- preparation of intramuscular depot injectable formulations,
- drug absorption via the pulmonary route,
- increased potency of topically applied formulations, and
- increased plasma protein binding.
Acid–base characteristic of drugs
It influences their ionization in biological fluids. Using the Bronsted–Lowry definition, acids donate a proton to become ionized, whereas bases accept a proton to become ionized.
1. The ionization constant (Ka) indicates the relative strength of the acid or base by indicating the ratio of the unprotonated species to the protonated species. An acid with a Ka of 1× 10^-3 is stronger (more ionized than an acid with a Ka of 1× 10^-5, whereas a base with a Ka of 1× 10^-7 is weaker (less ionized species) than a base with a Ka of 1× 10^-9.
2. The ionization constant is more commonly reported as the pKa or the negative log of the ionization constant. The pKa also indicates the relative strength of the acid or base. Using the aforementioned examples, an acid with a Ka of 1× 10^-3 has a (pKa of 3) and is stronger than an acid with a Ka of 1× 10^-5 (pKa of 5), whereas a base with a Ka of 1× 10^-7 (pKa of 7) is weaker than a base with a Ka of 1× 10^-9 (pKa of 9).
3. Acids can be described as strong or weak acids based on their ability to donate a proton.
- Strong acids are completely ionized when placed in water. Strong acids include hydrochloric acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3), hydrobromic acid (HBr), iodic acid (HIO3), and perchloric acid (HClO4).
- Weak acids are partially ionized when placed in water. Most organic acids contained in drugs are weak acids. The following functional groups are weak acids.
4. Bases can be described as strong or weak bases based on their ability to accept a proton.
- Strong bases are completely ionized when placed in water. Strong bases include sodium hydroxide (NaOH), potassium hydroxide (KOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), barium hydroxide (Ba(OH)2), and quaternary ammonium hydroxides.
- Weak bases are partially ionized when placed in water. Most organic bases contained in drugs are weak bases. The following functional groups are weak bases.
5. Drug salts are made by the combination of an acid and a base. Because most drugs are organic molecules, drug salts can be divided into two classes based on the chemical nature of the substance forming the salt.
- Inorganic salts are made by combining drug molecules (a weak base or acid) with strong inorganic acids or bases such as hydrochloric acid, sulfuric acid, potassium hydroxide, or sodium hydroxide. The salt form of the drug made from a strong inorganic and a weak organic generally has increased water solubility in comparison with the parent molecule and increased aqueous dissolution.
- Organic salts are made by combining drug molecules with either small hydrophilic organic compounds (e.g., succinic acid, citric acid) or lipophilic organic compounds (e.g., procaine). Water-soluble organic salts are used to increase dissolution and bioavailability as well as to aid in the preparation of parenteral and ophthalmic formulations. Lipid-soluble organic salts are primarily used to make depot injections.
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