FACTORS AFFECTING PRODUCT STABILITY

Each ingredient, whether therapeutically active or pharmaceutically necessary, can affect the stability of drug substances and dosage forms. The primary environmental factors that can reduce stability include exposure to adverse temperatures, light, humidity, oxygen, and carbon dioxide.

The major dosage form factors that influence drug stability include particle size (especially in emulsions and suspensions), pH, solvent system composition (i.e., percentage of “free” water and overall polarity), compatibility of anions and cations, solution ionic strength, primary container, specific chemical additives, and molecular binding and diffusion of drugs and excipients. In dosage forms, the following reactions usually cause loss of active drug content, and they usually do not provide obvious visual or olfactory evidence of their occurrence.

Hydrolysis— Esters and beta -lactams are the chemical bonds that are most likely to hydrolyze in the presence of water.
For example, the acetyl ester in aspirin is hydrolyzed to acetic acid and salicylic acid in the presence of moisture, but in a dry environment the hydrolysis of aspirin is negligible. The aspirin hydrolysis rate increases in direct proportion to the water vapor pressure in an environment.

The amide bond also hydrolyzes, though generally at a slower rate than comparable esters.
For example, procaine (an ester) will hydrolyze upon autoclaving, but procainamide will not. The amide or peptide bond in peptides and proteins varies in the lability to hydrolysis.

The lactam and azomethine (or imine) bonds in benzodiazepines are also labile to hydrolysis. The major chemical accelerators or catalysts of hydrolysis are adverse pH and specific chemicals (e.g., dextrose and copper in the case of ampicillin hydrolysis).

Epimerization— Members of the tetracycline family are most likely to incur epimerization. This reaction occurs rapidly when the dissolved drug is exposed to a pH of an intermediate range (higher than 3), and it results in the steric rearrangement of the dimethylamino group. The epimer of tetracycline, epitetracycline, has little or no antibacterial activity.

Decarboxylation— Some dissolved carboxylic acids, such as p-aminosalicylic acid, lose carbon dioxide from the carboxyl group when heated. The resulting product has reduced pharmacological
potency.

Beta-Keto decarboxylation can occur in some solid antibiotics that have a carbonyl group on the Beta – carbon of a carboxylic acid or a carboxylate anion. Such decarboxylations will occur in the following antibiotics: carbenicillin sodium, carbenicillin free acid, ticarcillin sodium, and ticarcillin free acid.

Dehydration— Acid-catalyzed dehydration of tetracycline forms epianhydrotetracycline, a product that both lacks antibacterial activity and causes toxicity.

Oxidation— The molecular structures most likely to oxidize are those with a hydroxyl group directly bonded to an aromatic ring (e.g., phenol derivatives such as catecholamines and morphine), conjugated dienes (e.g., vitamin A and unsaturated free fatty acids), heterocyclic aromatic rings, nitroso and nitrite derivatives, and aldehydes (e.g., flavorings).

Products of oxidation usually lack therapeutic activity. Visual identification of oxidation, for example, the change from colorless epinephrine to its amber colored products, may not be visible in some dilutions or to some eyes.

Oxidation is catalyzed by pH values that are higher than optimum, polyvalent heavy metal ions (e.g., copper and iron), and exposure to oxygen and UV illumination. The latter two causes of oxidation justify the use of antioxidant chemicals, nitrogen atmospheres during ampul and vial filling, opaque external packaging, and transparent amber glass or plastic containers.

Photochemical Decomposition— Exposure to, primarily, UV illumination may cause oxidation (photo-oxidation) and scission (photolysis) of covalent bonds. Nifedipine, nitroprusside, riboflavin, and phenothiazines are very labile to photo-oxidation. In susceptible compounds, photochemical energy creates free radical intermediates, which can perpetuate chain reactions.

Ionic Strength— The effect of the total concentration of dissolved electrolytes on the rate of hydrolysis reactions results from the influence of ionic strength on interionic attraction. In general, the hydrolysis rate constant is inversely proportional to the ionic strength with oppositely charged ions (e.g., drug cation and excipient anions) and directly proportional to the ionic strength with ions of like charge. A reaction that produces an ion of opposite charge to the original drug ion because of the increasing ionic strength, can increase the drug hydrolysis rate as the reaction proceeds.

High ionic strength of inorganic salts can also reduce the solubility of some other drugs.

pH Effect— The degradation of many drugs in solution accelerates or decelerates exponentially as the pH is decreased or increased over a specific range of pH values. Improper pH ranks with exposure to elevated temperature as a factor most likely to cause a clinically significant loss of drug, resulting from hydrolysis and oxidation reactions. A drug solution or suspension, for example, may be stable for days, weeks, or even years in its original formulation, but when mixed with another liquid that changes the pH, it degrades in minutes or days. It is possible that a pH change of only 1 unit (e.g., from 4 to 3 or 8 to 9) could decrease drug stability by a factor of 10 or greater.

A pH buffer system, which is usually a weak acid or base and its salt, is a common excipient used in liquid preparations to maintain the pH in a range that minimizes the drug degradation rate. The pH of drug solutions may also be either buffered or adjusted to achieve drug solubility.

For example, pH in relation to pKa controls the fractions of the usually more soluble ionized and less soluble nonionized species of weak organic electrolytes.

The influence of pH on the physical stability of two phase systems, especially emulsions, is also important. For example, intravenous fat emulsion is destabilized by acidic pH.

Interionic (IonN + – IonN –) Compatibility — The compatibility or solubility of oppositely charged ions depends mainly on the number of charges per ion and the molecular size of the ions. In general,polyvalent ions of opposite charge are more likely to be incompatible. Thus, an incompatibility is likely to occur upon the addition of a large ion with a charge opposite to that of the drug.

Solid State Stability— Solid state reactions are relatively slow; thus, stability of drugs in the solid state is rarely a dispensing concern. The degradation rate of dry solids is usually characterized by first-order kinetics or a sigmoid curve. Therefore, solid drugs with lower melting point temperatures should not be combined with other chemicals that would form a eutectic mixture.

When moisture is present, the solid drug decomposition may change to zero-order chemical kinetics because the rate is controlled by the relatively small fraction of the drug that exists in a saturated solution, which is located (usually imperceptibly) at the surface or in the bulk of the solid drug product.

Temperature— In general, the rate of a chemical reaction increases exponentially for each 10 increase in temperature. This relationship has been observed for nearly all drug hydrolysis and some drug oxidation reactions. The actual factor of rate increase depends on the activation energy of the particular reaction. The activation energy is a function of the specific reactive bond and the drug formulation (e.g., solvent, pH, additives). As an example, consider a hydrolyzable drug that is exposed to a 20  increase in temperature, such as that from cold to controlled room temperature.

The shelf life of the drug at controlled room temperature should be expected to decrease to one-fourth to one-twenty-fifth of its shelf life under refrigeration.

Reproduced from : USP 30–NF 25

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