Kishore Kumar Hotha et al. Int. Res. J. Pharm.

2013, 4 (5)
INTERNATIONAL RESEARCH JOURNAL OF PHARMACY
www.irjponline.com ISSN 2230 8407
Review Article

FORCED DEGRADATION STUDIES: PRACTICAL APPROACH - OVERVIEW OF REGULATORY GUIDANCE

AND LITERATURE FOR THE DRUG PRODUCTS AND DRUG SUBSTANCES
Kishore Kumar Hotha1*, Satti Phani Kumar Reddy1, V. Kishore Raju2, L.K.Ravindranath3
1
Analytical Research and Development, IPDO, Dr. Reddys. Ltd. Hyderabad, India
2
Department of Pharmaceutical Analysis, Vasavi Institute of Pharmaceutical Sciences, Kadapa, A.P, India
3
Department of Chemistry, S.K. University, Anantapur, A.P, India
Email: [email protected]

Article Received on: 17/03/13 Revised on: 21/04/13 Approved for publication: 19/05/13

DOI: 10.7897/2230-8407.04517
IRJP is an official publication of Moksha Publishing House. Website: www.mokshaph.com
All rights reserved.

ABSTRACT
The Objective of the review article is to give a detailed description of the forced degradation studies as per the regulatory guidelines that are associated with
various regulatory agencies. This article summarizes the collective views of industry practices on the topic of forced degradation studies. The article includes
an overview of existing guidances and literature for best practices.
Keywords: Forced Degradation, ICH, FDA guidance, Validation, Method Development

INTRODUCTION To detect is there any low concentrations of potential

According to an FDA guidance document, a stability- degradation products
indicating method is a validated quantitative analytical To detect unrelated impurities in the presence of the
procedure that can detect the changes with time in the desired product and product-related degradants
pertinent properties of the drug substance and drug product. To separate product-related degradants from those derived
A stability-indicating method accurately measures the active from excipients and intact placebo.
ingredients, without interference from degradation products, To elucidate possible degradation path-ways
process impurities, excipients, or other potential impurities. To identify degradation products that may be
Forced Degradation (or stress testing) typically involves spontaneously generated during drug storage and use
exposure of drug substances to heat, heat and humidity and To facilitate improvements in the manufacturing process
light for solid-state studies. For solution-state studies the drug and formulations in parallel with accelerated
substance is exposed to a range of pH values. The pharmaceutical studies.
experimental samples produced are then used to demonstrate
that a proposed analytical method is Stability Indicating, Overview of Regulatory Guidance
i.e., the method is capable of detecting the loss in content of Forced degradation studies are described in various
the active component and subsequent increase in degradation international guidelines. The International Committee for
products. Ideally, loss in content of the active component and Harmonization of Technical Requirements for Registration of
increase in degradation products should be monitored by a Pharmaceuticals for Human Use (ICH) has published a set of
single analytical method. However, in some cases, this is not guidelines which have been discussed, agreed upon and
possible and separate assay and impurity methods have to be adopted by the American, European and Japanese regulatory
developed. This guidance document describes how forced authorities. In the majority of cases, the ICH guidelines only
degradation studies are used to develop stability-indicating apply to the marketing applications for new products, i.e.,
methods 1-10. they do not apply during clinical development. However,
since the conditions used for forced degradation are only
Requirements defined in general terms, it is possible to apply them for
This relates to the specificity section of the validation studies. developing stability indicating methods during clinical
It is important to recognize that forced degradation studies development. The same forced degradation conditions can
are not designed to establish qualitative or quantitative limits then be applied to the drug substance during development and
for change in drug substance or drug product. Testing of commercialization. The ICH guidelines that are applicable to
stressed samples is required to demonstrate the following forced degradation studies are 1-2, 17-20.
abilities of analytical techniques employed in stability ICH Q1A Stability Testing of New Drug Substances
studies: Stress studies may be useful in determining whether and Products
accidental exposures to conditions other than normal ranges
ICH Q1B Photo stability Testing of New Drug
(e.g., during transportation) are deleterious to the product,
Substances and Products
and also for evaluating which specific test parameters may be
the best indicators of product stability 1-2,11-15. Figure-1 ICH Q2B Validation of Analytical Procedures:
represents the complete flow of forced degradation. Methodology
In ICH Q1A, section 2.1.2 (Stress Testing), there are
To estimate the stability of Drug Substance and Drug
recommended conditions for performing forced degradation
Product in solution
studies on drug substances and drug products. The
To Identify structural transformations of the drug
recommendations are to examine the effects of temperature
substance and drug product (above that for accelerated testing, i.e., >50C), humidity
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(75% relative humidity), oxidation and photolysis. Testing documented in the analytical method, manufacturing process,
in solution should also be performed across a wide pH range product handling, and etc.
either as a solution or suspension. These samples are then
used to develop a stability-indicating method. ICH Q1B Origin of degradation products
gives recommended approaches to assessing the photo The main reason of appearance of impurities in drug
stability of drug substances and drug products. Forced substance or product is due to its degradation. The chemical
degradation conditions are specified in Section II (drug instability of the drug substance under the conditions of heat,
substance) and Section III (drug product). Exposure levels for humidity, solvent, pH, and light encountered during
forced degradation studies are not defined, although they can manufacture, isolation, purication, drying, storage,
be greater than that specified for confirmatory (stability) transportation, and/or formulation is main cause of its
testing. The actual design of photo stability studies is left to degradation. It is governed by inherent chemical stability of
the applicant; however, scientific justification is required the drug substance. The major routes of degradation of any
where light exposure studies are terminated after a short time, drug substance include hydrolysis, oxidation, heat and
e.g., where excessive degradation is observed. Photo stability photolysis. The stress testing helps in generation all possible
testing can be performed on the solid or in degradation products that may form under different
solution/suspension. These samples are then used to develop conditions1.
a stability indicating method. Both guidances, Q1A and
Q1B, note that some of the degradation products formed Selection of experimental conditions
during forced degradation studies may not actually be There are many examples in the literature of experimental
observed to form during stability studies, in which case they conditions for conducting forced degradation studies and the
need not be examined further.ICH Q2B gives guidance on structural multiplicity of drug molecules makes it not
how to validate analytical methodology and in section B possible to identify a generic set of conditions for a forced
1.2.2 (impurities not available) there is a recommendation to degradation study. For an early phase molecule, using a set of
use samples from forced degradation studies to prove normal conditions by first intention makes sense since very
specificity. Specificity is a key factor in determining whether little may be known about the intrinsic stability. If early
or not the analytical method is stability indicating. Co-elution stability data are available which suggest the molecule is
of peaks or components being retained on the column will labile at a particular condition (e.g., high pH), the conditions
underestimate the amount of degradation products formed can be modified to take into account the instability (e.g.,
and could compromise quality and increase risk to the reduced temperature or time of study). Once a set of
patient.Q3A (R2) requires identification of each impurity conditions have been found, they may be repeated whenever
with respect to both chemistry and safety perspectives. The a new stability-indicating method is required during
chemistry perspectives include classification and development. Therefore, for later-phase molecules, the forced
identification of impurities, report generation, listing of degradation conditions are defined by the earlier work. By
impurities in specification and a brief discussion of analytical reprocess the same forced degradation conditions throughout
procedures while the safety perspectives include specific development a consistent approach is maintained 1-2, 30-34.
guidance for qualifying those impurities that were not present
or were present at substantially lower levels in batch of a new Conditions for degradation
drug substance and used in safety and clinical studies 1-15, 25- Hydrolytic condition
34
. Hydrolysis is one of the most common degradation chemical
reactions over wide range of pH. Hydrolysis is a solvolytic
FDA perspectives and scientific considerations process in which drug reacts with water to yield breakdown
Ragine Maheswaran provided a clear perspective on FDA products of different chemical compositions. Water either as
regarding the scientific considerations with respect to forced a solvent or as moisture in the air comes in contact with
degradation studies. If the substance does not show any pharmaceutical dosage forms is responsible for degradation
degradation under any of the stress conditions then the Stress most of the drugs. Hydrolytic study under acidic and basic
studies shall be repeated to obtain adequate degradation. If condition involves catalyzation of ionisable functional groups
degradation is not achievable, rationale shall be provided. present in the molecule. HCl and NaOH are employed for
The conditions employed for stress study are too harsh and generating acidic and basic stress samples, respectively. The
that most of the drug substance has degraded. The stress hydrolytic degradation of a new drug in acidic and alkaline
studies using milder conditions or shorter exposure time to condition can be studied by refluxing the drug in 0.1 N HCl /
generate relevant degradation products. Stressed samples 0.1 N NaOH. If reasonable degradation is seen, testing can be
shall be performed as per the assay method conditions. For stopped at this point. However in case no degradation is seen
the related substances method to be stability indicating, the under these conditions the drug should be refluxed in
stressed samples should be analyzed using related substances acid/alkali of higher strength and for longer duration of time.
method conditions. The attempts shall be made to ensure that Alternatively if total degradation is seen after subjecting the
all the impurities including the degradation products of the drugs to initial condition, acid/alkali strength can be
unstressed and the stressed samples are captured by the final decreased with decrease in reaction temperature. In general
analytical method. Summary of the amount of degradation temperature and pH are the major determinant in stability of
products (known and unknown) in the stressed samples shall the drug prone to hydrolytic decomposition. Hydrolysis of
be provided. The purity determinations shall be performed as most of the drugs is dependent upon the relative
per the established software. Mass imbalance of the stressed concentration of hydronium and hydroxyl ions. Hence pH at
samples shall be justified. The degradation products shall be which each drug is optimally stable can be determined 17-34.
identified that are formed due to drug-excipients interactions.
Photo stability studies shall be determined whether the drug
product is very sensitive to light or not. This shall be

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Procedure for conducting hydrolytic degradation follow the same pathway of decomposition at all
Conduct the following forced degradation studies to obtain temperatures. This assumption may not hold true for all drug
degraded samples wherever degradation possible from about molecules, and therefore great care must be taken in using the
1% to 30%.For Acid stress Reflux with 0.1N HCL at 60C extreme temperatures easily accessible in a sealed-vessel
for 30 minutes. For Base stress Reflux with 0.1N NaOH at microwave experiment for predictive degradation studies.
60C for 30 minutes. For water stress Reflux with water at
60C for 30 minutes. Stress agent can be changed to achieve Procedure for conducting thermal degradation
degradation if necessary Co-solvent can be used to dissolve Conduct the following forced degradation studies to obtain
and extract the drug, where necessary. Figure-2 represents the degraded samples wherever degradation possible from about
flow of hydrolytic degradation. 1% to 30%.Preferably, the following stress conditions are
recommended for specificity study, however stress condition
Oxidative Condition can be decided based on experimental data, or physical
Many drug substances undergo autoxidation i.e., oxidation properties of the analyte based on literature. If melting point
under normal storage condition and involving ground state of API is less than 150C, stress at 105C or 40C less than
elemental oxygen. Therefore it is an important degradation melting point whichever is higher. If melting point of API is
pathway of many drugs. Autoxidation is a free radical more than 150C stress at the nearest melting point and at
reaction that requires free radical initiator to begin the chain 105C. Figure-4 represents the flow of thermal degradation.
reaction. Hydrogen peroxide, metal ions, or trace level of
impurities in a drug substance act as initiators for Photolytic Condition
autoxidation. The mechanism of oxidative degradation of Exposure of drug molecules may produce photolytic
drug substance involves an electron transfer mechanism to degraded products. The rate of photo degradation depends
form reactive anions and cations. Amines, sulphides and upon the intensity of incident light and quantity of light
phenols are susceptible to electron transfer oxidation to give absorbed by the drug molecule. Photolytic degradation is
N-oxides, hydroxylamine, sulphones and sulphoxide. The carried out by exposing the drug substance (in solid as well as
functional group with labile hydrogen like benzyl carbon, in the solution form) or drug product to a combination of
allylic carbon, and tertiary carbon or positions with visible and UV light. The most commonly accepted
respect to hetro atom is susceptible to oxidation to form wavelength of light is in the range of 300-800 nm to cause
hydro peroxides, hydroxide or ketone. Products could be the photolytic degradation. The photolytic degradation can
rationalized with free radical-mediated autoxidation reactions occur through non oxidative or oxidative photolytic reaction.
involving alkene and alcohol sites.Hydrogen peroxide is very The non-oxidative photolytic reaction include isomerization,
common oxidant to produce oxidative degradation products dimerization, cyclization, rearrangements, decarboxylation
which may arise as minor impurities during long term and hemolytic cleavage of X-C hetero bonds, N-alkyl
stability studies. It can be used in the concentration range of bond(de alkylation and deamination), SO2-C bonds etc. and
3-30% at a temperature not exceeding 40 C for 2-8 days. while oxidative photolytic reaction occur through either
singlet oxygen(1O2) or triplet oxygen(3O2) mechanism. The
Procedure for conducting oxidative degradation singlet oxygen reacts with the unsaturated bonds, such as
Conduct the following forced degradation studies to obtain alkenes, dienes, poly nuclear aromatic hydrocarbon to form
degraded samples wherever degradation possible from about photo oxidative degradation products whereas triplet oxygen
1% to 30%.For oxidation stress: Treat with 1% H2O2 at less react with free radical of the drug molecule, which than react
than 30C for 30 min.The oxidative stress testing is initially with a triplet oxygen molecule to form peroxide. Hence, light
carried out in 3% H2O2 at room temperature for 6 hr and it can also act as a catalyst to oxidation reactions. Hence, the
can be increased/ decreased to achieve sufficient degradation. characterization of photo degradation process involves the
Stress agent can be changed to achieve degradation if study of the transient species and the interaction between
necessary. Co-solvent can be used to dissolve and extract the precursor and products, is a crucial way to understand the
drug, where necessary. Figure-3 represents the flow of potential Photo-toxicity of a drug and determining it.
oxidative degradation.
Procedure for conducting photolytic degradation
Thermal Condition Conduct the following forced degradation studies to obtain
In general, rate of a reaction increase with increase in degraded samples wherever degradation possible from about
temperature. Hence, the drugs are susceptible to degradation 1% to 30%. Expose the tablet powder contents of capsule to
at higher temperature. Many APIs are sensitive to heat or ultraviolet radiation up to minimum of 200 watts hour/m2 and
tropical temperatures. For example, vitamins, peptides, etc. minimum of 1.2 million lux hour for visible light and photo
Thermal degradation involves different reactions like stability chamber. If photo stability chamber is not available,
pyrolysis, hydrolysis, decarboxylation, Isomerization, expose the tablet powder/content of capsule to intense
rearrangement and polymerization. Effect of temperature on ultraviolet radiation (both at longer and shorter wavelengths)
thermal degradation of a substance is studied through up to minimum of 7 days in UV cabinet. Figure-5 represents
Arrhenius equation:K= Ae-Ea/RT Where k is specific the flow of photolytic degradation
reaction rate, A is frequency factor, Ea is energy of
activation, R is gas constant (1.987 cal/deg mole) and T is Humidity
absolute temperature. Thermal degradation study is carried Humidity is the Key factor in establishing the potential
out at 40C to 80C. The most widely accepted temperature is degradants in the finished product and active pharmaceutical
70C at low and high humidity for 1-2 months. High ingredient. Normally 90% Humidity for duration of one week
temperature (>80C) may not produce predictive degradation shall be recommended for the establishment of forced
pathway. The use of high-temperatures in predictive degradation samples.
degradation studies assumes that the drug molecule will

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Selection of samples amount of impurities (known and unknown) obtained under
The strength and duration of the stress conditions need to be each stress condition should be provided along with the
decided by experimenting to get the sample with required chromatograms (full scale and expanded scale showing all
degradation. Simultaneously subjects the Placebo (Excipients the peaks) of blanks, unstressed, and stressed samples.
mixture) as per the manufacturing formula to all the above Additionally, chiral drugs should be analyzed with chiral
stress conditions. For multi-drug product placebo formulation methods to establish stereo chemical purity and stability. The
containing one drug substance each shall be subjected to analytical method of choice should be sensitive enough to
forced degradation. Prepare test solutions using unstressed detect impurities at low levels (i.e., 0.05% of the analyte of
sample, placebo and the stressed samples, as per the test interest or lower), and the peak responses should fall within
method and inject into the HPLC system with diode array the range of detector's linearity 9-15.
detector. Record the chromatograms and calculate the The analytical method should be able to capture all the
Percentage degradation and percent net degradation as per impurities produced during a formal stability study at or
acceptance criteria. In case of stable molecules, percent net below ICH threshold limits. Degradation product
degradation may be difficult to achieve as per acceptance identification and characterization shall be performed based
criteria. Hence based on the experiments, study can be on stability results in accordance with ICH requirements.
concluded and summary of the experiments shall be Conventional methods (e.g., column chromatography) or
documented. Demonstrate the effective separation of the hyphenated techniques (e.g., LC MS, LC NMR) can be
analyte from the degradation product and peaks if any due to used in the identification and characterization of the
components of placebo mixture 1-15. Ensure that response of degradation products. Use of these techniques will provide
analyte peak in test solution is equal to or less than 1AU better insight into the structure of the impurities that could
(absorbance unit). If it is more, dilute the test solution add to the knowledge space of potential structural alerts for
accordingly and repeat the analysis. genotoxicity and the control of such impurities with tighter
limits. It should be noted that structural characterization of
Acceptance Criteria degradation products is necessary for those impurities that are
All requirements of the software are to be met while formed during formal shelf-life stability studies and are
evaluating peak purity. The purity angle should be less than above the qualification threshold limit. The detector should
purity threshold. The peak should not have any flag in purity contain 3D data capabilities such as diode array detectors or
result table. Mass balance of all stressed samples shall be mass spectrometers to be able to detect spectral non-
verified by calculating Mass balance: (% assay of stressed homogeneity. After the method finalization test method on
sample + % impurities) X 100/ % assay of unstressed sample. different detectors like RI/ELSD/CE detector with the
suitable method parameters and compare the data with other
Selection of analytical method in identification and detectors like UV, Fluorescence etc.The UV inactive
characterization of drug products compounds can be found with this exercise. If any such type
The preferred method of analysis for a stability indicating of components are there these shall be addressed based on the
assay is reverse-phase high-performance liquid process and cross checking to be made by using LC-MS
chromatography (HPLC). Reverse-phase HPLC is preferred technique 20-27.
for several reasons, such as its compatibility with aqueous Use the analytical mode of fraction collections for major
and organic solutions, high precision, sensitivity, and ability impurities /degradants and check the mass numbers or
to detect polar compounds. Separation of peaks can be develop chromatographic conditions suitable to LC-MS and
carried out by selecting appropriate column type, column identify the mass of major degradant which are found to be
temperature, and making adjustment to mobile phase pH. forming greater than 1.0% during stress studies. Try to
Poorly-retained, highly polar impurities should be resolved establish the structures of the major degradant, if possible and
from the solvent front. As part of method development, a compare the synthetic process for justification. Diode array
gradient elution method with varying mobile phase detection also offers the possibility of checking peak profile
composition (very low organic composition to high organic for multiple wavelengths. The limitation of diode array arises
composition) may be carried out to capture early eluting when the UV profiles are similar for analyte peak and
highly polar compounds and highly retained non polar impurity or degradant peak and the noise level of the system
compounds. Stressed samples can also be screened with the is high to mask the co-eluting impurities or degradants.
gradient method to assess potential elution pattern. Sample Compounds of similar molecular weights and functional
solvent and mobile phase should be selected to afford groups such as diastereoisomers may exhibit similar UV
compatibility with the drug substance, potential impurities, profiles. In such cases, attempts must be made to modify the
and degradants. chromatographic parameters to achieve necessary separation.
Stress sample preparation should mimic the sample An optimal wavelength should be selected to detect and
preparation outlined in the analytical procedure as closely as quantitation of all the potential impurities and degradants.
possible. Neutralization or dilution of samples may be Use of more than one wavelength may be necessary, if there
necessary for acid and base hydrolyzed samples. is no overlap in the UV profile of an analyte and impurity or
Chromatographic profiles of stressed samples should be degradant peaks. A valuable tool in method development is
compared to those of relevant blanks (containing no active) the overlay of separation signals at different wavelengths to
and unstressed samples to determine the origin of peaks. The discover dissimilarities in peak profiles 18-34.
blank peaks should be excluded from calculations. The

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Figure 1: Overview of forced degradation

Figure 2: hydrolytic degradation

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Figure 3: Oxidative Degradation

Figure 4: Thermal Degradation

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Figure 5: Photolytic Degradation

Figure 6: Humidity Degradation

CONCLUSION 2. Ragine Maheswaran.FDA Perspectives: Scientific Considerations of

Forced degradation studies of new drug substances and drug Forced Degradation Studies in ANDA Submissions. Pharmaceutical
Technology 2012; 36:73-80.
products are important to help develop and demonstrate 3. Michael. K. Forced Degradation Studies: Regulatory Considerations and
specificity of stability-indicating methods and to determine Implementation Stress testing studies are conducted to challenge
the degradation pathways and degradation products of the specificity of stability-indicating and impurity- monitoring methods as
active ingredients. They were also useful in the investigation part of validation protocol. BioPharm Int 2005; 1-7.
4. FDA. Guidance for Industry. Analytical Procedures and Methods
of the chemical and physical stability of crystal forms, the Validation: Chemistry, Manufacturing, and Controls Documentation,
stereochemical stability of the drug substance alone and in Draft Guidance, 2000 August.
the drug product and mass-balance issues, and for 5. ICH. Guidance for Industry, Q5C. Quality of Biotechnological
differentiating drug substancerelated degradation products Products: Stability Testing of Biotechnological/Biological Products.
ICH-Q5C. 1996 July 10.
in formulations. The ICH not provided any formal guidance. 6. Kovaleski J, Kraut B, Matiuz A, Giangiulio M, Brosbst G, Cango W.
Adequate degradation required to understand the probable Impurities in generic pharmaceutical development. Adverse Drug Rev
degradants for the evaluation of stability indicating method. 2007; 59: 56-63. http://dx.doi.org/10.1016/j.addr.2006.10.009
7. Rao RN, Nagaraju V. A overview of the recent trends in development of
HPLC methods for determination of impurities in drugs. J Phramaceut
REFERENCES
Biomed2003;33:335-337.http://dx.doi.org/10.1016/S0731-
1. Ranjit Singh and Rehman Z. Current trends in forced degradation study
7085(03)00293-0
for pharmaceutical product development. Journal of pharmaceutical and
8. Zhou L, Mao B, Novak T, Ge Z. Impurity profile tracking for act
educational research 2012; 2:54-63
pharmaceutical ingredients: Case reports. J Pharmaceut Biomed 2007;
44: 421-429. http://dx.doi.org/10.1016/j.jpba.2006.11.004

Page 84
 Kishore Kumar Hotha et al. Int. Res. J. Pharm. 2013, 4 (5)
9. ICH Q3A(R2) (October 2006). Impurities in New Drug Substances and 26. Alsante KM, Hatajik TD, Lohr LL, Santafianos D Sharp TR. Solving
Products (Step 4), International Conference on Harmonization impurity/degradation problems: case studies. pp: 380, In; handbook of
10. ICH Q3B (R2) (June 2006). Impurities in New Drug Substances and Isolation and Characterization of impurities in Pharmaceutical, Ahuja S,
Products (Step 4), International Conference on Harmonization. Alsante K, editors, Academics Press, New York. 2003
11. ICH Q3C (R3) (September 2002). Impurities: Guidelines for Residual 27. Alan RO, Brigitte ES, Yanqiu SA, Polshyna NM, Dunphy R, Barbara
solvents (Step 5), International Conference on Harmonization. LM, et al. Forced degradation studies of rapamycin: Identification of
12. Ahuja S. Impurities Evaluation of Pharmaceuticals. Marcel Dekker, autoxidation products. J Pharmaceut Biomed 2012; 59: 194-200
New York, 1998. http://dx.doi.org/10.1016/j.jpba.2011.10.017
13. Shirazi D, Ware E, Harper T, Pflaumer A. The Benefits of Using AAI 28. Trabelsi H, Hassen IE, Bouabdallah S, Bouzouita K, Safta F. Stability
Pharma Services for Elemental Impurity Analysis Using ICP-MS indicating LC method for determination of Pipamperone. J Pharmaceut
Technology. Am Pharmaceut Rev 2012; 1-10. Biomed 2005; 39: 914-919. Dorman DE, Lornez LJ, Occolowitz JL,
14. Qiu F Norwood DL, Identification of pharmaceutical impurities. J Liq Spangle LA, Collins, MW, Bashore FN, Baertschi SW. Isolation and
Chromatogr R T 2007; 30: 877-935. http://dx.doi.org/10.1080/ structure elucidation of the major degaradtion products of cefaclor in the
10826070701191151 solid state. J Pharm. Sci 1997; 86: 526-539.
15. Matthews BR. Regulatory aspects of stability testing in Europe. Drug 29. Bojana P, Markus D, Kappe CO. Microwave-assisted forced degradation
Dev Ind Pharm 1999; 25: 831-856. http://dx.doi.org/10.1081/DDC- using high-throughput microtiter platforms. J Pharmaceut Biomed 2011;
100102245 56:867-873 http://dx.doi.org/10.1016/j.jpba.2011.07.042
16. Kunzle IS, Swartz ME. Validated viewpoint: Laboratory Notebook 30. Baertschi SW, Thatcher SR. Sample presentation for photostability
Documuentation. Lc Gc N. Am 1997; 15: 1122- 1129. studies: problems and solutions, pp: 445, In; Pharmaceutical
17. Reynolds DW, Fachine KL, Mullaney JF, Alsante KM, Hatajik TD, Photostability and Stabilization Technology. Piechocki J, Editor, Taylor
Motto MG. Availiable guidance and best practices for conducting forced & Francis, New York. 2006 http://dx.doi.org/10.1201/
degradation studies. Pharm Tech 2002; 26, 48-56. 9781420014136.ch10
18. ICH Q1A (R2) (2003). Stabilty Testing of New Drug Substances and 31. Allwood M, Plane J. The wavelength-dependent degradation of vitamin
Products. International Conference on Harmonization , IFPMA, Geneva. A exposed to ultraviolet radiation. Int J Pharm J Pharm Educ Res Vol. 3,
19. Kovarikova P, Jiri K, Jiri D, Lucie T. HPLC study of glimepiride under Issue No. 1, June 2012 63 1986; 31: 17.
hydrolytic stress conditions. J. Pharmaceut Biomed 2004; 36: 205-209. 32. Baertschi SW, Alsante KM. Stress testing: the chemistry of the drug
http://dx.doi.org/10.1016/j.jpba.2004.05.005 degradation, pp: 99, In; Pharmaceutical Stress Testing, Baertschi SW,
20. Singh S, Bakshi M. Guidance on conduct of stress tests to determine editors, Taylor & Francis, New York. 2005 http://dx.doi.org/10.1201/
inherent stability of drugs. Phrama Tech 2000; 24: 1-14. 9780849359194.ch3
21. Skoog DA, West DM, Holler FJ. Analytical Chemistry, pp: 3-11, An; 33. Giuseppina L, Filomena O, Inmaculada A, Michele DL, Miguel AM,
Introduction, Saunders College Publishing, Philadelphia. 2002. Gaetano R. Different photodegradation behavior of barnidipine under
22. Cheekatla S, Ravichandrababu R, Reddy BN. Determination and natural and forced irradiation. J Photoch Photobio A 2010; 215: 205
characterization of degradation products of Anastrozole by LCMS/MS 213 http://dx.doi.org/10.1016/j.jphotochem.2010.08.019
and NMR spectroscopy. J. Pharmaceut Biomed 2011; 56: 962-968. 34. Alsante KM, Hatajik TD, Lohr LL, Santafianos D, Sharp TR. Solving
http://dx.doi.org/10.1016/j.jpba.2011.08.022 impurity/degradation problems: case studies, pp:380, In; handbook of
23. Gupta A, Yadav JS, Rawat S , Gandhi M. Method Development and Isolation and Characterization of impurities in Pharmaceuticals, Ahuja
Hydrolytic Degradation Study of Doxofylline by RPHPLC and LC- S, Alsante K, editors, Academics Press, New York. 2003.
MS/MS. Asian J Pharm Ana 2011; 1:14 18.
24. Skoog, DA, West DM. Principles of Instrumental Analysis. Saunderg Cite this article as:
Golden, Japan. 1980, 2-3. Kishore Kumar Hotha, Satti Phani Kumar Reddy, V. Kishore Raju,
25. Boccardi G. Oxidative susceptibility testing, : 220. In; pharmaceutical L.K.Ravindranath. Forced degradation studies: Practical approach: Overview
Stress Testing-Predicting Drug Degradation; Baertschi SW, editors, of regulatory guidance and literature for the drug products and drug
Taylor and Francis, New York. 2005 substances. Int. Res. J. Pharm. 2013; 4(5):78-85

Source of support: Nil, Conflict of interest: None Declared

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