Comparative Evaluation of Different Generic Formulations of Atorvastatin Calcium by UV Spectrophotometry Method

A generic medicine is a medication intended to be the same as a branded medication in terms of dosage form, strength, route of administration, quality, functionality characteristics, and intended use. Regulations and policies for the registration of generic drugs, however, vary by country. [1] Generic drugs are made available when the patent of a brand-name medicine expires or its marketing rights are made available at affordable cost. Regulatory agencies in each nation assess and certify generic drugs based on safety, efficacy, and bioavailability prior to marketing.[2] Generic drugs, while being therapeutically similar to their brand-name equivalents, can be dissimilar in appearance, scoring arrangement, release mechanisms, packaging, excipients (e.g., colours, flavouring, preservatives), and shelf life. Such differences will occasionally lead to confusion for patients when changing drugs. The main difference between generic and name- brand drugs differs in the quantity and quality of information needed to gain approval. Whereas name-brand drugs require a large number of preclinical and clinical trials to determine safety and efficacy, generic drugs only need to show bioequivalence to prove that they work as the original drug.[3] Although the word "generic drug" or "generic medicine" might signify different things in different markets, the World Health Organization (WHO) defines it as a pharmaceutical product that:

• Is marketed after the expiry date of the patent or other exclusive rights,
• Is usually intended to be interchangeable with an innovator product,
• Is manufactured without a license from the innovator company. [4]

Worldwide, generic drug consumption has risen progressively due to financial burdens on drug budgets. Consumer is used to mean an individual who purchases medicinal products for personal consumption or for the treatment of a Disease. Generic medicines offer the possibility of significant savings in health care expenditure directly to the consumers as well as the government, considering that they are generally cheaper compared to their brand-name counterparts.[5]

Differences Between Generic and Brand Drug:

One difference between brand name drug and generic drug is in the situation of manufacturing the drugs Whereas brand name drug is a name provided by the manufacturing company, generic drug is a drug manufactured subsequent to the active ingredient of brand name drug.[6]

Figure 1: Comparison Between Generic and Branded Drugs

The Process of Approving Generic Drug:

The New Medication Application process is different from the Abbreviated New Drug Application (ANDA) since it typically involves more non-clinical or clinical data to substantiate new claims, even if the drug is derived from an already approved product. The amount of data required varies with the particular claim being made. If the drug is already licensed in major world markets and demonstrates both pharmacology and bioequivalence, particularly without ethnic-related metabolic variations, the approval process can be streamlined. For serious or life-threatening diseases, requirements for animal or clinical studies can be minimized or waived. In India, the Central Drugs Standard Control Organization (CDSCO) assesses such requests on scientific rationale and can refer them to expert committees for additional review and advice before issuing permission for production or import.[7]

Figure 2: Generic Drug Approval Process in India

Approval Process for Branded Drug:

The U.S. Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research (CDER) is a science-based organization responsible for monitoring the drug approval process prior to marketing a drug. CDER makes sure that both brand-name and generic drugs function properly and that the benefits to health are greater than the known risks. They scrutinize every drug thoroughly with an independent group of clinicians and scientists who assess safety, effectiveness and labeling of the drug product. Once approved, FDA follow-up continues to ensure new drugs remain safe and effective.

The four stages of a drug approval process are:

• Pre-clinical, INDA
• Clinical
• New Drug Application (NDA) Review
• Post-marketing risk assessments

The entire research, development and approval process may take 12 to 15 years. In early stages of drug discovery (preclinical studies) by the manufacturer, testing and screening a drug candidate for toxicity in animals prior to the medicine advancing to human trials. The sponsor submits an Investigational New Drug (IND) Application that includes details such as chemistry, manufacturing and the initial human testing plans. The IND is examined by the FDA to guarantee clinical trials will be safe for human being and that proper informed consent is present to safeguard human being subjects. Human drug studies can start only after the IND is examined by the FDA and a local Institutional Review Board (IRB). The board is a committee of scientists and non-scientists in research institutions and hospitals that monitors clinical research.[8]

Figure 3: Branded drug approval process by food and drug administration.

Review of Literature:

1. Alburyhi et al. (2024): Evaluated the quality of five Atorvastatin 20 mg tablet brands in Sana'a, Yemen, focusing on their interchangeability. While all brands met pharmacopoeia standards for weight variation, hardness, disintegration time, and dissolution, only Lipitor passed the assay test. The brands were ranked based on USP and BP quality control as Lipitor Clostat > Ateroz > Atorlip > Atorva.
2. Omar Z. Ameer (August 2023): A study of five atorvastatin tablet brands in Saudi Arabia found that all brands met USP specifications, except for brands C and D, which had disintegration time issues. Tablets exhibited rapid dissolution (over 89% in 15 minutes), with similar dissolution efficiency. The Weibull model best described drug release, indicating minor manufacturing variations.
3. Ali AlMuhsin et al. (2022): A study on atorvastatin tablets from various brands in Saudi Arabia found that all products, including one innovator and five generic brands, met quality standards. Over 90% of atorvastatin was released within 15 minutes, with some brands achieving near 100% release in 60 minutes. The generics met pharmacopoeia standards, confirming that all brands were of good quality and interchangeable.
4. Sholichah Rohmani et al. (2020): A study in Indonesia assessed the quality of innovator, branded, and generic atorvastatin tablets, finding all samples met physical property standards and contained active substances within the required range (90.0%110.0%). Branded atorvastatin tablets showed a dissolution profile similar to the innovator, while generic tablets did not.
5. Mohamed Rahamathulla (2018): A study in the Asir region of Saudi Arabia evaluated the quality and interchangeability of Atorvastatin calcium tablets from various brands. All brands passed quality tests, with dissolution profiles showing 90% drug release within 1 hour, and A and C achieving 100%. Code A (Lipitor) was the most expensive, and release mechanisms varied, with A and D showing non-Fickian diffusion, while B and C exhibited Fickian diffusion. All brands were found to be clinically interchangeable.
6. Bagbi Baribefe M (2014): A study in Southern Nigeria assessed the quality and interchangeability of seven Atorvastatin Calcium tablet brands. While all brands passed friability and disintegration tests, some failed weight variation and hardness tests, and only a few met the required potency. European-sourced tablets were more expensive than Asian- sourced ones, and several brands showed poor dissolution rates. The study cautioned against interchangeability due to potential chemical non-equivalence, which could lead to therapeutic failure.

Drug Profile

Mechanism of Action:

Atorvastatin is a statin medication and a competitive inhibitor of the enzyme HMGCoA (3- hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG- CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis.1,8 Atorvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low-density lipoprotein (LDL) receptors, which increases hepatic uptake of LDL. Atorvastatin also reduces Very-Low-Density Lipoprotein-Cholesterol (VLDL- C), serum triglycerides (TG) and Intermediate Density Lipoproteins (IDL), as well as the number of apolipoprotein B (apo B) containing particles, but increases High-Density Lipoprotein Cholesterol (HDL-C). In vitro and in vivo animal studies also demonstrate that atorvastatin exerts vascular protective effects independent of its lipid-lowering properties, also known as the pleiotropic effects of statins. These effects include improvement in endothelial function, enhanced stability of atherosclerotic plaques, reduced oxidative stress and inflammation, and inhibition of the thrombogenic response. Statins were also found to bind allosterically to β2 integrin function-associated antigen-1 (LFA-1), which plays an essential role in leukocyte trafficking and T cell activation.

Pharmacokinetic:

• Absorption: Atorvastatin is quickly absorbed from the oral route of administration and has peak plasma levels (T max) in 1 to 2 hours. Because it undergoes extensive first-pass metabolism, its absolute bioavailability is about 14%.
• Distribution: The drug possesses a large volume of distribution (~381 liters) and is strongly bound to plasma proteins (≥98%).
• Metabolism: Atorvastatin is mainly metabolized in the liver by the cytochrome P450 3A4 enzyme to form active ortho- and Para hydroxylated metabolites, which are responsible for its lipid-lowering action.
• Excretion: The drug is primarily excreted through hepatic biliary excretion, and less than 2% is excreted in urine. The half-life of elimination of atorvastatin is approximately 14 hours, but its HMG-CoA reductase inhibitory activity lasts for 20 to 30 hours because of active metabolites.

Adverse Effects:

While atorvastatin is generally well-tolerated, some adverse effects have been reported:

• Common Adverse Effects: These include nasopharyngitis (8.3%), diarrhea (6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
• Muscle-Related Effects: Patients may experience myalgia (muscle pain) and, in rare cases, rhabdomyolysis, a serious condition involving muscle breakdown.
• Liver Enzyme Abnormalities: Elevations in hepatic transaminases have been observed, indicating potential liver function alterations.
• Gastrointestinal Symptoms: Some individuals report nausea and diarrhea. It's essential for healthcare providers to monitor patients for these adverse effects, especially during the initial stages of therapy or when adjusting doses.[9]

Aim and Objectives:

Aim:

The aim of the research work was to compare evaluation of different generic formulation of atorvastatin calcium with standard drug atorvastatin calcium by using UV-Visible Spectrophotometric method. A precise and accurate UV-Visible spectrophotometric method was developed to optimize dissolution parameters, utilizing 900 mL of phosphate buffer (pH 6.8) as the dissolution medium and a padel-type apparatus operating at 75 rpm. This study evaluates various parameters of a generic atorvastatin calcium tablet. Additionally, the percentage purity and label claim of the generic drug sample are determined using the equation derived from the absorbance graph.

Objectives:

1. To calculate label claim.
2. To find out percentage purity of generic medicines.
3. To estimate evaluation parameters of atorvastatin calcium tablets.
4. To find out absorbance spectra of different brands of generic medicines.

EXPERIMENTAL WORK:

Details of Procured Drugs:

Table 1: PROCURED STANDARD DRUG

Procurement of Generic Tablet Formulation:

Table 2: PROCUREMENT OF GENERIC TABLETS

Chemicals and Solvent:

• Disodium Hydrogen Phosphate
• Potassium Dihydrogen Phosphate
• Hydrochloric Acid
• Distilled Water

Preparation of Solutions:

Preparation of 0.1N HC: In a 1000 ml beaker, add 8.5 ml of concentrated HCl and dilute with distilled water up to the 1000 ml mark to prepare 0.1 N HCl.

Preparation of 6.8 pH Phosphate Buffer

About 28.80 gm of Disodium Hydrogen Phosphate and 11.45 gm of Potassium Dihydrogen Phosphate were dissolved in sufficient water to produce 1000 ml. [32]

Evaluation Parameter of Atorvastatin Calcium Tablet:

1. Colour and Shape
2. Thickness Measurement Test
3. Hardness Test
4. Weight variation
5. Friability Test
6. Disintegration
7. Dissolution

Colour and Shape:

All the procured tablets were subjected to physical examination and the observation are shown in Table 3.

Table 3: PHYSICAL APPEARANCE OF TABLET

Thickness Measurement:

Three tablets of each procured generic formulation were used, and the results are shown in Table 4.

Table 4: THICKNESS MEASUREMENT TEST

Hardness Test:

The hardness tester (Monsanto's hardness tester) was used for determination of tablets hardness strength. After random selection of 3 tablets from the sample of each brand, the force was exerted by placing each tablet between two anvils. The force needed to break the tablet was recorded as a hardness strength of that tablet. The results hardness tests are shown Table 5.

TABLE 5: HARDNESS TEST

Weight Variation Test:

The weight variation test was done by taking 20 tablets from each of the six generic formulation and weighed individually with an analytical balance. Weight variation of individual tablet is determined with respect to average weight and percent weight variation evaluated according to IP The results of weight variation tests are shown Table 6.

TABLE 6: WEIGHT VARIATION TEST

Friability Test:

Ten tablets of each brand were initially weighed and transferred into the friabilator (FB400) one by one. The friabilator was operated at 25 rpm for 4 minutes (up to 100 revolutions). The tablets were then weighed again, and the % friability was calculated. The official limit is not more than 1% (NMT 1%). The results of the friability tests are shown in Table 7.

% Friability: Initial Weight (IW) - Final Weight (FW) / Initial Weight(W)

TABLE 7: FRIABILITY TEST

Disintegration Test:

The disintegration time was done as per IP 2018 specifications,

0.1N HCL Acidic Medium:

The test was conducted on six tablets by single unit disintegration test apparatus made by HYTEK INDIA Ltd. Approximately 500ml 0.1N HCI was employed as a disintegration media. The whole setup was kept firmly in water bath at constant temperature of 37±2° C. The apparatus was then run for a defined time in minutes.

6.8 pH Phosphate Buffer Solution:

The acidic fluid was substituted by 6.8 pH Phosphate Buffer solution. The complete setup was safely positioned in water bath at constant temperature of 37±2°C. The apparatus was then run for a given time and time in minutes taken for complete disintegration of tablets with no palable mass left in the apparatus was measured immediately after 2 hours and the disintegration time was recorded. The tablets were taken to be fully disintegrated when all the particles went through the wire mesh. The disintegration time results are presented in Table 8.

TABLE 8: DISINTEGRATION TEST

Standard Drug

An accurately weighed quantity of Atorvastatin calcium 10 mg was transferred to the 100 ml volumetric flask and dissolved in methanol. The volume was made up to the mark with methanol.

Study of Spectra and Study of Wavelength:

The aliquot portions of stock solutions of atorvastatin calcium is diluted appropriately with solvent water to obtain concentration of 10 mg/ml for atorvastatin calcium. The solution was scanned in the range of 400-200 nm in l cm cell against solvent blank. The overlain UV absorbance spectrum of atorvastatin calcium is shown in Table 9.

TABLE 9: VALUES OF STANDARD CALIBRATION CURVE

Figure 6: Standard Calibration Curve.

Dissolution Test:

The dissolution test was done as per IP 2018 specifications,

0.1N HCL Acidic Medium

0.1N HCI acidic medium: IP type II Dissolution Apparatus manufactured by LABINDIA Pvt. Ltd. was used to study in vitro drug release. The dissolution was carried out in 0.1N HCL at 75 rpm for 2 hrs. The results of dissolution tests are shown in table 10.

TABLE NO. 10: DISSOLUTION TEST

pH 6.8 Phosphate Buffer Solution:

The tablet was placed in 900 ml of 6.8 pH Phosphate Buffer solution for the next 1 hr. The entire setup was securely placed in water bath maintained at constant temperature of 37°C. The padel was rotated at 75 rpm by using speed motor. About 10 ml of dissolution samples were withdrawn at prescheduled intervals and replaced with an equal volume of fresh dissolution medium. Each sample was diluted suitably with the phosphate buffer and analyzed for the drug content at 246 nm using a UV-Visible Spectrophotometer. The results of dissolution tests are shown in Table No.10.

TABLE NO. 11: PERCENT DRUG RELEASED OF GENERIC FORMULATION 6.8 PH PHOSPHATE BUFFER

               TABLE 12: ABSORBANCE OF DIFFERENT GENERIC FORMULATION AT 246nm

Formula for Label Claim

% Label Claim

where,

Cx: Concentration of Atorvastatin Calcium in gm/ 100 ml. d: dilution factor.

W: Average Weight of tablet.

Wn: Weight of Sample taken.

L: Label Claim of Sample Taken.

TABLE 13: % LABEL CLAIM

Cost Comparison:

Cost of branded drug (F1) as per 10 tablets = 54.66 (Rs)

TABLE 14: COST COMPARISON OF VARIOUS GENERIC DRUGS

RESULT AND DISCUSSION: