Development and Evaluation of Valsartan Fast Disintegrating Films

Asian Journal of Pharmaceutic s • Jan-Mar 2022 • 16 (1) | 51 Development and Evaluation of Valsartan Fast Disintegrating Films Balakrishna Talamanchi, Vidyadhara Suryadevara, Abhigna Nelluri, Akhila Nalabothu, Lakshmi Sravanth Sudi, Vardhan Gattu, Anjali Linga Department of pharmaceutics, Chebrolu Hanumaiah Institute of Pharmaceutical sciences, Chandramoulipuram, Chowdavaram, Guntur, Andhra Pradesh, India Abstract Objective: The aim of the present work was to develop and evaluate the fast disintegrating films (FDF) of valsartan which is used for the treatment of hypertension and heart failure. Method: The valsartan fast disintegrating films were prepared by solvent casting method using hydroxylpropyl cellulose, poly vinyl alcohol (PVA), HPMC E 5 as film forming agents, Polyethylene glycol 400 as plasticizers and dimethylsulfoxide as penetration enhancer. Results: Valsartan FDF were developed and evaluated for weight uniformity, drug content, film thickness, and folding endurance, the results obtained were within the specified limits. The in vitro diffusion studies were performed using Franz diffusion cell apparatus containing 6.8 pH phosphate buffer as a dissolution media Conclusion: The FDF prepared with HPMC E 5 at 1:3 ratio released the drug up to 98.7% within 5 min which showed the increased solubility, dissolution rate flexibility, and tensile strength of the films when compared to formulation prepared with hydroxypropyl cellulose and PVA. The Fourier-transform infrared studies were conducted for pure drug, polymers and optimized formulation V 9 which indicated that were no incompatibilities found between the drug and polymers used in the present studies. Scanning electron microscopy analysis was performed for pure drug, polymers, and optimized formulation V 9 which showed that they were no surface fractures and cracks in the films Keywords: Valsartan, Fast disintegrating films, Solvent casting method, Polymers, Plasticizers, Penetration enhancer and superdisintegrants Address for Correspondence: Dr. T. Balakrishna, Department of Pharmaceutics, Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Chandramoulipuram, Chowdavaram, Guntur - 522 019, Andhra Pradesh, India E-mail: balakrishnathalamanchi@gmail.com Received: 06-01-2022 Revised: 14-03-2022 Accepted: 25-03-2022 INTRODUCTION F ast disintegrating films (FDF) are a sort of solid dosage form that was developed based on the technology of transdermal patches for medication delivery via the oral route. This delivery device consists of a thin film that is simply applied on the patient’s tongue or mucosal tissue and quickly dissolves when wet by saliva. The medicine is then rapidly disintegrated and dissolved for oral mucosal absorption [1-3] The huge surface area of the film, which wets quickly when exposed to the moisture environment, contributes to the fast-dissolving activity. FDF is made with a hydrophilic polymer that dissolves quickly on the tongue or in the buccal cavity, allowing the medicine to enter the systemic circulation through the buccal mucosa [4] For the increase of bioavailability, quick-dissolving drug delivery systems are specifically designed for medicines with substantial first-pass metabolism and low dosage [5,6] In the shape of breath strips, this technology evolved over the last few years from the confection and oral care businesses, becoming a novel and well-accepted form by consumers. These films have the ability to administer the medication systemically through intragastric, sublingual, or buccal routes of administration, as well as for local action [7-9] Valsartan is an antihypertensive that is exclusively soluble in alcohols since it has a BCS Class II moiety. VAL is an angiotensin II receptor antagonist with a high affinity for the type I (AT 1) angiotensin receptor pharmacologically [10,11] As a result, it necessitates rapid absorption and high bioavailability from ORIGINAL AR TICLE

Talamanchi, et al .: Valsartan fast disintegrating films Asian Journal of Pharmaceutic s • Jan-Mar 2022 • 16 (1) | 52 the standpoint of the patient. Valsartan takes 4 h to absorb and has a bioavailability of only 20–25%. Valsartan absorption is delayed in fed circumstances [12] Blood pressure often rises in chronic hypertension individuals, necessitating quick drug reduction. VAL is an effective antihypertensive with fewer adverse effects than angiotensin II receptor antagonists and the ability to treat hypertension with frequent dosage In the present studies, valsartan is taken as a drug candidate for the development of FDF which were prepared by using hydroxylpropyl cellulose, PVA, HPMC E 5 as film-forming agents, dimethylsulfoxide as a penetration enhancer, polyethylene glycol 400 and crospovidone were used as plasticizers and superdisintegrants, and they were prepared by solvent casting method to improve the solubility and dissolution rate of valsartan MATERIALS AND METHODS Valsartan is a gift sample from M/S Aurobindo Pharma Ltd, Hyderabad. HPC, HPMC E 5, and PVA were obtained from Mylan Pharma limited Hyderabad. PEG 400 and dimethyl sulfoxide were obtained from SD Fine Chem., Ltd., and Mumbai Preparation of valsartan FDF The solvent casting method was used to make valsartan fastdissolving oral thin films. To obtain transparent solutions, film-forming polymers such as HPC PVA and HPMC E 5 were dissolved in alcoholic solutions individually in 100 ml beakers. Specified amounts of valsartan, crospovidone, dimethyl sulfoxide, and PEG 400 were weighed and dissolved in the alcoholic solution, then well mixed to obtain a homogenous solution. The resulting solution was cast on a non-adhesive base plate and cured for 24 h under an infrared lamp. The films were trimmed into desired sizes once they had dried completely. Several attempts were conducted to improve the formula for making valsartan fast-dissolving oral thin films [13-16] The composition of valsartan fast-dissolving oral thin films is given as follows. The compositions of prepared films are given in Table 1 Evaluation of physical parameters for valsartan FDF The valsartan oral thin films were evaluated for physical parameters such as weight uniformity, drug content, film thickness, and folding endurance. The results are given in Table 2 Weight uniformity The weight uniformity of the films can be done manually using a digital electronic balance Uniformity of drug content An UV visible spectrophotometric method was used to assess the drug content uniformity of the films, measuring their absorbance at a wavelength of 250 nm. The percentage drug content of various films was determined and is given in Table 2 Film thickness At various locations on the film, the thickness of the film was measured using a screw gauge with a least count of 0.01 mm. The average weight was calculated after measuring the film thickness at three separate locations. The obtained results are given in Table 3 Folding endurance Folding endurance was determined by repeatedly folding a tiny strip of film in the same spot until the film cracked, at that spot, the number of times the film could be folded in the same area was noted as folding endurance. The film was folded at an angle of 1800° in the same location until it broke, or it was folded 100 times without breaking. The experiments were completed in a timely manner, and the average mean was computed Dispersion test Strips of film equivalent to 10 mg of drug are placed in 200 ml of pH 6.8 phosphate buffer and stir with glass rod for 3 min Table 1: Composition of valsartan fast disintegrating films Ingredients (w/w) V 1 V 2 V 3 V 4 V 5 V 6 V 7 V 8 V 9 Valsartan 40 40 40 40 40 40 40 40 40 HPC 40 80 160 ‑ ‑ ‑ ‑ ‑ ‑ Polyvinyl alcohol ‑ ‑ ‑ 40 80 160 ‑ ‑ ‑ HPMC E 5 ‑ ‑ ‑ ‑ ‑ ‑ 40 80 160 PEG 400 50 75 100 50 75 100 50 75 100 Dimethyl sulfoxide 5 5 5 5 5 5 5 5 5 Crospovidone 20 20 20 20 20 20 20 20 20 Methanol QS QS QS QS QS QS QS QS QS

Talamanchi, et al .: Valsartan fast disintegrating films Asian Journal of Pharmaceutic s • Jan-Mar 2022 • 16 (1) | 53 and pass through 22 meshes the film is passed dispersion test only when no residue left on the mesh In vitro diffusion studies In vitro diffusion studies were conducted on all the valsartan FDF using Franz diffusion cell apparatus containing pH 6.8 phosphate buffer as dissolution medium. The dissolution studies were carried out over a period of 15 min for all the formulations. Dissolution studies were carried out in triplicate, maintaining the sink conditions for all the formulations. A 5 ml aliquot of samples was withdrawn at regular time intervals, filtered, and assayed spectrophotometrically at 250 nm. The drug release profiles for all the film formulations are shown in Figure 1 Evaluation of various in vitro dissolution parameters Dissolution parameters such as T 50 , T 90 , DE 5% , and first-order rate constants were calculated from the dissolution data obtained, and the results are given in Table 3 Characterization of valsartan FDF Based on the diffusion studies performed on all the formulations, the optimized formulations were selected and the following characterization studies were done on pure drug, polymers, and optimized formulation Fourier-transform infrared (FTIR) spectroscopy To investigate the interaction between drug and carrier in films, the FTIR spectra of valsartan, HPC, PVA, and HPMC were acquired using a Bruker FTIR spectrophotometer. The samples were produced on KBr discs (2 mg of sample in 200 mg of KBr), with a sampling range of 400-4000/cm and a resolution of 4/cm. The FTIR spectra are shown in Fig ures 2-5 Table 2: Evaluation of physical parameters for valsartan fast disintegrating films Formulation Weight uniformity (mg) Drug content (mg/film) Film thickness (mm) Folding endurance (no) Dispersion test V 1 149 37.21 0.030 97 Passed V 2 188 38.64 0.032 98 Passed V 3 269 39.51 0.033 99 Passed V 4 148 37.11 0.031 90 Passed V 5 190 38.23 0.032 89 Passed V 6 271 39.09 0.033 92 Passed V 7 153 38.89 0.032 97 Passed V 8 192 38.90 0.033 98 Passed V 9 275 40.11 0.034 101 Passed Table 3: Evaluation of In vitro Dissolution Parameters for valsartan fast disintegrating films S.No Formulation T 50 (min) T 90 (min) DE 5% First order K (min −1 ) R 2 3 V 1 4.2 14.1 21.8 0.232 0.911 4 V 2 2.1 13.5 23.7 0.211 0.933 5 V 3 2.3 9.5 25.6 0.267 0.929 9 V 4 4.8 14.0 22.7 0.289 0.956 10 V 5 4.0 13.1 24.8 0.233 0.965 11 V 6 2.2 8.6 27.9 0.255 0.956 15 V 7 2.0 13.8 18.9 0.222 0.978 16 V 8 1.7 12.5 26.9 0.311 0.988 17 V 9 1.1 4.8 33.89 0.354 0.994 Figure 1: Drug release profiles for valsartan fast disintegrating films

Talamanchi, et al .: Valsartan fast disintegrating films Asian Journal of Pharmaceutic s • Jan-Mar 2022 • 16 (1) | 54 Scanning electron microscopy (SEM) analysis The SEM photo graphs were taken for the optimized film formulation V 9 and valsartan pure drug. The SEM photographs are shown in Figures 6 and 7 RESULTS AND DISCUSSION Preparation of valsartan FDF Based on the physiochemical and biopharmaceutical properties, the aim of the present study was to prepare FDF of valsartan using the solvent casting method, which should possess a suitable approach in enhancing the disintegration and dissolution characteristics in more faster with increased bioavailability of poorly soluble valsartan drug. Hydroxylpropyl cellulose, PVA, and HPMC E 5 were chosen as the film-forming agents, polyethylene glycol 400 as plasticizers, and crospovidone and dimethyl sulfoxide as superdisintegrant and penetration enhancer. The valsartan FDF formulations were prepared by 1:1, 1:2, and 1:3 ratios of drug and film-forming agents by solvent casting method. The composition of valsartan FDF formulations is shown in Table 1 Evaluation of physical parameters for valsartan FDF The physical parameters such as weight uniformity, drug content, film thickness, and folding endurance were performed for all the valsartan FDF. The weight uniformity of all valsartan FDF prepared with hydroxylpropyl cellulose, PVA, and HPMC E 5 were maintained in the range of 149–275 mg. The drug content of all valsartan FDF was maintained in the range of 37.21–40.11 mg. which indicates that the drug is evenly dispersed in all the FDF formulations. The film thickness of all FDF formulations was maintained at the range of 0.030 ± 0.034 mm. The folding endurance values for all the FDF formulations were maintained in the range of 89–101 folding, which indicates that the FDF formulations were found to be stable and should have good tensile strength. The dispersion test for all the prepared films were passed. The results of evaluated parameters such as weight uniformity, drug content, film thickness, and folding endurance are shown in Table 2 In vitro diffusion studies of valsartan FDF formulations Diffusion studies were conducted on all the valsartan FDF formulations using Franz diffusion cell apparatus containing pH 6.8 phosphate buffer as dissolution medium. The FDF formulations V 1–V 3 which were prepared by Figure 4: Fourier‑transform infrared spectrum of HPMC E 5 Figure 3: Fourier‑transform infrared Spectrum of poly vinyl alcohol Figure 2: Fourier‑transform infrared spectrum of hydroxylpropyl cellulose

Talamanchi, et al .: Valsartan fast disintegrating films Asian Journal of Pharmaceutic s • Jan-Mar 2022 • 16 (1) | 55 using hydroxypropyl cellulose (HPC) showed an average drug release of 91.88 to 97.67 % within 15 min. The FDF formulations V 4–V 6, which were prepared by using PVA, showed an average drug release of 90.81–96.23% within 15 min. The FDF formulations V 7–V 8 which were prepared by using HPMC E 5 showed an average drug release of 95.11–96.23% within 15 min. when compared to the entire FDF formulations, the FDF formulations that were prepared by using HPMC E 5 at 1:3 ratio showed better drug release up to 98.11% within 5 min. The drug release profiles are shown in Figure 1 Evaluation of various in vitro dissolution parameters All the film formulations were found to be linear with first-order release rate with R 2 values in the range of 0.911–0.994. Thus, the rates of drug release from all the film formulations were concentration dependent and were linear with first-order release rate constant (K 1 ). The results of the evaluation of physical parameters for valsartan oral thin films are given in Table 3 FT-IR spectroscopic analysis The FTIR spectra of valsartan exhibited significant peaks at wave numbers of 2613 cm −1 (O-H), 2963 cm −1 (C-H), 1204 cm −1 (C≡N vibrations), 1732 cm −1 (C=O stretching), 1602 cm −1 (N-H bending), and aliphatic 3⁰ amine 1105 cm −1 . For Hydroxypropyl cellulose, the peaks were observed at 2595 cm −1 (O-H), 2927 cm −1 (C-H), 1198 cm −1 (C≡N vibrations), 1729 cm −1 (C=O stretching), 1603 cm −1 (N-H bending), and aliphatic 3⁰ amine 1068 cm −1 . For PVA, the peaks were observed at 2581 cm −1 (O-H), 2926 cm −1 (C-H), 1196 cm −1 (C≡N vibrations), 1728 cm −1 (C=O stretching), 1602 cm −1 (N-H bending), and aliphatic 3⁰ amine 1068 cm −1 . For HPMC E 5, the peaks were observed at 2422 cm −1 (O-H), 2728 cm −1 (C-H), 1218 cm −1 (C≡N vibrations), 1559 cm −1 (C=O stretching), 1490 cm −1 (N-H bending), and aliphatic 3⁰ amine 1447 cm −1 . For optimized formulation (V 9), the peaks were observed at 2522 cm −1 (O-H), 2877 cm −1 (C-H), 1144 cm −1 (C≡N vibrations), 1768 cm −1 (C=O stretching), 1640 cm −1 (N-H bending), and aliphatic 3⁰ amine 1218 cm −1 . The spectra of optimized formulation V 9 exhibited all the principle peaks present in the valsartan pure drug. Thus, there was no appearance or disappearance of any characteristics peak which shows that there is no chemical interaction between the drug and the polymer used. The FTIR spectra of drug, polymers, and optimized formulation V 9 are shown in Figures 2-5,8, and the interpretation is shown in Table 4 Table 4: Interpretation of FTIR Spectrum Group Valsartan HPC Poly vinyl alcohol HPMC E 5 Optimized Formulation (V 9) O‑H Stretching 2613.05 cm− 1 2595.55 cm− 1 2581.72 cm− 1 2422.89 cm− 1 2522.45 cm− 1 C‑H Stretching 2963.20 cm− 1 2927.53 cm− 1 2926.22 cm− 1 2728.77 cm− 1 2877.44 cm− 1 C ≡ N Vibration 1204.62 cm− 1 1198.42 cm− 1 1196.51 cm− 1 1218.12 cm− 1 1144.90 cm− 1 C=O Stretching 1732.41 cm− 1 1729.56 cm− 1 1728.85 cm− 1 1559.76 cm− 1 1768.32 cm− 1 N‑H Bending 1602.40 cm− 1 1603.78 cm− 1 1602.52 cm− 1 1490.22 cm− 1 1640.11 cm− 1 Aliphatic 3 ⁰ amine 1105.70 cm− 1 1068.98 cm− 1 1068.81 cm− 1 1447.18 cm− 1 1218.65 cm− 1 Figure 5: Fourier‑transform infrared spectrum of optimized formulation (V 9) Figure 6: Scanning electron microscopy photograph of valsartan pure drug Figure 7: Scanning electron microscopy photograph of optimized formulation (V 9)

Talamanchi, et al .: Valsartan fast disintegrating films Asian Journal of Pharmaceutic s • Jan-Mar 2022 • 16 (1) | 56 SEM analysis The SEM analysis was performed for valsartan pure drug and optimized formulation V 9. The results indicated that the optimized formulation V 9 showed surface texture was smooth and uniform without any cracks on its surface. The SEM images are shown in Figures 6 and 7 CONCLUSION Valsartan oral thin films prepared by solvent casting method showed good flexibility and film characteristic properties. The optimized formulation V 9 containing HPMC E 5 at 1:3 ratio released the drug 98.11% within 5 min, which was desirable for faster dissolution and absorption. Valsartan oral thin films prepared by solvent casting technique were found to be suitable for the prevention and treatment of hypertension ACKNOWLEDGMENT The authors express their gratitude to Aurobindo Pharma Limited, Hyderabad, Andhra Pradesh, India, for providing gift samples. The authors are thankful to the management of Chebrolu Hanumaiah Institute of Pharmaceutical Sciences, Guntur, for providing the facilities to carry out the research work AUTHOR CONTRIBUTIONS T. Balakrishna has performed the basic methodology of this work. S. Vidyadhara has guided the entire formulation of the research work. Abhigna and Akhila have helped in the development of valsartan FDF. Sravanth and Vardhan helped in the interpretation of FTIR data. Anjali helped in the SEM analysis of valsartan FDF REFERENCES 1. Bajaj H, Bisht S, Yadav M, Singh V. Bioavailabilty enhancement: A review. Int J Pharma Bio Sci 2011;2:202-15 2. Dixit RP, Puthli SP. Oral strip technology: Overview and future potential. J Control Release 2009;139:94-7 3. Vollmer U, Galfetti P. Rapid film: Oral thin films as an innovative drug delivery system and dosage form. Drug Dev Rep 2006;2:1-5 4. Mahajan A, Chhabra N, Agarwal G. Formulation and characterization of fast dissolving Buccal film: A Review. Der Pharm Sin 2011;3:152-65 5. Suresh B, Halloran D, James L. Quick dissolving films: A novel approach to drug delivery. Drug Dev Technol 2006;3:1-7 6. Gavaskar B, Kumar SV, Sharan G, Madhusudan Y. Overview on fast dissolving films. Int J Pharm Pharm Sci 2010;3:29-33 7. Prabhu P, Malli R, Koland M, Vijaynarayana K, Souza U, Harish N . Formulation and evaluation of fast dissolving films of levocitirizine dihydrochloride. Int J Pharm Investig 2011;1:99-4 8. Tora GJ, Gorahowski SR. Principles of Anatomy and Physiology. Vol. 7. United States: Wiley and Sons, Incorporated, John; 1992. p. 770-4 9. Beg S, Swain S, Singh HP, Patra CN, Rao MB. Development, optimization and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers. Pharm Sci Tech 2012;2:112-4 10. Markham A, Goa KL. Valsartan: A review of its pharmacology and therapeutic use in essential hypertension. Drugs 1997;54:299-11 11. Flesch G, Lloyd P, Muller PH. Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol 1997;52:115-20 12. Rajesh K, Raju YP, Nagaraju R. Dissolution enhancement of valsartan using natural polymers by solid dispersion technique. Der Pharm Lett 2013;5:126-34 13. Vidyadhara S, Sasidhar RL, Balakrishna T, Santhavardhan M. Formulation of rizatriptan benzoate fast dissolving buccal films by emulsion evaporation technique. Int J Pharm Investing 2015;5:101-6 14. Balakrishna T, Vidyadhara S, Murthy TE, Sasidhar RL. Formulation and evaluation of lansoprazole fast dissolving buccal films. Asian J Pharm 2018;12:101-35 15. Balakrishna T, Vidyadhara S, Murthy TE, Ramu A, Sasidhar RL. Formulation and evaluation of esomeprazole fast dissolving buccal films. Asian J Pharm Clin Res 2018;11:193-9 16. Balakrishna T, Vidyadhara S, Murthy TE, Sasidhar RL, Venkateswarao J. Formulation and evaluation of lansoprazole fast dissolving buccal films. Asian J Pharm 2016;10:313-9 Source of Support: Nil. Conflicts of Interest: None declared Figure 8: Fourier‑transform infrared spectrum of valsartan Pure Drug

Other Health Sciences Concepts:

[back to top]

Discover the significance of concepts within the article: ‘Development and Evaluation of Valsartan Fast Disintegrating Films’. Further sources in the context of Health Sciences might help you critically compare this page with similair documents:

Adverse effect, Blood-pressure, Heart failure, Bioavailability, Drug delivery system, Dimethyl sulfoxide, Solid dosage form, Hypertension, Oral route, Scanning Electron Microscopy, Fourier transform infrared spectroscopy, Systemic circulation, First Pass Metabolism, Local action, Dissolution rate, Tensile strength, Physical parameter, SEM analysis, FTIR, PVA, Solvent casting method, Folding endurance, Plasticizer, Crospovidone, Franz diffusion cell, Dissolution studies, FTIR Spectroscopy, Optimized formulation, Drug content, Dissolution medium, Gift sample, Phosphate buffer, Drug release, Dissolution media, Solid Dispersion Technique, Spectroscopic analysis, Fast dissolving drug delivery system, Drug content uniformity, In-vitro Diffusion Studies, Drug release profile, Dissolution parameters, Superdisintegrant, Penetration enhancer, Buccal Mucosa, Drug delivery, Polyethylene Glycol 400, Solvent casting technique, FTIR spectra, Film thickness, Oral thin film, Buccal cavity, Dissolution data, Fast dissolving film, Weight Uniformity, First order rate constant, Valsartan, Buccal route, First order, Hydroxypropyl cellulose, Angiotensin II, Film forming polymer, Surface texture, Sublingual route, Sink condition, Dimethylsulfoxide, Biopharmaceutical properties, In vitro dissolution parameters, Poly vinyl alcohol, Physiochemical properties, UV-Visible spectrophotometric method, PH 6.8 phosphate buffer, Antihypertensive, Pure Drug, HPMC E-5, AT-1 receptor, Electronic balance, Dispersion test, Drug candidate, Alcoholic solution, Increased bioavailability, Film Forming Agent, Homogenous solution, Polymer, Bruker FTIR spectrophotometer, R 2 value, Infrared lamp, Oral mucosal absorption, Screw gauge, Pharmaceutic, T 50, T 90, Transparent solution, Glass rod, Sampling range, Surface fractures.