Why pH of Pharmaceutical Solutions Changes by Holding Time?
1. Degradative effects of Active Pharmaceutical ingredients which may be:
- hydrolysis (in water vehicle formulations).
- oxidation (usually using of anti-oxidants covers this).
- decarboxylation
- racemization
e.g. Epinephrine in solution undergoes racemization and oxidation, but if the pH is maintained at 3.0 or lower, little reaction occurs.
Atropine sulfate rapidly hydrolyzes in solution, but if the pH is maintained with a buffer system at about 3.5 to 4.0 ,hydrolysis does not occur at a significant rate.
2. Change in solubility & degree of ionization of API in the vehicle of liquid dosage form:
If the pH of a solution of either a weakly acidic drug or a salt of such a drug is reduced, then the proportion of unionized acid molecules in the solution increases.
- Precipitation may occur, therefore, because the solubility of the unionized species is LESS than that of the ionized form.
- Conversely, in the case of solutions of weakly basic drugs or their salts, precipitation is favored by an increase in pH.
- Such precipitation is an example of one type of chemical incompatibility that may be encountered in the formulation of liquid dosage forms.
- This relationship between pH and solubility of ionized solutes is extremely important with respect to the IONIZATION of weakly acidic and basic drugs as they pass through the gastrointestinal tract and can experience pH changes between about 1 and 8.
- This will affect the DEGREE OF IONIZATION of the drug molecules which in turn influences their solubility and their ability to be absorbed.
- Using of buffers & stabilizers to overwhelm that.
3. Temperature
- is mainly effects the solubility & ionization of API makes we go back to factor <2> (Narnest equation).
- can cause changes in a chemical system, affecting its equilibrium state and pH level.
An increase in temperature causes the system’s equilibrium to shift, absorbing the excess heat and leading to the formation of H+ ions, which results in a decrease in the solution’s pH.
So the probable effect of temperature is greatest for highly basic solutions.
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