Meloxicam Nanocrystals with HPMC and Decyl Glucoside for Enhanced Solubility
DOI:
https://doi.org/10.36733/medicamento.v12i1.12523Keywords:
meloxicam, nanocrystals, solubility, stabilizersAbstract
Background: Low solubility in water is a major obstacle for Meloxicam (MLX) and has implications for its limited bioavailability. Nanocrystallization techniques show potential for improving drug solubility, but nanoparticles tend to aggregate, suggesting the use of a combination of Hydroxypropyl Methylcellulose (HPMC) and Decyl Glucoside (DG) as stabilizers to overcome this problem.
Objective: This study aims to develop and characterize meloxicam nanocrystals (MLX-NC) with a combination of HPMC and DG in an effort to improve solubility. MLX-NC was synthesized using ultrasonication and dried by lyophilization.
Methods: The resulting formulation exhibited excellent physical stability over 28 days, as evidenced by consistent particle size (~11 nm) and polydispersity index (<0.3). Physical evaluation and characterization were performed, including particle size analysis (DLS), zeta potential, particle morphology (SEM), thermal analysis (DSC), X-ray diffraction (XRD), and saturated solubility testing.
Results: The MLX-NC formulation showed a more than 200-fold increase in solubility compared to pure MLX, from 0.005 mg/mL to 1.064 mg/mL. XRD and DSC analyses confirmed that the nanocrystallization process converted the crystalline phase of MLX into an amorphous phase. These results indicate that induced amorphization can significantly improve solubility.
Conclusion: The solubility of MLX can be significantly improved using ultrasonication combined with HPMC and DG. This approach has the potential to overcome the solubility limitations of BCS Class II drugs.
References
1. Lakshmi D, Geetha V, Murali V. From prescription to pollution: The ecological consequences of NSAIDs in aquatic ecosystems. Toxicol Reports. 2024;13:101775. doi:10.1016/j.toxrep.2024.101775
2. Zhong Y, Zhou Y, Ding R, Zou L, Zhang H, Wei X, He D. Intra-articular treatment of temporomandibular joint osteoarthritis by injecting actively-loaded meloxicam liposomes with dual-functions of anti-inflammation and lubrication. Mater Today Bio. 2023;19:100573. doi:10.1016/j.mtbio.2023.100573
3. Tinjacá DA, Martínez F, Almanza O, Jouyban A, Acree WE. Solubility of Meloxicam in Aqueous Binary Mixtures of Formamide, N-Methylformamide and N,n-Dimethylformamide: Determination, Correlation, Thermodynamics and Preferential Solvation. J Chem Thermodyn. 2021;154:106332. doi:10.1016/j.jct.2020.106332
4. Hanna PA, Al-Abbadi H, Hashem MA, Mostafa AE, Mahmoud YK, Ahmed MF. Development of a novel intramuscular liposomal injection for advanced meloxicam delivery: Preparation, characterization, in vivo pharmacokinetics, pharmacodynamics, and pain assessment in an orthopedic pain model. Int J Pharm X. 2024;8. doi:10.1016/j.ijpx.2024.100284
5. Alatas F, Stiawan D, Al-Hakim NA. Solubility and Scale-Up Potency of Norfloxacin-Urea Co-Crystal Prepared by Ultrasound-Assisted Slurry Co-Crystallization Method. Borneo J Pharm. 2023;6(2):158-167. doi:10.33084/bjop.v6i2.4173
6. Li S, Kou L, Qin Y, Wang Y, Sun Y, Liu X. A ternary system of meloxicam with matching hydrophilic polymer and cyclodextrin for improved stability in liquid preprations. RSC Adv. 2024;14(30):21260-21268. doi:10.1039/d4ra02811b
7. Annisa R, Hendradi E, Melani D. Pengembangan Sistem Nanostructured Lipid Carriers (NLC) Meloxicam dengan Lipid Monostearin dan Miglyol 808 Menggunakan Metode Emulsifikasi. J Trop Pharm Chem. 2016;3(3):156-169. doi:10.25026/jtpc.v3i3.102
8. Ratan R. Improving Oral Bioavailability of Meloxicam: Development and Characterization of Solid Dispersions. J Biomed Pharm Res. 2024;13(1):84-99. doi:10.32553/jbpr.v13i1.1081
9. Bartos C, Motzwickler-Németh A, Kovács D, Burián K, Ambrus R. Study on the Scale-Up Possibility of a Combined Wet Grinding Technique Intended for Oral Administration of Meloxicam Nanosuspension. Pharmaceutics. 2024;16(12):1512. doi:10.3390/pharmaceutics16121512
10. Ambrus R, Alshweiat A, Szabó-Révész P, Bartos C, Csóka I. Smartcrystals for Efficient Dissolution of Poorly Water-Soluble Meloxicam. Pharmaceutics. 2022;14(2). doi:10.3390/pharmaceutics14020245
11. Tabatabaei MS, Tabatabaei FAS, Moghimi HR. Drug self-delivery systems: A comprehensive review on small molecule nanodrugs. Bioimpacts. 2024;15. doi:10.34172/bi.30161
12. Sutarna TH, Alatas F, Purnamasari N, Alifah M. Utilization rhizome of jahe merah ( Zingiber officinale Roscoe ) as a bioreductant in the manufacture of gold nanoparticles with addition of polyvinylpyrrolidone 90 ( PVP K90 ) as a stabilizer. 2023;8(3):1367-1378. doi:10.30604/jika.v8i3.1964
13. Mohammad IS, Hu H, Yin L, He W. Drug nanocrystals: Fabrication methods and promising therapeutic applications. Int J Pharm. 2019;562:187-202. doi:10.1016/j.ijpharm.2019.02.045
14. Joshi K, Chandra A, Jain K, Talegaonkar S. Nanocrystalization: An Emerging Technology to Enhance the Bioavailability of Poorly Soluble Drugs. Pharm Nanotechnol. 2019;7(4):259-278. doi:10.2174/2211738507666190405182524
15. Vadher B, Shah S, Dudhat K, Dhaval M, Sing S, Prajapati BG. Ketoconazole Nanocrystals Fortified Gel for Improved Transdermal Applications. Nanofabrication. 2024;9:1-15. doi:10.37819/nanofab.009.1885
16. Liu Y fen, Li Y, Xu P, Shen Y, Tang B, Wang Q. Development of Abiraterone Acetate Nanocrystal Tablets to Enhance Oral Bioavailability: Formulation Optimization, Characterization, In Vitro Dissolution and Pharmacokinetic Evaluation. Pharmaceutics. 2022;14(6):11-34. doi:10.3390/pharmaceutics14061134
17. Macedo LOD, Masiero JF, Bou-Chacra N. Drug Nanocrystals in Oral Absorption: Factors That Influence Pharmacokinetics. Pharmaceutics. 2024;16. doi:10.3390/pharmaceutics16091141
18. Mohd NK, Khalik W, Azmi AA. Synthesis and Characterization of Silica-Silver Core-Shell Nanoparticles. Malaysian J Anal Sci. 2019;23(2):290-299. doi:https://doi.org/10.17576/mjas-2019-2302-13
19. Nurmayansih A, Hariani P, Said M. Synthesis NiFe2O4 Nanoparticles by co-Precipitation Method for Degradation of Congo Red Dye. Indones J Fundam Appl Chem. 2020;6(3):115-121. doi:10.24845/ijfac.v6.i3.115
20. Yang DX, Wang L, Zhang L, Wang M, Li D. Construction, characterization and bioactivity evaluation of curcumin nanocrystals with extremely high solubility and dispersion prepared by ultrasound-assisted method. Ultrason Sonochem. 2024;104. doi:https://doi.org/10.1016/j.ultsonch.2024.106835
21. Shi S, Mandal P, Chen T. Mechanical Properties and Tribological Behavior of MoS2-Enhanced Cellulose-Based Biocomposites for Food Packaging. Polymers (Basel). 2021;13(11):18-38. doi:10.3390/polym13111838
22. Kumar M, Shanthi N, Mahato AK, Soni S, Rajnikanth P. Preparation of luliconazole nanocrystals loaded hydrogel for improvement of dissolution and antifungal activity. Heliyon. 2019;5(5). doi:10.1016/j.heliyon.2019.e01688
23. Bhakay A, Rahman M, Davé R, Bilgili E. Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation–Processing Aspects and Challenges. Pharmaceutics. 2018;10(86). doi:10.3390/pharmaceutics10030086
24. Ahire ED, Thakkar S, Darshanwad M, Misra M. Parenteral nanosuspensions: a brief review from solubility enhancement to more novel and specific applications. Acta Pharm Sin B. 2018;8(5):733-755. doi:10.1016/j.apsb.2018.07.011
25. Chung KH, Park H, Jeon K, Park Y, Jung S. Microporous Zeolites as Catalysts for the Preparation of Decyl Glucoside from Glucose with 1-Decanol by Direct Glucosidation. Catalysts. 2016;6(12):216. doi:10.3390/catal6120216
26. Cortés H, Hernández-Parra H, Bernal-Chávez SA, Prado-Audelo MLD, Magaña J, Leyva-Gómez G. Non-Ionic Surfactants for Stabilization of Polymeric Nanoparticles for Biomedical Uses. Materials (Basel). 2021;14:3197. doi:10.3390/ma14123197
27. Lu L, Xu Q, Wang J, Wu S, Luo Z, Lu W. Drug Nanocrystals for Active Tumor-Targeted Drug Delivery. Pharmaceutics. 2022;14. doi:10.3390/pharmaceutics14040797
28. Köpke D, Pyo S. Symurban Nanocrystals for Advanced Anti-Pollution Skincare. Cosmetics. 2020;7(1). doi:10.3390/COSMETICS7010017
29. Yu Q, Wu X, Zhu Q, Chen Z, Li Y, Lu Y. Enhanced transdermal delivery of meloxicam by nanocrystals: Preparation, in vitro and in vivo evaluation. Asian J Pharm Sci. 2017;13(6):518-526. doi:10.1016/j.ajps.2017.10.004
30. Iurian S, Tomuțǎ I, Rus L, Achim M, Leucuta S. Optimization of the sonication process for meloxicam nanocrystals preparation. Clujul Med. 2015;88:366-372. doi:10.15386/cjmed-445
31. Ubgade S, Bapat A, Kilor V. Effect of various stabilizers on the stability of lansoprazole nanosuspension prepared using high shear homogenization: Preliminary investigation. J Appl Pharm Sci. 2021;11(9):085-092. doi:10.7324/JAPS.2021.110910
32. Tang S, Chen Z, Chen F, Wei Q, Chen X, Jiang C. Extraction and Surface Functionalization of Cellulose Nanocrystals from Sugarcane Bagasse. Molecules. 2023;28(14). doi:10.3390/molecules28145444
33. Wang Y, Wang S, Xu Y, Wang P, Liu M, Jin X. Etoposide amorphous nanopowder for improved oral bioavailability: Formulation development, optimization, in vitro and in vivo evaluation. Int J Nanomedicine. 2020;15:7601-7613. doi:10.2147/IJN.S265817
34. Party P, Bartos C, Farkas Á, Szabó-Révész P, Ambrus R. Formulation and In Vitro and In Silico Characterization of “Nano-in-Micro” Dry Powder Inhalers Containing Meloxicam. Pharmaceutics. 2021;13. doi:10.3390/pharmaceutics13020211
35. Alatas F, Ratih H, Sutarna TH, Fauzi ML. The Binary and Ternary Amorphous Systems of Candesartan Cilexetil Preparation To Improve Its Solubility. Int J Appl Pharm. 2024;16(5):367-372. doi:10.22159/IJAP.2024V16I5.51141
36. Kemenkes RI. Farmakope Indonesia-Edisi VI. Dirjen Kefarmasian dan Alat Kesehatan, Kementerian Kesehatan RI.; 2020.
37. Sheskey PJ, Cook WG, Cable CG. Handbook of Pharmaceutical Excipients, 8th Edition. London : Pharmaceutical Press ; Washington, DC : APhA; 2017. doi:10.1016/B978-0-12-820007-0.00032-5
38. Nikolaychuk PA. UV-Spectrophotometric Determination of the Active Pharmaceutical Ingredients Meloxicam and Nimesulide in Cleaning Validation Samples with Sodium Carbonate. J. 2023;6(2):248-266. doi:10.3390/j6020019
39. Jiao H, Mao Q, Razzaq N, Ankri R, Cui J. Ultrasound technology assisted colloidal nanocrystal synthesis and biomedical applications. Ultrason Sonochem. 2024;103:106798. doi:10.1016/j.ultsonch.2024.106798
40. Ghasemian E, Rezaeian B, Alaei S, Vatanara A, Ramezani V. Optimization of Cefixime Nanosuspension to Improve Drug Dissolution. Pharm Sci. 2015;21:136-144. doi:10.15171/PS.2015.28
41. Touqeer SI, Jahan N, Abbas N, Ali A. Formulation and Process Optimization of Rauvolfia serpentina Nanosuspension by HPMC and In Vitro Evaluation of ACE Inhibitory Potential. J Funct Biomater. 2022;13. doi:10.3390/jfb13040268
42. Pinar SG, Oktay AN, Karakucuk A, Çelebi N. Formulation Strategies of Nanosuspensions for Various Administration Routes. Pharmaceutics. 2023;15(5):1520. doi:10.3390/pharmaceutics15051520
43. Jacob S, Nair AB, Shah J. Emerging Role of Nanosuspensions in Drug Delivery Systems. Biomater Res. 2020;24(1). doi:10.1186/s40824-020-0184-8
44. Elshafeey A, El-Dahmy RM. Formulation and Development of Oral Fast-Dissolving Films Loaded with Nanosuspension to Augment Paroxetine Bioavailability: In Vitro Characterization, Ex Vivo Permeation, and Pharmacokinetic Evaluation in Healthy Human Volunteers. Pharmaceutics. 2021;13. doi:10.3390/pharmaceutics13111869
45. Awan AM, Farid A, Shah S, Khan D, ur Rehman F, Dar MJ, Iftikhar T, Ghazanfar S, Galanakis CM, Alamri A, Asdaq SM, Shah K. Nanocrytals-Mediated Oral Drug Delivery: Enhanced Bioavailability of Amiodarone. Pharmaceutics. 2022;14. doi:10.3390/pharmaceutics14061300
46. Moreira FF, Ziebarth J, Babinski TP, Mainardes R. Development and Characterization of Zein/Eudragit Composite Nanoparticles for Insulin Intranasal Delivery. ACS Omega. 2025;10:21236-21249. doi:10.1021/acsomega.4c10474
47. Jeyaraj M, Gurunathan S, Qasim M, Kang M, Kim JH. A Comprehensive Review on the Synthesis, Characterization, and Biomedical Application of Platinum Nanoparticles. Nanomaterials. 2019;9. doi:10.3390/nano9121719
48. Qureshi S, Nizamuddin S, Xu J, Vancov T, Chen C. Cellulose nanocrystals from agriculture and forestry biomass: synthesis methods, characterization and industrial applications. Environ Sci Pollut Res Int. 2024;31:58745-58778. doi:10.1007/s11356-024-35127-3
49. Elmowafy M, Shalaby K, Al-Sanea MM, Hendawy O, Salama A, Ibrahim MF. Influence of Stabilizer on the Development of Luteolin Nanosuspension for Cutaneous Delivery: An In Vitro and In Vivo Evaluation. Pharmaceutics. 2021;13(11). doi:10.3390/pharmaceutics13111812
50. Chantaburanan T, Teeranachaideekul V, Jintapattanakit A, Chantasart D, Junyaprasert V. Enhanced stability and skin permeation of ibuprofen-loaded solid lipid nanoparticles based binary solid lipid matrix: Effect of surfactant and lipid compositions. Int J Pharm X. 2023;6. doi:10.1016/j.ijpx.2023.100205
51. Miocić S, Torić J, Juretić M, Đoković JB, Randjelović D V, Filipović-Grcić J. Characterisation and Stabilisation Mechanisms of Azelaic Acid Nanosuspensions: Insights from a Dual Stabiliser System. Pharmaceutics. 2025;17(4). doi:10.3390/pharmaceutics17040439
52. Nooshkam M, Varidi M, Zareie Z, Alkobeisi F. Behavior of protein-polysaccharide conjugate-stabilized food emulsions under various destabilization conditions. Food Chem X. 2023;18. doi:10.1016/j.fochx.2023.100725
53. Yu Y, Tian Y, Zhang H, Du Y, Song S, Zheng A. The Evaluation of Meloxicam Nanocrystals by Oral Administration With Different Particle Sizes. Molecules. 2022;27(2):421. doi:10.3390/molecules27020421
54. Dinte E, Muntean D, Andrei V, Boșca B, Dudescu C, Barbu-Tudoran L. In Vitro and In Vivo Characterisation of a Mucoadhesive Buccal Film Loaded with Doxycycline Hyclate for Topical Application in Periodontitis. Pharmaceutics. 2023;15(2). doi:10.3390/pharmaceutics15020580
55. Han S, Zhao L, Jiang Q, Lian J. Deformation-induced localized solid-state amorphization in nanocrystalline nickel. Sci Rep. 2012;2. doi:10.1038/srep00493
56. Willmann AC, Berkenfeld K, Faber T, Wachtel H, Boeck G, Wagner K. Itraconazole Nanosuspensions via Dual Centrifugation Media Milling: Impact of Formulation and Process Parameters on Particle Size and Solid-State Conversion as Well as Storage Stability. Pharmaceutics. 2022;14. doi:10.3390/pharmaceutics14081528
57. Budiman A, Ivana H, Huang KA, Huang SA, Nadhira MS, Rusdin A. Biocompatible Natural Polymer-Based Amorphous Solid Dispersion System Improving Drug Physicochemical Properties, Stability, and Efficacy. Polymers (Basel). 2025;17(15). doi:10.3390/polym17152059
58. Shen B de, Shen C ying, Zhu W, Yuan H. The contribution of absorption of integral nanocrystals to enhancement of oral bioavailability of quercetin. Acta Pharm Sin B. 2021;11(4):978-988. doi:10.1016/j.apsb.2021.02.015
59. Kumar S, Raghu S, Demappa T, Sannappa J. Effect of NaBr on the Structural, Thermal and Mechanical Properties of HPMC:NaBr Composite Films. Asian J Chem. 2022;34(2):305-310. doi:10.14233/ajchem.2022.23507
60. Ashfaq R, Tóth N, Kovács A, Berkó S, Katona G, Ambrus R, Polgár T, Szécsényi M, Burián K, Budai-Szűcs M. Hydrogel–Nanolipid Formulations for the Complex Anti-Inflammatory and Antimicrobial Therapy of Periodontitis. Pharmaceutics. 2025;17(5):620. doi:https://doi.org/10.3390/pharmaceutics17050620
61. Nugroho RWN, Tardy B, Eldin SM, Ilyas RA, Mahardika M, Masruchin N. Controlling the critical parameters of ultrasonication to affect the dispersion state, isolation, and chiral nematic assembly of cellulose nanocrystals. Ultrason Sonochem. 2023;99. doi:10.1016/j.ultsonch.2023.106581
62. Maggi L, Friuli V, Cerea B, Bruni G, Berbenni V, Bini M. Physicochemical Characterization of Hydroxyapatite Hybrids with Meloxicam for Dissolution Rate Improvement. Molecules. 2024;29(11). doi:10.3390/molecules29112419
63. Bartos C, Jójárt-Laczkovich O, Katona G, Budai-Szűcs M, Ambrus R, Szabó-Révész P. Optimization of a combined wet milling process in order to produce poly(vinyl alcohol) stabilized nanosuspension. Drug Des Devel Ther. 2018;12:1567-1580. doi:10.2147/DDDT.S159965
64. Li J, Wang Z, Zhang H, Gao J, Zheng A. Progress in the development of stabilization strategies for nanocrystal preparations. Drug Deliv. 2021;28(1):19-36. doi:10.1080/10717544.2020.1856224
65. Tao J, Chow SF, Zheng Y. Application of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticles. Acta Pharm Sin B. 2018;9:4-18. doi:10.1016/j.apsb.2018.11.001
66. Li G, Chen L, Ruan Y, Guo Q, Liao X, Zhang B. Alkyl polyglycoside: a green and efficient surfactant for enhancing heavy oil recovery at high-temperature and high-salinity condition. J Pet Explor Prod Technol. 2019;9(4):1-10. doi:10.1007/s13202-019-0658-1
67. Ghani L, Kim S, Ehsan M, Liu X, Im W, Chae PS. Melamine-cored glucosides for membrane protein solubilization and stabilization: importance of water-mediated intermolecular hydrogen bonding in detergent performance. Chem Sci. 2023;14(45):13014-13024. doi:10.1039/d3sc03543c
68. Gigliobianco MR, Casadidio C, Censi R, Di Martino P. Nanocrystals of poorly soluble drugs: Drug bioavailability and physicochemical stability. Pharmaceutics. 2018;10(3). doi:10.3390/pharmaceutics10030134
69. Uddin A, Halder S, Deb N, Das H, Shuma ML, Hasan I, Shill M, Haider SS. Impact of Methods of Preparation on Mechanical Properties, Dissolution Behavior, and Tableting Characteristics of Ibuprofen-Loaded Amorphous Solid Dispersions. Adv Pharmacol Pharm Sci. 2024;2024. doi:10.1155/2024/2303942
70. Silva JFC, Rosado MTS, Maria T, Silva PSP, Silva M, Eusébio M. Introduction to Pharmaceutical Co-amorphous Systems Using a Green Co-milling Technique. J Chem Educ. 2023;100(4):1627-1632. doi:10.1021/acs.jchemed.3c00036
Downloads
Submitted
Accepted
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Nur Achsan Al-Hakim, Titta Hartyana Sutarna, Hestiary Ratih, Karina Putriani Azzara
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
