Stress studies in Drugs

Chemical stability of pharmaceutical molecules is most important as it has impact on the safety and efficacy of the drug products.

Stress testing or forced degradation is an analytical tool to study  the behaviour of the products as well as to understand the resolving power of  the analytical method used.

Stress testing reveals the quality of  pharmaceutical products exposed over the time period as well as different environmental conditions viz.,  heat, hydrolysis, oxidation, photolytic etc.

ICH guideline defines stress testing as:
Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.

Stress studies provides more valuable information about the degradation impurities, called as degradants, which are likely to form during the shelf life of the product lifecycle in a very short period compared to formal stability studies.

Since these likely degradants may be toxic at above certain level in the drug, pharmaceutical scientists are keen to identify these impurities and use this information as a tool to control in the process of drug development.

These studies reveals the chemical behavior of the molecule which in turn helps in the development of formulation and  suitable  packages.

However, it  may not be necessary to examine specifically for certain degradation products if it has been
demonstrated that they are not formed under accelerated or long-term stability storage conditions.

Sometimes over stressing the products may produce secondary degradants which may not likely to form in real-time stability studies. Similarly milder conditions may not produce degradants and leads to  wrong conclusion that the product is most  stable. In such cases, exposing the drugs for longer duration as well as usage of higher concentration will provide more information.

Hence the purpose of forced degradation is to get  meaningful degradation, about 5 to 20%.

Hence these studies are useful in establishing degradation pathways of drugs  and  are useful in developing and validating suitable analytical procedures. These analytical methods are therefore called as stability indicating methods and usage of such methods are highly recommended by regulatory agencies in pharmaceutical stability studies analysis.

In general, stress testing is likely to be carried out on a single batch of the drug substance. The various conditions used for forced degradation are

1. Thermal degradation

The effect of temperature is studied by heating the product above the accelerated temperature in 10°C increments (e.g., 50°C, 60°C, etc.)

Information on rate of degradation and primary and secondary
degradation products can be well understood by generating results from multiple time points like 1 hour, 3 hours and 5 hours samples etc .

The effect of temperature on drug product  is studied through the Arrhenius equation:

k = Ae-EaRT

where k is reaction rate, A is frequency factor, Ea is energy of activation, R is gas constant (1.987 cal/deg mole) and T is absolute temperature

2. Hydrolysis


Hydrolysis is the  study of chemical reaction over a wide range of pH. Hydrolytic study under acidic and basic condition involves catalysis of ionizable functional groups present in the molecule.

Hydrolysis of drug products is achieved by exposing the sample at different pH viz., pH 2 to pH 12 by  treating with suitable acid or base.   The effect of degradation of drug is then  studied. The most  commonly used acid is hydrochloric acid and in some cases sulphuric acid is used. Similarly base like NaOH or KOH can be  used. 

Depends upon the nature of product, the rate of degradation can be varied by altering the  strength of acid or base  used (0.1 N , 1 N , 2 N etc).
Similarly incase the degradation rate is poor, it can be accelerated by heating or refluxing the solution for few hours.
Always remember one should analyse these acid or base treated samples in instruments like HPLC after neutralising with suitable base or acid   to preserve the life of theanalytical column.

3. Oxidation

The oxiding power of the drug  is studied by exposing the product with varying oxiding agents like Hydrogen peroxide, azobisisobutyronitrile, metal ions etc.

In order to achieve better degradation, different concentration of oxidising agents as well as duration of exposure time can be varied. 

The oxidation  of drug involves an electron transfer to form reactive
anions and cations. The drugs containing functional groups of sulfides and phenols are more susceptible to electron transfer and  form likely degradation impurities like  N-oxides, hydroxylamine,
sulfones and sulfoxide. The drugs with functional groups of benzylic carbon, allylic carbon and tertiary carbon are susceptible to oxidation to form hydro peroxides, hydroxides etc.

4. Photo stability

The intention of this study is to understand the behaviour of drug under the influence of light and it's impact.

Light stress conditions can induce photo oxidation by free radical mechanism.

It provides useful information about the sensitivity of the drug towards light and helps to select appropriate packing conditions for stable  drug products.
ICH recommends to study
photostability of products with a  light exposure  of 1.2 million lux hours and 200 Watt hours/meter2 .

Photolytic degradation is effective when  the exposed  light is capable of producing an intensity with a wavelength range of 300– 800 nm  Incase of no degradation, we can extend upto 6 million lux hours.

Drug products with functional groups viz., carbonyls,  N-oxide, alkenes, aryl chlorides, weak C–H and O–H bonds, sulfides, polyenes are likely to introduce drug photosensitivity.

Hence meaningful stress studies provide to help
1. To establish degradation pathways
2. To determine the intrinsic stability
3. Structural identification of degradants
4. To understand the chemical properties of drug molecules.
5. To reveal the degradation mechanisms 
6. To establish stability indicating nature of a developed method.
7. To generate more stable formulations.
8. To solve stability-related problems

Comments

Post a Comment

Popular posts from this blog

Analytical Quality by Design (AQbD)

The concept of quality by design (QbD) in pharmaceutical industry has been introduced to enhance robust manufacturing process and to facilitate product quality. Quality is built in the product and process by design and scientific approach. As the number of  out-of-trend (OOT) results, out-of-specification (OOS) results are increasing in pharmaceutical industry and the current quality system is unable to address the growing concern,  a strategy to make a robust manufacturing process is felt and a cocept if QbD has emerged. FDA has implemented the QbD concept first in drug formulation manufacturing processes as the finished drug products are directly consumed by the patients and any variation in the quality will adversaly affect the safety of the patients. Similar to robust product development, an equally important analytical methods employed to test the quality of product must be robust and capable of producing accurate results.  The benefits of implementing AQbD are 1.con...
Read more

Elemental Impurities

Elemental impurities are traces of metals carried from raw materials, residual catalysts, manufacturing equipments, process water, excipients, containers that can be observed in finished drug products.  These elemental impurities do not have any therapeutic effect  and is harmful to patients due to their toxicity beyond certain limit. The presence of trace elements were tested classically by using USP's Heavy metals test,  <231> , which uses as a colorimetry test by forming as a sulphide precepitate with elements. In the last decade, PDE (permitted daily exposure) of almost all elements are found which leads to monitor and  control the individual elements in the drugs by measuring their level by using modern instruments like ICP OES, ICP MS etc. ICH developed a  guideline specifically on Elemental impurities as Q3D and list the PDE values for each element. Based on PDE value and the route of administration ( orals, parenteral, nasal)  values are diffe...
Read more

Polymorph in Drugs

Image
Molecules exist in nature in any of the three states viz., solid. liquid and vapour. But most of the molecules, organic and inorganic , exist in solid states. It is very interesting that if these solid state molecules  have therapeutic benefits, they’re used as a drug substance.   In a solid state, the  molecules or the elements   exist as crystals  which are  oriented in a organised or disorganised ways. Hence multiple orientations are possible for a molecule. In a pharmaceutical drug, these different crystalline orientations are named as Polymorphs.  Polymorphism may be defined as the ability of a compound to crystallize in two or more crystalline phases with different arrangements and/or conformations of the molecules in the crystal lattice. Hence, polymorphs are different crystalline forms of the same pure chemical compound.  Since these crystalline forms are oriented differently, their free energies are also different which makes them as uniq...
Read more