Extrapolation Based Shelf Life Establishment of Sacubitril and Valsartan Floating Tablet as per ICH Q1e

Anil Kumar Goyal¹*, Vinesh Kumar¹, Seema Yadav², Radhey Shyam Kumawat³,

Monika Maheshwari⁴

¹L.B.S. College of Pharmacy, Jaipur, Rajasthan, India.

²Maharishi Arvind Institute of Pharmacy, Jaipur, Rajasthan, India.

³Maharishi Arvind Institute of Pharmacy, Jaipur, Rajasthan, India.

⁴Geetanjali Institute of Pharmacy, Udaipur, Geetanjali Institute of Pharmacy, Udaipur.

*Corresponding Author E-mail: anilpharma077@gmail.com, vineshkc@gmail.com, seemayadav2128@gmail.com, radheyshyam.kumawat13@gmail.com, mona30mph@gmail.com

ABSTRACT:

According to ICH Q1A(R2) of Stability Testing, the purpose of stability testing is to establish a shelf life for drug product and recommended storage conditions. The aim of this research is to evaluate the shelf life of Sacubitril and Valsartan Floating Tablet using extrapolation on basis of data collected from Stability studies and Forced Degradation Studies. The RP-HPLC method to determine the drug content was validated as per guidelines of ICH Q2(R1). The parameter covered for validation were specificity, accuracy, method, precision and intermediate precision, linearity, all parameters achieved the results within predefined acceptance criteria. The Stability studies were performed on accelerated condition at 40^oC±2^oC/75%±5% and Long Term condition at 25^oC±2^oC/60%±5% for 6 months. Forced Degradation Studies were performed on Oxidation, Thermal, and Photolytic degradation for 5 days. Extrapolation was performed such that the extended retest period or shelf life was validated using Statistical tools for a future batch formulation for any industry with test results close to the release acceptance criteria. The drug product was unstable in open atmosphere as it failed drug content test with 96.79 % in oxidation degradationon 4^th day. There was no significant changes observed in the stability studies and stability data was evaluated using extrapolation method and statistical tools. Hence, it was proved that the dosage form of Floating Tablet is stable at ambient temperature for estimated 12 months. These studies confirmed that physical and chemical stability of Sacubitril and Valsartan were enhanced in Floating Drug Delivery System. This research study can be fruitful and useful for researchers and pharmaceutical industries to acquire the technique and data of stability of drug product-Floating Tablet of Sacubitril and Valsartan.

KEYWORDS: Stability, Forced Degradation, Shelf life, Sacubitril, Valsartan, Floating Tablet, Validation, Packaging, Extrapolation.

INTRODUCTION:

Stability testing is concerned with the well-being of the patient suffering from the disease for which the product is designed. Because of this concern, it has become a legal requirement to provide data for certain types of stability tests to the regulatory agencies before the approval of a new product.

The evaluation of stability data as per the ICH Q1E describes when and how extrapolation can be considered when proposing a retest period for a drug substance or a shelf life for a drug product that extends beyond the period covered by "available data from the stability study under the long-term storage condition.”^1-2

Forced degradation studies include the degradation of new drug substances and drug products under conditions more severe than accelerated conditions. These studies illustrate the chemical stability of the molecule, which further facilitates the development of stable formulations with suitable storage conditions.^3-4Analytical Method Validation of Method of Analysis is major requirement of regulatory bodies to assess the reliability, accuracy, and consistency of the result obtained from the method and it is performed as per ICH guidelines Q2(R1).^5-6

Sacubitril and Valsartan are used in combination as a neprilysin inhibitor and an angiotensin II receptor blocker. It treats heart failure. By using synthetic polymers such as HPMC, the floating tablet of sacubitril and valsartan was prepared and evaluated. The research work stability study was defined as an accelerated term condition of 40^oC±2^oC/75%±5%.⁷ The Sacubitril and Valsartan are available in markets and are prepared using synthetic polymers by Cidmus (Lupin), Azmarda (Cipla). Sacubitril and valsartan floating tablets with low density polymer based on natural polymers are unrivaled. It was developed and validated as the comprehensive stability-indicating HPLC-DAD method for determination of favipiravir, which is a novel and emerging antiviral option in COVID-19 treatment.⁸ It was determined that the pharmacokinetic profile, histological evaluation, and stability studies of an orodispersible film of tizanidine and meloxicam.⁹ An improved high performance liquid chromatography (HPLC) method for quantifying methadone hydrochloride in a new oral solution with methylhydroxybenzoate (methylparaben) and propylhydroxybenzoate (propylparaben) was developed and validated for use in physicochemical stability studies.¹⁰Due to the time consuming procedure of stability studies of any drug product, there is a lack of data, articles available related to stability studies, shelf life determination of drug products, and drug substances. Researchers have performed stability indicating methods rather than stability studies on the drug product, which gives us the opportunity to work in this field. Full-fledged stability studies using extrapolation and forced degradation studies become very useful and referable to researchers and industries to learn and execute the stability studies with full compliance methodology as per the ICH guidelines.

The purpose of this research is to determine the packaging and shelf life of the drug product Sacubitril and Valsartan Floating Tablet via stability studies and forced degradation studies using stability indicating parameters such as descriptive tests, drug content, dissolution time, and so on. The packaging of the Sacubitril and Valsartan Floating Tablet is the Blister Packaging. The stability data was evaluated in order to determine the shelf life of the drug product.

METHOD AND MATERIALS:

Drug, Chemical and Reagents:

Sacubitril and Valsartan Floating Tablet was formulated and evaluated in L.B.S College of Pharmacy, Jaipur, Rajasthan, India. Blister Packaging was applied on the Formulated Floating Tablet. Chemicals and Reagents used throughout the study were of analytical grade and were used as received.

Instruments and Equipments:

High Performance Liquid Chromatography (HPLC) (Make: Amkette Analytics), Dissolution Apparatus (Electrolab), Stability Chambers (Tempo Instruments) and other instruments like analytical balance, Ultra-sonicator, pH meter, etc were utilized in the research study.

Formulation of Floating Tablet of Sacubitril and Valsartan:

Floating matrix tablet of Sacubitril and Valsartan was formulated by direct compression method using gas generating agent (sodium bicarbonate) and low-density polymers (Like HPMC K4M, Guar gum etc).

Characterization of Tablet Formulation of Sacubitril and Valsartan:

Tablets were characterized by weight, hardness, friability, and loss on drying according to pharmacopeial limits. The average weight was obtained for at least 20 units. Hardness was determined for at least 10 tablets using a Hardness Tester and adopting a minimum hardness of 3kg/f as the acceptance criterion. For each formula, friability was evaluated for a sample of 20 tablets, using the acceptance criterion of a maximum loss of 1.5% of the initial weight. Loss on drying was carried out with 1 g of sample; at 105°C for 1h.

Tablet Coating and Blister Packaging:

A tablet coating solution was formed by adding 30 g of Opadry II white to 120g of purified water and stirring for 2 min in Cota RD coating machine. Pan rotation was set to 40rpm, and tablets were coated using a Binks Model spray gun. The coating solution was pumped using a peristaltic pump. Tablet bed temperature was maintained between 41 and 45°C during the spray coating process. After coating, coated tables were blistered in PVC blister and sealed with an aluminium foil.

RP-HPLC method for quantification of Sacubitril and Valsartan in a dosage form:^11-13

Instrument Parameters and Chromatographic conditions:

HPLC chromatography was carried out utilising an Amkette Analytics LC-100 liquid chromatographic system, an ultraviolet (UV) detector, and a fixed injector fitted 20µL loop. A C18 250×4.6mm, 5 micronKromasil column kept at room temperature was utilised for the chromatographic separation. Acetonitrile: Methanol and Potassium dihydrogen phosphate pH 3.8 (30:50:20 v/v) was the ideal mobile phase, and VWD detection was carried out at 263nm with a flow rate of 1.0mL/min. Methanol was used as the diluent.

Preparation of Sacubitril 25µg/mL and Valsartan 25 µg/mL standard solution:

Accurately weighed 25mg of Sacubitril and Valsartan standard, it was then transferred to a volumetric flask with a 100ml capacity and made up with the diluent. Pipette 1mL from the above solution in a 10mL volumetric flask and made up till the mark with diluent.

Forced Degradation Studies of Floating Tablet of Sacubitril and Valsartan:

In order to prepare degradation sample, for each of the tablet sampleSacubitril and Valsartanwere kept under the defined condition. Thermal degradation was performed by keeping for 5 days in 60°C. Studies of possible oxidation products were carried out by adding 3% H2O2, incubated for 5 days in ambient temperature. Photolytic degradation was performed under UV light ICH guidelines for 5 days. The frequency for sampling and analysis was kept as Initial, 1^st day, 3^rd day and 5^th day. The parameter used to analyze the degradation of drug product was Drug Content.

Stability Studies of Floating Tablet of Sacubitril and Valsartan:

The manufactured tablets were placed to accelerated, intermediate and long term stability test. The frequency of testing and condition of stability was maintained as mentioned in Table No. 1. The stability indicating parameters to evaluate the stability of Sacubitril and Valsartan Floating Tablet were weight variation, friability, drug content and dissolution. If the result of the test parameter reports out of specification (OOS), it will consider as significant change and study will be concluded.

Table No. 1: Stability Condition for Drug Product

Sr. No.	Condition	Temperature/Relative Humidity	Time Period for Analysis
1.	Accelerated Term Condition	40^oC±2^oC/75%±5%	Initial, 3 months, 6 months
2.	Long Term Condition	25^oC±2^oC/60%±5%	Initial, 3 months, 6 months,

Evaluation of Stability Data:

Data for all attributes were presented in an appropriate format (e.g., tabular, graphical) and an evaluation of such data was included in the article. The values of quantitative attributes at all time points were reported as measured (e.g., drug content). Statistical analysis was performed, the procedure used and the assumptions underlying the model were stated and justified. A tabulated summary of the outcome of statistical analysis and graphical presentation of the long-term data was presented. The shelf life was determined using the long term data as per ICH Q1E guidelines.

RESULTS AND DISCUSSION:

Floating matrix tables were successfully obtained by direct compression. Different polymers and molecular weights did not interfere in the technological process. These results demonstrated that the tablets were reliable on drug content and dissolution.

Characterization of Floating Tablet of Sacubitril and Valsartan:

IR Spectroscopy:

Figure No.1 IR Spectra of Floating Tablet of Sacubitril and Valsartan

Analytical Method Validation of RP-HPLC method:

The chromatograms of Sacubitril and Valsartan shows no interference with the chromatogram of Sacubitril and Valsartan blank, so the method is found to be Specific (Fig 2). A solution comprising 10-50µg/ml of Sacubitril and 10-50µg/ml of Valsartan were prepared. Sacubitril and Valsartan were able to attain correlation coefficients of 0.999 and 0.998 respectively.

The data for Method Precision of peak area measurement for Sacubitril and Valsartan based on six measurements of the same solution of Sacubitril (25 μg/ml) and Valsartan (25μg/ml) was analyzed to evaluate the %RSD. The %RSD for Sacubitril and Valsartan was found to be 0.51 % and 0.16% respectively. Intermediate precision was determined through standard solution containing (25µg/ml) of Sacubitril and (25µg/ml) of Valsartanwere analyzedin 3 replicates on the different day and %R.S.D was calculated. Sample solution was taken in three different flask label A, B and C with different concentration at 80%, 100%, and 120% of standard solution spiked in it and diluted up to 10ml. The area of each solution peak was measured at 263nm. The amount of Sacubitril and Valsartanwas calculated at each level and % recoveries were computed (Table No. 02).

Figure No. 2 Chromatogram of Specificity

Table No. 2: Analytical Method Validation Datasheet of Sacubitril and Valsartan

Sr.No.	Parameters	Result						Acceptance Limit
		Sacubitril			Valsartan
1.	Specificity	No interference observed			No interference observed			No interference should be observed
2.	Accuracy	80 %	100 %	120 %	80 %	100 %	120 %	97 % - 103 %
		102.1%	100.3%	102.1%	101.5%	100.3%	100.9%
3.	Method Precision	0.51 %			0.16 %			RSD NMT 1.0 %
4.	Intermediate Precision	1.05 %			1.53 %			RSD NMT 2.0 %
5.	Linearity	0.999			0.998			NLT (R²) 0.998

Table No. 3 Photolytic Degradation Datasheet of Floating Tablet

Frequency	Initial	1^st Day	2^nd Day	3^rd Day	4^th Day	5^th Day
Parameters	Initial	1^st Day	2^nd Day	3^rd Day	4^th Day	5^th Day
Appearance	Complies	Complies	Complies	Complies	Complies	Complies
Solubility	Complies	Complies	Complies	Complies	Complies	Complies
Drug Content (Sacubitril)	98.45 %	98.18 %	98.20 %	98.28 %	97.89 %	97.30 %
Drug Content (Valsartan)	97.93 %	97.95 %	97.86 %	97.73 %	97.81 %	97.70 %
Loss on Drying	0.56 %	0.57 %	0.58 %	0.57 %	0.55 %	0.59 %
Dissolution Time @ 18 hr	96.12 %	95.92 %	95.26 %	95.38 %	95.32 %	95.39 %

Table No. 4 Thermal Degradation Datasheet of Floating Tablet

Frequency	Initial	1^st Day	2^nd Day	3^rd Day	4^th Day	5^th Day
Parameters	Initial	1^st Day	2^nd Day	3^rd Day	4^th Day	5^th Day
Appearance	Complies	Complies	Complies	Complies	Complies	Complies
Solubility	Complies	Complies	Complies	Complies	Complies	Complies
Drug Content (Sacubitril)	98.45 %	98.47 %	98.46 %	98.68 %	98.71 %	98.66 %
Drug Content (Valsartan)	97.93 %	98.53 %	98.42 %	97.35 %	97.39 %	97.33 %
Loss on Drying	0.56 %	0.48 %	0.47 %	0.44 %	0.45 %	0.46 %
Dissolution Time @ 18 hr	96.12 %	96.34 %	95.27 %	95.75 %	95.54 %	95.62 %

Table No. 5: Oxidation Degradation Datasheet of Floating Tablet

Frequency	Initial	1^st Day	2^nd Day	3^rd Day	4^th Day	5^th Day
Parameters	Initial	1^st Day	2^nd Day	3^rd Day	4^th Day	5^th Day
Appearance	-NA-	-NA-	-NA-	-NA-	-NA-	-NA-
Solubility	-NA-	-NA-	-NA-	-NA-	-NA-	-NA-
Drug Content (Sacubitril)	98.45 %	98.38 %	98.10 %	97.86 %	97.43 %	97.04 %
Drug Content (Valsartan)	97.93 %	97.42 %	97.25 %	97.01 %	96.79 %	96.58 %
Loss on Drying	-NA-	-NA-	-NA-	-NA-	-NA-	-NA-
Dissolution Time	-NA-	-NA-	-NA-	-NA-	-NA-	-NA-

Table No. 6: Accelerated Term Condition Datasheet of Floating Tablet (40^oC/75%)

Frequency	Accelerated Term Condition			Long Term Condition
Parameters	Initial	3 month	6 month	Initial	3 month	6 month
Appearance	Complies	Complies	Complies	Complies	Complies	Complies
Solubility	Complies	Complies	Complies	Complies	Complies	Complies
Weight Variation	952.4 mg	954.2 mg	950.9 mg	952.45 mg	953.31 mg	951.87 mg
Friability	0.2 %	0.1 %	0.2 %	0.2 %	0.3 %	0.1 %
Drug Content (Sacubitril)	98.45 %	98.27 %	97.86 %	98.45 %	98.28 %	98.72 %
Drug Content (Valsartan)	97.93 %	97.84 %	97.78 %	97.93 %	97.86 %	97.84 %
Loss on Drying	0.56 %	0.53 %	0.61 %	0.56 %	0.63 %	0.59 %

Evaluation of Stability Data:

Figure No. 03 Extrapolation Analysis Accelerated Term Condition of SAC+VAL FLT Tablet

Figure No. 04 Extrapolation Analysis Long Term Condition of SAC+VAL FLT Tablet

DISCUSSION:

Stability studies at the developmental stage or of the marketed products are to provide a database that may be of value in selection of adequate formulations, excipients and container closure systems for development of a new product, to determine shelf life and storage conditions for development of a new product, preparation of registration dossier, to substantiate the claimed shelf life for the registration dossier and to verify that no changes have been introduced in the formulation or manufacturing process that can adversely affect the stability of the product. Packaging and Storage is major concern for patient safety, because at the time of evaluation after formulation. The topic of full fledge stability studies using extrapolation and Forced degradation studies become very useful and referable to researchers and industries to learn and execute the stability studies with full compliance methodology used as per the ICH guidelines. The Floating Tablet of Sacubitril and Valsartan were formulated and initial evaluation was performed. Tablets were characterized by weight, hardness, friability, and loss on drying according to Pharmacopeial limits. Coated tables were blistered in transparent PVC blister and sealed with an aluminium foil. The optimized chromatographic method was validated by evaluating specificity, linearity, precision, accuracy, and robustness. The validation of the method was performed as per ICH Guidelines Q2(R1). The Forced degradation studies was executed on three conditions which reported complies result except oxidation degradation. It is concluded that the Blister Packaging of the Dosage form can be stable for Stability studies on different term conditions. Photolytic Exposure doesn’t degrade or affect the stability of the dosage form of Sacubitril Valsartan, Hence, It is concluded that the Drug Product is not Photosensitive. Thermal Exposure doesn’t degrade or affect the stability of the dosage form of Sacubitril and Valsartan; it showed slight increase in drug content because of decrease in LOD. Hence, it is concluded that the Drug Product is stable in Extreme climatic zones. Oxidative Exposure degraded or affected the stability of the dosage form of Sacubitril and Valsartan; It showed decrease in Drug Content of both the Drug Sacubitril and Valsartan, Valsartan was reported OUT OF SPECIFICATION. Hence, it is concluded that the Drug Product is quite unstable in open atmosphere as it oxidises and it should be kept in Packaging of Blister Packaging. Stability study of Accelerated Term Condition of Sacubitril and Valsartan Floating Tablet was performed and concluded that there is no significant change in the samples observed. Stability study of Long Term Condition of Sacubitril and Valsartan Floating Tablet was performed and concluded that there is no significant change in this condition, as the data can be evaluated to determine the shelf life of drug product. Stability Data of Accelerated Term and Long Term conditions were evaluated using the Trend Analysis Tools and Statistical Tools in order to determine the shelf life of the drug product with a study of 6 months. Extrapolation was used to extend the retest period or shelf life beyond the period covered by long-term data was proposed in the application, particularly no significant change was observed at the accelerated condition. Statistical Analysis of this data defines that the pre-determined shelf life in term of retest date of Sacubitril and Valsartan Floating Tablet will be 12 months.

CONCLUSION:

Stability study and evaluation of stability data using extrapolation technique, it can be proved that the dosage form of Floating Tablet of Sacubitril and Valsartan is stable at ambient temperature for estimated 1 year as per allowance of ICH Q1E Evaluation of Stability Data. The Blister Packaging of dosage form is stable and appropriate which is proven by degradation studies. These studies confirmed that physical and chemical stability of Sacubitril and Valsartan were enhanced in the Floating Drug Delivery System. This research study can be fruitful and useful for researchers and pharmaceutical industries to acquire the technique and data of stability of drug product-Floating Tablet of Sacubitril and Valsartan.

CONFLICT OF INTEREST:

We declare that we have no conflict of interest.

ACKNOWLEDGEMENT:

We express our gratitude to L.B.S. College of Pharmacy, Jaipur, Rajasthan, India for providing various resources and facilities used during the research study.

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Received on 29.12.2022 Modified on 24.07.2023

Research J. Pharm. and Tech. 2024; 17(3):1289-1295.

DOI: 10.52711/0974-360X.2024.00202