INTRODUCTION:
Polyethyleneglycol (PEG) is a well-known non-ionic polymer which is used in polymer-based drug delivery system1. In the drug delivery system, PEGs with different molecular weights (MW) are used2. PEGylation is a popular prodrug delivery system in which the interested molecule is covalently attached to PEG3. Protein molecules are associated with a good number of PEG molecules4. PEG is widely used in drug delivery and in preparation of bio-conjugates which are useful for diagnosis5. Due to cheap and environmentally safe nature, PEGs are popular solvent media to carryout reactions6. PEG-400 is recommended for momentary relief or protection against eye problems (like dryness irritation or burning)7. PEG 400 (Polyethylene glycol 400) belongs to low-molecular-weight grade of PEG series. A spectrum of pharmaceutical formulations use PEG-400, in view of its low toxicity. The other applications of PEG (200 to 8,000,000) include cosmetic field8. PEG-200 to PEG-600 are liquid PEGs and they are used as water miscible solubilizer in parenterals as well as oral liquids.
PEG-400 is used in drugs delivery of injection dosage forms as per US FDA’s Inactive Ingredient Guide (IIG)9.
Exploration of reaction mechanism and deriving the laws which describe the reaction characteristics are possible by the study of reaction kinetics10. Out of the inorganic oxidants, well studied reactions used ceric11, vanadate12 and periodate13,14. 2,6-dichloro-quinone-4-chloro-imide15,16, dichloro isocyanuric acid17-20, chloromine-T21 and N-bromo succinimide22,23 were some of the well-used N-halo oxidants.
Many research papers discussed about oxidation of various types of substituted alcohols21-23. Fenton24-26 and ceric (IV) ions27,28 were the well-used oxidants in the oxidation of PEG. Inspite of non-disclosure of complete mechanism involved in the PEG oxidation by ceric ions, participation of free radicals was well established27. Mn/Ce composite oxide involved oxidation of PEG confirmed the participation of radical mechanism29. Formation of poly(oxyethylene)‐dicarboxylic acids in high yields was reported in the oxidation by Jone's reagent at room temperature30. Rate law were proposed in the uncatalyzed and Ru (III) catalyzed permanganate oxidation of PEG31. Hence, in the present study, kinetic study of periodate oxidation of pharmaceutical importance of PEG-400 was carried out in aqueous alkaline medium.
EXPERIMENTAL:
In the current study, all the chemicals used were of analytical grade. Studied the reaction kinetics by iodometry. Periodate oxidation capacity was followed till its conversion to iodate, i.e., in the PEG-400 oxidation, two electrons transfer or one oxygen atom loss was observed per each periodate
RESULTS AND DISCUSSION:
Reaction orders of oxidant, substrate and alkali:
Order of reaction with respect to a particular reactant (oxidant/substrate/alkali) was measured by varying its concentration while concentration of each of other reactants was maintained at constant value. In the case of periodate, its concentration was changed from 0.00025 to 0.002 M. Plots of log (a-x) vs time (Fig. 1) resulted in linear curves (up to 85-90% of reactions) which shows that order of reaction w.r.t. [periodate] is unity. Rate constant values were found to be fairly constant in the studied range of [oxidant] (Table-1). It confirms the first order in [oxidant].
Fig. 1: Plot of log(a-x) versus time at [KIO4]
= 0.002 M, [PEG-400] = 0.025M, [O
] = 0.1 M and Temperature = 35 oC
Table 1: Rate Constants in the Variation of Periodate Concentration
|
Reaction Conditions |
Conc of Periodate (M) |
k1 x 104 (min-1) |
|
[PEG-400] = 0.025M [O Temperature = 35oC |
0.00025 |
15.25 |
|
0.0005 |
14.90 |
|
|
0.001 |
14.03 |
|
|
0.002 |
13.80 |
Literature reports the substrate inhibition in sugar
alcohols oxidation by KIO4
in alkaline medium13,14. However, in the present case, rate
constant is almost constant with the variation of [PEG-400] from 0.0025 to 0.1
M (Table-2). It indicates the zero
order dependence of reaction on [substrate]. An increase of [OH–]
from 0.05 to 0.5 M had resulted in a decrease of reaction rate. The plot of log
k1 vs log [O
] shows the slope as –0.47 (Fig. 2) which indicates
inverse fractional order w.r.t. [alkali].
Table 2. Reaction Rate Dependence on Concentrations of PEG-400 And Alkali
|
General Reaction Conditions |
Variant |
Conc of Variant (M) |
k1 x 104 min-1 |
|
[PEG-400] = 0.025 M [KIO4] = 0.0005 M [OH-] = 0.1 M Temperature = 35oC |
[Substrate] |
0.0025 |
15.08 |
|
0.0125 |
15.43 |
||
|
0.025 |
14.90 |
||
|
0.050 |
14.64 |
||
|
0.10 |
14.45 |
||
|
[Alkali] |
0.05 |
18.55 |
|
|
0.1 |
14.90 |
||
|
0.2 |
10.58 |
||
|
0.5 |
6.40 |
Fig. 2. Effect of alkali concentration on oxidation of PEG-400 by periodate
In
alkaline medium, KIO4 dissociates and equilibria (1–3) establish
between the reactants and products32. The concerned equilibrium
constants are shown below, which were measured by Aveston32 at 298.2
K. The magnitude of periodate species distribution in aqueous alkaline solution
can be calculated from the following equilibria. Out of the four periodate
species, 
and 
are considerable as [I
] and [
] are insignificant in the range of used alkali concentrations.
Crouthamel’s data33 was used to calculate their concentrations which
are found to be in lines with other researcher’s findings34-36.
à (1)
à (2)
à (3)
As per Shan37, the given below equations (4) and (5) can be obtained from the above equilibria (2) and (3)
à (4)
à (5)
Where, [I
represents
the actual total concentration of periodate. Since and are the two chief species of periodate, sum of their concentrations is nearly corresponding
to [I
. Therefore, these two species complex with PEG-400. Concentrations
of these two species were calculated using the above equations at various alkali concentrations in the range
of 0.025 to 0.5 M. Concentrations
of and at different concentrations (0.025, 0.05, 0.10, 0.20 and 0.50) are (0.000107,
0.000180, 0.000267, 0.000349 and 0.000427) and (0.000364, 0.000308, 0.000228,
0.000149 and 0.000073) respectively. It indicates that is the
predominant species at higher concentration of alkali but it was at
lower alkali concentration.
Temperature dependence:
Increase of temperature from 35 to 50 oC raised k1 (first order rate constants). A plot of log (k1) vs. 1/T (Fig.3) resulted in a straight line. Calculated the activation parameters from Eyring equation and slope of the plot38. Values are listed out in the Table – 3.
Fig. 3: Effect of temperature on oxidation of PEG-400 by periodate
Table 3: Arrhenius Parameters at 308 K
|
Activation energy ( KJ/mole) |
Enthalpy of activation ( |
Entropy of activation ( J/K/mole) |
log10 PZ |
Gibb’s free energy ( KJ/mole) |
|
75.48 |
72.92 |
96.65 |
8.19 |
102.69 |
KJ/mole)
Effect of boric acid and salts:
As per the earlier reports, the rate of reaction was increased by the boric acid addition in alkaline medium. Because, borate ions form complexes with sugar alcohols (inositol/sorbitol/mannitol) in view of favored condtions13,14. In those cases, substrate inhibition was described in terms of a competition in the formation the above complex with that of a stable complex between periodate and sugar alcohol(s). However, reaction rate was not affected by the addition of boric acid in the present case (Table-4). PEG-400 has a hydroxyl value39 of 264 to 300. So, out of the good number of hydroxyl groups present on each PEG-400, some of the hydroxyl groups on it involve in the formation of complex with the highly dissociating potassium borate. Hence, the balance hydroxyl groups on substrate will be free. A decrease in the reaction rate was observed by the adding salts of halides (chloride and iodide ions). But the reaction rate was doubled by the addition of bromide ions.
Table 4: Effect of Salt and Boric Acid Concentrations on Reaction Rate
|
General Reaction Conditions |
Variant |
Nature of Variant / Variant Conc (M) |
k1 x 104 min-1 |
|
[PEG-400] = 0.025 M [KIO4] = 0.0005 M [Salt] = 0.1M [O Temperature = 35oC |
Salt |
Nil |
14.90 |
|
KCl |
14.47 |
||
|
KBr |
30.22 |
||
|
KI |
3.04 |
||
|
KNO3 |
19.47 |
||
|
[Boric Acid] |
0 |
14.90 |
|
|
0.01 |
14.13 |
||
|
0.025 |
13.46 |
||
|
0.05 |
14.90 |
Nature of reaction and rate law:
Spot tests were used to recognize the reaction end products40. The major reaction products were long chain aldehydes. In addition, because of complete oxidation, a slight amount of carboxylic acids were also observed. Further conversion to 2,4-dinitrophenyldrazone derivatives established the formation of aldehydes. The stated products nature in the present study is substantiated from the earlier reports of Szymański et al27. End –OH groups present on PEGs display considerable effect on their properties (both physical and chemical properties). Therefore, ‘polyethylene glycols’ is the prevailing name for these molecules where, ‘polyethylene oxides’ is their technical name41. Besides to the active nature of hydroxyl groups, their hydroxyl values are high. Consequently, oxidation of end –OH groups takes place to yield the above mentioned products. But, definite stoichiometry was not observed. A rate law is offered taking into consideration of the above mentioned orders of the reactants. In addition to the available simple methods for the pharmaceutical formulations42-43, the usage of biocompatible polymers is the thrust research area in the pharmaceutical field44-53. Hence, a rate law is proposed as shown below for the oxidation of the pharmaceutically significant PEG-400 in alkaline medium.
The two main periodate species (
and 
) form complexes (C1 and C2) with
PEG and equilibria exist between them. At a slower rate, these two complexes
decompose to yield products with rate constants of k1 and k2
respectively.
, total concentration of periodate can be written as
= [
] + [] + [] + [] + [Complex C1] + [Complex C2]
In view of insignificant concentrations of [IO4–] and [H2I2O104–], the above equation turns to
= [] + [] + [Complex C1] + [Complex C2]
It is known that hydroxyl value of PEG-400 ranges39
from 264 to 300 and hence, good number of hydroxyl groups is available on every
PEG-400 molecule. In addition, the concentration of PEG-400 is almost fifty
times higher than periodate concentration. It leads to complexation of almost
all and species with –OH groups present on PEG-400.
Henceforth, free oxidant species will not be further available. Therefore, in
the above equation, the first two terms can be ignored. It leads to the
following equation.
= [Complex C1] + [Complex C2]
= 
[PEG-400] [I] [O] + [PEG-400] [I] [O
= [] [PEG-400] + [] [PEG-400]
where [] = [I] [O] and [] = [I] [O
Rate = [I] [O] [PEG-400] { + [O]}
First order reaction in [oxidant] and independence of reaction w.r.t. [PEG-400] are explained by the above rate law. Since k2<<1, hydroxide ion value is lower in the numerator in comparison to that of denominator. It helps to explain the inverse fractional order in alkali concentration.
CONCLUSION:
In order to learn the stability of pharmaceutically significant PEG-400 in presence of oxidants and nature of products formed, its oxidation was carried out in alkaline medium. Two electrons transfer or one oxygen atom loss was observed per each periodate in the PEG-400 oxidation. The reactions were independent of PEG-400 concentration. Inverse fractional order dependence of reaction was observed with alkali concentration. In consistent with the observed results, a suitable rate law was postulated.
ACKNOWLEDGEMENT:
KVSK is thankful to UGC - New Delhi for financial support in the form of Minor Research Project, F.No.4-4/2015-15(MRP-SEM/UGC-SERO), November 2014
CONFLICT OF INTEREST:
The authors declare no conflict of interest.
LIST OF SYMBOLS AND ABBREVIATIONS:
PEG : Polyethylene Glycol,
NBS : N-Bromosuccinimide,
DCICA : Dichloroisocyanuric Acid,
DCQCI : 2, 6-Dichloroquinone-4-Chloro-Imide
CAT : chloramine-T
k1 : First order rate constant.
:
Activation
energy
:
Enthalpy of activation
:
Gibb’s
free energy
: Entropy of activation
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Received on 09.06.2019 Modified on 14.07.2019
Accepted on 10.08.2019 © RJPT All right reserved
Research J. Pharm. and Tech. 2019; 12(12): 5899-5903.
DOI: 10.5958/0974-360X.2019.01023.0