Kinetics of periodate oxidation of polyoxyethylene – 300, a biodegradable pharmaceutical polymer

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  Polyoxyethylene-300 (POE) is a well-known biodegradable pharmaceutical polymer. In order to understand the stability of POE and to derive the reaction rate law, the title reaction was carried out in aqueous alkaline medium. Reaction was found to be
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  VenkataNadh R et al.„ Int. J. Res. Pharm. Sci., 10(4), 2830-2836 OA IJ R PS Published by JK Welfare & Pharmascope Foundation Journal Home Page: www.pharmascope.org/ijrps Kineticsofperiodateoxidationofpolyoxyethylene–300,abiodegradablepharmaceuticalpolymer Koteswara Rao K.V.S 1 , VenkataNadh R *2 , VenkataRatnam K 21 Departmentof Chemistry, GVSMGovernmentDegree College, Ulavapadu-523292, India 2 GITAMUniversity, Bengaluru Campus, 561203, Karnataka, India    Article History: Received on: 20.03.2019Revised on: 08.06.2019Accepted on: 12.06.2019 Keywords: Periodate,Oxidation,POE,PEG-300,Alkaline medium,Kinetics A Polyoxyethylene – 300 (POE) is a well-known biodegradable pharmaceuticalpolymer. In order to understand the stability of POE and to derive the reac-tion rate law, the title reaction was carried out in aqueous alkaline medium.Reaction was found to be irst order dependent on the concentration oxidant (periodate)andindependentofsubstrate(POE)concentration. Aretardationofreactionratewithanincreaseinhydroxideconcentrationshowsaninversefractional order in it. Based on the studies of the temperature dependence of reaction, evaluated the activation parameters. * Corresponding AuthorName: VenkataNadh RPhone: +91-9902632733Email: doctornadh@yahoo.co.in ISSN: 0975-7538 DOI: https://doi.org/10.26452/ijrps.v10i4.1558 Production and Hosted by Pharmascope.org © 2019 |  All rights reserved. INTRODUCTION Poly oxyethylene (POE) is a freely obtainable poly-mer in an array of molecular weights. A varietyof POEs exhibit solubility in water and some of theorganic solvents. The other name is PEG (poly ethy-lene glycol) when its molecular weight is less thanonelakh. PEGs(havingamolecularweightlessthana thousand) are colorless and viscous liquids (Bai-ley and Koleske, 1976). Polyethylene glycols (PEGs) are well-known excipients (Debotton and Dahan,2017). In controlled drug delivery, PEG copolymerswithpolylacticacid(PLA)areused(Xu et al. ,2019).Protein-based medications accumulate the proteindeposits in the blood, which can be reduced by opt-ing PEG surface coating on them (Antwerp  et al. ,2002). Osmotic action of PEG supports its usage asa laxative (Savino  et al. , 2012). Liquid PEGs (200- 600) are used in pharmaceutical preparations of oral and intravenous administration (D’souza andShegokar,2016). Asantidotes,theyremovethetoxic substancesfromthesurfaceofburnedskin(Cartotto et al. , 1996).In addition, a spectrum of industrial applicationsis shown by PEGs. In view of low toxicity, cheapcost, biodegradability and ready availability, PEGspossess high advantage for solvents (Zhang  et al. ,2004). Inaddition,PEGisawell-knownphasetrans-fer catalyst (Xie  et al. , 2000) and reducing agent inorganicsynthesisinthepresenceofmicrowaveirra-diation (Bendale and Khadilkar, 2000; Sauvagnat  et al. ,2000). Chromeno[3,4- b ]quinolinederivativesweresynthesizedeficientlyina”green”solventlikePEG 300 using Cu(II)BHPPDAH complex as hetero-geneouscatalyst(Sharghi etal. ,2013). Inmostofthecross-coupling reactions, PEGs are used as effectivegreen solvents (Razler  et al. , 2009). PEG-300 wasproved to be an excellent medium to result in highyieldsofthebiarylnucleusinacross-couplingofarylchlorides and phenylboronic acids through Suzuki– 2830 © InternationalJournal of Research in Pharmaceutical Sciences  VenkataNadh R et al.„ Int. J. Res. Pharm. Sci., 10(4), 2830-2836 Miyaura cross-coupling (Yin  et al. , 2006). Underthermal conditions, high yields (98%) of 1-iodo-4-nitrobenzeneandphenylboronicacidwereobtainedby carrying out Suzuki cross-coupling reactions inPEG-300(Silva,2010).Dziurka(2005)includedPEG 300inresinmixtureandstudieditsinluenceontheproperties of PMDI resin. PEG is also used as a sol-vent in the preparation of inorganic nano-materialslike TiO 2  nanoparticles in a sol-gel method (Liu et al. , 2000) and silver nanorods by an electro-chemical technique (Zhu  et al. , 2001) Bhattachar- jee  et al.  (2002) proposed a method to synthesizeCdS nanoparticles implanted in a matrix made upof PEG 300. Variation of PEG-300 concentrationplayed a critical role in the size and orientationof formed PbS nanoparticles. Increase in [PEG]decreased the reaction rate. It leads to a decreasein ilm thickness and hence an increase in trans-mittance of ilm. At the same time, optical bandgaps increase with an increase in [PEG] (Kaci  et al. ,2010). 1D nanostructural materials are preparedby using structure-directing agents like PEG poly-mers (Shi  et al. , 2007). Hexagonal ZnO micro nuts(HZMNs) were prepared in a hydrothermal methodby using Zn(II)-PEG 300 globules as a soft tem-plate (Shi  et al. , 2009). PEG-300 was used as a sur-factant in a hydrothermal route for the preparationof rectangle rod-like shaped 4ZnO.B 2 O 3 .H 2 O, whichcanbeusedasalame-retardantillingmaterial(Shi et al. , 2007). Similarly, the two-phase system con-sisting of PEG along with aqueous KCl, was used toextractthemetalions(likeZn +2 andCu +2 )(Ammar et al. , 2011).Ulbricht   et al.  (2014) reported the oxidative degra-dation of PEGs in appropriate conditions. (Per)Oxidation of PEGs is very well known (Han  et al. ,1997). PEG200and300aredegradedby  Alcaligenes faecalis  var.  denitriicans  during their anaerobicgrowth (Grant and Payne, 1983). Literature survey shows the oxidation of PEGs by different oxidantslike ceric (IV) ions Szymansi  et al.  (2015) (Nagara- jan  et al. , 1994), Mn/Ce composite oxide (Imamura et al. , 1986), permanganate (Hassan  et al. , 2018),Jone’sreagent(LeleandKulkarni,1998)andFenton reagent (Chen  et al. , 2014; Prousek and Duriskova, 1998). Since the oxidation of PEG-300 by periodatewas not studied so far, it is considered for the cur-rentstudy. MATERIALSANDMETHODS Differentconcentrationsofoxidant(potassiumperi-odate), the substrate (POE) were thermostatted at a constant temperature (35 ± 0 . 1  o C) for two hours.In all the cases, substrate concentration was kept higher compared to oxidant. Determined the unre-acted oxidant concentration by iodometry. Repro-ducibility of reaction rate constants was found tobe with in  ±  5%. Transfer of two electrons or lossof one atom of oxygen per oxidant molecule wasmeasured, i.e., conversion of periodate up to iodate,as the latter is incapable of oxidizing the PEG-300(POE) molecules. Iodate was used to conduct sep-arate experiments to endorse the above reactions.Alkalinity was maintained by using sodium hydrox-ide. Taking into consideration of the maintainedfair alkali concentrations in the present condition,its effect was studied. Reaction vessels surface hasno effect on the reaction rate, and it was conirmedfrom the obtained identical results with acrylic andquartz ware. Dissolved oxygen has no inluence onreaction as the difference is insigniicant in the rateconstants obtained in the presence of air and undernitrogen atmosphere. RESULTSANDDISCUSSIONReactionorders Adopted the uni-variant method to determine thereaction orders w.r.t. concentrations of periodate/ POE / alkali, in which rate constants were mea-sured by changing the concentration of one vari-antwhilemaintainingconstantexperimentalcondi-tions as well as concentrations of balance reagentsinvolved (Table 1). Varied the periodate concen-tration over the range of 0.00025 to 0.002 M at ixed conditions of [POE], [OH − ] and temperature(Table 1). Insigniicant effect of periodate concen-trationonthereactionratewasnoticed,i.e.,pseudo-irst-orderrateconstants(k  1 )werealmostconstant with the variation of periodate concentration in theaboverange. First-ordernatureofreactionwasalsoevident from the linearity of plots obtained in log[periodate] versus time (Figure1). Figure1: Plotoflog(a-x)versustimeat35 o Candperiodate(0.002M),POE(0.025M)andhydroxide(0.1M) Logarithmic values of rate constants were plotted © InternationalJournal of Research in Pharmaceutical Sciences 2831  VenkataNadh R et al.„ Int. J. Res. Pharm. Sci., 10(4), 2830-2836 Table1: Rateconstantsinthevariationofreactionparametervalues [KIO 4 ] M [POE] M [Alkali] M Temp ( 0 C) k  1  x 10 4 min − 1 0.00025 0.025 0.1 35 16.780.0005 0.025 0.1 35 16.420.0010 0.025 0.1 35 15.500.0020 0.025 0.1 35 14.670.0005 0.0025 0.1 35 16.940.0005 0.0125 0.1 35 17.150.0005 0.025 0.1 35 16.420.0005 0.050 0.1 35 17.990.0005 0.100 0.1 35 16.770.0005 0.025 0.05 35 18.200.0005 0.025 0.1 35 16.420.0005 0.025 0.2 35 11.360.0005 0.025 0.5 35 7.740.0005 0.025 0.1 35 16.420.0005 0.025 0.1 40 35.630.0005 0.025 0.1 45 55.270.0005 0.025 0.1 50 63.90against logarithmic values of variant concentration,and the slope was used to determine the respec-tive reaction order in the case of POE and hydrox-ide ion concentrations. Changed the substrate (POE/PEG-300)concentrationfrom0.0025to0.1Mandmeasured the reaction rates. It was found to be thereactionrateisindependentofsubstrateconcentra-tion. Hence, the order was zero in the case of [POE]whereas, substrate inhibition was reported in theliterature in the oxidation of different sugar alco-holsundersimilarreactionconditions(Kumar et al. ,2014). Figure2: Alkalieffectontherateofoxidationof POE Alkali concentration effect on the reaction rate wasstudiedbyincreasingitsconcentrationfrom0.05to0.5M.Retardationofratewasobserved,whichindi-catestheinversenatureofthereaction. Astheslopevaluewaslessthanone(–0.388)intheplotoflogk  1 vs log [OH − ] (Figure 2), inverse fractional order inalkali concentration was concluded.Equilibrium exists between potassium perio-date and its dissociation products in alkalinemedium (Aveston, 1969). Equations (1–3) along with concerned equilibrium constants (at 298.2 K)are given below.Under these equilibrium conditions, the extent of periodate species availability in aq. alkaline condi- 2832 © InternationalJournal of Research in Pharmaceutical Sciences  VenkataNadh R et al.„ Int. J. Res. Pharm. Sci., 10(4), 2830-2836 tions can be calculated. At the maintained [OH − ]  IO − 4   , and   H  2 I  2 O 4 − 10   are insigniicant among thepossible four periodate species, whereas, higherconcentrations are observed for   H  3 IO 2 − 6    and  H  2 IO 3 − 6    (i.e., species – 3 and 4). In a similar lineto other researchers (Tuwar  et al. , 1992; Shan  et al. ,2005; Kulkarni and Nandibewoor, 2006), the con- centrations of these two predominant species canbecalculatedbytakingthehelpof  Crouthamel et al. (1951).   IO − 4   ex  denotes the total concentration of periodateandisconsideredasequivalenttothesumof   H  3 IO 2 − 6    and   H  2 IO 3 − 6   . Based on the two equi-librium conditions (2) and (3), (Shan  et al. , 2009)has proposed two Equations (4) and (5).  H  2 IO 3 − 6    β  3  OH  −  2    β  2  OH  −    β  3  OH  −  2  IO − 4   ex   f   OH  −  IO − 4   ex (4)  H  3 IO 2 − 6    β  2  OH  −    β  2  OH  −    β  3  OH  −  2  IO − 4   ex  ∅  OH  −  IO − 4   ex (5)In molar units, hydroxide concentrations (cor-responding   H  3 IO 2 − 6    &   H  2 IO 3 − 6   ) are 0.025(0.000107 & 0.000364), 0.05 (0.000180 &0.000308), 0.10 (0.000267 & 0.000228), 0.20(0.000349 & 0.000149) and 0.50 (0.000427 &0.000073). It shows a simultaneous increasein   H  2 IO 3 − 6   and decrease in   H  3 IO 2 − 6    with anincrease in [OH − ]. These two predominant perio-date species complex with POE-300.  ActivationparametersFigure3: Effectoftemperatureonratereaction Studied the effect of temperature on the reactionrate by measuring irst-order constants (k  1 ) at 35,40, 45 and 50  o C. Values of k  1  increased with anincreaseoftemperature. Leastsquaresmethodwasapplied to the plot of log k  1  versus 1/T (Figure 3).Eyring equation (Wynne-Jones and Eyring, 1935) was used to determine activation parametersand the values are presented in Table 2. Effectofaddedboricacidandsalts Kumar et al. (2012,2014)studiedtheeffectofboric acid presence on sugar alcohols oxidation by peri-odate in alkaline medium. The increased reactionrate was attributed to a favourable environment forthe formation of a complex between borate ion andsugar alcohols, which contributes to the substrateinhibition. But no appreciable effect of boric acidis noticed in the present case (Table 3). It can beexplained taking into consideration of the presenceof more hydroxyl groups on POE (PEG-300) as itshydoxyl value ranges between 340 and 394 (htmllink). Though, some of the hydroxyl groups of POEcomplex with borate ions, a good number of free –OH will be available on the substrate. Inclusion of bromide ions increased the reaction rate, but in thecontrary,aretardedreactionratewasobservedwiththe other two halide ions (chloride, iodide). Effectofsolvent: Tostudytheeffectofsolventonthereactionrate,thereaction was carried out at different proportions of t-butyl alcohol and water (Table 4). The addition of t-butyl alcohol reduced the rate of reaction, indicat-ing that a decrease in the dielectric constant of themedium reduces the reaction rate. Ratelawequation Long-chain Carboxylic acids were the minor prod-ucts along with aldehydes as the prime reactionproducts in the oxidation of POE by periodate inalkaline medium. Spot tests were used to detect soformed products (Feigl, 1956). Aldehydes forma- tion in the present study was further conirmed byconverting to 2,4-dinitrophenyldrazones. Szymansi et al.  (2015) reported the products with the samenature. It shows that terminal –OH groups areactive, which corroborates with the common nameof these substrates as ‘polyethylene glycols’ (Hen-ning, 2001). Moreover, its hydroxyl value is prac- tically high. So, the observed inal products canbeunderstoodfromterminal–OHgroupsoxidation.However, stoichiometry was unable to determineaccurately. Derived a suitable rate law as givenbelow, by considering the reactions orders in oxi-dant, substrate and alkali. © InternationalJournal of Research in Pharmaceutical Sciences 2833  VenkataNadh R et al.„ Int. J. Res. Pharm. Sci., 10(4), 2830-2836 Table2: Arrheniusparametersat308k  ∆ E ̸ = KJ/mole ∆ H ̸ = KJ/mole ∆ S ̸ = JK − 1 / molelog 10  P Z   ∆ G ̸ = KJ/mole75.02 72.46 97.34 8.16 102.44 Table3: Reactionratevariationwithsaltconcentration Salt [Salt] M k  1  x 10 4 min − 1 Nil Nil 16.42KCl 0.1 12.80KBr 0.1 25.71KI 0.1 4.29KNO 3  0.1 15.90Boric Acid 0.01 15.43Boric Acid 0.025 14.91Boric Acid 0.05 15.80 [periodate] = 0.0005 M [POE] = 0.025 MTemperature= 35 o C [OH − ] = 0.1 M Table4: Effectofsolvent  t-butylalcohol : water (v/v) k  1  x 10 4 min − 1 0 : 100 16.425 : 95 6.9810 : 90 6.5620 : 80 6.6840 :60 6.63C 1  and C 2  are the complexes formed between thesubstrate (POE) and the active species -of perio-date (   H  3 IO 2 − 6    and   H  2 IO 3 − 6   ). Then the prod-ucts are formed by rate-determining dissociation of these complexes. Species  −     S   k 4 ⇋  Complex C  1 k 1 −→  ProductsSpecies  −     S   k 5 ⇋  Complex C  2 k 2 −→  Products Rate=k  1  [C 1 ]+k  2  [C 2 ]=  IO − 4   [OH − ][S]{k  1 K 2 K 4  +k  2 K 3 K 5 [OH − ]}Outof   IO − 4   , H  2 I  2 O 4 − 10  ,H  3 IO 2 − 6  ,H  2 IO 3 − 6  ,  ComplexC 1  and Complex C 2 , the irst two species are neg-ligible, overall periodate concentration,   IO − 4   T   isrewritten as given below.  IO − 4   T   = [species-3] + [species-4] + [C 1 ] + [C 2 ]As the hydroxyl values of POE (PEG-300) is in therangeof340-394(htmllink),alargenumberof–OHareavailableandhence,species-3andspecies-4arecompletely complexed with them. Therefore, con-centrationsofthosetwospeciescanbeneglectedtorewrite the above equation as  IO − 4   T   =[C 1 ]+[C 2 ]=K 2  K 4  [S]  IO − 4   [OH − ]+K 3 K 5 [S]   IO − 4    [OH − ] 2 The above equation can be rearranged to get   IO − 4     IO − 4   T   OH  −  S    { K  2  K  4    K  3  K  5   OH  −   } Bysubstitutingthevalueof   IO − 4   intherateexpres-sion, we can conclude that  Rate    IO − 4   T   { k 1 K  2 K  4    k 2 K  3 K  5  OH  −   }{  K  2 K  4    K  3 K  5   OH  −   } The above rate law explains the observed reactionorders (irst order in [oxidant] and independenceof reaction to [substrate]). In comparison to thedenominator,thevalueof[OH − ]valueinthenumer-ator is small due to k  2 <<1. And hence, inverse frac-tional order in [OH − ] can be explained. CONCLUSIONS PeriodateoxidationofPOE(orPEG-300,akeypoly-mer in the pharmaceutical industry) followed irst order kinetics in [oxidant], independent of [sub-strate]andinversefractionalorderin[OH − ]. Postu-latedasuitableratebyconsideringtheexperimentalresults. 2834 © InternationalJournal of Research in Pharmaceutical Sciences
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