chapter 5shodhganga.inflibnet.ac.in/bitstream/10603/8340/10/10_chapter 5.pdf · process. among...

MCM-41/Amino Functionalized MCM-41 Vital Carrier

for Indomethacin and In Vitro Release Evaluation

Chapter 5

Chapter 5

Manu V. 170 Ph. D. Thesis

5.1. Introduction

In the recent years, ordered mesoporous materials were investigated as

materials for applications in many areas, such as catalysis [1], sorption [2],

separation [3], drug delivery/controlled drug release [4-8]. The drug delivery systems

are of special interest since controlled and prolonged release of the drug could lead

to prolonged efficiency, less frequent doses and consequently to minimalization of

the negative side effects of the drugs. Several mesoporous materials were studied as

drug delivery supports such as MCM-41, SBA-15, SBA-16, MSU-3, FDU-12 [1, 9-

12]. Regi et al. used hexagonal mesoporous silica MCM-41 for controlled release of

analgesic drug, ibuprofen [7]. The released amount of ibuprofen was 70 and 90.72

%, after 24 and 72 h respectively. Munoz et al. [13] studied the amine modification

of mesoporous silica MCM-41 materials with different pore size. Their results

showed that amino functionalization of MCM-41 decreases the rate of drug release.

This observation was explained by interactions of the amine groups with acidic

groups of ibuprofen. Manzano et al. [14] deal with ibuprofen delivery from amino-

modified MCM-41 of different particle diameter. The higher amount of ibuprofen

(up to 10%) can be loaded into the amino modified mesoporous silica MCM-41 than

into the unmodified mesoporous material.

Wang et al. [15] presented the comparative study of synthesis procedures

(grafting or co-condensation method) to functionalize mesoporous silica MCM-41

with various functional groups (3-aminoprypyl, 3-mercaptopropyl, vinyl and

secondary amine groups). Two different molecules (ibuprofen and rhodamine) were

used as model drugs to investigate adsorption and release properties. Their results

showed that while mercaptopropyl and vinyl functionalized MCM-41 showed high

adsorption capacity for rhodamine, amine functionalized samples exhibit higher

adsorption capacity for ibuprofen. On the other hand the tested samples

functionalized with vinyl and mercaptopropyl by post grafting method released

rhodamine faster than the corresponding sample synthesized by co- condensation.

Doadrio and Regi [8, 16] prepared mesoporous silica SBA-15 and used it for

gentamicin and amoxicillin delivery. They applied two forms of mesoporous silica

SBA-15, powder and disk. In the case of gentamicin no significant differences

between release rates from the both forms. But in the case of amoxicillin, the release

rate from disk was faster. Yu et al. [17] studied release of ninodiphine from SBA-15

mesoporous silica. The external surface of the SBA-15 was modified with phenyl-

Chapter 5


trimethoxysilane or trimethylchlorosilane. No difference in the release properties has

been found for samples after modification. The release efficiency was 100 % in 24 h.

In the present chapter the uptake and subsequent release of indomethacin by

MCM-41 silica is documented. The mesoporous silica was modified with

aminopropyl groups, indomethacin loading and its release profiles from MCM-41

and amino functionalized MCM-41 matrices was investigated. The administration of

the indomethacin molecules by a mesoporous silica matrix MCM-41 would provide

advantages over conventional drug therapies. It can enhance curative effect of the

indomethacin, because this NSAID drug is insoluble in water. Indomethacin (IM), 1-

(4-chlorobenzoyl)-5-methoxy-2-methyl-1H indole-3-acetic acid (Fig. 5.1) belongs to

the group of nonsteroidal anti-inflammatory drugs (NSAID). It is a nonselective

inhibitor of cyclooxygenase (COX) 1 and 2, enzymes that participate in

prostaglandin synthesis from arachidonic acid. Prostaglandins are hormone-like

molecules normally found in the body, where they have a wide variety of effects,

some of which lead to pain, fever, and inflammation [18]. This group of drugs is

widely used to treat arthritis, musculoskeletal and postoperative pain, as well as

headache and fever. NSAIDs include acetylsalicylic acid, traditional NSAIDs (e.g.

diclofenac, ibuprofen, indomethacin and naproxen) [19]. Indomethacin has several

functional groups, which may contribute to the interactions influencing the loading

process. Among these groups, the carboxylic acid group is likely to play an essential

role. Carboxylic acid groups are able to form cyclic acid-acid dimers or chains via

hydrogen bonding, and hydrogen bonding may naturally occur with any suitable

functional groups of e.g. solvent molecules as well.

Figure: 5.1. Molecular structure of indomethacin

The carboxylic acid group may also react e.g. with alcohols in esterification

reactions. According to Watanabe et al., esterification reaction may occur also with

Chapter 5


silanol groups upon grinding of indomethacin with silica. In alkaline conditions

indomethacin exists in ionic form.

The polymorph form of indomethacin depends on the crystallization solvent.

Indomethacin is also known to form solvates with various solvents, for instance with

acetone, benzene, chloroform, dimethylether, dichloromethane, methanol, propanol,

and t-butanol. These pseudo-polymorphs are generally denoted as beta-form. Solvate

formation may distort the results of solubility measurements and affect the drug

loading process, so it must be taken into account. Indomethacin crystallization

studies in solvent mixtures have not been reported. Indomethacin is vulnerable to

photolytic degradation, so the samples have to be protected from light during all the

experiments. Furthermore, both basic and acid hydrolysis reactions are feasible. A

typical degradation route is via hydrolysis of the amide linkage.

5.2. Experimental

Details of Chemical used for the study of adsorption and release of

indomethacin on row and amino functionalized MCM-41 are given in table 5.1.

Table 5.1. List of chemicals Chemicals Grade Suppliers Chemical

formula

Sodium Chloride AR s. d. Fine Chem, Ltd, India NaCl

Cetyltrimethylammonium bromide AR s. d. Fine Chem, Ltd, India C19H42BrN

Hydrochloric acid AR s. d. Fine Chem, Ltd, India HCl

Toluene AR s. d. Fine Chem, Ltd, India C7H8

Fused calcium chloride AR s. d. Fine Chem, Ltd, India CaCl2

Isopropanol AR s. d. Fine Chem, Ltd, India C3H8O

Methanol AR s. d. Fine Chem, Ltd, India CH4O

sodium hydroxide AR s. d. Fine Chem, Ltd, India NaOH

potassium chloride AR s. d. Fine Chem, Ltd, India KCl

potassium dihydrogen orthophosphate AR Sigma. Aldrich, USA KH2PO4

3-aminopropyltrimethoxysilane 97% Sigma. Aldrich, USA C6H17NO3Si

3- mercaptopropyltrimethoxysilane 97% Sigma. Aldrich, USA C6H16SO3Si

Indomethacin 99% Fluka, USA C19H16ClNO4

Sodium silicate# Commercial Kadvani Chemicals Pvt. Ltd

Na2O3Si

# 23.31 SiO2%; 7.48 Na2O %, H2O % w/w (SiO2/Na2O (M/M)

Chapter 5


5.2.1. Synthesis of MCM-41

Detailed of synthesis producer of MCM-41 is given in section 2.2.3 of

chapter 2.

5.2.2. Surface Functionalization of MCM-41

The detailed study of surface functionalization of the MCM-41 with

APTMS is given in section 2.2.5 of chapter 2. The aminofunctionalized MCM-41

samples were prepared by reaction of calcined MCM-41 with APTMS using

APTMS: silica ratio (w/w) viz.0.6 samples were designated as MCM-41N.

5.2.3. Preparation of the Indomethacin-MCM-41 and MCM-41N Hybrid

For maximum indomethacin loading in pores of MCM-41 and MCM-41N

were attained through several experiments in trial and error basis, among optimized

reaction conditions were brief explained here with. The MCM-41 (0.5 g) suspension

was prepared by dispersing in 100 ml methanol under vigorously stirring for 3 h.

Indomethacin solution (1 wt. %, pH 3) was added drop wise into the MCM-41

dispersion at 35 ± 2 °C and the pH of the entirety suspension was accustomed to pH

3. The mixed solution was further stirred at 500 rpm for 24 h, filtered, washed

several times with methanol to remove the surface indomethacin and indomethacin

loading was quantified by UV-visible spectral analysis. The drug loaded material

was dried at 60 °C. The sample was designated as MCM-41IM. Similar procedure

was adopted for incorporating the drug in amino functionalized MCM-41. This

sample designated as MCM-41NIM.

5.2.4. Adsorption Isotherms of Indomethacin on MCM-41 and Functionalized MCM-

41

The adsorption study of indomethacin was carried out by batch equilibrium

experiments. Known weight (~0.1 g) of calcined MCM-41 and functionalized MCM-

41 was taken in 50 ml vial and was equilibrated with 20 ml solutions of different

concentration of indomethacin for 24 h at room temperature (30 ± 2 ºC) while

shaking the vial in the help of shaker bath. Concentration of indomethacin in the

solution before and after equilibrium was analyzed by UV–visible spectroscopy at

λmax = 323 nm using Shimadzu, UV-2550, Japan equipped with a quartz cell having

a path length of 1 cm. Adsorption of indomethacin (Qe) was calculated using Eqn.1

in chapter 3.

Chapter 5


5.2.5. Effect of pH The effect of pH on adsorption of indomethacin into amino functionalized

MCM-41 was studied by treating indomethacin and amino functionalized MCM-41

at different pH. One hundred milligrams of amino functionalized MCM-41 was

dispersed in 20 ml of methanol containing 127.9 mg of indomethacin, and the pH

was adjusted to 1, 2, 3, 4, 5, 6 and 7 using HCl and NaOH solution. The suspensions

were shaken for 24 h at 35 ± 2 °C. The reaction mixtures were filtered, and the

concentration of indomethacin in the filtrates was determined by UV–visible

spectroscopy as stated above.

5.2.6. In Vitro Release Study

In vitro release behavior of indomethacin was carried out with the help of

USP eight stage dissolution rate test apparatus (VEEGO, Mumbai, India) using

dialysis bag technique. The indomethacin release experiments were carried out at pH

1.2 (1000 ml of 0.2M HCl and 588 ml of 0.2M KCl) and at pH 7.4 (1000 ml of 0.1M

KH2PO4 and 782 ml of 0.1M NaOH). The dialysis bags were equilibrated with the

release medium for few hours prior to release studies. The weighed quantities of

MCM-41IM and MCM-41NIM were placed in dialysis bag containing 5 ml of the

release medium. The dialysis bags were placed in stainless steel baskets and were

immersed in container containing 500 ml of release medium. The temperature was

maintained to 37 ± 1 °C and rotation frequency of basket was kept at 150 rpm. 5 ml

of aliquots was withdrawn at regular time interval and the same volume was replaced

with a fresh release medium. Samples were further diluted and analyzed for

indomethacin content by UV–visible spectrophotometer.

5.3. Results and Discussion

5.3.1. Powder X-ray Diffraction

Powder X-ray diffraction (PXRD) patterns of calcined MCM-41, amino

functionalized MCM-41, Indomethacin, indomethacin loaded MCM-41 and MCM-

41N is shown in Fig. 5.2. The PXRD patterns of MCM-41 featured three well-

resolved peaks of (100), (110), and (200) planes characteristic of the hexagonal

MCM-41 phase [20-22]. For crystalline indomethacin (Fig. 5.2b), we observed

strong characteristic crystalline diffraction peaks at 2θ= 11.6°, 19.6° 21.8° and

26.6°; in good agreement with previously reported [23]. Literature values for the γ-

crystal form of indomethacin, [23-24] with small discrepancies attributed to

Chapter 5


differences in crystal size between samples. The four diffraction peaks with high

intensity were measured to minimize systematic error due to crystal orientation [25].

Fig. 5.2a shows that grafting organic moieties on the surface of MCM-41 introduces

disorders. The intensities of (110) and (200) peaks decreased after the addition of

surface aminopropyl groups. For both the indomethacin loaded MCM-41 and

indomethacin-loaded amino functionalized MCM-41 (Fig. 5.2c), we observed a

diffraction pattern that was identical to that of the row MCM-41, indicating either an

absence of any crystalline indomethacin material or that any crystalline material

present is below the detection limit of the instrument. These observations suggest

that the indomethacin is present within the MCM-41 and amino functionalized

MCM-41 in an amorphous or molecular form [23, 26]

Figure: 5.2. PXRD patterns of a) MCM-41 and MCM-41N, b) Indomethacin and c) indomethacin loaded MCM-41 and MCM-41N

5.3.2. N2 Sorption

The textural characteristics of the samples were determined by nitrogen

adsorption/desorption and the results are summarized in the table 5.2. The MCM-41,

MCM-41N and indomethacin loaded samples (MCM-41IM and MCM-41NIM) were

characterized by N2 adsorption at liquid N2 temperature and adsorption isotherms and

pore size distribution is presented in Fig. 5.3. All the nitrogen adsorption-desorption

isotherms are found to be of type IV according to the IUPAC classification [27].

MCM-41 showed a very sharp step between 0.2 and 0.4 p/p0 partial pressure region

due to pore filling of uniform pores of hexagonal lattice. Micropores adsorption and

multilayer film formation on the pore walls is observed for the initial part of the

curve. No hysteresis was observed below 0.8 p/p0 however, hysteresis was seen at

higher p/p0 (p/p0 > 0.8) which is assigned to sorption in large inter-particles

Chapter 5


mesopores and macropores. BET surface area of MCM-41 sample was 734 m2/g,

pore volume 0.91 cm3/g and pore diameter about 25.4 Å. The grafting of organic

functional moieties on MCM-41 results in the decrease of the specific surface area

and pore size (table 5.2). The surface area of MCM-41 decreased ~25 % after

grafting the aminopropyl groups on the surface of MCM-41. The pore volume

reduced from 0.91 to 0.62 cm3/g indicating that the pores were filled by the

aminopropyl groups.

In the case of indomethacin loaded MCM-41 the BET surface area decreased

to 558 m2/g from 734 m2/g. The pore volume was reduced from 0.91 to 0.59 cm3/ g.

It indicates that most of the pores were blocked by the indomethacin. Indomethacin

loaded amino functionalized MCM-41 has drastically affected the N2

adsorption/desorption isotherms and BET surface area of MCM-41 (table 5.2) In

addition, the pore volume was reduced from 0.62 to 0.32 cm3/g. The capillary

condensation step corresponding to frame work pores, was significantly reduced for

the samples MCM-41N and MCM-41IM, which completely disappeared in the case

of MCM-41NIM indicating that the frame work pores are almost completely filled

up with indomethacin as this can also be seen in pore size distribution curves of

figure 5.3b.

Figure: 5.3. Nitrogen adsorption/desorption isotherms at 77K (a) and pore size distribution curves (b) of MCM-41, aminofunctionalized MCM-41 and indomethacin loaded MCM-41 and MCM-41N

Chapter 5


Table 5.2. Textural properties of MCM-41, amino functionalized MCM-41 and indomethacin loaded samples

MCM-41 MCM-41N MCM- 41IM MCM-41NIM

BET surface area (m2/g) 734 553.5 557.8 115.6

Total pore volume (cm3/g) 0.91 0.62 0.59 0.32

BJH desorption pore size

(Å)

25.4 21 22.0 31.0

5.3.3. Thermo Gravimetric Analysis and Differential Thermo Gravimetric

Analysis

Thermo gravimetric and differential thermo gravimetric analysis is shown in

Fig 5.4. TGA analysis resulted in the mass loss of 8.8 %, 12.9 %, 10.6 % and 13.3 %

for MCM-41, MCM-41N, MCM-41IM and MCM-41NIM respectively (Fig. 5.4),

similar observations have been reported [28-30]. For MCM-41 weight loss occurred

up to 150 ºC due to the loss of physically adsorbed water molecule [31], and at high

temperature the remaining weight loss was due to the condensation of silanol groups

[32]. For the amine functionalized mesoporous silica sample, MCM-41N the mass

loss occurred in the temperature range 300-650 °C corresponding to the

decomposition of amino groups [30, 33].

Figure: 5.4. Thermo gravimetric curves of MCM-41, aminofunctionalized MCM-41, indomethacin loaded MCM-41 and MCM-41N

Chapter 5


The sample loaded with the drug, MCM-41IM and MCM-41NIM, resulted in the

weight loss in temperature range from 200 to 350 °C corresponds to loaded

indometacin [34]. Similar type of weight loss also observed in differential thermo

gravimetric analysis (Fig 5.4b).

5.3.4. Electron Microscopy

The scanning electron micrograph (SEM) of the calcined MCM-41 (given

chapter 2, Fig. 2.15a) showed the agglomerates of MCM-41; consisted of hexagonal-

to-round shape sub-micrometer size particles. The transmission electron micrograph

of MCM-41, MCM-41N, MCM-41IM and MCM-41NIM (Fig. 5.5) clearly depict

the well-ordered, hexagonal pore structure of MCM-41 [21-22]. After

functionalization of aminopropyl groups (MCM-41N) the hexagonal structure was

retained (Fig. 5.5b). After drug loading hexagonal pores were filled by drug

molecules. Fig. 5.5c and d wherein the hexagonal pore structure of MCM-41 and

MCM-41N were fully covered with uniform smear of the indomethacin.

(a)

(c)

(d)

Figure: 5. 5. TEM image of the same samples disguised as for MCM-41 (a) MCM-41IM (b), MCM-41N (c) and MCM-41NIM (d)

(b)

Chapter 5


5.3.5. Elemental Analysis

Amino functionalized MCM-41 was prepared by calcined MCM-41 and

APTMS solution. Results of elemental analysis of the amino functionalized MCM-

41 are summarized in table 5.3. Elemental analysis shows that 1.82 mmol/g amino

group was loaded on the surface of MCM-41

Table 5.3. Elemental analysis of amino functionalized MCM-41

Samples C % N % NH2 (mmol/g) C/N

MCM-41N 7.37 2.54 1.82 3.38

5.3.6. Adsorption at different pH

The adsorption capacity of indomethacin on amino functionalized MCM-41

gradually increases at initial pH (1 to 3) and decreases with the increase in the pH of

the reaction medium (Fig. 5.6).

Figure: 5.6. Adsorption of indomethacin on MCM-41 at different pH

5.3.7. Adsorption of Indomethacin on MCM-41 and MCM-41N

Studies on adsorption behaviour of indomethacin on MCM-41 and amino

functionalized MCM-41N was undertaken by batch adsorption method at 30 ± 2 °C.

Adsorption behaviour of indomethacin at different pH was studied. The isotherms

models of Langmuir (Eqn. 4), Freundlich (Eqn. 5), and Sips (Eqn. 6) all equations

are given in table 3.4 of chapter 3.

The analysis of equilibrium data is essential to develop an equation that can

be used to compare different adsorbents. To examine the relationship between

Chapter 5


sorption and aqueous concentration at equilibrium, various sorption isotherm models

are widely employed for fitting the data. In the present work, a two-parameter

models (Langmuir and Freundlich) and three parameters modal (Sips) were used to

describe the equilibrium between the indomethacin and adsorbent (MCM-41 and

MCM-41N). The isotherms constants, values of regression coefficient (R2) and

values of error function are presented in table 5.4. The lower the error function; the

lower will be the difference of the experimental Q values and Q value calculated by

the model. Values of error function calculated using Langmuir model for all the

isotherms were found to be lowest; and hence in the present work Langmuir model

has been considered to be best fitted amongst all the three models. Therefore the

monolayer capacity Qm for all the isotherms was calculated using Langmuir model,

considered to be the nearest to the real values of monolayer adsorption capacity.

Adsorption of indomethacin on MCM-41 and amino functionalized MCM-41

were carried out at different pH. Maximum amount of indomethacin was adsorbed at

pH-3 (Fig. 5.6). Further study of adsorption of indomethacin was carried out at the

pH 3 using different initial concentrations of indomethacin, C0. Langmuir monolayer

adsorption capacity of indomethacin on calcined MCM-41 showed 142.8 mg/g,

whereas amino functionalized samples adsorbed 212.8 mg/g of indomethacin. The

high adsorption capacity of indomethacin on amino functionalized MCM-41 is due

to the organic moieties (amino groups) grafted inside the MCM-41 pores are

responsible for indomethacin adsorptions; and are readily accessible despite the

decrease in the pore size following the surface modifications. The Langmuir model

adsorption isotherms of indomethacin on MCM-41 and MCM-41N are shown in Fig.

5.7. Regression coefficients (R2) of the both samples are 0.99. Error function is

0.00081 and 0.00378 in MCM-41 and MCM-41N respectively. The adsorbent, for its

practical application for adsorptive separation of indomethacin, should have high

adsorption capacity at low concentration of the adsorbate. It is also desirable that

affinity for adsorbate should be such that it can be easily regenerated by releasing the

indomethacin.

Chapter 5


Figure: 5.7. Adsorption isotherms of indomethacin on MCM-41 and amino functionalized MCM-41. Points show experimental values, lines show calculated plot using Langmuir model

Table 5.4. Parameters for the adsorption of indomethacin on MCM-41 and amino functionalized MCM-41

Isotherm Model MCM-41IM MCM-41NIM Langmuir Qmax (mg/g) 142.8 212.8 KL 0.098 0.030 R2 0.9918 0.9993 Error function, Ferror 0.00081 0.00378 Sips Qmax (mmol/g) 156.3 217.8 KS 0.0104 0.0074 nS 1.03 1.03 R2 0.9922 0.9919 Error function, Ferror 0.0070 0.0042 Freundlich KF 4.364 23.039 nF 1.674 2.414 R2 0.9821 0.9451 Error function, Ferror 0.0068 0.0063

Adsorption isotherm gives the idea about the release profile of indomethacin

on MCM-41 and MCM-41N. However, the drug release process is very dynamic and

different properties of the particles can compensate for each other, making it difficult

to directly predict which particle type is the most suitable for drug release. Here, the

Chapter 5


comparison between the MCM-41 and MCM-41N materials gives further insights on

the effects of the overall profile of the drug release.

Distribution coefficients for five different initial concentrations were

calculated for MCM-41 and MCM-41N using Eqn. 10, (see table 3 4 in chapter 3)

and results are summarized in table 5.5. It showed that with an increase in initial

concentration of indomethacin, C0, there was a decrease in Kd for the both materials.

Distribution coefficients of amino functionalized MCM-41 shows more than five

times greater than that MCM-41 at initail concentration ~12 mg/dm3.

Table 5.5. Distribution coefficient for the adsorption of indomethacin on MCM-41 and amino functionalized MCM-41

C0

(mg/dm3)

Ce

(mg/dm3)

Qe

(mg/g)

Kd

(ml/g)

MCM-41

11.394 9.963 13.844 1389.5

34.526 31.06 32.587 1049.11

57.572 52.648 46.454 882.35

103.69 96.364 69.999 726.41

230.12 219.86 98.45 447.78

MCM-41N

12.15 6.871 50.761 7387.8

36.45 27.627 83.003 3004.48

60.75 47.381 130.054 2744.88

109.35 93.1001 159.623 1714.51

243 223.93 183.331 818.68

5.3.8. In Vitro Release Behavior

The indomethacin release profiles of MCM-41 and MCM-41N were

observed both in gastric (pH 1.2) and intestinal environments (pH 7.4). At gastric

environments 26 % of the indomethacin was released within 10 h from MCM-41IM

(Fig. 5.8 and table 5.6). But in the case of intestinal environments 48 % of

indomethacin was released. Indomethacin release of amino functionalized MCM-41

at gastric environments 21 % of realease was observed. In intestinal environments

only 12 % release was observed at 10 h. This slow release of indomethacin indicated

Chapter 5


that there is a acid-base interaction between the –COOH groups indomethacin and

amino groups of aminofunctionalized MCM-41.

Figure: 5.8. In vitro release behaviors of IMC in physiological pH

Table 5.6. Parameters of release of indomethacin on MCM-41 and amino functionalized MCM-41

pH 1.2 (%) pH 7.4 (%)

MCM-41IM 25.7 20.6

MCM-41NIM 48.6 12.1

In summary, we have shown the adsorption of indomethacin into MCM-41

and MCM-41N, and in vitro release of indomethacin from MCM-41 and MCM-41N.

Langmuir adsorption isotherm is the best fit among the other models. The monolayer

adsorption capacity of indomethacin obtained was 142.8 mg/g and 212.8 mg/g on

MCM-41and MCM-41N respectively. Adsorption of indomethacin into adsorbents

depends on the pH of the interaction medium. Surface area of the parent and amino

functionalized materials decreases after the adsorption of indomethacin. In vitro

release study showed that about 26 and 21 % of indomethacin was released MCM-

41IM hybrid in simulated gastric fluid (pH 1.2) and intestinal fluid (pH 7.4),

respectively. In vitro release of MCM-41N was 49 % gastric fluid and 12 % in

intestinal fluid. These studies indicate that MCM-41N can be used as the sustained

release carrier of indomethacin in oral administration.

Chapter 5


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Chapter 5


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