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Summer Research Fellowship Programme of India's Science Academies

Synthesis and characterization of LDH drug complexes

Ms. Supan

Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India

Prof. S.Vasudevan

Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bengaluru 560012, India

Abstract

​The core idea behind this project is to make a thorough study of the host-guest chemistry and to understand in detail the 3-D structure of a host, the shape and size of the guest and the various interactions involved when a specific guest is intercalated in a various different types of hosts and vice versa. Basically, it is a study of interaction of metal atoms of the layers with the interlayer anions which could be either organic or inorganic. Then, by frequently changing the interlayer anions by different guest molecules, various combinations could be prepared. Thus, by intercalating the anions (which may be different drugs or other useful organic moieties), these metal-organic frameworks could be built, which may help in controlled release of various compounds in the surrounding environment that may help in exploiting the various physical and chemical properties of the compound concerned. The main emphasis of this project is to study in detail the Layered Double Hydroxides (LDH's), their synthesis, intercalation by various guests and then the modification by functionalization. Its main aim is a detailed study of LDH's and how their behaviour is modified by introduction of different host species. The nature and physical characteristics of LDH and other guest species are studied via various spectroscopic techniques and a very clear estimate could be made regarding the extent of intercalation, the position of various peaks and their significance so as to know about the purity and usage of these host-guest moieties. So, this project will teach us about the various supramolecular interactions responsible to hold the two interacting species together and thereby their role in transporting a specific guest species to its target point. It will also teach about the efficient data interpretation, usage of various spectroscopic techniques to evaluate the data, handling of various instruments and many more things.

Keywords: LDH's, intercalation, supra molecular interactions, recrystallization

Abbreviations

Abbreviations
LDH Layered Double Hydroxide
CD Cyclodextrin
CMCD Carboxymethyl-β-Cyclodextrin
IBU Ibuprofen
RBF  Round Bottomed Flask 

INTRODUCTION

Background/Rationale

Synthetic inorganic materials which have well arranged voids and surfaces come under the category of metal-organic frameworks and show very useful properties that could solve the various environmental and industrial problems. Layered Double Hydroxides are a type of layered materials which belong to a class of ionic solids with the general formula [M'²​+(1-x)M3+x(OH)2](An-)x/n.zH2O; where M3+ and M'2+ represents the metal ions and An- represents the interlamellar ions. These layered materials have been in use since long as they have easily exchangeable anions in the interlamellar region which could be used to modify LDH's. They are a family of both natural and synthetic materials referred to as anionic clays. They are the most promising layered materials due to their properties such as unique structure, ease of synthesis, uniform distribution of metal cations, flexible tunability, high chemical and thermal stability, surface OH groups and many more. These are the materials which have strong iono-covalent bonding within the layers and weak vanderwaal forces in between the layers. Due to the weak forces in the inter layer anions, these anions could be easily exchanged i.e. the replacement is a reversible process. Thus, by changing the number and type of intercalated anions a large number of metal-anion combinations can be synthesized. These lamellar solids have the advantage of having well arranged voids that have brilliant properties of solving the various industrial and environmental problems. LDH's have the property of having high chemical stability and a huge chemical dependence.

Problems

The basic problem that demands the formation of such modified metal-organic frameworks is the fact that many toxic gases are being released in the atmosphere that may cause several environmental issues. Moreover, the excessive use of pesticides in the fields may cause several problems to the crop yield and to the health of the population consuming them. Also, the dosage and location of drug delivery is also uncertain and any irregularity in its transfer may lead to several irregularities, be that in a human body or in any other artificial system. These sort of intercalations could benefit to a larger diversity of population ranging from micro-organisms to human beings. So, the modification of the host with the guest species would increase the functional diversity which thereby increases the applications of LDH in various ways such as role in waste water treatment, acting as catalytic precursors, adsorbents,controlled drug release systems etc. The main challenge in the intercalation process is not the simple introduction of a guest species inside the host but rather the intercalation of a guest species inside the cavity of another guest which itself has already been intercalated inside a suitable host i.e. a guest within a guest. The main factors to be taken into consideration are the various charges carried by the host-guest species, the size of the cavity in which the guest species is to be placed, the various interactions involved etc. The stability of the complex formed after intercalation is to be carefully observed as - in case an anion with larger dimensions is intercalated in the inter layer region, it may increase the inter layer spacing resulting in the formation of an imbalanced complex which is not stable enough. Working with LDH is a very fruitful task because once something useful is synthesised, it could be used in very diverse fields i.e. the scope of this topic is very vast.

Objectives of the Research

It is very clear that the introduction of various guest species improves the applications and efficiency of the host and the very important and foremost use of such an intercalation is the systematic and controlled drug delivery, be that in the human body or in other organisms. Other use of the modified LDH is that it can act as an adsorbent that can help in the removal of pesticides and other harmful, poisonous gases prevailing in the atmosphere. These LDH's could be used to remove several water contaminants such as DNP, 2-methyl-4,6-dinitrophenol. Also these could be used as anion exchangers which could hold the pesticides inside their cavity and thus according to the surrounding pH and other factors, its release in the surrounding environment is controlled wisely and the soil is not contaminated by the excess release of harmful pesticides and other chemicals.

Scope

The present topic i.e. host guest chemistry in case of metal organic frameworks is a very useful topic with a huge emphasis on the formation of new intercalated complexes with abundant usage and simplicity that once something worthful is made out of it, it will make the work more efficient and less time consuming. The most useful benefit of it is that if such an complex and nano scale intercalation is ever done, it will leave a mark not only in one or two fields but in multiple fields. It is just that a consistency, efficiency and determination is required in such useful and sensitive intercalations.

LITERATURE REVIEW

Information

LDH's consist of layers of divalent and trivalent ions with intercalated weakly held layers of anions which are easily exchangeable i.e. the insertion of guest species is reversible. Thus, by changing the number and type of intercalated anions a large number of metal-anion combinations can be synthesized. It is necessary that M3+ and M'2+ must have almost similar ionic radii. Due to the high tunability and anion exchange capacity, LDHs have turned into an emerging class of layered materials which are suitable for the preparation of layered crystal nano composites. The special Mg-Al LDH is a hydrotalcite due to the presence of OH- ions in Hexagonal Close Packing where the Mg/Al ratio range between 2 and 4. The divalent and trivalent ions are usually taken from the third and fourth periods of the periodic table.

Picture2.png
    General structure of LDH Composites

    Some anions that can be intercalated to modify LDH are given below :

    Various anions to be intercalated in CMCD
    Type of Anions Examples
    Inorganic Anions Halides, silicates, borates, PO43-, NO3-, CO32-
    Organic Anions Carboxylates, alkane sulphonates, alkyl sulphates, chlorocinnamates, glycolate, organic dyes and drug molecules
    Polymeric Anions Polyvinylsulfonate, polyacrylate, polyaniline, polyethylene glycol, ionized poly vinyl alcohol, polystyrene oligomer anion
    Biologically Important Anions Various amino acids, DNA, CMP,ATP, ADP, vitamins, enzymes and phospholipids

    Likewise, the guest species, in order to maintain the charge neutrality are required to be anionic in nature as the insertion of non polar or weakly water soluble guest molecules is not possible. To overcome this limitation, a variety of guest molecules are required to be included inside the inner walls of LDH. So, CD's are the cyclic oligomers consisting of 6-8 d-gluco-pyranose units which form inclusion complexes with various low molecular weight compounds. The driving force for the formation of inclusion complexes in aqueous media are mostly hydrophobic or vanderwaals interactions. A wide variety of guest molecules could be introduced inside β-CD cavity which may include neutral species like iodine or bromine and organometallics like ferrocene that forms 1:1 complexes with the host. The guest species that is intercalated in this report is the carboxy methyl derivative of β-CD. Moreover, the intercalation of IBU have also been tried out and further a guest within a guest( which is already intercalated inside a specific host) species have also been prepared.

    METHODOLOGY

    Concepts

    The very basic method involved in all types of synthesis included in this report work is Co-precipitation which is the very elementary way of carrying out any reaction process.

    Just before we start the intercalation of one sort of ionic species into the other the very first task is to synthesize the basic host and guest species individually. The prime host over which all the modifications are based in this report is LDH. So, the very first step would be the synthesis of LDH. As it is mentioned earlier also that layered double hydroxides have the hydroxyl ions arranged in the Hexagonal Close Packing lattice with divalent and trivalent ions occupying adjacent layers with the anions intercalated in between the layers. Anions are intercalated in between the layers for charge balance.

    Objective

    Numerous applications of LDH are based on ion-exchange reactions, so it is very important to choose an anion that undergo easy ion exchange reactions. Generally, LDH's containing nitrate ions are preferred starting materials for ion-exchange reactions as nitrates have less affinity to interlayer region. The first task is to prepare LDH which is followed by its intercalation and further modifications.

     Synthesis

    Preparation of LDH

    The synthesis of LDH can be carried out by Co-precipitation, ion-exchange and hydrothermal methods etc. The method used in this report work is Co-precipitation.

    • METHOD

    Co-precipitation method is used in the formation of LDH in which two different metal nitrate solutions of known volume have been mixed and added drop wise to an alkaline medium which is maintained at a specific pH of 8-9. The reaction is carried out at constant pH. The Mg-Al LDH has been prepared by taking 10mmol of Mg(NO3)2.6H2O and 5mmol of Al(NO3)3.9H2O (i.e. the ratio of Mg to Al is 2:1) in a RBF and dissolving in 30 ml of distilled water. Sodium Hydroxide was added drop wise to the solution with constant stirring and the pH maintained at 8. Then this mixture was heated at 60°C in oil bath and vigorously stirred for one hour and aged overnight(24 hours). The precipitates thus obtained have been washed, filtered and dried.

    Preparation of CMCD

    CMCD is the guest species which is supposed to be intercalated in between the layers of the host i.e. LDH. CMCD is basically a derivative of CD which is easily available commercially. The specific CD form used here is the β-form of CD which is derivatized following a specific route.

    • METHOD

    Took 5gm of β-CD and 4.65gm of NaOH and dissolved them in 18.5ml of water. In a separate beaker, 16.3% mono chloro acetic acid was prepared and then mixed with the solution containing CD and NaOH. Then the reaction mixture was heated at 50°C and kept for 5 hours. After the completion of 5 hours, the reaction mixture is kept for cooling at room temperature and pH adjusted to (6-7) using 1N HCl solution. Then excess of methanol has been added to the neutral solution (taken in small fractions) which resulted in the formation of white precipitates. These precipitates were properly washed with excess of methanol and the white solid precipitates obtained have been filtered and dried in vacuum to give carboxymethylated β-CD.

    Once CMCD have been prepared, it is required to know the exact number of carboxy methyl groups introduced to β-CD which is done by titrating it with NaOH solution using Phenolphthalein as an indicator. From the calculations thus made, the number of carboxy methyl groups introduces come out to be 2.2

    Intercalation of CMCD to LDH

    Now as both the host and guest species are prepared, the next step would be the intercalation of the guest moiety to the host. This guest species would be introduced into the interlayer spacing of the host i.e. LDH. The intercalation of β-CD cavities in Mg-Al LDH was achieved by replacing the NO3- ions by methyl-carboxylate derivatized β-cyclodextrin via ion-exchange method.

    • METHOD

    100mg of Mg-Al LDH-NO3 has been added to 10ml of 10mmol aqueous β-CMCD and the solution kept for stirred and heating at 65°C for 24 hours. After this, the precipitates have been centrifuged and washed extensively and properly with normal distilled water. They have been kept for drying and after some time pure crystals obtained have been preserved in which CMCD is intercalated in between the layers of LDH which thereby balance the positive charge accumulated in the adjacent layers.

    Intercalation of Ibuprofen to LDH

    Ibuprofen-structure.png
      Ibuprofen

      Till now we are clearly aware of the fact that a guest species carrying negative charge is required to be placed in the inter layer cavities to replace the already present anions. This intercalation is also performed via ion-exchange method where a specific solvent ratio is required to be maintained to carry out the reaction.

      •  METHOD

      IBU is obtained commercially in the form of tablets (drug to be consumed in case of any illness) which may contain many other chemical salts, so pure IBU is required to be recrystallized before it is used for the intercalation. The process of recrystallization was carried out by dissolving the IBU tablets in minimum amount of methanol solvent and then filtered the solution to remove the undissolved part and then kept the solution for cooling so that the solvent evaporates and pure crystals of IBU are obtained.

      Now as the pure form of IBU is obtained, it can be intercalated in LDH. Took 100mg of LDH and 5mmol of IBU and added to it 10ml of 3:2 methanol: water solution and took this entire mixture in RBF and the entire reaction was carried out in nitrogen atmosphere at room temperature with continuous stirring for 24 hours. The resulting precipitates were filtered and washed with hot distilled water. These precipitates are allowed allowed to dry to give the intercalated IBU derivative of LDH.

      Intercalation of IBU in CMCD

      IBU can be intercalated in the cavity of Carboxymethyl derivative of β-CD. Though their intercalation is not an easy job as both of them have the same COO- group i.e. the same negative charge but still we happen to get some intercalation.

      Intercalation of CMCD in Ibu derivatized LDH

      Now as the intercalation of LDH by IBU is successfully done, the introduction of CMCD into the layers could be done. This process would be exactly similar to the one followed for the addition of CMCD into LDH interlayer spacing.

      •  METHOD

      50mg of IBU intercalated Mg-Al LDH-NO3 was added to 5ml of 5mmol aqueous β-CMCD and the solution was stirred and heated at 65°C for 24 hours. After this, the precipitates obtained were centrifuged and extensively washed with normal distilled water. They were then kept for drying and after some time the crystals were obtained in which CMCD was intercalated in the IBU derivatized LDH.

      RESULTS AND DISCUSSION

      All the synthesis carried out in this project i.e. all the samples perpared have been tested via various techniques such as X-Ray Diffraction, IR Spectroscopy, Raman Spectroscopy which in one way or other helps us to know the purity and accuracy of the sample prepared.

      So, here the various XRD plots, IR patterns and Raman Spectra are discussed.

      XRD Plot for the Formation of LDH

      Picture1.png
        XRD plot of LDH

        The above plot clearly shows that LDH prepared is in perfect crystalline form without any impurity. This is because of the layered morphology of LDH's that the crystallites exhibit a pronounced preferred orientation and thus only 00l reflections are possibly seen in XRD pattern. The 00l reflections can be indexed with the interlayer spacing (d) of 8.9Å which is similar to theliterature value. The thickness of Mg-Al LDH layer is 4.8Å which is same as that for a brucite-layer and if the thickness of the brucite-like layer is subtracted from the d value, the galary height could be estimated as 4.1Å. This is rougly the vanderwaal's diameter for nitrate ion.

        Mg-Al-NO3 is used as the starting material for the preparation of CD and IBU functionalized LDH.

        IR Pattern for the Formation of CMCD

        CMCD_2.jpg
          IR peaks for CMCD

          IR Spectra for CMCD Intercalated LDH

          LDH_CMCD_1.jpg
            IR pattern of Mg-Al LDH - CMCD
            IR data comparison (cm-1)
            β-CMCD  Mg-Al LDH-CMCD  Assignment 
            3422  3333  O-H stretch 
            2921  2935  C-H stretch 
            1593  1577   C-O stretch of -COO
            1419  1409   O-C-H, C-C-H
            1156  1160   C-O stretch
            1033  1013   C-C stretch
            427   M-OH stretch

            XRD Data for CMCD Intercalated LDH

            LDH_CMCD_XRD.jpg
              XRD peaks for Mg-Al LDH-CMCD

              The ion exchange intercalation of β-CMCD with an average degree of carboxy-methyl substitution of 3.8 per β-cyclodextrin molecule occurs with an increase in the inter-layer lattice spacing from 8.9Å to 24.5Å(apprx.) is shown by the XRD data. The observed spacing for intercalation ranges between 20.63Å and 26.8Å, depending on the degree of carboxy-methyl substitution.

              Raman Data for CMCD Intercalated LDH

              raman.png
                Raman spectra for CMCD intercalated LDH

                IR Data for the Intercalation of IBU to LDH

                LDH_IBU_1.jpg
                  IR pattern for IBU intercalated LDH
                  IR data for LDH-IBU
                   LDH-IBU Assigmnents 
                   2968 CH3 asym. stretch 
                   2956 CH3 sym. stretch 
                   1588 C=O asym. stretch of COO- 
                  1462  CH2 stretch 
                   665,524 M-OH stretching of LDH layers 

                  IR Data for the Intercalation of CMCD to LDH-IBU Complex

                  LDH_IBU_CMCD_IR.jpg
                    IR pattern for intercalation of CMCD to LDH-IBU complex

                    Purpose

                    This project deals with the functionalization of Mg-Al LDH by anchoring anionic surfactants or cyclodextrin cavities to the galary walls. The main motive is to extend the host guest chemistry of LDH from simple ion exchange reactions to the inclusion of non-polar or poorly water soluble species in the same way as cyclodextrin cavities can solubilize these species in aqueous media. The host is chosen such that the charge density of the layers can be tuned by tailoring the Mg/Al ratio, which in turn control the density of intercalated anions. They are non-toxic and economically viable. Moreover, the offer a convenient spectral window in IR and Raman and we can even go for the XRD analysis of data. The anionic form of non-steroidal, anti-inflamatory drug molecule like ibuprofen have been ion exchange intercalated and the confined drug molecules characterized by XRD and other spectroscopic techniques. In case of intercalation of CMCD, the anchored cavities are arranged as bilayers with their opening faces away from layers and hence the interior is accessible to guest molecules.

                    CONCLUSION

                    Inorganic solids possessing layered structure in which the guest molecules and ions reside in the inter lamellar sites offer unique route for the design of hybrid materials. In most of these solids, the interactions are coulombic with the guest species compensating for the charge deficit in the inorganic layer as a result of which the host-guest chemistry is limited to ion-exchange reactions only. The range of guest species varies from being neutral to poorly water soluble just by proper functionalization of the internal walls of the galleries of the layered solid. So, In this report a detailed description of the varied functionalization of Mg-Al LDH (be that using CMCD or IBU) and anchoring the anionic species to the cavity walls is discussed. Moreover, a new sort of intercalation is also been discussed that includes the introduction of CMCD into the already intercalated host-guest complex of IBU in LDH. Though such an intercalation is not an easy job due to the various charge imbalances or other spacial hinderance or the undesired interactions, but still working in this field may result in many fruitful outcomes that may bring many useful activities being done at a very cheap, easy, affordable and efficient manner. Although the present work is mainly based on Mg-Al LDH as the only inorganic host, the methods discussed here can easily be exchanged to other inorganic solids by appropriate choice of derivatized cyclodextrin or other drugs.

                    REFERENCES

                    • M. Meyn, K, Beneke and G. Lagaly, Inorg. Chem. 29, 5201 (1990)

                    • V. Ambrogi, G. Fardella, G. Grandolini and L. Perioli, Int. J. Pharm. 220, 23 (2001)

                    • H. Zhao and G. F. Vance, J. Chem. Soc. Dalton. Trans. 11, 1961(1997)

                    • L. Mohanambe and S. Vasudevan, Host-Guest Chemistry of a Functionalized Layered Double Hydroxides; J.Phys. Chem.B, 109, 15651-15658 (2005).

                    • L.. Mohanambe and S. Vasudevan, Host-Guest Chemistry of a Functionalized Layered Double Hydroxides; Langmuir, J.Phys. Chem.B, 21, 10735-10742 (2005)

                    ACKNOWLEDGEMENTS

                    I express my sincere gratitude to IAS/INSA/NASI for giving me the opportunity to work at IISc, Bangalore. I thank the Department of Inorganic and Physical Chemistry, IISc for providing me with all the facilities and all the indirect help that somehow helped me to successfully complete my project.

                    I would like to express my reverent gratitude and indebtedness to my guide Prof. S.Vasudevan for his consistent help and excellent guidance all through my two months of internship that allowed me to accomplish my target on time. I owe a lot to him for providing me with all the necessary facilities.

                    I would also like to express a sincere thanks to Ms. Ritu Ghanghas for her presence all time around me, to help me all throughout with her most valuable guidance. A very special thanks goes to Mr. Manoj Kumar and Mr. Sohel Reja who ended up being the most supporting and helpful lab mates with the most lively and encouraging spirit. All this work would not have been possible without their consistent guidance and consent. Lastly, I would like to mention a big thanks to Mr. Aman and Ayesha for maintaining a cozy and enthusiastic environment inside the lab. It was all due to their consistent support that I was able to conclude all my task nicely and well on time.

                    I would also like to mention a big thanks to my parents, family members and friends out there for their help and trust that inspired me to do my work well on time.

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