Formulation Development And In Vitro Characterization of Orally Disintegrating Tablets for Enhanced Antihypertensive Drug Delivery

Oral drug delivery is the most preferred and widely used route for systemic administration of drugs, offering convenience and flexibility through a variety of pharmaceutical dosage forms ¹. Tablets and capsules are the most common oral dosage forms due to their simplicity and convenience. However, swallowing difficulties in geriatric, pediatric, and psychiatric patients present a significant drawback. To improve compliance, fast-disintegrating tablets (FDTs) have been developed, which rapidly dissolve or disperse in the mouth and can be swallowed easily, potentially bypassing hepatic first-pass metabolism^{2 3}. Fast-disintegrating tablets are also known by various other names, including orally disintegrating tablets (ODTs), quick-melt or rapid-melt tablets, fast/rapid dissolving tablets (FDTs), mouth-dissolving/disintegrating tablets (MDTs), and porous tablets^{4 5}. Orally disintegrating tablets (ODTs) offer advantages over conventional tablets, including rapid fragmentation, quick onset of action, and improved patient compliance, especially for pediatric, geriatric, psychiatric, paralyzed, and bedridden patients. Since ODTs are absorbed through the pre-gastric mucosa within seconds, they help overcome swallowing difficulties 6 7 8. Furthermore, ODTs avoid the first-pass metabolism, which enhances the bioavailability of the drug and reduces frequent administration of drugs9. ODTs are formulated using excipients such as film-forming polymers, plasticizers, superdisintegrants, and active pharmaceutical ingredients (APIs), making them a cost-effective dosage form. Superdisintegrants play a key role by breaking the tablet into smaller fragments, enabling rapid dissolution. Calcium channel blockers (CCBs) are used in the treatment of hypertension due to their vasodilatory effect, which reduces total peripheral resistance and, consequently, lowers blood pressure ¹⁰. Research has shown that CCBs are as effective as other antihypertensive drugs in lowering blood pressure and may help prevent the onset of heart failure. ^{11 12}.  Amlodipine besylate is a third-generation, long-acting dihydropyridine calcium channel blocker. It has an oral bioavailability of 60–65%, with peak plasma concentration (Cmax) occurring approximately 6 to 8 hours after administration ¹³. Amlodipine besylate is chemically described as (4R, S)-3-ethyl-5-methyl2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate monobenzene sulfonate. It is a third-generation dihydropyridine calcium channel  blocker¹⁴. Amlodipine is a first-line agent for hypertension¹⁵ and angina pectoris¹⁶. Patient compliance is crucial for amlodipine besylate, especially in elderly, pediatric, and special-needs patients. It’s available as oral tablets in 5 mg and 10 mg doses, with 6.9 mg of the besylate salt equivalent to 5 mg of amlodipine. Amlodipine is well absorbed (96%) with a bioavailability of 64–90%¹⁷. It belongs to the BCS class I drugs, making it easier to be manufactured as a mouth-dissolving tablet¹⁸.

Materials and Methods

2.1. Chemicals and Reagents: Amlodipine Besylate (IPCA Laboratories, Mumbai, India; Stock solution Batch no. 22005AK5RH); Crospovidone, Magnesium Stearate, and Sodium Starch Glycolate (SSG) (HiMedia Laboratories Pvt. Ltd., Maharashtra, India); Saccharin Sodium, PVP K-30, and Aerosil (Central Drug House Pvt. Ltd., New Delhi, India); Mannitol (Thermo Fisher Scientific India Pvt. Ltd., Mumbai, India).

2.2 Determination of λ_max of Amlodipine Besylate: To determine the wavelength of maximum absorption, the UV spectrum of amlodipine besylate was recorded using a Shimadzu UV-visible spectrometer. A stock solution (100 µg/mL) was prepared by dissolving 10 mg of the drug in 100 mL of distilled water. Working solutions of 10, 20, 30, 40, and 50 µg/mL were made by diluting 1, 2, 3, 4, and 5 mL of the stock solution to 10 mL, respectively. These solutions were scanned from 400 nm to 200 nm, and the maximum absorption wavelength (λmax) was identified at 238 nm.

2.3 Preparation of standard calibration curve. Solutions ranging from 0 to 30 µg/mL, in 5 µg/mL increments, were prepared. Absorbance for each solution was measured at 238 nm using distilled water as a blank with a Shimadzu UV spectrophotometer.

2.4 Drug excipients compatibility study by IR Spectroscopy. The drug and excipients were mixed in a 1:1 ratio and stored in a desiccator for 2 months. Afterward, they were analyzed for any degradation using infrared spectroscopy.

2.5 Analytical Method Validation

The parameters for analytical method validation are:

2.5.1 Linearity

To construct calibration curves and determine regression equations, amlodipine besylate solutions of various concentrations (10, 15, 20, 25, and 30 µg/mL) were prepared. Their absorbance was measured using a UV-visible spectrophotometer and plotted with concentration on the X-axis and absorbance on the Y-axis. The calibration curve for amlodipine in the 10–30 µg/mL range is shown in Figure 1.

2.5.2 Accuracy

Accuracy was assessed at three concentrations of amlodipine—12 µg/mL, 15 µg/mL, and 18 µg/mL—representing 20% below, at, and 20% above the assay concentration. Each concentration was tested in triplicate using the assay method. Accuracy was calculated using the formula: Accuracy = [Analytical result/ True result] *100

2.5.3 Specificity

This was performed by measuring the absorbance of amlodipine besylate and all excipients used in the formulation at 238 nm.

2.6. Preparation of Amlodipine besylate ODTs.

The experimental design involved varying the concentrations of the superdisintegrants, crospovidone and sodium starch glycolate (SSG), with levels selected based on guidelines from The Handbook of Excipients¹⁹.  According to The Handbook of Excipients, sodium starch glycolate (SSG) is used at concentrations of 2–8%, while crospovidone is used at 2–5%. Based on this, eight formulations were prepared: F1, F2, F3, and F4 contained 2%, 4%, 6%, and 8% SSG, respectively; F5, F6, F7, and F8 contained 2%, 3%, 4%, and 5% crospovidone, respectively. All other ingredients remained constant across formulations. Amlodipine besylate, crospovidone, SSG, and mannitol were sieved through a #40 mesh and collected separately. Fast-disintegrating tablets (FDTs) were prepared using the direct compression method. The drug and diluents were mixed geometrically and blended for 20 minutes. The mixture was then lubricated with aerosil and magnesium stearate (sieved through #60 mesh) for 5 minutes. Finally, tablets were compressed using an 8 mm circular flat punch on a tablet compression machine.

2.7 Pre-compression parameters of the tablet

2.7.1 Bulk density

Bulk density is defined as the ratio of the total mass of a powder to its bulk (untapped) volume. It was determined by pouring 100 g of the powder blend into a graduated cylinder and recording the bulk volume (Vb). The bulk density (ρb) was then calculated using the formula:

ρb= M/Vb

Where,

M is the weight or mass of the powder

2.7.2 Tapped density

Tapped density is the ratio of the total mass of the powder to its tapped volume. To determine tapped density, 100 g of the powder blend was placed into a graduated cylinder, which was mechanically tapped 500 times to record the initial tapped volume. Tapping continued for a total of 750 taps, and the final tapped volume (Vt) was noted. The tapped density (ρt) was calculated using the formula:

ρt = M/Vt

Where,

M is the mass or weight of the powder.

2.7.3 Carr’s Index

Carr’s index, named after Ralph J. Carr, Jr., indicates the compressibility of a powder. It is calculated using the formula:

Carr’s Index = [Tapped Density-Bulk density]/Tapped density * 100%

2.7.4 Hausner ratio

The Hausner ratio, named after engineer Henry H. Hausner, indicates the flowability of a powder or granular material. It is calculated using the formula:

Hausner ratio (H) = Tapped density/Bulk density

2.7.5 Angle of Repose

The angle of repose is defined as the steepest angle relative to the horizontal plane at which a material can be piled without slumping. It was measured using the fixed funnel method. A 75 g powder blend was poured through a funnel fixed 10 cm above a flat surface. The diameter (d) and height (h) of the resulting powder heap were measured. The angle of repose (θ) was calculated using the formula:

θ = tan^-1 (2h/d)

2.8 Post-compression Parameters of the tablet

2.8.1 Weight variation

Twenty tablets from each batch were weighed individually on an analytical balance, and the average values and deviation from the average value were calculated.

2.8.2 Thickness variation

Thickness variation was measured using a Vernier caliper on 10 tablets from each batch. The average thickness was calculated and reported as mean ± SD.

2.8.3 Hardness

The hardness of 10 tablets from each batch was measured using a Labinda hardness tester. The average hardness was calculated and reported as mean ± SD.

2.8.4 Friability

Tablets weighing approximately 6.5 g were tested for friability using a Roche friabilator at 25 rpm for 4 minutes (100 revolutions). After testing, the tablets were weighed, and the percentage weight loss was calculated.

Friability (%) = (W1 – W2)/ W1 X 100

Where,

W1 = Weight before a test

W2 = Weight after a test

2.8.5 Disintegration

One tablet was placed in each of six tubes in the basket assembly, which was then suspended in water maintained at 37°C ± 2°C. The apparatus was operated, and the time taken for all tablets to disintegrate was recorded.

2.9 Dissolution studies

2.9.1 Preparation of dissolution medium

0.1N Hydrochloric acid was used as a dissolution medium.

2.9.2 Method for dissolution

The release rate of amlodipine besylate from the fast-dissolving tablets was determined using the previously described method. The dissolution study parameters were as follows:

• Dissolution medium: 900 mL of 0.1 N HCl.
• Dissolution apparatus: Paddle
• Rotating speed: 75 rpm
• Temperature: 37±0.5 degrees Celsius
• Time: 15sec, 30sec, 45sec, 60sec, 75sec.

2.9.3 Analysis of dissolution sample

Samples of 10 mL were withdrawn from the dissolution apparatus at regular intervals (15, 30, 45, 60, and 75 seconds) and immediately replaced with an equal volume of fresh dissolution medium. The samples were filtered through filter paper, and their absorbance was measured at 238 nm using a Shimadzu UV/Vis spectrophotometer. The cumulative percentage of drug release was calculated and plotted graphically.

2.9.4 Assay [By UV-VIS spectrophotometer]

To measure the assay, 20 tablets were weighed and crushed using a mortar and pestle. Powder equivalent to 10 mg of amlodipine was dissolved in 100 mL of water to prepare a 100 µg/mL stock solution. This stock was diluted by taking 1 mL and making up the volume to 10 mL to obtain a 10 µg/mL working solution. The absorbance of this solution was measured at 238 nm, and the assay was calculated by comparing the absorbance to the standard calibration curve.

RESULTS AND DISCUSSION

Development of Master Formula for Amlodipine Besylate Tablets

This tablet formulation aims to develop an optimal 10 mg amlodipine besylate direct compression tablet by varying the proportion of disintegrants while keeping other excipients constant. The primary goal is to evaluate the effects of sodium starch glycolate (SSG) and crospovidone on tablet disintegration and dissolution for effective ODT delivery. Formulations F1–F4 contain increasing amounts of SSG (2%–8%), which swells on water absorption to break the tablet apart, while F5–F8 have increasing crospovidone concentrations (2%–5%), promoting disintegration via capillary action. Other excipients remain unchanged: magnesium stearate as a lubricant, aerosil to improve flowability, saccharin sodium for taste masking, PVP K-30 as a binder, and mannitol as a filler to achieve a 200 mg tablet weight. The final formulation will be selected based on a comprehensive evaluation of hardness, friability, disintegration time, and dissolution profile to ensure optimal drug performance.

Table 1: Master Formula of the Formulation details the composition of eight Amlodipine Besylate tablet formulations with varying disintegrants and excipients.

Pre and Post-Compression Evaluation Results of Tablet Formulations (F1 to F8)

Table 2 presents the results of pre-compression evaluation of the powder blends and post-compression evaluation of the amlodipine fast-disintegrating tablets (FDTs). Pre-compression parameters indicated good free-flowing properties, with low Hausner’s ratio, compressibility index, and angle of repose reflecting fair flowability. The tablets were free from defects such as chipping, sticking, capping, and lamination, and exhibited uniform weight with acceptable variation between 190 mg and 210 mg. Hardness values ranged from 3.0 to 3.3 kg/cm², and friability loss was less than 1%, indicating good mechanical strength and binding properties suitable for handling and transport. Drug content ranged from 102.7% to 109.6%, within the acceptable limit of 90% to 110%. Disintegration time, a critical parameter for FDTs, ranged from 18 to 65 seconds. Formulations containing sodium starch glycolate showed comparatively slower dissolution rates. The tablet with 5% crospovidone exhibited the fastest disintegration time of 18 seconds, while the one with 2% SSG had the longest disintegration time of 65 seconds. The shortest disintegration time of 18 seconds at a low concentration highlights crospovidone as a superior superdisintegrant compared to sodium starch glycolate (SSG). This rapid disintegration is attributed to crospovidone’s faster capillary action, swelling 4 to 10 times quicker than SSG²⁰. In this study, disintegration time decreased with increasing concentrations of superdisintegrants. These results suggest that higher superdisintegrant levels lead to faster tablet disintegration. Both sodium starch glycolate (SSG) and crospovidone met the criteria for fast-disintegrating tablets, disintegrating in under one minute within their respective concentration ranges². FDTs of amlodipine prepared by Krishna Mohan Pr et al (2010) using crospovidone and Sodium Starch Glycollate (at the concentration of 4%, 6% and 8%) also showed the disintegration time of less than 50 seconds^{21 22}. FDTs of amlodipine Besylate were also prepared using crospovidone and SSG, and the disintegration time of all the formulations was in the range of 22sec-35sec²². The researchers found the disintegration time of 10 seconds for all formulations²³.

Table 2: Comprehensive Pre- and Post-Compression Characterization of Tablet Formulations (F1 to F8), Including Physical and Performance Evaluation Parameters

Analytical Method Validation Results for Linearity, Specificity, and Accuracy

Figure 1 shows the plot of absorbance versus drug concentration, with an R² value of 0.9999, confirming the method’s excellent linearity (R² > 0.99). Specificity testing revealed minimal interference from excipients in the placebo solution, with only 1.55% interference—well below the acceptable limit of 2%—demonstrating that excipients do not significantly affect the drug’s absorbance measurement. Accuracy, evaluated at 80%, 100%, and 120% of the target drug concentration (Table 4), showed percent recoveries consistently within the acceptable range of 98% to 102%. Recovery ranged from 100.75% to 101.91% at 80%, 99.53% to 101.8% at 100%, and 99.61% to 100.94% at 120% concentration levels. Low standard deviation and relative standard deviation (both under 1%) further confirm the method’s precision and reliability for accurately determining drug concentration.

Figure 1 shows a linear calibration curve, confirming the accuracy of the method.

Table 3: Results for Specificity

Table 3 confirms the method’s specificity, with excipient interference well below the acceptable limit.

Table 4 confirms the method’s accuracy, with recovery percentages within the acceptable range and minimal variation.

Comparison of Cumulative Drug Release Profiles for SSG and Crospovidone in Tablet Formulations In vitro release studies showed that over 80% of the drug was released from all formulations within 75 seconds. Formulation F5 demonstrated the fastest drug release among them. Overall, crospovidone exhibited a higher dissolution rate compared to sodium starch glycolate. Other researchers have reported similar findings; for example, Krishna Mohan Pr et al. (2010) prepared amlodipine FDTs using crospovidone and sodium starch glycolate at concentrations of 4%, 6%, and 8%, observing dissolution profiles ranging from 74.33% to 96.78%. In their study, formulations containing sodium starch glycolate showed a comparatively higher dissolution rate than those with crospovidone, with the enhancement order being Sodium Starch Glycolate > Crospovidone21. However, in our case, crospovidone has a relatively higher dissolution rate than SSG.  Previously, FDTs of amlodipine besylate were prepared using crospovidone and sodium starch glycolate as superdisintegrants. The dissolution profile of the formulations ranges from 77.84% - 87.55%23. Similar to our result, the order of the dissolution rate was found to be crospovidone > Sodium starch glycolate.

Figure  1(a): Cumulative Drug Release Profile for SSG

Figure 2(b): Cumulative Drug Release Profile for Crospovidone