The process of dissolution of drug particles from the formulation or the drug particles surrounded by tissue fluids is the rate limiting step. Based on this concept, the rate of drug absorption can be controlled by slow dissolution of drug particles.

Drug dissolution rate under sink conditions is given as

 

(Q/t)d = Sa Ds Cs/hd

 

where Sa is the surface area of the drug particles in contact with the medium, Ds is the diffusion coefficient of drug molecules in the medium, Cs is the saturation solubility of drug in the medium, and hd is the thickness of the hydrodynamic diffusion layer surrounding each drug particle.

There are two approaches that can be utilized to control the dissolution of drug particles and also to prolong the absorption of the drug.

Formation of Ester or Complexes with Low Aqueous Solubility: Examples are preparations of penicillin G procaine and penicillin G benzathine from the highly water-soluble alkali salts of penicillin G and preparations of naloxone pamoate from the water-soluble hydrochloride salt of naloxone.

Suspension of Macrocrystals: Crystals of large particle size (macrocrystals) dissolve more slowly than microcrystals. Typical example is the aqueous suspension of testosterone isobutyrate for intramuscular administration.