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Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements.
Mol Pharm. 2012 Nov 05; 9(11):3023-33.MP

Abstract

A solid dispersion (SPD) of carbamazepine (CBZ) with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was prepared by the spray drying method. The apparent solubility (37 °C, pH 7.4) of CBZ observed with the SPD was over 3 times higher than the solubility of unprocessed CBZ. The supersaturated solution was stable for 7 days. A higher concentration of CBZ in aqueous medium was also achieved by mixing with Poloxamer 407 (P407), a solubilizing agent. From permeation studies of CBZ using Caco-2 monolayers and dialysis membranes, we observed improved CBZ permeation across the membrane in the supersaturated solution of CBZ/HPMC-AS SPD. On the contrary, the CBZ-solubilized P407 solution exhibited poor permeation by CBZ. The chemical shifts of CBZ on the (1)H NMR spectrum from CBZ/HPMC-AS SPD solution were not altered significantly by coexistence with HPMC-AS. In contrast, an upfield shift of CBZ was observed in the CBZ/P407 solution. The spin-lattice relaxation time (T(1)) over spin-spin relaxation time (T(2)) indicated that the mobility of CBZ in the HPMC-AS solution was much lower than that in water. Meanwhile, the mobility of CBZ in P407 solution was significantly higher than that in water. NMR data indicate that CBZ does not strongly interact with HPMC-AS. CBZ mobility was suppressed due to self-association and microviscosity around CBZ, which do not affect permeation behavior. Most of the CBZ molecules in the CBZ/P407 solution were solubilized in the hydrophobic core of P407, and a few were free to permeate the membrane. The molecular state of CBZ, as evaluated by NMR measurements, directly correlated with permeation behavior.

Authors+Show Affiliations

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

22970935

Citation

Ueda, Keisuke, et al. "Mechanistic Differences in Permeation Behavior of Supersaturated and Solubilized Solutions of Carbamazepine Revealed By Nuclear Magnetic Resonance Measurements." Molecular Pharmaceutics, vol. 9, no. 11, 2012, pp. 3023-33.
Ueda K, Higashi K, Limwikrant W, et al. Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements. Mol Pharm. 2012;9(11):3023-33.
Ueda, K., Higashi, K., Limwikrant, W., Sekine, S., Horie, T., Yamamoto, K., & Moribe, K. (2012). Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements. Molecular Pharmaceutics, 9(11), 3023-33. https://doi.org/10.1021/mp300083e
Ueda K, et al. Mechanistic Differences in Permeation Behavior of Supersaturated and Solubilized Solutions of Carbamazepine Revealed By Nuclear Magnetic Resonance Measurements. Mol Pharm. 2012 Nov 5;9(11):3023-33. PubMed PMID: 22970935.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanistic differences in permeation behavior of supersaturated and solubilized solutions of carbamazepine revealed by nuclear magnetic resonance measurements. AU - Ueda,Keisuke, AU - Higashi,Kenjirou, AU - Limwikrant,Waree, AU - Sekine,Shuichi, AU - Horie,Toshiharu, AU - Yamamoto,Keiji, AU - Moribe,Kunikazu, Y1 - 2012/09/28/ PY - 2012/9/14/entrez PY - 2012/9/14/pubmed PY - 2013/5/1/medline SP - 3023 EP - 33 JF - Molecular pharmaceutics JO - Mol. Pharm. VL - 9 IS - 11 N2 - A solid dispersion (SPD) of carbamazepine (CBZ) with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) was prepared by the spray drying method. The apparent solubility (37 °C, pH 7.4) of CBZ observed with the SPD was over 3 times higher than the solubility of unprocessed CBZ. The supersaturated solution was stable for 7 days. A higher concentration of CBZ in aqueous medium was also achieved by mixing with Poloxamer 407 (P407), a solubilizing agent. From permeation studies of CBZ using Caco-2 monolayers and dialysis membranes, we observed improved CBZ permeation across the membrane in the supersaturated solution of CBZ/HPMC-AS SPD. On the contrary, the CBZ-solubilized P407 solution exhibited poor permeation by CBZ. The chemical shifts of CBZ on the (1)H NMR spectrum from CBZ/HPMC-AS SPD solution were not altered significantly by coexistence with HPMC-AS. In contrast, an upfield shift of CBZ was observed in the CBZ/P407 solution. The spin-lattice relaxation time (T(1)) over spin-spin relaxation time (T(2)) indicated that the mobility of CBZ in the HPMC-AS solution was much lower than that in water. Meanwhile, the mobility of CBZ in P407 solution was significantly higher than that in water. NMR data indicate that CBZ does not strongly interact with HPMC-AS. CBZ mobility was suppressed due to self-association and microviscosity around CBZ, which do not affect permeation behavior. Most of the CBZ molecules in the CBZ/P407 solution were solubilized in the hydrophobic core of P407, and a few were free to permeate the membrane. The molecular state of CBZ, as evaluated by NMR measurements, directly correlated with permeation behavior. SN - 1543-8392 UR - https://www.unboundmedicine.com/medline/citation/22970935/Mechanistic_differences_in_permeation_behavior_of_supersaturated_and_solubilized_solutions_of_carbamazepine_revealed_by_nuclear_magnetic_resonance_measurements_ L2 - https://dx.doi.org/10.1021/mp300083e DB - PRIME DP - Unbound Medicine ER -