Formulation and Evaluation of Press-Coated Pulsatile Tablets of Fimasartan Potassium Trihydrate for Morning Cardiovascular Treatment

 

Anuradha Parixit Prajapati, Hardik Bharatbhai Prjapati, Kantilal Narkhede, Neha Desai, Mansi Barot, Shailesh Luhar, Sachin Narkhede

Department of Pharmaceutics, Smt. BNB Swaminarayan Pharmacy College, Salvav, Vapi,

Gujarat, India, 396191.

 

ABSTRACT:

Objective: This study aimed to develop a press-coated pulsatile tablet of Fimasartan Potassium Trihydrate (FPT) to enhance bioavailability and achieve timed drug release for effective morning hypertension management. Methods: To improve the solubility and permeability of BCS Class IV FPT, an inclusion complex with Hydroxypropyl-β-Cyclodextrin (HP-β-CD) in a 1:2 molar ratio was prepared using the kneading method. Characterization using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) confirmed complex formation. Core tablets, formulated with Croscarmellose sodium as a superdisintegrant, were press-coated with Hydroxypropyl Methylcellulose (HPMC K4M) and Ethyl cellulose. A 3² factorial design was applied to evaluate the impact of HPMC K4M concentration and coating polymer amount on lag time and drug release. Results: Pre- and post-compression studies confirmed satisfactory tablet properties. The optimized formulation exhibited a lag time of 266 minutes and achieved 90% drug release within 302 minutes, ensuring drug availability during the early morning blood pressure surge. Conclusion: The developed press-coated pulsatile tablet successfully provided controlled, time-specific drug release, improving therapeutic effectiveness and patient adherence. This formulation represents a promising chronotherapeutic approach for hypertension and heart failure management.

 

 

 

INTRODUCTION:

Hypertension, often termed the "Silent Killer," is a major risk factor for cardiovascular diseases, including heart failure, coronary artery disease, and chronic renal          failure^1-2. Clinical studies indicate that patients with hypertension face a higher risk of cardiovascular complications in the early morning hours due to a surge in blood pressure, increased sympathetic activity, and reduced vascular compliance. This morning spike significantly elevates the likelihood of myocardial infarction, stroke, and sudden cardiac arrest, making chronotherapy a crucial approach in hypertension management³.

 

Angiotensin II receptor blockers (ARBs), such as Fimasartan Potassium Trihydrate (FPT), effectively control hypertension by inhibiting vasoconstriction and reducing aldosterone secretion. However, as a BCS Class IV drug, FPT exhibits poor solubility and permeability, limiting its bioavailability⁴.

 

A pulsatile drug delivery system, designed to release the drug following a predetermined lag time, offers a strategic advantage by synchronizing drug release with the circadian rhythm of blood pressure fluctuations. This study focuses on the formulation and evaluation of press-coated pulsatile tablets of FPT to enhance bioavailability and ensure time-specific drug release, thereby optimizing chronotherapeutic efficacy and improving patient adherence, particularly in addressing the morning cardiovascular risk associated with hypertension⁶.

 

MATERIALS AND METHODS:

Materials:

Ami Lifesciences, Vadodara, Gujarat, provided the Fimasartan Potassium Trihydrate; Roquette, India, provided the Hydroxypropyl-β-Cyclodextrin; Croscarmellose Sodium, Microcrystalline Cellulose, Dicalcium Phosphate, Magnesium Stearate, Talc, HPMC K4M, and Vishal Chem, Mumbai, India, provided the Ethyl cellulose.

 

Methods:

Inclusion Complex Preparation:

The kneading procedure was used to prepare the inclusion complex. Small amounts of water were added to the medication and complexing agent to mix them in the proper ratio. The resulting mass was stored after being dried.

 

Direct Compression Method for Press-Coated Pulsatile Tablet Preparation:

Setting Up the Core Tablet: MCC, DCP, CCS, and the drug-cyclodextrin complex were precisely weighed, combined, and blended for 20minutes. After weighing the magnesium and talc, the mixture was mixed for two minutes. Tablets were compressed using a round, flat-faced punch measuring 8mm⁷.

 

Press-coated tablet preparation:

Place half of the coating powder at the bottom. The central core tablet was filled, crushed, and punched using a 10mm tool.

 

Experimental Section:

1.     Using the kneading approach to prepare the inclusion complex

2.     Creating the Initial Trial Batch to Determine the Super disintegrant Type in Core Tablets

3.     Creating the Initial Trial Batch to Check the Super disintegrant Content in Core Tablets

4.     Preliminary Trial Batch Formulation: Coating Polymer Selection

 

The kneading approach was used to create an inclusion complex. In the experimental batch, three different super disintegrants and concentrations were used; the best one was chosen. A trial batch was used to choose the coating polymer.

 

Experimental Design:

The current investigation used a 3² randomized complete factorial design. In this approach, experimental trials were conducted at all 13 potential combinations, and two factors were investigated at three levels each. Preliminary research was used to choose the criteria. Selecting Dependent and Independent Variables for DoE is shown in Table No. 1.

 

All 13 batches' formulations, including constituent concentrations, are displayed in Table 2.

 

Table No.1: Selection of Dependent and Independent Variables for DoE

Translation of Coded Value in Actual Units
Independent Variables	Variable Level
	Low (-1)	Medium (0)	High (+1)
Conc. of HPMC K4M % (X1)	20	40	60
Total Weight of Coating (mg) (X2)	180	200	220
Dependent Variables
1	Drug Release Lag Time (Y1)
2	Time Required For 90% Drug Release (Y2)

Table No.2: Formulation of Factorial Batches

Ingredients	Formulation Code with Quantity (mg)
	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12	F13
Core Tablet
FPT: HP-β-CD	138	138	138	138	138	138	138	138	138	138	138	138	138
MCC	27.75	26.5	25.25	27.75	26.5	25.25	27.75	26.5	25.25	26.5	26.5	26.5	26.5
DCP	27.75	26.5	25.25	27.75	26.5	25.25	27.75	26.5	25.25	26.5	26.5	26.5	26.5
CCS	2.5	5	7.5	2.5	5	7.5	2.5	5	7.5	5	5	5	5
Mg. St.	2	2	2	2	2	2	2	2	2	2	2	2	2
Talc	2	2	2	2	2	2	2	2	2	2	2	2	2
Coating Layer
HPMC K4M	36	72	108	40	80	120	44	88	132	80	80	80	80
EC	144	108	72	160	120	80	176	132	88	120	120	120	120
Total Weight	380	380	380	400	400	400	420	420	420	400	400	400	400

 

Evaluation Parameters of Press Coated Pulsatile Tablets^:

The pre-compressional parameters include the angle of repose, which assesses powder flowability using the funnel method. Bulk and tapped densities are determined by measuring the volume occupied by a fixed weight of powder in a graduated cylinder before and after tapping. Carr’s Index and Hausner Ratio evaluate the compressibility and interparticle interactions of the powder blend.

 

Post-compressional parameters include tablet thickness, measured using a Vernier caliper, and weight uniformity, where 20 tablets are weighed to ensure consistency as per IP 2007 standards. Hardness is tested using a Monsanto tester, while drug content is analyzed by dissolving a known quantity of powder in pH 6.8 buffer and measuring absorbance. Friability is determined using a Roche Friabilator, ensuring tablets can withstand handling. Disintegration time is recorded to confirm tablet breakdown, and in vitro drug release is studied using a USP Type II dissolution apparatus under controlled conditions⁸.

 

Analysisofstatistics:

Expert 12 software, which carries out statistical optimization, analysis of variance (ANOVA), and multiple regression analysis (MRA), was used to assist in the statistical optimization process. To investigate the impact of independent factors on independent variables, a polynomial equation was created^9,10.

 

Building of Contour and Surface Plots:

Using expert 12's design, contour and surface plots were created to visually represent the impact of each component on the answer. Statistical software enabled the construction of charts using the quadratic equation from regression analysis, where the dependent variables Y1 and Y2 were represented by a curvature as a function of independent variables X1 and X2.

 

Research on stability:

The optimized formulation was used for the expedited stability study. For a month, the tablet sample was kept in the stability chamber at 40±2ºC and 75±5% relative humidity after being covered in laminated aluminium foil. Samples were taken at pre-arranged intervals of 0, 15, and 30 days and analysis of sample was done ¹¹.

 

RESULT AND DISCUSSION:

Solubility Study of Fimasartan in Different Complexing Agents:

Figure 1 illustrates the solubility of Fimasartan in various complexing agents, with HP-β-CD showing the highest solubility improvement. This result confirms that HP-β-CD is a suitable carrier for enhancing Fimasartan's solubility. The increased solubility can be attributed to the formation of inclusion complexes between Fimasartan and HP-β-CD, which was chosen for further studies.

 

Figure No.1: Solubility of Fimasartan in Different Complexing Agent

 

Response Surface Analysis for Y1 and Y2:

The response surface methodology was employed to evaluate the effects of independent variables on the dependent variables Y1 (lag time) and Y2 (drug release). The 2-D response surface plot for Y1 (Figure 2) and the 3-D response surface plot for Y1 (Figure 3) demonstrate the influence of HPMC K4M and Ethyl cellulose concentrations on the lag time. Similarly, the 2-D and 3-D response surface plots for Y2 (Figures 4 and 5) highlight the effects of these variables on drug release at the target time. The response surface analysis provided a clear visualization of the relationship between the formulation components and the performance of the pulsatile tablets.

Figure No.2: 2-D Response Surface Plot for Y1	Figure No.3: 3-D Response Surface Plot for Y1

 

Figure No.4: 2-D Response Surface Plot for Y2	Figure No.5: 3-D Response Surface Plot for Y2

 

Checkpoint Batch Optimization:

Table 3 outlines the formula for the checkpoint batches O1, O2, and O3, each differing slightly in the quantities of the coating layer components. These formulations were optimized based on the desirability function (Figure 6), which sought to minimize lag time and maximize drug release within the specified target time. The overlay plot for the checkpoint batch (Figure 7) further confirmed the formulation space that meets the desired criteria.

 

Table No.3: Formula for Check Point Batch

Ingredients	Quantity in mg
	O1	O2	O3
Core Tablet (200mg)
FPT: HP-β-CD	138	138	138
Croscarmellose Sodium	7.5	7.5	7.5
Microcrystalline Cellulose	25.25	25.25	25.25
Dicalcium Phosphate	25.25	25.25	25.25
Magnesium Stearate	2	2	2
Talc	2	2	2
Coating Layer
HPMC K4M	(38.4726%)  76.958	(41.7313 %)  79.306	(43.4351%)  78.423
Ethyl cellulose	123.077	110.734	102.13
Total weight	400.035	390.61	380.553

 

Figure No.6: Desirability for Check Point Batch	Figure No.7: Overlay Plot for Check Point Batch

Table No.4: Pre-compressional Parameters of Checkpoint Batch:

Batch	Angle of Repose (0)	Bulk Density (gm/ml)	Tapped Density (gm/ml)	Carr’s Index (%)	Hausner’s Ratio
O1	26.81 ± 0.1232	0.4320 ± 0.0035	0.4829 ± 0.0035	10.54	1.117
O2	26.25 ± 0.1855	0.4324 ± 0.0013	0.4832 ± 0.0014	10.51	1.117
O3	27.42 ± 0.1759	0.4907 ± 0.003	0.5486 ± 0.0023	10.55	1.118

 

Pre-Compressional and Post-Compressional Parameters:

The pre-compressional parameters of the checkpoint batches (Table 4) indicate good flow properties with an angle of repose ranging from 26.25° to 27.42°, and Hausner’s ratio below 1.12, which is indicative of good powder flowability. These results confirm that the blend is suitable for tableting without flow issues.

 

The post-compressional parameters (Table 5) of the checkpoint batches show uniform thickness, hardness, and drug content across all formulations, with minimal variations. The lag time of the optimized batch (O1) was 262.93 minutes, which aligns well with the desired pulsatile drug delivery profile.

 

Pre-Compressional and Post-Compressional Evaluation of Factorial Batches:

The pre-compressional parameters of the factorial batches (Table 6) also showed acceptable flow properties, with all batches exhibiting Carr’s index values below 12%, indicating good compressibility. The post-compressional parameters (Table 7) further demonstrated that all batches met the required pharmacopeial limits for thickness, hardness, and drug content, confirming the robustness of the formulations.

 

Table No.5: Post-compressional Parameters of Checkpoint batch

Batch	Thickness (mm)	Hardness (kg/cm2)	Weight Variation	Drug Content %	Lag Time (min)
O1	3.67 ± 0.094	5.6 ± 0.1632	Pass	99.36	262.93
O2	3.34 ± 0.09	5.534 ± 0.094	Pass	99.15	262.87
O3	3.47 ± 0.0912	5.467 ± 0.1885	Pass	99.21	263.55

 

Table No.6: Pre-compressional Parameters of Factorial Batches

Batch	Angle of Repose (0) Mean±SD	Bulk Density (gm/ml) Mean±SD	Tapped Density (gm/ml) Mean±SD	Carr’s Index (%)	Hausner’s Ratio
F1	25.75 ± 0.1606	0.4746 ± 0.004	0.5339 ± 0.0049	11.10	1.124
F2	29.55 ± 0.1746	04794 ± 0.004	0.5393 ± 0.0048	11.10	1.125
F3	28.81 ± 0.1	0.486 ± 0.0027	0.5468 ± 0.003	11.11	1.125
F4	28.15 ± 0.1576	0.4716 ± 0.0023	0.5306 ± 0.0025	11.12	1.124
F5	26.83 ± 0.1232	0.462 ± 0.0015	0.4891 ± 0.0016	5.54	1.058
F6	26.25 ± 0.1855	0.4324 ± 0.0013	0.4832 ± 0.0014	10.51	1.117
F7	26.81 ± 0.1232	0.4320 ± 0.0035	0.4829 ± 0.0035	10.54	1.117
F8	27.42 ± 0.1759	0.4907 ± 0.003	0.5486 ± 0.0023	10.55	1.118
F9	28.62 ± 0.008	0.5529 ± 0.0019	0.6319 ± 0.0023	12.50	1.142
F10	27.44 ± 0.1811	0.5730 ± 0.0051	0.6113 ± 0.0055	6.26	1.066
F11	28.00 ± 0.1342	0.5795 ± 0.0053	0.6181 ± 0.0057	6.24	1.067
F12	29.48 ± 0.118	0.6182 ± 0.0035	0.6623 ± 0.0038	6.65	1.071
F13	28.91 ± 0.1673	0.5181 ± 0.0029	0.5828 ± 0.0033	11.10	1.124

Table No.7: Post-compressional Parameters of Factorial Batches

Batch	Thickness(mm)	Hardness (kg/cm2)	Weight Variation	Drug Content
F1	3.34 ± 0.094	5.2 ± 0.000	Pass	99.43
F2	3.34 ± 0.094	5.267 ± 0.094	Pass	98.14
F3	3.267 ± 0.094	5.6 ± 0.1632	Pass	99.28
F4	4.067 ± 0.094	5.334 ± 0.094	Pass	99.95
F5	3.87 ± 0.094	5.8 ± 0.1632	Pass	99.88
F6	3.67 ± 0.094	6.134 ± 0.094	Pass	98.76
F7	3.34 ± 0.094	5.534 ± 0.094	Pass	99.36
F8	3.47 ± 0.094	5.467 ± 0.1885	Pass	99.21
F9	3.67 ± 0.094	5.6 ± 0.1632	Pass	99.15
F10	3.37 ± 0.094	5.467 ± 0.094	Pass	98.52
F11	3.67 ± 0.094	5.334 ± 0.1885	Pass	99.65
F12	3.54 ± 0.094	6.00 ± 0.000	Pass	99.11
F13	3.87 ± 0.094	5.334 ± 0.094	Pass	98.32

 

In-vitro Drug Release Studies:

The in-vitro drug release profiles for the factorial batches are shown in Table 8 and Figure 8. Batch F1 demonstrated the fastest drug release, with 99.21% cumulative release by 230 minutes, while other batches showed varying release profiles depending on the composition of the coating materials. The optimized batch (O1) provided a controlled release profile, achieving 90% release at around 302 minutes, aligning with the pulsatile release design.

 

Table No.08: In-vitro Drug Release Study of Factorial Batches

Time (min)	% Cumulative Drug Release
	F1	F2	F3	F4	F5	F6	F7
0	0	0	0	0	0	0	0
60	0	0	0	0	0	0	0
120	0	0	0	0	0	0	0
180	0	0	0	0	0	0	0
210	2.53 ± 0.14	0	0	0	0	0	0
220	64.85 ± 0.3013	0	0	0	0	0	0
230	99.21 ± 0.0865	0	0	3.52 ± 0.0987	0	0	0
240		0	0	34.57 ± 0.1641	0	0	0
250		0	0	65.05 ± 0.1877	0	0	0
260		13.12 ± 0.19201	0	92.26 ± 0.2583	0	0	0
270		31.42 ± 0.1922	0		4.26 ± 0.1388	0	3.76 ± 0.1855
280		57.21 ± 0.2083	0		36.87 ± 0.2903	0	29.4 ± 0.1396
290		80.67 ± 0.2593	0		61.18 ± 0.2898	0	71.7±0.30507
300		98.79 ± 0.2662	0		87.59 ± 0.2242	0	94.07±0.1796
310			0		99.65 ± 0.1922	0
320			0			0
330			6.72 ± 0.2478			0
340			13.16 ± 0.2141			0
350			31.46 ± 0.1768			7.46 ± 0.1452
360			45.92 ± 0.2898			36.89 ± 0.1818
370			80.65 ± 0.1922			65.09 ± 0.2691
380			97.11 ± 0.3029			92.3 ± 0.2303
390

 

Table No.08: Cont…….

Time (min)	% Cumulative Drug Release
	F8	F9	F10	F11	F12	F13
0	0	0	0	0	0	0
60	0	0	0	0	0	0
120	0	0	0	0	0	0
180	0	0	0	0	0	0
210	0	0	0	0	0	0
220	0	0	0	0	0	0
230	0	0	0	0	0	0
240	0	0	0	0	0	0
250	0	0	0	0	0	0
260	0	0	0	0	0	0
270	0	0	8.446 ± 0.2989	1.059 ± 0.1253	5.51 ± 0.1569	5.49 ± 0.1419
280	0	0	19.82 ± 0.6828	23.96 ± 0.33008	23.98 ± 0.2708	19.8 ± 0.4352
290	0	0	50.46 ± 0.2671	57.1 ± 0.1195	50.47 ± 0.1429	50.45 ± 0.8257
300	3.76 ± 0.2332	0	71.95 ± 0.3572	78.6 ± 0.2246	71.96 ± 0.1737	71.93 ± 0.5444
310	20.04 ± 0.38337	0	92.52 ± 0.2969	94.8 ± 0.3088	98.89 ± 0.1309	98.87 ± 0.30772
320	34.68 ± 0.2209	0
330	65.17 ± 0.3501	0
340	84.98 ± 0.345	0
350	99.74 ± 0.22005	0
360		14.11 ± 0.1596
370		45.71 ± 0.2092
380		78.48 ± 0.1184
390		98.54 ± 0.2054

 

Figure No.8: In-vitro Drug Release Study of Factorial Batches

 

Stability Study:

The stability study results (Table 09) indicate that the optimized batch (O1) remained stable over 30 days when stored at 40°C±2°C and 75%±5% RH. No significant changes were observed in physical appearance, hardness, thickness, drug content, friability, lag time, or drug release (Figure 9). The drug release profile after 30 days (Figure 10) was comparable to the initial release profile, ensuring the formulation's long-term stability. Additionally, the principal peaks of the FTIR spectra remained unchanged. Thus, it was determined that the batch was stable.

 

Table No.09: Results of Stability Study

Sampling interval days	Storage condition 40 ± 20 C and 75 ± 5% RH
	Physical appearance	Hardness	Thickness	Drug Content	% Friability	Drug Release Lag Time(min)	Time Required For 90% Drug Release (min)
0	No change	5.867 ±0.094	3.87±0.094	99.11	0.824	268	303
15	No change	5.8 ± 0.1633	3.87±0.094	98.76	0.801	266	302
30	No change	5.8 ± 0.1632	3.87±0.094	98.52	0.801	266	302

 

Figure No.9: FTIR Spectra of Optimized Batch After Stability Study

 

Figure No.10: Comparison of In-vitro Drug Release Profile

 

CONCLUSION:

In conclusion, the direct compression method was used to create the formulation of press-coated pulsatile tablets of fimasartan potassium trihydrate. All of the checkpoint batches' evaluation parameters were found to be appropriate for press-coated pulsatile delivery. Using the kneading process, the inclusion complex of FPT with HP-β-CD (1:2) demonstrated increased solubility and a greater product yield (96.49%). There appears to be no interaction between the medicine and the excipients, according to FTIR measurements. 90% drug release at 302 minutes and a lag time of 266minutes were observed in the optimized batch. Its drug concentration is 99.88%, its thickness is 3.87±0.094mm, and its hardness is 5.8±0.1632kg/cm². It also has excellent flow properties.

 

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Received on 20.06.2025      Revised on 13.09.2025 Accepted on 06.11.2025      Published on 06.07.2026 Available online from July 20, 2026 Asian J. Pharm. Res. 2026; 16(3):221-228. DOI: 10.52711/2231-5691.2026.00033 ©Asian Pharma Press All Right Reserved
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