chapter 7 - development and validation of novel...

Chapter7‐NovelMathematicalModelforS‐LPTCatalyzedChlorpyrifosMethylSynthesis.

StudiesinMixedSurfactantSystemsandVegetableOilEmulsions 179

Chapter 7 - Development and Validation of

Novel Mathematical Model for Solid-Liquid

Phase Transfer Catalyzed Chlorpyrifos Methyl

Synthesis



7.1 Introduction

Chlorpyrifos methyl (O, O-dimethyl-O-3, 5, 6-trichloro-2-

pyridylphosphorothioate) is a homologue of chlorinated organophosphate (OP)

insecticide, nematicide and acaricide chlorpyrifos proposed by R. H. Rigterink and which

has been in the commercial market for more than 45 years.380 Chlorpyrifos methyl

(CPFSM) has emerged as a reliable rotation partner for insect management due to very

rare instances of developing significant resistance.381 Conventionally CPFSM is

synthesized by the liquid-liquid phase transfer catalyzed (LL-PTC) condensation of

Sodium salt of 3, 5, 6-trichloropyryridin-2-ol (Na(+)TCP(-)) and O, O-dimethyl phosphoro

chloridothioate (DMTPCl). A range of quaternary ammonium salts as phase transfer

catalysts (PTC)382 and sterically hindered tertiary amines (TA)383 as DMTPCl hydrolysis

preventing agents are employed for this process.

This method suffers from severe drawbacks such as environmental pollution by

the aqueous effluent, formation of impurity Sulfotep [(H3CO)2P(S)2O], maintenance of

pH throughout the reaction, loss of hydrophilic PTC and tertiary amine (TA) in aqueous

phase and use of sterically hindered tertiary amine.384 In such reactions PTC forms the

reactive ion pair with Na(+)TCP(-) which further reacts with DMTPCl with regeneration

of PTC.385 Thus in a cyclic reaction, PTC is utilized in the first step and is regenerated in

the second step with the formation of CPFSM.386 In such cases on one hand PTC was the

rate enhancing agent and on the other hand it was the major reason for sulfotep formation.

Water based work up and addition of aqueous buffer tempon also made TA and PTC

recovery difficult and uneconomical.387 In the recent years Solid-Liquid phase transfer

catalysis (S-L PTC) has gained tremendous importance in greener and selective chemical

synthesis388 - 391 as it leads to selective product formation and eliminates the undesirable

product formation due to the presence of aqueous phase.

In the present research work we have developed TA and buffer tempon free Solid-

Liquid phase transfer catalyzed, novel, greener, economically feasible synthesis for

CPFSM using potassium salt of 3, 5, 6-trichloropyryridin-2-ol (K(+)TCP(-)) and DMTPCl

where in the formation of the major impurity sulfotep is eliminated.



7.2 Experimental

7.2.1 Materials and Methods

7.2.1.1 Chemicals

Potassium salt of 3, 5, 6-trichloropyryridin-2-ol (Anhydrous: HPLC - Internal

Standard Purity (ISP) ~ 99.7%) and O, O-dimethyl phosphoro chloridothioate (GLC

Purity ~ 99.5%) were procured from Sigma Aldrich, India. HPLC solvents were procured

from M/s. Ranchem Chemicals, India. Benzyl trimethyl ammonium chloride (BTMAC),

tetraethyl ammonium bromide (TEAB), cetyl dimethyl ammonium bromide (CDMAB),

cetyl pyridinium bromide (CPB), hexadecyl trimethyl ammonium bromide (HDTMAB)

were procured from M/s. Merck India Ltd. All other chemicals used were of analytical

grade purchased from M/s. S. D. Fine Chemicals Ltd. India and were used without further

purification.

7.2.1.2 Experimental Procedure

The CPFSM synthesis was carried out in a 4.5 cm Internal Diameter (ID)

mechanically stirred glass vessel of 160 mL capacity equipped with a six-blade turbine

impeller (1.8 cm diameter) and a reflux condenser. The impeller was mounted at a

distance of 0.5 cm from the bottom of the vessel. This reactor set up assured excellent

mass transfer through rapid and continuous solid-liquid mixing. The vessel was mounted

in an isothermal bath maintained at the desired temperature and was mechanically

agitated at a desired RPM with an electric motor. In a typical bench scale synthesis 0.01

mol of [K(+)TCP(-)] was condensed with 0.0105 mol of DMTPCl in presence of 2.5× 10-5

mol of BTMAC. The solvent dichloro ethane was added to make up the final reaction

mass volume to 100mL. At a specified time the reaction mass samples were removed and

analyzed by high performance liquid chromatography (HPLC) by dissolving in mobile

phase.

7.2.1.3 Analytical Methods

Reaction progress was monitored by HPLC apparatus (Jasco Tokyo, Japan)

consisting of Plus Intelligent LC pump PU-2080 equipped with a JascoUV-2075 Intelli-

gent UV–Vis detector (with 1.0 AUFS sensitivity) and a Rheodyne 7725 injector

(Rheodyne, Cotati, CA, USA) with fixed internal volume 20µL. The chromatographic

separations were achieved on Hi-Q-Sil reverse phase (RP) column (C-18, 250 mm × 4.6

mm) at 30°C. The 1mL min-1 flow rate was maintained with a mobile phase consisting of

a mixture of Acetonitrile (ACN): Millipore water: Acetic acid (AcOH) in 70:29.5:0.5

volume ratios respectively. The UV absorbance was measured at 300nm wavelength.



7.3 Results and Discussion

KTCP DMTPCl Chlorpyrifos methyl

Figure 7.1 - General reaction scheme for chlorpyrifos methyl synthesis.

7.3.1 Phase Transfer Mechanism and Kinetic Model

The lipophilicity of PTC plays a key role in this reaction. The PTC brings the

reactive anion in to the organic phase where the actual reaction takes place. This active

anion is otherwise insoluble in organic phase along with its metal cation counterpart. The

active anion brought in the organic phase reacts quickly with the substrate which is

already present in the organic phase and regenerates the PTC. This cycle of utilization

and regeneration of PTC continues to bring the reaction forward.

In case of S-L PTC two different mechanisms are proposed depending upon the

solubility of solid reactant in organic phase and the location of the reaction. They are

homogeneous solubilisation and heterogeneous solubilisation mechanism392. In case of

homogeneous solubilisation model the solid reactant have appreciable solubility in

organic phase enhancing the ease of formation of active ion pair by means of

instantaneous ion exchange with PTC. On the other hand in case of heterogeneous

mechanism the solid reactant is insoluble in organic phase and the PTC is adsorbed on the

suspended solids. Here, K(+)TCP(-) was insoluble in solvent and thus remained suspended

in the reactor under the influence of external agitation. PTC diffused to the solid surface

in the first step and brought the active anion from the solid phase to the organic phase in

the second step with the help of quaternary cation (Q+). In third step the active anion

reacted with the DMTPCl in the organic phase leading to the formation of CPFSM.

Finally in fourth step the co-product anion [X-] reacted with the quaternary cation to

regenerate the PTC in its original form. In this case, the probability of formation of

omega phase was eliminated as both the solid and liquid reactants were dry. Preliminary

experiments showed the SN2 type of reaction. The overall reaction can be represented as,

DMTPCl K TCP

/ DMTP. TCP KCl (1)

Where,



Q+Cl- is quaternary ammonium salt in a weakly bound form. The solid reactant K+TCP- is

in equilibrium with its solution in organic solvent.

K TCP ⇔ K TCP (2)

The loosely bound form of quaternary ammonium catalyst (Q+Cl-) reacts with K+TCP- to

form active anion in the organic phase.

Q Cl K TCP ⇔ Q TCP K Cl (3)

K Cl / K Cl (4)

The substrate DMTPCl reacts with active ion pair Q+TCP- as follows,

DMTPCl Q TCP ⇔DETP TCP Q Cl (5)

Thus, in a cyclic process the quaternary catalyst (Q+Cl-) is consumed and

regenerated continuously to continue the catalytic cycle of the reaction. In contrast to L-L

PTC reaction there is no actual transfer of the quaternary catalyst across the interface. The

solubility parameter can be defined by combining eq. (3) and (4) and represented in terms

of equilibrium constant ‘Ke’

K

(6)

K –

– (7)

K

(8)

K (9)

The rate of reaction from the eq. (5) is given by,



k DMTPCl Q TCP

(10)

Substituting the value of [Q+TCP-] (org) from eq. (8)

k K DMTPCl Q Cl

(11)

Since, the total concentration of PTC in organic phase is the sum of its concentration in

active ion pair form and original form in organic phase.

Q0 = [Q+TCP-] (org) + [Q+Cl-] (org) (12)

The fractional conversion of reactant DMTPCl at time‘t’ is given by,

X (13)

Where,

is the initial moles of DMTPCl at time t=0.

The initial mole ratio (M) of (K+TCP-) to DMTPCl is given by,

M (14)

Converting eq. (11) in the form of XA and Q0. Separating variables and integration gave,

k Q t dX (15)

Eq. (15) was solved by method of partial fractions to get the following,

k Q t ln ln 1 X (16)

The value of ‘Ke’ and ‘kr’ can be obtained from eq. (16) as follows,

(17)

Thus, plotting of

against

will give,



Slope = i. e. k (18)

and

Intercept = i. e. K (19)

However, in case of the reaction with equimolar quantities of both (K+TCP-) and

DMTPCl i. e. M=1

k Q t 1 K ln 1 X (20)

On further simplification eq. (20) becomes

k Q

1 K (21)

Therefore, plotting of

against

will give slope = k Q and intercept

= 1 K .

The above model was validated by performing series of experiments. In each

experiment the influence of different variables is expressed in terms of conversion trends

and initial rate of particular reaction. This proposed kinetic model was verified by plotting

appropriate reaction parameters.

Chapt

Studi

7.3.2

[KTC

mol/m

time:

using

signif

indic

exper

7.2)

ter7‐Novel

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CP: 0.01 mo

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2 h]

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ficant rise

ated that th

riments were

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peed of Agit

ol, DMTPCl

n mass volu

F

rpyrifos cond

as PTC at 45

in conversi

he reaction

e conducted

calModelfor

ystemsandV

tation

: 0.0105 mo

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Figure 7.2 -

densation wa

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at 1000 rpm

S‐LPTCatal

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Effect of sp

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ture: 45°C,

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yrifosMethy

atalyst loadi

solvent: dic

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fferent speed

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other param

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18

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ds of agitatio

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86

0-5

ne,

on

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his

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ngst all PTC

other catalys

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experiment w

rimethyl am

dimethyl am

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hlorpyrifos c

ction conver

l, DMTPCl:

lume: 100 m

F

r of PTC act

TMAC has

tested. This

sts facilitatin

calModelfor

ystemsandV

alysts

without PTC

mmonium ch

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ammonium

condensation

rsion.

: 0.0105 mo

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Figure7.3 -

ivity was BT

shown exc

indicates th

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C gave only

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m bromide (

n. It has been

l, 1000 rpm

ture: 45°C, s

Effect of va

TMAC > TE

ellent react

he faster ion

n of reactive

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7.3% conve

MAC), tetrae

DMAB), ce

HDTMAB)

n observed t

m, catalyst loa

solvent: dich

arious cataly

EAB > CDM

tion rate an

exchange of

e anion.

yrifosMethy

ersion. A se

ethyl ammon

etyl pyridin

were scree

that the PTC

ading: 2.5×

hloro ethane,

ysts.

MAB > CPB

nd maximum

f BTMAC w

ylSynthesis.

18

ries of PTC

nium bromid

ium bromid

ened to judg

C significantl

10-5 mol/mL

time: 2 h]

> HDTMAB

m conversio

with K(+)TCP

87

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de

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ge

ly

L,

B.

on

P(-)

Chapt

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7.3.4

[KTC

volum

5 mol

ion c

cataly

relati

rate w

were

valid

.

ter7‐Novel

esinMixedS

Effect of C

CP: 0.0105 m

me: 100 mL,

A series o

l mL-1 were

atalyst conc

yst can be p

onship betw

was observed

performed

ated by the m

Mathematic

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Catalyst Loa

mol, DMTPC

, temperature

of reaction w

carried out

centration. (F

properly quan

ween the rate

d at 2.5 × 10

at 2.5 × 10

model and th

calModelfor

ystemsandV

ading

Cl: 0.0105 m

e: 45°C, solv

Figure 7.4 -

with varying

t. The K(+)TC

Figure 7.4) T

ntified by ap

e of reaction

0-5 mol mL-1

0-5 mol mL-

he results are

S‐LPTCatal

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mol, 1000 rp

vent: dichlor

- Effect of c

catalyst con

CP(-) conver

The increase

pplying the

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of catalyst -1 loading. T

e depicted in

lyzedChlorp

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pm, catalyst

ro ethane, tim

atalyst load

ncentration fr

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rate eq. 10,

st concentrat

loading henc

The experim

n Figure 7.5.

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: BTMAC, r

me: 2 h]

ding.

from 0.5 × 10

sed linearly

ion with con

which show

tion. The hig

ce all furthe

mental data

ylSynthesis.

18

reaction mas

0-5 to 2.5 ×1

with increas

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wed the linea

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ss

0-

se

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ar

on

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as

Chapt

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7.3.5

[1000

solve

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Fig

Effect of M

0 rpm, cata

ent: dichloro

Figure 7.6 –

Mathematic

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gure 7.5 – M

Mole Ratio

alyst: BTMA

ethane, time

– Effect of d

calModelfor

ystemsandV

Model valida

AC, reactio

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different mo

S‐LPTCatal

VegetableOil

ation at diff

n mass vol

ole ratios on

lyzedChlorp

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ferent cataly

lume: 100

n limiting re

yrifosMethy

yst loading.

mL, temper

eactant conv

ylSynthesis.

18

rature: 45°C

version.

89

C,

Chapt

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The

High

condu

0.666

obser

7.3.6

in th

increa

ter7‐Novel

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The mole

conversion

est reaction

ucted at M =

67, and 0.51

rved data (Fi

F

Effect of T

The effec

he range of

ased signific

Mathematic

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ratio of K(+

increased w

rate was o

= 1. The pro

28 (K(+)TCP

igure 7.7).

Figure 7.7 –

emperature

ct of tempera

25-45°C (F

cantly with i

calModelfor

ystemsandV

)TCP(-) to DM

with concen

obtained for

oposed kinet

P(-)/DMTPC

– Model vali

e

ature was stu

Figure 7.8).

ncrease in th

S‐LPTCatal

VegetableOil

MTPCl was

ntration of K

mole ratio

tic model w

l), and it wa

idation at d

udied under

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he temperatu

lyzedChlorp

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varied from

K(+)TCP(-) u

of 1 hence

was tested for

as found to

ifferent mol

otherwise si

served that

ure.

yrifosMethy

m 0.5128 to 1

under simila

e all further

r mole ratio

be in agreem

le ratios.

imilar reacti

the initial

ylSynthesis.

19

1 (Figure 7.6

ar condition

studies wer

M at 0.952

ment with th

ion condition

reaction ra

90

6).

ns.

re

3,

he

ns

te

Chapt

Studi

[KTC

2.5 ×

statis

ter7‐Novel

esinMixedS

CP: 0.01mol

10-5 mol/ml

Fi

The prop

tical fit (Fig

Mathematic

SurfactantSy

l, DMTPCl:

l, reaction m

Fi

igure 7.9 – M

posed model

gure 7.9).

calModelfor

ystemsandV

0.0105 mol

mass volume:

gure 7.8 – E

Model valid

l was tested

S‐LPTCatal

VegetableOil

l, 1000 rpm,

: 100 mL, so

Effect of tem

dation at dif

d for each

lyzedChlorp

lEmulsions

, catalyst: B

olvent: dichlo

mperature.

fferent temp

reaction tem

yrifosMethy

BTMAC, cat

oro ethane, t

peratures.

mperature to

ylSynthesis.

19

alyst loading

time: 2 h]

o get a goo

91

g:

od

Chapt

Studi

‘Ke’ t

ter7‐Novel

esinMixedS

The three

thus the app

Mathematic

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different eq

arent activat

calModelfor

ystemsandV

Figure 7.10

quilibria are

tion energy w

S‐LPTCatal

VegetableOil

0 - Arrheniu

combined in

was calculat

lyzedChlorp

lEmulsions

us plot.

n eq. 6 to get

ted as 18.84

yrifosMethy

t the equilib

kcal mol-1 (F

ylSynthesis.

19

rium constan

Figure 7.10)

92

nt

.



7.4 Conclusion

Chlorpyrifos methyl is commercially important insecticide produced worldwide

with energy intensive and atom uneconomical process. A simple, environmentally greener

and economically feasible process for chlorpyrifos methyl synthesis was developed. The

use of sterically hindered and expensive tertiary amine to suppress the side reaction is

eliminated from this process. The recyclable phase transfer catalyst and absence of

aqueous phase were the added advantages. Use of only organic phase facilitated recovery

and recyclability of the catalyst. The cheaper phase transfer catalyst and 100% selective

chlorpyrifos methyl formation is observed throughout. The influence of various

physicochemical parameters on reaction progress was studied independently. A promising

method for HPLC internal standard purity is developed and applied successfully for

monitoring the reaction progress as well as purity of the final product. The reaction rate

data was obtained from the comprehensive theoretical analysis. The proposed kinetic

model was validated by performing series of experiments. The apparent activation energy

of this process is found to be 18.84 kcal mol-1. Thus an atom economical and scale-up

feasible process for chlorpyrifos methyl is proposed.

7.5 Nomenclature

k1 Second order rate constant for forward reaction in organic

phase

(cm3 /mL s)

T Temperature (K)

Q0 Total concentration of phase transfer catalyst in organic

phase

(mol /mL)

V (org) Total volume of organic phase (mL)

Q+ Quaternary ammonium cation

XA Fractional conversion of reactant ‘A’

TCP- Nucleophile



7.6 Characterization and spectral data

7.1 Chlorpyrifos methyl (Colorless solid, Melting point - 38.0 to 38.5°C) 1H NMR (TMS, CDCl3, 300 MHz, Bruker): 3.658 (d, JP-H 3H-CH3), 7.849 (s, 1H-Ar); 13C NMR (TMS, CDCl3, 75 MHz, Bruker): 55.76, 120.41, 126.93, 141.22, 143.93, 150.49

ppm; 31P NMR (CDCl3, 120 MHz, Bruker): 60.0 (m) ppm

Elemental composition (Element – Calculated% / observed %): C – 26.07% / 26.06%, H

– 2.19% / 2.28%, Cl – 32.98% / 32.93%, N – 4.34% / 4.35%, O – 14.88% / 14.82%, P –

9.60% / 9.61%, S – 9.94% / 9.95%

FTIR (KBr pellet): 635 (m), 665 (m), 700 (m), 733 (m), 830 (vs), 949 (vs), 1012 (vs),

1051 (s), 1080 (s), 1155 (s), 1230 (m), 1259 (m), 1321 (m), 1400 (vs), 1531 (m), 2909

(w), 2968 (w), 3022 (w) cm-1.

GCMS (m/z): 47, 63, 79, 93, 109, 125, 197, 286 (100), 288, 290, 322, 324(M+2)

Figure 7.11 - 1H NMR spectra of chlorpyrifos methyl.



Figure 7.12 - 13C NMR spectra of chlorpyrifos methyl.

Figure 7.13 - 31P NMR spectra of chlorpyrifos methyl.

ConclusionandFutureOutlook

StudiesinMixedSurfactantSystemsandVegetableoilEmulsions 196

Conclusion and future outlook

In conclusion various efficient, cost effective and active emulsion products and

their manufacturing processes were efficiently developed for cosmeceutical, health care

and biopesticidal applications. Apart from developing the emulsion based formulation

strategy, the long term storage stability, biological as well as pharmaco-cosmeceutical

activity of each emulsion system was thoroughly investigated. This study revealed an

excellent task specific activity of these emulsions. The influence of commonly used

rheological thickener carboxy methyl cellulose-sodium salt (CMC-Na) on the viscosity

properties of low fat almond oil in water (O/W) emulsion was proposed using multiple

regression methodology. The effect of concentration of CMC-Na and temperature on

apparent viscosity of almond oil emulsion was proposed by an empirical equation.

Next, we developed environmentally benign protocols for chlorpyrifos and its

derivatives using HLB attained blend of non-ionic surfactant in organic solvent/water

system. The product obtained by this strategy was free from sulphotep impurity and

superior in purity. The chlorpyrifos methyl synthesis being very prone for hydrolysis and

ultimately forming methyl sulphotep impurity was modified to solid-liquid phase transfer

catalysed (S-L PTC) process using benzyl trimethyl ammonium chloride as a single and

recyclable catalyst.

In spite of the recent advancement, potential of the vegetable oil based emulsion

formulations has not been explored in sufficient details which may be due to the slight

variation in vegetable oil composition, complexity of interactions between the emulsion

constituents and limitations of instrumental sophistication in attaining and analyzing the

emulsion systems. Still, the development of newer emulsion systems for enhanced

activity and accuracy needs to be explored.

With regards to sustainability, a major challenge will be the development of

extraordinarily stable emulsions or their derivatives which will ensure the physic-

chemical stability of emulsion vehicle and incorporated actives also. The advantages of

such methods would be natural goodness, cheaper products, less energy consumption and

minimum waste.

Most of the phase transfer catalyzed reactions commercially employ quaternary

and phosphonium based catalysts. There is a wide scope for efficient utilization of HLB

attained combinations of non-ionic surfactant to make the process greener, efficient and

yielding cleaner product. Thus, phase transfer reactions using such catalysts are indeed an

area yet to discover.

chapter 7 - development and validation of novel...

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