Improving Dissolution of Artesunate from Immediate Release Tablet by Inclusion with Beta ?-Cyclodextrin: In Vitro Characterization

One of the most important health issues the nation is dealing with is malaria. Multiple drug resistance is the primary drawback of conventional chemotherapy for malaria. Derivatives of artemisinin are among the few antimalarial medications that continue to work against strains of Plasmodium falciparum malaria that are resistant to several medicines^1,2. To improve solubility and bioavailability, several liposomes and nanoparticles have been used. Nevertheless, there aren't many thorough investigations on cyclodextrin complexes available. Therefore, the current study focusses on the beta-cyclodextrin inclusion complex in order to enhance the solubility and dissolution of immediate-release tablets.^2,3.

MATERIALS AND METHODS

MATERIALS

The source of artesunate was Aquatic Remedies in Mumbai, India. High-purity analytical grades were used for all other compounds, and beta-cyclodextrin was acquired from Modern Industries in Nashik, Maharashtra, India.

METHODS

Spectrometric analysis

In accordance with IP, artesunate was recognized using formal identification tests, such as melting point, solubility, and description. Artesunate dissolved in methanol was examined in the UV spectrum between 200 and 400 nm to find high absorption bands that are indicative of the drug. 10 mg of the drug were precisely weighed and added to a 100 ml volumetric flask in order to reach a concentration of 100 μg/ml. Further diluting this resulted in a solution with a concentration of 5–30 μg/ml. Plotting the absorbance of these solutions versus concentration allowed for the creation of the standard calibration curve^3,4.

Phase solubility Studies

Using a gravimetric approach, the solubility of Artesunate in different solvents was assessed. A precisely weighed graded quantity of the drug was introduced to 10 millilitres of the various solvents in a stoppered glass container⁴. A shaker was used to shake the bottles following every addition. When no more drug entered the solution, the additional drug was stopped, and the bottles were shaken for a full day. To determine the solubility of a medication in a given solvent system, the weight of the drug up to the "saturation point," which is the point at which no more drug dissolves in the solvent, was taken into account^5,6.

Preparation of Inclusion complex                                              

This was made using PVP K-30 (1:0.5,1:1,1:0.5) and artesunate and the β-cyclodextrin in different molar ratios (1:3, 1:2, and 1:1), as indicated in Table 1. Initially, β-cyclodextrin was combined with a small amount of 50% ethanol to make a paste, they were triturated in a glass mortar⁷. After adding the API kneaded for an hour. The result was then ground up, sieved through an 80 μm sieve, and kept in a desiccator over fused calcium chloride after being air dried for 24 hours at room temperature (28ºC)^7,8.

Table 1: Formulation code for inclusion complexes

Infrared spectroscopy

An IR spectrophotometer (Brooker) was used to perform Fourier transform infrared spectroscopy experiments on artesunate, β-cyclodextrin, and inclusion complex. Spectra were obtained using the KBr disc procedure. The spectra that were acquired were examined^6,8.

Characterization of inclusion complex

The flow characteristics of inclusion complexes for batches IC1 to IC6 were assessed. The tapped density device was used to determine bulk density and tapped densities three times. A precisely weighed 10-gramme powder of inclusion complex was added to a 100 ml graduated cylinder, and the cylinder was then left to tap after the initial volume was noted^5,6,9.

Percentage practical yield

The yield obtained from the process is what determines its efficiency. In order to determine the yield or efficiency, the percentage of practical yield was computed; this aids in the selection of the most suitable production process. To calculate the practical yield using the following equation, beta CD complexes were gathered and weighed^6,7,8.

% Practical Yield= Practical mass inclusion complextheoretical Mass   Drug+Carrier X 100

In-Vitro release

Dissolution tests were conducted for all formulations (IC1 to IC6) at 50 rpm and 37 ± 0.5°C. The dissolution medium used was 900 mL of 0.1 N HCl. The samples were taken out at appropriate intervals of 5, 10, 15, 20, 30, 45, and 60 minutes, and their volume was replaced with an equivalent volume of the same medium. The samples underwent filtration and dilution. Using a UV-visible spectrophotometer, the absorbances of the resultant solutions were determined at 230 nm^7,9,10.

Drug content

In a 50 ml volumetric flask, 100 mg of precisely weighed compound was dissolved in 40 ml of methanol. Methanol was used to bring the solution up to volume. After that, the solution was appropriately diluted with 0.1 N HCl, and the drug concentration was measured at 230 nm using the UV spectrophotometric technique^7,11.

Saturation solubility study

Saturation solubility tests were performed to assess the rise in artesunate solubility following complex formation with CDs: A known excess of CD compounds was added to 10 millilitres of distilled water. A rotary flask shaker was used to shake the samples for 24 hours at room temperature. After filtering and appropriately diluting the samples, they were spectrophotometrically examined at 230 nm. The pure drug's saturation solubility was also ascertained^7,11,12.

Formulation of Immediate release tablet

The artesunate: β-CD complex, which included 25 mg of artesunate, was compressed using the direct compression method to create tablets. After combining the complex, lactose, and maize starch were added and stirred for a further five minutes. After that, the mixture was compacted into tablet form. The tablets thickness, diameter, weight consistency, hardness, friability, dissolution time, and disintegration were all assessed^12,13.

Table 2: Formulation code of Artesunate inclusion complex tablet

Evaluation of Immediate release tablet

To determine the tablet thickness, Vernier callipers were used.  All the IPQC tests were carried out. A glass mortar and pestle were used to weigh five tablets and grind them into powder. In a 50 ml volumetric flask, 100 mg of precisely weighed powder was dissolved in methanol. Drug estimation was carried out using UV spectrophotometer at 230 nm^14,15,16.

In-vitro dissolution study

Dissolution equipment Type II was used to conduct the dissolution experiments of immediate-release tablets. 900 mL of 0.1 N HCl was used for the dissolution study. The temperature was kept at 37 ± 0.5°C while the stirring speed was set at 50 rpm. At regular intervals, the samples were taken out and replaced with new dissolving media. UV spectrophotometer was used to filter, dilute, and analyze the materials at 230 nm^16,17,18.

RESULTS AND DISCUSSION

Spectrometric analysis

The Artesunate solution's wavelength of maximum absorbance was determined to be 230 nm, which was consistent with the literature that was provided. As seen in Fig. 1, the absorbance versus concentration curve for artesunate was found to be linear across the 5–30 mg/ml range, demonstrating adherence to Beer and Lambert's laws³.

Figure 1: (a) Chemical structure of Artesunate (b) UV Spectrum of Artesunate (c) chemical structure of beta-cyclodextrin (d) calibration curve of Artesunate

Phase solubility Studies

A variety of solvents were used to test Artesunate solubility. According to the findings, the drug is sparingly soluble in 0.1 N HCl and acetic acid and insoluble in water. Fig. 2 displays the solubility findings. Pure artesunate has a low aqueous solubility, as evidenced by its 1.32 mg/ml solubility in distilled water^5,9,11.

Figure 2: Solubility Study of Artesunate in Different Solvent

IR

Figure 3 shows the IR spectra of artesunate and its complexes over the 500–4500 cm-1 frequency range. The O-H stretching vibration caused the distinctive IR peaks of the artemether to appear at 3198.08 cm-1. The FTIR spectrum of the inclusion complex corresponds to the beta-cyclodextrin, with no major peaks corresponding to Artesunate^6,7,18.

(a)

(b)

(c)

Solubility Study

Solubility study findings demonstrated that β-CD was a useful carrier for improving the solubility of medications that were not very soluble.

Figure 4: Saturation solubility study of ART-BCD inclusion complex in water

Characterization of inclusion complex

The percentage yield and drug content of each batch of drug inclusion complexes were assessed. Table 3% yield from 94.60 to 98.89, while the percentage drug content ranged from 96.56 to 99.36.

Table 3: Characterization of Inclusion complexes

Figure 5: Percentage of drug content of BCD inclusion complexes

All of the formulation's angles of repose were observed to range between 21.56 and 30.54º. These have adequate flow characteristics because they are all less than 40º. Tapped density ranged from 0.63 to 0.66 g/cm³, whereas bulk density was determined to be between 0.51 and 0.58 g/cm³. In all of the formulations, Carr's index values are less than 20 %. As a result, the formulations have suitable flow characteristics^10,11,19.

Table 4: Micrometric properties of inclusion complexes

Table 5: Percent Cumulative dissolution of Inclusion Complexes

Figure 6: In vitro release study of BCD complexes

Evaluation of Immediate release tablet

All of the formula tablets dissolve rapidly. The manufactured immediate-release tablet has a disintegration duration of 18 to 30 seconds. Within 18 seconds, the formulation containing the Artesunate-β-CD (1:2:1) – PVP K-30 inclusion complex completely disintegrated.

Table 6: Physicochemical Properties of Artesunate BCD inclusion tablet

In vitro release study

Drug release from formulations including BCD complexes ranged from 73.79 to 96.76%, according to in vitro release tests. Compared to other formulations, Formulation F5 demonstrated a quicker rate of drug release^11,12,13,20.

Table 7: Percent Cumulative Drug Release of BCD Inclusion Immediate Release Tablet

Figure 7: In vitro release study of BCD complex immediate-release tablet