Development and Evaluation of Sublingual Tablet of Lercanidipine by Solid Dispersion Method
Anuradha Prajapati*, Patel Mehulkumar Pramodbhai, Shruti Jagdish Patel, Soniya Remeshing Sharan, Abhishek Shivshankar Shukla, Kriti Rajesh Singh, Shailesh Luhar, Sachin Narkhede
Department of Pharmaceutics, Smt. B.N.B. Swaminarayan Pharmacy College,
Salvav, Vapi, Gujarat, India 396191.
*Corresponding Author E-mail: anupatel03@gmail.com
ABSTRACT:
The purpose of this study was to develop and evaluate a sublingual tablet of lercanidipine hydrochloride for the direct compression method of treating hypertension by using a solid dispersion technique. The dihydropyridine calcium-channel blocker lercanidipine Hydrochloride is used to treat hypertension, Prinz metal’s variant angina, and chronic stable angina pectoris. It can be administered alone or in combination with an angiotensin-converting enzyme inhibitor. The biological half-life of lercanidipine hydrochloride is 8–10hours, and its duration of action is up to 24hours. Because of its first pass metabolism, lercanidipine hydrochloride has a less than 10% oral bioavailability. BCS class II was applied to lercanidipine hydrochloride due to its high permeability and poor solubility. The aforementioned features and attributes render Lercanidipine Hydrochloride a fitting contender for a sublingual tablet created by robust dispersion and integrating Gelucire 50/13. When compared to pure lercanidipine Hydrochloride, the solubility is high when Gelucire 50/13 was used at the highest concentration. This is the first attempt to improve the solubility of pure lercanidipine HCl free base by the use of various solid dispersion methods, including solvent evaporation, fusion, and physical mixing. Lercanidipine HCl kneading solid dispersion, made with Gelucire 50/13 (1:1)., The prepared lercanidipine HCl sublingual tablets prevent first pass metabolism, avoid swallowing-related issues, particularly in elderly patients, and enhance solubility. The tablet disintegrated in 50 seconds, according to the results. Similarly, a dissolution study conducted in vitro revealed 96.68% drug release in 10 minutes. The prepared lercanidipine HCl sublingual tablets containing a complex with Gelucire 50/13 solid dispersion were found to significantly improve patient compliance and bioavailability.
KEYWORDS: Lercanidipine Hydrochloride, Solid Dispersion, Sublingual Tablets, Solubility, Bioavailability.
INTRODUCTION:
Hypertension, a medical disorder characterized by chronically raised blood pressure in the arteries, is sometimes referred to as high blood pressure1,2. While the WHO uses the value 160/95mm Hg, the American Heart Association defines hypertension as an arterial blood pressure value greater than 140/90 mm Hg. Systolic and diastolic blood pressure readings are obtained3. In order to determine the risk of heart disease, both measurements are crucial. Hypertension is defined as a consistent diastolic blood pressure of more than 90mm Hg accompanied by a rise in the systolic blood pressure to more than 140mm Hg. An abnormally high blood pressure is caused by an increase in peripheral vascular smooth muscle tone, which also causes an increase in arteriolar resistance and a decrease in the venous system's capacitance4-6.
Primary and secondary hypertension, which are categorized based on factors like age, family history, and being less physically active, Being overweight or obese, smoking cigarettes, High salt consumption, Less potassium intake, Heavy drinking of alcohol, Stress and Chronic illnesses like diabetes and renal failure7. Hypertension is rarely accompanied by symptoms, some persons with high blood pressure describe headaches, as well as light headedness, vertigo, tinnitus, impaired vision or episodes.
When a medication is administered sublingually, it is inserted beneath the tongue and enters the bloodstream through the floor of the mouth and the tongue's ventral surface8. When no fluids or water are consumed, the fast- dissolving tablet format is intended to allow the administration of an oral solid dose form. Usually, just the saliva in the buccal cavity is sufficient to dissolve these tablets9-10.
With an almost 100% bioavailability and a 3–7-hour elimination half-life, oral absorption is quick, homogeneous, and thorough. Thus, the goal of the New Drug Delivery Systems is to improve patient compliance by creating a dose form that is easy to deliver11.
Consequently, oral mucosal drug delivery has become more popular as a substitute system drug delivery technique that has a number of benefits over injectable and internal delivery methods that have the same effect as intravenous routes12-13.
A calcium channel blocker called lercanidipine hydrochloride was first made available to treat hypertension. Its first pass metabolism occurs in the gut wall and liver, and its oral bioavailability is 10%14-15. The sublingual dosage form provides a quicker release of the medication into the bloodstream, avoiding the liver's metabolism of nifedipine and providing quicker and more effective relief from hypertension and anginal discomfort.
Solid dispersion is defined as the dispersion of one or more active ingredients in an inert carrier that has been created utilizing various solid dispersion technology techniques while it is in a solid form. The medication is released at the point where the solid dispersion and aqueous medium come into contact by a hydrophilic inert carrier16-17.
Gelucire 50/13 carrier is a highly crucial and significant factor in particle wettability; if wettability is good, solubility will naturally increase, which will enhance bioavailability. Gelucire 50/13 carrier is a highly crucial and significant factor in particle wettability; if wettability is good, solubility will naturally increase, which will enhance bioavailability18.
In lipid-based formulations, Gelucire 50/13 is a non-ionic water-dispersible surfactant that improves the oral bioavailability of weakly water-soluble APIs by solubilizing them. In aqueous media, it self-emulsifies to form a fine dispersion19. The two primary functions of the bioavailability enhancer and solubilizer are for poorly soluble APIs.
There are various methods for creating the sublingual tablets, but the direct compression approach is the most practical since it just calls for adding a lercanidipine hydrochloride Gelucire 50/13 solid dispersion to the mixture. For pharmaceuticals that are sensitive to heat or moisture, direct compression is the best option since it eliminates the need for heat or water during the formulation process20.
In this study, a direct compression method was employed to analyze the sublingual lercanidipine hydrochloride tablets using the Gelucire 50/13 solid dispersion. Numerous metrics, such as bulk density, tapped density, hardness, friability, in vitro disintegration, and dissolving time tests, were used to assess the quality of the formulations21.
Materials:
Lercanidipine hydrochloride was obtained as a gift sample from CTX Life Sciences Pvt. Ltd., Surat, India. Gelucire 50/13 was obtained as a gift sample from Gattefosse SAS, India. Vishal Chem, Mumbai, India provided D-mannitol, D- sorbitol, Avicel Ph 101, Avicel Ph 102, Crospovidone, Sodium starch glycolate, Cross Carmellose Sodium, Polyvinyl povidone K-30, Methanol, Magnesium stearate, and Talc. Analytical grade solvents and chemicals were used only.
Drug-Excipient compatibility studies:
To determine whether lercanidipine hydrochloride was compatible with other excipients, FTIR analysis was performed. utilizing a mortar and pestle, the 1 mg sample of lercanidipine hydrochloride was triturated utilizing pallets of Gelucire 50/13. To obtain uniform particles, the prepared solid dispersion was run through a sieve. Compressed solid dispersion was combined with other excipients. The final tablets were put in the proper holder within the FT-IR spectrophotometer, and the full range spectra of all the crystals, ranging from 4000 cm to 400cm, were recorded. The unique peaks were observed.
Formulation of sublingual tablets:
By using a solid dispersion (Lercanidipine hydrochloride with Gelucire 50/13) and additional excipients, the direct compression method was used to manufacture the sublingual tablets of lercanidipine hydrochloride. The following excipients were used: methanol, magnesium stearate, talc, cross-povidone, sodium starch glycolate, cross- Carmellose sodium, Avicel Ph 101, Avicel Ph 102, and D-mannitol22.
Several sublingual tablet formulations were made with varying excipient concentrations. Table 1 displays various formulations' compositions. Using a pestle and mortar, all of the sublingual tablet's contents were measured out and combined. The combined mixture was then compressed using an 8-station Karnavati Minipress Rotary tablet machine using a 6mm flat-biconvex punch (Ahmedabad, Gujarat). The formulation's overall weight was kept at 100 mg.
Studies on the formulation of Lercanidipine Hydrochloride sublingual tablets pre- and post-compression:
Following normal protocols, the pre-compression investigations of lercanidipine hydrochloride sublingual tablets were evaluated. The evaluation included the following parameters: Hausner's ratio, bulk density, tapered density, compressibility index, and angle of repose26. The evaluation of post-compression parameters, including drug content, dissolving studies, uniformity of weight, hardness, friability, thickness, disintegration time, wetting time, and water absorption ratio, was conducted using the same standard methodology27.
Table No. 1: Formulations from F1 to F6 23-25
Ingredients (% w/w) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
Solid Dispersion of Lercanidipine HCl + Gelucire 50/13 (1:1) |
20 |
20 |
20 |
20 |
20 |
20 |
Avicel Ph 102 (Diluent) |
57 |
58 |
57 |
58 |
57 |
58 |
Sodium Starch Glycolate (Super disintegrant) |
4 |
3 |
- |
- |
- |
- |
Croscarmellose sodium (Super disintegrant) |
- |
- |
4 |
3 |
- |
- |
Cross povidone (Super disintegrant) |
- |
- |
- |
- |
4 |
3 |
Polyvinyl povidone K-30 (Binder) |
4 |
4 |
4 |
4 |
4 |
4 |
Sorbitol (sweetener) |
10 |
10 |
10 |
- |
- |
- |
D- Mannitol (sweetener) |
- |
- |
- |
10 |
10 |
10 |
Magnesium stearate (lubricant) |
2.5 |
2.5 |
2.5 |
2.5 |
2.5 |
2.5 |
Talc (Glidant) |
2.5 |
2.5 |
2.5 |
2.5 |
2.5 |
2.5 |
Total |
100 mg |
100 mg |
100mg |
100 mg |
100 mg |
100mg |
API Characterization:
Melting point:
It was discovered that lercanidipine hydrochloride has a melting point between 1940 and 1960C, this is compliant with the benchmark.
Lercanidipine Hydrochloride Solubility:
According to table No. 2 below, the solubility of lercanidipine hydrochloride was investigated in a range of solvents.
Table No. 2: Lercanidipine Hydrochloride Solubility in Various Solvents
Sr. No. |
Solvents |
Solubility |
1 |
Methanol |
Freely soluble |
2 |
Water |
Insoluble |
3 |
pH 6.8 phosphate buffer |
soluble |
FTIR of lercanidipine hydrochloride:
Fig. No.1: FTIR Spectra of Lercanidipine Hydrochloride
Standard Lecanidipine Hydrochloride Calibration Curve in Phosphate Buffer pH 6.8:
To prepare the stock solution, 10mg of the drug was dissolved in a mixture of Phosphate Buffer pH 6.8 and 10% methanol to obtain a concentration of 100µg/mL. Generate a calibration curve by preparing working solutions ranging from 4 to 20µg/mL line was displayed on the graph (Fig.2). Measure the absorbance of each working solution at 236nm λmax, and plot the absorbance values against the concentrations using regression analysis to establish the calibration curve.
Fig. No.2: Lecanidipine Hydrochloride Calibration Curve in pH 6.8 Phosphate Buffer Drug-Excipients
Compatibility Study:
FTIR spectroscopy was used to investigate the drug and excipients' incompatibility. Fig. displays the spectrum data of different drug-excipient mixes as well as pure drug. 3-5. The findings show that the medicine and the excipients utilized in the formulation did not have any chemical incompatibilities.
Fig No. 3: FTIR Spectrum of lercanidipine hydrochloride with Gelucire 50/13
Fig No. 4: FTIR Spectrum of Optimized Sublingual Lercanidipine HCl Tablet
Pre-Compression Evaluation:
Formulation ranging from F1 to F6. Bulk density, tapped density, angle repose, % compressibility (or) Carr's index, and Hausner's ratio have no external limitations. The results are shown in Table 3.
Angle of repose: from 25.34 to 21.01 (gm/ml) Bulk density: 0.530 to 0.535, Density (grams/milliliter): 0.650 to 0.670 Carr’s Index (compressibility index): 18.50–20.59; Hausner’s Ratio: 1.22-1.25.
Table No. 3: Tablet Blend Pre-compression Study
Batch. N0. |
Angle of Repose (0) |
Bulk Density (g/ ml) |
Tapped bulk density (g/ ml) |
Carr’s index (%) |
Hausner’s Ratio |
F1 |
23.320±0.23 |
0.535±0.011 |
0.668±0.014 |
19.91±0.13 |
1.24±0.052 |
F2 |
24.180±0.13 |
0.532±0.010 |
0.670±0.023 |
20.59±0.13 |
1.25±0.043 |
F3 |
21.160±0.21 |
0.532±0.004 |
0.667±0.017 |
20.23±0.28 |
1.24±0.023 |
F4 |
25.340±0.15 |
0.530±0.018 |
0.661±0.023 |
19.81±0.15 |
1.24±0.058 |
F5 |
21.01±0.31 |
0.533±0.014 |
0.650±0.025 |
18.50±0.29 |
1.22±0.045 |
F6 |
22.18±0.13 |
0.533±0.004 |
0.662±0.014 |
21.22±0.28 |
1.23±0.023 |
Table No. 4: Tablet Blend's Physical Properties
Formulation |
Weight Variation (mg) |
Hardness (kg/cm2) |
Thickness (mm) |
Friability (%) |
F1 |
100±0.05 |
3.633±0.208 |
1.83±0.057 |
0.715 |
F2 |
101±0.51 |
3.366±0.208 |
1.76±0.057 |
0.834 |
F3 |
99±0.71 |
3.466±0.115 |
1.83±0.057 |
0.598 |
F4 |
100±1.935 |
3.500±0.057 |
1.86±0.057 |
0.719 |
F5 |
99±1.894 |
3.300±0.264 |
1.73±0.057 |
0.718 |
F6 |
101±2.179 |
3.466±0.057 |
1.83±0.057 |
0.952 |
The obtained results verify that the batches with good packing characteristics also have good flow qualities.
Post- Compression Evaluation:
The weight variation, hardness, thickness, friability, and disintegration time of batches of sublingual tablets ranging from F1 to F6, as well as their water absorption ratio, wetting time, drug content, and in vitro dissolution studies, were all evaluated.
The purpose of the weight variation was to verify that the tablet weight was consistent. The weight variation of the tablets, which ranged from 99 to 101mg, was enough. Every batch satisfies the United States Pharmacopoeia variation. Every batch had a hardness of between 3.300 and 3.633kg/cm2. The thickness was displayed between 1.73±0.057 and 1.86±0.057mm. When determined, the friability of every formulation was less than 1%. It demonstrates the tablets' mechanical stability and ability to withstand handling and shipping conditions. (Shown in Table 4)
Water absorption ratio and wetting time:
The key factors in figuring out a disintegrates' ability to swell in the presence of minimal water are the soaking time and the water absorption ratio. It was discovered that the water absorption ratio and wetting time for formulations F1 through F6 ranged from 17.254±0.325 to 19.624±0.172 and 18 to 48 seconds, respectively. Table 5 presents the findings. The batch F5 tablet had the greatest results, displaying a wetting time of 18 seconds and a water absorption ratio of 19.624±0. 172. According to the results, the preparation will dissolve more quickly since it has a higher water absorption ratio and a shorter wetting time.
Table No. 5: Compressed Tablet Evaluations
Formulation |
Disintegration time (sec) |
Wetting time (sec) |
Water Absorption ratio (%) |
Drug Content (%) |
F1 |
85±1 |
48±1 |
17.254± 0.325 |
91.34 ± 0.71 |
F2 |
80±1 |
44±1 |
18.909± 1.267 |
91.12 ± 0.84 |
F3 |
74±0 |
39±1 |
19.170± 0.253 |
90.30 ± 0.63 |
F4 |
67±1 |
35±1 |
18.196± 0.127 |
95.40 ± 1.00 |
F5 |
64±0 |
18±1 |
19.624± 0.172 |
94.96± 1.08 |
F6 |
58±1 |
26±1 |
17.954± 0.319 |
90.14 ± 0.47 |
The duration of disintegration in vitro:
Sublingual pills should have a small disintegration time because they should dissolve fully in a little period of time. Using several super disintegrants, it was discovered that the disintegration times for formulations F01 through F6 varied from 48 to 85 seconds. The findings are shown in Table 5. With a disintegration duration of 64 seconds, batch F5 tablets once again showed the best performance. In conclusion, disintegration time decreases as super disintegrant concentration rises.
In-vitro dissolution study:
An in vitro dissolving experiment was performed on each formulation (F1 through F6). The results are shown in Fig No.5. The medication concentration for formulations F1 through F6 varied between 90.14% and 94.96%. 94.96% was found to be the highest percentage of medication concentration in formulation F5.
Fig no.5: % Drug Release Percentage for Each Formulation (F1-F6)
In Vitro Drug Release Studies:
Table 6 lists the in vitro drug release for each final formulation batch (F1–F5). In all formulation batches, more than 50% drug release was seen in less than five minutes. All of the formulations, however, demonstrated a drug release of above 80% in 25 minutes. Based on the dissolution data, the F5 batch showed promise, releasing over 99% of the medication within 35 minutes.
A variety of criteria were taken into consideration when developing and evaluating lercanidipine hydrochloride solid dispersion sublingual tablets. The inclusion of Gelucire 50/13 significantly affects the drug's release, disintegration, and dissolving characteristics. However, the release and disintegration of the medicine were negatively impacted by higher concentrations of Gelucire 50/13. Combining cross povidone with other excipients as a super disintegrant agent yielded the best in-vitro drug release reported in formulation F5. Formulation F5 showed the largest water absorption ratio, the lowest wetting time, and the lowest disintegration time when compared to the other formulations. Consequently, the combination of Lercanidipine hydrochloride solid dispersion sublingual tablet and hypertension medication works well.
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Received on 14.09.2024 Revised on 28.12.2024 Accepted on 22.02.2025 Published on 09.05.2025 Available online from May 12, 2025 Res. J. Pharma. Dosage Forms and Tech.2025; 17(2):91-96. DOI: 10.52711/0975-4377.2025.00013 ©AandV Publications All Right Reserved
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