Solid Dispersion Approaches for Clozapine Solubility Enhancement: A Comparative Review of Solvent Evaporation and Melt Fusion Methods
DOI:
https://doi.org/10.22270/ajprd.v14i3.1792Abstract
Clozapine, an antipsychotic belonging to the dibenzodiazepine family, continues to be the benchmark therapy for refractory schizophrenia even after being identified as having a difficult biopharmaceutics profile. The BCS Class II drug is highly permeable but poorly soluble in water (~0.2–0.5 mg/mL at physiological pH), which leads to poor oral bioavailability (27–50%) and high interpatient variability in pharmacokinetics. Solid dispersions are considered among the most potent techniques to deal with this issue through converting the drug from the crystalline form to the amorphous phase suspended in hydrophilic carrier matrices. This paper conducts a comparative study of two key solid dispersion approaches, namely solvent evaporation (spray drying and freeze drying) and melt fusion (hot melt extrusion and melt granulation), when applied to clozapine formulation. The physicochemical and biopharmaceutics characteristics of clozapine are thoroughly discussed regarding formulation design principles. Selection criteria for carriers, which include solvent solubility, glass transition temperature, miscibility indices (Flory-Huggins interaction parameter, χ), and thermal stability, are thoroughly analyzed. The mechanisms responsible for improving solubility, including amorphization, wetting enhancement, prevention of drug crystallization, and drug-polymer interactions, are examined with particular emphasis on current characterization methods such as differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance, and dissolution studies. Preclinical and formulation work from 2015 to 2026 is briefly reviewed in the context of achieving 4-10 fold increases in clozapine dissolution and bioavailability. Future directions concerning scale up, physical instability, residual solvents, and regulation, particularly the use of continuous manufacturing and artificial intelligence-based formulation, are explored.
Downloads
References
Charlson FJ, Ferrari AJ, Santomauro DF, et al. Global epidemiology and burden of schizophrenia. JAMA Psychiatry. 2018;75(9):928–937. https://doi.org/10.1001/jamapsychiatry.2018.1381
Leucht S, Corves C, Arbter D, et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia. Lancet. 2009;373(9657):31–41. https://doi.org/10.1016/S0140-6736(08)61764-X
Siskind D, Siskind V, Kisely S. Clozapine response rates among people with treatment-resistant schizophrenia. Can J Psychiatry. 2017;62(11):772–777. https://doi.org/10.1177/0706743717718167
Meltzer HY. The mechanism of action of novel antipsychotic drugs. Schizophr Bull. 1991;17(2):263–287. https://doi.org/10.1093/schbul/17.2.263
Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Curr Psychiatry Rep. 2016;18(7):68. https://doi.org/10.1007/s11920-016-0708-5
Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification. Pharm Res. 1995;12(3):413–420. https://doi.org/10.1023/a:1016212804288
Jann MW, Grimsley SR, Gray EC, Chang WH. Pharmacokinetics and pharmacodynamics of clozapine. ClinPharmacokinet. 1993;24(2):161–176. https://doi.org/10.2165/00003088-199324020-00006
Taylor DM, Greengrass M, Pilowsky LS. Pharmacokinetics of clozapine in renal and hepatic disease. Eur J Drug MetabPharmacokinet. 1999;24(1):85–90. https://doi.org/10.1007/bf03190010
Sekiguchi K, Obi N. Studies on absorption of eutectic mixture. I. A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem Pharm Bull. 1961;9(11):866–872. https://doi.org/10.1248/cpb.9.866
Chiou WL, Riegelman S. Pharmaceutical applications of solid dispersion systems. J Pharm Sci. 1971;60(9):1281–1302. https://doi.org/10.1002/jps.2600600902
Vasconcelos T, Sarmento B, Costa P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov Today. 2007;12(23–24):1068–1075. https://doi.org/10.1016/j.drudis.2007.09.005
Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. EurJ Pharm Biopharm. 2000;50(1):47–60. https://doi.org/10.1016/s0939-6411(00)00076-x
Hippius H. A historical perspective of clozapine. J Clin Psychiatry. 1999;60(Suppl 12):22–23. PMID: 10399918
Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry. 1988;45(9):789–796. https://doi.org/10.1001/archpsyc.1988.01800330013001
Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia. Arch Gen Psychiatry. 2003;60(1):82–91. https://doi.org/10.1001/archpsyc.60.1.82
Remington G, Lee J, Agid O, et al. Clozapine's critical role in treatment resistant schizophrenia. Adv Ther. 2016;33(1):11–25. https://doi.org/10.1007/s12325-015-0274-4
Stroup TS, Gerhard T, Crystal S, et al. Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. Am J Psychiatry. 2016;173(2):166–173. https://doi.org/10.1176/appi.ajp.2015.15030332
Patel MX, Haddad PM, Chaudhry IB. Schizophrenia: patients' experiences of illness and its treatment. AdvPsychiatr Treat. 2005;11(3):184–193. https://doi.org/10.1192/apt.11.3.184
Nordström AL, Farde L, Halldin C. Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology. 1992;106(4):433–438. https://doi.org/10.1007/BF02244811
Meltzer HY, Massey BW. The role of serotonin receptors in the action of atypical antipsychotic drugs. CurrOpinPharmacol. 2011;11(1):59–67. https://doi.org/10.1016/j.coph.2011.02.007
Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148(10):1301–1308. https://doi.org/10.1176/ajp.148.10.1301
Bhatti MS, Ahmed W. Physicochemical properties of clozapine and implications for formulation design. Int J Pharm Sci Rev Res. 2019;58(1):23–31.
Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption. Pharm Res. 1998;15(1):11–22. https://doi.org/10.1023/a:1011984216775
Grunenberg A, Otterpohl J, Dörfler G. Solid state characterization of clozapine polymorphs. Int J Pharm. 1995;118(1):11–21. https://doi.org/10.1016/0378-5173(94)00378-9
Dahl SG. Pharmacokinetics of clozapine. ClinNeuropharmacol. 1990;13(Suppl 2):S6–S11. PMID: 2194249
Kawabata Y, Wada K, Nakatani M, et al. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system. Int J Pharm. 2011;420(1):1–10. https://doi.org/10.1016/j.ijpharm.2011.08.032
Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J PharmacolToxicol Methods. 2000;44(1):235–249. https://doi.org/10.1016/s1056-8719(00)00107-6
Bergström CA, Holm R, Jørgensen SA, et al. Early pharmaceutical profiling to predict oral drug absorption. Eur J Pharm Sci. 2014;57:173–199. https://doi.org/10.1016/j.ejps.2013.10.015
Pouton CW. Formulation of poorly water-soluble drugs for oral administration. Eur J Pharm Sci. 2006;29(3–4):278–287. https://doi.org/10.1016/j.ejps.2006.04.016
Vo CLN, Park C, Lee BJ. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013;85(3):799–813. https://doi.org/10.1016/j.ejpb.2013.09.007
Pawar JN, Dand N, Misra A. Third-generation solid dispersions with amphiphilic polymers for solubility enhancement. Asian J Pharm Sci. 2022;17(3):315–331. https://doi.org/10.1016/j.ajps.2022.02.006
Yu L. Amorphous pharmaceutical solids: preparation, characterization and stabilization. Adv Drug Deliv Rev. 2001;48(1):27–42. https://doi.org/10.1016/s0169-409x(01)00098-9
Williams HD, Trevaskis NL, Charman SA, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315–499. https://doi.org/10.1124/pr.112.005660
Marsac PJ, Shamblin SL, Taylor LS. Theoretical and practical approaches for prediction of drug-polymer miscibility. Pharm Res. 2006;23(10):2417–2426. https://doi.org/10.1007/s11095-006-9063-9
Zhao Y, Inbar P, Chokshi HP, et al. Prediction of the thermal phase diagram of amorphous solid dispersions by Flory-Huggins theory. J Pharm Sci. 2011;100(8):3196–3207. https://doi.org/10.1002/jps.22541
Friesen DT, Shanker R, Crew M, et al. Hydroxypropyl methylcellulose acetate succinate-based spray-dried dispersions. Mol Pharm. 2008;5(6):1003–1019. https://doi.org/10.1021/mp8000793
Konno H, Handa T, Alonzo DE, Taylor LS. Effect of polymer type on the dissolution profile of amorphous solid dispersions. Eur J Pharm Biopharm. 2008;70(2):493–499. https://doi.org/10.1016/j.ejpb.2008.05.023
Newa M, Bhandari KH, Li DX, et al. Preparation, characterization and in vivo evaluation of ibuprofen binary solid dispersions with poloxamer 188. Int J Pharm. 2007;343(1–2):228–237. https://doi.org/10.1016/j.ijpharm.2007.04.021
Vasconcelos T, Marques S, das Neves J, Sarmento B. Amorphous solid dispersions: rational selection of a manufacturing process. Adv Drug Deliv Rev. 2016;100:85–101. https://doi.org/10.1016/j.addr.2016.01.012
Vemula VR, Lagishetty V, Lingala S. Solubility enhancement techniques. Int J Pharm Sci Rev Res. 2010;5(1):41–51.
Paudel A, Worku ZA, Meeus J, et al. Manufacturing of solid dispersions of poorly water soluble drugs by spray drying. Int J Pharm. 2013;453(1):253–284. https://doi.org/10.1016/j.ijpharm.2012.07.015
Sharma D. Formulation development and evaluation of solid dispersion of poorly water soluble drug. Eur J Biomed Pharm Sci. 2016;3(9):56–65.
Weuts I, Van Dycke F, Voorspoels J, et al. Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for solid dispersions. Eur J Pharm Biopharm. 2011;77(2):275–286. https://doi.org/10.1016/j.ejpb.2010.11.007
Suresh S, Bhatt M, Saha RN. Solid dispersion of clozapine: formulation and in vitro evaluation. Drug Dev Ind Pharm. 2015;41(3):345–354.
Bhatt P, Lalani R, Vhora I, Patil S, Amrutiya J, Misra A. Solid dispersions—a review on principle, methods and applications. J Drug Delivery Sci Technol. 2018;47:95–112. https://doi.org/10.1016/j.jddst.2018.06.010
ICH Q3C (R7). Residual solvents. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. 2018.
Tian Y, Booth J, Meehan E, Jones DS, Li S, Andrews GP. Construction of drug-polymer thermodynamic phase diagrams using Flory-Huggins interaction theory. Mol Pharm. 2013;10(1):236–248. https://doi.org/10.1021/mp300386v
Kolter K, Karl M, Gryczke A. Hot-melt extrusion with BASF pharma polymers: extrusion compendium. 2nd ed. Ludwigshafen: BASF SE; 2012.
Mehuys E, Vervaet C, Remon JP. Hot-melt extruded ethylcellulose cylinders containing a HPMC-Gelucire core for sustained drug release. J Control Release. 2004;94(2–3):273–280. https://doi.org/10.1016/j.jconrel.2003.09.014
Crowley MM, Zhang F, Repka MA, et al. Pharmaceutical applications of hot-melt extrusion: Part I. Drug Dev Ind Pharm. 2007;33(9):909–926. https://doi.org/10.1080/03639040701498759
Huang S, Morgen M, Lowinger M, et al. Preferable loading level of stable amorphous solid dispersions made by hot-melt extrusion. Mol Pharm. 2019;16(11):4561–4571. https://doi.org/10.1021/acs.molpharmaceut.9b00618
Hamdani J, Moës AJ, Amighi K. Physical and thermalcharacterisation of Precirol and Compritol as lipophilic glycol-glycerides used for the preparation of controlled-release matrix pellets. Int J Pharm. 2003;260(1):47–57. https://doi.org/10.1016/s0378-5173(03)00222-4
Raza K, Kumar P, Ratan S, Malik R, Arora S. Polymorphism: the phenomenon affecting the performance of drugs. SOJ Pharm Pharm Sci. 2014;1(2):10.
Nair R, Nyamweya N, Gönen S, et al. Influence of various plasticizers on mechanical and thermal properties of cellulose acetate phthalate films. Drug Dev Ind Pharm. 2001;27(8):815–825. https://doi.org/10.1081/DDC-100107253
Gupta SS, Solanki N, Serajuddin AT. Investigation of thermal and viscoelastic properties of polymers relevant to hot melt extrusion. J Pharm Sci. 2016;105(7):2254–2259. https://doi.org/10.1016/j.xphs.2016.04.010
Baghel S, Cathcart H, O'Reilly NJ. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-state characterization, and aqueous solubilization. J Pharm Sci. 2016;105(9):2527–2544. https://doi.org/10.1016/j.xphs.2015.10.008
Hoy KL. New values of the solubility parameters from vapor pressure data. J Paint Technol. 1970;42(541):76–118.
Lee SL, O'Connor TF, Yang X, et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J Pharm Innov. 2015;10(3):191–199. https://doi.org/10.1007/s12247-015-9215-8
Bhugra C, Pikal MJ. Role of thermodynamic and kinetic factors in crystallization from the amorphous state. J Pharm Sci. 2008;97(4):1329–1349. https://doi.org/10.1002/jps.21138
Serajuddin AT. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88(10):1058–1066. https://doi.org/10.1021/js980403l
Newman A, Engers D, Bates S, et al. Characterization of amorphous API: polyanion mixtures using X-ray powder diffraction. J Pharm Sci. 2008;97(11):4840–4856. https://doi.org/10.1002/jps.21352
Shmeis RA, Wang Z, Krill SL. A mechanistic investigation of an amorphous pharmaceutical and its solid dispersions, part I: molecular mobility and activation thermodynamic parameters. Pharm Res. 2004;21(11):2025–2030. https://doi.org/10.1023/b:pham.0000048196.24169.2b
Aso Y, Yoshioka S, Shiraishi S. Determination of the molecular mobility of sucrose and nifedipine glasses by 13C NMR relaxation. Chem Pharm Bull. 1994;42(2):398–406. https://doi.org/10.1248/cpb.42.398
Kalantzi L, Reppas C, Dressman JB, et al. Biowaiver monographs for immediate release solid oral dosage forms. J Pharm Sci. 2006;95(1):13–22. https://doi.org/10.1002/jps.20481
Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm Sci. 2009;98(8):2549–2572. https://doi.org/10.1002/jps.21650
Alonzo DE, Zhang GG, Zhou D, et al. Understanding the behavior of amorphous pharmaceutical systems during dissolution. Pharm Res. 2010;27(4):608–618. https://doi.org/10.1007/s11095-009-0021-1
Yamashita K, Nakate T, Okimoto K, et al. Establishment of new preparation method for solid dispersion formulation of tacrolimus. Int J Pharm. 2003;267(1–2):79–91. https://doi.org/10.1016/j.ijpharm.2003.07.010
Chen Y, Liu C, Chen Z, Su C, Hageman M, Hussain M. Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions. Mol Pharm. 2015;12(2):576–589. https://doi.org/10.1021/mp500660g
Pham TN, Watson SA, Edwards AJ, Chavda M, Clawson JS, Strohmeier M. Analysis of amorphous solid dispersions using 2D solid-state NMR and 1H T1 relaxation measurements. Mol Pharm. 2010;7(5):1667–1691. https://doi.org/10.1021/mp100205g
Ivanisevic I. Physical stability studies of miscible amorphous solid dispersions. J Pharm Sci. 2010;99(9):4005–4012. https://doi.org/10.1002/jps.22127
Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci. 1997;86(1):1–12. https://doi.org/10.1021/js9601896
Qian F, Huang J, Hussain MA. Drug-polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci. 2010;99(7):2941–2947. https://doi.org/10.1002/jps.22074
Patel BB, Patel JK, Chakraborty S. Review of patents and application of spray drying in pharmaceutical, food and flavor industry. Recent Pat Drug DelivFormul. 2014;8(1):63–78. https://doi.org/10.2174/1872211308666140220121755
FDA. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms. U.S. Food and Drug Administration; 2017.
Baxendale IR, Braatz RD, Hodnett BK, et al. Achieving continuous manufacturing: technologies and approaches for synthesis, workup and isolation of drug substance. J Pharm Sci. 2015;104(3):781–791. https://doi.org/10.1002/jps.24252
Raza MA, Bhatti MA, Iqbal HS, et al. Machine learning techniques in pharmaceutical formulation development: a comprehensive review. Eur J Pharm Sci. 2022;172:106142. https://doi.org/10.1016/j.ejps.2022.106142
Vertzoni M, Augustijns P, Grimm M, et al. Impact of regional differences along the gastrointestinal tract of healthy adults on oral drug absorption. Eur J Pharm Sci. 2019;134:153–175. https://doi.org/10.1016/j.ejps.2019.04.013
Published
How to Cite
Issue
Section
Copyright (c) 2026 Pradnya Nitesh Valavi, Yogesh.P. Sharma, Dr.Sunil. K. Mahajan
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
AUTHORS WHO PUBLISH WITH THIS JOURNAL AGREE TO THE FOLLOWING TERMS:
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
. 