Keywords: Metal Organic Frameworks; Isoleucine; Copper; Single Crystal XRD Analysis; High Performance Liquid Chromatography (HPLC); Terazosine Hydrochloride; Telmisartan; Glimpiride
As the MOFs are based on the organic linker molecules and the coordinating metal cations so their synthesis and structural diversity mainly depend upon the selection of linker as well as metal cations [6,7]. One key advantage is that the possible linker molecules for synthesis of MOFs are infinite including phosphonates, sulfonates, polycarboxylates, pyridyl, phenolates and amines etc [8-10]. So MOFs of desired properties can be designed for synthesis by functionalization of MOFs with suitable linkers and metal cations [11-13].
For synthesis of MOFs with better drugs storage properties, nitrogen containing linkers such as amino acids are the best choices which have no toxic effects [14]. Similarly bio compatible metal cations like copper, nickel and manganese are suitable to synthesize MOFs both for In vitro and in vivo drugs adsorption studies [15].
According to some preliminary research reports, amino group containing linker molecules were used for the construction of frameworks suitable for the drugs adsorption [21-23]. MIL-100, MIL-101(Fe), MIL-101(Cr), MIL-53(Fe), MIL-53 (Cr) have been reported with amount of adsorbed drug 1.37, 0.35, 0.35, 0.22, 0.21 g/g and with time release (days) 6, 3, 3, 21, 21 respectively. Also Bio-MOF-1 and Bio-MOF-100 have been reported in recent years with special topology of amino based linker molecules having drugs storage capacity of 0.2 g/g [24,25].
The present work is based on the hydrothermal synthesis of a new bio metal organic framework (Bio-MOF-30) in which bio linker isoleucine and copper cation (trace element necessary for human health) have been used. This new Bio-MOF-30 has been designed to be used as a drug carrier. In vitro studies of drug adsorption have been carried out in the present work, which may lead to the in vivo drug adsorption investigations.
In a cleaned glass beaker Isoleucine (0•17 g, 0•2 mmol) and copper chloride CuCl2•2H2O (0•35 g, 0•2 mmol) were dissolved in 10mL distilled water. This solution was well stirred for half an hour. pH of the solution was maintained at 10 by using sodium carbonate (Na2CO3). This solution was then transferred to a 23 mL teflon lined autoclave. The autoclave was placed in oven at 150°C for three days. After three days fine quality blue colored elongated crystals were obtained from it. These crystals were collected, washed with water and acetone and were dried.
Elemental Analysis of Bio-MOF-30, [C12H26N2O5Cu],
Theoretical: Cu= 18.59 %, C= 42.15 %, H= 7.68 %, N= 8.19 %,
Experimental: Cu= 18.67 %, C= 42.17 %, H= 7.72 %, N=8.23%.
(KBr 4000-400 cm-1) : 3641.4(br), 3188.1(br), 3089.8(br), 2636.5(br), 1633.6(br 1548.7(m), 1416.70(m), 1334.6(m), 1274.9(s), 1218.9(s) 1141.8(s), 1029.9(s), 794.6(s), 511.1(s), 459.0 (s), 412.7 (s).
Thermograms of Bio-MOF-30 before and after drug loading were recorded on SDT Q600 under a N2 atmosphere from 0°C to 600°C at a heating rate of 10°C/min. FT-IR spectra of Bio-MOF-30 (see supplementary material) were obtained from Shimadzu 8400 FT-IR by preparing KBr pellets of Bio-MOF-30. Powder XRD pattern of Bio-MOF-30 before and after drug adsorption were recorded on Bruker D2 Phaser. HPLC studies of the drugs soaked Bio-MOF-30 were carried out on an HPLC instrument, Waters 2695 Separation Module to estimate the amount of drugs adsorbed and also to observe its slow release after intervals.
For the determination of an XRD crystal structure of Bio- MOF-30, a single crystal was used on a Brucker Smart Apex II CCD area detector diffractometer with graphite monochromated MoKα ( λ= 0.71073 Å) radiation. A crystal of Bio-MOF-30 was mounted in a glass capillary and data were collected at 273 K. For the sake of the data collection and refinements all computer programs used were contained in the Bruker program packages Smart, Saint, and SHELXTL [27].
Direct methods have been used to solve the structure in order to locate the position of copper and most of the hydrogen atoms. Subsequent Fourier Transformation Techniques were used to locate and expand the position of the remaining non hydrogen atoms. Final difference Fourier syntheses described only chemically insignificant electron density. All the hydrogen atoms were placed in surely idealized positions. All non hydrogen atoms were refined by anisotropic method and were further refined with the aid of program SHELXL97 (Sheldrick 1997) by the use of a full- matrix least-square calculation on F2.
One dimensional growth of the crystal lattice has been shown in Figure 2. Certain spaces in the crystal lattice are maintained through hydrogen bonding and this packing through one dimensional pillar of lattice results in the development of pores of discrete sizes which can be used for the storage of drug molecules. CCDC-1417408 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge crystallographic data centre, 12 Union Road Cambridge CB21EZ, UK (fax: (+44)1223-336-033; or E-mail; deposit@ccdc.cam.ac.uj). The crystal data parameters have been summarized in Table 1.
Empirical formula |
C12 H26 N2O5Cu |
Formula weight |
341.90 |
Temperature |
273(2) K |
Wavelength |
0.71073 A |
Crystal system, space group |
Orthorhombic, P2(1)2(1)2(1) |
Unit cell dimensions |
a=5·0212(7)Å |
Volume |
1564·22(12) A3 |
Z, Calculated density |
2, 1·452 Mg/m3 |
F(000) |
723 |
Crystal size |
0·32 x 0·17 x 0·11 mm |
Theta range for data collection |
2·50 to 25·49o |
Limiting indices |
-8<=h<=9, 8<=k<=11, 26<=l<=23 |
Reflections collected / unique |
9255 / 2901 [R(int) = 0·0197] |
Completeness to theta = 25·49 |
99·8 % |
Maximum and minimum Transmission |
0·8598 and 0·6601 |
Refinement method |
Full-matrix least-squares on F2 |
Data / restraints / parameters |
2901 / 0 / 205 |
Goodness-of-fit on F2 |
1·062 |
Final R indices [I>2sigma(I)] |
R1 = 0·0226, wR2 = 0·0609 |
R indices (all data) |
R1 = 0·0243, wR2 = 0·0620 |
Absolute structure parameter |
0·014(13) |
On the other hand the thermogram of the terazosine loaded Bio-MOF-30 indicates the first weight loss of nearly 11 % at 50°C which is due to the loss of adsorbed terazosine molecules. Then up to 145°C the framework shows stability after that weight loss of 24 % can be observed up to 166°C which is due to removal of coordinated water molecule. Gradual decomposition of framework and ligands starts after 300°C. After that maximum weight loss of 60 % at 596°C shows framework decomposition along with the remaining adsorbed terazosine molecules.
Thermogram of telmisartan loaded Bio-MOF-30 indicates the first weight loss of nearly 5 % at 35oC which is due to the loss of adsorbed telmisartan molecules. Then up to 150°C the framework shows stability, after that a weight loss of 13 % is observed up to 155°C which is due to the loss of coordinated water molecule. Then a gradual decomposition of framework and ligands starts which continues till 334°C with maximum weight loss of 68 %. After that at 590°C whole framework decomposes along with the remaining adsorbed telmisartan molecules.
While thermogram of glimpiride loaded Bio-MOF-30 indicates the first weight loss of nearly 4 % at 45oC which is due to the loss of adsorbed glimpiride molecules. The framework shows stability for some time and at 180°C the weight loss of 10 % is observed which is due to the loss of coordinated water molecule. Then up to 345°C the framework remains intact, after that gradual decomposition of framework and ligands starts which continues till 355°C with maximum weight loss of 45 %. At 598°C whole framework decomposes with weight loss of 65 % along with the remaining adsorbed glimpiride molecules.
582399.66, 23276347, 10678092 were mean peak areas calculated for standards of terazosine hydrochloride, telmisartan and glimpiride respectively. Chromatograms, peak areas of all the samples of water containing released drugs (terazosine hydrochloride, telmisartan, glimpiride) collected after different time intervals for HPLC studies for estimation of drug contents, calculations and estimations of different drugs in Bio-MOF-30,have been given as supplementary material.
In Bio-MOF-30 three different drugs (terazosine hydrochloride, telmisartan and glimpiride) have been successfully adsorbed. 0.21 g/g material of terazosine hydrochloride has been estimated in Bio-MOF-30. Highest release of terazosine contents from drug adsorbed Bio-MOF-30 was estimated after one day, which gradually decreased with passage of time as has been determined from HPLC calculation of samples collected at different times (see supplementary material) but no terazosine contents were found in aliquot of Bio-MOF-30 taken on the eleventh day.
0.1 g/g material of telmisartan has been estimated in Bio- MOF-30. Highest release of telmisartan contents were estimated in aliquot of water containing released drug after one day which decreased on the third day and no telmisartan contents were found in aliquot of water containing released drug taken on fifth day.
0.6 g/g material of glimpiride has been estimated in Bio- MOF-30. Highest release of glimpiride contents were estimated in aliquot of water containing released drug after one day. Next release was observed after three days. But no glimpiride contents were found after three days.
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