Development and Characterisation of Valsartan Immediate Release Dosage Form Using Solubility Enhancement Technique

VAL, poloxamer 188, β-cyclodextrin, polyvinyl pyrrolidone K30 (PVP K30), SSG and lactose were obtained from Yarrow Chem Products (Mumbai India), and microcrystalline cellulose, talc and magnesium stearate were obtained from Biochemical Reagents, Otto Chemica Biochemica Reagents.

Identification of drugs: The absorbance values of VAL at various concentrations (2, 4, 6, 8, 10 and 12 μg/mL) were determined using ultraviolet (UV)-visible spectrophotometer.

Solubility enhancement of VAL by preparing solid dispersions: Solid dispersion (SD) mixtures of VAL were formulated using different carriers (β-cyclodextrin, poloxamer 188 and PVP K30) at three different ratios (1:3, 1:4 and 1:5) and employing a physical mixing (PM) technique. In this technique, the drug and the carrier were placed in a mortar and pestle and were mixed gently until a homogenous mixture was obtained. The prepared homogenous mixture was passed through a sieve (no. 44) and then packed and stored in desiccators for further use. A formulation table for solubility enhancement of VAL is shown in Table 1.

Preparation of VAL IR tablets: Based on physicochemical characterisation and drug release studies, the PM8 formulation, which contains the drug and poloxamer 188 in a 1:4 ratio, was selected to formulate IR tablets with 3%, 4% and 5% SSG as superdisintegrant.² VAL PM, SSG, magnesium stearate and talc were added in a mortar and pestle and gently mixed for a few minutes. The prepared formulations (IF1–IF3) were evaluated in terms of precompression parameters, and by direct compression technique compressed into IR tablets using an 8-mm punch. The formulation for the IR tablet ingredients is given in Table 2.

Compatibility studies to determine drug–polymer compatibility were performed using differential scanning calorimetric studies (DSC), scanning electron microscope (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction studies (XRD).

Fourier transform infrared spectroscopy: An FTIR spectrometer from Agilent Technologies (Cary 630 FTIR, Germany) was used to obtain FTIR spectra. VAL, PM and IR formulation samples were directly placed on the sample holder and subjected to scanning from 400 to 4000 cm⁻¹.

Differential scanning calorimetry: DSC study was performed using DSC-6100 with a thermal analyser to confirm the drug’s physical state in PM and IR formulation and to ensure its compatibility with the excipients. DSC thermograms were analysed by taking 1 mg of accurately weighed samples in covered aluminium pans under nitrogen flow (20 mL/min) at a rate of 10°C min⁻¹. Scanning was done with the oven heated from 25°C to 350°C.

X-ray diffraction: The PW1710 X-ray diffractometer was used for XRD analysis at ambient temperature with an anode material Cu and graphite monochromatic, operated at 20 mA and 35 kV current. The Bragg’s law (nλ=2d sin θ) is satisfied when the sample forms constructive interference with the incident rays. These diffracted X-rays were then detected, processed and counted. At 2θ range the sample scanning through, due to the orientation of the powdered material at random in maximum possible diffraction directions of the lattice.¹⁰

The following precompression parameters were used to analyse the flow properties of the prepared formulation: angle of repose, bulk density, tap density, Carr’s compressibility index and Hausner’s ratio.^11,12

Angle of repose: The angle of repose was measured by funnel method. The maximum possible angle between the granules or powder surface of a pile and the horizontal plane explains the frictional forces of the loose powder. With a definite height fix the funnel to a stand and the powder was allowed to flow through the funnel. The heap radius (r) and height (h) of the granules or powder were measured, and the angle of repose (θ) was calculated using Eq. 1. (1) θ=tan−1hr \theta = {tan ^{ - 1}}\left[ {{h \over r}} \right]

Bulk density: Bulk density was measured by taking the mixture into a graduated cylinder from density apparatus. The weight of the powder (M) and the bulk volume (V₀) were determined, and the bulk density (ρ_o) was calculated using Eq. 2. (2) Bulk densityρo=MVo {\rm{Bulk}}\;{\rm{density}}\left( {{\rho _{\rm{o}}}} \right) = {{\rm{M}} \over {{{\rm{V}}_{\rm{o}}}}}

Tapped density: At a fixed time, the apparatus was allowed to tap. The weight of the mixture (M) and the tapped volume in the cylinder (V_t) were determined. The tapped density (ρ_t) of the sample can be calculated using Eq. 3. (3) Tapped densityρt=MVt {\rm{Tapped}}\;{\rm{density}}\left( {{\rho _{\rm{t}}}} \right) = {{\rm{M}} \over {{{\rm{V}}_{\rm{t}}}}}

Compressibility index: The rate at which it packed down and the powder sample’s ability to flow can be determined by comparing the tapped density with the bulk density of the mixture. Carr’s compressibility index can be calculated using Eq. 4. (4) Carr's compressibility index=ρt−ρoρt×100 {\rm{Carr's}}\;{\rm{compressibility}}\;{\rm{index}} = \left[ {{{{\rho _{\rm{t}}} - {\rho _{\rm{o}}}} \over {{\rho _{\rm{t}}}}}} \right] \times 100

Hausner’s ratio: Hausner’s ratio is an indirect measure of the powder’s flow index and can be calculated using Eq. 5. (5) Hausner's ratio=ρtρo {\rm{Hausner's}}\;{\rm{ratio}} = {{{\rho _{\rm{t}}}} \over {{\rho _{\rm{o}}}}}

Postcompression parameters such as weight variation, thickness, hardness, friability, content uniformity, disintegration test and in vitro dissolution were determined.¹³

Weight variation: From each batch, 20 tablets were randomly taken, and using digital weighing balance their weights were individually determined. The collective weights of all the tablets gave an average weight.

Thickness: From each batch, 10 tablets were randomly taken, and using vernier callipers their thickness was measured. The readings were obtained and recorded in millimetres.

Hardness: From each batch, three tablets were randomly picked and the mean values were calculated. A Monsanto hardness tester was used to determine the hardness, expressed in kg/cm².

Friability: A sample of tablets equivalent to 6.5 g was weighed and the initial weight (W_o) was recorded. The sample was then placed in a Roche friabilator, with the rotation speed adjusted to 25 rpm for 100 revolutions. All the tablets were then removed from the friabilator, and the fines were dedusted and the sample weighed. The final weight (W_f) was recorded. Eq. 6 was used to calculate %friability. (6) %Friability=Wo−WfWo×100 \% {\rm{Friability}} = \left[ {{{{{\rm{W}}_{\rm{o}}} - {{\rm{W}}_{\rm{f}}}} \over {{{\rm{W}}_{\rm{o}}}}}} \right] \times 100

Disintegration test: A United States Pharmacopeia disintegration test apparatus was used to determine the disintegration time in a gastric fluid medium with a pH of 1.2 at a 37±0.5°C temperature. The apparatus contains six tubes, with one tablet taken in each tube and a disc placed in each tube. The time required to disintegrate the tablets into fragments and passed through the mesh of the tube was recorded as the disintegration time.

Content uniformity: To determine drug content, 10 tablets were randomly taken and grounded to powder. From the grounded powder, accurately weigh powder equivalent to 40 mg of VLR and dissolved in gastric fluid (100 mL) with a pH of 1.2. Stirring was continued for 15 min, make the volume up to with buffer and filtered if necessary. Absorbance was measured using a Cary 60 UV-visible spectrophotometer (Agilent Technologies) at 205 nm.⁹

Wetting time and water absorption ratio: The time taken for a tablet to disintegrate or break when kept stable in a Petri dish containing 6 mL of gastric fluid with a pH of 1.2 as buffer on the tissue paper is described as the wetting time. Wetting time was measured as the time required to completely wet the tissue paper. The weight of the tablet before wetting was obtained (W_b), and again after wetting the tablet (W_a). For each batch, three trials were performed and the standard deviation was determined. The water absorption ratio (R) was determined using Eq. 7. (7) R=100×Wa−WbWa R = 100 \times \left[ {{{{W_a} - {W_b}} \over {{W_a}}}} \right]

In vitro release studies: Dissolution studies of VAL, PMs and IR formulations were performed with 900 mL of gastric fluid with a pH of 1.2 as the dissolution medium. A USP type II dissolution apparatus at 50 rpm paddle rotation speed at 37±0.5ºC temperature was used. Using syringe, around 5 mL of the sample was withdrawn at a time interval of 5, 10, 15, 30, 45 and 60 min, and fresh dissolution medium maintained at 37°C was replaced to keep the volume constant throughout the test. The samples were then filtered using 0.45 μm filter and then analysed for VAL content using a Cary 60 UV-visible spectrophotometer (Agilent Technologies, Germany) at 205 nm. The dissolution tests were carried out in triplicates in all formulations.⁹

Stability studies: Long-term and accelerated stability studies were performed as per the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

FTIR spectroscopy: The FTIR peak of VAL, optimised PM8 SD formulation and optimised IF2 formulation is shown in Figure 2. The FTIR spectrum of VAL shows two carbonyl absorption bands at 1600 and 1710 cm⁻¹, assigned to the amide carbonyl and carboxyl carbonyl stretching, respectively.¹³ The FTIR spectrum of poloxamer 188 is characterised by absorption peaks of the C-H aliphatic stretch at 2800 cm⁻¹, O-H stretch at 1320 cm⁻¹ and C-O stretch at 1100 cm⁻¹, indicating the nature of poloxamer 188.¹⁴ The SSG spectrum shows a broad band at 3260 cm⁻¹, which indicates O-H stretching compound. At 1000–1590 cm⁻¹, overlapping bands reflect symmetric and asymmetrical stretching of the C-O-C group.¹⁵

Figure 2.

DSC studies: DSC analyses of VAL and the excipients were performed to evaluate any possible drug to polymer interaction. DSC thermograms were analysed to confirm the physical state of the drug in SDs and to determine its compatibility with the excipients. The thermograms of VAL, poloxamer 188, SSG and optimised IF2 formulation are shown in Figure 3. The VAL showed a melting endotherm at 117.5°C,¹⁵ whereas at 60.80°C a melting endotherm was shown by poloxamer 188.¹⁶ SSG reached its peak at 204.8°C.¹⁶ The optimised IF2 formulation showed a melting endotherm at 116.3°C.

Figure 3.

XRD analysis: XRD results for VAL, poloxamer 188, SSG and the optimised IF2 formulation are shown in Figure 4. The XRD spectrum of VAL showed the crystalline form of the drug, demonstrated by distinct values of 19.24º, 23.78º and 38.50º at 2θ. The crystalline form of poloxamer 188 was achieved by two characteristic peaks at 19º and 23º broader peak.¹⁵ SSG reached its peak at 19.68º and 23.92º.

Figure 4.

Scanning electron microscopy: The SEM of VAL, SSG and the optimised IF2 formulation is shown in Figure 5. VAL appeared to be made of irregular crystalline structures.^15,17 SSG appeared globular to irregular in shape of varying sizes. In the optimised IF2 formulation, the structure of the VAL mixture crystals was completely different, which indicates the formation of a new structure in the optimised IF2 formulation containing poloxamer 188 and SSG. These findings indicate that the drug changed from crystalline to amorphous form.

Figure 5.

In vitro dissolution analysis of SDs: In vitro dissolution tests were carried out using a pH of 1.2 as buffer medium with 900-mL volume, at a temperature of 37±0.5°C and speed of 50 rotations per minute using a USP type II dissolution apparatus. The studies revealed a significant variation between the release profile of VAL and VAL with carriers. All formulations showed a higher amount of drug released when compared with pure drug. Of all the carriers, poloxamer 188 at 1:4% showed a drastic change in its dissolution profile. The data are given in Table 4.

The flow properties of the prepared VAL IR formulation (IF1–IF3) were analysed to determine their suitability for direct compression.¹⁸ The values are given in Table 5. The angle of repose was found lowest for IF2, with a value of 22.92°, and highest for IF3, with a value of 28.88°. A value less than 40° indicates the granules have good to moderate flow property. The compressibility index values for all the formulations varied between 1.42 and 6.66. An observed value less than 15% indicates the granules have good flow nature. Hausner’s ratios values were observed to be between in the range of 1.06 and 1.12, which were below 1.18, indicating all the values were as per standard range, thus suggesting good flow properties.

For all the prepared batches of tablets, the hardness was found to be in the range of 4–6 kg/cm². The friability of all the formulations ranged from 0.227% to 0.456%, which were less than 1%, while the drug content values ranged from 92.66% to 100.3%. The disintegration time of the IR formulations (IF1–IF3) was between 4.5 and 6.2 min. The values are depicted in Table 6.

In vitro drug release studies of the IF1–IF3 tablets indicated that drug release was based on the concentration of the superdisintegrant in the formulation. Formulations prepared with 4%, 5% and 6% SSG showed 88.63%–99.69% drug release in 60 min, as shown in Figure 6a. IF2, containing 4% SSG, demonstrated better drug release at 84.46% within 30 min; IF1, containing 3% SSG, demonstrated 72.17% drug release within 30 min; and IF3, containing 5% SSG, demonstrated 96.83% drug release.

The drug release profiles of the optimised IF2 formulation containing 1:4 ratio of drug and poloxamer 188 with 4% w/w SSG was compared with a marketed tablet (Figure 6b).

Stability data of the long-term and accelerated studies are depicted in Table 7. The results of all the evaluated parameters were within the range and no other significant changes were observed throughout the study period.

Figure 6.