Skip to main content
SpringerLink
Log in

Increase in Dissolution Rate of Zotepine via Nanomilling Process — Impact of Dried Nanocrystalline Suspensions on Bioavailability

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Zotepine is an atypical antipsychotic drug used in the treatment of schizophrenia. However, its poor dissolution properties limit its therapeutic efficacy. In this investigation, a series of nanosuspension-containing zotepine were prepared employing media milling method with an aim to improve its dissolution properties and oral bioavailability. Briefly, Box-Behnken design was applied to investigate the influence of various independent variables such as X1- amount of stabilizer, X2- amount of milling agent, and X3- milling time on the performance of the formulation. Dissolution studies revealed enhancement of dissolution rate as compared to pure drug. Solid state characterization (DSC, PXRD, and SEM) studies demonstrated no polymorphic changes in drug after lyophilization of media-milled nanosuspension. In vivo pharmacokinetic studies of lyophilized nanosuspension was carried out in rat and the results exhibited significant improvement in Cmax and AUC0-t, about 450.0 and 287.45%, respectively, suggesting amelioration in oral bioavailability by 2.87-fold higher as compared to pure drug. Accelerated stability studies of the optimized lyophilized formulation at 40°C and 75% RH suggested stability of the nanocrystals for at least a 6-month period. The obtained nanocrystals successfully showed dissolution enhancement and improved oral bioavailability of poorly water-soluble drug, zotepine.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015;5:442–53.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Boyd BJ, Bergström CAS, Vinarov Z, Kuentz M, Brouwers J, Augustijns P, et al. Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems. Eur J Pharm Sci. 2019;137:104967.

    Article  CAS  PubMed  Google Scholar 

  3. Bevernage J, Brouwers J, Clarysse S, Vertzoni M, Tack J, Annaert P, et al. Drug supersaturation in simulated human intestinal fluids representing different nutritional states. J Pharm Sci. 2010;99:4525–34.

    Article  CAS  PubMed  Google Scholar 

  4. Alshehri S, Imam SS, Altamimi MA, Hussain A, Shakeel F, Elzayat E, et al. Enhanced dissolution of luteolin by solid dispersion prepared by different methods: physicochemical characterization and antioxidant activity. ACS Omega. 2020;5:6461–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Popiołek I, Niziołek A, Kamiński K, Kwolek U, Nowakowska M, Szczubiałka K. Cellular delivery and enhanced anticancer activity of berberine complexed with a cationic derivative of γ–cyclodextrin. Bioorg Med Chem. 2019;27:1414–20.

    Article  PubMed  Google Scholar 

  6. Yamasaki K, Taguchi K, Nishi K, Otagiri M, Seo H. Enhanced dissolution and oral bioavailability of praziquantel by emulsification with human serum albumin followed by spray drying. Eur J Pharm Sci. 2019;139:105064.

    Article  CAS  PubMed  Google Scholar 

  7. Huang S, Mao C, Williams RO, Yang CY. Solubility advantage (and disadvantage) of pharmaceutical amorphous solid dispersions. J Pharm Sci. 2016;105(12):3549–61.

    Article  CAS  PubMed  Google Scholar 

  8. Saokham P, Muankaew C, Jansook P, Loftsson T. Solubility of cyclodextrins and drug/cyclodextrin complexes. Molecules. 2018;23:1161.

    Article  PubMed Central  Google Scholar 

  9. Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS)—challenges and road ahead. Drug Deliv. 2015;22(6):675–90.

    Article  CAS  PubMed  Google Scholar 

  10. Siwach R, Pandey P, Dureja H. Formulation and characterization of glimepiride nanoparticles for dissolution enhancement. Nanosci Nanotechnol-Asia. 2020;10(5):649–63.

    Article  CAS  Google Scholar 

  11. Koltermann-Jülly J, Keller JG, Vennemann A, Werle K, Müller P, Ma-Hock L, et al. Abiotic dissolution rates of 24 (nano) forms of 6 substances compared to macrophage-assisted dissolution and in vivo pulmonary clearance: grouping by biodissolution and transformation. NanoImpact. 2018;12:29–41.

    Article  Google Scholar 

  12. Mazumder S, Dewangan AK, Pavurala N. Enhanced dissolution of poorly soluble antiviral drugs from nanoparticles of cellulose acetate based solid dispersion matrices. Asian J Pharm Sci. 2017;12(6):532–41.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jacob S, Nair AB, Shah J. Emerging role of nanosuspensions in drug delivery systems. Biomater Res. 2020;24(3). https://doi.org/10.1186/s40824-020-0184-8.

  14. Taneja S, Shilpi S, Khatri K. Formulation and optimization of efavirenz nanosuspensions using the precipitation-ultrasonication technique for solubility enhancement. Artif Cells Nanomed Biotechnol. 2016;44(3):978–84.

    CAS  PubMed  Google Scholar 

  15. Sahu BP, Das MK. Nanosuspension for enhancement of oral bioavailability of felodipine. Appl Nanosci. 2014;4:189–97.

    Article  CAS  Google Scholar 

  16. Meruva S, Thool P, Gong Y, Agrawal A, Karki S, Bowen W, Mitra B, Kumar S. A novel use of nanocrystalline suspensions to develop sub-microgram dose micro-tablets. J Pharm Sci. 2021;110(9):3276–88.

    Article  CAS  PubMed  Google Scholar 

  17. Meruva S, Thool P, Shah S, Karki S, Bowen W, Ghosh I, et al. Formulation and performance of Irbesartan nanocrystalline suspension and granulated or bead-layered dried powders – Part I. Int J Pharm. 2019;568:118189.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang X, Zhao J, Guan J, Zhang X, Li L, Mao S. Exploration of nanocrystal technology for the preparation of lovastatin immediate and sustained release tablets. J Drug Deliv Sci Technol. 2019;50:107–12.

    Article  CAS  Google Scholar 

  19. Melian ME, Paredes A, Munguía B, Colobbio M, Ramos JC, Teixeira R, et al. Nanocrystals of novel valerolactam-fenbendazole hybrid with improved in vitro dissolution performance. AAPS PharmSciTech. 2020;21:1–15.

    Article  Google Scholar 

  20. Xiong S, Liu W, Zhou Y, Mo Y, Liu Y, Chen X, et al. Enhancement of oral bioavailability and anti-Parkinsonian efficacy of resveratrol through a nanocrystal formulation. Asian J Pharm Sci. 2020;15:518–28.

    Article  PubMed  Google Scholar 

  21. Xiong S, Liu W, Li D, Chen X, Liu F, Yuan D, et al. Oral delivery of puerarin nanocrystals to improve brain accumulation and anti-parkinsonian efficacy. Mol Pharm. 2019;16:1444–55.

    Article  CAS  PubMed  Google Scholar 

  22. Tashan E, Karakucuk A, Celebi N. Correction to: Development of nanocrystal ziprasidone orally disintegrating tablets: optimization by using design of experiment and in vitro evaluation (AAPS PharmSciTech, (2020), 21, 3, (115), 10.1208/s12249-020-01653-9). AAPS PharmSciTech. 2020;21:1–12.

    Google Scholar 

  23. Karakucuk A, Celebi N. Investigation of formulation and process parameters of wet media milling to develop etodolac nanosuspensions. Pharm Res. 2020;37:1–18.

    Article  Google Scholar 

  24. Qureshia MJ, Phina FF, Patrob S. Enhanced solubility and dissolution rate of clopidogrel by nanosuspension: formulation via high pressure homogenization technique and optimization using Box Behnken design response surface methodology. J Appl Pharm Sci. 2017;7:106–13.

    Google Scholar 

  25. Sridhar K, Rahman H, Sosnik A, Mukherjee U, Natarajan T, Siram K, et al. Production of Irbesartan nanocrystals by high shear homogenisation and ultra-probe sonication for improved dissolution rate. Curr Drug Deliv. 2016;13:688–97.

    Article  CAS  PubMed  Google Scholar 

  26. Tehrani AA, Omranpoor MM, Vatanara A, Seyedabadi M, Ramezani V. Formation of nanosuspensions in bottom-up approach: theories and optimization. DARU J Pharm Sci. 2019:1–23.

  27. Müller RH, Gohla S, Keck CM. State of the art of nanocrystals–special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm. 2011;78:1–9.

    Article  PubMed  Google Scholar 

  28. Möschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm. 2013;453:142–56.

    Article  PubMed  Google Scholar 

  29. Bhakay A, Merwade M, Bilgili E, Dave RN. Novel aspects of wet milling for the production of microsuspensions and nanosuspensions of poorly water-soluble drugs. Drug Dev Ind Pharm. 2011;37:963–76.

    Article  CAS  PubMed  Google Scholar 

  30. Siewert C, Moog R, Alex R, Kretzer P, Rothenhäusler B. Process and scaling parameters for wet media milling in early phase drug development: a knowledge based approach. Eur J Pharm Sci. 2018;115:126–31.

    Article  CAS  PubMed  Google Scholar 

  31. Ma YQ, Zhang ZZ, Li G, Zhang J, Xiao HY, Li XF. Solidification drug nanosuspensions into nanocrystals by freeze-drying: a case study with ursodeoxycholic acid. Pharm Dev Technol. 2016;21(2):180–8.

    Article  CAS  PubMed  Google Scholar 

  32. Hou Y, Shao J, Fu Q, Li J, Sun J, He Z. Spray-dried nanocrystals for a highly hydrophobic drug: increased drug loading, enhanced redispersity, and improved oral bioavailability. Int J Pharm. 2017;516(1-2):372–9.

    Article  CAS  PubMed  Google Scholar 

  33. Meruva S, Thool P, Karki S, Bowen W, Ghosh I, Kumar S. Downstream processing of irbesartan nanocrystalline suspension and mini-tablet development — part II. Int J Pharm. 2019;568:118509.

    Article  CAS  PubMed  Google Scholar 

  34. Meruva S, Thool P, Gong Y, Karki S, Bowen W, Kumar S. Role of wetting agents and disintegrants in development of danazol nanocrystalline tablets. Int J Pharm. 2020;577:119026.

    Article  CAS  PubMed  Google Scholar 

  35. Du B, Shen G, Wang D, Pang L, Chen Z, Liu Z. Development and characterization of glimepiride nanocrystal formulation and evaluation of its pharmacokinetic in rats. Drug Deliv. 2013;20:25–33.

    Article  CAS  PubMed  Google Scholar 

  36. Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci. 2015;10:13–23.

    Article  Google Scholar 

  37. Shekhawat P, Pokharkar V. Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: in-vitro characterization, PAMPA and in-vivo assessment. Int J Pharm. 2019;567:118415.

    Article  CAS  PubMed  Google Scholar 

  38. Green B. Zotepine: a clinical review. Expert Opin Drug Metab Toxicol. 2009;5:181–6.

    Article  CAS  PubMed  Google Scholar 

  39. Nakamura S, Ago Y, Itoh S, Koyama Y, Baba A, Matsuda T. Effect of zotepine on dopamine, serotonin and noradrenaline release in rat prefrontal cortex. Eur J Pharmacol. 2005;528:95–8.

    Article  CAS  PubMed  Google Scholar 

  40. Bishnoi RJ, Jhanwar VG. Tolerability of zotepine in Indian patients: preliminary experience. Ind Psychiatry J. 2010;19(2):130–1.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tirumalesh C, Suram D, Dudhipala N, Banala N. Enhanced pharmacokinetic activity of Zotepine via nanostructured lipid carrier system in Wistar rats for oral application. Pharm Nanotechnol. 2020;8:148–60.

    Article  CAS  PubMed  Google Scholar 

  42. Pailla SR, Talluri S, Rangaraj N, Ramavath R, Challa VS, Doijad N, Sampathi S. Intranasal zotepine nanosuspension: intended for improved brain distribution in rats. Daru. 2019;27(2):541–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Venugopal V, Kumar KJ, Muralidharan S, Parasuraman S, Raj PV, Kumar KV. Optimization and in-vivo evaluation of isradipine nanoparticles using Box-Behnken design surface response methodology. OpenNano. 2016;1:1–15.

    Article  Google Scholar 

  44. Nagaraj K, Narendar D, Kishan V. Development of olmesartan medoxomil optimized nanosuspension using the Box–Behnken design to improve oral bioavailability. Drug Dev Ind Pharm. 2017;43:1186–96.

    Article  CAS  PubMed  Google Scholar 

  45. Sattar A, Chen D, Jiang L, Pan Y, Tao Y, Huang L, et al. Preparation, characterization and pharmacokinetics of cyadox nanosuspension. Sci Rep. 2017;7:1–9.

    Article  CAS  Google Scholar 

  46. Jacobs C, Müller RH. Production and characterization of a budesonide nanosuspension for pulmonary administration. Pharm Res. 2002;19:189–94.

    Article  CAS  PubMed  Google Scholar 

  47. Verma S, Kumar S, Gokhale R, Burgess DJ. Physical stability of nanosuspensions: investigation of the role of stabilizers on Ostwald ripening. Int J Pharm. 2011;406:145–52.

    Article  CAS  PubMed  Google Scholar 

  48. Garala K, Patel J, Patel A, Dharamsi A. Enhanced encapsulation of metoprolol tartrate with carbon nanotubes as adsorbent. Appl Nanosci (Switzerland). 2011;1:219–30.

    Article  CAS  Google Scholar 

  49. Bolton S. Optimization techniques in pharmaceutical statistics: Practical and Clinical applications. New York: Marcel Dekker, Inc.; 1997.

    Google Scholar 

  50. Li W, Yang Y, Tian Y, Xu X, Chen Y, Mu L, Zhang Y, Fang L. Preparation and in vitro/in vivo evaluation of revaprazan hydrochloride nanosuspension. Int J Pharm. 2011;408(1-2):157–62.

    Article  CAS  PubMed  Google Scholar 

  51. Dolenc A, Kristl J, Baumgartner S, Planinšek O. Advantages of celecoxib nanosuspension formulation and transformation into tablets. Int J Pharm. 2009;376:204–12.

    Article  CAS  PubMed  Google Scholar 

  52. Kocbek P, Baumgartner S, Kristl J. Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. Int J Pharm. 2006;312(1-2):179–86.

    Article  CAS  PubMed  Google Scholar 

  53. Marzan AL, Tabassum R, Jahan B, Asif MH, Reza HM, Kazi M, Alshehri SM, de Matas M, Shariare MH. Preparation and characterization of stable nanosuspension for dissolution rate enhancement of furosemide: a Quality by Design (QbD) approach. Curr Drug Deliv. 2018;15(5):672–85.

    Article  CAS  PubMed  Google Scholar 

  54. Chung NO, Lee MK, Lee J. Mechanism of freeze-drying drug nanosuspensions. Int J Pharm. 2012;437(1-2):42–50.

    Article  CAS  PubMed  Google Scholar 

  55. Karakucuk A, Celebi N. Investigation of formulation and process parameters of wet media milling to develop etodolac nanosuspensions. Pharm Res. 2020;37(6):111.

    Article  CAS  PubMed  Google Scholar 

  56. Kakade P, Gite S, Patravale V. Development of atovaquone nanosuspension: quality by design approach. Curr Drug Deliv. 2019;17(2):112–25.

    Article  Google Scholar 

  57. Otsuka M, Fukura N, Abe H. Solid material characterization of freeze-dried gabexate mesilate containing D-mannitol by terahertz spectroscopy. J Infrared Millim Terahertz Waves. 2013;34:170–80.

    Article  CAS  Google Scholar 

  58. Taneja S, Shilpi S, Khatri K. Formulation and optimization of efavirenz nanosuspensions using the precipitation-ultrasonication technique for solubility enhancement. Artif Cells Nanomed Biotechnol. 2016;44:978–84.

    CAS  PubMed  Google Scholar 

  59. Sharma M, Mehta I. Surface stabilized atorvastatin nanocrystals with improved bioavailability, safety and antihyperlipidemic potential. Sci Rep. 2019;9:1–11.

    Article  Google Scholar 

  60. Sahoo NG, Kakran M, Shaal LA, Li L, Müller RH, Pal M, et al. Preparation and characterization of quercetin nanocrystals. J Pharm Sci. 2011;100:2379–90.

    Article  CAS  PubMed  Google Scholar 

  61. Maleki A, Hamidi M. Dissolution enhancement of a model poorly water-soluble drug, atorvastatin, with ordered mesoporous silica: comparison of MSF with SBA-15 as drug carriers. Expert Opin Drug Deliv. 2016;13:171–81.

    Article  CAS  PubMed  Google Scholar 

  62. He J, Han Y, Xu G, Yin L, Neubi MN, Zhou J, et al. Preparation and evaluation of celecoxib nanosuspensions for bioavailability enhancement. RSC Adv. 2017;7:13053–64.

    Article  CAS  Google Scholar 

  63. Shariare MH, Altamimi MA, Marzan AL, Tabassum R, Jahan B, Reza HM, et al. In vitro dissolution and bioavailability study of furosemide nanosuspension prepared using design of experiment (DoE). Saudi Pharm J. 2019;27:96–105.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Symed labs, Hyderabad, India for providing gift sample of antipsychotic drug, Zotepine.

Funding

Not applicable, part of employment; ROFEL Shri G. M. Bilakhia College of Pharmacy, Vapi, Gujarat, India

Author information

Authors and Affiliations

  1. ROFEL Shri G.M. Bilakhia College of Pharmacy, Vapi, Gujarat, 396191, India

    Komal Parmar & Kirti Oza

Authors
  1. Komal Parmar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kirti Oza
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Dr. Komal Parmar: Concept, Interpretation of data, Drafting of work

Ms. Kirti Oza: Practical Work

Corresponding author

Correspondence to Komal Parmar.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Parmar, K., Oza, K. Increase in Dissolution Rate of Zotepine via Nanomilling Process — Impact of Dried Nanocrystalline Suspensions on Bioavailability. AAPS PharmSciTech 23, 20 (2022). https://doi.org/10.1208/s12249-021-02172-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-02172-x

KEY WORDS

Search

Navigation