Quality By Design Approach for Developing a Validated Liquid Chromatographic Method for Simultaneous Quantification of Bosentan and Sildenafil Citrate with Applications in Dissolution and Robustness Studies
Abstract
Background: This research aims to establish a validated analytical procedure for the simultaneous quantification of bosentan and sildenafil citrate in a newly encapsulated mini tablet formulation. Methods: The chromatography was performed using a reverse-phase column with a mobile phase consisting of acetonitrile and phosphate buffer at pH 4.3 in a ratio of 75:25 (v/v). The flow rate was maintained at 0.9 mL/min, and detection was conducted at a wavelength of 280 nm. Results: The developed method demonstrated excellent linearity, with a concentration range of 1–160 µg/mL for both bosentan and sildenafil. Method validation results adhered to acceptable limits established by regulatory guidelines. Additionally, the use of a quality by design approach ensured optimum robustness of the analytical method. Conclusion: This validated procedure is suitable for routine quality control of bosentan and sildenafil in the newly developed combined solid oral dosage form, providing a reliable analytical framework for future studies.
Keywords:
Bosentan, dissolution, experimental design, sildenafil citrate
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References
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Ala'Y, S., AlRashdan, Y., Abbasi, N. U., Mostafa, A., Abudayeh, Z., Talhouni, A., & Al-Ebini, Y. (2023). Optimization and Validation of HPLC-UV Method for the Determination of Vardenafil, Sildenafil, and Tadalafil in Honey-Mixed Herbal Sachets Using a Design of Experiment. Jordan Journal of Pharmaceutical Sciences, 16(1), 148-162. https://doi.org/10.35516/jjps.v16i1.1075
Anandakumar, K., Jambulingam, M., Rmaesh, J., Subarla, S. J., Sangeetha, P., & Raja, M. (2018). Development and validation of RP-HPLC method for the dissolution study of bosentan in bulk and in pharmaceutical dosage form. Current Journal of Applied Science and Technology, 18(2), 97-110. https://doi.org/10.14456/cast.2018.5
Berger, R. M., Gehin, M., Beghetti, M., Ivy, D., Kusic‐Pajic, A., Cornelisse, P., ... & FUTURE‐3 investigators. (2017). A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE‐3. British Journal of Clinical Pharmacology, 83(8), 1734-1744. https://doi.org/10.1111/bcp.13267
Bhogal, S., Khraisha, O., Al Madani, A., Treece, J., Baumrucker, S. J., & Paul, T. K. (2019). Sildenafil for pulmonary arterial hypertension. American Journal of Therapeutics, 26(5), 520-526. https://doi.org/10.1097/MJT.0000000000000766
Carbone, F., & Tack, J. (2018). The effect of sildenafil on gastric motility and satiation in healthy controls. United European Gastroenterology Journal, 6(6), 846–854. https://doi.org/10.1177/2050640618766933
Chiarentin, L., Gonçalves, C., Augusto, C., Miranda, M., Cardoso, C., & Vitorino, C. (2023). Drilling into "Quality by Design" approach for analytical methods. Critical Reviews in Analytical Chemistry, 54(8), 3478-3519. https://doi.org/10.1080/10408347.2023.2253321
Cui, Z., & Geng, L. (2021). Bosentan-sildenafil combination in the treatment of patients with severe pulmonary hypertension, and its effect on cardiac function. Tropical Journal of Pharmaceutical Research, 20(12), 2619-2624. http://dx.doi.org/10.4314/tjpr.v20i12.23
Dural, E. (2020). Investigation of the presence of sildenafil in herbal dietary supplements by validated HPLC method. Turkish Journal of Pharmaceutical Sciences, 17(1), 56-62. https://doi.org/10.4274/tjps.galenos.2018.91249
Gaurkhede, R. M., & Chandewar, A. V. (2017). Stability indicating RP-HPLC method for Bosentan in tablet dosage form. International Journal of Biological and Advanced Research, 8(10), 388-392. https://doi.org/10.7439/ijbar.v8i10.4456
Hashmi, S. A., & Alegete, P. (2024). QbD green analytical procedure for the quantification of tolvaptan by utilizing a stability-indicating UHPLC method. BMC Chemistry, 18(1). https://doi.org/10.1186/s13065-024-01214-2
ICH Harmonised Tripartite Guideline. (2005). Validation of analytical procedures: text and methodology. Q2 (R1), 1(20), 05. Available at: https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf
Jawed, S., & Satish Cs (2023). Exploration of polymethacrylate and Hypromellose for the development of a non-sulfhydryl ACE inhibitor mucoadhesive system using Box-Behnken design: In-vitro and ex-vivo evaluation. Drug Development and Industrial Pharmacy, 49(1), 115–128. https://doi.org/10.1080/03639045.2022.2111234
Lajoie, A. C., Bonnet, S., & Provencher, S. (2017). Combination therapy in pulmonary arterial hypertension: Recent accomplishments and future challenges. Pulmonary Circulation, 7(2), 312-325. https://doi.org/10.1177/2045893217710639
Liu, W., Huo, Q., Wang, Y., Yu, N., & Shi, R. (2018). Investigation of the sustained-release mechanism of hydroxypropyl methyl cellulose skeleton type Acipimox tablets. Open Chemistry, 16(1), 333–339. https://doi.org/10.1515/chem-2018-0036
Martindale. (2024). The complete drug reference (41st ed.). Pharmaceutical Press. https://www.sigmaaldrich.com/IN/en/product/sigma/m5816?utm_source=google&utm_medium=cpc&utm_campaign=15000381723&utm_content=129438260635&gad_source=1&gclid=CjwKCAiAkc28BhB0EiwAM001Tbf1mEAF-MMJyB8NXrRo5FWCVRD1J3xI-TfqH8SMW0vaG4HQ8WatERoCDCcQAvD_BwE
Masarweh, O. M., & Bhardwaj, A. (2024). Bosentan. In Treasure Island (Internet). Stat Pearls Publishing. https://www.ncbi.nlm.nih.gov/sites/books/NBK542293/
Naeije, R., Richter, M. J., & Rubin, L. J. (2022). The physiological basis of pulmonary arterial hypertension. European Respiratory Journal, 59(6). https://doi.org/10.1183/13993003.02334-2021
Nahar, S., Kanda, S., Chatha, U., Odoma, V. A., Pitliya, A., AlEdani, E. M., ... & Yu, A. K. (2023). Current status of endothelin receptor antagonists in pulmonary arterial hypertension: a combined study results and pharmacology-based review. Cureus, 15(7). https://doi.org/10.7759/cureus.42748
Özyılmaz, E. D., & Comoglu, T. (2022). Development of pediatric orally disintegrating mini-tablets containing atomoxetine hydrochloride-β-cyclodextrin inclusion complex using experimental design. Drug Development and Industrial Pharmacy, 48(11), 667–681. https://doi.org/10.1080/03639045.2022.2154787
Panda, S. S., & Bera, R. K. V. V. (2024). Development and validation of a systematized liquid chromatographic method for estimation of roflumilast in tablets and in the presence of its degradation products. International Journal of Pharmaceutical Sciences and Nanotechnology, 17(3), 7375–7385. https://doi.org/10.37285/ijpsn.2024.17.3.7
Panda, S. S., Bera, V. V., & Sahu, B. (2018). Quality risk management (QRM) supported systematic development and validation of an UFLC method for determination of a novel anti-PAH agent in pharmaceuticals. World Journal of Pharmaceutical Research, 7(9), 360-375. Available at: https://wjpr.net/public/abstract_show/10199
Park, G., Kim, M. K., Go, S. H., Choi, M., & Jang, Y. P. (2022). Analytical quality by design (AQbD) approach to the development of analytical procedures for medicinal plants. Plants (Basel), 11(21). https://doi.org/10.3390/plants11212960
Pinto, M. A., Nicorena, K. F., Machado, M. M., Oliveira, L. F., Paim, C. S., Silva, F. E., & Malesuik, M. D. (2022). Tadalafil and sildenafil illicit association: Stability-indicating HPLC method, photodegradation kinetics, and toxicological studies. Brazilian Journal of Pharmaceutical Sciences, 58. https://doi.org/10.1590/s2175-97902022e19491
Politis, S. N., Colombo, P., Colombo, G., & Rekkas, D. M. (2017). Design of experiments (DoE) in pharmaceutical development. Drug Development and Industrial Pharmacy, 43(6), 889-901. https://doi.org/10.1080/03639045.2017.1291672
Sarangi, D. K., Patro, C. S., Patra, C. N., Pattnaik, G., & Panda, J. (2023). Basic formulation semblance and contemporary approach of mini tablets. International Journal of Pharmaceutical Sciences and Nanotechnology, 16(1), 6325-6336. https://doi.org/10.37285/ijpsn.2023.16.1.6
Sarangi, D. K., Patro, C. S., Patra, C. N., Sahoo, N. K., Das, N. R., Kaur, K., & Gupta, J. (2024). In vivo assessment, formulation, characterization, and enhancing pharmacotherapy of encapsulated mini tablets for immediate release sildenafil citrate and sustained release bosentan. Results in Chemistry, 9. https://doi.org/10.1016/j.rechem.2024.101652
Shahul, H. M., Jat, R. K., & Indulatha, V. N. (2017). Method development and its validation for quantitative determination of bosentan in tablet dosage form by RP-HPLC. Journal of Drug Delivery and Therapeutics, 7(2), 85-95. https://doi.org/10.22270/jddt.v7i2.1409
Shih, C. Y., Chen, C. Y., Lin, H. T., Liao, Y. J., & Liang, Y. J. (2023). Oral bioavailability and pharmacokinetics of sildenafil orally disintegrating tablets under various gastric pH levels following administration of omeprazole in rats. Life (Basel), 13(11). https://doi.org/10.3390/life13112126
Simeoni, P., Deissler, M., Bienert, R., Gritsch, M., Nerkamp, J., Kirsch, S., Roesli, C., Pohl, T., Anderka, O., & Gellermann, G. (2023). Using enhanced development tools offered by analytical Quality by Design to support switching of a quality control method. Biotechnology and Bioengineering, 120(11), 3299-3310. https://doi.org/10.1002/bit.28517
Sirhan, A., AlRashdan, Y., Abbasi, N. U., Mostafa, A., Abudayeh, Z., Talhouni, A., & Al-Ebini, Y. (2023). Optimization and validation of hplc-uv method for the determination of vardenafil, sildenafil, and tadalafil in honey-mixed herbal sachets using a design of experiment. Jordan Journal of Pharmaceutical Sciences, 16(1), 148–162. https://doi.org/10.35516/jjps.v16i1.1075
Smerikarova, M., Bozhanov, S., & Maslarska, V. (2021). HPLC determination of sildenafil in tablets. International Journal of Applied Pharmaceutics, 13(1), 253-256. https://doi.org/10.22159/ijap.2021v13i1.39719
Swain, S., Parhi, R., Jena, B. R., & Babu, S. M. (2019). Quality by Design: Concept to applications. Current Drug Discovery Technologies, 16(3), 240-250. https://doi.org/10.2174/1570163815666180308142016
Totea, A. M., Dorin, I., Laity, P. R., Sabin, J., Conway, B. R., Waters, L., & Asare-Addo, K. (2020). A molecular understanding of magnesium aluminium silicate–drug, drug–polymer, magnesium aluminium silicate–polymer nanocomposite complex interactions in modulating drug release: Towards zero order release. European Journal of Pharmaceutics and Biopharmaceutics, 154, 270-282.https://doi.org/10.1016/j.ejpb.2020.07.027
Tzimou, K., Catalán-Tatjer, D., Nielsen, L. K., & Lavado-García, J. (2024). Unlocking DOE potential by selecting the most appropriate design for rAAV optimization. Molecular Therapy Methods & Clinical Development, 32(4). https://doi.org/10.1016/j.omtm.2024.101329
Usta, D. Y., Timur, B., & Teksin, Z. S. (2022). Formulation development, optimization by Box-Behnken design, characterization, in vitro, ex-vivo, and in vivo evaluation of bosentan-loaded self-nanoemulsifying drug delivery system: A novel alternative dosage form for pulmonary arterial hypertension treatment. European Journal of Pharmaceutical Sciences, 174. https://doi.org/10.1016/j.ejps.2022.106159
Volta E Sousa, L., Gonçalves, R., Menezes, J. C., & Ramos, A. (2021). Analytical method lifecycle management in the pharmaceutical industry: A review. AAPS Pharm Sci Tech, 22(3). https://doi.org/10.1208/s12249-021-01960-9
Yaman, M. E., Atila, A., & Kadıoğlu, Y. (2022). Stability indicating RP-HPLC method development and validation for bosentan in pharmaceutical formulations. Chemistry, 9(2), 505 – 512. https://doi.org/10.18596/jotcsa.956110
Zagalo, D. M., Silva, B. M. A., Silva, C., Simões, S., & Sousa, J. J. (2022). A quality by design (QbD) approach in pharmaceutical development of lipid-based nanosystems: A systematic review. Journal of Drug Delivery Science and Technology, 70, https://doi.org/10.1016/j.jddst.2022.103207
Ala'Y, S., AlRashdan, Y., Abbasi, N. U., Mostafa, A., Abudayeh, Z., Talhouni, A., & Al-Ebini, Y. (2023). Optimization and Validation of HPLC-UV Method for the Determination of Vardenafil, Sildenafil, and Tadalafil in Honey-Mixed Herbal Sachets Using a Design of Experiment. Jordan Journal of Pharmaceutical Sciences, 16(1), 148-162. https://doi.org/10.35516/jjps.v16i1.1075
Anandakumar, K., Jambulingam, M., Rmaesh, J., Subarla, S. J., Sangeetha, P., & Raja, M. (2018). Development and validation of RP-HPLC method for the dissolution study of bosentan in bulk and in pharmaceutical dosage form. Current Journal of Applied Science and Technology, 18(2), 97-110. https://doi.org/10.14456/cast.2018.5
Berger, R. M., Gehin, M., Beghetti, M., Ivy, D., Kusic‐Pajic, A., Cornelisse, P., ... & FUTURE‐3 investigators. (2017). A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE‐3. British Journal of Clinical Pharmacology, 83(8), 1734-1744. https://doi.org/10.1111/bcp.13267
Bhogal, S., Khraisha, O., Al Madani, A., Treece, J., Baumrucker, S. J., & Paul, T. K. (2019). Sildenafil for pulmonary arterial hypertension. American Journal of Therapeutics, 26(5), 520-526. https://doi.org/10.1097/MJT.0000000000000766
Carbone, F., & Tack, J. (2018). The effect of sildenafil on gastric motility and satiation in healthy controls. United European Gastroenterology Journal, 6(6), 846–854. https://doi.org/10.1177/2050640618766933
Chiarentin, L., Gonçalves, C., Augusto, C., Miranda, M., Cardoso, C., & Vitorino, C. (2023). Drilling into "Quality by Design" approach for analytical methods. Critical Reviews in Analytical Chemistry, 54(8), 3478-3519. https://doi.org/10.1080/10408347.2023.2253321
Cui, Z., & Geng, L. (2021). Bosentan-sildenafil combination in the treatment of patients with severe pulmonary hypertension, and its effect on cardiac function. Tropical Journal of Pharmaceutical Research, 20(12), 2619-2624. http://dx.doi.org/10.4314/tjpr.v20i12.23
Dural, E. (2020). Investigation of the presence of sildenafil in herbal dietary supplements by validated HPLC method. Turkish Journal of Pharmaceutical Sciences, 17(1), 56-62. https://doi.org/10.4274/tjps.galenos.2018.91249
Gaurkhede, R. M., & Chandewar, A. V. (2017). Stability indicating RP-HPLC method for Bosentan in tablet dosage form. International Journal of Biological and Advanced Research, 8(10), 388-392. https://doi.org/10.7439/ijbar.v8i10.4456
Hashmi, S. A., & Alegete, P. (2024). QbD green analytical procedure for the quantification of tolvaptan by utilizing a stability-indicating UHPLC method. BMC Chemistry, 18(1). https://doi.org/10.1186/s13065-024-01214-2
ICH Harmonised Tripartite Guideline. (2005). Validation of analytical procedures: text and methodology. Q2 (R1), 1(20), 05. Available at: https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf
Jawed, S., & Satish Cs (2023). Exploration of polymethacrylate and Hypromellose for the development of a non-sulfhydryl ACE inhibitor mucoadhesive system using Box-Behnken design: In-vitro and ex-vivo evaluation. Drug Development and Industrial Pharmacy, 49(1), 115–128. https://doi.org/10.1080/03639045.2022.2111234
Lajoie, A. C., Bonnet, S., & Provencher, S. (2017). Combination therapy in pulmonary arterial hypertension: Recent accomplishments and future challenges. Pulmonary Circulation, 7(2), 312-325. https://doi.org/10.1177/2045893217710639
Liu, W., Huo, Q., Wang, Y., Yu, N., & Shi, R. (2018). Investigation of the sustained-release mechanism of hydroxypropyl methyl cellulose skeleton type Acipimox tablets. Open Chemistry, 16(1), 333–339. https://doi.org/10.1515/chem-2018-0036
Martindale. (2024). The complete drug reference (41st ed.). Pharmaceutical Press. https://www.sigmaaldrich.com/IN/en/product/sigma/m5816?utm_source=google&utm_medium=cpc&utm_campaign=15000381723&utm_content=129438260635&gad_source=1&gclid=CjwKCAiAkc28BhB0EiwAM001Tbf1mEAF-MMJyB8NXrRo5FWCVRD1J3xI-TfqH8SMW0vaG4HQ8WatERoCDCcQAvD_BwE
Masarweh, O. M., & Bhardwaj, A. (2024). Bosentan. In Treasure Island (Internet). Stat Pearls Publishing. https://www.ncbi.nlm.nih.gov/sites/books/NBK542293/
Naeije, R., Richter, M. J., & Rubin, L. J. (2022). The physiological basis of pulmonary arterial hypertension. European Respiratory Journal, 59(6). https://doi.org/10.1183/13993003.02334-2021
Nahar, S., Kanda, S., Chatha, U., Odoma, V. A., Pitliya, A., AlEdani, E. M., ... & Yu, A. K. (2023). Current status of endothelin receptor antagonists in pulmonary arterial hypertension: a combined study results and pharmacology-based review. Cureus, 15(7). https://doi.org/10.7759/cureus.42748
Özyılmaz, E. D., & Comoglu, T. (2022). Development of pediatric orally disintegrating mini-tablets containing atomoxetine hydrochloride-β-cyclodextrin inclusion complex using experimental design. Drug Development and Industrial Pharmacy, 48(11), 667–681. https://doi.org/10.1080/03639045.2022.2154787
Panda, S. S., & Bera, R. K. V. V. (2024). Development and validation of a systematized liquid chromatographic method for estimation of roflumilast in tablets and in the presence of its degradation products. International Journal of Pharmaceutical Sciences and Nanotechnology, 17(3), 7375–7385. https://doi.org/10.37285/ijpsn.2024.17.3.7
Panda, S. S., Bera, V. V., & Sahu, B. (2018). Quality risk management (QRM) supported systematic development and validation of an UFLC method for determination of a novel anti-PAH agent in pharmaceuticals. World Journal of Pharmaceutical Research, 7(9), 360-375. Available at: https://wjpr.net/public/abstract_show/10199
Park, G., Kim, M. K., Go, S. H., Choi, M., & Jang, Y. P. (2022). Analytical quality by design (AQbD) approach to the development of analytical procedures for medicinal plants. Plants (Basel), 11(21). https://doi.org/10.3390/plants11212960
Pinto, M. A., Nicorena, K. F., Machado, M. M., Oliveira, L. F., Paim, C. S., Silva, F. E., & Malesuik, M. D. (2022). Tadalafil and sildenafil illicit association: Stability-indicating HPLC method, photodegradation kinetics, and toxicological studies. Brazilian Journal of Pharmaceutical Sciences, 58. https://doi.org/10.1590/s2175-97902022e19491
Politis, S. N., Colombo, P., Colombo, G., & Rekkas, D. M. (2017). Design of experiments (DoE) in pharmaceutical development. Drug Development and Industrial Pharmacy, 43(6), 889-901. https://doi.org/10.1080/03639045.2017.1291672
Sarangi, D. K., Patro, C. S., Patra, C. N., Pattnaik, G., & Panda, J. (2023). Basic formulation semblance and contemporary approach of mini tablets. International Journal of Pharmaceutical Sciences and Nanotechnology, 16(1), 6325-6336. https://doi.org/10.37285/ijpsn.2023.16.1.6
Sarangi, D. K., Patro, C. S., Patra, C. N., Sahoo, N. K., Das, N. R., Kaur, K., & Gupta, J. (2024). In vivo assessment, formulation, characterization, and enhancing pharmacotherapy of encapsulated mini tablets for immediate release sildenafil citrate and sustained release bosentan. Results in Chemistry, 9. https://doi.org/10.1016/j.rechem.2024.101652
Shahul, H. M., Jat, R. K., & Indulatha, V. N. (2017). Method development and its validation for quantitative determination of bosentan in tablet dosage form by RP-HPLC. Journal of Drug Delivery and Therapeutics, 7(2), 85-95. https://doi.org/10.22270/jddt.v7i2.1409
Shih, C. Y., Chen, C. Y., Lin, H. T., Liao, Y. J., & Liang, Y. J. (2023). Oral bioavailability and pharmacokinetics of sildenafil orally disintegrating tablets under various gastric pH levels following administration of omeprazole in rats. Life (Basel), 13(11). https://doi.org/10.3390/life13112126
Simeoni, P., Deissler, M., Bienert, R., Gritsch, M., Nerkamp, J., Kirsch, S., Roesli, C., Pohl, T., Anderka, O., & Gellermann, G. (2023). Using enhanced development tools offered by analytical Quality by Design to support switching of a quality control method. Biotechnology and Bioengineering, 120(11), 3299-3310. https://doi.org/10.1002/bit.28517
Sirhan, A., AlRashdan, Y., Abbasi, N. U., Mostafa, A., Abudayeh, Z., Talhouni, A., & Al-Ebini, Y. (2023). Optimization and validation of hplc-uv method for the determination of vardenafil, sildenafil, and tadalafil in honey-mixed herbal sachets using a design of experiment. Jordan Journal of Pharmaceutical Sciences, 16(1), 148–162. https://doi.org/10.35516/jjps.v16i1.1075
Smerikarova, M., Bozhanov, S., & Maslarska, V. (2021). HPLC determination of sildenafil in tablets. International Journal of Applied Pharmaceutics, 13(1), 253-256. https://doi.org/10.22159/ijap.2021v13i1.39719
Swain, S., Parhi, R., Jena, B. R., & Babu, S. M. (2019). Quality by Design: Concept to applications. Current Drug Discovery Technologies, 16(3), 240-250. https://doi.org/10.2174/1570163815666180308142016
Totea, A. M., Dorin, I., Laity, P. R., Sabin, J., Conway, B. R., Waters, L., & Asare-Addo, K. (2020). A molecular understanding of magnesium aluminium silicate–drug, drug–polymer, magnesium aluminium silicate–polymer nanocomposite complex interactions in modulating drug release: Towards zero order release. European Journal of Pharmaceutics and Biopharmaceutics, 154, 270-282.https://doi.org/10.1016/j.ejpb.2020.07.027
Tzimou, K., Catalán-Tatjer, D., Nielsen, L. K., & Lavado-García, J. (2024). Unlocking DOE potential by selecting the most appropriate design for rAAV optimization. Molecular Therapy Methods & Clinical Development, 32(4). https://doi.org/10.1016/j.omtm.2024.101329
Usta, D. Y., Timur, B., & Teksin, Z. S. (2022). Formulation development, optimization by Box-Behnken design, characterization, in vitro, ex-vivo, and in vivo evaluation of bosentan-loaded self-nanoemulsifying drug delivery system: A novel alternative dosage form for pulmonary arterial hypertension treatment. European Journal of Pharmaceutical Sciences, 174. https://doi.org/10.1016/j.ejps.2022.106159
Volta E Sousa, L., Gonçalves, R., Menezes, J. C., & Ramos, A. (2021). Analytical method lifecycle management in the pharmaceutical industry: A review. AAPS Pharm Sci Tech, 22(3). https://doi.org/10.1208/s12249-021-01960-9
Yaman, M. E., Atila, A., & Kadıoğlu, Y. (2022). Stability indicating RP-HPLC method development and validation for bosentan in pharmaceutical formulations. Chemistry, 9(2), 505 – 512. https://doi.org/10.18596/jotcsa.956110
Zagalo, D. M., Silva, B. M. A., Silva, C., Simões, S., & Sousa, J. J. (2022). A quality by design (QbD) approach in pharmaceutical development of lipid-based nanosystems: A systematic review. Journal of Drug Delivery Science and Technology, 70, https://doi.org/10.1016/j.jddst.2022.103207
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Sarangi, D., Patro, C., Niranjan Patro, C., Panda, S., & Sahoo, N. (2025). Quality By Design Approach for Developing a Validated Liquid Chromatographic Method for Simultaneous Quantification of Bosentan and Sildenafil Citrate with Applications in Dissolution and Robustness Studies. International Journal of Advancement in Life Sciences Research, 8(1), 108-119. https://doi.org/https://doi.org/10.31632/ijalsr.2025.v08i01.010
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