Critical review: Significance of Force degradation study with respect to current Pharmaceutical Scenario

 

Nikita N. Patel¹*, Charmy S. Kothari²

¹Parul Institute of Pharmacy, Waghodia, Limda, Gujarat, India

²Institute of pharmacy, Nirma University, Ahmedabad, Gujarat, India

*Corresponding Author E-mail: nikita_9986@yahoo.com

 

Stress testing of the drug substance can help to identify the likely degradation products, which can in turn help to establish the degradation pathways and the intrinsic stability of the molecule. Quantitative estimation of degradation products and   establishment of mass balance should be done by various hyphenated techniques. After quantitative estimation of degradation, isolation of the degradation products can be done with the help of different methods like TLC, flash chromatography (column chromatography) and preparative HPLC. After concurrent isolation, characterization of the degradation products should be done with the help of Ultraviolet spectroscopy, IR spectroscopy, NMR Spectroscopy, Mass Spectroscopy and HPLC. From the literature survey of antihypertensive drugs, it was found that major alkaline degradation products were found in angiotensin-II receptor antagonist (containing tetrazole moiety) for e.g. Losartan, Valsartan and Telmisartan etc. Dihydropyridine moiety containing calcium channel blocker drugs shows major photo degradation products for e.g. Amlodipine, Felodipine, Nilvadipine, Nimodipine etc. Due to amide group in anticancer taxanes (for e.g. Paclitaxel, Docetaxel), they shows major alkali degradation. Tetracycline antibiotics show major thermal degradation due to epimerization of tetracycline. Fluoroquinone antibiotics show photo degradation due to 8^th position of Fluoroquinolone moiety containing halogen group. Deacetylation Causes acidic degradation of Cephalosporin antibiotics. Amide hydrolysis results in acidic degradation of β-lactum antibiotics such as Dicloxacillin, Sultamicillin and Temocillin. Hydroxylation of cyclohexane group in Glipizide and Glimipride (antidiabetic drugs) causes both acidic and alkaline degradation. This paper discusses importance of force degradation study and degradation products with suitable examples of different categories of drugs.

 

 

 

INTRODUCTION:

Forced degradation studies play a central role during analytical method development, setting specifications and design of formulations under the quality-by-design (QbD) paradigm ^[1]. Forced degradation is synonymous with stress testing and purposeful degradation. Purposeful degradation can be a useful tool to predict the stability of a drug substance or a drug product with effects on purity, potency and safety. Although the concept of stress testing is not new to the pharmaceutical industry, the procedure was not clearly defined until the International Conference on Harmonization (ICH) provided a definition in its guidance on stability.

 

The ICH guideline indicates that stress testing is designed to help determine the intrinsic stability of the molecule by establishing degradation pathways in order to identify the likely degradation products and to validate the stability indicating power of the analytical procedures used ^[2].In addition, stress testing can help in the selection of more-stable drug substance salt forms and drug formulations. Stress testing also is becoming increasingly important in testing new molecules. The work on stability was initiated by the World Health Organization (WHO) in 1988, Following the WHO process for consultation a general text on stability and the WHO Guidelines on stability testing for well established drug substances in conventional dosage forms were adopted in 1994 and 1996 respectively. In 2000, discussions were initiated between the International Conference on Harmonization (ICH) Expert Working Group Q1 (stability) and WHO in order to harmonize the number of stability tests and conditions undertaken worldwide. Discussions on the stability testing conditions for climatic zone IV (hot and humid) have been taken up internationally. Based on the various stability-related guidance’s published by national authorities, as well as regional harmonization groups, discussions are still ongoing and have triggered various changes to the WHO guidelines on stability testing. Based on the recommendations by the International Conference of Drug Regulatory Authorities and the abovementioned WHO Expert Committee, a revision of the WHO guidelines is currently underway. The nature of the stress testing depends on the individual drug substance and the type of drug product (e.g., solid oral dosage, lyophilized powders, and liquid formulations) ^[3-6].

 

Regulatory Guidance on Stability Study:                                                                                                                        

Forced degradation studies are described in various international guidelines. The International Committee for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [1] has published a set of guidelines which have been discussed, agreed upon and adopted by the American, European and Japanese regulatory authorities. In the majority of cases, the ICH guidelines only apply to the marketing applications for new products, i.e., they do not apply during clinical development. However, since the conditions used for forced degradation are only defined in general terms, it is possible to apply them for developing stability indicating methods during clinical development. The same forced degradation conditions can then be applied to the drug substance during development and commercialization. The ICH guidelines that are applicable to forced degradation studies are [7-10].Table 1 Indicates ICH Guidelines for Stability Study

 

TABLE 1: ICH Guidelines for Stability Study

 

In ICH Q1A, section 2.1.2 (Stress Testing), there are recommended conditions for performing forced degradation studies on drug substances and drug products. The recommendations are to examine the effects of temperature (above that for accelerated testing, i.e., >50°C), humidity (≥75% relative humidity), oxidation and photolysis. Testing in solution should also be performed across a wide pH range either as a solution or suspension. These samples are then used to develop a stability-indicating method[11].

 

ICH Q1B gives recommended approaches to assessing the photo stability of drug substances and drug products. Forced degradation conditions are specified in Section II (drug substance) and Section III (drug product). Exposure levels for forced degradation studies are not defined, although they can be greater than that specified for confirmatory (stability) testing. The actual design of photo stability studies is left to the applicant; however, scientific justification is required where light exposure studies are terminated after a short time, e.g., where excessive degradation is observed. Photo stability testing can be performed on the solid or in solution/suspension. These samples are then used to develop a stability indicating method. Both guidance’s, Q1A and Q1B, note that some of the degradation products formed during forced degradation studies may not actually be observed to form during stability studies, in which case they need not be examined further.[12]

 

ICH Q2B gives guidance on how to validate analytical methodology and in section B 1.2.2 (impurities not available) there is a recommendation to use samples from forced degradation studies to prove specificity. Specificity is a key factor in determining whether or not the analytical method is stability indicating. Co-elution of peaks or components being retained on the column will underestimate the amount of degradation products formed and could compromise quality and increase risk to the patient. ICH guidelines do not give any guidance as to how much degradation is required in forced degradation studies. If too little stress is applied, some degradation pathways may not be observed which would not challenge the method’s ability to detect and monitor degradation products during stability testing. If too much stress is applied then unrealistic degradation products may be observed and the resulting analytical method may be unsuitable for detecting actual degradation products formed during stability testing. Thus, the actual conditions need to be chosen carefully so that the amount of degradation of the drug substance produced during forced degradation is neither too excessive nor too little. [13]. Figure 1 indicates the significance of force degradation study with respect to current pharmaceutical scenario [14].

 

Figure1: Importance of Force Degradation in Pharmaceuticals (14)

Stress Conditions:

Typical stress tests include four main degradation mechanisms: heat, hydrolytic, oxidative, and photolytic degradation. Selecting suitable reagents such as the concentration of acid, base, or oxidizing agent and varying the conditions (e.g., temperature) and length of exposure can achieve the preferred level of degradation ^[15-20]. Over-stressing a sample may lead to the formation of secondary degradants that would not be seen in formal shelf-life stability studies and under-stressing may not serve the purpose of stress testing. The generally recommended degradation varies between 5-20% degradation^. This range covers the generally permissible 10% degradation for small molecule pharmaceutical drug products, for which the stability limit is 90%-110% of the label claim. ^[14]

 

Acid, base and Neutral hydrolysis:

Acid and base hydrolytic stress testing can be carried out for drug substances and drug products in solution at ambient temperature or at elevated temperatures. The selection of the type and concentrations of an acid or a base depends on the stability of the drug substance. A strategy for generating relevant stressed samples for hydrolysis is stated as subjecting the drug substance solution to various pHs (e.g., 2, 7, 10–12) at room temperature for two weeks or up to a maximum of 15% degradation .Hydrochloric acid or sulfuric acid (0.1 M to 1 M) for acid hydrolysis and sodium hydroxide or potassium hydroxide (0.1 M to 1 M) for base hydrolysis are suggested as suitable reagents for hydrolysis ^[10]. Prior knowledge of a compound can be useful in selecting the stress conditions. For instance, if a compound contains ester functionality and is very labile to base hydrolysis, low concentrations of a base can be used.Figure 2 suggests that in order to study hydrolytic degradation (under acidic and alkaline conditions) of a new drug, whose stability behaviour is not known, one can start by refluxing the drug in 0.1N HCl/NaOH for 8 h, considering that the drug is labile. If a reasonable degradation is observed on subjecting the drug to this treatment, no further studies need to be carried out. In case no degradation is seen, drug should be subjected to refluxing in 1N acid/alkali for 12 h. For a drug which can withstand even these conditions, more extreme conditions of acidity or alkalinity such as refluxing in 2 N HCl/NaOH for 24 h may be tried. The reaction should be monitored, and if still satisfactory change is not obtained, the drug should be refluxed in 5 N HCl/NaOH for up to 24 h. The drug may be declared to be “practically stable’’ if no hydrolytic products are formed on subjecting the drug to this harsh condition. Going to the other side of starting condition, if a total degradation is seen after refluxing in 0.1 N HCl/NaOH for 8 h, the strength of acid/alkali can be decreased to 0.01 N along with decrease of temperature to  40°C while keeping the time as same 8 h. A drug showing complete degradation even in these mild conditions should be treated with 0.01 N HCl/NaOH for 2 h at 25°C and if still complete degradation is taking place, drug is extremely labile and has to be tested under very mild conditions of temperature and pH ^[18-20].Stress testing under neutral conditions can be started by refluxing the drug in water for 12 h (Fig. 3). Refluxing time should be increased to 1 day in case no degradation is seen. It should be increased further to 2 days if no change is observed. In case of negligible degradation, the drug may be refluxed for a period of 5 days. If still found stable, the drug may be declared no degrading in neutral conditions. For this study, it may be advisable that a sufficient volume of solution should be taken for the reaction initially, so that the time period can be continually increased, as required, and there is no need to restart the reaction afresh. For a drug undergoing complete degradation on refluxing in water for 12 h, both time and temperature of exposure may be decreased to 8 h and 40 °C, respectively. More mild conditions, like keeping the drug in water up to 2 h at 25°C, should be tried if no intact drug is left after exposure to above mentioned conditions. ^[21]

 

Figure 2: Pathway of Acid and Base Degradation Study for Drug Substance and Drug Product (21)

 

Figure 3: Pathway of Hydrolysis in Neutral Condition for Drug Substance and Drug Product (21)

 

 

Oxidation:

Oxidative degradation can be complex. Although hydrogen peroxide is used predominantly because it mimics possible presence of peroxides in excipients, other oxidizing agents such as metal ions, oxygen, and radical initiators (e.g., azobisisobutyronitrile, AIBN) can also be used. Selection of an oxidizing agent, its concentration, and conditions depends on the drug substance. Solutions of drug substances and solid/liquid drug products can be subjected to oxidative degradation. It is reported that subjecting the solutions to 0.1%-3% hydrogen peroxide at neutral pH and room temperature for seven days or up to a maximum 20% degradation could potentially generate relevant degradation products. Samples can be analyzed at different time intervals to determine the desired level of degradation.^[15-18].For determining the susceptibility of the drug to oxidative decomposition, testing may be started by keeping the drug in 3% H₂O₂ for 6 h at room temperature (Fig. 4). The period of reaction should be increased to 24 h in case there is no sufficient degradation. Still if there is no change, the reaction should be conducted in 10% H₂O₂ for 24 h. For a drug which does not oxidize even under these conditions, more extreme conditions of 30% H₂O₂ for 24 h may be tried. The drug may be declared to be “practically stable’’ if no products are formed on subjecting the drug to this condition. In an event of decomposition of whole drug under the starting conditions, the strength of H₂O₂ should be decreased from 3% to 1% and the reaction may be monitored for a period sufficient to yield the desired percent of decomposition. The drugs undergoing complete degradation even under these conditions are highly prone and should be tested in very dilute oxidizing agent with an exposure for very short duration. ^[21]

 

 

Figure 4: Pathway of Oxidation Degradation Study for Drug Substance and Drug Product (21)

Photo stability:

Photo stability testing should be an integral part of stress testing, especially for photo-labile compounds. Some recommended conditions for photo stability testing are described in ICH Q1B Photo stability Testing of New Drug Substances and Products Samples of drug substance, and solid/liquid drug product, should be exposed to a minimum of 1.2 million lux hours and 200 watt hours per square meter light. The same samples should be exposed to both white and UV light. To minimize the effect of temperature changes during exposure, temperature control may be necessary. The light-exposed samples should be analyzed for any changes in physical properties such as appearance, clarity, color of solution, and for assay and degradants. The decision tree outlined in the ICH Q1B can be used to determine the photo stability testing conditions for drug products. The product labeling should reflect the appropriate storage conditions. It is also important to note that the labeling for generic drug products should be concordant with that of the reference listed drug (RLD) and with United States Pharmacopeia (USP) monograph recommendations, as applicable (16-18). In order to get an idea about photo stability (Fig. 5), the drug substance should be initially subjected to an illumination up to 1.2 ×10⁶ lox hours which is the ICH recommended exposure and the reaction should be monitored periodically. The exposure may be increased by 5 folds in case there is negligible degradation. The drug may be declared photostable if the increase in exposure to 6.0 ×10⁶ lux hours has no effect on the stability of the drug. ^[21]

 

Figure 5: Pathway of Photo Degradation Condition for Drug Substance and Drug Product (21)

Heat:

Thermal stress testing (e.g., dry heat and wet heat) should be more strenuous than recommended ICH Q1A accelerated testing conditions. Samples of solid-state drug substances and drug products should be exposed to dry and wet heat, whereas liquid drug products can be exposed to dry heat. It is recommended that the effect of temperature be studied in 10 °C increments above that for routine accelerated testing, and humidity at 75% relative humidity or greater . Studies may be conducted at higher temperatures for a shorter period. Testing at multiple time points could provide information on the rate of degradation and primary and secondary degradation products. In the event that the stress conditions produce little or no degradation due to the stability of a drug molecule, one should ensure that the stress applied is in excess of the energy applied by accelerated conditions (40 °C for 6 months) before terminating the stress study ^[18].

 

Methodology for Isolation and Characterization of Degradation Product:

Stress testing of the drug substance can help to identify the likely degradation products, which Can in turn help establish the degradation pathways and the intrinsic stability of the molecule.Study is conducted on different stress studies on antihypertensive drugs under ICH guidelines Like hydrolysis (acidic, neutral and basic), photolysis, oxidation and thermal stress. Quantitative estimation of degradation    products and   establishment of mass balance should be done. After Quantitative estimation of degradation, Isolation of the Degradation products can be done with the help of different methods like TLC, flash chromatography (column chromatography) and preparative HPLC. After concurrent Isolation, Characterization of the degradation products should be done with the help of Ultraviolet spectroscopy, IR spectroscopy, NMR Spectroscopy, Mass Spectroscopy and HPLC. Figure 6 indicates flow chart Structural elucidation of degradation products.

 

 

Figure 6: Flow Path for Structural Elucidation of Degradation Products (14)

Degradation Product of Different Categories of Drugs

From the literature survey of antihypertensive drugs, it was found that major alkaline degradation products were found in angiotensin-II receptor antagonist (containing tetrazole moiety) for e.g. Losartan, Valsartan and Telmisartan etc. ^[24-26].Dihydropyridine moiety containing calcium channel blocker drugs shows major photo degradation products for e.g. amlodipine, felodipine, nilvadipine, nimodipine etc.^[30-34].Due to amide group in Anticancer taxanes(for e.g. Paclitaxel, Docetaxel), they shows major alkali degradation^[37-38]. A tetracycline antibiotic shows major thermal degradation due to epimerization of tetracycline ^[41-42]. A Fluoroquinone antibiotic shows photo degradation due to 8^th position of Fluoroquinolone moiety containing halogen group ^[43-44]. Deacetylation Causes acidic degradation of Cephalosporin antibiotics ^[45-47]. Amide hydrolysis results in acidic degradation of β-lactum antibiotics such as Dicloxacillin, Sultamicillin and Temocillin ^[49-51] .Hydroxylation of cyclohexane group in Glipizide and Glimipride (antidiabetic drugs) causes both acidic and alkaline degradation ^[54-56].Table II indicates list of Degradation Product of Different Categories of Drugs.

 

 

 

Table 2: List of Degradation Products of Different Categories of Drugs

Drug name	Stress Studies	Stress Condition	Degradation Product
Anti Hypertensive drugs
Angiotensin-II receptor blockers
Losartan [22]	Long term stability testing for 3 years	40∙c at 75% RH		Degrade 1- aldehyde derivative of Losartan
				DP-2 dimeric degradation of losartan
				DP-3 dimeric degradation of losartan
Valsartan[23]	Photo condition	UV–VIS radiation (> 320 nm)		N-[2-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-N-isobutylpentanamide (DP-1) from decarboxylation of VAL
				N-(diazirino [1, 3-f] phenanthridin-4-ylmethyl)-N-isobutylpentanamide (DP-2). loss of nitrogen from the tetrazole moiety
Telmisartan [24]	Photo acidic	UV light in a photo stability chamber at 8500 lx and 0.05W/m2,		Form Tricyclic Lactone of drug (3-((1, 7-dimethyl-2_-propyl-1H, 3H-2, 5-bibenzo[d]imidazol-3-yl) methyl)-6H-benzo[c]chromen-6-one).
Irbesartan[25]	Acid	1N HCl at 80◦C for  24 hr		DP-1(Up to 4.5% degradation) (2-(1H-tetrazol-5-yl) biphenyl-4-yl) methanamine.
	Basic	2N NaOH for 48 hr		DP-2 (Up to 51.4% degradation) 1-(1-(2-(1H-tetrazol-5-yl)biphenyl-4- yl) methylamino) pentylideneamino) cyclopentane  carboxylic acid
	Photo	8500 lx fluorescent and 0.05W/m2 UV light		DP-3 (Up to 48.7% degradation) tetra cyclic compound, viz., 2-butyl-3-(tetrazolo[1,5- F]phenanthridin-6-ylmethyl)-1,3-diazaspiro[4.4]non-1-en-4-one.
Olmesartan[26]	Long term stability testing for 6 months	40°c at 75% RH		Dehydrated dimer of Olmesartan
ACE Inhibitors
Enalapril[27]	acid	0.1N HCl at 80 °C after 18 h.	∼20% degradation total five degradation products (I–V) were formed.
	Alkaline degradation	3 h in 0.1N NaOH at 80 °C.	Susceptible to alkaline degradation completely converted into single product.
Thiazide diuretics
Hydrochlor Thiazide[28]	Hydrolysis	15% in 1 mol L-1 HCl and 1 mol L-1 NaOH at 80 °C	4-amino-6-chloro-1,3-benzenedisulfonamide
	oxidative	3% H2O2, at 80 °C for 1 h	6-chloro-2-oxy-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide.
Calcium Channel blockers(non-dihydropyridines)
Diltiazem[29]	Oxidation	3% H2O2 at 80 °C for 1 h.	Diltiazem sulfoxide as a major degradation product, The drug was reduced to 43% on peroxide degradation.
Calcium Channel blockers(Dihydropyridines)
Nilvadipine[30]	Photolysis	Methanol solutions of Nilvadipine were irradiated with a high-pressure UV lamp λ=365.	5-isopropyl -3-methyl 4-(3-nitrophenyl)-6-methyl.
Nimodipine[31]	Photo Degradation	-	The drug  undergoing oxidation to its pyridine analogue (NMDP) with simultaneous transposition of the nitro group from the meta to para position
Amlodipine[32]	Photo degradation	280–360 nm UV lamp (30 W, at a Distance of 30 cm).	Pyridine analogue (AMLOX)
Nifedipine [33]	light	mercury vapor and fluorescent lamps as light sources	Nitrosopyridine, the degree of degradation reached the maximum at around 380 nm corresponding to the absorption band of the nitro group and dihydropyridine ring in the molecule. The degradation process followed apparent first-order kinetics
Isradipine[34]	Basic conditions	-	Conversion of the methyl ester to the corresponding carboxylic acid was found to occur under both ambient and 60°C temp.
Alpha-2 agonists
Moxonidine[35]	Alkaline	8 hr. in 0.1 M NaOH	No reported degradation product
Beta Blockers
Propranolol[36]	Photostability	-	(1)1-Naphthol (2)N-Acetylpropranolol (3)N-formylpropranolol
Anticancer drugs
Taxanes
Paclitaxel [37]	Acidic	HCl	10-deacetyl paclitaxel Oxetane ring opened product
	Basic	NaOH	10-deacetyl paclitaxel 7-epipaclitaxel
	Oxidation	H2O2	10-deacetyl paclitaxel
	Photo	4000 lux	Isomer which contains C3-C11 bridge
Docetaxel[38]	Hydrolysis	Base (0.005N NaOH at RT)	Major degradant is observed as 7-Epimer. Also some unknown degradation products were formed.
	UV(254 nm)	10 days	Major degradant is observed as DCT-1.
PAC-1 (4-benzyl-piperazin-1-yl)- acetic acid (3-allyl-2-hydroxy-benzylidene)-hydrazine.[39]	Acid degradation	80 ◦C for 10 h.	1) 2-allyl-6-((E)-((E)-(2-hydroxy-3-(2-hydroxypropyl)benzylidene)- Hydrazono) methyl) phenol. 2)2-hydroxy-3-(2-propenyl)-[[2-hydroxy-3-(2-propenyl)phenyl]methylene]- Hydrazone. 3)6,6-(1E,1_E)-hydrazine-1,2-diylidenebis(methan-1-yl-1-ylidene)bis(2-(2-hydroxypropyl)- Phenol. 4) 2-hydroxy-3-(2-hydroxypropyl) benzaldehyde.
Antischizophrenic drugs
Risperidon[40]	Thermal	40◦C/75%RH	3-[2-[4-[6-fluoro-1, 3-benzoxazol-2-yl] piperidin-1-yl] ethyl]-2-methyl-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a] pyrimidin-4-one.
Antibiotics
Tetracyclines
Tetracycline[41]	Heat, pH, and humidity.	-	Undergo reversible Epimerization at positions C-4 and C-6 to form a mixture of degradation products.
Doxycycline[42]	Thermal	At –20, 5, 25, 40, 50, 60, and 70°Cdifferent temp. & 75% RH or greater	Metacycline and 6-epidoxycyline are Identified as degradation products at high temperatures.
Fluoroquinolone Antibiotics
Sparfloxacin[43]	Photo degradation	UV light peak Wavelength 290 nm for 36 hours at room temp.	SPAX-PDP1 and SPAX-PDP2 with oxidation in the substituent on the C-7.
Clinafloxacin[44]	Photochemical degradation	Severe light exposure	Polar and nonpolar photochemical degradation products.
Cephalosporin Antibiotics
Cephalexin[45]	Acid	5M HCL in presence of Formaldehyde	2-Hydroxy-3-phenyl-6-methylpyrazine.
Cefaclor[46]	Acidic Aqueous degradation	37∙C in neutral aqueous medium	The degradent involves the condensation of two cefaclor degradation products ,in which both products have undergone contraction from a six-membered cephem ring to a five-membered thiazole ring.
Cefexime Trihydrate[47]	Dehydration		Partially Dehydration of Cefexime trihydrate gives highly disordered crystal structure caused by loss of its water of crystallization.
Carbapenem Antibiotics
Meropenem[48]	Long term stability	Stability profile at 4 and 25 °C for 24, 48 and 72 h..	Sample solutions were stable during 24 h when stored at 4 and 25 °C with degradation less than 5%. Meropenem was less stable at 25 °C with a degradation of 12.7% after 72 h
ß lactam antibiotic
Dicloxacillin[49]	Hydrolysis	-	Impurity-I. Penicilloic acids of dicloxacillin (dicloxacilloic acids).
	Oxidation	-	Penilloaldehyde a known impurity of the penicillin on atmospheric oxidation under the degradation conditions is the most Likely pathway for the formation of Impurity-II.
Sultamicillin[50]	Thermal exposure	60 ± 2◦C and analyzed at different time intervals: 12 h, 1 day, 2, 5, 10 and 15 days, respectively	Under thermal stress conditions sultamicillin degrades to ampicillin, sulbactam and formaldehyde is released as a byproduct. Formaldehyde further  reacts with amino group in sultamicillin leading to Formation of this impurity.
Temocillin[51]	Acidic conditions	-	Methoxypenillic acid
	Alkaline or enzyme hydrolysis	-	Results in the formation of the methoxypenicilloic acid and the C-5 epimer.
Antibacterial drug
Ertapenem[52]	Acidic conditions	0.1N hydrochloric acid at at room temperature for  2 hr	Main degradation product of ERTM is the open ß lactam ring structure
Metronidazole[53]	Photodegra-dation	Aqueous metronidazole solutions buffered with citrate: phosphate. Further degraded by light, heat or by addition of no aqueous solvents	Yellow photo degradation product           .
Antidiabetic
Sulfonylurea
Glipizide[54]	Acid hydrolysis	0.1M HCl at 85°C	5-methyl-N-[2-(4-sulphamoylphenyl) ethyl]pyrazine-2-carboxamide (II)   and methyl N-[4-[2-{(5-methyl-2-pyrazinoyl) amino} ethyl] phenyl]sulfonyl carbamate (III).
	Alkali Conditions	0.1M NaOH at 85°C.	5-methyl-2-pyrazinecarboxylic acid (IV), along with a small quantity of 4-(2-aminoethyl) benzenesulfonamide (I).   On extended heating in the same condition, a new product, 4-(2-aminoethyl)-N,Nbis[(cyclohexylamino)carbonyl] benzene sulfonamide (VI) is formed in small quantities. On extended heating in the same condition, a new product, 4-(2-aminoethyl)-N,Nbis[(cyclohexylamino)carbonyl] benzenesulfonamide (VI) is formed in small quantities.
Glimepiride[55]	Acid and neutral (water)hydrolytic conditions	0.1 N HCL	1) 3-Ethyl-4-methyl-2-oxo-N-(2-(4-sulfamoylphenyl)ethyl]-2,3-dihydro-1H-pyrrole-1-carboxamide 2) Methyl[4-[2-[3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl]phenyl]sulfonyl]carbonate
	Alkaline conditions.	0.1N NaOH	1)       [[4-[2-(N-carbamoyl) aminoethyl]phenyl]sulfonyl]-3-trans-(4-methylcyclohexyl)urea 2)       1-[4-(2-Aminoethyl)-phenylsulfonyl]-3-trans-(4-methylcyclohexyl)urea
Thiazolidinediones
Pioglitazone hydrochloride[56]	Oxidative degradation	10% H2O2	pioglitazone N-oxide
	Base degradation	0.1 M NaOH	3-(4-(2-(5-ethylpyridine-2yl) ethoxy) phenyl)-2-mercaptopropanoic acid and 2-(1-carboxy-2-{4-[2-(5-ethylpyridine-2yl)-ethoxy] phenyl}-ethyl disulfanyl)-3-{4-[2-(5-ethylpyridine-2yl)-ethoxy] phenyl propanoicacid

 

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Received on 10.01.2013         Modified on 17.01.2013

Accepted on 10.02.2013         © AJRC All right reserved