Compared to all other dosage forms, oral drug delivery is one of the best and preferred methods in terms of unit dose, patient compliance, high precision dosing, and so on. fast-disintegrating tablets and immediate release (IR) tablets have immediate onset of action, when compared with conventional dosage forms and other solid dosage forms, which can show immediate effects. The IR dosage form is one of the popular oral dosage forms as it eliminates the drawbacks of a conventional tablet and has a rapid onset of action. This novel drug delivery system improves the therapeutic activity of active pharmaceutical ingredients by delivering IR, fast-dissolving or fast-disintegrating dosages of the drug to the targeted site. Providing a better therapeutic amount of drug to the targeted or specific site and maintaining the required drug concentrations throughout the treatment period are the primary aims of this novel drug delivery system. Due to the advantages and benefits of using an oral drug form, there is a continuous growing interest in the development of IR dosage forms in the pharmaceutical industry.1
Hypertension is a condition where chronic elevation in systemic arterial pressure more than a certain threshold occurs. Cardiovascular risk is associated with a blood pressure elevation above 115/75 mmHg. Systolic blood pressure is the maximum pressure in the arteries when the heart contracts, while diastolic blood pressure is the minimum pressure in the arteries between heart contractions. Hypertension is a condition where symptoms do not generally show until the condition has become serious, hence known as the silent killer.2,3,4 It is a condition that continues for a prolonged period, characterised by persistent increase in blood pressure higher than the normal range.5 Due to its properties and characteristics, valsartan (VAL) is a drug of choice for treatment of hypertension. VAL is an angiotensin II receptor blocker (ARB), a group of drugs that also include olmesartan, candesartan, telmisartan, irbesartan and losartan.6
VAL is a specific angiotensin II antagonist which acts on the angiotensin receptor 1 (AT1). It helps by blocking a angiotensin II substance in the body which causes thickening of blood vessels and thereby relaxes the blood vessels and decreases blood pressure. The lower blood pressure increases the blood supply and thereby oxygen supply to the heart. VAL binds to angiotensin I and works as an antagonist, which shows difference from other Angiotensin-converting enzyme inhibitor drugs mechanism of action is preventing the transfer of angiotensin I to II. VAL generally belongs to the biopharmaceutics classification system class II drugs, which have low solubility and high permeability. VAL is not fully lipophilic but it exhibits solubility on pH-dependent bases. It is available in unionised form at lower pH in the stomach, which facilitates better permeation; however, a rate-limiting factor is the drug’s solubility.7 A few examples of hydrophilic drugs include buspirone and betahistine dihydrochloride, while examples of lipophilic drugs include simvastatin, VAL and triamcinolone acetonide.8 Most ARBs selectively bind to AT1, which prevents protein angiotensin II binding and leads to initiation of hypertensive effects, as well as stimulation, vasoconstriction and synthesis of aldosterone and anti-diuretic hormone and renal reabsorption of sodium. Generally, the physiological effects of VAL include reduced cardiac activity, reduced aldosterone levels, increased sodium excretion and reduced blood pressure. VAL also has low and variable oral bioavailability (BA) due to its poor aqueous solubility.9
The present investigation describes an approach to enhance the solubility and dissolution rate of VAL for better BA and pharmacokinetics for treatment of hypertension. The aim of the present work is to design and conduct an
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.
Formulation of solid dispersions of valsartan using different carriers.
PM1 | β-cyclodextrin | 1:3 |
PM2 | β-cyclodextrin | 1:4 |
PM3 | β-cyclodextrin | 1:5 |
PM4 | PVP K30 | 1:3 |
PM5 | PVP K30 | 1:4 |
PM6 | PVP K30 | 1:5 |
PM7 | Poloxamer 188 | 1:3 |
PM8 | Poloxamer 188 | 1:4 |
PM9 | Poloxamer 188 | 1:5 |
Formulation of valsartan immediate release tablets (IF1–IF3).a
IF1 | 200 | 6.9 | 20.8 | 2.3 | 230 |
IF2 | 200 | 9.2 | 18.5 | 2.3 | 230 |
IF3 | 200 | 11.5 | 16.2 | 2.3 | 230 |
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).
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
Postcompression parameters such as weight variation, thickness, hardness, friability, content uniformity, disintegration test and
The present work describes the formulation of SDs of VAL (PM1–PM8) prepared using different carriers (β-cyclodextrin, poloxamer 188 and PVP K30) at three different ratios (1:3, 1:4 and 1:5). From the optimised PM8 SD formulation, IR tablets of VAL (IF1–IF3) were prepared using a synthetic superdisintegrant (SSG) at 3%, 4% and 5% concentrations by a direct compression method. Standard calibration curve of the drug was initially established and the results are shown in Table 3. A graph is plotted showing the concentration versus absorbance values, known as the calibration curve. A linear equation was obtained from the calibration plot.5 The procedure was repeated three times. From all these three trails straight line equation whose intercept (c) values nearer to zero and coefficient of determination (r) values nearer to 1 was selected. The plotted graph and the scan are shown in Figure 1.
Concentration versus absorbance values of valsartan in 0.1 N Hydrochloric acid.
1 | 2 | 0.223±0.29 |
2 | 4 | 0.402±0.24 |
3 | 6 | 0.543±0.20 |
4 | 8 | 0.707±0.16 |
5 | 10 | 0.862±0.11 |
6 | 12 | 1.029±0.09 |
In vitro drug release data of valsartan solid dispersions (PM1–PM9) using different carriers.
5 | 6.12±0.2 | 7.42±1.3 | 10.2±2.4 | 14.8±0.2 | 12.9±1.1 | 12.7±2.1 | 11.7±1.0 | 26.4±0.3 | 34.4±0.2 |
10 | 10.3±0.5 | 11.8±1.4 | 14.7±2.1 | 20.0±0.4 | 25.8±1.3 | 19.4±1.2 | 37.3±1.2 | 51.9±0.5 | 60.1±2.0 |
15 | 12.1±0.7 | 16.5±1.6 | 22.1±2.6 | 25.6±0.2 | 36±1.4 | 60.3±1.1 | 57.3±1.3 | 70.5±0.6 | 74.5±2.2 |
30 | 22.4±0.9 | 31.7±1.9 | 27.0±2.7 | 43.5±0.1 | 72.2±1.1 | 72.9±0.2 | 68.3±1.5 | 94.2±0.8 | 96.8±2.0 |
45 | 27.7±1.2 | 41.8±2.6 | 46.3±2.8 | 49.4±0.2 | 98.7±1.1 | 79.8±0.2 | 85.9±1.0 | 96.9±0.9 | 99.6±1.0 |
60 | 39.8±1.5 | 44.8±2.1 | 58.3±2.1 | 75.7±0.9 | 100.2±1.6 | 99. 6±0.1 | 91.4±0.1 | 99.9±1.0 | 99.6±1.1 |
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.
Flow properties of valsartan immediate release formulations (IF1–IF3).
VAL | 42.54±0.2 | 542±0.2 | 522±1.1 | 27.38±1.1 | 1.37±2.0 |
IF1 | 28.36±0.3 | 600±0.6 | 666.6±1.2 | 9.99±1.2 | 1.11±1.3 |
IF2 | 22.92±0.6 | 500±0.5 | 600±1.5 | 6.66±2.0 | 1.12±0.6 |
IF3 | 28.88±0.5 | 461.5±30.9 | 491.8±2.0 | 6.15±2.5 | 1.06±3.2 |
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.
Postcompression parameters of valsartan immediate release formulations (IF1–IF3).
IF1 | 215.3±2.5 | 4.75±0.3 | 2.03±0.5 | 0.228±0.3 | 92.66±3.5 | 5.3±0.2 |
IF2 | 212.3±2.5 | 4.56±0.3 | 2.12±0.1 | 0.456±0.9 | 97.15±1.4 | 6.2±0.4 |
IF3 | 218.3±1.5 | 4.75±0.3 | 2.09±0.4 | 0.227±2.1 | 100.3±0.8 | 4.5±2.1 |
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.
Stability studies of valsartan immediate release formulation (IF2).
Initial | 0 | 97.15±1.4 | 6.2±0.4 | 99.69±0.01 |
Accelerated (40±2°C at 75±5% RH) | 6 | 96.99±1.1 | 6.1±0.2 | 99.64±0.02 |
Long term (25±2°C at 60±5% RH) | 12 | 97.11±0.9 | 6.1±0.5 | 99.59±0.03 |
The standard calibration curve of the drug was initially established, and the graph demonstrates a linear straight line showing a linear equation: y=0.079x+0.07. The correlation coefficient value was 0.999, which indicates the standard curve follows the Beer-Lambert’s law. The application of superdisintegrants in the IR tablet formulation is commercially feasible and highly effective. Superdisintegrants will help accelerate the disintegration of tablets due to their water absorption ability once the dosage form is exposed to an aqueous or gastric environment. The high water absorption property favours the breakdown of tablets, leading to faster disintegration. The disintegration has been reported to have an effect on drug dissolution.
The FTIR spectra of the VAL IR formulation showed the same characteristics, with carboxyl carbonyl and amide carbonyl stretching at 1700 and 1598 cm−1. This shows that there was no major shift in the peak values of IR formulation mixtures when compared with the pure drug. The characteristic peaks corresponding to the bands of the VAL should be preserved in the spectra of the PM8 and IF2 to indicate that no chemical changes took place during the formulation. The optimised IF2 formulation showed endotherm at 116.3°C, indicating that formulation containing VAL, poloxamer 188, SSG derived peak shows reduces intensity suggests decreased crystallinity and the drug might have got converted into amorphous form when compared with VAL. The values were within the standard melting point range, indicating the absence of drug–polymer interactions. DSC enables the quantitative detection of all processes in which energy is required or produced. DSC studies can be used to investigate and predict any physicochemical interactions between the components of a formulation and therefore used in the selection of chemically suitable and compatible excipients. The XRD of the optimised IF2 formulation containing poloxamer 188 and SSG showed at 38.51° that few peaks of VAL, SSG, poloxamer 188 were absent and reduced peak intensity was observed. Therefore, the results obtained indicate that the drug in the optimised IF2 formulation was converted to an amorphous form. The SEM analysis of VAL and the optimised IF2 formulation describes a change in the crystalline form of the drug in the optimised IF2 formulation, improving the solubility of VAL in the IR formulation. The
The present investigation describes the successful formulation and evaluation of the VAL IR tablet, an antihypertensive drug. VAL has poor water solubility and shows low and variable oral BA. For this purpose, solubility enhancement techniques were employed to increase the drug’s solubility and BA. After conducting preformulation studies, the optimum formulation was selected from all formulations. First, the solubility of VAL was enhanced using various carriers (β-cyclodextrin, PVP K30 and poloxamer 188) at various ratios (1:3, 1:4 and 1:5). Among all the formulations, poloxamer 188 showed better release. Hence, poloxamer 188 was selected as the polymer to use to prepare IR tablets, with SSG used as the superdisintegrant at various concentrations (3%, 4% and 5%, at three formulations, i.e., IF1, IF2 and IF3) by a direct compression technique using an 8-mm punch. Among the three formulations, IF2, which contains 4% SSG, demonstrated 84.46% drug release in 30 min and 99.69% drug release in 1 hr. FTIR compatibility studies revealed that there was no interaction between the drug and the excipients. Pre- and postcompression studies revealed that all the results were within the official standard limits.