Elsevier

Journal of Chromatography A

Volume 1488, 10 March 2017, Pages 37-44
Journal of Chromatography A

Evaluation of drug loading capabilities of γ-cyclodextrin-metal organic frameworks by high performance liquid chromatography

https://doi.org/10.1016/j.chroma.2017.01.062Get rights and content

Highlights

  • Structured γ-CD-MOFs as stationary phase was used for drug loading and retention.

  • High correlation between retention and drug loading was observed for γ-CD-MOFs.

  • New method is highly efficient to the conventional ways of drug loading into MOFs.

Abstract

Drug loading into γ-cyclodextrin-metal organic frameworks (γ-CD-MOFs) using the impregnation approach is a laborious process. In this study, a γ-CD-MOF construct (2–5 μm particle diameter) was used as the stationary phase under HPLC conditions with the aim to correlate retention properties and drug loading capability of the CD-based structure. Ketoprofen, fenbufen and diazepam were chosen as model drugs with m-xylene as a control analyte to investigate the correlation of drug loading and their chromatographic behaviour in the γ-CD-MOF column. Furthermore, γ-CD itself was also prepared as the stationary phase by coupling with silica in the column to illustrate the enhanced interaction between drugs and γ-CD-MOF as a reference. The retention and loading efficiency of the drugs were determined with different ratios of hexane and ethanol (10:90, 20:80, 50:50, 80:20, 90:10, v/v) at temperatures of 20, 25, 30 and 37 °C. With the increment in hexane content, the loading efficiency of ketoprofen and fenbufen increased from 2.39 ± 0.06% to 4.38 ± 0.04% and from 5.82 ± 0.94% to 6.37 ± 0.29%, respectively. The retention time and loading efficiency of ketoprofen and diazepam were the lowest at 30 °C while those of fenbufen had the different tendency. The excellent relation between the retention and loading efficiency onto γ-CD-MOF could be clearly observed through mobile phase and temperature investigation. In conclusion, a highly efficient chromatographic method has been established to evaluate the drug loading capability of γ-CD-MOF.

Introduction

Metal-organic frameworks (MOFs), with the advantages of diverse structures, highly porous topologies, accessible cages and tunnels [1], [2] have been applied in gas storage [3], [4], [5], separation [6], [7] and drug delivery [8], [9]. They are synthesized with organic and inorganic components under mild conditions via coordination-directed self-assembly processes to generate exceptional properties that exceed what would be expected for a simple mixture of the components [10], [11]. Recently, environment-friendly γ-cyclodextrin metal-organic frameworks (γ-CD-MOFs) synthesized through coordination of γ-cyclodextrins (γ-CD) and potassium ions have been reported [12], [13], [14], [15], [16]. The γ-CD-MOFs are body-centered cubic extended structures with molecular apertures of 0.78 nm in the structure of γ-CD and have larger spherical voids of 1.7 nm formed by regular arrangements of CDs [13].

The γ-CD-MOFs had been demonstrated as potential carriers of Rhodamine B4-Phenylazophenol and N2, H2, CO2 and CH4 gases by adsorption within their pores. The intrinsic nature of γ-CD-MOFs is able to provide excellent biodegradability, biocompatibility, and high loading capability to the drugs [17]. Though efforts on other MOF carriers have been made to pave the way for medical applications [18], [19], few papers have been devoted to drug loading into γ-CD-MOFs systems. In an MOF-based drug delivery system, the drug loading and releasing can be controlled by adjusting the ligand length or the connectivity and functionality [19], [20], [21]. However, it is challenging to achieve high loading efficiency through common methods such as time-consuming impregnation approaches that the mixture solution of the drug and γ-CD-MOF was shaken for 24–72 h to achieve maximum payload. Therefore, an efficient alternative is of interest to facilitate the evaluation of drug loading into γ-CD-MOF.

Information retrieved from the chromatographic data can indicate the interaction between the analytes and the solid phase materials. Therefore, measures of chromatographic retention have been employed as an approach to investigate the uptake of the analytes and the activity of drugs. Vanatta and Coleman [22] determined the role of HF, H3PO4, HNO3 in their mixture equilibrium reaction by evaluating their retention in ion chromatography. Detroyer et al. [23] analyzed the contribution of different chromatography systems to obtain the pharmacological activities of 83 drugs, with the method of the combination of chromatographic behaviour and chemometrics. The γ-CD is well known to exhibit chiral recognition ability, a per(3-chloro-4-methyl) phenylcarbamate-β-CD clicked chiral stationary phase (CSP) in high-performance liquid chromatography has been explored for the enantioseparation of 39 model racemic pairs including aromatic alcohols, flavonoids, β-blockers and amino acids [24]. Additionally, the chromatographic retention behaviour of the solute also could be used to evaluate the thermodynamic and kinetic interaction between the solute and the stationary phase. Since the 1980s, Hage’s group has employed chromatographic techniques based on High Performance Affinity Chromatography (HPAC) to study the drug-human serum albumin and antibody-antigen interactions [25], [26], [27], [28]. Furthermore, our previous work also investigated the interaction kinetics between the drug and β-CD by HPAC with β-CD bonded silica as solid phase materials [29]. On the other hand, the γ-CD-MOFs showed the advantage of the extended framework to separate a widely various mixtures, such as alkylaromatic compounds, saturated and unsaturated alicyclic compounds, as well as chiral compounds, which is different from the γ-CD column [16], [30]. Because γ-CD-MOFs represent an emergent class of materials to encapsulate drug molecules, it is essential to investigate the relationship between drug loading ability and the chromatographic retention characters on γ-CD-MOF column.

In this paper, we reported a novel high-efficiency chromatographic evaluation strategy for drug loading into γ-CD-MOF by measurement of drug retention on γ-CD-MOF columns, with γ-CD columns as comparators. Acidic and basic compounds were investigated to obtain the mechanism of interaction between drugs and γ-CD-MOF to result in complex interactions. In order to explain the mechanism, nonsteroidal anti-inflammatory drugs with similar structure were employed while some of them (such as ibuprofen, naproxen and indomethacin) possessed poor chromatographic peak shape on the γ-CD-MOF column. Therefore, ketoprofen, fenbufen, and diazepam were chosen as the model drugs to investigate chromatographic behaviours under different solvents and temperatures in the γ-CD-MOF and γ-CD columns and their efficiency for drug loadings. For the drugs, ketoprofen and fenbufen are structural isomers with the similar molecular sizes and functional groups, which are compared to explain the interaction between the MOF cavities and drugs. As for diazepam, with the larger molecular size (0.81 nm) to hardly pass through the cavities in the MOF (0.78 nm), it could be employed to analyze the interaction mechanism on the γ-CD-MOF surface. And the retentions of drugs under varied chromatographic conditions were evaluated as indication of the interaction between drugs and γ-CD-MOF or γ-CD in the columns. The drug loading conditions were also optimized to obtain the maximal drug loading efficiency. In summary, a new strategy for quick evaluation of drug loading into γ-CD-MOF using chromatography is demonstrated (Fig. 1).

Section snippets

Materials

All chemicals and reagents were of high purity (analytical grades or higher). The ketoprofen, fenbufen and diazepam (>99.5% purity) were purchased from the Dalian Meilun Biotech Co.,Ltd. The o-xylene (>98.0% purity), m-xylene (>99.0% purity), p-xylene (>98.5% purity) were purchased from Sinopharm Chemical Reagent Co., Ltd. (Beijing, China). Ethanol (EtOH), n-hexane, and dichloromethane (DCM) used as mobile phase solvents were of chromatographic grade and purchased from Sinopharm Chemical

Characterization of γ-CD-MOF

The synthesized γ-CD-MOF particles were characterized by SEM, powder-XRD and the particle size distribution (Fig. 2). The shapes of γ-CD-MOF crystals were recorded as cubic and uniform by SEM with an average size of 3 μm. The crystalline characteristics of synthesized γ-CD-MOF particles were in agreement with that reported in literature [15] with the 2–5 μm particle size distribution.

As for the stability of the γ-CD-MOF, we have investigated the crystalline transformation of γ-CD-MOF in solvents

Conclusions

In this research, a high efficient chromatography evaluation methodology for drug loading to γ-CD-MOF was successfully established. For its uniformed size and shape, γ-CD-MOF had been directly used as stationary phase without conventional chemical modification on the silica. The novel strategy was proved to be efficient in the rapid evaluation of interactions between γ-CD-MOF and drugs. The solvent and temperature were identified as key factors to the correlation between retention and loading

Acknowledgements

The authors are thankful to Prof. Xinmiao Liang and his group (the Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China) for the preparation of columns. The financial support from the National Natural Science Foundation of China (No. 81573392, 81430087, 81373358) and National Science and Technology Major Project (2013ZX09402103) are gratefully acknowledged.

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    These authors contributed equally to the manuscript.

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