Preparation and Evaluation of Valsartan Liquid Filling Formulations for Soft Gels

The present investigation includes the preparation of liquid filling formulations for soft gels using an antihypertensive drug, valsartan (VAL), in order to improve its dissolution properties and thereby its bioavailability. Formulations were prepared using excipients like polyethylene glycol 400 (PEG 400), propylene glycol (PG), polyvinylpyrrolidone (PVP K-30), antioxidants, ethanol, and purified water. Prepared formulations were evaluated for appearance, pH, drug content percentage, viscosity, stability, and in vitro dissolution studies. The compatibility between the drug and excipients in formulations was confirmed by FTIR spectra. The drug contents were in the range of 99.62-99.63 and the viscosity was in the range of 60.9–591.7 cps with all the formulations developed. Formulations containing 10 mg PVP K 30 gave better dissolution properties when compared to formulations without PVP K 30, and a complete drug dissolution was observed within 10 min and followed the first-order release kinetics. Stability studies were conducted for selected formulations (F4–F9) for a period of 6 months at room temperature (~30°C/65% RH). From the studies, it can be concluded that VAL liquid filling formulations for soft gels were successfully prepared with in vitro dissolution properties superior when compared to VAL itself.


Introduction
It is estimated that more than 40% of new chemical entities (NCEs) coming out of the current drug discovery process have poor biopharmaceutical properties, such as low aqueous solubility and/or permeability (BCS class II or class IV) [1,2]. ey show extremely low aqueous solubility throughout the physiological pH range, resulting in low and inconsistent bioavailability when administered as solid oral dosage forms. Liquids, in contrast, generally have better bioavailability and one such liquid dosage form is so gel [2]. e so gel dosage form offers several advantages over other oral solid dosage forms, such as delivering a liquid matrix designed to solubilize and improve the oral bioavailability of a poorly soluble compound as a unit dose solid dosage form, delivering low and ultralow doses of a compound [3].
VAL is a potent, highly selective and orally administered antihypertensive drug, with poor bioavailability ranging 10-35% because of the poor solubility and dissolution. VAL solubility is low in aqueous �uids, especially in gastric �uids its absorption is dissolution rate limited [4,5]. e drug is rapidly absorbed aer oral administration and median max values of 2.75 and 3 hours have been reported aer the oral absorption of tablet and capsule formulations, respectively. e reported absolute bioavailability is 23% for the capsule formulation and 39% for a buffer solution [6].

Preparation of Liquid Filling
Formulations. Drug �ll solution was prepared by accurately weighing required quantities of VAL along with various excipients as shown in Table 1.
Initially VAL was dissolved in a half amount of PEG 400 or PG and other ingredients were added under continuous mixing. e solution was mixed until it becomes clear and �nally the volume was ad�usted with PEG 400. e prepared formulations were sonicated for 3 minutes in order to remove any entrapped air.

FT-IR Analysis.
Samples were analyzed using an ATR-FTIR spectrometer (Bruker, Germany). ATR spectra were measured over the wave number range of 4000-500 cm −1 at a resolution of 1.0 cm −1 . e formulations of all samples were simply placed onto the ATR crystal and each sample spectrum was collected.  [13]. e developed VAL liquid �lling formulations were evaluated for pH by using Elico LI 120 pH meter and estimations were carried out in triplicate.

Drug Content.
Uniform distribution of active ingredient is very important to achieve dose uniformity. 10 mg of formulation was taken in a 10 mL volumetric �ask and dissolved in 5 mL methanol and the volume was made up with the methanol resulting in 2 mg of VAL per 10 mL solution. 1 mL of the above solution was suitably diluted with pH 6.8 phosphate buffer. Finally drug content was estimated using Elico SL 150 UV-visible spectrophotometer in triplicate.

Rheological Studies. e viscosity was measured using
Brook�eld DV-II � PRO viscometer. e formulation was taken into the cup of viscometer and measured using spindle CP52 at the rotation of 10-100 rpm. e viscosity measurements were made in triplicate using fresh samples each time.

In Vitro Dissolution Studies.
In vitro dissolution studies were conducted using 1000 mL of pH 6.8 phosphate buffer as a dissolution medium using a USP type II paddle method dissolution apparatus (DISSO 8000, LAB INDIA). A temperature of 37 ± 0.5 ∘ C and a rotation speed of 50 and 100 rpm were maintained. Liquid formulations were �lled into hard capsule (size 1) and dissolution studies were performed. As the capsule tends to �oat in the dissolution medium, sinkers were used. A 5 mL sample was withdrawn at predetermined time intervals over a period of 2 hrs and then replaced with the same volume of fresh dissolution medium. e �ltered samples were suitably diluted and analyzed at 250 nm using UV-visible Elico SL150 spectrophotometer. Dissolution experiments were conducted in triplicate [14].

Preparation of Liquid Filling Formulations.
Liquid �lling formulations were prepared using PEG 400, PG as water miscible solvents either alone or in combination, and water or ethanol as vehicle, with and without PVP K 30 and antioxidants. Prepared formulations were evaluated for further studies.

FT-IR Analysis.
VAL has two characteristic carbonyl absorption bands at 1730 and 1601 cm −1 that correspond to carbonyl and amide carbonyl stretching, respectively. e peak at 3563 cm −1 indicates the presence of N-H functional group. e band at 2926 cm −1 indicates the presence of C-H group stretching vibration. e spectrum reveals the characteristic peaks in the typical range at 1205-1065 cm −1 con�rms the presence of characteristic tetrazole ring in the VAL. e complex region of 900-600 cm −1 indicates skeletal vibration and an aromatic ring in the drug substance. From the overlaid FT-IR spectra as shown in Figure 1, it was con�rmed that VAL in liquid state was compatible with different excipients used in the formulation.

Rheological Studies.
Viscosity is one of the important parameters which provide vital information during the optimization of the liquid �lling formulation for so gels. In general, the viscosity of liquid �lling formulations for so gels is in the range of 0.222-3000 cps [15]. From Table 2, the viscosity of the formulations (without PVP) F1, F2, F3, F4, and F5 was low when compared to the formulations (with PVP) F6, F7, F8, and F9 based on their consistency. Formulations F1, F2, F3, F4, and F5 were �uid like consistency, whereas formulations F6, F7, F8, and F9 were slightly thick in consistency. e viscosity of formulations F10 and F11 were thicker in consistency and they failed to give viscosity at a higher shear rate (above 10 rpm). e consistency and viscosity of the �lling formulations were related to each other because both were dependent on the concentration of PVP K 30. It was clearly evident that the viscosity and consistency of liquid �lling formulations were affected by concentrations of PVP K 30 and PEG 400.

In Vitro Dissolution Studies.
Totally 11 different liquid �lling formulations of VAL were prepared with and without PVP K 30 and antioxidants. e dissolution pro�les showed that VAL dissolution was in�uenced by the solvents containing PVP K 30 rather than antioxidants incorporated in the formulation of the �ll liquid. e in�uence of the solvent system on VAL dissolution was con�rmed by comparing the percentage drug release at 10 min (DP 10 ) among the investigated formulae. All formulations exceeded 75% of VAL released aer 10 min, whereas only 25.4% was dissolved from the pure drug. VAL dissolution from F1 was 7 .58 ± 1.96 at the end of 10 min. is was due to the improper solubilization of VAL in PEG 400 and PG. PG was decreased to 10% w/w in F2, resulted in 85.98 ± 0.79 of VAL dissolution at the end of 10 min. is showed that PG in a lower concentration was suitable for dissolution. e effect of PEG 400 on dissolution was studied by preparing F3 without cosolvents and showed 86.75 ± 1.91 of VAL dissolution at the end of 10 min. In the next step, PG as a co solvent at 5% w/w was incorporated in F4 and F5 for increasing the viscosity and thereby reduces the leakage. In F5, water was replaced with ethanol to evaluate the effect on VAL dissolution. F4 and F5 showed 88.98 ± 0.86 and 100.01 ± 0.66 at the end of 10 min and these results indicated that the presence of ethanol in F5 signi�cantly increased the dissolution of VAL. e comparative dissolution pro�le for formulations F1, F2, F3, F4, and F5 was shown in Figure 2. Formulations F6 and F7, were prepared by adding PVP K 30 at 5% w/w to evaluate any effect on dissolution of VAL. Addition of PVP K 30 to the formulation F6 when compared to the formulation F4 signi�cantly increased the dissolution properties of VAL and a complete dissolution was observed within 10 min. In the case of F5 and F7, a complete dissolution was observed within 10 min and the addition of PVP K 30 had no effect on the dissolution of VAL to F7. Formulations F8 and F9 were prepared by adding antioxidants (SBS and BHT) to evaluate any effect on dissolution of VAL. e addition of antioxidants in the formulations F8 and F9 did not change/affect dissolution of VAL compared to the F6 and F7 and showed 100.04 ± 0.18 and 100.07 ± 0.02 at the end of 10 min. Formulations F10 and F11 were prepared by adding PVP K 30 at 10% w/w and antioxidants to evaluate any effect on the dissolution of VAL. ey showed 81.28±1.82 and 83.81±3.68 of dissolution at the end of 10 min and these values were signi�cantly lower when compared to the values obtained with formulations F8 and F9 and is may be due to the increase in the viscosity and thereby the decrease in the miscibility of li�uid �lling formulations with the dissolution medium. e dissolution pro�les for formulations with and without PVP K 30 were shown in Figures 3 and 4. Overall, formulations F6, F7, F8, and F9 containing 5%, w/w (10 mg/capsule) of PVP K 30 resulted superior dissolution properties of VAL when compared to formulations without PVP K 30 (F1, F2, F3, and F4) and pure VAL.   e increase in dissolution was observed for formulation F4 at 100 rpm when compared to 50 rpm. But the formulations F8 and F9 showed a complete dissolution within 10 min irrespective of speed. e comparative dissolution pro�le was shown in Figure 5. e initial increase in dissolution of formulations at 100 rpm was may be because of the miscibility of li�uid �lling formulations at higher rpm. �ence, the selection of appropriate rpm was important in the development of so gel formulations.