Introduction to Drug Stability
Stability studies ensure the maintenance of drug/product quality, safety, and efficacy throughout the shelf life.
Stability studies are considered a prerequisite for the acceptance and approval of any pharmaceutical product.
Stability testing is a routine procedure performed on drug substances and products.
Stability studies are employed at various stages of product development.
Stability of a Pharmaceutical Product
“The capability of a particular formulation, in a specific container/closure system, to remain within its physical, chemical, microbiological, therapeutic, and toxicological specifications.”
Stability of a Drug
“The time from the date of manufacture and packaging of the formulation until its chemical or biological activity is NLT a predetermined level of labeled potency and its physical characteristics have not changed appreciably or deleteriously.”
Objectives of Drug Stability
- To determine maximum expiration date/ shelf life.
- To provide better storage conditions.
- To determine the packaging components.
- To gather information during pre-formulation stage to produce a stable product.
Reasons Behind Stability Study
- There may be chemical degradation of the active drug, leading to substantial lowering of the quantity of the therapeutic agent in the dosage form.
- Chemical degradation of the active drug may not be extensive, a toxic product may be formed in the decomposition process.
- The instability of drug products can lead to a decrease in its bioavailability rather than loss of drug or formation of toxic degradation products.
- There may be substantial changes in the physical appearance of the dosage form.
- While the drug substance itself may retain its potency, excipients such as antimicrobial preservatives, solubilizers, emulsifying or suspending agents may degrade, compromising the integrity of the product.
Advantages of Stability Studies
- The stability studies are essential for well being of the patient suffering from the disease for which the product is designed.
- Stability studies assure the identity, potency, and purity of ingredients, as well as those of formulated products.
- Accelerated stability studies are performed to find out the rate of degradation of the product is stored for a longer period under specific conditions.
- A forced degradation study is carried out to check the effect of stressed external conditions on the drug product.
- A stability study is to provide evidence to establish shelf life for the drug and recommended storage conditions.
- Stability studies are used to find out degradation pathways (physical, chemical, or microbiological).
Expiry Date or Shelf Life of Drug Product
Definition: “Drug can not be used after this date because the concentration of a drug is decreased and become lower than therapeutic concentration. In addition, some products of drug degradation are toxic and harmful to patients.”
The International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use guidance document Q1A(R2) (ICH Q1A) defines shelf life as, “The time period during which a drug product is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.”
- An expiration date, which is expressed traditionally in terms of month and year, denotes the last day of the month.
- The expiration date should appear on the immediate container and the outer retail package.
- However, when single-dose containers are packaged in individual cartons, the expiration date may be placed on the individual carton instead of the immediate product container.
- If a dry product is to be reconstituted at the time of dispensing, expiration dates are assigned to both the dry mixture and the reconstituted product.
- Tamper-resistant packaging is used where applicable.
- Shelf life is typically expressed in units of months, i.e. 24 months, 36 months, to a maximum of 60 months.
- The phrase “shelf life” and “expiry date” is often interchangeably used in the industry, as both terms reflect the same concept: there is a period of time where a product is stable and safe for use but is made limited based on thorough stability research.
- Shelf life/expiry dates reflect the time when a product will work both safely and effectively.
- This is why “shelf-life testing” is also referred to as “stability testing”.
- The amount of time a product can stay stable under certain environmental conditions equates to its shelf life.
- After the opening of the drug container, the expiry date will be shorter as a result of the decreased concentration of the drug during usage and the effects of external factors.
- Shelf-life is also defined as the time required for the concentration of the reactant to reduce to 90% of its initial concentration. Represented as t90 and the units of time /conc.
- The time from the date of manufacture and packaging of the formulation until its chemical or therapeutic activity is maintained to a predetermined level of labeled potency and, its physical characteristic has not changed appreciably or deleteriously.
Factors Affecting Drug Stability:
The primary factors affecting drug stability-
pH, Temperature, Moisture, Humidity, Light, Storage Containers & Closures and Oxygen
The major factors affecting drug stability are-
Particle size (suspension and emulsion), pH, additives and molecular binding, and diffusion of drugs and excipients.
Effect of Temperature
High temperature accelerates oxidation, reduction, and hydrolysis reaction which lead to drug degradation.
Effect of pH
Acidic and alkaline pH influences the rate of decomposition of most drugs. Many drugs are stable between pH 4 and 8.
Weekly acidic and basic drugs show good solubility when they are ionized and they also decompose faster when they are ionized.
So if the pH of a drug solution has to be adjusted to improve solubility and the resultant pH leads to instability then a way out of this tricky problem is to introduce a water-miscible solvent into the product.
It will increase stability by:
- suppressing ionization
- reducing the extreme pH required to achieve solubility
- enhancing solubility and reducing the water activity by reducing the polarity of the solvent.
For example, 20% propylene glycol is placed in chlordiazepoxide injection for this purpose.
Some buffers such as acetate, citrate, lactate, phosphate, and ascorbate buffers are utilized to prevent drastic changes in pH.
As little as 1 pH unit change in pH can cause a change of tenfold in the rate constant.
So when we are formulating a drug into a solution we should carefully prepare a pH–decomposition profile and then formulate the solution at a pH that is acceptable physiologically and stability-wise also.
Effect of Moisture
Water catalyzes chemical reactions such as oxidation, hydrolysis, and reduction reaction.
Water promotes microbial growth.
The presence of moisture influences chemical stability, crystal structure, powder flow, compaction lubricity, dissolution rate, and polymer film permeability in solid dosage forms and lead to the growth of microorganisms, change in thixotropy in semi-solid dosage forms.
Moreover, unit operations obviously depending on the amount and state of water present is also influenced by it.
Therefore, moisture influences the properties of individual active ingredients and excipients, and it is essential to characterize the effect of moisture on these individual components.
Also Read: Importance of Rabbit & LAL Pyrogen Test
Effect of Light
Exposure to light causes substantial degradation of the drug molecules. When molecules are exposed to electromagnetic radiation they absorb light (photons) at a characteristic wavelength which cause an increase in energy which can:
A. Cause decomposition
B. Retained or transferred
C. Be converted to heat
D. Result in light emission at a new wavelength (fluorescence, phosphorescence)
Natural sunlight lies in the wavelength range (290-780nm) of which only the higher energy (UV) range (290-320) causes photodegradation of drugs.
Example of phototoxic drugs:
Furosemide, Acetazolamide, Cynocobalamine.
Sodium Nitroprusside in aqueous solution (which is administered by IV infusion for management of acute hypertension).
If protected from the light it is stable to at least 1yr.
If exposed to normal room light it has a shelf life of 4 hrs.
Use of amber-colored bottles.
Storing the product in dark, packaging in cartons also acts as a physical barrier to light.
Coating of tablets with polymer films.