- Salt Expansion strategy/program is vital for drug and drug-product development

- The following factors are critical in determining salt-selection......
    - Solubility
    - Physical and chemical stability
    - Safety (of the fragment)
    - Polymorphism
    - Industrial Processing
    - Extension of patent (protection)
   

- If a drug doesn't have a salt form, it's in "neutral form"
- Parent (neutral) drug form is the most marketed
- Sulfate salt is EXTREMELY hydrophilic (clogP=-1.58)
- You can increase solubility by associating water soluble fragment with the drug, to increase solubility
- "clogP" is an indication of lipophilicty.  The higher the number, the more lipophilic it is.
- Different Salt forms have different lipophilicities.
- Greater lipophilicity will give you greater bioavailability.
- Drugs which contain acidic groups combined in base yield a salt form.

- Dealing with a drug that is difficult ot handle or a drug that is hydrophilic, will have problems with diffusion

- Prodrug strategy/program is vital for drug and drug-product development.

- Prodrug is an inactive, bioreversible derivative of an active agent.   

1.  Take original active drug and make it inactive (prodrug)

2.  In the body it is activated by enzymes or chemicals when injected.
3.  When in vivo, prodrug will become drug at target tissue and become activated very fast. 

4.  In non-target tissue, there will be fast elimination of pro-drug plus fast elimination of drug 

- Improve transport across biological membranes

- Site-specific targeting and elivery

- Minimize toxicity

- Prevent undesirable metabolism

- Increase solubility and stability

- Prolong (sustain) release

- Facilitate formulation (eg., of a liquid to a solid drug)

- Encourage patient acceptance 

- Improve clinical utility of drugs

- Improve efficiency of drug discovery

- Increase length of action, so less of a chance patient will forget to take drug

- Many of today's drugs are actually pro-drugs!

- Functional groups change when it transforms from a pro-drug! ("Masking of final good") 

                   A x t             h

- Complexation results in the formation of a complex between a ligand and a substrate

- Upon complexation, the physico-chemical properties of both the ligand the substrate are altered (eg., solubility, stability). 

- Theophylline complexation with ethylenediamine forms aminophylline which posesses high solubility; - Inclusion complexes of labile drugs with cylcodextrins can enhance drug-stability in solution, and also against heat, moisture, light, oxidation

- complexation can be used to convert liquid drugs into powder-form; and the masking of unpleasant taste or odor of drugs.   

- Ion-exchange Resins are complexes 

- Other important pharmaceutical uses of cyclodextrins are in enhancing partitioning, absorption and hence, in imporoving bioavailability.  In addition, cyclodextrin complexation of indomethacin ahs been found to reduce GI-toxicity of the drug. 

- Can also affect drug distribution and pharmacokinetics in vivo, eg., protein binding of drugs.  Complexation of drugs with cyclodextrins can enhance excretion (by keeping drugs in-solution and facilitating renal excretion especially, for anticancer agents!).  This can be the case with other hydrophobic drugs, as well. 

- Complexation can also help to optimize drug-delivery from ion-exchange resins

- Many anti-cancer agents are toxic to kidneys; you can add cyclodextrins to decrease this toxicity. 

- Type of complexation which is based upon elecrostatic interactions between the surface-bound ions on a solid particle (or resin) and the oppositely-charged ions in an aqueous solution.  The electrostatic intereactions are controlled by pH and ionic strength of the solution and the nature of the resin.  

- *Treat them like salt forms 

- Principle ion exchange in a drug delivery system.  

- Cation exchangers such as "poly(styrene sulfonate) will complex with positively charged drug (D+) and release by exchanging with a cation (H⁺, Na⁺, K⁺) in the gastrointestinal fluid 

- Principle of ion exchange in drug delivery systems

- Anion exchangers complex with negatively charged (D-) drugs and released by exchanging with anions. 

- Assume resin is negatively charged; then it is surrounded by cationic (+) counter ions.    

- Cationic Drug, not yet associated with Resin, is associated with an anionic ion.

- Next, the drug effectively displaces the cationic counterions on the resin, making Resinate.    

- From GI, HCl can now displace the drug

- Drug is now bioavailable (free to go wherever) 

- Resin material is ready for excretion.

- Ion-exchange resins are used for controlled drug delivery

- Ex., Dextromethorphan-resin complex is encapsulated in a water-insoluble polymer (ethylcellulose) coating for a 12 hour sustained, controlled release oral suspension formula.

- Enhancement of disintegration and dissolution of tablets

- Masks taste

- Ion exchange resins also used in chromatography

- In drug-delivery, the drug-resin complex is prepared by exposing the resin to the drug until saturation of all available ion-exchange sites on the resin (complex is washed, dried, made into dosage form).