Significance of Stability Studies on Degradation Product

Poonam Kushwaha

Faculty of Pharmacy, Integral University, Lucknow-226026 (India)

*Corresponding Author E-mail:


Drug degradation in formulations is a very complex and often unpredictable process. Degradation products arise during manufacture and storage of formulation. Common degradation products are derived from oxidation (by air, light, trace metal), hydrolysis, dehydration, adduct formation, dimerization, rearrangement, excipient reaction, and often the combination of these processes. For ensuring the stability of drug products over entire self life, various regulatory authorities requires, the stability data must be submitted with the NDA or ANDA. ICH and various other regulatory authorities have published guidelines on stability studies. Stress testing and stability indicating assays are also conducted to obtain stability data.


KEYWORDS: degradation product; degradation mechanism; stability studies; stress testing; stability indicating assay.



Degradation of the drug substance is one of the main sources of impurities in both bulk drug and formulated product. Degradation of the drug substance is caused by chemical instability of the drug substance under the conditions (e.g., heat, humidity, solvent, pH, light, etc.) of manufacturing, isolation, purification, drying, storage, transportation, and interactions with other chemical entities in the formulation (e.g., excipients and coating materials) [1].


The definition of degradation product in the ICH guideline is “a molecule resulting from a chemical change in the substance brought about by over time and/ or action of e.g.: light, temperature, PH or water by reaction with excipient and/or the immediate container closure system” [2].


Drug degradation in formulations is a very complex and often unpredictable process. Depending on the structure of a drug molecule, its degradation process could be influenced by the composition of the formulation, the process by which the formulation is prepared, and the storage conditions of the formulation including temperature, humidity, light, and containers. Common degradation products are derived from oxidation (by air, light, trace metal), hydrolysis, dehydration, adduct formation, dimerization, rearrangement, excipient reaction, and often the combination of these processes [3].  The job of the medicine is to give the therapeutic effect and so the most important thing is that the required drug content is available till the expiry date is over [4]. The researchers in charge of the formulation development do extensive studies to understand the mechanism of degradation and the rate of degradation.


It is imperative that the medicine that we are giving, is stable in its entirety from every angle throughout its shelf life period. Often for a new formulation many batches go into the market and a lot of time elapses before all angles of the stability of the product are understood [5].


The international conference on harmonizaton (ICH) of technical requirements for registration of pharmaceuticals for human use has published guidelines for reporting, identification and qualification of degradation product in new drug products (ICH Q3B) [6, 7].


The threshold for reporting, identification and qualification of degradants in new drugs are shown below [6, 7]:

Reporting Thresholds

Maximum Daily Dose 1


≤1 g


> 1 g



Identification Thresholds

Maximum Daily Dose1


< 1 mg

1.0% or 5 µg TDI, whichever is lower

1mg – 10mg

0.5% or 20 µg TDI, whichever is lower

>10 mg - 2 g

0.2% or 2 mg TDI, whichever is lower

> 2 g



Qualification Thresholds

Maximum Daily Dose 1


< 10 mg

1.0% or 50 µg TDI, whichever is lower

10 mg - 100 mg

0.5% or 200 µg TDI, whichever is lower

>100 mg - 2 g

0.2% or 3 mg TDI, whichever is lower

> 2 g


NOTE:  TDI – total daily intake

1-The amount of drug substance administered per day

2-Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic.

3- Higher thresholds should be scientifically justified.

Stability: Stability is the capacity of a drug product to remain within specifications established to ensure its identity, strength quality and purity. The stability of pharmaceutical ingredients and the products containing them depends on (a) the chemical and physical properties of the materials concerned (including the excipients and container systems used for formulated products) and (b) environmental factors such as temperature, humidity, and light and their effect on the substances in the product [8]. Stability data on the drug substance and the formulated product are required in connection with applications for marketing authorizations for pharmaceutical products containing new active substances, for products containing known active substance (including reformulations), for additional strengths or dosage forms, for new containers, and for amendments or variations to existing marketing authorizations, including new sources for active ingredients, extensions to the shelf life, and so on. At the time of marketing authorization application it should be kept in mind that there are also requirements for stability data generation in connection with other parts of the regulatory process [5, 8]. This includes data generation during the conduct of safety studies under good laboratory practice conditions (e.g., the stability of the drug in the medium being used for administration in animals and the stability of the radiolabel used in tracer studies), for clinical trial approvals in many countries (in which both the investigational product and any active comparator may need to be investigated for stability), as well as for preclinical and clinical studies (for which the stability of the analyte in biological specimens may need to be investigated in addition to the stability of the product under test). In addition, such studies may be needed to meet good manufacturing practice requirements (including the retention of reference samples and starting materials) after the product has been approved for marketing, to undertake stability studies on manufactured batches, and to meet the requirements of the rapid alert system with respect to products that have stability problems during distribution [9].

Any drug product must have three types of stability:


Physical stability: implies that the formulation is totally unchanged throughout it shelf life and has not suffered any changes by way of appearance, organoleptic properties, hardness, brittleness, particle size etc. The drug release nature (rate and mechanism) should not be altered. Different formulations suffer from different physical challenges and are tested for different stability criteria. Drug release is important from safety and efficacy angle and the physical stability of the formulation is significant because of its effect on pharmaceutical elegance and on drug content uniformity and drug release rate.


Physical changes include appearance, consistency, product uniformity, clarity of solution, absence of particulates, Color, odor or taste, hardness, friability, disintegration, dissolution, sedimentation and resuspendability, weight change, moisture content, particle shape and size, pH, package integrity.

Chemical stability:  implies the lack of any decomposition in the chemical moiety that is incorporated in the formulation as the drug. Chemicals present in the formulation as preservatives or as other excipients may also decompose and their decomposition may influence the physical and chemical stability of the drug. But to test for the chemical stability of a formulation we have to test for the drug content of the formulation.


Chemical changes include degradation product formation, loss of potency (active ingredient), loss of excipient (antimicrobial preservatives, antioxidants)


Microbiological stability:  implies that the formulation has not suffered from any microbiological attack and is meeting the standards with respect to lack of contamination/sterility which we have claimed when we kept the product on the shelf.

Microbial changes include proliferation of microorganisms in nonsterile products, maintenance of sterility, preservative efficacy changes [4, 5].


So it is absolutely essential that for all formulations all areas in which instability is likely to occur are understood and stability is tested for [5].


Mechanisms of Degradation:

The most common degradation mechanisms are hydrolysis, oxidation and photolysis. Other process include adduct formation with excipients, dimerization and rearrangement [14].



The molecules having ester or amide functional groups are most susceptible to hydrolysis. Anesthetics, antibiotics, vitamins and barbiturates are examples of drugs that decompose due to hydrolysis [11]. Hydrolysis of the drug substance is often followed by further degradation. Primary hydrolytic degradation products can further undergo dehydration, decarboxylation, cyclization, or rearrangement, etc., to form the final degradation products [1, 11].


Table 1    Functional groups susceptible to hydrolysis in drugs [1, 14 and 15]

Function group

Examples of drugs


Aspirin, cisatracurium besylate, nicergolin, lovastatin, alkaloids, Dexmethasone sodium phosphate, Estrone sulfate. Nitroglycerin


Lovastatin and warfarin


Acetaminophen, indinavir, and indomethacin


Amoxicillin, penicillin, cephalosporin, bromazepam , diazepam




Adinazolam, famotidine, diazepam,

Carbamic ester

Benzimidazole anthelmintics, zolmitriptan,



Rivastigmine, triamcinolone acetonid 21-phosphate


Diphenhydramine hydrochloride,






Erythromycin, ECyd acetal  derivatives, triamcinolone






Table 2 Functional groups susceptible to oxidative degradation in drugs [1, 11, 14 and 17]

Function groups

Examples of drugs


Tipranavir, methoxamine hydrochloride, impipramine hydrochloride.


Tetrazepam, Reserpine

Tertiary C











Pergolidemesylate, fluphenazine enanthate,  tipredane

Tertiary Amine

Pipamperone, dibucaine hydrochloride, raloxifene hydrochloride

Primary/secondary amine



Ester hydrolysis:

An ester can be thought of as being derived by reaction of an alcohol with a carboxylic acid, with the elimination of a molecule of water. The hydrolysis of an ester into a mixture of an acid and alcohol involves the rupture of a covalent bond between a carbon atom and oxygen atom. These reactions usually happen in the presence of water but happen much faster when either an acid or an alkali is present. Acids, alkalies and certain enzymes, which are capable of supplying the hydrogen or hydroxyl ions to the reaction mixture, catalyse this hydrolysis. The alkaline hydrolysis of an ester is irreversible and an acid hydrolysis is reversible [1, 14].


Amide hydrolysis:

Pharmaceutical compounds containing an amide group can undergo hydrolysis in a manner similar to that of an ester type compound instead of the acid and alcohal that form as a result of ester hydrolysis, hydrolytic cleavage of an amide result in the formation of an acid and an amine [11, 14]. Drugs such as niacinamide, phenethicillin, barbiturates, and chloramphenicol have been reported to degrade by amide hydrolysis [1].



Oxidation is the mot important pathway of drug decomposition. The oxidative decomposition of pharmaceutical compound is responsible for the instability of a considerable number of pharmaceutical preparations for example: steroids, vitamins, antibiotics and epinephrine undergo oxidative degradation [11]. These reactions are mediated either by free radical or by molecular oxygen. The most common form of oxidative decomposition occurring in pharmaceutical preparations is autoxidation [1].Common functional groups in drugs that are sensitive to oxidation and examples of drugs that contain these functional groups are summarized in Table 2.



When exposed to light, many types of organic molecules can undergo photochemical reactions and form photolytic degradation products. There are two main types of photochemical reactions that are relevant to degradations of drugs [1]. The first type is a non-oxidative photochemical reaction, which includes light induced isomerization, cyclization, dimerization, rearrangement, hydrolysis, decarboxylation, and homolytic cleavage of X-C hetero bonds, such as halogen bond, ether bond, N-alkyl bond in amine (dealkylation or deamination), SO2-C bond, etc. Other types of photochemical degradations of drugs, such as light induced hydrolysis of halogen, rearrangement, dealkylation, and cyclization were also reported. Photo-oxidative degradation is the other type of photolytic degradation of drugs. Photo-oxidative degradation products can be formed from either triplet oxygen (3O2) or a singlet oxygen (1O2) mechanism, depending on the electronic state of the oxygen molecule [1, 18 and 19].


Isomerization and Oligomerization:

Isomerization and oligomerization are common degradation pathways of drugs. Commonly seen isomerizations include photo-induced cis/trans isomerization of drugs with a C=C double bond, other asymmetric double bonds (e.g., C=N-OH and C=N-NH2) and racemization or epimerization of drug substance with chiral centers [1]. Drug molecules with chiral centers can undergo racemization and epimerization under light, heat, acidic, and basic conditions. Rearrangement is also a source of isomeric impurities [11]. Other types of dimerization or oligomerization can also occur. For example, thiols can dimerize under oxidative conditions to form disulfides; indoles can dimerize under acidic conditions; nalidixic acid dimerizes through a thermo-decarboxylation pathway, and losartan dimerization is induced by moisture and acid. It was reported that formaldehyde, which is a potential impurity in some excipients (e.g., PEG and PVP), can react with primary or secondary amine drug substance to form a cross-linked dimer with an addition of CH2 group in between the highly electrophilic carbonyl carbon of b-lactam antibiotics (e.g., ampicillin and ceftazidime) can readily oligomerize in drug formulations [1].


Reasons for stability studies:

The main purpose of conducting stability testing of pharmaceutical products is:

·        To ensure the efficacy, safety and quality of active drug substance and dosages forms.

·        To establish self-life or expiration period.

·        To support label claim [20]


Stability data are produced to establish the storage conditions and retest interval of the active ingredient and the storage conditions and shelf life for the manufactured products. Part of the information can also be used to justify overages included in products for stability reasons. In its recently adopted stability guidelines, the Committee for Proprietary Medicinal Products (CPMP) indicates that the objective of stability testing is ‘‘to provide evidence on how the quality of an active substance or medicinal product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended storage conditions, re-test periods and shelf-lives to be established’’ [8, 20]


Regulatory consideration on stability of pharmaceuticals:

The importance of stability testing in the development of pharmaceutical dosages forms is well recognized in the pharmaceutical industry. Increased filing abbreviated new drug application (ANDA) and paper new drug application (PNDA) by generic and non generic drug manufacturers have resulted in an increase in submissions of stability data to the food and drug administration (FDA) [11].


There are several sections of the federal food drug and cosmetic act that relate to the stability of pharmaceutical products.


Section 505 (b) (4): concern itself with of the characteristics of the new drug and its basis for requiring stability data in new drug application.

Section 501 (a) (2) (B):  concern itself with drug adulteration. A drug is considered adulterated if it does not meet the quality and purity characteristics that it is represented to posses.


Section 505 (h): states that a drug shall be deemed to be misbranded if found by the health education and welfare agency to be liable to deterioration unless it is packaged in such a form and manner with its label bearing a statement of such precautions, as are necessary for the protection of the public health [11, 21].


Of the three sections mentioned, the one that pertain most directly to stability testing of drugs is section 505 (b) (4).

FDA regulation dealing with this section is 314.1(8) (p) under new drug applications and requires:

“A complete description of and data derived from the studies of the stability of drug, including information showing the suitability of the analytical methods used. It further states that stability data should be submitted for the new substance, for the finished dosages form in the container in which it is to be marketed, and if it is reconstituted at the time of dispensing, for the solution so prepared.


It requires that an expiration date appear on the label to preserve the identity, strength, quality and purity of the drug until it is used. In fact it states, “If no expiration date is proposed, the applicant must justify its absence”.


Further FDA cGMP regulations under section 211.166 and 211.167 set forth basic guidelines for stability of all drugs and the requirement for expiration dates on pharmaceutical products. No drug product in a container-closure system is indefinitely stable and the manufacturer or packer of a drug product is responsible for determining the stability characteristics for each of the products [11, 22].


In the preamble to the good manufacturing guidelines published in the federal register of sept. 29, 1978, the commissioner of the FDA indicated that valid expiration dates must be established for all drug products [11].


Stress testing (or Forced degradation studies):

Stress testing is defined as the stability testing of drug substances and drug products under condition exceeding those used for accelerated testing. Stress testing of the drug substance can help to identify the likely degradation products, which in turn help to establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved [23].


Stress testing will not only be necessary for the API method but will also have to be conducted for the formulated and packaged product [24].

Determining the presence of degradation products involves forced degradation studies in which intentionally expose the API to conditions that produce degradation. The goal is to achieve approximately 10 percent degradation of the drug substance. Degrading the drug substance beyond that generally creates additional degradation that may not be relevant [8, 20 and 23].


Recommended stress factors include high and low pH, elevated temperature, photolysis, and oxidation. The extent of the stress applied in forced degradation studies should ensure formation of the desired amount (usually 10 to 20%) of degradation [20]. Usually, exposing the drug substance to all of the conditions in a controlled fashion and then assaying the sample using the developed method will provide information on the presence of most degradants [24].


Stress testing should be done on a single batch of the product, which must be of same composition and quality as marketing batch, including the packaging. The stress test is normally conducted for the total period of sixth months. The samples are observed for physical changes at regular intervals and drawn for analysis either fortnightly or monthly or a period suitable. The study can be discontinued in between, if it serves the purpose of establishment of the specificity of an analytical method [20].


Degradants may be characterized by collecting fractions of the chromatographic column and using standard characterization techniques, such as FTIR, NMR and optical rotation, to provide additional information about the degradant’s identity. These fractions can be purified and used for toxicological tests or for synthesizing reference standards.


Moving into the formulation stages, the drug substance is evaluated in the presence of excipients. Information gained from the early studies can be used to choose excipients that are compatible with the drug substance. At this point, the analytical method must not only be specific for the drug substance and its degradants, but also for the excipients. Stress testing are useful to determine degradants and more importantly, to establish preliminary stability data for the formulation. These short-term studies can also determine any drug substance and excipient interactions before the product is placed into a long-term ICH study. It also allows a method to evolve to become specific for these degradation products.


Once a drug product formulation is selected, interactions with the proposed packaging material must be determined. Stress testing can generate information quickly to eliminate packaging configurations that may generate degradant products. Once a packaging configuration is selected, however, the drug product in the packaging must undergo ICH stability testing to confirm whether the packaging material is appropriate.


Determining the degradant specifications is also part of the development process. The manufacturer wants to prevent formation of the products early on and to monitor their presence to ensure quality of the product. The specifications for stability will also ensure that potentially deleterious degradants are not present and do not grow beyond the safety threshold during storage and shipping [20, 23 and 24].

·        Objectives of stress studies:

According to the ICH and FDA guidance documents, stress testing is conducted to fulfill three main purposes: to provide a stability assessment of the drug substance or the drug product to elucidate the possible degradation pathways of the drug substance or the active pharmaceutical ingredient in the drug product; and to investigate the stability indicating power of the analytical procedures applied for the drug substance and the drug product [20].

Stress studies may be useful in determining whether accidental exposures to conditions other than normal ranges (e.g., during transportation) are deleterious to the product, and also for evaluating which specific test parameters may be the best indicators of product stability [8].


·        Extent of Degradation:

 The question of how much degradation is sufficient to meet the objectives of stress studies is widely discussed, especially with respect to conventional therapeutics. A degradation level of 10 to 15% is considered adequate for validation of a chromatographic purity assay. The apparent consensus among pharmaceutical scientists is that samples degraded ~10% are optimal for use in analytical method validation. These considerations apply to small organic pharmaceuticals for which stability is dictated by the typical pharmaceutical limit of 90% of label claim [23, 25 and 26].

The stress testing does not necessarily result in product decomposition. The study can be stopped if no degradation is observed after DS (drug product) and DS (drug substance) has been exposed to a stress that exceeds conditions of accelerated stability protocol. Protocols for generation of product-related degradation may differ for DS and DP due to differences in matrices and concentrations [24].


·        Selection of Stress Conditions:

Stress testing is normally carried out under more severe conditions than those used for accelerated studies. The choice of stress conditions should be consistent with the product's decomposition under normal manufacturing, storage, and use conditions which are specific in each case. The ICH guidance recognizes it is impossible to provide strict degradation guidelines and allows certain freedom in selecting stress conditions .The choice of stress testing conditions should be based on data from accelerated pharmaceutical studies and sound scientific understanding of the product's decomposition mechanism under typical use conditions. A minimal list of stress factors suggested for forced degradation studies must include acid and base hydrolysis, thermal degradation, photolysis, and oxidation [25, 26].

The Stability-Indicating Method (SIM):

A SIM is a quantitative analytical procedure used to detect a decrease in the amount of the active pharmaceutical ingredient (API) present due to degradation. According to FDA guidelines, a SIM is defined as a validated analytical procedure that accurately and precisely measures active ingredients (drug substance or drug product) free from potential interferences like degradation products, process impurities, excipients, or other potential impurities, and the FDA recommends that all assay procedures for stability studies be stability indicating [25].


Developing and validating stability-indicating methods requires a careful balance with timelines, budget and formulation development. Should the drug substance’s synthetic pathway or the formulation change, the method may have to change, or at least be revalidated. Forced degradation studies may also have to be repeated [24].


Ultimately, the drug product will be placed in an ICH stability study. The stability program will represent long-term storage of the product and its packaging configurations. The goal is to determine when the product begins to degrade. Conducting the stability program provides the information needed to establish an expiration date for the product. The cornerstone of these studies is having a stability-indicating method that is validated and specific for the degradants of interest [20, 24].


Throughout the drug development process, from synthesis to commercialization of the formulated product, the developer must understand the generation and presence of degradations. Developing an analytical method to monitor these products early in the process is essential. Forced degradation studies are a tool to help with the method development of a stability-indicating method [20].


The method and forced degradation work must be reviewed as the development process advances to ensure that changes to the synthesis, formulation and packaging do not change the degradation characteristics. Eventually, the early study results will be confirmed by ICH stability studies. Forced degradation studies, though, can save a lot of time and money [23].


Taking steps early in the drug development process to generate stability-indicating analyses will provide a quicker path to drug approval. When these assays are delayed until late in the drug development process, time lines are impacted by the need to more fully study the drug and develop appropriate analytical methods. Finding and quantitating previously overlooked toxic degradants too late in the process can delay approval of the drug formulation, and these delays can add significantly to the cost of a drug development program. The overall goal of degradant analysis is to develop and maintain a high quality, safe product in a timely fashion [25, 26].



Stability Programmes and Stability Testing:

When a manufacturer plans to design, manufacture and market a drug product it is his responsibility to provide to the regulatory authorities assurance that the drug product meets with all the labelled claims and is stable in all senses till the expiry date is over. This responsibility implies that he/she undertake stability testing studies in a systematic way right from the Phase-I studies level. Upto the seventies these studies were undertaken by different companies in different manner. But today ICH guidelines help the manufacturers to adopt a stability programme that is suitable for them. The final draft of the ICH Harmoised Tripartite Guideline “Stability Testing of New Drug Substances and Products was issued by the International Conference on Harmonization (ICH) Expert Working Group of the ICH on technical requirements for the registration of pharmaceuticals for human use in October 1993. The storage requirements and the sampling times are very clearly specified by the ICH guidelines [8, 9 and 20].


Stability programme for a new drug

These guidelines divide the world into four zones and specify the temperature and relative humidity conditions to be maintained by each zone for stability studies. For example, if a manufacturer plans to sell his products in Zone III he has to submit stability data of his batches of products maintained at the temperature and relative humidity suggested by ICH for Zone III [8, 9].


Stability testing is done in five different occasions when an NDA is being contemplated.

1. Preformulation and compatibility

2. Preclinical formulation

3. Clinical and NDA formulation

4. Commitment and product monitoring

5. Post NDA change of formulation [9]


Quality Guidelines:  Stability:

Q1A (R2) Stability Testing of New Drug Substances and products (Second Revision)

Q1B Stability Testing: Photostability Testing of New Drug Substances and Products.

Q1C Stability Testing for New Dosage Forms

Q1D Bracketing and Matrixing Designs for Stability Testing of Drug Substances and  Products.

Q1E Evaluation of Stability Data

Q1F Stability Data Package for Registration Application in Climatic Zones III and IV [9].


Stability Testing for Established Drug Substances:

WHO has issued guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms. The stability of finished pharmaceutical products depends on environmental factors and on product related factors. So stability considerations should be given, the highest priority in the design and formulation of a product. The shelf life should be established with due regard to the climatic zones. To ensure both patient safety and the rational management of drug supplies, it is important that the expiry date and storage conditions are properly indicated on the label [27].


Analysis and identification of degradation products in pharmaceuticals:

Analysis and monitoring of degradation product in formulated pharmaceuticals are essential for ensuring that no compound with deleterious effects is generated during their shelf life. The identification of degradation products will aid in the understanding of potential side effects associated with degradation and in the design of more favorable formulation and synthesis of new drugs with greater stability [28, 29].


All major analytical techniques such as HPLC-mass spectrometry and HPLC-tandem mass spectrometry (LC-MS/MS), NMR and IR have been used in the characterization of degradation products. LC-MS and LC-MS/MS are often the techniques of choices for identifying degradation products because of their high sensitivities and separation power in addition to the rich structural information that MS/MS produces [30, 31].



Stability studies plays significance role in control of degradation products. ICH has published gudelines for stability testing on new drug substances and products.  WHO has published guidelines on stability testing for established substances. Before marketing of any new drug product stress testing must be performed.  It provides information about degradation mechanism and potential degradation product. This information then can be used to develop manufacturing processes or to select proper packaging.


Stability indicating methods are also employed during drug development. It detects the decrease in the amount of the active pharmaceutical ingredient (API) present due to degradation.


Identification of degradation products also plays an important role in drug development process. Various analytical techniques are employed to identify and characterize degradation products.



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Received on 09.04.2009       Modified on 13.06.2009

Accepted on 12.07.2009      © RJPT All right reserved

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 621-627