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Summary,of Ph.D thesis Development and evaluation of novel preservatives from simple organic acids i Introduction In an era of increasing bacterial resistance to classical antibacterial agents, it has been postulated that the development of resistance to known antibiotics could be overcome by identifying new drug targets via genomic, improving existing antibiotics and most importantly by identifying the new antibacterial agents with novel structures and mode of action (Salahuddin et al., 2009). Non-sterile products such as pharmaceuticals, cosmetics, food items etc. with a high degree of water availability may be contaminated with microorganisms which may cause spoilage of the product with loss of therapeutic properties and, if they are pathogenic, serious infections can arise (Zani et al., 1997). To inhibit the growth of contaminating microorganisms, antimicrobial preservative systems have been developed and introduced into the pharmaceutical, cosmetic or food products during manufacturing process and/or throughout its use by consumers (Denyer et al., 1988). The commonly used chemical preservatives may cause very serious side effects. For example, benzalkonium chloride may cause mucosal damage and was also reported as genotoxic and cytotoxic (Deutschle et al., 2006 and Graf, 2006); thiomerosal used in ocular and nasal preparations was reported to be cytotoxic by Liao et al. (2011), the use of parabens may cause skin cancer, genotoxicity and breast cancer as reported by the study of Dabre and Harvey (2008). In several cases, the microorganisms become resistant to antimicrobials and are able to degrade many commonly used preservatives especially p-hydroxybenzoates, e.g., parabens (Close and Nielsen, 1976). Microbial resistance has been reported to some of the existing commonly used chemical preservatives like benzalkonium chloride, dibromodicyanobutane, chloramine, chlorhexidine, cholorophenol, benzoic acid, dimethyl oxazolidine, dimethyl dithiocarbamate, dimethoxy dimethyl hydantoin, formaldehyde, glutaraldehyde, hydrogen peroxide, iodine, methylene bischlorophenol, methylparaben, propylparaben, phenylmercuric acetate, mercuric salts, povidine-iodine, sorbic acid and quaternary ammonium compounds (Chapman, 1998). The antimicrobial potential of simple organic acids is well established in the literature viz. sorbic acid (Nararasimhan et al., 2003), cinnamic acid (Narasimhan et al., 2004), anacardic acid (Narasimhan et al., 2006a), veratric acid (Narasimhan et al., 2009), myristic acid
Transcript

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids i

Introduction

In an era of increasing bacterial resistance to classical antibacterial agents, it has been

postulated that the development of resistance to known antibiotics could be overcome by

identifying new drug targets via genomic, improving existing antibiotics and most

importantly by identifying the new antibacterial agents with novel structures and mode

of action (Salahuddin et al., 2009). Non-sterile products such as pharmaceuticals,

cosmetics, food items etc. with a high degree of water availability may be contaminated

with microorganisms which may cause spoilage of the product with loss of therapeutic

properties and, if they are pathogenic, serious infections can arise (Zani et al., 1997). To

inhibit the growth of contaminating microorganisms, antimicrobial preservative systems

have been developed and introduced into the pharmaceutical, cosmetic or food products

during manufacturing process and/or throughout its use by consumers (Denyer et al.,

1988).

The commonly used chemical preservatives may cause very serious side effects. For

example, benzalkonium chloride may cause mucosal damage and was also reported as

genotoxic and cytotoxic (Deutschle et al., 2006 and Graf, 2006); thiomerosal used in

ocular and nasal preparations was reported to be cytotoxic by Liao et al. (2011), the use

of parabens may cause skin cancer, genotoxicity and breast cancer as reported by the

study of Dabre and Harvey (2008).

In several cases, the microorganisms become resistant to antimicrobials and are able to

degrade many commonly used preservatives especially p-hydroxybenzoates, e.g.,

parabens (Close and Nielsen, 1976). Microbial resistance has been reported to some of

the existing commonly used chemical preservatives like benzalkonium chloride,

dibromodicyanobutane, chloramine, chlorhexidine, cholorophenol, benzoic acid,

dimethyl oxazolidine, dimethyl dithiocarbamate, dimethoxy dimethyl hydantoin,

formaldehyde, glutaraldehyde, hydrogen peroxide, iodine, methylene bischlorophenol,

methylparaben, propylparaben, phenylmercuric acetate, mercuric salts, povidine-iodine,

sorbic acid and quaternary ammonium compounds (Chapman, 1998).

The antimicrobial potential of simple organic acids is well established in the literature viz.

sorbic acid (Nararasimhan et al., 2003), cinnamic acid (Narasimhan et al., 2004), anacardic

acid (Narasimhan et al., 2006a), veratric acid (Narasimhan et al., 2009), myristic acid

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids ii

(Narasimhan et al., 2006b), caprylic acid (Chaudhary et al., 2008), anthranilic acid (Mahiwal

et al., 2012) and dodecanoic acid (Sarova et al., 2011).

Further, the literature reports reveals that the ferulic acid possess antimicrobial,

antioxidant and preservative activities (Proestos et al., 2006 and Ou et al., 2004). The

gallic acid and its derivatives possess wide spectrum of biological activities like

antimicrobial, anticancer, antiviral, anti-inflammatory, analgesic and anti-HIV activities

(Chanwitheesuk et al., 2007; Saxena et al., 2008; Thapa et al., 2012; Arunkumar et al.,

2009; Krogh et al., 2000 and Kratz et al., 2008). Also, the p-coumaric acid and its

derivatives possess wide spectrum of biological activities like antimicrobial and

antioxidant potentials (Proestos et al., 2006 and Caia et al., 2004). Hence, the present

research work was envisaged towards development and evaluate the novel preservatives

from simple organic acids.

Objective

Development and evaluation of novel preservatives from simple organic acids.

Plan of work

In light of abovementioned facts and with the aim of obtaining new antimicrobial

preservatives, the present work was planned as follows:

I. Synthesis of organic acid derivatives.

II. Physicochemical and spectral characterization of synthesized compounds

III. Evaluation of antimicrobial activity of synthesized compounds.

IV. Preservative efficacy testing of selected antimicrobial agents in

pharmaceutical products as per USP guidelines.

V. Stability studies of pharmaceutical products containing the test

preservatives as per ICH guidelines.

The aforementioned plan of work is executed as follows:

I. A review of literature regarding the problems associated with the existing

chemical preservatives and their alternatives.

II. Synthesis and antimicrobial evaluation of ferulic acid derivatives (Series I).

III. Synthesis, antimicrobial evaluation and QSAR studies of gallic acid

derivatives (Series II).

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids iii

IV. Synthesis, antimicrobial evaluation and QSAR studies of p- coumaric acid

derivatives (Series III).

V. Evaluation of preservative effectiveness of ferulic acid derivatives in

aluminium hydroxide gel- USP

VI. Evaluation of preservative effectiveness of gallic acid derivatives in

aluminium hydroxide gel- USP

VII. Evaluation of preservative effectiveness of p- coumaric acid derivatives in

aluminium hydroxide gel- USP

VIII. Stability studies of the selected derivatives of ferulic acid, gallic acid and

p- coumaric acid as per the ICH guidelines.

I. A review of literature regarding the problems associated with the existing chemical

preservatives and their alternatives.

Preservatives are very essential ingredient among the food and pharmaceutical products as

chances of contamination of such products is very high and their shelf life becomes short.

However, the preservatives which are used for this purpose may pose several serious

complications such as the benzalkonium chloride may cause nasal mucosal damage and

genotoxicity, thiomerosal may cause neonatal neurodevelopmental disorders, and parabens

may cause skin cancer, genotoxicity and breast cancer. So, the use of preservatives becomes

a challenge and there is a strong need to overcome these problems by finding alternatives to

existing preservatives. This includes the use of novel preservatives such as polyquad, sodium

perborate, purite, sofZia etc. or use of speciallized packaging or exploration of novel

antimicrobial preservatives from natural acids.

Publication from aforementioned work

Khatkar A, Nanda A, Narasimhan B. Preservatives- associated problems and possible

alternatives, in: Tiwari SK, Singh B (Eds.), Current Trends in Biotechnology, Lambert

Academic Publisher, Germany, 2012: 100-120.

II. Synthesis and antimicrobial evaluation of ferulic acid derivatives (Series I).

A series of ferulic acid derivatives (1-38) was synthesized and characterized by

physicochemical and spectral means (Scheme 1). The synthesized compounds were

evaluated in vitro for their antimicrobial activity against different Gram positive and Gram

negative bacterial as well fungal strains by tube dilution method. Results of antimicrobial

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids iv

screening indicated that compound 1 was the most active antimicrobial agent (pMICam = 1.83

µM/ml). The structural requirements for the antimicrobial activity of synthesized compounds

are summarized in Fig. 1.

HO

COOH R-OH

H2SO4 HO

COOR

SOCl2

HO

COClR-OH

HO

COOR

N

HO

HO

CO

N

O

HO

COOH HO

COCl

SOCl2

HN

O

HO

CON

O

NH2

R7

R6

R5

R4

R3

HN

R7 R6

R5

R4R3

HO

CO

H3CO

H3CO

H3CO

H3CO

H3CO

H3CO

H3CO

H3CO

H3CO

HO

CONHRH3CO

37

R-N

H2

H2N

NH

HO

H3CO

O

34

2

9, 12, 13

1, 3-8, 10, 11, 14

33, 35, 36, 38

15-32

Scheme 1. Scheme for the synthesis of ferulic acid derivatives (Series I)

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids v

Comp. R Comp. R Comp. R

1 NH2

5 .

9 CH3

2 - 6

.

10

.

3 .

7 NO2

.

11

.

4 C4H9 8 .

12 C2H5

13 C3H7 14

.

Comp. R R3 R4 R5 R6 R7

15 - H H H H H

16 - CH3 H H NO2 H

17 - Cl H NO2 H H

18 - H Cl H H H

19 - Cl H H H H

20 - H CH3 H H H

21 - OCH3 H H H H

22 - CH3 CH3 H H H

23 - CH3 H CH3 H H

24 - CH3 H H CH3 H

25 - NO2 - - - -

Comp. R R3 R4 R5 R6 R7

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids vi

26 - H H NO2 H H

27 - H NO2 H H H

28 - CH3 H H H H

29 H Cl F H H

30 - H H CH3 H H

31 H H OCH3 H H

32 F H - H H

33 .

- - - - -

34 - - - - - -

35 C3H7 - - - - -

36 C4H9 - - - - -

37 - - - - -

38 N

O

.

- - - - -

HO

COOH

MorpholineIncreased antibacterial activity against E. coli

Increased antimicrobial activity against S. aureus, C. albicans and A. niger

HO

C

HO

COOR

HO

CONH

R Anilides Do not showed the antimicrobial activity against microbial strains

H3CO

H3CO

H3CO

H3CO

O

N O

NH2

Figure 1. Structural requirements for the antimicrobial activity of ferulic acid derivatives

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids vii

Publication from aforementioned work

Anurag Khatkar, Arun Nanda, Pradeep Kumar, Balasubramanian Narasimhan. Synthesis

and antimicrobial evaluation of ferulic acid derivatives. Research on Chemical

Intermediates (Communicated).

III. Synthesis, antimicrobial evaluation and QSAR studies of gallic acid derivatives

(Series II)

A series of gallic acid derivatives (1-33) was synthesized and characterized by

physicochemical and spectral means (Scheme 2). The synthesized compounds were

evaluated in vitro for their antimicrobial activity against different Gram positive and

Gram negative bacterial as well fungal strains by tube dilution method. Results of

antimicrobial screening indicated that compound 6 was the most active antimicrobial

agent (pMICam = 1.92 µM/ml). The structural requirements for the antimicrobial and

anticancer activities of synthesized compounds are summarized in Fig. 2. The results of

QSAR studies demonstrated that antibacterial, antifungal and overall antimicrobial

activity of synthesized gallic acid derivatives was governed by the electronic parameters,

cosmic total energy (Cos E) and nuclear energy (Nu. E).

HO

HO

HO

COOH

Anilides

HO

HO

HO

COOR

O

NIncreased antimicrobial activityagainst C. albicans and E. coli

HO

HO

HO

CONR1

HO

HO

HO

CONH R

R2

Less active antimicrobial agents

Di-phenyl group Increased antibacterial activity against B. subtilis

Di-methyl group Increased antifungal activity against A. niger

Increased antibacterial activity against S. aureus

Figure 2. Structural requirements for the antimicrobial activity of synthesized

gallic acid derivatives (Series III)

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids viii

HO

HO

HO

COOHR-OH

H2SO4

HO

HO

HO

COOR

SOCl2

HO

HO

HO

COClR-OH

HO

HO

HO

COOR

HO

HO

HO

COOHSOCl2

HO

HO

HO

COCl

R-N

H2

HO

HO

HO

CO NHR

NHR 1

R 2

HO

HO

HO

CO N

R1

R2

NH2

R7

R6

R5

R4

R3

HO

HO

HO

COHN

R7 R6

R5

R4R3

N

HO

OH

OH

OH

C

O

O

N

12, 22

3-5, 10, 19, 23-24, 26, 32

6

H2N

HO

HO

HO

COHN

.

33

1, 8, 9, 11, 14-17, 25, 27-29, 31

2, 13, 30

7, 20-21

O

NH

HO

HO

HO

CO N

O

18

Scheme 2. Scheme for the synthesis of gallic acid derivatives (Series II)

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids ix

Comp. R Comp. R Comp. R

3 NO2

.

10

.

23 .

4 .

12 CH3 24 .

5

.

19 .

26 .

6 - 22 C2H5 32

NH2

Comp. R R1 R2 R3 R4 R5 R6 R7

1 - - - H H Cl H H

8 - - - CH3 H CH3 H H

9 - - - H H CH3 H H

11 - - - NH2 H H H H

14 - - - CH3 H H NO2 H

15 - - - H H NO2 H H

16 - - - Cl H NO2 H H

17 - - - H NO2 H H H

18 - - - - - - - -

25 - - - H H OCH3 H H

27 - - - NO2 H H H H

28 - - - H Cl Cl H H

29 - - - Cl Cl H H H

31 - - - H NO2 Cl H H

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids x

Comp. R R1 R2 R3 R4 R5 R6 R7

2 - CH3 CH3 - - - - -

7 C6H13 - - - - - - -

13 - C6H5 C6H5 - - - - -

20 N

.

O

- - - - - - -

21 .

O

- - - - - - -

30 - C2H5 C2H5 - - - - -

33 - - - - - - - -

LR-mt-QSAR model for antimicrobial activity

pMICam = 0.0000211 Nu. E + 1.033 Eq. 1

n = 23 r = 0.848 q2 = 0.671 s = 0.054 F = 53.57

Research article communicated from aforementioned work

Anurag Khatkar, Arun Nanda, Pradeep Kumar, Balasubramanian Narasimhan. Synthesis,

antimicrobial evaluation and QSAR studies of p- coumaric acid derivatives. Arabian

Journal of Chemistry (Communicated).

IV. Synthesis, antimicrobial evaluation and QSAR studies of p- coumaric acid

derivatives (Series III)

A series of p- coumaric acid derivatives (1-36) was synthesized and characterized by

physicochemical and spectral means (Scheme 3). The synthesized compounds were

evaluated in vitro for their antimicrobial activity against different Gram positive and

Gram negative bacterial as well fungal strains by tube dilution method. Results of

antimicrobial screening indicated that compound 17 was the most active antimicrobial

agent (pMICam = 1.73 µM/ml). The structural requirements for the antimicrobial activities

of synthesized compounds are summarized in Fig. 3. The mt-QSAR model of

antimicrobial activity (Eq. 2) depicted the importance of topological parameter, Wiener

index (W) in describing antimicrobial activity of synthesized compounds.

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xi

HO

COOH R-OH

H2SO4 HO

COOR

SOCl2

HO

COClR-OH

HO

COOR

N

HO

HO

CO

N

O

HO

COOH HO

COCl

SOCl2

HN

O

HO

CON

O

NHR 1

R 2

NH2

R7

R6

R5

R4

R3

HN

R7 R6

R5

R4R3

HO

CO N

R2

R1

HO

CO

34

17

HO

CONHRR-N

H2

H2N

NH

HO

O

302, 4, 5

10, 23, 24

1, 11, 18-22, 25-26

8, 16, 29, 35 6, 7, 9, 12-15, 27-28, 31-33, 36

O

HN

HO

CO N

O3

Scheme 3. Scheme for the synthesis of p- coumaric acid derivatives (Series III)

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xii

Comp. R Comp. R Comp. R

1 .

18 .

22 .

10 C3H7 19 C4H9 23 C2H5

11 NH2

20

.

24 CH3

17 - 21 .

25 NO2

.

26 .

Comp. R R1 R2 R3 R4 R5 R6 R7

3 - - - - - - - -

6 - - - H Cl NO2 H H

7 - - - OCH3 H H H H

9 - - - NO2 H H H H

12 - - - H Cl Cl H H

13 - - - H H NO2 H H

14 - - - CH3 H H NO2 H

15 - - - NH2 H H H H

27 - - - H NO2 H H H

28 - - - H H Cl H H

31 - - - Cl H NO2 H H

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xiii

Comp. R R1 R2 R3 R4 R5 R6 R7

32 - - - H Cl H H H

33 - - - H H H H H

36 - - - CH3 H CH3 H H

2 C6H13 - - - - - - -

4

O

.

- - - - - - -

5 N

.

O

- - - - - - -

8 - C2H4OH C2H4OH - - - - -

16 - C4H9 C4H9 - - - - -

29 - C6H5 C6H5 - - - - -

30 - - - - - - - -

34 - - - - - - - -

35 - CH3 CH3 - - - - -

HO

COOH

O

NIncreased antibmicrobial activityagainst S. aureus, C.albicans, A.niger

Diphenyl amineIncreased antimicrobial activity against E.coli

HO

COOR

HO

C

HO

COOR

HO

CONH

R Anilides Electron withdrawing substituents increased antimicrobial activityagainst E.coli

O

N

NO2

Increased antimicrobial activityagainst S. aureus

Increased antibmicrobial activityagainst B.subtilis

Cl

R1

R2

Figure 3. Structural requirements for antimicrobial activity of p- coumaric acid derivatives

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xiv

LR mt-QSAR model for antimicrobial activity

pMICam = 0. 000312 W + 1.016 Eq. 2

n = 32 r = 0.823 q2 = 0.635 s = 0.065 F = 62.98

Publication from aforementioned work

Anurag Khatkar, Arun Nanda, Pradeep Kumar, Balasubramanian Narasimhan. Synthesis,

antimicrobial evaluation and QSAR studies of p- coumaric acid derivatives. Arabian

Journal of Chemistry (Communicated).

V. Evaluation of preservative effectiveness of ferulic acid derivatives in aluminium

hydroxide gel- USP

The ferulic-p-amino ester, ferulic-morpholino amide, ferulic 8-hydroxy quinoline ester,

ferulic naphthyl amide were subjected to preservative efficacy testing in an official antacid

preparation (Aluminium Hydroxide Gel-USP) against Staphylococcus aureus, Bacillus

subtilis, Escherichia coli, Candida albicans and Aspergillus niger as representative

challenging microorganisms as per USP 2004 guidelines. The selected derivatives were

found to be effective against all selected strains and showed preservative efficacy comparable

to that of standard and even better in case B. subtilis and C. albicans. The 8- hydroxy

quinoline ester of ferulic acid showed better preservative efficacy than standard as well as

other derivatives and has the potential to be used as preservative in the pharmaceutical

preparations.

Publication from aforementioned work

Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Evaluation of preservative

effectiveness of ferulic acid derivatives in aluminium hydroxide gel- USP. International

Journal of Pharmaceutical Science and Research (Accepted).

VI. Evaluation of preservative effectiveness of gallic acid derivatives in aluminium

hydroxide gel- USP

The selected amide, anilide and ester derivatives of gallic acid were subjected to

preservative efficacy testing in an official antacid preparation, (Aluminium Hydroxide Gel-

USP) against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans

and Aspergillus niger as representative challenging microorganisms as per USP 2004

guidelines. The selected derivatives were found to be effective against all selected strains

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xv

and showed preservative efficacy comparable to that of standard and even better in

case E.coli, C. albicans and A.niger. The 8- hydroxy quinoline ester of gallic acid showed

better preservative efficacy than standard as well as other tested derivatives and have

potential to be used as preservative in the pharmaceutical preparations.

Publication from aforementioned work

Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Evaluation of preservative

effectiveness of gallic acid derivatives in aluminium hydroxide gel- USP. Chronicles of

Young Scientists (Accepted).

VII. Evaluation of preservative effectiveness of p- coumaric acid derivatives in

aluminium hydroxide gel- USP

The selected amide (N,N-diphenyl amide and naphthyl amide), anilide (3-chloro 4-nitro

anilide) and ester (8-hydroxy quinoline ester) derivatives of p-coumaric acid were subject

to preservative efficacy testing in an official antacid preparation, (Aluminium Hydroxide

Gel-USP) against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida

albicans and Aspergillus niger as representative challenging microorganisms as per USP

2004 guidelines. The selected derivatives were found to be effective against all selected

strains and showed preservative efficacy comparable to that of standard and even better

in case E.coli, C. albicans and A.niger. The 8- hydroxy quinoline ester of p- coumaric

acid showed better preservative efficacy than standard as well as other derivatives and

have potential to be used as preservative in the pharmaceutical preparations.

Publication from aforementioned work

Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Evaluation of preservative

effectiveness of ferulic acid derivatives in aluminium hydroxide gel- USP. Chronicles of

Young Scientists (Accepted).

VIII. Stability studies of the selected derivatives of ferulic acid, gallic acid and p-

coumaric acid as per the ICH guidelines.

Samples of aluminium hydroxide gel containing the selected amide, anilide and ester

derivatives of ferulic acid, gallic acid and p- coumaric acid as preservative were stored at

400

± 20 C at 75% RH ± 5% RH (as per ICH guidelines) and were analyzed for the pH

and cfu/ml of the product at 0, 1, 2, 3, 4, 5 and 6 months. The results indicated that the

change in pH was comparable to that of standard and the microbial growth was observed

Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xvi

in samples containing the preservatives gallic N,N-dimethyl amide, gallic naphthyl

amide, p- coumaric N,N-diphenyl amide, ferulic naphthyl amide, p- coumaric -2-chloro

4-nitro anilide, ferulic morpholino amide and p- coumaric naphthyl amide in last two

months. No microbial growth in samples of aluminium hydroxide gel containing the 8

hydroxy quinoline derivative of gallic acid, p- coumaric acid and ferulic acid and the p-

amino ester derivative of ferulic acid was observed and hence these derivatives were

stable over a period of six months and can be used as an alternative to the existing

chemical preservatives.

Publication from aforementioned work

Anurag Khatkar, Arun Nanda, Balasubramanian Narasimhan. Stability studies of the

selected derivatives of ferulic acid, gallic acid and p- coumaric acid as per the ICH

guidelines. HYGEIA: Journal of Drugs and Research (Communicated).

Conclusion:

Summarizing, the amide, anilide and ester derivatives of ferulic acid, gallic acid and p-

coumaric acid were synthesized and evaluated for their in vitro antimicrobial activity and

the most active compounds were further evaluated for their preservative efficacy. The

results showed that the 8-hydroxy quinoline ester of ferulic, gallic and p-coumaric acids

were found to be effective during the preservative efficacy testing as well during the

stability studies as per the ICH guidelines.

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Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xvii

Chaudhary J, Rajpal AK, Judge V, Narang R, Narasimhan B. Synthesis, antimicrobial

evaluation and QSAR analysis of caprylic acid derivatives. Scientia Pharm. 2008; 76

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Summary,of Ph.D thesis

Development and evaluation of novel preservatives from simple organic acids xviii

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