PDD 02: Drug Release and Dissolution Flashcards
Why is dissolution of a drug important?
necessary for drug to exert its response
- drug must be in solution before it can be absorbed, cross membranes, enter cells, and have an effect in the body
Why is water solubility of a drug important?
medium in which drugs must dissolve in the body is usually aqueous
What is a solution?
mixture of two or more components that form a single phase that is homogenous down to the molecular level
What is a solvent?
determines the phase of a solution
- usually also constitutes the largest proportion of the system
What is a solute?
dispersed as molecules or ions throughout the solvent
For weak electrolyte drugs:
What is (intrinsic) solubility (S0)?
concentration of solute (ie. un-ionized drug) in a saturated solution in a given solvent at a given temperature (and pressure)
- S0 = [un-ionized drug]_solution
What is a saturated solution?
solute (un-ionized drug) in solution is in equilibrium with solid phase
- drug_solution ⇆ drug_solid
What is the USP definition of solubility?
part(s) of solvent required for one part solute
USP Definition of Solubility
What solubility can be formulated as oral solutions? (3)
- very soluble (< 1 parts of solvent for one part of solute)
- freely soluble (1 to 10 parts of solvent for one part of solute)
- soluble (10 to 30 parts of solvent for one part of solute)
USP Definition of Solubility
What solubility requires co-solvent/excipients? (2)
- sparingly soluble (30 to 100 parts of solvent for one part of solute)
- slightly soluble (100 to 1000 parts of solvent for one part of solute)
USP Definition of Solubility
What solubility is an alternative dosage form (ie. suspension)? (2)
- very slightly soluble (1000 to 10,000 parts of solvent for one part of solute)
- practically insoluble (>10,000 parts of solvent for one part of solute)
For weak electrolyte drugs:
What is total solubility (S)?
total concentration of drug (ionized + un-ionized) in solution
- S = [un-ionized drug]_solution + [ionized drug]_solution = S0 + [ionized drug]_solution
Total Solubility
Is aqueous solubility of ions or their corresponding un-ionized form greater?
aqueous solubility of ions > solubility of corresponding un-ionized form
Is intrinsic solubility or total solubility greater?
total solubility ≥ intrinsic solubility, depending on ionization of the drug (pKa, pH)
What does the intrinsic solubility of a compound/therapeutic agent depend on? (4)
- physicochemical properties of the drug – MW, density, number of rotatable bonds, hydrogen bond donors, hydrogen bond acceptors, etc.
- solid-state structure of the drug – crystal habit, crystalline/amorphous properties
- temperature, pressure (only for gas)
- solvent
What does total solubility of weak acid and base drugs depend on?
- intrinsic solubility
- ionization of the solute (pKa, pH of solution)
How does the solubility of weak acids/bases change as degree of ionization increases?
solubility increases as degree of ionization increases
What happens to solubility when pH > pKa?
solubility of acidic drugs increases
What happens to solubility when pH < pKa?
solubility of basic drugs increases
What is dissolution?
process by which a solid phase/substance (ie. tablet, powder, drug, etc.) solubilizes/goes into a solution phase (ie. water)
What is often the limiting (or rate-controlling) step in drug absorption?
dissolution rate
What are the models/theories of drug dissolution? (3)
- diffusion layer model – film theory
- Danckwert’s model – surface renewal theory
- interfacial barrier model – double barrier or limited solvation theory
What is the diffusion layer model (film theory)?
- formation of diffusion layer by interfacial reaction – instantaneous
- solvent molecules replace the drug at the surface
- drug begins to dissolve at the surface of the solid particle, forming a thin film (diffusion layer) which is saturated with the drug at the solid/liquid interface
- diffusion of soluble solute from stagnant layer to bulk of solution – slower, rate-limiting step
- results in the formation of a concentration gradient, with a high drug concentration in the diffusion layer and a low concentration in the bulk solvent
What is the rate of dissolution more frequently determined by?
rate of the slower step of diffusion of dissolved solute through the static diffusion layer of liquid that exists at the solid/liquid interface
What does the rate of diffusion obey?
Fick’s Law of Diffusion
- D: diffusion coefficient
- dC/dx: concentration gradient
- C: concentration
- x: distance of movement perpendicular to the surface of the barrier
What is the rate of dissolution given by?
Noyes-Whitney equation
- D: diffusion coefficient
- A: surface area of the exposed solid to dissolution medium (undissolved solid)
- Cs: concentration of the drug at the surface of the solid (ie. the saturated solubility of the drug at the surface of the solid)
- CB: concentration of the drug in the bulk solution
- (Cs - CB)/h: concentration gradient
- k: intrinsic rate constant (D/h)
What factors can influence dissolution? (4)
- surface area (A)
- concentration of drug in bulk solution (CB)
- intrinsic dissolution rate constant (k)
- concentration of drug at surface of the solid (CS)
How can surface area (A) influence dissolution? (3)
- size of solid particles/surface area
- dispersibility of powdered solid in dissolution medium
- porosity of solid particles
How can the concentration of drug in bulk solution (CB) influence dissolution? (2)
- volume of the dissolution medium
- any process that removes dissolved solute from the dissolution medium
How can the intrinsic dissolution rate constant (k) influence dissolution? (2)
- temperature
- thickness of the diffusion layer – agitation, volume of dissolution medium, shape and size of the container, viscosity of the dissolution medium
How can the concentration of drug at surface of the solid (CS) influence dissolution? (4)
- temperature
- nature of dissolution medium – solubility parameters, co-solvents, pH
- molecular structure of the solute – appropriate selection of drug salt, esterification of the neutral compound
- MW of the solute
What are the formulation methods that enhance/optimize the aqueous solubility of therapeutic agents? (5)
- appropriate selection of drug salt
- optimization of pH of the formulation
- addition of co-solvents
- complexation (with cyclodextrins)
- addition of surface-active agents (surfactants)
What is drug bioavailability?
fraction of an administered dose of drug that reaches the systemic circulation
What factors does the rate and extent of drug absorption depend on? (3)
- solubility
- dissolution (rate)
- permeability (partition coefficient)
Partitioning of Drugs and their Distribution
- balance between lipophilicity and hydrophilicity dictates permeability of drug – how quickly it can pass through bilayer
What are some applications of the biopharmaceutical classification system (BCS)? (3)
- prediction of in vivo performance (ie. PK) of oral drug product using solubility and permeability
- in early stages of drug discovery research
- in pre-clinical and clinical drug development processes
Biopharmaceutical Classification System (BCS)
What is class I?
high solubility, high permeability
- ideal for oral route of administration
- well absorbed (> 90%) because: dissolve rapidly, rapidly traverse the gut wall
- ie. acetaminophen
Biopharmaceutical Classification System (BCS)
What is class II?
low solubility, high permeability
- dissolve slowly, solubility is too low to have completed absorption
- rapidly traverse the gut wall
- drugs in this class may require formulation approaches to improve dissolution rate to enhance bioavailability
- just need to get drug into solution
- ie. ketoconazole
Biopharmaceutical Classification System (BCS)
What is class III?
high solubility, low permeability
- dissolve rapidly
- unable to permeate the gut wall quickly enough for absorption to be completed
- drugs in this class may require formulation approaches to improve permeation rate to enhance bioavailability
- ie. ranitidine
Biopharmaceutical Classification System (BCS)
What is class IV?
low solubility, low permeability
- dissolves slowly, solubility is too low for complete absorption
- poorly permeable across the gut wall
- both solubility and permeability limitation
- formulation approaches (prodrug, lipid based drug delivery) may be required
- ie. amphotericin B
