Drug Intercalated Layered Double Hydroxides As A Molecular Container: Study Of Assembly And In Vitro Release Mechanism

A series of drug intercalated layered double hydroxide (drug-LDHs) are prepared by ion-exchange and coprecipitation method, respectively. The inherent interrelations of synthesis routes, layer charge density, supramolecular structure, and thermal property were deeply studied using XRD, FT-IR, ICP, CHN, SEM, TG-DTA, Raman, and UV-Vis analyses. The mechanisms of both synthesis routes are revealed. The ion exchange product was originated from gradual topological mechanism. The coprecipitation product was resulted from in situ self-assembly mechanism. The inherent interrelation between in vitro release behavior of drug-LDHs and its composition, crystal structure, and crystallite size has been systematically studied. The structure and compostion of both quasi-guest ion-cluster/pair (QIC) and reaction product (RP) in restricted spacing of LDHs have been studied, respectively. The release behavior and thermal property of LDHs with QIC and RP have been studied, respectively. The kinetic studies indicate that the release mechanism of drug-LDHs is intra-particle diffusion. The drug release rate of drug-LDHs can be controlled by tunning the crystallite size of LDHs in (110) phase direction (D₁₁₀).5-aminosalicylate (5-ASA) intercalated ZnAl-LDHs with variable Zn/Al molar ratios have been synthesized by both direct coprecipitation (CP) and indirect ion exchange (EX) methods. The supramolecular structure and the loading percentage are highly dependent on the synthesis routes and the layer charge density of 5-ASA intercalated ZnAl-LDHs. The EX intercalates was originated from a gradual topological mechanism. The CP intercalates was resulted from the in situ self-assembly mechanism. Four schematic supramolecular structural models of 5-ASA intercalates have been proposed, including the staggered dentate-like monolayer arrangement, the vertically adjacent monolayer arrangement, the vertically distant bilayer arrangement, and the vertically adjacent bilayer arrangement. The EX products exhibit highly ordered crystallite than CP ones, and the intercalates with higher layer charge density, i.e. the lower Zn/Al ratios, exhibit more ordered crystal structure than higher thermal stability than those with lower layer charge densities. The ion exchange products have broad potential applications due to their fine crystal structure and high thermal stability.Diclofenac (DIC) and ibuprofen (IBU) intercalated MgAl-LDHs (DIC-LDHs and IBU-LDHs) with variable crystallite sizes (D₁₁₀) have been successfully prepared via ion-exchange method. The in vitro release behavior of them has been systematically studied. The in vitro release studies show that the cumulative release percentages increase with increasing release time until the equilibrium attained. The release rate is fast at beginning and following a slower rate as the release time increases. The release rate decreases with increasing D₁₁₀ of drug-LDHs. The release rate also decreased with decreasing temperature of release medium. The drug release kinetics is analyzed by fitting the release data using Bhaskar equation, indicating the intra-particle diffusion mechanism. The diffusion active energy of DIC and IBU intercalates are 88～93 KJ/mol and 59～70 KJ/mol, respectively. The IBU-LDHs depicts faster drug release rate and lower active energy than those of DIC-LDHs. The strong guest-guest interaction and the change in the geometry of the intercalated DIC anions in restricted spacing of the LDHs matrices demonstrate the possibility of QIC in the gallery of the intercalate. The QIC including 2 or 3 DIC anions is formed through conjugated interaction, hydrogen bonding, and van der waals force between interlayer DIC anions. The QIC may result in larger diffusion resistance and different intergradations during the release process, which results in lager diffusion active energy and slower drug release rate. The thermal stability of the intercalated IBU anion is significantly enhanced compared with that of pure IBU. This phenomenon is attributed to the host-guest interaction between the positively charged LDHs layer and intercalated IBU anion. However, with respect to DIC-LDHs, thermal decomposition temperature of DIC anion obviously decreases upon intercalation. The QIC induces the change in the minimum energy geometry of intercalated DIC anion, and consequently weakening the thermal stability of the intercalated DIC anion. It is proposed that the flexible organic molecule containing phenyl ring with substituted polar group trend to assemble the QIC in LDHs matrices, such as diclofenac, indomethacin, tolfenamic acid, and long-chain anionic surfactants.Captopril (Cpl) intercalated MgAl-LDHs (Cpl-LDHs) has been assembled by coprecipitation method. The Cpl-LDHs shows a successful intercalation of Cpl between the LDHs layers with a vertically interdigitated bilayer orientation containing plausible S-S linkage. SEM photo indicates that as-synthesized Cpl-LDHs possesses compact and non-porous structure with approximately and linked elliptical shape particles of ca. 50 nm. TG-DTA analyses suggest that the thermal stability of Cpl is largely enhanced upon intercalation. The in vitro release studies show that both the release rate and release percentages markedly decrease with increasing pH from 4.60 to 7.45 due to possible change of release mechanism during the release process. The XRD and FT-IR analyses for samples recovered from release media indicate that the dissolution process are mainly responsible for the release behavior of Cpl-LDHs at pH 4.6, while the ion-exchange one responsible for that at pH 7.4. The drug release kinetics is analyzed by fitting the release data using Bhaskar equation, indicating the intra-particle diffusion mechanism. It is noticed that the release mechanism of Cpl-LDHs is same as that of IBU-LDHs and DIC-LDHs. The drug release mechanisms of drug-LDHs with interlayer guest species of single anion, QIC, or RP, are intra-particle diffusion. The drug release rate of drug-LDHs can be controlled by tunning the in-plane dimension of LDHs (D₁₁₀). The drug-LDHs exhibits the broad potential applications in drug slow/controlled release system, improving the thermal property of drugs, protecting the active and air-sensitive functional group of drugs, and so on.Assembly of LDHs and magnetic materials may provide a novel route fordeveloping magnetic targeting drug delivery system. A spinel magnetic core(NiFeO) was synthesized using LDHs layered precursor method. Then,MgAl-LDHs with interlayer CO₃^2- was in situ growth on the surface of spinelin the presence of urea (MgAl-LDHs/NiFeO). The XRD, FT-IR, ICP, andSEM-EDS techniques were employed to characterize the core/shell structureof MgAl-LDHs/NiFeO, demonstrating the interaction between theMgAl-LDHs and NiFeO. The core/shell structure of MgAl-LDHs/NiFeOexhibits quite stablity within the NiFeO content of 20 30 wt%. It is believedthat a part of Al³⁺ has moved into the clearance of crystal lattice in NiFeO. Themeasured saturation magnetization intensity falls in range of 10.4 12.8emu/g. In situ HT-XRD, TG-DTA-MS and BET were used to monitor thethermal decomposition process of MgAl-LDHs/NiFeO, indicating thegradually losing of absorption and interlayer water, interlayer CO₃^2-, andlayered O-H group. The specific surface area of MgAl-LDHs/NiFeO is 26.9m²/g at 20℃, and increases to 102.0 m²/g after calcining at 500℃, which is lower than that of pure CO₃-LDHs calcined at same temperature, ascribing to the interaction between the magnetic core and CO₃-LDHs. The MgAl-LDHs/NiFeO and its calcined product can be used as a novel magnetic targeted antacid drug.