Formulation optimization of solid dispersion of candesartan cilexetil

Sachin Namdeo Kothawade; Vishal Vijay Pande

doi:10.4103/ajprhc.ajprhc_104_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 15 | Issue : 1 | Page : 59-63

Formulation optimization of solid dispersion of candesartan cilexetil

Sachin Namdeo Kothawade, Vishal Vijay Pande
Departments of Pharmaceutics, RSM's N. N. Sattha College of Pharmacy, Ahmednagar, Maharashtra, India

Date of Submission	21-Nov-2022
Date of Decision	07-Feb-2023
Date of Acceptance	20-Feb-2023
Date of Web Publication	31-Mar-2023

Correspondence Address:
Sachin Namdeo Kothawade
Department of Pharmaceutics, RSM's N. N. Sattha College of Pharmacy, Ahmednagar - 414 001, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajprhc.ajprhc_104_22

Abstract

Context: Antihypertensive effects were achieved by quickly hydrolyzing candesartan cilexetil (CC), an inactive prodrug of candesartan, into active candesartan during absorption in the gastrointestinal tract. Due to its weak water solubility, CC has an inadequate intestinal absorption and a low oral bioavailability. Aim: The goal of this study was to make the medication CC more soluble in water. Materials and Methods: Low viscosity hydroxypropyl methylcellulose (HPMC) E5LV was used to prepare the solid dispersions through spray drying. Results: Study of dissolution, Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), differential scanning calorimeter (DSC), and X-ray diffraction characterized the prepared solid dispersions. CC amorphized from its crystallized state, as shown by the findings from the SEM, DSC, and X-ray powder diffraction experiments. Comparing pure CC and solid dispersion, the dissolution rate was higher with the former. The surfactant and wetting property of HPMC E5LV slowed devitrification and had an anti-plasticization impact, increasing the solubility and stability of the solid dispersion. Conclusion: The final results indicated that the CC, a weakly water-soluble medication, dissolved much better in the solid dispersions.

Keywords: Candesartan cilexetil, poorly water-soluble, solid dispersions, solubility

How to cite this article:
Kothawade SN, Pande VV. Formulation optimization of solid dispersion of candesartan cilexetil. Asian J Pharm Res Health Care 2023;15:59-63

How to cite this URL:
Kothawade SN, Pande VV. Formulation optimization of solid dispersion of candesartan cilexetil. Asian J Pharm Res Health Care [serial online] 2023 [cited 2023 Jun 8];15:59-63. Available from: http://www.ajprhc.com/text.asp?2023/15/1/59/373369

Introduction

One of the technical obstacles in producing an appropriate dosage form is the poor solubility of many active medicinal compounds. New chemical entities generated in the pharmaceutical sector now account for more than 40% of those that are virtually insoluble in water.^[1] There are three key parameters considered by the Biopharmaceutical Classification System (BCS): solubility, intestinal permeability and dissolution rate. All of which control the pace and amount of oral drug absorption from immediate-release solid oral-dose forms. Drugs in BCS class II undergo a dissolution process that acts as a rate controller, dictating how quickly and how much they are absorbed.^[2],[3] Poorly water-soluble pharmaceuticals may benefit from the “Liquisolid compact technique,” a proven method for increasing their solubility, dissolution, and bioavailability.^[4]

One chiral center at the cyclohexyloxy-carbonyloxy ester group is found in candesartan cilexetil (CC), an inactive racemic prodrug commonly utilized in the treatment of hypertension. It is a BCS class II hydrophobic medication with a half-life of 5.1 h and a bioavailability of 15%–40%.^[5] CC is immediately and totally bio activated by ester hydrolysis at the ester link to create the active achiral candesartan following absorption from the gastrointestinal tract (GI) because double esters are easily hydrolyzed in the blood or tissues.^[6] To produce antihypertensive effects, candesartan, an angiotensin II type 1 (AT1) receptor antagonist with high potency and selectivity, can inhibit angiotensin II's vasoconstrictor and aldosterone-secreting activities. CC may be used as a monotherapy or in conjunction with other antihypertensive drugs, such as diuretic drugs, in clinical practice application. It's also been shown to be beneficial in the treatment of heart failure whether used alone or with angiotensin-converting enzyme (ACE) inhibitors.^[7] Even though it's water-insoluble, CC doesn't fully absorb in the GI tract (pKa 6.0). CC has a relatively poor absolute bioavailability after oral dosing.^[8]

However, until recently, only Nekkanti et al. found that Nano suspension increased candesartan's oral bioavailability by nearly 1.5 times.^[9] This meant that improving intestinal absorption and oral bioavailability of CC remained a serious challenge. Several biopharmaceutical criteria favor novel drug delivery methods over traditional ones, including controlled/prolonged release solid dispersions^[10],[11] and micro particles/microspheres.^[12],[13] These innovative drug delivery systems include these. Over a longer length of time and with improved patient compliance, these methods may attain therapeutically appropriate drug concentration in systemic circulation.^[14],[15] To create a controlled release formulation, water-insoluble carriers are often employed. The release profile of the dispersed medication is heavily influenced by the carrier's features, particularly those of the second generation of carriers. Several other carriers may be used, including hydroxypropyl cellulose, methacrylic acid copolymers, Chitosan, ethyl acetate, and cellulose acetate phthalate.^[16]

Materials and Methods

Materials

CC was provided by Micro Labs Ltd in India as a gift sample. Dr. Reddy's Laboratory donated hydroxypropyl methylcellulose (HPMC) E5 LV. Mumbai-based S.D. Fine Chemicals makes Midland and methylparaben. All other reagents, such as ethanol and acetonitrile, were of analytical grade.

Methods

Ratio optimization by solubility method

The CC/HPMC E5 (PM) physical combination was made utilizing a basic mortar and pestle mixing procedure in various weight-to-weight ratios ranging from 1:1 to 1:5. The solubility determination approach was used to optimize the ratio.

Preparation of solid dispersions by spray drying

The hydroalcoholic solution of CC and HPMC E5 LV was evaporated in an optimal ratio (1:5 w/w) using a spray dryer to produce the CCSD solid dispersions (LU- 222, Labultima, India). The solution was prepared by dissolving 500 mg of CC in 25 ml of ethanol and 2.5 g of HPMC E5 LV in 50 ml of distilled water and mixing both solutions, which produce a clear solution. Using an input temperature of 120°C, an output temperature of 80°C, a feed pump speed of 10 ml/min and an aspiration speed of 30%, the solvent was evaporated.

Characterization of solid dispersions

Solubility study

In a pH 1.2 buffer, the solubility of CC, physical mixture (PM), and CCSD were all tested. The solubility was assessed by putting 30 mg of CC in Teflon-facing screw-capped vials and mixing it with 10 ml of pH 1.2 buffer corresponding to 30 mg of CC. We used an orbital shaking incubator (CIS-24, Remi instrument, Mumbai, India) set to 37.05°C and 100 rpm to keep the vials balanced for a period of 24 h. A UV spectrophotometer (1700, Shimadzu, Japan) set at 210 nm was used to evaluate the contents of the vials after they were filtered through a 0.2 mm membrane filter.^[17]

Differential scanning calorimeter

For the sake of studying thermo tropic characteristics using differential scanning calorimetry, differential scanning calorimeter (DSC) profiles of CC, PM, and CCSD were created (Model: DSC 60, Shimadzu, Japan). On average, 10°C/min was used to heat the aluminum pans filled with the sample, which covered an 80°C–330°C temperature range under nitrogen.

Powder X-ray diffraction

Philips analytical X-ray diffractometry (Model: PW3710, Holland), with a copper target, at a voltage of 40 kV and current of 30 mA, was used to characterize the crystallinity state using X-ray powder diffraction. The scanning angle was from 0 to 50° of 2θ, with a counting rate of 0.4 steps per second (s/s).

Scanning electron microscopy

A scanning electron microscope (JSM 6390, JEOl, Japan) with 10-kV accelerating voltage was used to take scanning electron microscopy (SEM) photos of candesartan cilexetil (CC) and candesartan cilexetil solid dispersion (CCSD) generated by the spray drying technique.

Fourier transform infrared spectroscopy

The KBr disc approach was used to record fourier transform infrared spectroscopy (FTIR) spectra of CC, PM, and CCSD using an FTIR instrument (8400S, Shimadzu, Japan) (20 mg sample in 200 mg KBr). The scanning range of the device was 4000—400 cm 1 and it was operated with a dry air purge. FTIR can detect changes in functional group bonding caused by structural alterations or the absence of a crystal structure.

In vitro drug release study

The dissolution of pure CC and CCSD was tested at 100 rpm and 370.5°C with 0.1 N HCl (pH 1.2) as a dissolving medium in the USP dissolution test equipment II (paddle type). Each time a sample (5 ml) was taken, new dissolving media were added to the system, and the temperature was maintained at 370.5°C. After filtering (using a membrane filter with a mesh size of 0.45 mm), diluting, and testing the samples, the results were analyzed spectrophotometrically at 210 nm. A total of three dissolution tests were carried out.^[18]

Statistical evaluation

All data are shown as mean values standard deviation. P <0.05 were deemed statistically significant differences between two linked measures. Unpaired Student's t-tests were used to examine the optimization of the drug to polymer ratio, the calculation of solubility, and the dissolving efficiency findings.

Results and Discussion

Solubility study

[Table 1] summarizes the drug-to-polymer ratio optimization results. [Table 2] contains solubility information for CC, PM, and CCSD. HPMC E5 improved the solubility of CC by spray drying solid dispersions, according to solubility data. Using a polymer at a 1:5 ratio increases IBS solubility substantially (P < 0.05). It was found that optimizing the drug: polymer ratio required testing its solubility in a pH 1.2 buffer solution. Solubility of the drug: polymer at a ratio of 1:5 is considerably improved (P < 0.05). It is possible that the improved solubility and dissolution of CC from the drug: polymer system is due to a variety of variables, such as a reduction in crystallinity, surfactant and wetting properties, and a slower devitrification process.

Table 1: Drug to polymer ratio optimization

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Table 2: Solubility study of candesartan cilexetil, physical mixture of drug and polymer and solid dispersions prepared by spray drying method

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Differential scanning calorimetry

[Figure 1] shows the DSC profiles of spray-dried CC, CC with PM and CCSD. As can be seen from the DSC results, there was only one distinct melting point for the material, which was determined to be 164.10°C. CC utilized in this study was in its purest crystallized condition, as shown by the strong endothermic peak. Because of this, the drug's distinctive endothermic peak may have shrunk in sharpness and intensity, suggesting that most of the crystalline form has been converted to the amorphous form.

Figure 1: DSC profiles of CC, CC with PM and CCSD. CC: Candesartan cilexetil, DSC: differential scanning calorimeter, CC: Candesartan cilexetil

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Powder X-ray diffraction

[Figure 2] shows the X-ray powder diffraction (XRD) patterns of several materials, including pure CC, HPMC E5, PM, and CCSD. There were five distinct peaks in the XRD of CC revealing a typical crystalline structure of pure candesartan: 10.2°, 17.4°, 20.5°, 21.22°, 23.26° and a 27.77° diffraction angle 2θ. However, the diffractograms of PM and CCSD showed all of the key crystalline peaks, although at low intensities, showing that the crystallinity of CC had decreased. At various angles of observation, the distinctive peaks of CC's XRD results demonstrated that the substance was crystalline. However, in the instance of CCSD, a reduction in the strength of the distinctive CC peaks suggested that part of the crystalline CC had been converted to an amorphous form. For both PM and CCSD, the XRD results indicate that the CC is more amorphous in CCSD than it is in PM. As a consequence, the XRD data verify the DSC findings.

Figure 2: XRD patterns of CC, CC with PM and CCSD. CC: Candesartan cilexetil, XRD: X-ray powder diffraction, CC: Candesartan cilexetil

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Scanning electron microscopy

[Figure 3] shows the SEM images of CC and CCSD. The morphology of the CC particles was quite particular, but the SEM picture of the CCSD particles exhibited irregular and discrete particles. It was discovered using SEM pictures that the crystalline CC had been degraded to an amorphous state, and this was verified by DSC and XRD analysis.

Figure 3: SEM image of CC and CCSD. SEM: Scanning electron microscopy, CC: Candesartan cilexetil

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Fourier transform infrared spectroscopy

[Figure 4] shows the FTIR spectra of CC and CCSD. CC's IR spectra showed unique peaks at 1080 cm-1 due to ethereal linkage stretching, 1752 cm-1 because the carboxyl ion's –C double bond O stretched, and at 1351 cm-1 because of C–N aromatic stretching in the IR spectroscopy. It was discovered via the use of FTIR technology that the typical peaks of CC couldbe seen in both the PM and CCSD. FTIR analysis verified that there is no interaction between the medication and the excipients.

Figure 4: FTIR spectra of CC and CCSD. FTIR: Fourier transform infrared spectroscopy, CC: Candesartan cilexetil

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In vitro drug release study

As shown in [Figure 5], CC and CCSD in vitro dissolution profiles demonstrate a substantial (P < 0.05) increase in the dissolution rate of CC from CCSD when compared to pure IBS. According to the results of the dissolving investigation, spray drying enhanced the dissolution rate of CC from solid dispersions with HPMC E5 LV. In the dissolving medium, amorphous CC is devitrifiable. Devitrification may, however, be delayed by preparing solid dispersions of the material.

Figure 5: In vitro dissolution profiles of CC and CCSD. CC: Candesartan cilexetil

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Conclusion

For this reason, spray drying solid dispersions of weakly water-soluble CC with HPMC E5 LV, which can be scaled up industrially, are a viable option for improving solubility and dissolution rate. Surfactant and wetting properties, delaying devitrification, and HPMC E5's anti-plasticization impact due to its high “Tg” value may be responsible for the mechanism enhancing CC's solubility and dissolving rate.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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