Drug Solubility and Dissolution Rate

Most drugs will “function” in solution in the body. Poorly soluble compounds tend to be eliminated from the GI tract before dissolution Drugs must dissolve before being absorbed: Need to determine the rate and extent of absorption; bioavailability (BA).  Low aqueous solubility  frequent BA problems = Poor bioavailability

Molecular dispersion formed by 2 or more components which form a ‘one phase’ homogeneous system. A mixture of two or more components that forms a single phase which is homogeneous down to the molecular level. Can be applied to solid, liquid and gaseous state miscibility

The component that determines the phase of the solution is termed ‘solvent’. Solvent usually constitutes the largest proportion of the system.

Are other components of the solution. Are dispersed as molecules or ions throughout the solvent. i.e. Are dissolved in the solvent

Solute is in equilibrium with the solid phase (solute).

The concentration of solute in a saturated solution at a certain temperature Commonly as ‘the maximum mass or volume of solute that will dissolve in a given mass or volume of solvent at a particular temperature’. e.g. The solubility of ‘nitrofurantoin’ (antibiotic for urinary infections) in water at 37oC is 174mg dm-3.

The spontaneous interaction of 2 or more substances to form a homogenous molecular dispersion.

The dissolved solute is in concentration below that necessary for complete saturation at a definite temperature.

Contains more of the dissolved solute that it would normally contain at a definite temperature. E.g. Salts such as sodium thiosulfate and sodium acetate Dissolution in large amounts at an elevated temperature.  upon cooling, fail to crystallize from the solution.

For a drug to be absorbed, it must first be dissolved in the fluid at the site of absorption. e.g. Oral administered tablet -> dissolved/solubilized by the GI fluids -> absorption Dissolution describes the process by which the drug particles dissolve.

The rate of dissolution is determined by the slower step. The interfacial steps ( I& II) are virtually instantaneous. The rate of dissolution is determined by the diffusion of the solute through the static boundary layer. The rate of mass transfer of solute molecules (or ions) through a diffusion layer is: Directly proportional to the area available for migration and the C across the boundary layer • Inversely proportional to the thickness of the diffusion layer in solution Dissolution rate can be raised by: increasing the surface area of the drug by reducing particle size increasing drug solubility in diffusing layer.  Increasing k

If dissolution fast/or drug delivered remained in solution: The rate of absorption is primarily dependent upon its ability to traverse the absorbing membrane. If drug dissolution slow (physicochem. properties/formulation factors): Dissolution may be the rate-limiting step in absorption -> influence drug bioavailability.

A- size of particles, dispersibility, surfactants and bile salts Cs- temp, solvent and solute, ph , crystalline from, micelles C- volume of dissolution, any process that removes solute and solution D- viscosity of solvent, Prescence of food h- stirring GI mobility

Dissociation in water -> endothermic Its solubility increases with rise in ToC until 32.5oC is reached. Above 32.5oC, the solid is converted to the anhydrous form. Dissolution-> exothermic Change of slope from (+) to (-) as the ToC exceeds the transition value. structure of solute - use of salt increases solubility Salt form of a drug instead of the free acid (a weak acid). The sodium salt has a higher degree of dissociation in water Increased interaction with the solvent Increased solubility

~70% of drugs are weak bases- cocaine metoclopramide ropinirole chlopromazine many amine drugs usually hydrochloride salts ~20% of drugs are weak acids-naproxen non-steroidal anti-inflammatories phenobarbital barbiturates nitrofurantoin phenylbutazone ~5% are non-ionic, amphoteric, or alcohols

changes in ionisation ionised forms are more soluble than unionised hence, solubility will change with pH a drug must dissolve before it can be absorbed drug solubility determines the rate and extent of absorption

pH > pKa

pH < pKa

pH > pKa

pH < pKa

HA equilibrium arrow H+ + A- unionized (free) form, low solubility (So)* Decrease pH (add H+) Increase proportion of unionised form (less soluble) Low solubility ionized form, higher solubility Increase pH (remove H+) Increase proportion of ionised form (more soluble) High solubility Weak acids can form salts with positive ions (cations When, for example, Na+A- is dissolved in water, a different equilibrium is established: Na+A- + H2O HA + NaOH Dissolution of salt of a weak acid  pH increased The solubility of a weakly acidic drug can be predicted given: (a) the pH of the solution, (b) the pKa, and (c) the solubility of the free (unionised) form of the drug (its so-called intrinsic solubility, S0) The solubility of a weakly acidic drug: (a) increases by about 10x for each unit of pH above the pKa, (b) approaches S0 as pH decreases below the pKa, and (c) equals {2 x S0} when the pH equals the pKa.

The pH of the solution increases The solubility increases BUT, if solution pH is lowered, precipitation of free acid form may occur

The pH of the solution falls The solubility increases BUT, if pH is increased, precipitation of the free base may occur The solubility of a weakly basic drug: (a) increases by about 10x for each unit of pH below the pKa, (b) approaches S0 as pH increases above the pKa, and (c) equals {2 x S0} when the pH equals the pKa.

A weak base has a high dissolution rate in the stomach, but the dissolution rate falls as the pH of the GI tract rises. A weak acid has minimal dissolution in the stomach but its dissolution rate increases down the gut.