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Comparative analysis of zaleplon complexation with cyclodextrins and hydrophilic polymers in solution and in solid state.
J Pharm Biomed Anal. 2012 Dec; 71:35-44.JP

Abstract

The aim of this work was to investigate the potential synergistic effect of water-soluble polymers (hypromellose, HPMC and polyvinylpyrrolidone, PVP) on zaleplon (ZAL) complexation with parent β-cyclodextrin (βCD) and its randomly methylated derivative (RAMEB) in solution and in solid state. The addition of HPMC to the complexation medium improved ZAL complexation and solubilization with RAMEB (K(ZAL/RAMEB)=156±5M(-1) and K(ZAL/RAMEB/HPMC)=189±8M(-1); p<0.01), while such effect was not observed for βCD (K(ZAL/βCD)=112±2M(-1) and K(ZAL/βCD/HPMC)=119±8M(-1); p>0.05). Although PVP increased the ZAL aqueous solubility from 0.22 to 0.27mg/mL, it did not show any synergistic effects on ZAL solubilization with the cyclodextrins tested. Binary and ternary systems of ZAL with βCD, RAMEB and HPMC were prepared by spray-drying. Differential scanning calorimetry, X-ray powder diffraction and scanning electron microscopy demonstrated a partial ZAL amorphization in spray-dried binary and ternary systems with βCD, while the drug was completely amorphous in all samples with RAMEB. Furthermore, inclusion complex formation in all systems prepared was confirmed by solid-state NMR spectroscopy. The in vitro dissolution rate followed the rank order ZAL/RAMEB/HPMC>ZAL/RAMEB=ZAL/βCD/HPMC>ZAL/βCD≫ZAL, clearly demonstrating the superior performance of RAMEB on ZAL complexation in the solid state and its synergistic effect with HPMC on drug solubility. Surprisingly, when loaded into tablets made with insoluble microcrystalline cellulose, RAMEB complexes had no positive effect on drug dissolution, because HPMC and RAMEB acted as a binders inside the tablets, prolonging their disintegration. Oppositely, the formulation with mannitol, a soluble excipient, containing a ternary RAMEB system, released the complete drug-dose in only 5min, clearly demonstrating its suitability for the development of immediate-release oral formulation of ZAL.

Authors+Show Affiliations

Department of Analytical Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22898722

Citation

Jablan, Jasna, et al. "Comparative Analysis of Zaleplon Complexation With Cyclodextrins and Hydrophilic Polymers in Solution and in Solid State." Journal of Pharmaceutical and Biomedical Analysis, vol. 71, 2012, pp. 35-44.
Jablan J, Szalontai G, Jug M. Comparative analysis of zaleplon complexation with cyclodextrins and hydrophilic polymers in solution and in solid state. J Pharm Biomed Anal. 2012;71:35-44.
Jablan, J., Szalontai, G., & Jug, M. (2012). Comparative analysis of zaleplon complexation with cyclodextrins and hydrophilic polymers in solution and in solid state. Journal of Pharmaceutical and Biomedical Analysis, 71, 35-44. https://doi.org/10.1016/j.jpba.2012.07.027
Jablan J, Szalontai G, Jug M. Comparative Analysis of Zaleplon Complexation With Cyclodextrins and Hydrophilic Polymers in Solution and in Solid State. J Pharm Biomed Anal. 2012;71:35-44. PubMed PMID: 22898722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparative analysis of zaleplon complexation with cyclodextrins and hydrophilic polymers in solution and in solid state. AU - Jablan,Jasna, AU - Szalontai,Gábor, AU - Jug,Mario, Y1 - 2012/07/31/ PY - 2012/05/31/received PY - 2012/07/19/revised PY - 2012/07/24/accepted PY - 2012/8/18/entrez PY - 2012/8/18/pubmed PY - 2013/3/15/medline SP - 35 EP - 44 JF - Journal of pharmaceutical and biomedical analysis JO - J Pharm Biomed Anal VL - 71 N2 - The aim of this work was to investigate the potential synergistic effect of water-soluble polymers (hypromellose, HPMC and polyvinylpyrrolidone, PVP) on zaleplon (ZAL) complexation with parent β-cyclodextrin (βCD) and its randomly methylated derivative (RAMEB) in solution and in solid state. The addition of HPMC to the complexation medium improved ZAL complexation and solubilization with RAMEB (K(ZAL/RAMEB)=156±5M(-1) and K(ZAL/RAMEB/HPMC)=189±8M(-1); p<0.01), while such effect was not observed for βCD (K(ZAL/βCD)=112±2M(-1) and K(ZAL/βCD/HPMC)=119±8M(-1); p>0.05). Although PVP increased the ZAL aqueous solubility from 0.22 to 0.27mg/mL, it did not show any synergistic effects on ZAL solubilization with the cyclodextrins tested. Binary and ternary systems of ZAL with βCD, RAMEB and HPMC were prepared by spray-drying. Differential scanning calorimetry, X-ray powder diffraction and scanning electron microscopy demonstrated a partial ZAL amorphization in spray-dried binary and ternary systems with βCD, while the drug was completely amorphous in all samples with RAMEB. Furthermore, inclusion complex formation in all systems prepared was confirmed by solid-state NMR spectroscopy. The in vitro dissolution rate followed the rank order ZAL/RAMEB/HPMC>ZAL/RAMEB=ZAL/βCD/HPMC>ZAL/βCD≫ZAL, clearly demonstrating the superior performance of RAMEB on ZAL complexation in the solid state and its synergistic effect with HPMC on drug solubility. Surprisingly, when loaded into tablets made with insoluble microcrystalline cellulose, RAMEB complexes had no positive effect on drug dissolution, because HPMC and RAMEB acted as a binders inside the tablets, prolonging their disintegration. Oppositely, the formulation with mannitol, a soluble excipient, containing a ternary RAMEB system, released the complete drug-dose in only 5min, clearly demonstrating its suitability for the development of immediate-release oral formulation of ZAL. SN - 1873-264X UR - https://www.unboundmedicine.com/medline/citation/22898722/Comparative_analysis_of_zaleplon_complexation_with_cyclodextrins_and_hydrophilic_polymers_in_solution_and_in_solid_state_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0731-7085(12)00433-5 DB - PRIME DP - Unbound Medicine ER -