European Journal of Cardiovascular Medicine

Nearly 40% of newly produced active pharmaceutical ingredients (APIs) impart inadequate aqueous solubility, resulting in poor bioavailability and therapeutic failure [1]. This poses a significant difficulty for the pharmaceutical industry when it comes to medication formulation. Miceronisation, solid dispersion, and lipid based formulations are comes of the more conventional approaches, although they frequently encounter problems with stability, scaling and insufficient dissolving enhancement [2-4].  Mesoporous silica nanoparticles (MSNs) are now new method that is attracting a lot of interest because of its unusual structural features, such as its large surface area (> 500 m2/g), adjustable pore size (2 – 50nm), and capacity to stabilize amorphous drug forms [5]. Because of their biodegradability, chemical interness and compatibility with living organism, MSNs are perfect for use as a carrier to increase the solubility and dissolution of drugs [6]. Their nanoscale dimension enable quick in gastrointestinal fluids and their porous nature permits substantial drug loading [7]. The steady kinetics of dru8g release are ensured by MSNs, as opposed by nanoparticles, because they do not swell or degrade unexpectedly [8]. Fenofibrate, Valsartan, and Celecoxib are examples of BCS Class II & IV medicatiob that have recently show promise in increasing bioavailability [9-11]. The antihypertensive medication Azilsartan medoxomil (AZM) has pH dependant dissolution rate and a poor water solubility ( ~7 µg/mL), which cause its oral absorption to be variable [12]. MSNs provide a potential subst6itute vby encasing AZM in their mesopores, which inhibits recrystallisation and improve wettability [13]. Despite the efficacy of MSNs based delivery for other ARB S SUCH AS Valsartan and Telmisartan, no prior have investigated this method for AZM [14,15].  Although MSNs have been thoroughly for solubility, their potential use in AZM has not been investigated yet. The following are some of the main benefits of MSNs that this study aims to addresses: 1. Creating MSNs using the sol-gel method to achieve a high AZM loading (>20%). 2. Analyzing the physiochemical interactuion between AZM and MSNs using techniques such as FTIR, DSC and XRD.  3. Improving the dissolving properties of immediate- release tablets (>80% in 30 min.) by formulation.

Azilsartan medoxomil. TEOS (Tetra-ethyl-orthosilicate) and  CTAB was procured from Chempure Pvt Ltd, Diethalonamine, Purified water and Ethanol were procured from School of Pharmacy.

Procedure:

 The sol-gel method is employed to synthesize mesoporous silica nanoparticles.   5.2 grams of CTAB were measured, and a solution was prepared by combining 32 milliliters of water with 7 milliliters of ethanol.  Add 0.1 grams of dimethylamine to the solution.  Place it in a water bath and heat it until it attains 30⁰C.  A meticulous dosage of 3.65 milliliters of TEOS was subsequently conducted drop by drop.  Continue to whisk the mixture for an additional two hours until it becomes white.  Following cleansing with water and subsequent repetition of the technique, Watman's filter paper may be employed as a filter.  The material is initially calcined at 823 Kelvin for six hours at 550⁰C, followed by drying for 72 hours at 318 k.

Drug loading:  The solvent evaporation technique is employed for drug loading.  The pharmaceutical compound is solubilized in ethanol.  Additionally, the fluid was augmented with MSNs. The solution was agitated for two hours.  An additional two hours were devoted to loading  process.  The result solidified as the solvent evaporated during stirring. MSNs was stored in sealed containers for subsequent analysis.

Method of direct compression:

The table was used to figure out how much each ingredient should weigh.  Azilsartan medoxomil, sodium starch glycolate, and crosspovidone were put through sieve number 60 and then mixed together. They were then put in a container and left alone for 15 minutes.  At the same time, talc and magnesium stearate were both having sieving through screen number 60.  After that, it was added to the Azilsartan medoxomil and mixed for 20 minutes so that it was ready to be tablet compress.  Next, the mixture was pressed on tablet punching machine with a twenty-station single rotating and a single puch (8 mm) to make round pills that were 200 mg each.  When the compression force is applied, tablets that are 3 to 5 kg/cm2 hard can be made.

Chacterization of Mesoporous silica nanoparticles:

1. Particle size: The Zetasizer is used to measure the size of MSN particles. The study took place at 25º c and used water as the dispersion medium.
2. Entrapment efficiency: An ultraviolet (UV) spectrophotometer was used to find out how much Azilsartan medoxomil was caged in MSNs. To aid the organic solvent evaporate, 10 mg of exactly measured MSNs were dissolved in 10 ml  of ethanol, extracted in a phosphate buffer with a pH of 1.2, and agitated for half an hour without stopping.  After being filtered with Whatman filter paper, the solution is looked at with a UV spectrophotometer at 246 nm.  .
3. FTIR analysis: The FTIR spectra of Azilsartan medoxomil and Azilsartan medoxomil MSNs were taken at room temperature with a FTIR    The KBr pellet method was used  to look at infrared spectra with a resolution of 4 cm ^-1 spanning the range of 4000 to 400 cm^-1.
4. X-ray diffraction (XRD): We used diffractometer to look at the X-ray diffraction (XRD) patterns. We used monochromated Copper K-alpha (Cu K-a) radiation (1.542 Å) to load the sample and took pictures of the diffraction patterns between 5º and 50º.  The study uses a voltage of 30 kV.
5. Differential scanning colorimetry (DSC): The Differential Scanning Colorimeter was used to do differential scanning colorimetry (DSC). We measured temperature and enthalpy using metal crucibles that were hermetically sealed.  The temperature stayed the same at 10º/min between 20 and 250º.  We did more tests on the medicine and MSN by using a nitrogen gas purge with a flow rate of 50 ml/min.
6. Solubility study: A study of solubility is done using the method that Higuchi and Connors came up with. MSN was filtered via Whatman filter paper after being dissolved in a solvent for a whole day.   The solution's absorbance at 246 nm was measured with a UV spectrophotometer.
7. TEM Study: To study mesoporous silica nanoparticles (MSNs) using TEM, you need to make samples, take pictures of them with a TEM device, and then look at the pictures to figure out their size, shape, and pore structure. Usually, MSNs are first spread out or put on a TEM grid, and then they are scanned at different levels of magnification, including high-resolution TEM.

Chacterization of immediate release tablet:

Tablet appearance: Examining the tablet's appearance include looking for flaws like chipping or capping as well as checking the tablet's form.

Uniformity of tablet: To ensure consistency in tablet weight, twenty tablets were picked at random from each formulation and weighed one by one using an electrically sensitive balance.   We determined the mean weight and standard deviation.

Hardness test: As a means of determining the hardness, the breaking force was measured using a hardness tester.   Testing was carried out before, during, and after tablet production to ensure uniform hardness throughout. 

Friability test:  The tablets' friability was evaluated using a friability tester.   Before they were put in the Friabilator, twenty pills were weighed (Weight).   Four minutes were spent operating the Friabilator at 100 rpm. The tablets were weighed again later on.

Disintegration study: The disintegration apparatus was used to analyze the disintegration time according to USP standards in the disintegration study.   With each tablet in its own container, we timed how long it took for each of the six tablets to dissolve.

Dissolution study:  The USP dissolution testing apparatus, a paddle-type device, is used to determine the pattern of drug release of immediate release tablets in a dissolution research.  The stirring speed was 50 rpm and the temperature was 37°C ± 0.5°C during the dissolving process.  At 5,10,15,30, and 45 minutes, we removed 5 ml of solution from the dissolving device and replaced it with fresh dissolving medium to maintain the sink state.   After passing the sample through a membrane filter, the absorbance of Azilsartan medoxomil  at 246 nm was measured and calculated using a UV-visible double beam spectrophotometer. A linear equation, based on a standard curve, was employed to determine the cumulative percentage of drug release.

1. Synthesis and Particle Size Analysis: MSNs synthesised using the sol-gel technique had a narrow particle size distribution of 98-100 nm (Zetasizer) and ~100 nm via TEM (Fig. 9), indicating ideal drug delivery dimensions for improved cellular uptake and dissolution. The spherical morphology and honeycomb pore structure (TEM) are consistent with MSN features, with pore homogeneity facilitating high drug loading. Similar investigations on aripiprazole MSNs revealed diameters ranging from 104 to 142 nm, resulting in improved solubility . Larger size of MSNs shows greater drug release percentage of drug .

2. FTIR Spectroscopy: Drug-Carrier Compatibility: FTIR spectra confirmed the integrity of Azilsartanmedoxomil (AZM) post-loading into MSNs (Fig. 3–5). Si-O-Si asymmetric stretch (1100 cm⁻¹) and Si-OH (460 cm⁻¹) validated MSNs' silica framework [6]. AZM peaks (C=O at 1821–1619 cm⁻¹, C-H at 2926 cm⁻¹) remained unshifted, indicating no chemical interaction (Fig. 5). This absence of covalent bonding is advantageous for controlled release. The preservation of AZM’s functional groups suggests physical entrapment within MSN pores, a phenomenon observed with other BCS Class II drugs like tamoxifen .

3. Entrapment Efficiency and Drug Loading: An 81% entrapment efficiency was achieved using solvent evaporation, attributed to MSNs' high surface area (322 m²/g) and pore volume (0.26 cc/g). This aligns with studies on nitroimidazole loaded MSNs (86% efficiency).

4. XRD and DSC: Amorphization and Stability: XRD (Fig. 8): Sharp crystalline peaks of pure AZM (e.g., at 2θ = 10°) diminished in AZM-MSNs, confirming amorphization within pores. This mirrors findings for silymarin-loaded MSNs, where pore confinement inhibited recrystallization [20]. DSC (Fig. 6): AZM’s melting endotherm (220°C) broadened in MSNs, indicating reduced crystallinity. The slight onset shift (213°C vs. 218°C) suggests molecular dispersion, as seen with itraconazole-MSN systems .
5. Saturated solubility: Solubility Investigations: pH-Related Improvement Table 4 shows that AZM-MSNs significantly improved solubility:  Concentration in water: 0.521 mg/mL (4.7 times that of pure AZM).  crucial for absorption in the stomach: pH 1.2, 0.392 mg/mL (6 -fold).  Drug release was improved by protonated silanol groups at low pH in olmesartan-loaded MSNs, according to similar reported trend.
6. TEM: The prepared MSNs shows honeycomb structure with many pores. It is shown that the hexagonal straight paths go along the spherical particles. The particles observed that they are having cylinder-shaped pores that are straight and one-dimensional.   The channels are shown as a honeycomb cage in this top view of the particles.  The MSNs shown in these pictures look like semi-irregular nanospheres clumped together, as seen.

7. BET Analysis: Porosity and Drug Release Kinetics: The MSNs displayed a Type IV isotherm (Fig. 10), indicative of mesoporous materials, featuring: Surface area: 322 m²/g. Pore width: 3.18 nm, optimal for the encapsulation of AZM (molecular weight: 568.5 g/mol).  A substantial surface area promotes fast wetting, whereas pore confinement preserves the amorphous state of AZM, inhibiting recrystallisation during storage.

8. Tablet Characterization: Immediate-Release Performance:

Tablet appearance: White colored round shaped uncoated tablet was prepared.

Hardness test Friability test: The hardness was uniformly sustained and it was found to be within 3.10 ± 0.200  to 4.44 ± 0.180 range. A friability tester was employed to assess the friability of the tablets.  Initially, 20 tablets were weighed (Weight) prior to their placement in the Friabilator.  The Friabilator was operated at 100 rpm for four minutes.  A subsequent weighing of the tablets was conducted. The range of friability of tablet were found to be 0.22 ± 0.642 to 0.42 ± 0.112. Hardness (3.10–4.44 kg/cm²) and friability (<0.42%) met USP standards (Table 2).

Table no. 01:  Composition of Immediate release silica mesoporous Azilsartan medoxomil Tablets.

Table no. 02: Characterization of Immediate release silica mesoporous Azilsartan medoxomil Tablets.

Table no. 03:  In-vitro study of Immediate release mesoporous silica nanoparticles- Azilsartan medoxomil Tablets.

Table no. 04 :  Solubility study of pure Azilsartan medoxomil and MSNs loaded Azilsartan medoxomil.

Fig. no. 01: Schematic represetation of preparation of MSNs

Fig. no. 02: UV Spectra for Azilsartan medoxomil at 246 nm

Fig. no. 03:  Calibration linear curve of Azilsartan medoxomil

Fig. no. 4: FTIR of Azilsartan medoxomil

Fig. no. 05: FTIR of MSNs

Fig. no. 06 : FTIR of MSNs with AZM

Fig. no. 07: FIIR of MSNs  Azilsartan medoxomil tablet

Fig. no. 08: DSC of Azilsartan medoxomil

Fig. no. 09 : Particle of MSNs

Fig. no. 10 : TEM study of MSNs

Fig. No. 11: BET isotherm of MSNs

Fig. no. 12: Cumulative drug release of Batch F1 to F7

Fig. no. 13: Cumulative drug release of Batch F8  to F13

Fig. no. 14:  Drug release at 45 minute

Disintegration study: The disintegration time was evaluated in accordance with USP criteria using the disintegration apparatus.  The disintegration time was measured in second for each of the six tablets, with each tablet placed in an own vessel. The disintegration time found to be in range of 112 ± 0.714 to 170 ± 0.126 seconds. Disintegration (112–170 sec)  due to MSNs' wicking effect.

Dissolution study: In dissolution study All batches F1 to F13 shows increase in drug release rate as in crease in time. The drug release from formulations shows the immediate release pattern for a period of 45 min. Immediate release tablets of Azilsartan medoxomil having drug loaded into MSNs shows Drug release was more than 68%. F1 batch had a medication release range of 68% while F11 batch had an 82% range. Batch F11 (82%) fared better than pure AZM in terms of dissolution (68-82% in 45 min). The study shows that the high porosity of MSNs is compatible with their rapid release. The increased sodium starch glycolate (SSG) concentration (6.25-10.6 mg) in the superior batches (F6, F11) indicates that SSG has a role in pore accessibility. The ratio of lactose to monocrotinate had no effect on solubility but did affect hardness.

This study successfully developed  mesoporous silica nanoparticles (MSNs) with sol-gel method to improve the water solubility and dissolution of the poorly water soluble antihypertensive drug Azilsartanmedoxomil (AZM). The size of MSNs found to be in range of  98–100 nm. with 322 m²/g surface area and 3.07 nm pores diameter.  FTIR confirmed no chemical interactions. As expected by the Gibbs-Thomson effect, pore confinement prevented recrystallisation, and the high pore volume (0.26 cc/g) resulted in an 82% drug loading. 82% of the drug was released in 45 minutes, and AZM-MSNs were 6.5 times more soluble at pH 1.2 (F11 batch). As per the USP requirements the AZM MSNs having hardness (3.10–4.44 kg/cm²) and friability (<0.42%), and its faster disintegration (112–170 sec) gives idea about immediate gastrointestinal drug release. Mesoporous silica nanoparticles (MSNs) were successfully prepared in this study using the sol-gel method to improve the solubility and dissolution of Azilsartan medoxomil (AZM), a poorly water-soluble.

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