Pharmaceutics (Part I) Spring 2004 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.

edu

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BONDING
Bonding and molecular interactions: Understanding the basic forces that hold molecules together is important for understanding how molecules interact with each other. These interactions affect solubility, stability and other properties of drugs. BOND TYPES Covalent Bonds - the strongest bond (arrows), worth anywhere from -40 to -110 kcal/mol in stability. Bonds in the molecule at right are all covalent even though some are single, double or triple bonds. Not shown are the carbon-hydrogen bonds that are also covalent. Although most drug interactions are non-covalent, alkylation of DNA for example in cancer chemotherapy is an example of covalent bond formation by drugs. Ionic Bonds a.k.a. Electrostatic interactions can be attractive or repulsive, depending on the relative charges. Like charges repel each other and opposite charges attract. For ionic bonds, opposite charges hold ions together. Electrons are not shared, but are transferred. As an example, at physiologic pH basic side chains of certain amino acids like arginine, lysine, and, in part, histidine are protonated and therefore provided a cationic environment. Acidic groups like aspartic and glutamic acid are deprotonated to give negatively charged groups. Therefore, drugs and their target receptors can be mutually attracted by opposite charges on their surfaces, e.g., cationic drug with anionic receptor site. A simple ionic attraction can provide as much as -5.0 kcal/mol and declines as the square of the distance between the charged sites. If an ionic attraction is reinforced by other interactions (H-bonding, etc) is can provide up to -10.0 kcal/mol. Ion-dipole and dipole-dipole Interactions - by virtue of varied electronegativity values when compared to carbon certain groups have an asymmetric distribution of electrons that produce dipoles. Dipolar interactions refer to unequal distribution of charge within a bond or a molecule. Dipoles exist where one atom (X) is more electronegative than another (H). The dipoles in a drug molecule, therefore, can find complementary dipole interactions in the receptor. However, since the net charge on a dipole is less than on a full ion, the interaction is generally weaker (G ranges from -1 to -7 but is usually -1 to -2).

O +

+ +

+ F

O- H

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Hydrogen Bonds - simply a variation of a dipole-dipole interaction formed between the proton of one group and an electronegative atom of another group. In molecules of biological interest the hydrogen bonds most widely experienced are when X = O, N, S. Hydrogen bonds are usually denoted by a dashed or dotted line as in the case of the DNA bases at right sharing two hydrogen bonds: What makes hydrogen bonds so unique is that hydrogen is the only atom that can carry a positive charge at physiologic pH while remaining covalently attached to a molecule. Further, hydrogen is small enough to permit close approach by another electronegative atom or molecule to accept the hydrogen bond.
O N

N H O H N

NH

N H

NH2

There are two forms of hydrogen bonds - intramolecular (within a single molecule) and intermolecular (between two molecules). Hydrogen bonds for example, are important in maintaining the structural integrity of peptides and proteins - -helical structure and -sheets derive their structure from hydrogen bonds. The G for hydrogen bonding ranges from -1 to -7 kcal/mol but in biosystems is usually between -3 and -5 kcal/mol. Charge Transfer Complexes - this attraction comes about when molecules containing a good electron donor group (on an aromatic ring) interact with a molecule that contains an electron-withdrawing (acceptor) group. The interaction involves transfer of charge from donor to acceptor. Electron donor groups or molecules usually contain a -bond (alkene, alkyne, aromatic moiety) that bears a good electron donating group (alkyl, methoxy, OR, SR, etc.). Acceptor groups or molecules usually contain a -bond with electron withdrawing groups attached (e.g., cyano, carbonyl, halogen, etc.). The interaction is rare and most likely found with the tyrosine residue on certain receptors (as the donor). The G for charge-transfer complexes range from -1 to -7 kcal/mol. Hydrophobic Interactions - involve a non-polar/non-polar interaction between receptor and drug. Usually alkyl chains are found to stack as in the lipid bilayer except this is for a single interaction. It is important to consider in this interaction that each receptor and drug molecule aliphatic chain is surrounded by water molecules, and as the chains approach each the water molecules are squeezed out to permit the non-polar chains to align with each other in a "side by side" position. This orienting results in a drop in the free energy of about 0.1 to -2.0 kcal/mol. Van der Waals or London Forces - Some atoms on mostly non polar molecules experience or exert a temporary nonsymmetric distribution of electrons to cause a dipole. As these atoms approach each other in different molecules, the opposite dipoles attract forming an interaction. The G varies greatly and values from -0.1 to -2.0 are reasonable.
drug molecule R1
O
R4HN

R2

+
NHR R3

receptor target

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SOLUBILITY
Solubility is the maximum concentration that can be attained by a solute in a specific solvent. A saturated solution is one in which the solvent has dissolved all of the solute that it can, and addition of further solute will not increase the concentration of the solute in the solvent. When excess solute is added to a saturated solution, an equilibrium will exist between the solid solute and the solute in solution. Solutions are the result of intermolecular attractive forces between solutes and solvents. Electrostatic, dipole-dipole (van der Waals) and hydrogen-bonding forces may be involved in solute-solvent interactions. In order for a solute to dissolve in a solvent, the intermolecular attractive forces between solute molecules and between solvent molecules must be overcome and replaced with solute-solvent attractive forces. Solubility can be affected by temperature, pH, and the physical form of the solute. temperature: Increasing temperature generally increases solubility. Most solutes absorb heat upon dissolution and have a positive heat of solutions. In comparison, a few solutes have a negative heat of solution which means that they give off heat during dissolution and solubility decreases with increasing temperature. pH: Weak acids and bases are more soluble in their ionized (conjugate base or conjugate acid) forms than their unionized forms, so pH is very important for the solubility of weak electrolytes. physical form: Non-crystalline (amorphous) solids are generally more soluble than crystalline solids. Also, different polymorphic forms, solvates and hydrates will have different solubilities. These terms will be discussed later. Water as solvent. Why is water important toward an understanding of drug action? It is the universal solvent, delivery agent, dispersing agent, nucleophile, and primary source of H+ and OH- in vivo. Therefore, water is not inert. It also is responsible for certain aspects of protein structure (conformation), the formation and structure of the lipid bilayer and other important intra- and extracellular domains, and other phenomena where H-bonding plays a role. In the figure below, some basic properties of water are illustrated: bond angles, charge distribution and H-bonding. The water molecule is not linear. Aggregates of water form easily based upon hydrogen bonding. Ice takes on a tetrahedral geometry and although the structure of ice does not play a significant role in vivo, the structure of water does vary depending on its environment and local temperature. Packets of water exist in flux, a vibrating, rotating, rapidly reorganizing environment. Solubility (water as a solvent): In part, the flux adds to the "solvent" properties of water. Due to a high dipole, water has a very high dielectric constant (Debeye = D = 80) as compared to the organic solvents

Pharmaceutics (Part I) Spring 2004 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu

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acetone (D = 21) or hexane (D = 1 to 2). [Note: highly polarized solvents favor "polarized" transition states.] With a high dielectric constant, water is capable of breaking the electrostatic attraction of ions (crystal lattices) to favor hydration. When the heat of solvation is favored over the energy stored in the stability of the crystal lattice, the compound dissolves (e.g., NaCl). Recall that certain organic compounds forms "ions," for example, carboxylic acids (oxyanions) and amines (nitrogen cations). Charged species are generally more soluble in water and neutral compounds. For some neutral organic molecules a different physicochemical process is involved. As a result of solvation, the structure of the water cluster also is altered to form an envelope or "breaker" in the structure. Think of a microscopic droplet of oil surrounded by water (as represented by an organic compound). The water exerts a solvation effect on the compound and the compound exerts a "disturbance" on the H-bonded water environment. Such complexes between a solvated species and the water are called "clathrates." Compare this phenomena to a truly ionic compound in solution that is fully ionized, H-bonded and intermingled. Within this description, some organic molecules have an ionic character and fall somewhere in between an "inclusion" complex and solvation. To effect a spectrum of solubility characteristics, we ask the following question: To what extent are organic molecules soluble in water? Consider the body as a huge separatory funnel, filled with water (aqueous layer; e.g., serum) and fat (organic layer). Where will the drug go? Why is this important? This question is important because all biochemistry processes are based upon small amounts of organic molecules dispersed in the aqueous or lipid (organic) phase or both. Circulating fluids (blood) have aqueous characteristics, but tissues (e.g., tissue membranes) and the cavities of certain proteins have an organic environment. Some trends for organic molecule solubility in water: a. up to five carbons with one functional group are usually soluble, b. molecule with branched chains are more soluble than linear chain c. water solubility deceases with increase in molecular weight Some nomenclature used to describe solubility that you should be familiar with:
o o o

Hydrophobic (a.k.a lipophilic); fat phase loving, aqueous phase hating Hydrophilic; aqueous phase loving, fat phase hating Amphiphilic; has atomic characteristics to permit solubility in both phases

Solvent-solute interactions: As a general rule: like dissolves like so polar solvents dissolve polar solutes and non-polar solvents dissolve non-polar solutes. Polar solvents Polar solvents (e.g. water, methanol) readily dissolve polar solutes such as salts (ionic compounds), sugars and other polyhydroxy compounds. Water can also dissolve (to some extent) other O- and N-containing compounds including alcohols, amines, ketones, aldehydes, phenols. These compounds contain polar groups

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which can hydrogen bond with water. Water can also dissolve the salt (ionic) forms of weak acids and weak bases (the conjugate base and conjugate acid forms of weak acids and weak bases). Water is miscible with other liquids such as ethanol and methanol meaning that they can be mixed in any (unlimited) proportion to form a homogeneous liquid. Non-polar solvents: Ionic and polar solutes are poorly or not soluble in non-polar solvents because the solvent cannot reduce the attractive forces between the solute molecules (ionic or dipolar or hydrogen bonding). Non-polar solvents can dissolve non-polar solutes through induced dipolar interactions (non-polar solutes are held together weakly unlike polar solutes) Overall:

acetone = ketone solvent.

Solubility Terms:

Pharmaceutics (Part I) Spring 2004 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu

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THINGS TO NOTE IN TABLE 6.2. Alcohol is synonymous with ethanol. The salt of a drug is more soluble in water than in ethanol The neutral form of a drug is usually more soluble in ethanol than in water.

Lipid vs. aqueous solubility: Drug substances must exhibit some degree of both lipid and aqueous solubility. Lipid solubility for crossing biological membranes and aqueous solubility for distribution into the systemic circulation and other biological fluids. Substances that are relatively insoluble in water may exhibit poor absorption characteristics such as erratic or incomplete absorption. The graph below shows the correlation between lipid/aqueous solubility (log P, well get to this later) and drug effect.

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Modification of aqueous solubility: salt formation or structural modification adjust pH if a liquid formulation use co-solvent complexation

Rate of solution: While solubility is constant at a given temperature and pressure, rate of solution can vary depending on the particle size of the solute and the agitation rate of the solution. pH, pKa and solubility: Solubility is influenced by the degree of ionization of the substance. Total aqueous solubility of an ionizable substance can be expressed as: ST = [HA] + [A-] S = [B] + [BH+] or ST = SHA + [A-] S = S + [BH+]
T T T

for a weak acid for a weak base for a weak acid for a weak base

where ST is the total solubility and SHA and SB are the solubilities of the unionized weak acid or weak base. For a non-ionizable substance, a non-electrolyte: ST = SNE For a weak acid, the following equation can be derived: ST = SHA + KaSHA [H3O+]

which indicates that solubility of a weak acid increases with increasing pH (decreasing H3O+ concentration): so as pH then HA, A-, and ST

Correlation with Henderson Hasselbalch: Maximum aqueous solubility for weak acids is attained at pH-pKa 2, where 99% is in the ionized (A-) form. Minimum solubility is at pH-pKa -2 where 99% is in the unionized (HA) form. The logarithmic form can be used to predict the pH (pHp) below which the unionized weak acid would precipitate from solution: pHp = pKa + log ST-SHA SHA

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For a weak base, the following equation can be derived: ST = SB + [H3O+]SB

Ka which indicates that solubility of a weak base increases with decreasing pH (increasing H3O+ concentration): as the pH then the B, BH+, and ST Maximum aqueous solubility for weak bases is attained at pH-pKa -2, where 99% is in the ionized (BH+) form. Minimum solubility is at pH- pKa 2 where 99% is in the unionized (B) form. The logarithmic form can be used to predict the pH (pHp)above which the weak base would precipitate from solution: pHp = pKa + log SB ST-SB Solubility of weak acids and weak bases in buffers vs. water: The solubilities of a weak acid and its conjugate base are identical in a buffer solution. The pH of the buffer solution determines the B/A ratio and the solubility will be the same for either form (weak acid or conjugate base). The same is true for a weak base and its conjugate acid. The solubilities of a weak acid and its conjugate base are different in water. Addition of the weak acid makes the water acidic so there is more of the unionized weak acid form present and solubility is low. Addition of the conjugate base makes the water basic so there is more of the ionized form present and solubility is high. The solubilities of a weak base and its conjugate acid are also different in water for a similar reason. Addition of the weak base makes the water basic so there is more of the unionized weak base form present and solubility is low. Addition of the conjugate acid makes the water acidic so there is more of the ionized form present and solubility is high. PARTITION COEFFICIENTS Distribution/partition coefficients: In order to produce a biological response, a drug molecule must cross a mostly lipid biological membrane. Its ability to do this depends on its lipophilicity/hydrophilicity balance and, if ionizable, its degree of ionization.

Pharmaceutics (Part I) Spring 2004 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu

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Distribution coefficients: The partition coefficient (P, K) is also known as the distribution coefficient or distribution ratio. Higher P or K values indicate higher lipid solubility relative to aqueous solubility. The true distribution coefficient (K) is the concentration of a substance in an oil phase ([HA]O), such as octanol, divided by the concentration of unionized substance (e.g. weak acid or weak base) in the aqueous phase ([HA]W): K = [HA]O [HA]W

Since substances do not ionize significantly in the oil phase: [HA]O = CO (where CO is the total concentration in the oil phase). The expression can then be written: K = CO [HA]W The apparent distribution coefficient (K) is the experimentally observed ratio, and it includes the ionized fraction of the substance in the water phase. K = [CO] [HA]W + [ A ]W The total concentration in the aqueous phase (CW) is: CW = [HA]W + [A-]W
-

so the apparent distribution coefficient can be expressed: K = CO/CW

Degree of ionization: The degree of ionization is the fraction ionized () in solution and is equal to: = [A-]W [HA]W + [A-]W

The degree of ionization depends on the pH of the aqueous phase and the pKa of the substance. The fraction unionized (1-) is equal to: 1- = [HA]W [HA]W+[A-]W

The true distribution coefficient for non-ionizable substances may be expressed: K = Co/CW (since K and K are the same for non-ionizable substances)

Pharmaceutics (Part I) Spring 2004 Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu

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DISSOLUTION The dissolution rate is the time required for a drug substance to dissolve in the fluids at the absorption site. Dissolution rate is often the rate-limiting step in the absorption process and can control the overall bioavailability of the drug from the dosage form. Dissolution is important for the bioavailability of solid dosage forms including oral capsules, tablets and suspensions and intramuscular suspensions. Methods for increasing dissolution rates: Decrease particle size. This increases the available surface area to the dissolving fluid. [Note: In rare cases, agglomeration of the particles may occur leading to decreased dissolution rates.] Increase solubility in the diffusion layer. The ionized form of the drug (salt of the weak acid or salt of the weak base) will have greater solubility in the diffusion layer than the unionized weak acid or weak base. (e.g. penicillin V potassium will dissolve faster than penicillin V itself). Alter pH of dissolution medium (e.g. buffered aspirin). Increase agitation of dissolution medium (e.g. effervescent, buffered aspirin). Noyes-Whitney equation: The Noyes-Whitney equation shows how factors such as solubility and surface area can affect dissolution rate: dM dt where: dM/dt = the dissolution rate D = the diffusion coefficient of the solute in the solution S = the surface area of the exposed solid h = the thickness of the diffusion layer CS = the concentration of the drug in the diffusion layer (solubility of the drug since diffusion layer is assumed to be saturated) C = the drug concentration in the bulk solution at time t. Dissolution is therefore driven by surface area (S) and the concentration gradient (CS-C). = DS(CS-C) h