PARTIAL AMORPHIZATION OF POORLY-SOLUBLE SIMVASTATIN USP USING MEDIA MILLING IN SYNERGISM WITH SPRAY-DRYING
Objective: The objective of the current study was to explore top down methods of size reduction like high speed homogenisation and media milling in synergism with spray drying in amorphization and solubility enhancement of BCS Class II antilipidemic drug Simvastatin USP.
Methods: Spray-dried micronized simvastatin USP was formulated by homogenisation and media milling of drug suspension in optimized stabilizer solution. Stabilizer combination, duration of homogenisation and ball milling and drug: stabilizer ratio was optimized. The obtained dispersion was transformed into solid powder using spray drying. The obtained Spray-dried micronized Simvastatin USP was evaluated for visual morphology, Infrared spectroscopy, Differential scanning calorimetry, in vitro drug release studies, X-Ray diffractometry, Scanning electron microscopy, contact angle measurement, solubility studies, dispersibility studies and intrinsic dissolution rate testing.
Results: Spray-dried micronized simvastatin USP was found to show amorphization of crystalline Simvastatin USP as confirmed by the absence of drug peak in Differential scanning calorimetry and lowered signal intensity in X-Ray diffraction studies. Spray-dried micronized Simvastatin USP was found to show enhanced drug hydrophilicity and solubility as confirmed by lowering in contact angle and increase in solubility and ease of dispersibility observations. In vitro dissolution testing and intrinsic dissolution rate testing were found to show an increase in drug release from 11% to 79% and 4 mg min-1 cm-2 to 17 mg min-1 cm-2 for drug and Spray-dried micronized Simvastatin USP respectively.
Conclusion: Media milling in synergism with spray-drying was found to be a prospective solubility enhancement technique for poorly-soluble Simvastatin USP.
2. Basavaraj S, Betageri GV. Can formulation and drug delivery reduce attrition during drug discovery and development-review of feasibility, benefits and challenges. Acta Pharm Sin B 2014;4:3-17.
3. Di Costanzo A, Angelico R. Formulation strategies for enhancing the bioavailability of silymarin. Molecules 2019;24:2155.
4. Narayan R, Pednekar A, Bhuyan D, Gowda C, Koteshwara KB, Nayak U. A top down technique to improve the solubility and bioavailability of aceclofenac: in vitro and in vivo studies. Int J Nanomed 2017;12:4921-35.
5. Rein MJ, Renouf M, Cruz Hernandez C, Actis Goretta L, Thakkar SK, Pinto M. Bioavailability of bioactive food compounds: a challenging journey to bioefficacy. Br J Clin Pharmacol 2013;75:588-602.
6. Tsume Y, Mudie DM, Langutt P, Amidon GE, Amidon GL. The biopharmaceutical classification system: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. Eur J Pharm Sci 2014;57:152-63.
7. Sathisaran I, Dalvi S. Engineering cocrystals of poorly-water soluble drugs to enhance dissolution in aqueous medium. Pharmaceutics 2018;10:108.
8. Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci 1997;86:1–12.
9. Brittain HG. Methods for the characterization of polymorphs and solvates. In: Brittain HG. Editor. Polymorphism in Pharmaceutical Solids. New York: Marcel Dekker; 1999. p. 227–78.
10. Mottu F, Laurent A, Rufenacht DA, Doelker E. Organic solvents for pharmaceutical parenterals and embolic liquids: a review of toxicity data. PDA J Pharm Sci Technol 2000;54:456-69.
11. Bhadoriya S, Madoriya N, Shukla K, Parihar MS. Biosurfactants a new pharmaceutical additive for solubility enhancement and pharmaceutical development. Biochem Pharmacol 2013;2:1-5.
12. Savjani K, Gajjar A, Savjani J. Drug solubility: importance and enhancement techniques. International Scholarly Research Network (ISRN) Pharmaceutics; 2012. p. 1-10.
13. Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs. I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm 1995;125:91–7.
14. Jinno J, Kamada N, Miyake M, Yamada K, Mukai T, Odomi M, et al. Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs. J Controlled Release 2006;111:56–64.
15. Kesisoglou F, Panmai S, Wu Y. Nanosizing-oral formulation development and biopharmaceutical evaluation. Adv Drug Delivery Rev 2007;59:631–44.
16. Srivastava V, Mishra G. Dissolution enhancement of a poorly soluble model drugs using different formulation approaches for immediate release solid dosage form. Asian J Pharm Clin Res 2013;7:63-6.
17. Vengala P, Vanamala R. Nanocrystal technology as a tool for improving dissolution of poorly soluble drug, lornoxicam. Int J Appl Pharm 2018;10:162-8.
18. Van Eerdenbrugh B, Van den Mooter G, Augustijns P. Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm 2008;364:64–75.
19. Hu J, Johnston KP, Williams RO. Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs. Drug Dev Ind Pharm 2004;30:233–45.
20. Salazar J, Muller RH, Moschwitzer JP. Combinative particle size reduction technologies for the production of drug nanocrystals. J Pharm 2014;1-14. https://doi.org/10.1155/2014/265754
21. Swain RP, Pendela S, Panda S. Formulation and evaluation of gastro-bilayer floating tablets of simvastatin as immediate release layer and atenolol as sustained release layer. Indian J Pharm Sci 2016;78:458-68.
22. Parmar S, Mishra R, Shirolkar SV. Spherical agglomeration a novel approach for solubility and dissolution enhancement of simvastatin. Asian J Pharm Clin Res 2016;9:65-72.
23. Gupta D, Mandowara V, Patel S, Shelat P. Improvement of efficacy and safety profile of simvastatin in comparison to reference product (zocor tablets) using nanoparticulate formulation approach. Int J Curr Pharm Res 2016;8:39-47.
24. Miyama M, Yang Y, Yasuda T, Okuno T, Yasuda H. Static and dynamic contact angles of water on polymeric surfaces. Langmuir 1997;13:5494-503.
25. Issa M, Ferraz H. Intrinsic dissolution as a tool for evaluating drug solubility in accordance with the biopharmaceutical classification system. Dissolution Technol 2011;6-13. DOI:10.14227/DT180311P6
26. Palla BJ, Shah DO. Stabilization of high ionic strength slurries using the synergistic effects of a mixed surfactant system. J Colloid Interface Sci 2000;223:102-11.
27. Liu T, Hao J, Yang B, Hu B, Cui Z, Li S. Contact angle measurements: an alternative approach towards understanding the mechanism of increased drug dissolution from ethylcellulose tablets containing surfactant and exploring the relationship between their contact angles and dissolution behaviors. AAPS PharmSciTech 2018;19:1582-91.
28. Liu C, Liu Z, Chen Y, Chen Z, Chen H, Pui Y, et al. Oral bioavailability enhancement of ?-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion. Eur J Pharm Biopharm 2018;124:73-81.
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