Preparation, In Vitro Evaluation and Characterization studies of Clozapine Nanosuspension
DOI:
https://doi.org/10.31351/vol33iss(4SI)pp336-348Keywords:
Clozapine, Nanosuspension, Particle Size, Solubility, solvent-antisolvent methodAbstract
Clozapine (CLZ) is a tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent. It belongs to the Biopharmaceutical Classification System (BCS) class II drug (High Permeability, Low Solubility), with a high first-pass effect. The current study used a technique called the solvent-antisolvent method to prepare a nanosuspension of clozapine with different stabilizers and solvents in an effort to increase the drug's solubility and dissolution. (Soluplus®, HPMC E15, PVA, Poloxamer 188, Poloxamer 407, PVP K30, PVP K90, and Tween 40) were used to produce the formula. Evaluations were done on particle size, PDI, zeta potential, and in vitro dissolution investigations. According to the data, all developed clozapine formulations had particle size values in the nano-size range. The best formula, A7, had a particle size of 80.43 nm and contained 1:3 Soluplus® as a stabilizer. Methanol was used as a solvent in a 1:5 ratio, with water acting as an anti-solvent, and a stirring speed of 1000 rpm was employed. The optimized freeze-dried nanoparticles underwent some characterization tests, including FTIR, XRD, and FESEM, which revealed smooth, uniform particles within the nano size. The location of the CLZ nanosuspension functional group was not altered by FTIR, while XRD revealed that clozapine had changed from a crystalline to an amorphous form. In conclusion, the solubility and dissolution rate of the drug were considerably increased when clozapine, which is weakly soluble in water, was prepared as a nanosuspension.
How to Cite
Publication Dates
Received
Revised
Accepted
Published Online First
References
Ainurofiq A, Putro DS, Ramadhani DA, Putra GM. A review on solubility enhancement methods for poorly water-soluble drugs. J Reports Pharm Sci. 2021;10(1):137–47. https://doi.org/ 10.4103/jrptps.JRPTPS_ 134_19.
Bazzo GC, Pezzini BR, Stulzer HK. Eutectic mixtures as an approach to enhance solubility, dissolution rate and oral bioavailability of poorly water-soluble drugs. Int J Pharm. 2020;588(August):119741. https://doi.org/ 10.1016/j.ijpharm.2020.119741.
Abbas KH, Hussein WF, Abood NA. Preparation and evaluation of ketoprofen nanosuspension using solvent evaporation technique. Iraqi J Pharm Sci. 2017;26(2):41–55. https://doi.org/10.31351/vol26iss2pp41-55.
Jayaprakash R, Krishnakumar K, Dineshkumar B, Jose R, Nair SK. Nanosuspension in drug delivery-a review. Sch Acad J Pharm. 2016;5(5):2320–4206.
Ferrar JA, Sellers BD, Chan C, Leung DH. Towards an improved understanding of drug excipient interactions to enable rapid optimization of nanosuspension formulations. Int J Pharm. 2020;578(January):119094. https://doi.org/10.1016/j.ijpharm.2020.119094.
Gera S, Sampathi S, Maddukuri S, Dodoala S, Junnuthula V, Dyawanapelly S. Therapeutic potential of naringenin nanosuspension: in vitro and in vivo anti-osteoporotic studies. Pharmaceutics. 2022;14(7):1–12. https://doi.org/10.3390/pharmaceutics14071449.
Vishal R, Patel, Agrawal YK. Nanosuspension: An approach to enhance solubility of drugs. J. Adv. Pharm. Tech. Res. 2011;2(2):81-87. https://doi.org/10.4103/2231-4040.82950
Ravichandran R. Nanoparticles in drug delivery: potential green nanobiomedicine applications. Int J Nanotechnol: biomedicine. 2009;1:B108-b130. https://doi.org/10.1080/19430850903430427
Abdulla NA, Balata GF, El-ghamry HA, Gomaa E. Intranasal delivery of Clozapine using nanoemulsion-based in-situ gels: An approach for bioavailability enhancement. Saudi Pharm J. 2021;29(12):1466–85. https://doi.org/10.1016/j.jsps.2021.11.006.
Agrawal MB, Patel MM. Design, development and in vivo evaluation of clozapine loaded adhesive diffusion controlled system for the treatment of schizophrenia. J Drug Deliv Sci Technol. 2021;64(April):102629. https://doi.org/10.1016/j.jddst.2021.102629.
Patel HP, Chaudhari PS, Gandhi PA, Desai B V., Desai DT, Dedhiya PP, et al. Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies. Int J Pharm. 2021;600(2021):120474. https://doi.org/10.1016/j.ijpharm.2021.120474
Lombardo R, Ruponen M, Rautio J, Ghelardini C, Di Cesare Mannelli L, Calosi L, et al. Development of lyophilised eudragit® retard nanoparticles for the sustained release of clozapine via intranasal administration. Pharmaceutics. 2023;15(5):1554. https://doi.org/10.3390/pharmaceutics15051554
Alzalzalee RA, Kassab HJ. Factors affecting the preparation of cilnidipine nanoparticles. Iraqi J Pharm Sci. 2023;32(November):235–43. https://doi.org/10.31351/vol32issSuppl.pp235-243.
Mahmood AAA, Alhammid SNA. Preparation and ex-vivo evaluation of stabilized cefdinir nanosuspension. Pakistan J Med Heal Sci. 2022;16(12):789–94. https://doi.org/10.53350/pjmhs20221612789.
Ali AH, Abd-Alhammid SN. Enhancement of solubility and improvement of dissolution rate of atorvastatin calcium prepared as nanosuspension. Iraqi J Pharm Sci. 2019; 28 (2):46–57. https:// doi. Org /10. 3135 1/ vol2 8 iss2pp46-57.
Panda A, Meena J, Katara R, Majumdar DK. Formulation and characterization of clozapine and risperidone co-entrapped spray-dried PLGA nanoparticles. Pharm Dev Technol. 2016;21(1):43–53. https://doi.org/10.3109/10837450.2014.965324.
Khafeef H k., Rajab NA. Eplerenone crystal nanosuspension for solubility enhancement: preparation and evaluation. Maaen J Med Sci. 2023;2(2):73–80. https:// doi.org/ 10. 55810 /2789 -9128.1024.
Al Hazzaa SA, Rajab NA. Cilnidipine nanocrystals, formulation and evaluation for optimization of solubility and dissolution rate. Iraqi J Pharm Sci. 2023;32(4):127–35. https:// doi.org/10.31351/vol32issSuppl.pp127-135.
Rashid AM, Abd-Alhammid SN. Formulation and characterization of itraconazole as nanosuspension dosage form for enhancement of solubility. Iraqi J Pharm Sci. 2019;28(2):124–33. https:// doi. org/ 10. 31351 /vol28iss2pp124-133.
Wang R, Yang M, Li G, Wang X, Zhang Z, Qiao H, et al. Paclitaxel-betulinic acid hybrid nanosuspensions for enhanced anti-breast cancer activity. Colloids Surfaces B Biointerfaces. 2019;174:270–9. https:// doi. org/10.1016/j.colsurfb.2018.11.029.
Malik B, Systems MH, Al-khedairy EBH. Enhancement of silymarin solubility and dissolution by nicotinamide-based solid dispersion employing the kneading method. J Popul Ther Clin Pharmacol. 2023; 30(13) :e386–93. https://doi.org/10.47750/jptcp.2023.30.13.028.
Toma NM, Abdulrasool AA. Formulation and evaluation of montelukast sodium nanoparticles for transdermal delivery. Int J Drug Deliv Technol. 2021;11(2):530–8. https:/ doi.org/10.25258/ijddt.11.2.52.
Saja AM, Khalid KA. Formulation and in vitro evaluation of meloxicam as a self-microemulsifying drug delivery system. F1000Research. 2023;12(315):1–23. https://doi.org/10.12688/f1000research.130749.2.
Pali A, Ordean GC, Pomian GM, Rus LL, Iovanov RI. A study on the influence of the dissolution test factors on in vitro release of ibuprofen from sustained release tablets. Rom J Pharm Pract. 2020;13(2):79–86. https://doi.org/10.37897/rjphp.2020.2.6.
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 (February):118415. https:// doi.org /10. 1016 /j.ijpharm.2019.06.006.
Jassim ZE, Hussein AA. Formulation and evaluation of clopidogrel tablet incorporating drug nanoparticles. Int J Pharm Pharm Sci. 2014;6(1):838–51.
Mohammed AA, Alhammid SN. Formulation and characterization of clozapine nanosuspension as a sublingual film. Al-Rafidain J Med Sci. 2024;6(2):82-88. https:// doi.org/10.54133/ajms.v6i2.772
Alwan RM, Rajab NA. Nanosuspensions of selexipag: formulation, characterization, and in vitro evaluation. Iraqi J Pharm Sci. 2021; 30(1 ):144–53. https:// doi. org/ 10. 31351 /vol 30 iss1pp144-153.
Dora CP, Singh SK, Kumar S, Datusalia AK, Deep A. Development and characterization of nanoparticles of glibenclamide by solvent displacement method. Acta Pol Pharm - Drug Res. 2010;67(3):283–90.
Elsa FA, Sherli S, Adik A. Effect of stirring speed and stirring time on characterization of clindamycin Hcl ethosomal and Ich Q1A (R2) satibility test. Farmacia. 2023;71(5):956-965. https://doi.org/10.31925/farmacia.2023.5.10.
Shuai Y, Yan C, Shichao D, Yan W. Thermodynamic analysis of the solubility of clozapine in organic solvents. J. Chem. Thermodynamics. 2021;158: 106451. https:// doi.Org /10.1016/j.jct.2021.106451
Venables DS, Schmuttenmaer CA. Spectroscopy and dynamics of mixtures of water with acetone, acetonitrile, and methanol. J. Chem. Phys. 2000;113(24):11222-35. https://doi.org/10.1063/1.1328072
Gera S, Talluri S, Rangaraj N, Sampathi S. Formulation and evaluation of naringenin nanosuspensions for bioavailability enhancement. AAPS PharmSciTech. 2017;18(8):3151–62. https:// doi.org /10. 1208 /s12249 -017-0790-5
Vijaykumar G, Patel J, Kapadiya J, Upadhyay U. Use of the liquisolid technique for improvement of the solubility and dissolution of clozapine. PharmaTutor. 2014;2(9):101–14.
Nehal D, Ossama YA, Magda E, Hamdy A. Formulation and characterization of itraconazole oral nanosuspension: methyl cellulose as promising stabilizer. Ely J Pharm Res. 2015;1(1):1-8.
Rashid A, Abd-Alhammid SN. Formulation and characterization of itraconazole as nanosuspension dosage form for enhancement of solubility. Iraqi J Pharm Sci. 2019;.28(2).
Gokce Y, Cengiz B, Yildiz N, Calimli A, Aktas Z. Ultrasonication of chitosan nanoparticle suspension: Influence on particle size. Colloids Surfaces A Physicochem Eng Asp. 2014;462:75–81. https:// doi. org/ 10. 1016 /j.colsurfa.2014.08.028
Panthi VK, Jha SK, Pangeni R, Paudel KR. Formulation and development of adapalene topical nanohydrogel using different surfactants and cosurfactants for antiacne activity: in vitro and ex vivo evaluation. J Nanomater. 2022;2022:1–19. https:// doi .org /10 .1155/2022/6889293.
Liu Z, Bode V, Hadayati P, Onay H, Sudhölter EJR. Understanding the stability mechanism of silica nanoparticles: The effect of cations and EOR chemicals. Fuel. 2020;280(May):1–11. https://doi.org/ 10.1016/j.fuel.2020.118650
Zuo J, Gao Y, Bou-Chacra N, Löbenberg R. Evaluation of the DDSolver software applications. Biomed Res Int. 2014;2014. https://doi.org/10.1155/2014/204925.
Migana R, Venu MK. Preparation and evaluation of clozapine loaded solid lipid nanoparticles for treatment of schizophrenia. Int J Pharm Res Technol. 2023;13(2):115–25. https://doi.org/10.31838/ijprt/13.02.12.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Iraqi Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
