1. Drug incompatibilites

2. Common incompatibilities
Physical incompatibility
Chemical incompatibility
Therapeutic incompatibility

3. Physical incompatibility
Describes preventable or reversible precipitation or insolubility.
The main chemical causes of visibly observable precipitation, such as crystals, haziness, or turbidity, in mixed and diluted drug solutions are summarized in the following six subsections.

4. Manifestations of physical incompatibility
Insolubility of prescribed agent in vehicle
Immiscibility of two or more liquids
Liquification of solids mixed in a dry state (called eutexia)

5. Acid-Base reactions
More than 90% of drugs are organic and weak electrolytes (weak acids or weak bases).
Acid-base reactions are the most common causes of drug incompatibility as precipitation of nonionized drug forms.
The ratio or percentages of ionized and nonionized forms of weak electrolytes depend on the solution's pH and drug pKa values via the Henderson-Hasselbalch equation.

6. Insoluble concentrations of nonionized drug forms may occur in clinical preparations when:
Organic anions and organic cations (i.e., opposite salts) are combined.
Diluting organic drug salt solutions such that resulting pH values generate more nonionized forms than were present in the original drug solutions.
Mixing organic drug ions that have the same charge, such as sodium salts of different drugs or hydrochloride salts of different drugs, where there is more than 1 unit of difference in drug pKa and solution pH values. In such cases, the drugs act as an acid and base relative to each other.

7. incompatible combinations are formed when hydrochloride drug salts are mixed with each other and likewise sodium drug salts.
Non-dissociated salts of organic ions precipitate when oppositely charged, organic drug ions that contain aromatic rings are combined in relatively strong concentrations.

8. Salting out
Salting out results when highly hydrated inorganic ions (e.g., Cl-, K+, Na+) deprive organic ions and molecules of adequate water molecules to remain dissolved.
An example of salting out would be the immediate release of carbon dioxide gas from carbonated beverages when sodium chloride is added.
The weaker induced dipole-dipole forces between carbon dioxide and water are displaced by stronger sodium-water and chloride-water ion-dipole forces.

9. Desolvation of Nonionized Organic Drugs
Precipitation on dilution in aqueous i.v. fluids is common with nonionized drugs, such as diazepam and lorazepam, formulated as injections with ≥40% by volume of alcohols (e.g., alcohol, ethanol, glycerin, polyethylene glycols, propylene glycol).
When such injections are diluted in aqueous solutions (e.g., 5% dextrose solution and 0.9% sodium chloride), the intermolecular hydrogen bonding of the water-alcohol deprives the drugs of weaker van der Waals forces by which the alcohols solubilize the drugs.

10. Precipitation is also possible when injections formulated as colloidal solutions with surfactant micelles (and alcohols), such as etoposide, are improperly diluted for i.v. infusion. Extensive dilution results in the loss of drug-solubilizing micelles when the surfactant concentration falls below its critical micelle concentration.

11. Organic Ion-inorganic Ion Salts
When ceftriaxon (a divalent organic anion) is mixed with calcium (divalent inorganic cation salt).
The approved generic name, ceftriaxone sodium, is actually a disodium salt formed from two structurally different acid groups with pKa values of 3 and 4.
WHY?
calcium salts of divalent organic acids are less soluble than the sodium salts. For example, calcium succinate and tartrate are slightly soluble, but the sodium salts of those carboxylic acids are freely soluble, or 100 times more soluble than the calcium salts.

12. Chemical incompatibilites
Oxidation
Hydrolysis
Polymerization
Isomerization
Decarboxylation
Absorption of CO2
Combination
Formation of insoluble complexes

13. Oxidation-loss of electrons or gain of oxygen
Factors leading to oxidation:
Presence of oxygen
Light- triggers photo-chemical reactions
Temperature- elevated temperature accelerate oxidation reaction pH
Type of dosage form- oxidation reaction occur in solutions faster than in solid

14. Presence of pre-oxidants as metals and peroxides
Type of solvent used- oxidation reaction occur faster in aqueous solution than others.
Presence of unsaturated bonds- double and triple bonds in unsaturated fatty acids (oils) undergo oxidation easily than the oils containing saturated bonds (margarine)

15. Protection of drugs from oxidation
Addition of Antioxidants: Vitamin E, vitamin C and inorganic sulfur compounds such as thiosulfate and polysulfide
Addition of chemicals which form complexes with metals i.e. EDTA, Benzalkonium chloride
Protection from light by using a dark container and storing drug formulations in dark places
Packaging with substances which absorbed light i.e. Oxybenzene

16. Choice of suitable pharmaceutical dosage forms which reduce the possibility of oxidation, like solid dosage forms versus solutions
Maintenance of pH using buffered solutions
Choice of suitable solvent (rather than water)
Storage at low temperature
Protection from air by:
a. using good closed containers
b. Replacement of oxygen by nitrogen

17. Chemical groups subjected to oxidation
Phenolic compounds: Phenylephrine
Catechol derivatives: Adrenaline and noradrenaline
Some antibiotics: Tetracyclines
Oils (fixed and volatile)
Vitamins (lipid and water soluble)

18. How to detect oxidation
Change of color, odor, viscosity of the formulation.
For fixed and volatile oils: rancidity change of color, taste, odor, and viscosity.