chemistry modification of pmma-g-peg copolymer

Chemistry Modification of PMMA-g-PEG copolymer

Juliana dos Santos Rosa,2 Benila Maria Silveira,1 Kátia Monteiro Novack,1

Viviane Martins Rebello dos Santos,*1 Leonardo César de Moraes Teixeira1

Summary: Copolymers are polymers consisting of different repeat units and their

production is usually motivated by the changing of polymers properties. An

important application are the transportation of drugs within the organism with the

aim of controlling the release of the substance. The synthesis of these new

copolymers is based on simple semi-synthesis and low cost. The synthetic routes are

based on the interaction of the graft copolymer (PMMA-g-PEG) with a variety of

reagents such as acetic anhydride, acetic acid, methyl iodide, sulfuric acid and

hydrochloric acid. The products from these reactions of esterification, methylation,

acetylation and halogenation will be characterized by Fourier-transforminfrared

spectroscopy (FTIR). The use of this technique allowed us to detect the main

absorption bands related to the C¼O bonds, C-Cl, R-COOR and CO, thus confirming

the efficiency of modification reactions of the graft copolymer chain.

Keywords: chemistry modification; Differential Scanning Calorimeter; graft copolymers;

infrared spectroscopy; Scanning Electron Microscopy (SEM); thermogravimetric analysis;

X-rays diffraction (XRD)

Introduction

Nowadays, some polymers are developedto operate as drug delivery at specific sitesin the organism. Currently, modified poly-meric compounds are being used as drugdelivery systems, acting as carriers of drugsable to target tissues or tumor cells andprotecting the premature inactivation of theactive ingredient of the drug during trans-port.[1–5] Polymers used as a matrix in drugdelivery system shall be chemically inertand free of impurities, have a properphysical structure and be easily processableby the organism. Due to the characteristicsderived from their origin polymers such astransparency and strength of PMMA[6–8]

and an appropriate structure and easyprocessing of PEG,[9] our research grouphas studied the modification of the copoly-mer PMMA-g-PEG from various organic

reactions.[10] One of the most current formsfor controlled release is the development ofnew polymeric materials, which allows theuse of various techniques for encapsulationof many compounds in multiparticulatesystems such as microspheres and micro-capsules, in order to protect, stabilize, ormask undesirable flavors modify the releaseproperties. Research in this area hasbecome very important due to the abilityof the microspheres to modify certainkinetic parameters and biodistribution ofthe molecules transported, allowing itsapplication in the area of selective andcontrolled delivery of drugs.[11] The use offormulations that allow the optimization ofthe speed of transfer and dosage of drugshas been an area of intense research inrecent decades. Polymeric microparticlesas microcapsules and microspheres, havebeen proposed as modulators and driversin drug release at specific sites in theorganism, as a strategy for stabilizing againstagents such as pH or light drugs, maskorganoleptic characteristics[12] and decreasethe side effects of certain drugs, highlightingthe nonsteroidal anti-inflammatory drugs

1 Departament of Chemistry, Federal University ofOuro Preto, UFOPFax: (31) 3559 1707;E-mail: [email protected]

2 Campus Morro do Cruzeiro, Ouro Preto, MG, Brasil

Macromol. Symp. 2014, 343, 78–87 DOI: 10.1002/masy.20130019778 |

� 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com

(diclofenac and indomethacin), which oftencause irritation to the intestinal mucosa.[13]

Polymers are selected according to theformulation and the desired release mecha-nism, for example, parenteral enteral or thedosage form. Two criteria must be followedin the preparation of a polymer formulation.The chemical characteristics of the polymershould not compromise the action of theactive ingredients, and the physical proper-ties of the polymer must be consistent andreproducible from batch to batch.[5]

Because of its various applications andfeatures, especially in therapies for con-trolled release of the drug, polymersexcipients are the most used for obtainingpharmaceutical forms.[5] After modifyingthe polymer properties, a matrix systemmay be prepared for sustained or controlledrelease of drugs.[13] The initial objective ofthis work was to modify the copolymerchains of PMMA-g-PEG with the insertionof different chemical groups to enable, inthe future, their biomolecular interactions(antigen-antibody, enzyme-substrate anddrug-receptor) with various types of drugdelivery systems.[14,15]

Experimental Part

Chemical Reagents

Sodium hydroxide (NaOH), dichloromethane(CH2Cl2), acetic anhydride (CH3COO-COCH3), acetic acid (CH3 COOH), hydro-chloric acid (HCl), sodium bicarbonate(NaHCO3), sulfuric acid (H2SO4) were

purchased from Vetec. Methyl iodide(CH3I), chloride sodium (NaCl), benzoylperoxide, methyl methacrylate (MMA),polyethylene glycol were purchased fromSigma Aldrich and distilled water.

Synthesis of the Graft Copolymer(PMMA- g-PEG)[10,16]

General Reactions

Synthesis:The copolymer was prepared in abeaker by dissolving 40.00 g of PEG in100.00mL of dichloromethane. The con-tents of the beaker were transferred to around bottom flask along with 2.80mL ofMMA and 0.05 g of benzoyl peroxideinitiator. Then the reaction mixture wasleft under magnetic stirring at 80 �C for 6hours. At the end of the reaction wereadded 50.00mL of dichloromethane and50.00mL of distilled water, producing acolorless homogeneous solution. The con-tents of the flask were transferred to aseparatory funnel and the organic layerseparated from the aqueous phase withdichloromethane. The copolymer (COPGRAFT) obtained in the reaction wastransferred to a beaker and left at roomtemperature to evaporate the solvent andsolidify.

Synthesis of the Copolymers[17]

General Scheme

Synthesis 1:Methylation of Graft CopolymerPMMA-g- PEG- (1)

In a beaker were solubilized 2 g of graftcopolymer in 10mL of CH2Cl2. Then wereadded 10mL of 10% NaOH solution. The

OH CH2-CH2 OHn O

+

O

CH2 C

CH3

C

CH2

O

O

CH3 n

C

CH3

CO

O

CH2

CH2

OH n

i

i= Benzoyl peroxide

General Reactions:

Figure 1.

General reaction to the synthesis of Graft Copolymer (PMMA- g-PEG).

Macromol. Symp. 2014, 343, 78–87 | 79

� 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.ms-journal.de

reaction mixture was transferred to a roundbottom flask and heated in an oil bath withmagnetic stirring for 45minutes.Was added2.4mL of CH3I and the reaction mixturewas maintained at the temperature of 40 �Cfor 4 hours. After reaction, the mixture wastransferred to a separatory funnel and wasadded 10mL of water, 20mL of CH2Cl2 anda saturated NaCl solution for phase separa-tion. The organic phase was collected. FT-IR characterization was made after com-plete solvent evaporation was taken.

Synthesis 2: Acetylation of Graft Co-polymer PMMA-g-PEG (2)

In a round bottom flask were added 2 gof graft copolymer and it was solubilized in10mL of CH2Cl2. In another beaker wasprepared a solution of 5ml of aceticanhydride with 5ml of acetic acid. Thissolution was added to the flask containingthe copolymer. The reaction mixture wasmaintained at the temperature of 40 �C for30 minutes. Upon completion of the reac-tion, the mixture was poured into a beakerwith 100mL of ice water. The modifiedcopolymer solidified and was separated bysimple filtration. FT-IR characterizationwas made after complete solvent evapora-tion was taken.

Synthesis 3: Esterification Followed byHydrolysis of Graft Copolymer PMMA-g-PEG (3)

2 g of the graft copolymer were dissolvedin 10mL of CH2Cl2. A mixture wasprepared with 0.1mL of concentratedH2SO4 and 7mL of CH3COOH. This

mixture was added to the solubilizedcopolymer and was maintained at thetemperature of 40 �C for 65 minutes. Aftercooling it were added 10mL of water. FT-IR characterization was made after dryingof the modified copolymer.

Synthesis 4: Halogenation of GraftCopolymer PMMA-g-PEG (4)

1 g of graft copolymer was dissolved in10mL of CH2Cl2 and. then was added0.5ml of HCl. The reaction mixture wasmaintained at the temperature of 30 �C andafter the reaction was completed themixture was placed in a separatory funnel.When the phase separation was finalized. Itwas added 5mL of 5% NaHCO3. Theorganic phase was collected and aftersolvent evaporation the sample was char-acterized by FT-IR.

Solubility Test

About 200mg of each copolymer (Graft,methylated, hydrolyzate and halogenated)were placed in tests tubes and wereimmersed in 2ml of: water, ethanol, ace-tone, diethyl ether, chloroform and hexane.The tubes were agitated to solubilize thecopolymers. Samples that do not solubilizedat room temperature were heated in a waterbath for complete solubilization.

Characterization

The modifications of the graft copolymerchains PMMA-g-PEG (COP GRAFT)were based on basic organic reactions suchas methylation, acetylation, hydrolysis and

H2C C

C

CH3

CH2

O

OCH3

CH3

C

CH3

O

O

CH2

CH2

OHn

x-1

H2C C

C

CH3

CH2

O

OCH3

CH3

C

CH3

O

O

CH2

CH2

Xn

x-1

1

i

General Scheme:

Compound 1: i= CH3I/ NaOH(aq)/T=40°C; X=OCH3 Compound 2: i= CH3CO2H/(CH3CO)2CO; X= -COCH3 Compound 3: i= CH3CO2H/H2SO4/ refluxo; X= -COOH

Compound 4: i= HCl/ refluxo/ NaHCO3(aq); X= Cl

Figure 2.

General reaction to the synthesis of Graft Copolymer (PMMA- g-PEG) derivatives.

Macromol. Symp. 2014, 343, 78–8780 |


esterification, halogenation in the presenceof a variety of chemical reagents, generatingnew copolymers structures with methylated(COP MET), acetylated (COP ACET),esterified/hydrolyzed (HIDROLYZADE)and halogenated (COP HAL). Upon com-pletion of the reaction the products wereisolated and purified by the technique ofliquid-liquid extraction using organic sol-vents such as dichloromethane and chloro-form to separate the organic phase fromthe aqueous phase. After the extraction theaqueous phase was discarded and thenthe organic phase was left at room temper-ature to evaporate the solvent and solidify.Then the modified copolymers were char-acterized by the techniques of infrared (IR),differential scanning calorimetry (DSC) andthermogravimetric analysis (TGA).

Infrared Analysis (IR)

Infrared analyzes were carried out usinggraft copolymer and the modified co-polymers that were synthesized in anInfrared Spectrometer Varian 640 FTIR.IR spectra were reproduced by ResolutionsPro software.

Thermogravimetric Analysis (TGA)

The graft copolymer and its derivatives wereevaluated by thermogravimetric analysisequipment on a TA Instruments ModelSDT 2960 Simultaneous DTA-TGA using aheating rate of 20 �C/min, temperature rangeof 20–700 �C and under air atmosphere.

Differential Scanning Calorimeter (DSC)

The DSC analysis of the graft copolymerand its derivatives were conducted in anequipment of TA Instruments, modelDSC 2010 operating at a heating rate of20 �C/min, temperature range of 20–350 �Cunder air atmosphere.

X-rays Diffraction (XRD)

The X-ray diffraction was performed atroom temperature and the samples wereanalyzed in the region of 5–70 �C (2u) and2 �C/mim�1. The apparatus used was adiffractometer Shimadzu model XRD-6000, equipped with the monochromator

and iron pipe graphite. Samples wereprepared in the form of 2cm diameter disk.Use of this method enables knowledge ofthe content of crystallinity of the sample.

Scanning Electron Microscopy (SEM)

The SEM analyzes were performed on anTescam equipment, Vega 3, and samplepreparationwas done in aQuorun evaporator.

Results and Discussions

In the reactions with the graft copolymerPMMA-g-PEG (COP24H), was necessaryto test the condition of the reaction formore efficient syntheses in order to avoidlosses of reactants and formation of unde-sirable products. The obtained compoundspresented in yields ranging from 50% rangeaccording to Table 1.

The modified copolymers showed differ-ent aspects (Figure 3).

At the end of each synthesis andevaporation of the solvent solubility testswere performed with different organicsolvents. Each compound showed differentsolubilities, since they have different chem-ical groups inserted in the copolymerchains.

Table 2 shows the solvents used, and thebehavior of each compound.

It was observed that compound 3 wassoluble in the most polar solvent (water)due to carboxyl groups present in thecopolymer chains, that made strong hydro-gens bonds interactions with water. How-ever, other less polar compounds weresoluble in solvents of low to mediumpolarity. The different solubilities of themodified copolymers indicate that therewas modification of the starting copolymerproperties. FTIR spectroscopy indicated

Table 1.Yields of modified copolymers.

Copolymers Yields(%)

COPMET (1) 66,10COPACET (2) 49,11HYDROLIZATE (3) 97,09COPHAL(4) 55,33

Macromol. Symp. 2014, 343, 78–87 | 81


that all derived copolymers showed theabsorption band related to the bond C - OHin approximately 3500 cm�1 equal to thisabsorption band in Cop GRAFT, but lowintensity, except compound 3 (Hydrolyzed)having a more broad absorption banddue introduce a carboxyl group whichcarries strong bonds between the carboxylhydrogens leading to dimer formation. Itwas also possible to observe the decrease inthe band related to the stretching of thebond C-O of primary alcohol at about1050 cm�1. Interestingly, the attenuationband was significant for compound 3 inwhich the bond CO was partly replaced bybond C-Cl with the appearance of theabsorption band at 750 cm�1. Compounds 1and COP GRAFT showed the sameabsorption band related to the stretchingbond of the C¼O in approximately1750 cm�1, as was to be expected. Com-pounds 2 and 4 showed two absorptionbands relating to bond C¼O at about

1750 cm�1 (already present in COP24h),and an average intensity at 1700 cm�1 dueto the electron withdrawing effect of groupsCl and OCOCH3. The compound 3 hadthe appearance of absorption band C¼Otypical of carboxyl and intense band at1700 cm�1. For different values of absorp-tion bands relating to the bonds C- OH andC¼O is possible to notice the chemicalmodification of the graft copolymer PMMA-g- PEG (Figure 4).

Figure 5 shows the TGA and DSCcurves of the graft copolymer beforemodification reactions of its structure withnew inserts of organic groups.

The analysis of the TGA curve shows aCOPGRAFT with two sharper weight loss,the first starting around 50 �C and thesecond at around 250 �C, with no apparentresidue. The DSC curve shows an endo-thermic peak on the melting temperature ofthe graft copolymer around 50 �C andexothermic transitions above 200 �C which

Figure 3.

Modified graft copolymers: COPMET (1), COPACET (2), HYDROLIZATE (3), COPHAL (4).

Table 2.Solubility Test of the modified graft copolymers.

Copolymer Water Ethanol Acetone diethyl ether Chloroform Hexane

Ta) Tb) Ta) Tb) Ta) Tb) Ta) Tb) Ta) Tb) Ta) Tb)

COP GRAFT X X X12 X X X X3 X X4 X X X X

a) room temperature.b) heating temperature.The areas marked with the letter X of the table indicate that the corresponding compounds are soluble in thesolvent.

Macromol. Symp. 2014, 343, 78–8782 |


may be related to a crystallization processand subsequently thermal degradation ofthe sample. In the TGA and DSC curves inFigure 6 it is possible to perceive a change inthe thermal behavior of the graft copolymerafter insertion of organic functional groupsof high, low and medium polarity on thepolymer chain. These groups have led to amodification of the initial degradationtemperature of the COP GRAFT from50 �C to about 100 �C. The results obtainedbyDSC and TGA showed that the modifiedcopolymer presented endothermic transi-tion temperature and degradation behaviorprofile compatible with the polymer chains.

In the case of TGA curves it was observedtwo levels of weight loss for all copolymers,where the second level showed a sharpinclination in approximately 90 �C. In thosecases the number of stages in whichdegradation occurs is related to the mecha-nism of degradation of the samples. It wasalso observed that the modification of thegraft copolymer chain resulted in a decreaseof its thermal resistance, in addition topresenting an increased amount of residuessamples. The transitions observed in theDSC curves showed peaks of broad basewith characteristic of materials with highmolecular weight and medium sizes chains.

7006005004003002001000-1

0

1

2

3

4

5

WE

IGH

T (%

)

TEMPERATURE (°C)

COP GRAFT

0 100 200 300 400 500

-20

-10

0

10

20endo

HE

AT

FLO

W (m

W)

TEMPERATURE (°C)

COP GRAFT

a) b)

Figure 5.

Curves (a) TGA and (b) DSC of COP GRAFT.

Figure 4.

IR spectra of modified copolymers and COPGRAFT.

Macromol. Symp. 2014, 343, 78–87 | 83


In the DSC curves endothermic tran-sitions referring the melting temperature ofthe copolymers at temperatures between28 �C and 60 �C (Figure 6) may be ob-served. The displacement of the meltingtransitions is a evidence to the efficiency ofthe reaction modification of graft copoly-mer chain. The differences between theprofiles of the transitions related to themelting temperatures of the modifiedcopolymers are given by inserting groupsof high, low and medium polarity in thepolymer chains of the graft copolymer that

before modification by organic reactionshave only polar groups in their chains.These differences can be observed bywidening of melting peak. The inclusionof apolar character groups results in avariation of melting temperature of thegraft copolymer, and consequently onmodification of the structure and thermalbehavior of this copolymer. The exothermictransitions observed in the temperatureranges between 200–275 �C and 350–475 �Cmay be related to the crystallization of thesamples, which is accompanied by the

Figure 6.

Curves (a) TGA and (b) DSC of derivatives copolymers from COP GRAFT.

0 100 200 300 400 500

0

20

0 100 200 300 400 500

endo

HE

AT

FLO

W (m

W)

TEMPERATURE (°C)

COP ACET

endo

COP HALOG

Figure 7.

DSC curves COP ACET and COP HALOG.

Macromol. Symp. 2014, 343, 78–8784 |


release of latent heat process, generating anexothermic peak. These exothermic peaksappearing during heating of the samplesbefore decomposition of them. This behav-ior is illustrated in Figure 7, showing thethermal transitions of the COP ACET andCOP HALOG.

Thermogravimetric analysis showedthe degradation of the graft copolymerwith a initial weight loss of about 5% at50 �C and a second weight loss of 95% inthe range of 250 � to 450 �C. Figure 8shows the curves of the COP ACET andCOP HALOG with weight losses in therange of 10� to 100 �C and 250� to 450 �C.The difference between the temperature

ranges of the copolymers happens bythe decreasing of the polar character ofgraft copolymer due to the inclusion ofgroups of low polarity and higher carbonchain, which decreases the strength ofintermolecular graft copolymer chainsand consequently decreases its tempera-ture initial degradation, thus proving theefficiency of the modification of its chains.Considering the efficiency of purificationperformed by extraction and character-ized by other technique such as FTIR, notmentioned in this work, we can evaluatethat the first weight loss is related tocopolymer chains and not to weight loss ofwater molecules.

0

20

40

60

80

100

7006005004003002001000

WE

IGH

T (%

)

TEMPERATURE (°C)

COP GRAFT

COP HALOG

0

20

40

60

80

100

7006005004003002001000

HE

IGH

T (%

)

TEMPERATURE (°C)

COP GRAFT

COP ACET

a) b)

Figure 8.

DSC curves of the derivatives copolymers from COP GRAFT/COP ACET and COP GRAFT/COP HALOG.

Figure 9.

X-ray diffractograms of derivatives copolymers from COP GRAFT.

Macromol. Symp. 2014, 343, 78–87 | 85


The X-ray diffraction patterns confirmthe results found by DSC and TGA. Thehydrolyzed copolymer showed crystallineorganization, without amorphous regionsthat were present in other chains. Thisbehavior is characteristic of semi-crystallinecopolymers. All samples showed the peaks

related to graft copolymer (Figure 9).Larger peaks of derivatives copolymersindicated a decreased of the chains organi-zation after modification reactions.

Scanning Electron Microscopy wasmade after the modification reactions ofCOP GRAFT (Figure 10). From the SEM

Figure 10.

Photomicrographs of COP HALOG and COP MET.

Figure 11.

Photomicrographs of the derivatives copolymers from COPGRAFT.

Macromol. Symp. 2014, 343, 78–8786 |


images of COP HALOG and COP METwas possible to observe the microspheresformation.

HYDROLYZED and COP ACET poly-mers showed slight microspheres formation(Figure 11) while COP GRAFT showed asmooth surface with few microspheres.

Conclusion

Yields were satisfactory and the use ofsolvent is essential, because chemical reac-tion do not happen if the copolymer is notcompletely solubilized. The COP GRAFTshowed different behavior and the forma-tion of new products in the presence of acidor basic characters reagents.

Acknowledgements: The authors thank UFOP-DEQUI; PROPP-UFOP, REDEMAT and Tu-torial Education Program Pharmacy for financialsupport.

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chemistry modification of pmma-g-peg copolymer

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