INTRODUCTION:

Oral drug delivery systems are intended to transfer the active ingredient directly through the oral cavity with the mouth serving as site of administration application and absorption. Drug diffusion through sublingual mucosa or the non-keratinized buccal results in absorption into the blood capillaries. In this manner, the drug has direct systemic circulation access by passing hepatic portal system, permitting a considerable decrease of "first-pass effect" (orally administered drugs’ metabolism by hepatic enzymes or by GI and hepatic enzymes), results in a decreased amount of unmetabolized drug reaching the systemic circulation. One or more active ingredients are included in tablets. Excipients such as binders, glidants, diluents, coloring agents, disintegration agents, lubricants, and flavoring ingredients may be present. When using such excipients, it is important to check that they do not negatively impact the stability, rate of dissolution, bioavailability, safety, or efficacy of the active ingredients; there must be no incompatibility between any of the dosage form's components.

Sustained release of dosage forms is intended to have a long therapeutic impact by gradually releasing the drug for a long time period after a single dose has been provided.

A sustained drug delivery system's main objective is to maximize a drug's pharmacokinetic, biopharmaceutical, and pharmacodynamic properties so that its usage is increased by minimizing side effects and curing or controlling a condition in a short time while using a small amount of drug^1,2.

ATORVASTATIN CALCIUM:

Atorvastatin calcium is an anti-hyperlipidemic drug. It lowers triglycerides and low-density lipoprotein, or bad cholesterol, in the blood. Atorvastatin is utilized to cure high cholesterol and reduce risk of heart attack, stroke, or other cardiac issues in persons having coronary heart disease, type-II diabetes, and various risk factors, in addition to raising levels of good cholesterol (high-density lipoprotein)³.

CATEGORY:

Anti-hyperlipidemic agent.

CHEMICAL STRUCTURE:

Chemical name:

[R-(R*, R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5- (1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate.

METHODOLOGY:

COMPATIBILITY STUDY:

Using the (Fourier Transformer Infrared Spectrometric) FTIR method, drug, and excipients selected for formulation have been examined for compatibility.

FTIR:

A compound's identity and the mixture's composition can both be investigated using infrared spectroscopy. FTIR investigations were performed using a Schimadzu FTIR spectrometer model to examine the interactions in pure drug, polymers, excipients, and drug excipients mixture. The test samples' IR spectra were acquired using the pressed pellet method and potassium bromide, with a 1:100 ratio of samples⁴.

ATORVASTATIN CALCIUM’s STANDARD CURVE CONSTRUCTION:

Atorvastatin calcium has been evaluated at 246nm spectrometrically as it obeys beer's lamberts law having a limit ranged from 5 to 25ml.

Formation of The Standard Stock Solution:

A 50ml volumetric flask was filled with precisely weighed 50mg of pure atorvastatin calcium. Methanol was used to dissolve the drug, and a volume of 50ml was made. The drug's concentration was 1mg/ml. A volumetric flask measuring 25ml was filled with 2.5ml of this solution and the volume was made up to the required level. As a result, 100ml of atorvastatin calcium was attained.

Atorvastatin Calcium’s Calibration Curve Procedure:

From the stock solution (standard), dilutions of 0.5, 1, 2, and 2.5ml were prepared in a volumetric flask of 10ml, and the volume has been brought up to required level using “methanol” to form a content in the range between 5 to 25ml. At 246nm, absorbance was estimated spectrophotometrically, and a calibration curve was plotted^5,6,7.

Atorvastatin Calcium Extended-Release Tablets Formulation By Wet Granulation Method

A natural polymer (HPMC) was used in the wet granulation process to create extended-release matrix tablets containing atorvastatin calcium. All of the components listed in the table, excluding talc and magnesium stearate, were weighed and added to a mortar, and mixed well. The needed amount of granulation fluid was then added, and the dough mass was well-mixed. To obtain the moist granules, mass was run via “mesh No. 20”. The moist granules were dried for 30 minutes at 60°C. To break up the aggregates, dried granules were run via “mesh No. 22”. The dry granules were combined with talc along with magnesium stearate, and then dried granules were compacted into tablets^8,9.

Composition of Different Tablets Formulations:

S. No.	Ingredients	F1	F2	F3
1	Atorvastatin Calcium	40	40	40
2	HPMC	20	40	60
3	Lactose	64	44	24
4	Microcrystalline	30	30	30
5	TALC	3	3	3
6	Magnesium Stearate	3	3	3

All the created formulations were estimated for various important parameters such as friability, hardness, weight variation, thickness, in-vitro dissolution test, and drug content uniformity.

Thickness Test:

Digital Vernier Calliper scale was utilized for the evaluation of the thickness of tablets, that allows precise measurements and provides information on the tablets’ variation. The average thickness of each formula in millimeters was determined by taking five tablets from each formulation.

Weight Variation Test:

The study of weight variation has been conducted using 20 tablets, weighed and determine the average weight individually. The weight variation was established as the difference between the weight of the pills and their average weight. The individual weights of more than 2 tablets should not differ from the average weight by more than the percent deviation, and none shall differ by more than twice the percent IP weight variation constraints.

Average Weight of a Tablet	Limits
≤80 milligrams	10%
> 80 or < 250 milligrams	7.5%
≤250 milligrams	5%

HARDNESS TEST:

“Hardness test is demarcated as force needed to break tablet at the diametric compression test and is termed as tablet crushing strength”. It was calculated by utilizing “Monsanto hardness tester” and presented in kg per cm.

Friability Test:

The friability of prepared tablets has been estimated with “Roche friabilator”. Pre-weighed 10 tablets and put in friability apparatus and run for 4min at 25rpm. Tablets have been dedusted and weighed again. The optimum range for friability is 0.5% -1.0%. This test is additionally to check the crushing strength of tablets by this test one can check capping and or lamination.

Initial tablets weighed – Final tablets weight

% Friability = ---------------------------------------- X 100

Final tablets weight

Drug Content Analysis:

Standard Curve Preparation:

Take 40mg “pure Atorvastatin calcium” in a volumetric flask (100ml), mix, and makeup with pH 6.8 phosphate buffer that contains 400ml concentration. Take 5ml of the above solution and make a 50ml volume, dilute it further by taking 5ml of the above solution to make a 10ml volume that has a 20ml concentration.

Sample Preparation:

Take 5 tablets and crush them into a fine powder. Tablet powder of 200mg was weighed and put into a volumetric flask (250ml), dissolve and make up with pH-6.8 phosphate buffer that comprises 800ml concentration. Take 5ml from the above solution and make 100ml volume. Take 5ml from the above solution to further dilute it and make 10ml having 20ml concentration^10,11,12.

Calculation:

The Atorvastatin calcium (%) in tablets was determined by the following formula:

A_t /A_S W_s /100 x 5/50 x 5/10 x 250 / W_t x 100/5 x 10/5 x Purity / 100 x 1115.32 / 1155.4

Here,

As = Absorbance of standard preparation

At = Absorbance of sample preparation

Ws = Weight of pure atorvastatin calcium taken

Wt = Weight of tablet taken

In- vitro Dissolution Study:^13,14

Dissolution Parameter:

Medium: Phosphate buffer (pH 6.8)

Apparatus: USP XX111- Type 2 Paddle

RPM: 50

Temperature: 37+0.5^◦C

Volume: 900ml

Procedure:

Preparation of Phosphate Buffer (pH 6.8)

Dissolve disodium hydrogen phosphate (28.80gm) and potassium Di hydrogen phosphate (11.45gm) in water to make 1000ml.

In-vitro Drug Release Studies:

The atorvastatin calcium release from the matrix tablets has been investigated in 900ml to pH-6.8 phosphate buffer for up to 18hours. An aliquot (1ml) was taken at particular time intervals and replaced by an equal dissolution medium volume. After being diluted to 10 ml with the dissolving media, the samples were examined for the presence of atorvastatin calcium with a UV-Visible spectrometer at 246nm”. Studies on the “In vitro drug release have been carried out three times, with the mean value being taken. Using equation derived from a standard curve, the cumulative percentage of drug release was computed¹⁴.

RESULTS:

Preformulation Studies:

Compatibility Studies:

The FTIR spectra of the Atorvastatin calcium and HPMC were studied. The most intensive absorption band at 1650.95cm was stacked and in the spectra was attributed to C=O group of stretching vibration. The absorption band at 3363.23 and 3247.90 indicated the presence of -OH stretching vibration. All the functional groups in atorvastatin calcium were maintained in the spectrum of the extended-release formulation. The results indicate that no chemical interaction occurred between atorvastatin calcium with HPMC in the extended-release formulation.

Standard Curve of Atorvastatin Calcium:

A UV-VISIBLE spectrometer set at 246 nm was used to determine the atorvastatin calcium standard curve in methanol. The graph was created by measuring absorbance (nm). X-axis plot of concentrations (gml) vs. and it adheres to Beer's rule on the y-axis.

Standard Curve of Atorvastatin Calcium in pH 6.8

S. No.	Concentration (µg)	Absorbance at 247 nm
1	5	0.12
2	10	0.393
3	15	0.59
4	20	0.787
5	25	0.992

POST COMPRESSION STUDIES

TEST	F1	F2	F3
Thickness (mm)	4.06	4.03	4.04
Hardness (Kg per cm²)	5.2	5.5	5.4
Friability (%)	0.61	0.56	0.50
Weight variation (7.5%)	199.9	200.35	201
Drug content analysis (%)	96.65	94.85	94.51

Comparative release profile for Atorvastatin calcium in (F1 –F3)

Time (hrs)	F1	F2	F3
o mins	0	0	0
15mins	52.15	56.09	41.55
30mins	54.65	58.96	43.87
1hrs	61.68	60.39	45.98
2hrs	65.98	61.81	48.29
3hrs	67.25	64.37	52.49
4hrs	70.3	69.45	58.16
6hrs	78.37	83.47	64.03
8hrs	96.92	88.56	68.54
10hrs		95.78	73.83
12hrs		97.22	78.05
14hrs			82.69
16hrs			92.81
18hrs			97.63

Comparative graph for Atorvastatin calcium in (F1 –F3)

DISCUSSION:

In the current analysis, formulations of extended-release Atorvastatin calcium tablets have been made and assessed utilizing HPMC polymer at varied doses.

The analysis of polymer and drug composition compatibility was investigated by using FT-IR. The main properties of the polymer's absorption bands are seen in the spectra of the drug and polymer in HPMC with hardly detectable differences in absorption band values. Therefore, the FT-IR spectrum did not show any variation in the position or nature of the absorption band, demonstrating no chemical interaction in Atorvastatin Calcium and HPMC.

The tablet's physical attributes were assessed for hardness, weight fluctuation, and drug content friability. Good weight homogeneity is provided by all formulations. Atorvastatin calcium drug content in all formulations was found within permissible limits, indicating a consistent quantity of drug in all formulations.

All formulations passed the uniformity of weight test by official standards since the average deviation percent of 20 tablets of every formulation < 7.5 percent, which is the IP limit.

The in-vitro release properties has been studied using the USP XXIII dissolving equipment type-II (paddle-type) technique in 900ml of buffer pH-6.8 for up to 18 hours. The findings of in-vitro investigations show that the F1, F2, and F3 have greater polymer concentrations and have higher sustained drug release rates at the sustained period of 18 hours maximum drug release of 97.63%

CONCLUSION:

The present research demonstrated that the extended-release tablets comprising Atorvastatin calcium have been formed by wet granulation method and their estimation was done. The in-vitro drug release studies from the developed formulation (F3) show the extended release and it was observed to be the most promising formulation and kept the drug release of 97.63% up to 18hours.

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Received on 08.03.2023 Modified on 17.11.2023

Research J. Pharm. and Tech 2024; 17(6):2459-2462.

DOI: 10.52711/0974-360X.2024.00384

Formulation Development and Evaluation of Atorvastatin Calcium Extended-Release Tablets