INTRODUCTION:

The chemical stability of pharmaceutical drug molecules requires great center of attention due to its effect on the efficacy and safety of drug products^1. ICH [International conference on harmonization] and FDA [Food and Drug Administration] have guidelines which state the requirement of stability testing data for understanding various Environmental barriers and factors.²Forced deteriorations is a technique in which a product's or material's natural degrading rate is accelerated by adding stress to it.

Stress testing, according to ICH recommendations, is used to find degradation outcomes that can help determine intrinsic molecular stability, develop degradation routes, and validate stability-indicating methodologies. ICH Guidelines for stability testing are ICH Q1A i.e. Stability testing of new drug substance, ICH Q1B: Photostability testing of new drug substance, ICH Q2: Validation of analytical procedure methodology³. Stress test should be consistent with product specific storage conditions, decomposition, manufacturing and normal use conditions in each case.⁴ Based on good scientific understanding of the mechanism of decomposition of a product under typical condition the choice of force degradation should be selected. Decomposition of 10-15% is considered for validation of chromatographic purity test.⁵ Stress factors suggested for forced degradation studies consist of acid or base hydrolysis, oxidation, thermal degradation, and photolysis.⁶

HMG-COA reductase enzyme plays a central role in production of cholesterol in the liver. HMG-COA Reductase catalyze the conversion of HMG-COA to Mevalonate, a rate limiting step in cholesterol synthesis. Statin, inhibitor of HMG-COA reductase is used to lower cholesterol. atorvastatin, Fluvastatin, simvastatin and pitavastatin are completely synthetic compounds.⁷ The bioavailability of statins have low bioavailibity due to their poor aqueous solubility, low permeability & high molecular of their members.⁸ The bioavailability of statins varies from different to different.⁹Formulation of atorvastatin nanoparticle with single emulsion diffusion method procedure 50% dose reduction without affecting its efficacy.¹⁰Bioavailibility of atorvastatin is increased by coating with sodium alginate as a hydrophilic polymer due to atorvastatin has 12% low bioavailability.¹¹ Orally administration of a drink of liquorice with atorvastatin results in enhancement of drug bioavailability in healthy rats.¹² Statins have a high risk of hydrolysis they are susceptible to high temperature and humidity.¹³ Therefore, this review discussed the study of forced degradation on statins drugs (atorvastatin, Fluvastatin)¹⁴. Based on the knowledge of the degradation process and its degradation results, it is expected to assist in the process of formulation, packaging selection, and determination of drug shelf life and storage conditions when the drug is distributed to the public.

Search Criteria:

Articles related to forced degradation study, stress testing, drug stability, and statin drugs were used in this review. Authors selected and took the important points from many references that were published in 1996-2018.

Forced Degradation Studies of Statin Drugs:

Forced Degradation Studies of Atorvastatin:

The degradation study of atorvastatin (ATV) was investigated by some researchers with a various method such as liquid chromatography-mass spectroscopy (LC-MS)¹⁶ ultra-performance liquid chromatography (UPLC)^17-19 and high- performance liquid chromatography (HPLC)^20-24. Lakka et al. HPLC technique was used to conduct stress tests on ATV. The sample was subjected to stress tests that included reflux with 0.1 N HCl at 60 °C for 30 minutes, reflux with 0.1 N NaOH at 60°C for 30 minutes, and reflux with 0.1 N NaOH at 60°C/30 min, reflux with 1% H2O2 60°C/30 min, exposed to dry heat at 105°C/6 h in the oven, reflux at 60°C/30 min in water, exposed to visible light 1.2 million lux-hours, UV light 200Watt-hours/m2, and stored in humidity chamber at 25°C/90% RH for 7 d. Acid hydrolysis, alkaline hydrolysis, and oxidative conditions did not result in significant degradation. In stress testing using visible light, UV, moisture, and water hydrolysis, no degradation was seen. However, thermal stress indicated significant degradation²⁵. Aiyalu et al. studied the high-performance thin layer chromatography (HPTLC) method was used to study ATV stress tests. TV sample was subjected to stress tests such as neutral hydrolysis (80°C, 1 h), acid (0.1 M HCl, 8 h, 80°C), and acid (1 M HCl, 8 h, 80°C). acid (0.1 M HCl, 8 h, 80°C), acid (1 M HCl, 8 h, elevated temperature (80°C), base (0,1 M NaOH, 8 h, 80°C), base (1M NaOH, 8 h, elevated temperature (80°C), oxidative (3% H₂O₂, 6 h, room temperature), oxidative (30% H₂O₂, 24 h, room temperature), dry heat (30 d, 50°C), and photolysis (UV, 2 d). ATV had significant degradation in acid hydrolysis (86.14% degraded at 80°C, 89.63% degraded at elevated temperature (80°C)) and oxidative stress (52.23% degraded at 3% H₂O₂, 45.32% degraded at 30% H₂O₂)²⁶. Goel et al. conducted a stress test with UPLC method. ATV was subjected to acid (1 N HCl, 25°C, 5 min), base (0.01 N NaOH, 25°C, 5 min), neutral (water, 80°C, 4 h), strong oxidation (30% H₂O₂, 80°C, 1 h), thermal (80°C, 1 d) and photolysis stress conditions (UV at 254 nm, 1 d). ATV was found to be sensitive to acid hydrolysis (80.9% assay). The lactone form of ATV was the primary degradation product in the 1 N HCl degradation study, with a retention time (Rt) of 1.941 min. ATV was stable in alkaline hydrolysis, in water at room temperature, in 30% H₂O₂ at room temperature, in dry heat at 80°C and UV light for one day. However, after water hydrolysis at 80°C, ATV was found to be unstable and produced a major degradation product in Rt 1.932 min. After heating in H₂O₂ at 80°C, ATV produced two minor degradation products in Rt 2.292 and 2.661 min²⁷. S. Naidu et al. performed the stress test on ATV with HPLC method. Acid hydrolysis, alkaline hydrolysis, oxidation, and light stress were all used on the samples. ATV was relatively stable at photolysis stress (UV, 24 h), slightly degraded on alkaline hydrolysis (0.1 M NaOH), oxidation stress (3% H₂O₂), and acid hydrolysis (0.1M HCl)²⁸

Forced Degradation Study of Fluvastatin:

Akabari et al. used HPLC to perform a stress test on Fluvastatin (FVS). Samples for degradation studies underwent basic hydrolysis (0.1 M NaOH, 70°C, 120 min), acid (0.1 M HCl, 70°C, 120Min and 1 M HCl, 70 °C, 30 min), Thermal (80°C, 24 h), oxidative (3 percent H₂O₂, 70°C, 120 min), and photolysis (direct sunlight, 24 h). Acid, alkaline hydrolysis, and oxidative stress were found to be harmful to FVS. FVS was unstable and degraded rapidly (about 45%/ hour, 10.1% assay) when exposed to acidic conditions in 0.1 M HCl. Base and oxidative stress resulted in 61.2% and 43% drug decomposition, a decrease in original peak area and no additional peaks were observed in the chromatogram. FVS was mildly degraded by heat and photolysis (2.65% and 6.47%), respectively, and no new peaks were identified in the chromatogram²⁹. Gomes et al HPLC was used to conduct a degradation study on FVS. The sample had neutral hydrolysis (water, 80°C, 2h), chemical oxidation (3% H₂O₂, 80°C, 2 h), acid hydrolysis (1.0mol/l HCl, 80°C, 2h), and alkaline hydrolysis (1.0mol/l NaOH, 80°C, 2h). FVS was stable in neutral hydrolysis. The chromatogram, however, had changed after the chemical oxidation test. Following acid and base hydrolysis, the chromatogram revealed numerous additional degradation product peaks.³⁰

Forced Degradation Study of Pitavastatin:

Aglawe et al. studied a stress test on pitavastatin (PTV) with UV- Visible spectrophotometry method. The PTV stress test was performed in acid hydrolysis (0.1 N HCl, 5h, 60°C), basic hydrolysis (0.1 N NaOH, 5 h, 60°C), neutral hydrolysis (water, 5h, 60°C), oxidative (3% H₂O₂, dark conditions, 6h), heat (60°C, 12 h), and photolysis (direct sunlight, 12 h and UV light, 48h). PTV degraded significantly under acidic, alkaline, neutral, photolysis, thermal, oxidation, and light stress conditions, according to the degradation studies (23.35 percent -82.31 percent drug degraded) 31 Another study investigated degradation using the HPTLC method. Samples were exposed to Another study looked at degradation using the HPTLC method. Posed to acid (0.1 M HCl, 4 h, 75°C), base hydrolysis (0.1 M NaOH, 2 h, 75°C), oxidation (3% H₂O₂, 2 h, 75°C), heat (75°C, 24 h), and photodegradation study (254nm UV radiation, 24 h). PTV was sensitive to acid hydrolysis (degraded ±7.5%/h) and an additional band (retention factor (Rf) 0.53) appeared in the chromatogram. PTV was stable in alkaline conditions and demonstrated an additional band at Rf 0.55. PTV was stable in thermal, and UV (>90% recovery). In oxidative stress, there were two extra bands (Rf 0.28 and 0.58) and three additional bands (Rf 0.53, 0.58, and 0.61), and in thermal deterioration, there were three additional bands (Rf 0.53, 0.58, and 0.61) Samples exposed to UV light showed an additional band at Rf 0.55³²

Damle et al. investigated PTV degradation results by HPTLC method. The drug was tested with stress on acidic (0.1 N HCl, 30 min, room temperature), base (0.1 N NaOH, 2 h, room temperature), neutral (water, 30 min, room temperature), oxidation (3% H₂O₂, 2 h, room temperature), thermal degradation (80°C, 6 h), and photolysis (UV light, 200 Watt-hours/m2 and fluorescence light, 1.2million lux- hours) conditions. PTV had significant degradation in photolysis conditions, thermal and alkaline hydrolysis. PTV underwent degradation slightly in acid hydrolysis, and the chromatogram showed one additional band at Rf 0.70. Mild degradation occurred in neutral hydrolysis and oxidative stress³³ Panchal et al. Performed a stress test with the HPLC method. The drug was tested with acid (0.01 M HCl, 1 h, 60°C), base (0.01 M NaOH, 10 min, 60°C), neutral (water, 1 h, 60°C) hydrolysis, oxidation (0.3% H₂O₂, 1 h, 60°C), heat (60°C, 4 h), and photodegradation studies (visible light, 12 h and UV light, 4 h). PTV was heavily degraded (47%) in basic media and moderately degraded (27%) in acidic media, yielding major and minor degradation products at Rt 2.60 and 3.90 min. Under neutral conditions, 10% of the drug was degraded, with no major degradation products and two minor degradation products at Rt of 2.60 and 3.90 min. However, PTV was relatively stable in neutral conditions. PTV was 70% degraded in oxidative stress, with no major degradation products and minor degradation products at RT within 1.5-3.0 min. In thermal stress conditions, PTV was quite stable (11% degradation) and minor degradation products were found at Rt range 1.5-3.0min. After PTV was exposed to visible and UV light, the drug was degraded with 10% and 9% degradation, respectively³⁴. A stress test by HPLC method was studied by Sujatha et al. The degradation studies were performed in acid hydrolysis (2 M HCl, 30 min, 60°C), alkaline hydrolysis (2 M NaOH, 30 min, 60°C), neutral hydrolysis (water, 6 h, 60°C), oxidative (20% H₂O₂, 30 min, 60°C), thermal (105°C, 6 h), and photolysis (UV room, 7 d). The degradation study obtained additional peaks in the chromatogram compared to standard PTV (Rt 3.823 min), acid hydrolysis (2 additional peaks Zat 2.889 and 5.143 min), alkaline hydrolysis (2 additional peaks at 2.733 and 13.376 min), neutral hydrolysis (an additional peak at 13.025 min), oxidative (2 additional peaks at 2.733 and 13.376 min), thermal (2 additional peaks at 5.366 and 6.071 min) and photolysis (2 additional peaks at 5.290 and 5.988 min)³⁵

Forced Degradation Study of Pravastatin:

Onal and Sagirli performed degradation study on pravastatin (PRV) with HPLC method. The stress conditions are carried out in acid hydrolysis (1 N HCl, 1 h, 80°C), alkaline hydrolysis (1 N NaOH, 1 h, 80°C), neutral hydrolysis (water, 1 h, 80°C), oxidative (30% H2 O2, 1 h, 80°C), thermal (105°C, 5 h), and photolysis (366nm UV light, 10 h). Neutral hydrolysis caused 10% reduction in original drug peak and two additional peaks at Rt 1.53 and 3.20 min. In base hydrolysis, chromatogram showed ±90% reduction of the original drug peak and two additional peaks at Rt 0.99 and 1.82 min. Under oxidative stress, the peak of the chromatogram was reduced ±30% of the original drug peak and a new peak appeared at Rt 1.54 min. In acid hydrolysis, the peak corresponding to the parent drug disappeared and two new peaks appeared at Rt 1.53 and 1.71 min The chromatogram did not alter as a result of the thermal stress. Drugs degraded 50% and new small peak appeared at Rt 1.60 min on UV exposure³⁶

Athota et al. The HPLC technique was used to test PRV deterioration. Stress studies were performed in acid (0.1 N HCl, 30 min), base (0.1 N NaOH, 30 min), oxidative (30% H2O2, 30 min), thermal (105°C, 30 min), and photolysis (sunlight, 24 h). PRV was more degraded in acid hydrolysis and less degraded in oxidative stress. The test results showed 4.35% of the drug was degraded under acidic conditions, 4.21% in basic, 2.20% in oxidative stress, 3.27% in thermal stress and 2.88% in photolysis^37. Ahmad et al. conducted a stress test by HPTLC method. Samples were tested with acid, base, oxidative, thermal, UV, and photolysis stress. Acid degradation was slower than the basic condition. The degradation products were observed at Rf 0.28 and 0.53 when the drug was heated with HCl 1 M at 80°C for 8 h. The drug underwent very fast basic degradation in 1 M NaOH at 80°C, about 80% of the drug was degraded within 5 min and degradation products were observed at Rf 0.24, 0.40, and 0.52. Under oxidative stress (30% H2O2, room temperature, 24 h), the degradation products were observed at Rf 0.24, 0.40, and 0.52. PRV decayed slowly in the presence of UV light (254nm), generating four new peaks at Rf 0.29, 0.37, 0.55, and 0.78. In heat and sunlight, the drug was largely steady, with further maxima at Rf 0.53 and Rf 0.29³⁸

Forced Degradation Study of Rosuvastatin:

The previous study used several methods to stress test rosuvastatin (RSV), including HPLC³⁹, UPLC⁴⁰, TLC⁴¹, and UV spectrophotometry⁴². was conducted in the previous study. Trivedi et al. conducted stress test with UPLC method in acid hydrolysis (0.1 N HCl, 80°C, 2 h), alkaline hydrolysis (0.5 N NaOH, 80°C, 6 h), oxidative (3% H2 O2, 80°C, 6 h), thermal (100°C, 8h), and photolysis (UV light). No significant degradation was observed in oxidative stress, thermal stress, and alkaline hydrolysis. In contrast, significant degradation was observed in acid hydrolysis and UV light. Anti-rosuvastatin isomer and unknown impurities were formed⁴³. Shah et al. conducted degradation study under stress conditions determined by ICH Guidelines with the HPLC method. Stress studies were performed in acid (0.1 N HCl), base (2 N NaOH), oxidative (30% H2O2), thermal (50°C for 21 d), and photolysis stress (fluorescence ~ 8,500 lux and UV light ~ 0.5 W/m2). Drugs degraded mainly in hydrolysis and photolysis conditions. Five degradation products were formed in acid hydrolysis and acidic photolysis conditions. One degradation product was formed in neutral and oxidative conditions. Two degradation products were produced at all photolysis conditions, including solid photolysis. The drug was stable against alkaline hydrolysis and thermal stress. The LC- MS analysis showed that five degradation products had the same molecular mass as in the drug, while the other six had a molecular mass of 18 Da less than the drug⁴⁴.

Ashfaq et al. studied RSV degradation with HPLC method. Stress conditions were performed under acid hydrolysis (5 M HCl, 60°C, 4 h), alkaline hydrolysis (5 M NaOH, 60°C, 4 h), oxidative (6% H2O2, room temperature, 24h), thermal (60°C, 4h), and photolysis (366 nm UV light, 10 h). RSV was highly degraded in acidic condition (40%). At oxidative and basic stress, RSV had mild degradation with 6% and 5% degradation, respectively. Thermal stress had no effect on drug degradability⁴⁵ However, other study stated that the drugs contained RSV and ezetimibe are highly sensitive towards alkaline conditions in comparison to other stress conditions⁴⁶. Bellal et al. performed a stress test with the TLC method. The stress conditions were oxidative (10% H2O2, 100°C, 10 min), photolysis (UV light 254nm, 30-120 min), thermal (100°C, 10 min), acid (0.1 M HCl, 100°C, 5 min), and base (0.1 M NaOH, 100°C, 5 min) hydrolysis. Under acid hydrolysis conditions, four major degradation products were detected with Rf values of 0.16, 0.27, 0.74, and 0.77. In alkaline hydrolysis, one major degradation product was detected at Rf 0.73. At thermal stress, two major degradation products were formed at Rf 0.74 and 0.77. The drug was more susceptible to oxidative stress than other conditions because five major degradation products are formed at Rf 0.15, 0.25, 0.30, 0.71, and 0.77. At photolysis stress, two major degradation products were detected at Rf 0.70, and 0.78⁴⁷. Shah et al. conducted degradation study under stress conditions determined by ICH Guidelines with the HPLC method. Stress studies were performed in acid (0.1 N HCl), base (2 N NaOH), oxidative (30% H2O2), thermal (50°C for 21 d), and photolysis stress (fluorescence ~ 8,500 lux and UV light ~ 0.5 W/m2). Drugs degraded mainly in hydrolysis and photolysis conditions. Five degradation products were formed in acid hydrolysis and acidic photolysis conditions. One degradation product was formed in neutral and oxidative conditions. Two degradation products were produced at all photolysis conditions, including solid photolysis. The drug was stable against alkaline hydrolysis and thermal stress. The LC- MS analysis showed that five degradation products had the same molecular mass as in the drug, while the other six had a molecular mass of 18 Da less than the drug.

Forced Degradation Study of Simvastatin:

The degradation in simvastatin (SIM) was conducted in previous study with HPLC method^48-49, UPLC⁵² and UV derivative spectrophotometry⁵³. Samples were tested with neutral hydrolysis (water, 100°C, 4 h), acid (1 N HCl, 100°C, 4 h) and base (1 N NaOH, 100°C, 4 h), oxidation (30% H₂O₂ , 100°C, 4 h), dry heat (105°C, 4 h), and UV exposure (254nm, 4 h). By HPLC method simvastatin was still observed in the presence of their degradation products after acid hydrolysis. However, simvastatin was more sensitive to alkaline hydrolysis and underwent complete degradation. The peak (Rt 4.2 min) after alkaline and neutral hydrolysis could be identified as hydroxyl acid form of simvastatin. After oxidation, the degradation product peak was detected at Rt 2.55min and did not interfere with simvastatin retention time (Rt 6.5min). SIM showed no signs of deterioration when subjected to thermal stress and UV exposure.

Ghodke undertook degradation study with HPLC method. The sample under various conditions such as neutral (water, 70°C, 1 h), acid (3 M HCl, 70°C, 6 h), basic (1 M NaOH, 80°C, 3 h) hydrolysis, oxidation (30 % H₂O₂, 8h, 25°C), thermal (80°C), and photolysis (exposure to short and long UV radiation, 48h) conditions. Chromatograms of acid and base degradation showed an additional peak at Rt 6.2 min and Rt 6.3 min. Peaks of degradation product were not found in neutral hydrolysis, oxidative, thermal and photolysis stress conditions⁵⁵. Chavhan and Ghante conducted the stress test on simvastatin with UV spectrophotometry method. The stability studies were carried out under acidic (0.1 N HCl, 60°C, 3 h), base (0.1 to 5 N NaOH, 60°C, 36 h), neutral (water, 60°C, 3 h), oxidative (3% H₂O₂ , 60°C, 14 h), thermal (80°C, 4 h), and photolysis (sunlight, 4 h) conditions. SIM was found to be stable in basic (5 N NaOH up to 36 h) and photolysis conditions (in sunlight up to 8 d) when compared to other conditions. SIM was found to be unstable in acid, neutral, oxidative, and thermal conditions⁵⁶

Sawant and Ghante reported simvastatin stability based on a study of forced degradation with HPLC method. The stability studies of the simvaststin were performed under acidic (0.1 N HCl, 80°C, 3 h), base (0.1 N NaOH, 80°C, 2 h), neutral (water, 80°C, 3 h), oxidative (3% H₂O₂, 60°C, 14 h), thermal (50°C, 21 d), and photolysis (fluorescence light 8500 lux-hours and UV light 0.5 Watt-hours/m² at 40°C/75% RH, 13 d) conditions. The drug was degraded under all stress conditions except photolysis. No significant degradation (<0.45%) occurred in photolysis conditions. The degradation product of SIM was identified as 2 dihydroxy derivatives of simvastatin⁵⁷. Malenovic et al. analyzed the degradation product using microemulsion liquid chromatography. The degradation was expected that simvastatin as lacton would be very susceptible to hydrolysis⁵⁸. Nalaiya et al. tested the forced degradation of simvastatin with HPLC method. Active substances and finished products are tested with acid, alkaline, oxidation, heat, and photolysis stress conditions. Within 24 h, simvastatin was totally degraded under acidic conditions (1 N HCl, 50°C) and 90% degraded in its finished products. simvastatin was also degraded under oxidative stress (0.3% H₂O₂, 50°C) and neutral hydrolysis (water, 90°C). However, simvastatin was relatively stable under alkaline hydrolysis (1N NaOH, 50 °C) and photolysis (UV light, 24 h)⁵⁹

Importance of Force Degradation:

Forced degradation study (FD) studies (stress testing) are an intrinsic part of pharmaceutical product development. It is a process in which the normal degradation rate of a product or material is accelerated by adding additional stress. It demonstrates a molecule's chemical behaviour, which aids in the development of pharmaceutical formulation and packaging. It is vital to describe the specificity of the stability indication techniques, as well as provide insight into the drug substance's degradation pathways and degradation products. an elucidation of the structure of the degradation products. This review discusses the regulatory aspects of force degradation and the study of stability and also the analytical hyphenated methods used for the development of the forced degradation study⁵⁹. The developed method is superior when compared to the reported method with less retention time and composition of the mobile phase with good separation.⁶⁰ The design and execution of These investigations necessitate meticulous planning and coordination at all stages of development, as well as commercial operations after approval. This is particularly crucial in the case for protein-based therapeutics due to complexity of the molecular structure as well as the potential influence of the manufacturing process on product attributes. FD research applications are frequently tied to individual product development on a phase-by-phase and case-by-case basis, with varying aims and focuses. Expert opinions: Throughout the course of the investigation, this document summarises various significant FD methodologies typically used in the industry and includes recommendations on study design tactics and database management. the product lifecycle⁶¹. Analyze the impurities as per the method to verify the retention times. In order to assess the stability indicating nature of the HPLC method, samples will be stressed by acid, base, hydrogen peroxide, heat and UV radiation. The degraded samples will be analysed using a PDA detector for determining the peak purity

Forced degradation studies are carried out for the following reasons:

· To develop and validate a stability indicating method

· To determine degradation pathways of drug substances and drug products (e.g., during development phase)

· To identify impurities related to drug substances or excipients

· To understand the drug molecule chemistry

· To generate more stable formulations

· To generate a degradation profile that mimics what would be observed in a formal stability study under ICH conditions

· To solve stability-related problems (e.g., mass balance)

Impurities are unavoidable in all pharmaceutical substances, and the ethical pharmaceutical industry's responsibility is to define an impurity profile that is acceptable for the drug's intended purpose, without compromising its therapeutic safety and efficacy. The stability of a drug product or a drug substance is a critical parameter in which may affect purity, potency and safety.^61,62Changes in drug stability can risk patient by forming harmful degradation product(s) or by delivering a lesser dose than planned, you can ensure your safety. Therefore, it is essential to know the purity profile and behavior of a drug substance under various environmental conditions which could be possible by stability testing.^63,64

Stress testing is defined as drug substance and drug product stability testing performed to elucidate intrinsic stability features. Stress testing involves subjecting drug compounds and drug products to harsh circumstances such as pH, photolysis, oxidation, and temperature for a brief period of time. It also referred to as forced degradation studies.^65,66

Pharmaceutical companies perform forced-degradation studies during preformulation to help select compounds and excipients for further development, to facilitate salt selection or formulation optimization, and to produce samples for developing stability-indicating analytical methods. Stress testing elucidates degradation mechanisms and probable degradation products. This data can then be utilized to build manufacturing procedures or to pick appropriate packaging. It could also aid in the preparation of reference material for identified degradation products. It may also help in preparing reference material of identified degradation products. Although preformulation work is part of early-phase drug development, stress testing often is repeated when manufacturing processes, product composition, and analytical procedures are refined and reach a more final state.⁶⁷

Timing of stress testing studies:

The majority of companies do preclinical investigations on the drug substance and the drug product. The practice of repeating stress testing tests differs depending on the stage of development. Studies on the drug substance are repeated between the preclinical and registration stages, while studies on the drug product are repeated between Phase I and registration as the last stage. in development

CONCLUSION:

Forced degradation studies provide knowledge of possible degradation pathways and degradation of active ingredients and help to explain degradation structure. The degradation product resulting from forced degradation studies is potential degradation studies on statin drugs, all drugs have a tendency to degrade in all stressful condition like acid, base, neutral, hydrolysis, oxidation, thermal and photolysis of a certain degree depending on the concentration and duration of stress exposure. This demonstrates the instability of statin drugs so it requires special treatment starting from active ingredient, formulation, packing distribution and storage of the final product.

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Received on 03.11.2021 Modified on 11.12.2021

Asian J. Pharm. Ana. 2022; 12(2):135-141.

DOI: 10.52711/2231-5675.2022.00024