Dissolution and Liberation

• all immediate release dosage forms need to distingrate and dissolve in the medium around the absorption site

  • exception = solutions (already dissolved)

• Noyes Whitney

  • rate of dissolution is governed by the rate of diffusion of a very thin layer of saturated solution that forms around each particle

    • like a halo

• sink condition: drug instantaneously absorbed as soon as it dissolves

  • used to describe different models of absorption, metabolism, clearance, etc.

USP Dissolution Testing

• detailed description of in vitro dissolution tests for almost all dosage forms

• different guidelines for uncoated tablets vs. coated tablets vs. enteric-coated tablets

• strict adherence is essential to ensure reproducibility

  • failure = recall

Factors of Drug Dissolution

• particle size and surface area

• unionized and ionized

• drug formulation

• gastric emptying and intestinal transit times

Particle Size and Surface Area

• general rule → increase in particle size (decrease in surface area) = decrease in dissolution rate

• important in poorly soluble drugs

• micronization: ultra-milling of each drug particle

  • increases surface area significantly → increases dissolution rate

Unionized vs. Ionized Forms of Drugs

• salt forms of weak bases or acids are much more water soluble than the unionized form

  • weak acids = more soluble in stomach

  • weak bases = less soluble in stomach

For acids

• when pKa of drug = pH of environment; ratio of ionized to unionized is 1:1

  • for every integer that pH decreases, ratio moves in favor of unionized

    • 1 molecule ionized to 10 molecules unionzied

For bases

• when pKa of drug = pH of environment; ratio of ionized to unionized is 1:1

  • for every integer that pH decreases, ratio moves in favor of ionized

    • 1 molecule unionized to 10 molecules ionized

Drug formulation

• addition of appropriate disintegrants that will swell the product and burst it open

• lubrication agents may slow the dissolution process in theory because lubricants create a hydrophobic film

Gastric emptying and intestinal transit times

• longer time = slower rate

• gastric emptying time much shorter when fasting than with food in stomach

  • ex: wegovy → take on an empty stomach

Liberation

• prior to drug absorption, drug must be “liberated” from dosage form

  • then particles must dissolve in body fluids