pH and Solubility, Stability, and Absorption, Part II
pH and Drug Stability
pH is one of the most important factors affecting the stability of a product. Stability is the extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e., its shelf-life) the same properties and characteristics that it possessed at the time of its manufacture or compounding.
Factors altering stability can include temperature, light, humidity, radiation, air, particle size, solvents, pH, and the presence of other chemicals resulting from contamination or from the intentional mixing of different products.
Stability is associated with chemical kinetics or is describable by some equation system which resembles those encountered in chemical kinetics, especially solution kinetics. Mostly involved are solution dosage forms, especially oral, parenteral, nasal, ophthalmic, and otic solutions. Generally, the parenteral and ophthalmic solutions are chemically simpler than the others and often times are dilute systems. When a drug product is placed in a compounded preparation, such as an intravenous admixture, the overall pH may be altered to be within the range for faster degradation.
Drug degradation often occurs by hydrolysis that can be dependent on the pH of the medium. It is customary to develop "pH-Rate profiles" for drugs to determine the pH at which they are most susceptible to degradation and then formulate at a different pH along with the use of buffers to minimize degradation. The pharmacist can use published pH/stability profiles to determine the pH that will ensure the maximum stability of the preparation. After determining the pH range, the pharmacist can prepare buffers to maintain the pH for the expected shelf life of the preparation. We will not get into the orders of reactions at this point.
Appearance of decomposition products and disappearance of the drug are detected by stability-indicating assay methods. When a drug hydrolyzes in aqueous solution, the reaction may be catalyzed by various ionic species or it may be noncatalytic. The rate of a reaction is (or may be) a function of the acidity of the medium in which it occurs.
pH profiles are important and can lead to the establishment of the best buffer to use in the formulation and/or the optimal pH range to obtain for the final preparation. The stability of solutions should include the study of pH changes, especially when the active ingredients are soluble salts of insoluble acids or bases. The rate of hydrolysis of an ester or amide linkage prone to hydrolysis depends on the temperature and the pH of solution. The pH-rate profile is a plot of the degradation rates vs pH values and is used for visual comparisons.
To develop a pH-Rate profile, it is important to develop stability-indicating assays for the intact drug at the various pH values to be studied. Buffer solutions are prepared at the different pH values to be studied. A known concentration of the active drug in the various pH buffers is prepared and initial samples are taken, followed by samples at defined time periods that are then analyzed.
The results of the studies provide degradation plots of a drug with time vs concentration, and the slope of the line will be negative. A composite illustration of the photodegradation of ciprofloxacin at various pH values is shown in Figure 1.
The degradation rate constants are calculated for each pH value. Then, the degradation rate constants are plotted vs pH to provide a log K:pH profile, examples of which are shown in Figures 2 (aspirin), 3 (codeine sulfate), 4 (5-Fluorouracil), 5 ( methotrexate), 6 (thiamine HCl), and 7 (hydrochlorothiazide). To interpret these, the minimum points on the graphs are the areas of best stability, for example, a pH between about 2 and 3 is the most stable for aspirin and as the pH goes above pH 8 the hydrolysis is more rapid and the drug is less stable.
|Figure 2: Aspirin
|| Figure 3: Codeine sulfate
|Figure 4: Fluorouracil
||Figure 5: Methotrexate
|Figure 6: Thiamine HCl
|| Figure 7: Hydrochlorothiazide
Another method of plotting data is to plot the "amount decomposed" vs "time" as shown in Figure 8, and the plot with the lowest slope of the line will be the most stable.
It is the responsibility of the pharmacist to ensure that the preparations under his/her supervision meet acceptable criteria of stability. Stability of a pharmaceutical must be known to ensure that the patient receives the prescribed dose of a drug and not a therapeutically inactive degradation product, and pH can significantly alter the stability of a drug formulation.
Loyd V. Allen, Jr., Ph.D., R.Ph.