ChemCases.Com
Drug Pathways and Chemical Concepts

Prof. Sally Boudinot

13. Drug Absorption/Effective Delivery

Please remember these concepts:

  1. Many processes can be at equilibrium.   But with changes in condition - concentration, temperature -  the system will no longer be at equilibrium and will adjust to try to get there again.
  2. The equilibrium concentrations of H3O+ and OH- are vanishingly small in pure water. 
  3. A weak acid or a weak base drug, in water, will disassociate to some extent.  The pH of the drug solution  will depend upon the pKa.
  4. Buffers stabilize pH.  This stabilized acidity determines the form of drug disassociation in systems.  The Henderson-Hasselbach equation conveniently handles drug ionization questions for buffered systems like the body.

It is almost ALWAYS desirable to have a drug compound that can exist in a solution. Even if ultimately the drug will not be administered as a solution (either oral or intravenous), researchers involved in the initial phases of drug development need the compound to be soluble. During pre-clinical trials, any animal studies that are done will initially use intravenous administration of the drug. Initial stability studies of the drug may be carried out with the drug in solution. 

Of course, water solubility is preferred, but that is not always possible. Water is the ideal solvent: it is inexpensive, it has no pharmacological activity of its own, it is widely available, and its characteristics are well known. 

As stated previously, it is desirable to be able to make a solution, preferably aqueous, during the drug discovery process. Medicinal chemists employ several techniques to accomplish this, among them preparing a prodrug, a complex, changing the crystalline state, and, most importantly for our discussion, preparation of salt forms.

Drug Absorption

Drug molecules may be active in only the undissociated state. Unfortunately, they are also LEAST soluble in the unionized or undissociated form. So the dilemma for the chemist is to synthesize a salt form of the compound that is water soluble, but that will not negatively impact the other characteristics of the compound. 

Another consideration is the absorption of the drug from the gastrointestinal tract, assuming oral administration. The drug must get from the lumen or cavity of the gastrointestinal tract to the circulation on the other side. Membranes of the GI tract are lipoidal or fatty in nature, as is the membrane surrounding the brain. Unionized molecules cross these lipoidal membranes much more rapidly than the ionized species. In fact, without another transport mechanism such as a pump or enzyme transport system, ionized substances don’t cross these membranes at all!  (Go here to see why the phrase "Never say never" applies!)

Schematically, this is the problem we face:
 

Drug in Gastrointestinal Lumen
Degree of Ionization is dependent on pH, which varies with location 
along GI tract
Unionized (more lipophilic) drug crosses membrane of GI into bloodstream
Drug in Blood
Degree of Ionization is dependent on pH which is 7.4 in normal, healthy humans
Unionized (more lipophilic) drug crosses the blood brain barrier
Drug in Central Nervous System, the site of action for phenobarbital

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College of Science and Mathematics
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email
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email hayden@islc.net

Prof. Sally Boudinot
College of Pharmacy
University of Georgia
Athens, GA
sallyb@rx.uga.edu