Formulation and evaluation of valsartan solid dispersion for improvement of dissolution profile

In terms of physicochemical factors, solubility is the most crucial to medication absorption and therapeutic efficacy. Bioavailability is low because the medicine is poorly soluble in water and is absorbed poorly in aqueous GIT fluid. In this research, a solid dispersion version of the hypertension drug valsartan was developed to improve its bioavailability and blood pressure-lowering effects. The solubility of Valsartan is improved by using the solid dispersion (kneading method) technique using Soluplus as a carrier (also act as taste masking agent). They were distinguished from one another based on studies examining solubility, in vitro dissolution, dissolving efficiency, and stability. X-ray diffraction, FT-IR spectroscopy, and differential scanning Calorimetry were used to investigate the solid state properties of dispersions (XRD). A 1:1 medication-to-polymer solid dispersion showed 97.77% drug release after 30 minutes. FTIR, DSC, and XRD analyses of solid dispersions all corroborated their formation. A DSC study shown that under accelerated climate settings, kneaded solid dispersion remained stable for 30 days longer than other solid dispersions

Syrup, emulsions, suspensions, solutions, and elixirs are all examples of liquid oral dosage forms that are designed to carry a single dose of medication in volumes ranging from 5 mL to 30 mL. When it comes to orally administered medications, the tablet has clear advantages over the capsule (5,6).
The difficulty of a medication to dissolve in water might be a greater barrier to absorption than the gut mucosa. Many medications that are absorbed rapidly in the small intestine have a delayed onset of action due to the time it takes for the drug to breakdown and the dosage form to release its contents. Drugs with a slow rate of dissolution are less bioavailable because it takes longer for the drug to dissolve than for it to leave its absorption sites. When it comes to how fast a pharmaceutical dissolves in water, "poorly soluble" medicines often have a water solubility rating of less than 100 mg/ml. examining the drug's solubility in water is another method for identifying "poorly soluble" medications. How much gastrointestinal (GI) fluids are required to dissolve a given dosage is the dose: solubility ratio. When this quantity is more than the volume of fluids that may be utilised, the bioavailability of a solid oral dose form can be estimated. Subpar drug absorption is associated with medications that don't dissolve well in water. This indicates that the medications are not functioning optimally or regularly. Drugs are classified into Classes II and IV by the Biopharmaceutics classification system (BCS) depending on how efficiently they are absorbed by and eliminated from the body. Medicines in the Class II BCS are very soluble in air but not water. Certain medicinal medicines' solubility improvement is connected to their bioavailability improvement (7-9).

Determination of Solubility of Valsartan
By utilizing the shake flask method, we determined that valsartan was soluble in 0.1 N HCL, methanol, and a phosphate buffer at pH 6.8.

Determination of Melting point of drug
The melting point of Valsartan was determined using melting point testing equipment.

Determination of ‫ﮑ‬max of Valsartan
The optimal dosage ‫ﮑ(‬ max) of valsartan was determined by employing a solution consisting of methanol, water, and phosphatebuffer (pH 6.8).

IR Spectrum of Valsartan
Valsartan's infrared spectra were collected using a Fourier transform infrared spectrophotometer. Just after collecting a sample, it was transferred to the IR platform. The spectral wavelength was then swept between 4000 and 400 cm-1 .

IR Spectrum of carrier
The infrared spectra of the carrier was evaluated using a Fourier Transform Infrared spectrophotometer. Just after collecting a sample, it was transferred to the IR platform. The spectral wavelength was then swept between 4000 and 400 cm-1 .

Interaction between Valsartan and carrier
The Valsartan and carrier mixture's physical infrared spectrum was obtained using a Fourier Transform infrared spectrophotometer (Alpha E Bruker). A little sample was taken and placed straight onto the IR apparatus. Afterwards, the spectrum was scanned from a wavelength of 4,000 to 400 cm -1 .

Calibration curve of Valsartan
The optimal dosage ‫ﮑ(‬ max) of valsartan was determined by employing a solution consisting of methanol, water, and phosphatebuffer (pH 6.8).

Phase solubility studies
Solubility was measured using the protocol described by Higuchi and Connors. The phase solubility experiment included a wide variety of hydrophilic carriers, including PEG 6000, PVP K30, and Soluplus. When the carrier concentration in the aqueous solutions increased (from 0.2 to 0.4 to 0.6 to 0.8 to 1.0 to 1.5 to 2% w/v), additional Valsartan was added. The resulting mixes were shaken for 48 hours at 37°C. The supernatant was filtered through a membrane with a pore size of 0.45 microns. The filtrate was analyzed using spectrophotometry after appropriate dilution (shimadzu, Pharmspec UV 1700, Japan) (15).

Selection of appropriate ratio of drug and carrier
Preliminary studies were conducted to determine the optimum drug carrier ratio to maximize drug solubility enhancement. Several drug-carrier mixes (0.5:1, 1:1, 1:1.5, and 1:2) were tested for solubility and dissolution.
Preparation Methods (16)(17)(18) Physical mixtures (PM) Valsartan PMs were prepared by combining the drug with a suitable carrier at ratios of 1:0.5, 1:1, 1:1.5, and 1:2 using a mortar and pestle. After that, we put the physical mixtures in a desiccator until we were ready to utilise them.

Preparation of Solid dispersions
Using Soluplus, the procedures of solvent evaporation, kneading, and melting were used to generate solid dispersions of Valsartan.

Solvent evaporation method (SE)
Valsartan and the carrier were dissolved in methanol at specific weights to create solid dispersions. After dissolving all of the material, the solvent was evaporated at ambient temperature and reduced pressure. The solid mass was subsequently crushed, and the ready-to-use solids were stored in desiccators.

Kneading method (KM)
After combining valsartan and carrier (1:0.5, 1:1, 1:1.5, or 1:2 w/w) with methanol, the mixture was kneaded for 30 minutes in a glass mortar. For 24 hours, the mixture was dried in a vacuum. The powder was sieved through a No. 60# mesh before being stored in a desiccator for further testing.
Melting method (MM) The medication was dissolved in a hot carrier solution (at concentrations of 0.5%, 1.5%, 1.5%, and 2% by weight) and then chilled in an ice bath. After being dried in a desiccator, the resultant solid mass was crushed and sieved through a No. 60. (19,20) Drug content estimation Carefully measuring out 50 mg of medication required adding the solid dispersion complex to a 100 ml volumetric flask. It was dosed with 100 mL of methanol. To ensure that all of the medication was extracted, the resulting liquid was swirled for an hour. After proper filtering and methanol dilution, the solution is ready for use. Using methanol as a blank, UV spectrophotometer measurements determined the concentration of the medication.

Saturation solubility studies
Saturation solubility studies were performed in distilled water, 0.1N HCl, and pH 6.8 phosphate buffer using the Higuchi and Connors technique. In summary, an excess of the pure medication was added to 25 ml of distilled water, 0.1N HCl, and a phosphate buffer with a pH of 6.8. During 24 hours at 37°C, the vials were shaken in a shaker. The supernatant solutions were collected after equilibration and filtered through a 0.45 m membrane. Using a UV-visible spectrophotometer, the valsartan concentration in the purified solution was calculated.

IR spectral analysis
Using a Fourier transform infrared spectrometer, we were able to get the infrared spectra of pure Valsartan, carrier, Valsartan: carrier (physical mixing), and solid dispersion (Alpha E Bruker). The spectrum scanned was from 400 cm-1 to 4000 cm -1 .

Differential Scanning Calorimetry (DSC)
Thermogram of Valsartan, Valsartan Soluplus, and Valsartan alone: Solid dispersion complex and Soluplus (physical mixture) thermogram were produced using a Mettler-Toledo DSC 821e equipment with an intra-cooler (Mettler-Toledo, Switzerland). The samples were heated in a nitrogen environment at a rate of 10°C/min from 30 to 300 degrees Celsius.
X-ray Diffractiometry (XRD) X-ray diffractiometry (PW 1729, Philips, The Netherlands) was used to record the X-ray diffraction patterns of pure Valsartan, carrier, Valsartan: carrier (physical mixing), and solid dispersion. A copper target, 30 kV of voltage, and 30 mA of current were used.

SEM analysis (SEM)
Pure Valsartan, carrier, drug: carrier (physical combination), and solid dispersion complex were analyzed using the JSM 5600 LV scanning electron microscope. Joel, Japan, Swivel Eyepiece Refractor.
Dissolution study of Valsartan and its solid dispersion complex in Phosphate buffer pH 6.8 The solid dispersion and Valsartan were put into 900 cc of phosphate buffer pH 6.8 and stirred at 50 rpm to see if they would dissolve. For the dissolving test, a sample of medicine powder equal to 40 mg was used. At regular times, a 5 ml aliquot was taken out and replaced with the same amount of dissolving solution. Spectrophotometric analysis was done on the samples that had been filtered. Three different tests were done.

Determination of Solubility of Valsartan
Valsartan was shown to be easily soluble in acetone and methanol, and just weakly soluble in water and 0.1 N HCL.

Determination of melting point of drug
Valsartan's melting point was discovered to be between 116 and 117 degrees Celsius.

Determination of ‫ﮑ‬ max of Valsartan
In methanol Valsartan's ‫ﮑ‬ max in methanol was discovered to be 250 nm.

Figure 1 UV absorption spectra of Valsartan in Methanol
In distilled water Valsartan's maximum concentration was discovered to be 250 nm in distilled water.

Figure 2 UV absorption spectra of Valsartan in distilled water
In pH 6.8 Valsartan's maximum wavelength was determined to be 250 nm at pH 6.8.

Figure 3
UV absorption spectra of Valsartan in pH 6.8

IR spectrum of Valsartan
The calculated IR spectra of pure Valsartan is shown in fig. 3.4.      Figure 4 shows the IR spectra of both Valsartan and Soluplus when they are mixed together. Even though Soluplus barely changed Valsartan's absorption peak, the results show that the two drugs don't interact with each other.

Calibration curve of Valsartan in methanol
At a concentration range of 5-30 μg/ml, a linear calibration curve for valsartan in methanol was obtained (r2 = 0.999).  The linearity of the valsartan in water calibration curve was determined to be 0.997% between the 5 and 30 μg/m1 concentration range.  Calibration curve of Valsartan in PBS 6.8 was found to be linear in the range of 5 to 30 µg/ml and Coefficient of correlation was found to be 0.997.

Figure 9
Calibration curve of Valsartan PBS 6.8

Phase solubility studies
Soluplus was chosen for the phase solubility study out of Soluplus, PVP K30, and PEG 6000. In Table 3.8, you can see how the phase solubility of valsartan affects how it works with hydrophilic carriers. From these data, we may infer that just one of the several hydrophilic carriers tested turned out to be successful. Soluplus showed that Valsartan was more soluble in water than it was previously believed to be.

Figure 10
Phase solubility of Valsartan with Soluplus PVP K 30, PEG 6000 Soluplus solubility was improved because of Valsartan's phase solubility behaviour with a variety of hydrophilic carriers. Soluplus was used to create a solid dispersion of valsartan.

Drug Content
All solid dispersion formulations were evaluated for their medicine content, including those made by kneading, melting, and solvent evaporation. Kneading yielded SD with a drug content of 100.05 ±0.40, melting yielded SD with a drug content of 99.03 ±0.45, and solvent evaporation yielded SD with a drug content of 100.06 ± 0.15.

Saturation Solubility Studies
Valsartan's solubility in both pure water and phosphate buffer is shown in Table 3.9. (PH 6.8). Valsartan has a solubility in water of around 0.0271±0.009 mg/ml at 37 ± 2 degrees Celsius. Valsartan's solubility was drastically altered by the solution's pH. Water does not facilitate the dissolution of valsartan. The solubility of valsartan in phosphate buffer was determined to be 2.989±0.13 mg/ml (pH 6.8). Table 23 shows that the medication dissolves more easily in phosphate buffer (pH 6.8), thus that's what was used to make the solution.

IR Spectrum analysis
IR spectrum of solid dispersion (kneading Method 1:1)

Differential Scanning Calorimetry (DSC)
The DSC was used to examine the thermal stability of valsartan, Soluplus, PM, and a solid dispersion prepared through solvent evaporation. The DSC analysis of valsartan crystals revealed a single, distinct endothermic peak at 180.78°C. The drug's distinctive endothermic peak, as seen in a DSC thermogram of dispersed particles and solids, is losing its sharpness and intensity over time. Possible explanation: the medication has lost most of its crystalline form and become amorphous.

X ray diffraction analysis (XRD)
The XRD scan of pure Valsartan exhibits a significant crystallinity peak, whereas physical mixes and solid dispersions have fewer and weaker peaks. The mean and standard deviation for RDC were both 0.53. (PM). This finding suggests that treatment with Soluplus reduces the crystallinity of the drug, or causes it to become amorphous. It was found that the amorphene medication was reflected in a reduced peak intensity for the solid dispersion formulation compared to the PM.

Scanning electron microscopy (SEM)
The undiluted material has the appearance of a crystal with a slick, partially curled surface. Soluplus exists as spherical particles. Physical mixing of the drug and carrier at a weight ratio of 1:1 revealed that the drug was in crystalline form and was mixed with irregular Soluplus microparticles. Possible explanation: shrinking the physical mixture as part of the manufacturing process. The drug particles altered form, as seen by photomicrographs of the solid dispersion. They were discovered to be connected to the VAL crystal's surface and to have a more porous structure. The valsartan in the solid dispersion formulation was less crystalline, as seen by scanning electron microscopy (SEM) photomicrographs.

Drug release study
Effect of Soluplus on dissolution of Valsartan from its Physical mixture and solid Dispersion  Drug release of solid dispersion prepared by kneading method Figure 14 Drug release of solid dispersion prepared by kneading method An SD with a drug-to-polymer ratio of 1:1 had already released 84.84% of the medicament by the time it was 5 mm long. As compared to other formulations created by kneading, those made with a drug-to-polymer ratio of 1:1 exhibited greater solubility. It is hypothesized that the addition of the hydrophilic surfactant contributes to a quicker dissolving rate of the Valsartan particles with surfactant because it makes the formulation wetter. While using the kneading technique, even drugs that didn't dissolve readily were able to do so since the medicine was evenly distributed throughout the hydrophilic carrier. Possible causes include Valsartan's amorphous state, reduced particle size, ease of wetting and dispensing, and lack of crystals. Dissolution slowed significantly as the drug-to-polymer ratio changed from 1:1:0.5 to 1:2. This is probably due to the fact that, at greater concentrations, Soluplus forms a gel. The findings suggest that a carrier level of 1:1 polymer to medication is optimal for increasing Valsartan solubility. Nevertheless, the medication was not rendered more soluble at Soluplus ratios of 1:1.5 or 1:2. Research demonstrated that modifying the polymer's rheological characteristics and thereby slowing the release of Valsartan by raising its concentration.

Discussion
The solid dispersion of valsartan was shown to be more stable than that of other drugs when subjected to accelerated circumstances at room temperature for 30 days. Compared to the pure Valsartan medication, this solid dispersion was quicker and simpler to dissolve. The FTIR spectrum indicates that the medication and excipients in the formulation did not undergo any chemical reactions. Analysis scanning methods that vary the solvent evaporation solid dispersion formulation included amorphous valsartan, as determined by Calorimetry. Scanning electron microscopy research confirmed that Valsartan crystallized and then transformed into an amorphous state. The medication Soluplus significantly increased the solubility and dissolution rate of valsartan in solid dispersions.

Conclusion
In this research, the solubility rate of a solid dispersion of valsartan with Soluplus (PM) was significantly increased by co-grinding compared to that of valsartan in its natural form. The semi-crystalline phase may change to the amorphous phase during the co-grinding process.