FORCED DEGRADATION STUDY OF ROSUVASTATIN AND TENELIGLIPTIN, CHARACTERISATION OF ITS DEGRADATION PRODUCTS BY VARIOUS ANALYTICAL TECHNIQUES: A REVIEW

FORCED DEGRADATION STUDY OF ROSUVASTATIN AND TENELIGLIPTIN, CHARACTERISATION OF ITS DEGRADATION PRODUCTS BY VARIOUS ANALYTICAL TECHNIQUES: A REVIEW

Sheeja Velayudhankutty, C. M. Niranjana * and P. P. Sreelekha

Department of Pharmaceutical Analysis, Grace College of Pharmacy, Kodunthirapully P.O, Palakkad, Kerala, India.

ABSTRACT: Rosuvastatin is a widely used lipid-lowering medication that belongs to the class of “Statins” whereas Teneligiptin is a novel potent drug that belongs to the class of “DPP-4 inhibitors” which is used for the treatment of Type 2 Diabetes mellitus. The FDA recently approved the combination of these two drugs in 2021 since it proved to be highly effective for treating dyslipidemia associated with Type 2 Diabetes mellitus. Forced degradation studies have been performed on Rosuvastatin and Teneligliptin separately using various analytical techniques such as RP-HPLC, UV, RP-UFLC, RP-UPLC, UHPLC, HPTLC and TLC. Characterization of the degradation products generated during various stress conditions is also performed using various sophisticated techniques such as UPLC, LC/MS/MS, NMR, and FT-IR. These degradants can cause many adverse effects, such as carcinogenicity, mutagenicity, neurotoxicity, hepatotoxicity, skin sensitization, respiratory sensitization, etc. So, identifying and characterizing these degradation products will be very useful for their metabolic studies and in-silico toxicity assessment. In-silico toxicity studies are very helpful in predicting the toxic potential of these degradants, and it is performed using various software such as TOPKAT, Osiris, and DEREK. Thus, the present review aims to summarise the forced degradation studies as well as characterization of the degradation products generated from both rosuvastatin and teneligliptin using various modern analytical techniques so that it will significantly contribute in the future regarding their metabolic studies, determination of impurities during their bulk synthesis as well as toxicity predictions.

Keywords: Rosuvastatin, Teneligliptin, Forced degradation, characterization

INTRODUCTION: Degradation can be defined as the incapability of a particular substance to remain within its particular physical, chemical, microbiological, toxicological, and therapeutic specifications. “Forced degradation can be defined as the degradation of a New drug substance or new drug product at conditions more severe than the accelerated conditions.

Forced degradation studies depend on the type of product and the dosage form. It is mandatory to establish the specificity of the stability indicating methods and provide insight into degradation pathways and degradation products of the drug substance that are likely to be formed” ¹. It also helps in the structure elucidation of the degradation products.

According to FDA and ICH, stress testing is necessary to understand how the quality of a drug substance and product changes with time under the influence of various environmental factors. Felicitous knowledge about the molecule's stability helps in selecting proper formulation and package and provide proper storage conditions and shelf life, which are essential for regulatory documentation. Degradation products generated during these testing can be studied to determine the molecule's stability. “The stability studies include long-term studies (12 months) and accelerated stability studies (6 months).

But intermediate studies (6 months) can be performed at conditions milder than that used in accelerated studies. So the study of degradation products like separation, identification, and quantitation would take even more time. Compared to stability studies, forced degradation studies help generate degradants in a much shorter span of time, mostly a few weeks.

Objective of Forced Degradation Studies:

1. To establish degradation pathways of drug substances and drug products.
2. To differentiate degradation products related to drug products from those generated from non-drug products in a formulation.
3. To elucidate the structure of degradation products.
4. To determine the intrinsic stability of a drug substance in the formulation.
5. To reveal the degradation mechanisms such as hydrolysis, oxidation, thermolysis or photolysis of the drug substance and product.
6. To establish stability indicating the nature of a developed method.
7. To understand the chemical properties of drug molecules.
8. To generate more stable formulations.
9. To produce a degradation profile similar to what would be observed in a formal stability study under ICH conditions.
10. To solve stability-related problems.

Degradation of drug substances between 5% and 20% have been accepted as reasonable for validating chromatographic assays. It is recommended that the studies should be initiated at a concentration of 1 mg/mL. By using a drug concentration of 1 mg/mL, it is usually possible to get even minor decomposition products in the range of detection” ¹.

A combination of Rosuvastatin and Teneligliptin treats Type 2 DM and Dyslipidemias. Rosuvastatin (depicted in Fig. 1) belongs to a bunch of medication called “Statins”, which decreases LDL and Triglycerides and lift HDL within the blood. “It competitively inhibits the conversion of 3- hydroxy-3-methyl glutaryl coenzyme A to mevalonate (rate-limiting step in CH synthesis)  by the enzyme HMG CoA reductase. Therapeutic dose reduces CH synthesis by 20-50%. This results in a compensatory increase in LDL receptor expression on liver cells – increased receptor-mediated uptake and catabolism of IDL and LDL. All statins except rosuvastatin are metabolized primarily by CYP3A4. In patients with raised TG levels, rosuvastatin raises HDL-CH by 15 – 20%” ². Teneligliptin (depicted in Fig. 2) is an antidiabetic medication that decreases blood glucose levels by enhancing insulin release from the pancreas. Thereby fasting and post-meal sugar level reduces.

FIG. 1: ROSUVASTATIN CALCIUM: (E)-(3R, 5S)-7-{4-(4 - FLOUROPHENYL) – 6 – ISOPROPYL – 2 -[METHYL (SULPHONYLAMINO)] PYRIMIDIN-5-YL}-3,5- DIHYDROXYHEPTEN-6-OIC ACID CALCIUM

FIG. 2: TENELIGLIPTIN HYDROBROMIDE HYDRATE: {(2S, 4S)-4-[4-(3-METHYL-1-PHENYL-1H-PYRAZOL-5-YL) PIPERAZINE-1-YL] PYRROLIDINE-2-YL} (1, 3 - THIAZOLIDINE – 3 - YL) METHANONE HEMIPENTAHYDROBROMIDE HYDRATE

“Diabetes and increasing resistance to insulin, even in persons considered to have ‘‘normal’’ insulin sensitivity, has been associated with higher concentrations of cholesterol, LDL and  TG and lower concentrations of HDL cholesterol ^{3, 4}, which results in “Atherogenic Dyslipidemia” and worsens the prognosis of diabetic patients by synergistically accelerating atherosclerosis and development of CVD. It has been hypothesized that most oral anti-diabetic drugs have significant lipid lowering effect besides achieving effective glycaemic control. Thus, they can modify dyslipidemia and help decrease the risk of atherosclerosis, coronary heart disease, stroke, nephropathy and nephropathy and retinopathy” ⁵.

In patients with diabetes, adherence to statin therapy was poor, with a reduction from 87% in starting 3 months to less than 50% 6 months onwards. Through the combination, it has been proven to improve medication when compared to its free drug component treatment. There is also a remarkable reduction in HbA1c, a reduction in Low-density lipoprotein (LDL) level at 24 weeks, and a decreases threat of heart disease in diabetic patients ⁶. While going through the literature survey, it was found that no forced degradation studies have been done in this drug combination. Also, characterization of the degradation products generated during various stress conditions is not performed till now. This review aims to provide updated information about forced degradation studies done in this drug combination using various analytical techniques and characterization of degradation products which will be useful in the future for conducting in-silico toxicity studies.

METHODS:

Characterization of Degradation Products: Identifying the degraded products helps in future metabolic studies and related impurity determination during its bulk synthesis. Characterization can be done using various modern analytical techniques such as:

• UPLC
• LC/MS/MS
• NMR
• FT-IR

Various types of forced degradation studies on drug substances and products are depicted in Fig. 3 ⁷.

FIG. 3: FORCED DEGRADATION STUDY OF DRUG SUBSTANCE AND DRUG PRODUCT

Forced Degradation Study of Rosuvastatin using Various Analytical Techniques: The optimum conditions for performing forced degradation studies are summarised in Table 1, Table 2, Table 3 and Table 4.

TABLE 1: FORCED DEGRADATION STUDIES USING HPLC

Discussion and Interpretation: For the degradation study done by authors of reference ⁸, the drug was found to be unstable under acid hydrolysis and photolysis. It was stable under basic, neutral hydrolysis, oxidation and thermal conditions. Here, eleven degradation products were formed. Five degradation products were formed under acid hydrolysis – RS-1, RS-6, RS – 7, RS – 10, RS-11. Six degradation products were formed under photolysis conditions – RS-2, RS – 3, RS – 8, RS – 9, RS – 4, RS – 5. Merit of this work was RS-2, RS-3, RS-6, RS-10 and RS-11 are previouly unknown degradation products of rosuvastatin, got detailed information about these products. Structure elucidations of all the degradation products were done using LC-MS/TOF, LC-MSⁿ, on-line H/D exchange and LC-NMR. MS/TOF studies were performed in ESI positive mode. The fragmentation pathway of drug under various stress conditions, characterisation of the formed degraded products using various techniques along with their in-silico toxicity assessment was well explained. H¹ NMR and COSY spectra were recorded using the WET pulse sequences. In-silico toxicity of all degradation products was predicted using TOPKAT and DEREK software.

For reference ⁹, the merit of this work was that the objectives, time to perform degradation, selection of drug concentration, and limits for degradation are well explained. The demerit associated with this work is that the procedure for photolysis and thermal degradation is not well explained

Reference ¹⁰ found that the drug was stable under neutral and alkaline hydrolysis. Unstable under acidic, photolytic, and oxidation conditions. Photolytic degradation is observed to be very prominent. The demerit of this work was that the neutral hydrolysis is performed using phosphate buffer, as well as characterization of degraded products is not done. Merit of the present work is that, this method is very specific and can be used to determine rosuvastatin calcium in the presence of its various degradation products and excipients used in the tablet form.

Reference ¹¹, rosuvastatin has significantly undergone alkaline degradation due to the presence of carboxylic acid group in its structure. It is slightly sensitive toward photolytic degradation. Degree of degradation is very less under acidic, oxidation and thermal degradation. The advantage of this work was that it very useful for the long term stability studies of pharmaceutical dosage forms. The disadvantage is that degraded products generated under various stress conditions are poorly explained.

Reference ¹² shows the drug was highly unstable under acidic, oxidation, and photolytic conditions. Slightly sensitive to thermal degradation. It is comparatively stable in neutral and alkaline conditions. Seven degradation products were formed as a part of degradation studies. The merit of this work was that the degree of degradation under various stress conditions is well explained.

Reference ¹³, here, drug is highly unstable under thermal thermal degradation (20%) and acidic hydrolysis (16%). It was found to be stable under neutral hydrolysis. The advantage of the present work is that this method can be used to determine Rosuvastatin and Ezetimibe in the capsule dosage form. The disadvantage found in this work is that photolytic degradation is not performed.

Reference ¹⁴, major degradation of the drug has occurred under acidic hydrolysis (57%), 36% under alkaline conditions, 32% under oxidation, 30% under photolytic degradation, and 15% under thermal degradation. The main advantage of this work was that YMC packs C8 column was used, having several advantages like high resolving power, low tailing etc. Demerit of the present work is that the number of degradation products generated from each stress condition is not specified.

Reference ¹⁵ shows the drug's major degradation occurred under alkaline hydrolysis (12.9%). No degradation was found under oxidation and thermal conditions. The merit of this work is that this method explains the degradation characteristics of Rosuvastatin calcium and Fenofibrate in the combined dosage form. The main demerit is the long duration for all stress degradation studies (24 hours).

Reference ¹⁶, the drug was found to be highly degraded under acidic hydrolysis and oxidation conditions by forming two degraded products. In thermal degradation, the drug was found to be highly stable. The merit of this work is that, this method can be applied for the routine quality control analysis of Rosuvastatin calcium in bulk and tablet dosage form. Demerit is that the number of degradation products formed under each stress condition is not specified.

Reference ¹⁷ shows that rosuvastatin was unstable under acidic, alkaline, photolytic, and oxidation conditions. Major degradation has occurred under acidic hydrolysis (35.7%). Metformin was decomposed only under alkaline hydrolysis. The advantage of the present work is that this method can be used for simultaneous quantitation of Rosuvastatin and Metformin in a combined oral solid dosage form. The main disadvantage was that the thermal degradation duration is very long (1 week).

Reference ¹⁸, drug was found to be unstable under acidic, alkaline, oxidation, and thermal degradation. Two degradation products were formed under alkaline hydrolysis. 94% of the drug has degraded under oxidation conditions in the presence of 30% H₂O_2. The advantages of the present work are that it is cost-effective, a green mobile phase has been used, and speed of analysis. Disadvantages include very long duration for all forced degradation studies (2 days) and the degradation under neutral hydrolysis and photolysis condition is not performed.

Reference ¹⁹, drug was significantly degraded under acidic hydrolysis, oxidation and photolysis. New impurity was not generated during acidic, basic, neutral hydrolysis or under oxidation, photolysis, or humidity degradation. Only in thermal degradation 0.18% of the impurity was generated.

In this study, a new impurity of rosuvastatin was found during the analysis of accelerated stability samples by HPLC. Identification of impurity is done by LC-MS/MS using an Electrospray ionisation source and Q trap mass analyzer.

Based on the analysis, it was found that condensed product of Meglumine excipient with Rosuvastatin molecule was generated as the impurity. Characterization was done using LC-MS, HRMS (UPLC-TOF-MS), NMR and FT-IR spectroscopy. In NMR spectroscopy, both H1 and C13 NMR spectra were recorded.

In reference 20, the drug's Anti – isomer and lactone impurities were generated in acidic hydrolysis. In photolysis, two unknown impurities are formed. In thermal degradation, one unknown impurity was generated. The merit of this work is that the impurities were characterized using ESI – MS, HRMS, and NMR spectroscopic methods. ESI mass spectrum of Rosuvastatin impurity was recorded on Q trap LC-MS/MS system.

Mass spectral data indicate the formation of the condensed product of Meglumine with Rosuvastatin. HRMS spectrum confirms the molecular formula of the impurity as C₂₉H₄₄N₄0₁₀FS.

Recommendation: Among all the forced degradation studies done using the RP-HPLC technique, it is seen that references ^{8, 19, 20} are better when compared with the remaining references because only in these works, characterization of the degradation products or impurities generated during various stress conditions is performed using sophisticated techniques such as LC-MS/MS, HRMS, NMR, and FTIR spectroscopy.

Among these three references, reference ⁸ can be considered the best and will be very useful in the future, because only in this work is the in-silico toxicity assessment of the degradation products well explained using software such as TOPKAT and DEREK.

TABLE 2: FORCED DEGRADATION STUDIES USING UPLC

Reference ²¹ revealed four unknown degradation products when exposed to acidic conditions. The drug was relatively stable when exposed to basic, thermal, and oxidation conditions. Significant degradation of the drug was found under acid hydrolysis and photolysis condition.

Anti- rosuvastatin isomer and unknown impurities were formed. The main advantage of this method is the short run time, which helps in rapidly determining degradation products. The disadvantage is that the procedure for performing forced degradation studies is poorly explained. Reference ²², drug was found to be highly degraded under acid hydrolysis.

Lactone and an unknown impurity was the major degradation products formed under this hydrolysis. The drug was found to be comparatively stable under basic and photolytic conditions. An unknown degradant formed in acid hydrolysis was identified using UPLC-MS/MS analysis with Q-TOF mass spectrometer. A major degradant formed during acid stress was identified as ROS methyl ester. Analysis was performed using ESI in positive mode.

Advantages of the present work include a significant decrease in the consumption of solvent and time for separation and the identification of unknown impurities by coupling with QTOF mass spectrometer. The disadvantage is that forced degradation under neutral hydrolysis is not performed.

Recommendation: Here, reference ²² can be considered better because, in this work, the identification of the unknown degradant generated is performed using UPLC-MS/MS coupled with a Q-TOF mass spectrometer. Also, this work has various merits, such as less consumption of solvent and less time for separation of components.

TABLE 3: FORCED DEGRADATION STUDIES USING LC-UV-MS AND UV

Reference ²³ shows the drug was highly unstable under acidic and photolysis under UV light. It is slightly sensitive to oxidation and heat. In total, eleven degradation products were formed. It was found to be relatively stable under basic conditions. Merit of this work is that the quantitative determination of degradation products was done using highly sensitive ESI – MS method. Information about degradation kinetics of rosuvastatin under UV exposure was explained. The proposed chemical structure of the degradation products was characterized by studying their MS² fragmentation pattern using Ion-trap MS in its acid form. The drug showed a molecular ion peak at m/z 482. Characteristic degradation product generated during oxidative stress was found to be Rosuvastatin –N-oxide

Reference ²⁴ shows the drug's major degradation occurred under acid hydrolysis (15.64%). The degree of degradation of rosuvastatin is less when compared with that of metformin under various stress conditions. This method is useful for the quality control analysis of Rosuvastatin and Metformin in bulk and combined dosage forms. The disadvantage of the present work is that the number of degradation products formed under various stress conditions is not specified.

TABLE 4: FORCED DEGRADATION STUDIES USING TLC

Reference ²⁵, the drug was found to be highly susceptible to degradation under oxidation conditions, and five major degradation products were formed. Next significant degradation is seen under acidic hydrolysis, and four major degradants are formed. Two major degradation products are formed in the case of thermal degradation and photolysis. The mass spectroscopic analysis provided molecular ion peaks of different degradation products. Some of these degraded products were studied through their MS²-MS⁴ fragmentation pathway, while other unknown peaks cannot be interpreted. The chemical structures of four degradation products were characterized using LC-ESI-MS. The merit of this work is that the identification of the degradation products formed under various stress conditions is well explained. The degradation kinetics of the drug under UV irradiation is also explained. Demerit is that the forced degradation studies under neutral hydrolysis are not performed. Reference ²⁶, drug was found to be sensitive under acidic hydrolysis and oxidation conditions. Two degradation products are formed when the drug is refluxed under acidic conditions. The drug is comparatively stable under alkaline hydrolysis. The structure of the degradation products generated during acid hydrolysis was determined through FT-IR and Mass spectroscopy. The disadvantage of this work is that the degradation of the drug under other stress conditions is not explained.

Recommendation: Here, reference ²⁵ can be considered better and more useful in the future because, in this work, the characterization of degradation products generated during various stress conditions is performed using LC-ESI-MS, whereas in reference ²⁶, only the characterization of the degradants generated during acid hydrolysis is explained and degradation of the drug under various conditions is not explained.

Forced Degradation Study of Teneligliptin by Using Various Analytical Techniques: The optimum conditions for performing forced degradation studies are summarised in:

Table 5, Table 6, Table 7, Table 8, Table 9 and Table 10.

TABLE 5: FORCED DEGRADATION STUDIES USING RP- HPLC

Discussion and Interpretation: For the degradation study done by authors of reference ²⁷, degradation products formed are similar in the case of basic and thermal hydrolysis. Significant degradation of the drug was observed under oxidation, basic and thermal hydrolysis. Drug was found to be stable under acidic and photolysis condition. The degraded products were identified and characterized using UPLC with tandem mass spectroscopy (LC/MS/MS). The products were ionised by ESI mode for their mass data. The molecular ion peak for Teneligliptin was observed at 427.22. From the mass spectral data, the fragmentation pattern of Teneligliptin was portrayed. Fragmentation pattern of base, peroxide and thermally stressed drug was depicted. Disadvantage of this work is that the degradation of the drug under neutral conditions is not performed.

For reference ²⁸, major degradation of the drug was observed under alkaline (19.5%) and acidic (15.33%) hydrolysis. The drug was found to follow first-order kinetics under alkaline hydrolysis. It indicates that as the temperature increases, the degradation of teneligliptin also increases. The merit of this work is that the degradation kinetics of the drug under alkaline hydrolysis is well explained. Demerit is that the number of degradation products formed under various stress conditions is not specified.

Reference ²⁹, the drug was found to be significantly degraded under acidic hydrolysis (3.66%) and three degradation peaks were obtained. Two degradant peaks were found under alkaline hydrolysis and one peak under oxidation conditions. This method will be very useful for studying the degradation characteristics of Teneligliptin and Metformin in a combined dosage form.

Reference ³⁰, major degradation of the drug has been observed under thermal hydrolysis (7.23%). Disadvantage of this work is that degradation of the drug under neutral conditions is not performed. Reference ³¹, significant degradation of the drug was found under acid hydrolysis (4.98%). For performing the dry heat and photolytic degradation, the sample was presented in the solid state. Degradation conditions such as the concentration of degradation reagent and time of exposure were optimized, so the degradation is within the range of 10%. The main demerit associated with this work is the long duration of the photolytic degradation (7 days).

Reference ³², the maximum degradation of the drug was found under oxidative conditions i.e 9.26%. The peak of the degradant does not interfere with the API peak. The merit of this work is that the degraded product can be well separated, quantified, and characterized so that its safety profile can be studied. Demerit is that the degradation of the drug under photolysis and the neutral condition is not performed.

Reference ³³, the long duration of photolysis (15 days) and thermal degradation (3 months) is the main disadvantage of this work. Also, the degradation characteristics of the drug under various stress conditions are not explained.

Reference ³⁴, the drug was significantly degraded under oxidative stress (11.6%). There is no interference of the degradant peak at the retention time of the main analyte peak. The demerit of this work is that neutral hydrolysis of the drug is not performed

Reference ³⁵, the drug was found to be highly unstable under oxidation conditions (47%). It was found to be sensitive to acidic, alkaline, neutral, thermal, and photolytic degradation. The main disadvantage of this work is the long duration of photolytic degradation (1 month)

Recommendation: While going through all the forced degradation studies done using the RP-HPLC technique, it is seen that reference ²⁷ is better when compared with other references. Because only in that work the degradation studies, identification, and characterization of degradation products are well explained. While comparing the references in which teneligliptin has undergone neutral hydrolysis, it is shown that reference ²⁹ is better when compared with 33 and 35, because of the short duration of degradation studies and the number of degradant peaks are clearly mentioned here, when compared with other works.

TABLE 6: FORCED DEGRADATION STUDIES USING UHPLC

Reference ³⁶, major degradation of the drug was found under oxidation conditions (27.59 %). It was found to be stable under thermal, photolysis, and acidic hydrolysis. This is a high speed, high-resolution analytical technique for simultaneous determination of Teneligliptin and Metformin in fixed dose combination. Demerit of this work is that, degradation under neutral conditions is not performed.

TABLE 7: FORCED DEGRADATION STUDIES USING UPLC

Reference ³⁷, significant degradation of the drug was observed under oxidation and alkaline hydrolysis. Degradation products were found to be toxic when analyzed using Osiris software. The drug was found to be stable under thermal, photolysis and acidic hydrolysis. The degradation products were characterized using IR, NMR and MS techniques to get detailed information about their structure. H1 and C13 NMR were also recorded. The demerit of this work is that the degradation under neutral conditions is not performed.

TABLE 8: FORCED DEGRADATION STUDIES USING RP- UFLC

Reference ³⁸, the percentage recovery of the drug was found to be very less after oxidation conditions (22.23%). A disadvantage of this work is that degradation under neutral conditions is not performed as well as the number of degradation products formed under various stress conditions is not specified. Reference ³⁹, peak of Teneligliptin was completely destroyed under acidic and alkaline hydrolysis due to carbonyl moiety and heterocyclic moiety in the structure of the drug. Less than 5% degradation was observed under oxidation and neutral hydrolysis. The disadvantage of this work is that degradation under photolysis and thermal condition is not performed.

TABLE 9: FORCED DEGRADATION STUDIES USING UV

Reference ⁴⁰ found that when the amount of stress applied increases, the degradation rate also increases. Major degradation of the drug occurred under photolysis conditions using UV light. The area of the degraded peaks was less than the area of the standard drug peak; this indicates that the drug undergoes degradation in all conditions. The demerit of this work is that the degradation under neutral conditions is not performed. Reference ⁴¹, major degradation of the drug was found under oxidation and alkaline hydrolysis. In sunlight degradation, both Teneligliptin and Metformin show the lowest degradation. The disadvantage of this work is that the number of degradation products formed under various stress conditions is not explained.

Recommendation: While going through the forced degradation studies done using UV spectroscopy, it is shown that reference ⁴⁰ is better when compared with ⁴¹ because of the short duration of degradation studies. Also, this reference explains the procedure for performing degradation studies under various stress conditions.

TABLE 10: FORCED DEGRADATION STUDIES USING HPTLC

Reference ⁴², significant degradation of the drug was found under alkaline hydrolysis and oxidation stress conditions. This method can be applied for the routine quality control analysis of the drug in bulk and pharmaceutical dosage form. A disadvantage of this work is the long duration of photolysis and thermal hydrolysis (24 hrs) when compared with other stress conditions.

CONCLUSION: With the help of forced degradation studies, we can establish degradation pathways of the drug substance. It will also be very useful to understand the conditions in which the drug undergoes significant degradation. This information is vital for selecting proper formulation, packaging and the determination of shelf life. The above article explains the forced degradation studies conducted on rosuvastatin and teneligliptin using various analytical techniques. By going through this information, readers will understand the nature of the degradation of both drugs.

ACKNOWLEDGEMENT: Authors are highly grateful to the Principal, Prof. Dr. Y. Haribabu, Grace College of Pharmacy, for providing the necessary facilities to prepare the review article. We are also very thankful to Cochin University of Science and Technology for providing the library facilities.

CONFLICTS OF INTEREST: None to declare.

REFERENCES:

1. Blessy MR, Patel RD, Prajapati PN and Agrawal YK: Development of forced degradation and stability indicating studies of drugs- A review. Journal of Pharmaceutical Analysis 2014; 4(3): 159-165.
2. Tripathi KD: Hypolipidaemic Drugs and Plasma Expanders. Essentials of Medical Pharmacology. Jaypee Brothers Medical Publishers, India, Edition 7, 2013; 636-637.
3. Patil M, Jani H, Khoja S, Pirani N and Khoja S: A review on chemistry and pharmacological   activity of metformin hydrochloride and teneligliptin hydrobromide hydrate in combined dosage form. Pharma Tutor 2017; 5(3): 24-30.
4. Krauss RM and Siri PW: Dyslipidemia in type 2 diabetes. Medical Clinics of North America 2004; 88(4): 897- 909.
5. Motgi S, BNV RR and Sattar MA: Study of lipid lowering effects of oral antidiabetic drugs in type 2 diabetes mellitus patients. International Journal of Basic and Clinical Pharmacology 2018; 7(1): 126-132.
6. Bae JC, Min KW, Kim YH, Kim KA, Hong EG, Park CY, Han S and Cha BS: Efficacy and safety of fixed‐dose combination therapy with gemigliptin (50 mg) and rosuvastatin compared with monotherapy in patients with type 2 diabetes and dyslipidaemia (BALANCE): A multicentre, randomized, double‐blind, controlled, phase 3 trial. Diabetes Obesity and Metabolism 2019; 21(1): 103-111.
7. Ahmed H, Hassan W, Murtaza G, Bakht S and Iqbal FM: Methods and Protocols for Drug Stability Studies. Drug Stability and Chemical Kinetics. Springer Singapore 2020; 43-55.
8. Shah RP, Sahu A and Singh S:  LC-MS/TOF, LC-MSn, on-line H/D exchange and LC-NMR studies on rosuvastatin degradation and in-silico determination of toxicity of its degradation products: a comprehensive approach during drug development. Analytical and Bioanalytical Chemistry 2013; 405(10): 3215-3231.
9. Blessy MR, Patel RD, Prajapati PN and Agrawal YK: Development of forced degradation and stability indicating studies of drugs-A review. Journal of Pharmaceutical Analysis 2014; 4(3): 159-165.
10. Mehta TN, Patel AK, Kulkarni GM and Suubbaiah G: Determination of rosuvastatin in the presence of its degradation products by a stability-indicating LC method. Journal of AOAC International 2005; 88(4): 1142-1147.
11. Mukthinuthalapati MA, Bukkapatnam V and Bandaru SP: Stability indicating liquid chromatographic method for the simultaneous determination of rosuvastatin and ezetimibe in pharmaceutical formulations. Advanced Pharmaceutical Bulletin 2014; 4(4): 405-411.
12. Raj HA, Rajput SJ, Dave JB and Patel CN: Development and validation of two chromatographic stability-indicating methods for determination of rosuvastatin in pure form and pharmaceutical preparation. International Journal of Chem Tech Research 2009; 1(3): 677-689.
13. Patel Aesha A and Patel P: Development and validation of stability indicating RP-HPLC method for estimation of rosuvastatin and ezetimibe in capsule dosage form. World J of Pharmaceutical Research 2018; 7(7): 1502-1516.
14. Kaila HO, Ambasana MA, Thakkar RS, Saravaia HT and Shah AK: A new improved RP-HPLC method for assay of rosuvastatin calcium in tablets. Indian Journal of Pharmaceutical Sciences 2010; 72(5): 592-598.
15. Pimpale A and Kakde R: Development and Validation of Stability-Indicating Assay Method by RP-HPLC for Simultaneous Estimation of Rosuvastatin Calcium and Fenofibrate in Pharmaceutical Dosage Form. Journal of drug delivery and therapeutics 2020; 10(4): 79-86.
16. Pimpale A and Kakde R: Stability-Indicating Method Development and Validation for the Estimation of Rosuvastatin Calcium in Pharmaceutical Dosage Form By Reverse Phase-High Performance Liquid Chromatography. International Journal of Chemistry Research 2020; 4(4): 9-16.
17. Sangeetha D and Vadlamudi MK: Development and Validation of a Stability-indicating RP-HPLC Method for Estimation of Metformin and Rosuvastatin along with Impurities from a Combined Oral Solid Dosage Form. Indian Journal of Pharmaceutical Sciences 2019; 81(2): 365-374.
18. Haq N, Shakeel F, Alanazi F, Alshora DH and Ibrahim MA: Development and validation of a green RP-HPLC method for the analysis of rosuvastatin: a step towards making liquid chromatography environmentally benign. Green Processing and Synthesis 2018; 7(2): 160-169.
19. Koppala S, Rayam P, Reddy VR and Anireddy JS: Identification, isolation, characterization and quantification of a new impurity in Rosuvastatin calcium tablet dosage form. Analytical Chemistry: An Indian Journal 2016; 16(10): 417-432.
20. Kishore CR and Mohan GK: Structural identification and estimation of rosuvastatin calcium related impurities in Rosuvastatin calcium tablet dosage form. Analytical Chemistry Research 2017; 12: 17-27.
21. Trivedi HK and Patel MC: Development and validation of a stability-indicating RP-UPLC method for determination of rosuvastatin and related substances in pharmaceutical dosage form. Scientia Pharmaceutica 2012; 80(2): 393-406.
22. Reddy GV, Reddy BV, Haque SW, Gautam HD, Kumar P, Kumar AP and Park JH: Development and validation of a stability-indicating UPLC method for rosuvastatin and its related impurities in pharmaceutical dosage forms. Quimica Nova 2011; 34: 250-255.
23. Khedr A, Belal F, Ibrahim F and Elawady T: Analysis of rosuvastatin stress degradation behavior using liquid chromatography coupled to ultraviolet detection and electrospray ionization mass spectrometry. Analytical Methods 2013; 5(22): 6494-6502.
24. Dhepe B, Bende O, Chavhan VN, Yambal V and Bajare N: Development and validations of UV-Vis spectroscopy method for the determinations of Metformin hydrochloride and Rosuvastatine calcium in bulk drug and in pharmaceutical synthetic mixture. International Journal of Creative Research Thoughts 2020; 8(3): 2121-2132.
25. Belal F, Ibrahim F, Khedr A and Elawady T: Stability indicating TLC method for the determination of rosuvastatin and identification of some degradation products using electrospray ionization mass spectrometry. Journal of Liquid Chromatography and Related Technologies 2014; 37(8): 1114-1132.
26. Mostafa NM, Badawey AM, Lamie NT and Abd El-Aleem AE: Selective chromatographic methods for the determination of Rosuvastatin calcium in the presence of its acid degradation products. Journal of Liquid Chromatography and Related Technologies 2014; 37(15): 2182-2196.
27. Kumar TN, Vidyadhara S, Narkhede NA, Silpa YS and Lakshmi MR: Method development, validation and stability studies of teneligliptin by RP-HPLC and identification of degradation products by UPLC tandem mass spectroscopy. Journal of Analytical Science and Technology 2016; 7(1): 1-8.
28. Kothapalli LP, Bhimanwar RS, Malani AP and Thomas AB: Validated stability indicating high performance liquid chromatography (HPLC) method for determination of Teneligliptin hydrobromide in presence of its degradation products: Application to its kinetic degradation study. Pharmaceutical Resonance 2018; 1(2): 39-43.
29. Vetapalem R, Yejella RP and Atmakuri LR: Development and validation of a stability indicating RP-HPLC method for simultaneous estimation of teneligliptin and metformin. Turkish J of Pharma Sciences 2020; 17(2): 141-147.
30. Kommineni V, Chowdary KP and Prasad SV: Development of a new stability indicating RP-HPLC method for simultaneous estimation of Metformin hydrochloride and Teneligliptin hydrobromide and its validation as per ich guidelines. Indo American Journal of Pharmaceutical Sciences 2017; 4(5): 1109-1119.
31. Swetha A and Kuber BR: A novel stability-indicating reverse phase liquid chromatographic method for the simultaneous estimation of metformin and teneligliptin in pure and pharmaceutical formulations. International Journal of Applied Pharmaceutics 2018; 10(5): 274-280.
32. Luhar SV, Pandya KR, Jani GK, Sachin B and Narkhed S: Simultaneous estimation of teneligliptin hydrobromide hydrate and its degradation product by RPHPLC method. Journal of Pharmaceutical Science and Bioscientific Research 2016; 6(3): 254-261.
33. Dahikar GD and Bobade G: Development and Validation of Stability Indicating RP-HPLC method for Teneligliptin Hydrobromide Hydrate. American Journal of Pharm Tech Research 2021; 11(1): 1-12.
34. Musmade BD, Baraskar ML, Ghodke VN, Bhope SG, Padmanabhan S and Lohar KS: Impurity profiling method development and validation of metformin hydrochloride and teneligliptin hydrobromide hydrate in their combination tablet dosage form by using RP-HPLC with UV/PDA detector. FJPS 2021; 7(1): 1-10.
35. Ganorkar AV, Jibhkate RS and Gupta KR: Development of Stability Indicating and Robust RP-HPLC Method for Determination of Teneligliptin. Asian Journal of Applied Chemistry Research 2018; 1(4): 1-12.
36. Patel V, Pandya C, Patel Z, Patel D and Pandya A: Isocratic RP-UHPLC method development and validation of stability-indicating for simultaneous determination of teneligliptin and metformin in fixed-dose combination. Current Chemistry Letters 2021; 10(4): 503-516.
37. Sunitha PG and Narayane R: Development and Validation of Stability Indicating Ultra Performance Liquid Chromatography Method for the Quantification of Teneligliptin hydrobromide hydrate and Characterisation of its Degradation products by Spectroscopic techniques. Research Journal of Pharmaceutical, Biological and Chemical Sciences 2017; 8(2): 2264-2281.
38. Maruthi R, Chandan RS and Tengli AK: Method development, validation and stability indicating assay for Teneligliptin hydrobromide by RP-UFLC. International Journal of Pharmaceutical Sciences and Research 2019; 10(2): 728-735.
39. Annapurna MM, Almas S, Rajasree B and Narendra A: Stability indicating ultrafast liquid chromatographic method for the estimation of Teneligliptin (An Anti-diabetic agent). Asian Journal of Pharmaceutics 2018; 12(2): 477-483.
40. Tighare KV and Sawale AV: Development and validation of stress degradation studies for quantification of Teneligliptin by UV spectroscopic method. World Journal of Pharmaceutical Research 2021; 10(7): 901-918.
41. Kalyankar TM, Sasatte S, Bodhankar MR and K Anitha: Development and validation of stability indicating assay method for simultaneous estimation of Metformin and Teneligliptin hydrobroide combined dosage form. Journal of Emerging Technologies and Innovative Research 2020; 7(3): 97-105.
42. Chitlange SS, Rawat DG and Gandhi SP: Estimation of anti diabetic Teneligliptin in bulk and formulation by densitometric and spectrophotometric method. Analytical Chemistry Letters 2017; 7(4): 556-566.
    

    ---

    How to cite this article:

    Velayudhankutty S, Niranjana CM and Sreelekha PP: Forced degradation study of rosuvastatin and teneligliptin, characterisation of its degradation products by various analytical techniques: a review. Int J Pharm Sci & Res 2023; 14(9): 4292-03. doi: 10.13040/IJPSR.0975-8232.14(9).4292-03.

    ---

    All © 2023 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.