Cyclodextrin's Effect on Permeability and Partition of Nortriptyline Hydrochloride

Abstract

Cyclodextrin-based delivery systems have been intensively used to improve the bioavailability of drugs through the modification of their pharmaceutically relevant properties, such as solubility, distribution and membrane permeation. The present work aimed to disclose the influence of HP-β-CD and SBE-β-CD on the distribution and permeability of nortriptyline hydrochloride (NTT•HCl), a tricyclic antidepressant drug. To this end, the distribution coefficients in the 1-octanol/buffer and n-hexane/buffer model systems and the coefficients of permeability through the cellulose membrane and lipophilic PermeaPad barrier were determined at several cyclodextrin concentrations. The results demonstrated a dramatic decrease in both the distribution and the permeability coefficients as the cyclodextrin concentration rose, with the decrease being more pronounced in SBE-β-CD due to the charge-charge attraction and electrostatic interactions between NTT and SBE-β-CD. It is these interactions that were shown to be responsible for the greater value of the constant of NTT's association with SBE-β-CD than that with HP-β-CD. The findings of this study revealed similar trends in the 1-octanol/buffer 6.8 pH distribution and permeability through the PermeaPad barrier in the presence of CDs. These results were attributed to the determinative role of the distribution coefficient (serving as a descriptor) in permeation through the PermeaPad barrier modeling the lipophilic nature of biological barriers.

Keywords: HP-β-CD; PermeaPad barrier; SBE-β-CD; distribution; membrane permeability; nortriptyline hydrochloride.

Figure 1

Nortryptiline hydrochloride (NTT•HCl) (a), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (b) and sulfobutylether-β-cyclodextrin (SBE-β-CD) (c) structures.

Figure 2

Distribution coefficients, log$D_{app}^{oct/buf}$, log$D_{app}^{hex/buf}$, and ΔlogD parameter without cyclodextrins (1), with 0.0115 M of HP-β-CD (2) and with 0.0115 M of SBE-β-CD (3) in the aqueous phase for NTT•HCl at 37 °C: (a) pH of 6.8, (b) pH of 4.0 of the buffer phase.

Figure 3

Diagram illustration of the ratios between the distribution coefficients at pH of 6.8 ($D_{app}^{Org/buf(pH6.8)}$) and pH of 4.0 ($D_{app}^{Org/buf(pH4.0)}$) of the buffer phase; C_CD = 0.0115 M.

Figure 4

Diagram illustrating the trends of the variations in the distribution coefficients in the 1-octanol/buffer system ($D_{app}^{oct/buf}$) following the CD concentration growth at different pH values of the aqueous phases; the cyclodextrin concentrations are shown under the columns; 37 °C.

Figure 5

Plots of the dependencies used to calculate the association constants of NTT•HCl with cyclodextrins at a pH of 6.8 and a pH of 4.0 versus the experimental distribution coefficients in the 1-octanol/buffer system, log scale, 37 °C; the straight lines refer to a buffer pH of 6.8; the dash lines refer to a buffer pH of 4.0.

Figure 6

Comparison of the association constants of NTT•HCl with HP-β-CD and SBE-β-CD at a pH of 4.0 and a pH of 6.8 of the aqueous phase of the 1-octanol/buffer system, 37 °C.

Figure 7

Zeta potentials of NTT•HCl solutions in the presence of HP-β-CD and SBE-β-CD in comparison with those in pure buffer pH of 6.8. The CD concentrations are indicated under the columns of the diagram.

Figure 8

Coefficients of NTT•HCl permeability through the PermeaPad barrier (PP) and regenerated cellulose membrane (RC) in the absence and in the presence of HP-β-CD and SBE-β-CD; logarithmic scale; 37 °C.

Figure 9

Coefficients of permeability through the PermeaPad barrier (P_app (PP)) and distribution coefficients ($D_{app}^{oct/buf(pH6.8)}$) at different CD concentrations: P_app (PP) is denoted by filled points and straight lines, $D_{app}^{oct/buf(pH6.8)}$ is shown by empty points and dashed lines; HP-β-CD is represented in green, SBE-β-CD is represented in violet.