QUESTION:

a) Write short notes on the physicochemical properties of drug compounds

including molecular weight, pKa, logP, crystalline amorphous/solvated form. Drug molecules exist in various physical states e.g. amorphous, solid, hygroscopic solid, liquid or gas. The physicochemical properties of drug compounds are critical in dosage form design, the manufacturing processes and dosage form performance in vivo and in vitro. An understanding of these properties helps to:
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avoid drug-excipient interactions improve stability of dosage form manipulate drug release

Melting and Boiling Point The melting point (m.p) is the temperature at which a solid becomes a liquid and the boiling point (b.p) is the temperature at which the vapour pressure of the liquid is equal to the atmospheric pressure. The b.p can also be defined as the temperature a drug substance can change its state from a liquid to a gas throughout the bulk of the liquid at a given pressure. The m.p of a pure compound is always higher than the m.p of that compound when mixed with a small amount of impurity as in a drug component. B.p and m.p increase with increase in molecular weight. Acidic properties and pH Drugs can either be acidic, basic or neutral. An acid is an electron deficient species that accepts on electron pair and a species with electrons to donate is a base. A neutral species does not do either of these. The pH value is defined as the negative logarithm to base 10 of the concentration of the hydrogen iron. The acidity or basicity of a substance is defined most typically by the pH value pH= -log10 [H + ]

Dissociation constants (Ka and Kb) and pKa Upon dissociation in water, drug molecules ionize at different degrees depending on their chemical structure. Weak acids and weak bases will contain a mixture of ionized species and molecular (unionized) species in equilibrium. Thus the ionization of many drugs in aqueous solutions of the body fluids is an equilibrium process. For the determination of Ka and Kb the Browsted-Lowry acid-base theory works best. This describes an acid as a substance that can donate a proton (H ) and a base as a substance that can accept a proton (H + Now when an acid or base is dissolved in ). water the following acid-base equilibria are established. For the acid HA: HA + H2O For the base B: B + H2O The acid dissociation constant Ka is Ka = [H3O] [A-] [HA] The base dissociation constant Kb is Kb = [BH ] [OH-] [B] BH + OH + H3O + A+

The partition coefficient P If two immiscible phases came into contact, where one of the phases contains a solute which is soluble to same extent in both phases, the solute will become distributed between the two phases hence equilibrium will be achieved. Octanol is often used as the non-aqueous phase to measure the partition coefficient.

The partition coefficient is given by the following ratio: P= [drug in organic phase] [drug in aqueous phase]

log P log P is the logarithm of the partition coefficient. It is used as a measure of molecular hydrophobicity, where the hydrophobicity affects drug absorption, bio-availability, drug receptor interactions, metabolism of molecules and toxicity. The relationship between tissue penetration and partition coefficient for the drug generally is defined by the Hanch correlation which describes a parabolic relationship between the logarithm of the activity of a drug or its ability to be absorbed and the logarithm of its partition coefficient. The activity of a drug is a function of its ability to cross membranes and interact with the receptor. The more effectively a drug crosses the membranes the greater its activity. There is an optimum partition coefficient of a drug in which it most effectively penetrates the membranes and thus shows greater activity. Values of the partition coefficient below the optimum results in decreased lipid solubility and the drug will remain in the first aqueous phase it contacts. Values greater than the optimum results in poorer aqueous solubility and the drug will not partition out of the lipid membrane once it gets in. Crystal properties of drugs Drugs have different crystal properties. These properties include crystalline, amorphous (i.e. without regular molecular lattice arrangement), anhydrous, various degrees of hydration, solvated with other entrapped solvent molecules as well as varying in crystal hardness shape and size. Crystals are highly ordered arrangements of molecules and atoms held together by non-covalent interactions. Crystalline lattice are made up of repeating units in space known as unit cells. There are seven primitive unit cells cubic, hexagonal, trigonal, tetragonal, orthorhombic, monoclinic and tridining. Polymorphism arises when a given drug molecule has the ability to crystallize in more than one crystalline form.

b) How do these properties influence drug solubility, ionization and stability Solubility The solubility of a drug is important in the absorption of that drug into the body fluids and eventually its bio-availability. The boiling point of liquids and melting points of solids are useful in that both reflect the strength of the interactions between the molecules of the pure liquid or the solid state. The trend that is therefore shown by the m.p and b.p is that as m.p and b.p increase, and consequently the increase in the strength of the interactions, the less soluble the drug substance. pH influences solubility of most drugs that contain ionisable groups. Acidic drugs are less soluble in acidic solutions than in alkaline solution. This is because the predominant undissociated species cannot interact with water to the same extent as the ionized form of water (alkaline solution) in which it is readily hydrated. Basic drugs are more soluble in acidic solutions where the ionized form of the drug is predominant. In a liquid product adjustment of the pH of the solvent can be done to enhance solubility. Amorphous state of a drug is the form with the highest solubility. This form exhibits greater solubility in solvent than any other crystalline form. This is because the amorphous state is a high energy crystal form (less stable form) while all others are low energy forms. Lipinskis Rule of Five (ROF) was developed as a general guide to the physicochemical properties that can cause problems with respect to aqueous solubility in physiological fluids after release from the dosage form and permeability of biological barriers during absorption. PHYSICAL PROPERTY Molecular weight Partition coefficient Number of H-band donors Number of H-band acceptors VALUE THAT CAUSE PROBLEMS Greater than 500 Greater than 5 Greater than 5 Greater than 10

The rule states that problems with absorption can be avoided when two of the four rules Ionization

The degree to which drugs are ionized in solution is dependent upon the pKa of the drug and the pH of the solution in which the drug is dissolved. The extent of ionization of a drug has an important effect on its absorption, distribution and elimination. Stability Stability is the capacity of a drug product to remain within specifications established. Drugs in the crystalline state have lower ground state free energy hence slow reactivity. Since many drugs exhibit polymorphism each crystalline state has a different state free energy level, therefore different reactivity. The stability of drugs in their amorphous form is generally lower than that of drugs in their crystalline form due to high free energy level. Generally drugs which have high melting or boiling points show greater stability this is in relation to their strong interactions.

References 1. Florence A.T and Attwood D, 2006, Physicochemical Principles of Pharmacy, fourth edition, Pharmaceutical Press, page 75. 2. Aulton M.E, Pharmaceutics: The Science of Dosage Form Design, second edition, Churchill Livingstone, page 15 38. 3. Lemke L.T and William D.A, 2008, Foyes Principle of Medical Chemistry, sixth edition, Lippincott William and Wilkins, USA, page 80 84. 4. Wermuth G.C, 2000, The Practice of Medical Chemistry, first edition, Saunders publishing company, USA, page 525. 5. Remington J, 2006, The Science and Practice of Pharmacy, twenty first edition, Lippincottt Williams and Wilkins, USA, pages 162-181.