The Chemist Volume 94 | Number 1
ISSN 1945-0702
Formulation and Sustained Release Verapamil Hydrochloride Tablets *Zaid Hamid Mahmoud1, Ahmed B. Mahdi2, Yasir S. Alnassar3, and H. N. K. AL-Salman4 1 College of sciences, Diyala University, Diyala, Iraq 2 Anesthesia Techniques department, Al-Mustaqbel university college, Babylon, Iraq 3 The university of Mashreq, Baghdad, Iraq 4 Department of Pharmaceutical Chemistry, College of Pharmacy, University of Basrah, Iraq *Address for correspondence: E-mail: Zaidhameed_91@yahoo.com
Abstract: Verapamil hydrochloride effervescent tablets are the principal focus of this investigation. Material & Methods: Verapamil hydrochloride floating tablets were made using the direct compression method. HPMC-K15M, karaya gum, sodium bicarbonate, and diluents were homogenized for ten minutes before adding magnesium stearate to each tablet formulation. Each tablet had a total weight of 300 mg. HPMC was utilized in the range of 20- 40 mg, and karaya gum was used in the 40-90 mg range. We used a mortar and pestle for kneading the powder combination for another 5 minutes. A Rimek rotating tablet machine was used to compress the mixture into tablet form. The formulations were tested using a variety of criteria following their production. Results & Discussion: The tablet formulation friability range was between 0.3 ± 0.0064 and 0.59 ± 0.0077%. The manufactured tablet formulation's weight fluctuation is within USP guidelines. The range of thickness was discovered to be 4.1 ± 0.48 to 4.2 ± 0.76 mm. The assay for drug content range was between 96.52 ± 0.35 and 102.13 ± 0.53%. For B1, B5, B6, B9, and B10 at 12 hours, more than 75% of the medication was released. B1 showed a maximum of 30% drug release in the first hour and a steady release for up to 12 hours. One possible explanation for B8's low drug release is the creation of a thick gel barrier on top of the tablet. Key Words: Effervescent, Verapamil, bioequivalence, FDDS, floating tablet

Introduction

Floating drug delivery systems "FDDS" or hydrodynamically controlled systems are low-density systems to remain buoyant in the stomach for a long time without affecting the rate at which the stomach empties. While floating on the gastric contents, the drug is gradually taken from the body at the desired rate. Immediately after taking the drug, the stomach's remaining systems are flushed out. A longer period of stomach retention and improved control over plasma medication concentrations are achieved as a result [1]. Additionally, a certain level of floating force (F) is needed to maintain the dose form stable on the surface of the meal so that the buoyancy retention principle can be appropriately applied. Buoyant systems can be made using granules, powders, capsules, tablets, laminated films, and hollow microspheres, among other things [2-15].

Materials & Methods

Formulation of Effervescent Floating Tablets

Verapamil hydrochloride floating tablets were made using the direct compression method. We blended HPMC-K15M, karaya gum, sodium bicarbonate, and diluents for ten minutes before adding magnesium stearate to each tablet formulation, which included the medicine. Table 1 shows the formulation chart of effervescent floating Verapamil hydrochloride tablets. Each tablet had a total weight of 300 mg. HPMC was utilized in the range of 20-40 mg, and karaya gum was used in the 40-90 mg range. A mortar and pestle were used to knead the powder combination for another 5 minutes [16,17].

Table 1. Formulation Chart of Effervescent Floating Verapamil Hydrochloride Tablets

Technological Characteristics of Floating Tablets

Weight variation test
The average weight of 20 tablets from each formulation is calculated by weighing each tablet individually and averaging the results. The individual weights are compared with the overall average weight. The standard variation for tablets with an average weight of 350 mg is ±5% (equation 1).

Friability
We used a Roche friabilator to grind ten pills into fine powder for four minutes at 25 rpm. They were removed, dedusted, and weighed again. The formula for calculating the percentage of friability in the tablets (equation 2) is [18]:

where % F is percentage friability, W is the initial weight of the tablet, and Wt is the final weight of tablets after revolutions.

Hardness
The average of the three pills taken from each formulation was used in the study. As a result, the Inweka hardness tester is used to determine how hard each tablet is to the touch. It is measured in kilograms.

Thickness and diameter
Mitutoyo micrometer screw gauge is used to measure tablet thickness and diameter. Each formulation has an average of five pills taken. Millimeter (mm) is the unit of measurement.

Uniformity of drug content
Five pills were ground to powder at random to determine if the drug content was homogeneous. When the drug is dissolved for 5 hours with intermittent shaking, it dilutes to 100 ml of buffer and stores at room temperature. Filtration removes insoluble residue by diluting 1 ml of the filtrate to 10 ml with buffer. We decided to measure the absorbance at its highest using a U.V. visible spectrophotometer. The trials were repeated three times for each formulation, and the mean data was recorded for each.

Drug-excipient Compatibility Studies

Fourier transforms infrared spectroscopy (FT-IR)
Drug-excipient interaction studies were conducted to assess the drug's integrity and compatibility in the formulation. Fourier transforms infrared FT-IR spectroscopy was used to examine the pure medication and optimized formulations. FT-IR spectra of pure drug and its formulations were obtained by an "FT-IR Shimadzu 8400S" (Japan) spectrophotometer using the KBr pellet method. The samples were scanned from 400 to 4,000 cm-1 wave number.

Differential scanning calorimetry (DSC)
DSC was carried out on a pure sample of the medication and its powdered form. Calorimetric measurements were performed using high purity alpha-alumina discs as a reference cell. The dynamic scans were taken in a nitrogen atmosphere at the heat rate ± of 10°C min-1. The energy is measured as Joules per kilocalorie [19].

In vitro floating studies [20]
Floating lag time and total floating time were used to measure in vitro buoyancy. A USP dissolving device was used for the test type-II (basket) using 900 ml of 0.1 N HCl buffer solutions at 100 rpm at 37 ± 0.5°C. In this experi-ment, the floating lag and total time are recorded as the time it took for the formulation to reach the surface of the dissolving medium and the time it took for the formulation to remain there (Figure 1).

Figure 1. Effect on Floating Lag Time of Different Formulations

Water uptake studies [21]
The swelling of the polymers is based on their propensity to absorb water and expand. A USP dissolving apparatus type-II (basket) was used to dissolve the tablet in pH 1.2 hydrochloric acid buffer at 100 revolutions per minute to conduct a water absorption study (RPM). The medium was maintained at 37 ± 0.5°C throughout the study. Regularly, the tablets were taken out, weighed, and blotted to remove any extra water before being put back in. Water uptake (W.U.) (equation 4) is used to describe the swell ability of the tablets.

Results & Discussion

Technological characteristics of floating tablets

Figure 2. Effect on Hardness of Different Formulations

The hardness of floating tablets ranged from 4.1 ± 1.23 to 6.1 ± 0.306 kg (Figure 2), depending upon the mixture of the polymer used. The tablet formulation's friability ranged from 0.3 ± 0.0063 to 0.59 ± 0.0076%. The manufactured tablet formulation's weight fluctuation is within USP guidelines. The thickness is discovered to be between 4.1 ± 0.48 and 4.2 ± 0.76 mm (Figure 3). The drug content assays ranged from 96.52± 0.37 to 102.03 ± 0.53% (Figure 4).

Figure 3. Effect on Thickness of Different Formulations

Figure 4. Effect on Content Uniformity of Different Formulations

Fourier transforms infrared spectroscopy (FT-IR)

Potassium bromide dispersion is used to measure the spectra in the solid-state. The FT-IR technology was used to capture the bands. The FT-IR spectral study found that the pure drug and the drug formulation have similar distinctive peaks with slight changes (Table 2). As a result, it was determined that the medication and polymer utilized have no chemical interaction.

Table 2. FT-IR Spectral Data of Effervescent Floating Tablet of Verapamil Hydrochloride (B1) and Verapamil Hydrochloride Pure Drug

Differential scanning calorimetry (DSC)

Screening for compatibility between drugs and excipients is made more accessible with DSC, which provides a wealth of data on potential interactions in a short period (Table 3). Verapamil hydrochloride and formulation B1 underwent a DSC study. An endothermic peak at 138.25^oC, the drug's melting point, maybe seen on its thermogram. The melting point of the medication is found to be 139.53^oC in the matrix tablet formulation B1. The medication and excipients have no interaction, according to the analysis of thermograms obtained using DSC [22,23].

Table 3. DSC Thermogram Data of Effervescent Floating Tablet of Verapamil Hydrochloride (B1) and Verapamil hydrochloride Pure Drug

In vitro buoyancy studies

The tablet turns buoyant when its density drops below 1 g/ml. Tablets made with karaya gum, and HPMC has good gel strength, allowing CO2 gas to be trapped inside and resulting in a long-lasting buoyancy. The system must float for a few minutes after contact with stomach fluid to prevent the dose form from being pushed into the small intestine with food. Experiments show that as the effervescent agent and karaya gum increases in B13, it takes longer for the system to float in the medium. The more significant concentration of effervescent agents resulted in more CO2 being produced faster and at a higher rate. A high level of buoyancy necessitated sodium bicarbonate. In general, the gastric emptying time was 4 hours. Because Verapamil hydrochloride is absorbed mainly from the proximal section of the intestine, the longer the medicine is in the stomach, the more it is absorbed (Table 4) [24].

Table 4. Effect of Sodium Bicarbonate on Onset and Duration of Floatation of the Effervescent Floating Tablet of Verapamil Hydrochloride (B1)

Water uptake studies

At one hour, the B4, B6, and B7 swelled by a large percentage. At the end of 8 hours, B8 exhibited a steady increase in the proportion of swell. The use of karaya gum slows down the water intake in the first hour. During the 8 hours, the levels of B2, B3, and B5 decrease. Sodium bicarbonate concentration does not affect the swelling properties, but lactose concentration in B8 has the most significant effect (p ≥ 0.05) (Figure 5).

Figure 5. Effect on Max Swelling of Different Formulations

Seipmann and Peppas think that the water content of the tablet has a considerable impact on the diffusion of the medication. To understand why this can be the case, we need to understand how water affects the mobility of polymer chains. Polymer chain relaxation occurs with volume increase, resulting in a significant system swell. Higher water content can also indicate faster stomach fluid entry into the tablet, resulting in faster CO2 gas generation and reduced floating time. As a result, the tablet swells faster and more rapidly, increasing the tablet's dimensions and decreasing diffusion rates.

In vitro drug release studies

There is more than 75% drug release at 12 hours for each of the following: B1, B5, B6, B9, and B10. At a maximum of 30% in the first hour and for nearly 12 hours, the B1 maintained a steady release of the medication. B8 shows the lowest drug release of all the formulations, which may be due to the substantial gel barrier on the tablet. Other formulations with a more extensive swelling index were shown to have a similar effect on drug diffusion across the gel barrier. B1 had a more excellent lactose content than any of the other samples. An infusion media dispersed into the matrix, leading to drug diffusion and controlled release from tablets (Figures 6 and 7).

Figure 6. In-vitro Drug Release of Different Formulations

Figure 7. In-vitro Drug Release of Different Formulations

Mathematical model fitting of obtained drug release data

Stability studies

The optimized formulation B1 was subjected to stability testing to determine the effect of formulation additions on both the chemical and biological stability of the medicine. It was tested for 12 months at 25^oC/60 percent R.H., 30^oC/65 percent R.H., and 40^oC/75 percent R.H. During the course of the study, neither the external appearance nor the pharmacological content changed appreciably. Table 5 provides the results of drug content determination during the period when the stability tests were conducted. Long-term and accelerated storage data were analyzed using Sigmaplot 12.0 software, as was the 95 percent confidence interval. According to the findings, the changes in the parameters evaluated were minor and insignificant.

Table 5. Stability Study Data of Effervescent Floating Tablet Formulation (B1) of Verapamil Hydrochloride

Conclusion

Direct compression was used to make the tablets. They met pharmacopeial standards for floating tablet technology. More than 8 hours later, the tablets were still floating. After 8 hours, all of the produced formulations have reached complete swelling. Therefore, the percentage of swelling was calculated at that point. More than 75% of the medication was released after 12 hours in F1, F5, F6, F9, and F10. Maximum 30 percent drug release occurred in one hour and continued for over 12 hours with F1. Formulation F1 is deemed the most optimal based on the results of the in vitro testing.

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