Harunobu Kanaya,Keisuke Ueda,Kenjirou Higashi,Keiji Yamamoto, Kunikazu Moribe

Graduate School of Pharmaceutical Science,Chiba University,1-8-1 Inohana,Chuo-ku,Chiba 260-8675,Japan

Stabilization mechanism of nitrazepam supersaturated state in nitrazepam/ Eudragit?EPO/saccharin solution revealed by NMR measurements

Harunobu Kanaya*,Keisuke Ueda,Kenjirou Higashi,Keiji Yamamoto, Kunikazu Moribe

Graduate School of Pharmaceutical Science,Chiba University,1-8-1 Inohana,Chuo-ku,Chiba 260-8675,Japan

A R T I C L E I N F O

Article history:

Available online 23 November 2015

Solid dispersion

Supersaturation

NMR relaxation time

2D-NOESY

Aminoalkyl methacrylate copolymer,Eudragit?E PO(EPO),has been used as a polymeric carrier for solid dispersion to signifcantly enhance the drug dissolution.However,the improvement of the drug dissolution by the drug/EPO solid dispersion is limited only in acidic solution due to the pH-dependant solubility of basic EPO with its tertiary amino group. We previously reported that the blending of saccharin(SAC) in the drug/EPO solid dispersion led to the supersaturation formation of drug even at neutral pH[1].It was suggested that hydrophilic interaction between the tertiary amino group of EPO and the amide group of SAC in solid state enabled EPO to dissolve in the neutral condition.In this study,we focused on the stable drug supersaturation formed by the ternary solid dispersion.The molecular mobility and molecular interaction of drug,EPO,and SAC in the supersaturated solution was investigated by NMR techniques to reveal the stabilization mechanism of the drug supersaturation.Nitrazepam(NTZ)was used as a model of poorly water soluble drugs.Solid dispersion of NTZ/EPO/SAC was prepared by spray-drying of dichloromethane/methanol(1/1,v/v)solution containing NTZ/ EPO/SAC(0.5/3/1,w/w).The obtained solid dispersion was dispersed in 0.1 M phosphate buffer(D2O,pH6.8)to prepare NTZ supersaturated solution for NMR measurements.NMR relaxation time,spin-lattice relaxation time(T1),and spin–spin relaxation time(T2)were determined by inversion-recovery and Carr Purcell Meiboom Gill method,respectively.2D1H/1H nuclear Overhauser effect spectroscopy(NOESY)was performed at a mixing time of 10 ms.

The ratio of T1to T2of proton was calculated for the quantitative evaluation of molecular mobility of each component. The T1/T2value of NTZ in NTZ/EPO/SAC solution at 110.1 was much higher than that in unprocessed NTZ solution at 3.5.Theincrease ofT1/T2value indicated the mobility suppression of NTZ with the coexistence of EPO and SAC.Furthermore,the T1/T2value of NTZ in NTZ/EPO/SAC solution was similar to that of hydrophobic group of EPO(-CCHn)at 117.0,but not in accordance with that of hydrophilic group(-NCH3)at 29.2.In NOESY spectrum of NTZ/EPO/SAC solution,aromatic group of NTZ showed higher correlation with hydrophobic group(-CCHn)than hydrophilic group(-NCH3)of EPO(Fig.1).These results indicated that the aromatic group of NTZ formed hydrophobic interaction with EPO.Cross peaks of SAC protons with EPO protons were totally smaller compared to those of NTZ protons. In addition,the T1/T2value of SAC in NTZ/EPO/SAC solution at 11.7 was greatly different from that of NTZ(110.1)and EPO (117.0).On the other hand,the T1/T2value of SAC in NTZ/EPO/ SAC solution at 11.7 increased a little from that in unprocessed SAC solution at 3.5,indicating a slight mobility suppression of SAC.It was conceived that most of SAC molecules were freely dissolved,but small amount of SAC molecules formed the interaction with EPO in NTZ/EPO/SAC solution.

Fig.1–Comparison of the 1D spectrum of NTZ/EPO/SAC solution with the 1D-sliced spectrum at NTZ aromatic peak from 2D-NOESY spectrum.

Hydrophobic group of EPO(-CCHn)formed hydrophobic interaction with aromatic group of NTZ,leading to the stabilization of NTZ supersaturation in NTZ/EPO/SAC solution.Most of the SAC molecules were freely dissolved in NTZ/ EPO/SAC solution,and a small amount of SAC should contribute to the dissolution improvement of EPO at neutral pH.

R E F E R E N C E

[1]Higashi K,Seo A,Egami K,et al.Mechanistic insight into the dramatic improvement of probucol dissolution in neutral solutions by solid dispersion in Eudragit E PO with saccharin. J Pharm Pharmacol 2015;doi:10.1111/jphp.12469.in press.

*E-mail address:aefa3743@chiba-u.jp.

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2015.10.043

1818-0876/?2016 The Authors.Production and hosting by Elsevier B.V.on behalf of Shenyang Pharmaceutical University.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).