PDD 02: Drug Release and Dissolution

Question 1

Why is dissolution of a drug important?

Answer 1

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

Question 2

Why is water solubility of a drug important?

Answer 2

medium in which drugs must dissolve in the body is usually aqueous

Question 3

What is a solution?

Answer 3

mixture of two or more components that form a single phase that is homogenous down to the molecular level

Question 4

What is a solvent?

Answer 4

determines the phase of a solution

• usually also constitutes the largest proportion of the system

Question 5

What is a solute?

Answer 5

dispersed as molecules or ions throughout the solvent

Question 6

For weak electrolyte drugs:

What is (intrinsic) solubility (S0)?

Answer 6

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

Question 7

What is a saturated solution?

Answer 7

solute (un-ionized drug) in solution is in equilibrium with solid phase

• drug_solution ⇆ drug_solid

Question 8

What is the USP definition of solubility?

Answer 8

part(s) of solvent required for one part solute

Question 9

USP Definition of Solubility

What solubility can be formulated as oral solutions? (3)

Answer 9

• 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)

Question 10

USP Definition of Solubility

What solubility requires co-solvent/excipients? (2)

Answer 10

• 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)

Question 11

USP Definition of Solubility

What solubility is an alternative dosage form (ie. suspension)? (2)

Answer 11

• 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)

Question 12

For weak electrolyte drugs:

What is total solubility (S)?

Answer 12

total concentration of drug (ionized + un-ionized) in solution

• S = [un-ionized drug]_solution + [ionized drug]_solution = S0 + [ionized drug]_solution

Question 13

Total Solubility

Is aqueous solubility of ions or their corresponding un-ionized form greater?

Answer 13

aqueous solubility of ions > solubility of corresponding un-ionized form

Question 14

Is intrinsic solubility or total solubility greater?

Answer 14

total solubility ≥ intrinsic solubility, depending on ionization of the drug (pKa, pH)

Question 15

What does the intrinsic solubility of a compound/therapeutic agent depend on? (4)

Answer 15

• 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

Question 16

What does total solubility of weak acid and base drugs depend on?

Answer 16

• intrinsic solubility
• ionization of the solute (pKa, pH of solution)

Question 17

How does the solubility of weak acids/bases change as degree of ionization increases?

Answer 17

solubility increases as degree of ionization increases

Question 18

What happens to solubility when pH > pKa?

Answer 18

solubility of acidic drugs increases

Question 19

What happens to solubility when pH < pKa?

Answer 19

solubility of basic drugs increases

Question 20

What is dissolution?

Answer 20

process by which a solid phase/substance (ie. tablet, powder, drug, etc.) solubilizes/goes into a solution phase (ie. water)

Question 21

What is often the limiting (or rate-controlling) step in drug absorption?

Answer 21

dissolution rate

Question 22

What are the models/theories of drug dissolution? (3)

Answer 22

• diffusion layer model – film theory
• Danckwert’s model – surface renewal theory
• interfacial barrier model – double barrier or limited solvation theory

Question 23

What is the diffusion layer model (film theory)?

Answer 23

1. 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

2. 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

Question 24

What is the rate of dissolution more frequently determined by?

Answer 24

rate of the slower step of diffusion of dissolved solute through the static diffusion layer of liquid that exists at the solid/liquid interface

Question 25

What does the rate of diffusion obey?

Answer 25

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

Question 26

What is the rate of dissolution given by?

Answer 26

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)

Question 27

What factors can influence dissolution? (4)

Answer 27

- surface area (A) - concentration of drug in bulk solution (CB) - intrinsic dissolution rate constant (k) - concentration of drug at surface of the solid (CS)

Question 28

How can surface area (A) influence dissolution? (3)

Answer 28

- size of solid particles/surface area - dispersibility of powdered solid in dissolution medium - porosity of solid particles

Question 29

How can the concentration of drug in bulk solution (CB) influence dissolution? (2)

Answer 29

- volume of the dissolution medium - any process that removes dissolved solute from the dissolution medium

Question 30

How can the intrinsic dissolution rate constant (k) influence dissolution? (2)

Answer 30

- temperature - thickness of the diffusion layer – agitation, volume of dissolution medium, shape and size of the container, viscosity of the dissolution medium

Question 31

How can the concentration of drug at surface of the solid (CS) influence dissolution? (4)

Answer 31

- 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

Question 32

What are the formulation methods that enhance/optimize the aqueous solubility of therapeutic agents? (5)

Answer 32

- appropriate selection of drug salt - optimization of pH of the formulation - addition of co-solvents - complexation (with cyclodextrins) - addition of surface-active agents (surfactants)

Question 33

What is drug bioavailability?

Answer 33

fraction of an administered dose of drug that reaches the systemic circulation

Question 34

What factors does the rate and extent of drug absorption depend on? (3)

Answer 34

- solubility - dissolution (rate) - permeability (partition coefficient)

Question 35

Partitioning of Drugs and their Distribution

Answer 35

- balance between lipophilicity and hydrophilicity dictates permeability of drug – how quickly it can pass through bilayer

Question 36

What are some applications of the biopharmaceutical classification system (BCS)? (3)

Answer 36

- 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

Question 37

Biopharmaceutical Classification System (BCS) What is class I?

Answer 37

high solubility, high permeability - ideal for oral route of administration - well absorbed (> 90%) because: dissolve rapidly, rapidly traverse the gut wall - ie. acetaminophen

Question 38

Biopharmaceutical Classification System (BCS) What is class II?

Answer 38

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

Question 39

Biopharmaceutical Classification System (BCS) What is class III?

Answer 39

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

Question 40

Biopharmaceutical Classification System (BCS) What is class IV?

Answer 40

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