synthesis and characterization of new copolymers of ethyl methacrylate grafted on tapioca starch as...

European Polymer Journal 45 (2009) 1765–1776

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European Polymer Journal

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Synthesis and characterization of new copolymers of ethylmethacrylate grafted on tapioca starch as novel excipientsfor direct compression matrix tablets

Marta Casas a, Carmen Ferrero a, Ma Violante de Paz b, Ma Rosa Jiménez-Castellanos a,*

a Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Sevilla, c/Profesor García González no 2, 41012 Sevilla, Spainb Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, c/Profesor García González no 2, 41012 Sevilla, Spain

a r t i c l e i n f o

Article history:Received 19 January 2009Received in revised form 13 February 2009Accepted 23 February 2009Available online 1 March 2009

Keywords:Tapioca starchEthyl methacrylateGraft copolymersDirect compressionMatrix tabletsDrying process

0014-3057/$ - see front matter � 2009 Elsevier Ltddoi:10.1016/j.eurpolymj.2009.02.019

* Corresponding author. Tel.: +34 954556836; faxE-mail address: [email protected] (M.R. Jiménez-Cast

a b s t r a c t

In last years, the introduction of new materials for drug delivery matrix tablets has becomemore important. This paper evaluates the physicochemical and mechanical properties ofnew graft copolymers of ethyl methacrylate (EMA) on tapioca starch (TS) and hydroxypropyl-starch (THS), synthesized by free radical polymerization and dried in a vacuum oven (OD) orfreeze–dried (FD). Infrared and 13C NMR spectroscopies confirm the change of chemicalstructure of the copolymers and X-ray diffraction shows up the higher amorphization ofcopolymers respect to the carbohydrates. Particle size analysis and SEM indicate that graftcopolymerization leads to an increase of particle size and a more irregular shape. Graft copo-lymerization implies decrease of density and moisture content values. Heckel equationshows that copolymers have less densification by particle rearrangement and fragmentationthan carbohydrates. Concerning the drying methods, FD products have larger plasticity andlower elasticity than OD copolymers. Graft copolymerization produces a decrease of theapplied pressure necessary to obtain tablets, ejection force and friction work. Furthermore,graft copolymers show longer disintegration time than tablets from raw starches. These qual-ities suggest that these copolymers could be used as excipients in matrix tablets obtained bydirect compression, and with a potential use in controlled release.

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1. Introduction

Monolithic devices or matrices represent a substantialpart of the drug delivery systems. In pharmaceutical indus-try, the matrices for oral administration are commonlymanufactured as tablets by direct compression [1]. How-ever, it is well known that direct compression is possibleonly for a limited number of substances. Many of the mate-rials widely used for tablet formulation are difficult tocompress because of their elastic compression behaviourand poor flow properties [2].

In the last years, the introduction of new materials fordrug delivery devices has become more important. Among

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: +34 954556085.ellanos).

these, synthetic and some natural polymers have beenused and their production has grown in great extent.Starch is an abundant, inexpensive, natural biopolymerthat can be metabolised by the human body. Moreover, itis relatively inert and does not react with many active drugsubstances. These favourable properties promote its appli-cations for the production of pharmaceuticals [3–6]. How-ever, starches possess poor flow properties and undergoelastic deformation during the tableting process [7]. Incontrast, starch can be easily modified with a variety ofuseful monomeric and polymeric products by physicaland chemical means. Graft copolymerization of syntheticpolymers onto a polysaccharide backbone offers one ofthe best ways to get new copolysaccharides with enhancedproperties for important applications [8,9]. Thus, polyacry-lics occupy a significant position as grafted polymers [10].

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1766 M. Casas et al. / European Polymer Journal 45 (2009) 1765–1776

Recently, a new generation of graft copolymers combin-ing semi-synthetic (cellulose and potato starch derivatives)and synthetic (methyl methacrylate) polymers has beenintroduced [11–14]. However, it was probed that depend-ing on the type of carbohydrate and monomer used, theproperties of the copolymer will be different [9], and con-sequently, may not have identical properties as excipientsin tablet preparations. There is still a wide range of acrylicmonomers and natural polymers that can be tested. Whilein Europe potato starch is widely used, in most tropicalcountries there are many other sources for starch, whichcan be used in tableting. Commonly grown starch-contain-ing plants are maize, rice, and tapioca or cassava [15].

Native tapioca starch possesses many desiderable fillerproperties but it has poor flowability and compressibility[16]. The latter two parameters have a particular importancefor direct compression tablets [15,17]. Furthermore, the fil-ler should yield tablets of adequate crushing strength with-out having to apply an excessive compression force [18,19].Atichokudomchai et al. [17] have modified native tapiocastarch showing that these new products were useful as fillerin direct compression tablet preparation. Due to the good re-sults obtained with the described materials, we estimate ofinterest to synthesize and characterize new graft copoly-mers derived from tapioca starch and hydroxypropyl tapi-oca starch in order to evaluate its usefulness in directcompression matrix tablets. The chosen monomer for graft-ing is ethyl methacrylate (EMA), a synthetic monomer thatgives rise to biocompatible and non toxic acrylic polymersand possesses hydrophobic character and can be easily poly-merized [20,21]. A comparison among these new graftcopolymers and the native starches, used as received, willbe made. This paper also evaluates the effect of the carbohy-drate nature and drying process (vacuum oven and freeze–dried) on the physico-chemical and mechanical propertiesof the powdered materials as well as the porous structureof the tablets obtained from the new copolymers.

2. Experimental

2.1. Materials

Tapioca starch (TS) (Tapioca Starch, batch MCB 3053)(±17% of amylose) and hydroxypropyl tapioca starch(THS) (Tapioca Textra, Batch KCB 8010) were kindly sup-plied by National Starch & Chemical (Manchester, UK) asnatural and semi-synthetic polymers. Ethyl methacrylate(EMA) (Merck, Hohenbrunn, Germany) was chosen as ac-rylic monomer for graft copolymerization.

All the reagents used for the synthetic process were ofanalytical grade.

Before use, the materials were stored at constant rela-tive humidity (40%) and room temperature (20 �C).

2.2. Methods

2.2.1. Synthesis of graft copolymers and grafting yieldsCopolymers were synthesized by free radical copoly-

merization of EMA and different starches (tapioca starch– TS and hydroxypropyl tapioca starch – THS) followingthe procedure described by Echeverría et al. [12]. The car-

bohydrate (40 g), either tapioca starch or hydroxypropyltapioca starch, was dispersed in 550 ml of bidistilled water.The medium was purged with purified nitrogen and thebath temperature was maintained at 30 �C. Next, 118 mLof EMA was added, followed by the initiator solution(50 ml of 0.1 M ceric ammonium nitrate in 1 N nitric acid)15 min later. Grafting was allowed to proceed for 4 h undera constant light source (two lamps of 100 W in the viswavelength range). Thus, the synthesized TSEMA andTHSEMA were filtered off and washed with diluted nitricacid and bidistilled water until neutral pH was reached. Anoteworthy aspect to mention is that the use of water asreaction solvent guarantees, not only an effective disper-sion of all the reactants and reagents, but also the absenceof toxic substances in the final product [12].

The solids obtained were dried using two differentmethods: drying in a vacuum oven (Vacucell 22, Gräfelting,Germany) at 50 �C (0.5 Pa) until constant weight (ODcopolymers) or freeze–drying (at �80 �C for 48 h and0.1 Pa) in a Cryodos-80 apparatus (Terrasa, Spain) untilpowdered product was got (FD copolymers). Finally, thestarch-based copolymers (TSEMA) were crushed at10,000 rpm in a knives mill (Retsch ZM 200, Haan, Ger-many) to obtain powdery samples.

The reproducibility of the synthetic and drying pro-cesses were demonstrated by comparison of three batchesof each product (data not shown). Once the reproducibilityof the synthesis was established, the preparation in highextension of the copolymers was carried out.

In order to study the efficiency of the graft copolymer-ization reaction, the poly-ethylmethacrylate (PEMA)homopolymer was removed from the total reaction prod-uct, with tetrahydrofuran (THF), by soxhlet extraction for72 h. So, the pure graft copolymer was obtained. After-wards, the grafted PEMA was isolated from carbohydratechains by acid hydrolysis with perchloric acid (60%) in aglacial acetic acid medium [22]. The results are shown asthe mean values of two replicates. The quantification ofthe PEMA homopolymer and the grafted PEMA was re-corded by the following parameters [22]:

– Percent grafting efficiency (% GE) (Eq. (1)) was used toquantify the amount of homopolymer formed duringthe grafting reaction:

%GE ¼ Graft copolymer weightTotal product weight

� 100 ð1Þ

– Percentage grafting (% G) (Eq. (2)) was used to assess themetacrylic–carbohydrate ratio in the copolymer:

%G ¼ Grafted metacrylic polymer weightGrafted carbohydrate weight

� 100 ð2Þ

2.2.2. Spectroscopy characterization2.2.2.1. IR spectroscopy. IR-spectra were recorded on a FT-IR spectrometer Nicolet 510 (CA, USA), using potassiumbromide tablets. One hundred scans were collected foreach sample at a resolution of 4 cm�1 over the wavenum-ber region 4000–400 cm�1.

M. Casas et al. / European Polymer Journal 45 (2009) 1765–1776 1767

2.2.2.2. NMR spectroscopy. 13C NMR spectra measurementswere recorded at 30 �C on a FT-NMR Bruker Avance 500(Wissembourg, France) for each product. A mixture of d6-DMSO and d5-pyridine solvents (1/1) was used to give aconcentration of 3% w/v. Chemical shifts are quoted inppm relative to tetramethylsilane as internal reference.

2.2.2.3. X-ray diffraction measurements. X-ray powder dif-fraction (XRD) measurements were made with a SiemensKristalloflex D-5000 (Haan, Germany) diffractometer. Thesample was exposed to Ni-filtered CuKa radiation withthe X-ray generator running at 36 kV and 26 mA. The scanrate employed was 1� (2h)/min.

2.2.3. Powder and particle characterization2.2.3.1. Particle size analysis. Particle size analysis was car-ried out on a vibratory sieve shaker (Retsch Vibro, Haan,Germany) using 500, 355, 250, 180, 125, 90, 63, 45,38 lm calibrated sieves (Cisa, Barcelona, Spain). From plotsof powder weight (%) versus size (lm), typical parametersfrom a particle size distribution were determined: meanparticle diameter, relative standard deviation (RSD) andskewness (Eq. (3)) and kurtosis (Eq. (4)) coefficients (SPSS�

14.0):

S ¼ 3ð�x�medianÞSD

ð3Þ

where �x is mean particle diameter and SD is the standarddeviation.

K ¼ nPðx� �xÞ4

ðPðx� �xÞ2Þ2

� 3 ð4Þ

where x is any particle diameter, �x is mean particle diam-eter and n is number of particles.

2.2.3.2. Scanning electron microscopy (SEM). The morphol-ogy of particles was studied by means of a scanning elec-tron microscope (Philips XL-30, Eindhoven, Holland),after coating the samples with a thin layer of gold on asputter coater (Edwards Pirani 501 Scan-Coat Six, Crawley,West Sussex, UK). Microphotographs were obtained at amagnification appropriate for particle size.

2.2.3.3. Apparent particle density. The apparent particledensity of the products were determined, in triplicated,by means of an air comparison pycnometer (Ultrapycnom-eter 1000, Quantachrome, Boyton Beach, FL, USA), usinghelium as an inert gas, according to European Pharmaco-poeia [23]. Due to the high diffusivity of helium, this meth-od was considered to give the closest approximation to thetrue density [24].

2.2.3.4. IR balance moisture determination. The moisturecontent was determined, in triplicate, by means of an infra-red balance (Mettler Toledo LJ16, Zürich, Switzerland).Samples (500 mg) were tested at 50 �C until constantweight (weight variation less than 0.2 mg/s) was achieved.

2.2.3.5. Flow properties. An automated flowmeter systemdeveloped by Muñoz-Ruiz and Jiménez-Castellanos [25]

was used to estimate the flow rate of the different samples.A glass funnel with an internal diameter of 10 mm and anangle of 30� with respect to the vertical was selected asvessel [23]. Weight data were acquired by means of a bal-ance (Mettler AE50, Zürich, Switzerland) connected to apersonal computer, using adequate software. The resultsare shown as the mean value (g/s) of three replicates.

2.2.4. Compression behaviourTo allow direct comparison of all materials, the amount

of material required to produce a 3 mm thick compact attheoretical zero porosity was calculated from the apparentparticle densities. The quantities of powder (mg) wereaccurately weighed (Sartorius CP224S, Göttingen, Ger-many) and manually placed into the die. Tablets were ob-tained using an instrumented [26] single-punch tabletmachine (Bonals AMT 300, Barcelona, Spain) with 12 mmflat-faced punches at a speed of 30 cycles per min. Powderswere compressed at 25, 50, 100, 150, 200, 300 MPa of ap-plied pressure and four tablets per pressure were manufac-tured. The die was lubricated with a chloroformicsuspension of magnesium stearate (5% w/v) before eachcompression cycle.

Evaluation of the consolidation mechanism of powderswas made on the basis of Heckel equation [27,28] (Eq. (5)),using both the tablet-in-die and ejected-tablet methods.

lnð1=1� DÞ ¼ kP þ A ð5Þ

where D is the relative density of the compact at pressure P.In the case of the tablet-in-die method, the compression cy-cle corresponding to tablets with the thickness closest 3 mmwas chosen. The linear portion was determined mathemat-ically using suitable software, which calculated the firstderivative of the plot to give an evaluation of the pressurerange where constant slope started and ended. The least-squares method was used to obtain accurate slope and inter-cept values and the criterion to estimate the fit was the cor-relation coefficient. The relative precompression density(D0) was determined as the relative density of the powderbed at the point where a measurable force is applied. Inthe case of the ejected-tablet method, the packing fractionsat each maximum applied pressure were determined bymeasuring the dimensions of the tablets 24 h after ejectionfrom the die. The least-squares method was also employed,taking into account the pressure range more appropriate foreach derivative (generally, 25–150 MPa).

2.2.5. Preparation of tabletsThe different products were compacted into tablets

using the machine described previously. To investigatethe compression characteristics, a quantity of powder(500 mg) was preweighed and manually fed into the die(12 mm) and flat-faced compacts were prepared to havea constant crushing force of 70–80 N. No additives were in-cluded in order to get intrinsic information of the poly-meric material itself. Compression data were collectedfrom four tableting cycles.

Also, in order to produce enough tablets for physicaltesting, the copolymers were tableted in the same condi-tions outlined before (500 mg weight, 12 mm diameter,and 70–80 N crushing force).


2.2.6. Standard physical test of tabletsThe physical testing of tablets was performed after a

relaxation period of at least 24 h. The tablet average weightand the standard deviation (SD) were obtained from 20individually weighed (Sartorius CP224S, Göttingen, Ger-many) tablets according to European Pharmacopoeia [23].

The thickness and diameter of ten tablets were mea-sured individually using an electronic micrometer (Mitu-toyo MDC-M293, Tokyo, Japan).

The crushing force [23] of ten tablets was determinedby diametrical loading with a Schleuninger-2E tester (Grei-fensee, Switzerland).

Tablet friability [23] was calculated as the percentageweight loss of twenty tablets after 4 min at 25 rpm in anErweka TA (Heusenstamm, Germany) friability tester.

Disintegration testing [23] was performed at 37 �C indistilled water (800 ml), using an Erweka ZT3 (Heusen-stamm, Germany) apparatus without discs. The disintegra-tion times reported are averages of six determinations.

2.2.7. Mercury porosimetry measurementsMercury porosimetry runs were undertaken using an

Autopore IV 9510 (Micromeritics, Madrid, Spain) porosi-meter with a 3 cm3 penetrometer. The volume of samplewas roughly 20–90% that of penetrometer capacity. Work-ing pressures covered the range 0.1–60,000 psi and themercury solid contact angle and surface tension were con-sidered to be 130� and 485 nM m�1, respectively. Totalporosity and pore size distribution were determined, induplicate, for each tablet tested.

2.2.8. Statistical analysisApparent particle density, moisture content and com-

pression data were statistically analysed by one way anal-ysis of variance (ANOVA) using the SPSS� program version14.0. Post-ANOVA analysis was carried out according toBonferroni’s multiple comparison tests. Results werequoted as significant when p < 0.05.

3. Results and discussions

3.1. Synthesis of graft copolymers and grafting yields

In order to study the efficiency of the graft copolymer-ization reaction, the poly-ethylmethacrylate homopolymer(PEMA) was removed from the total reaction product, with

Table 1Percent grafting efficiency (% GE), percentage grafting (% G) and ratios of PEMA hstandard deviation and RSD the relative standard deviation (n = 2).

Copolymer % GE % G Reactio

PEMA

Homop

OD-TSEMA 93.0 (2.8) 148.6 (6.2) 7.00 (2RSD = 3.0% RSD = 4.1%

FD-TSEMA 92.5 (3.5) 170.7 (4.5) 7.50 (3RSD = 3.8% RSD = 2.7%

OD-THSEMA 99.5 (0.7) 213.5 (3.5) 0.50 (0RSD = 0.7% RSD = 1.7%

FD-THSEMA 98.5 (0.7) 229.7 (6.8) 1.50 (0RSD = 0.7% RSD = 3.0%

tetrahydrofuran (THF), by soxhlet extraction. PEMA homo-polymer is the only product that could be solubilized byTHF from the medium. In that way, PEMA homopolymerwas isolated and quantified after evaporation of the sol-vent. The remaining graft copolymer (the insoluble frac-tion) was hydrolyzed in acid medium, to give the PEMAratio in the copolymer composition. The ratios of the PEMAhomopolymer, the copolymer composition and the effi-ciency of the graft copolymerization reaction (% GE and %G parameters) were recorded in Table 1.

The low relative standard deviation values reportedconfirm the reproducibility of the synthesis and, as wouldbe expected, the similar yields for OD and FD products con-firm the absence of influence of the drying method used[11]. Also, the high % GE values and the lower content ofhomopolymer PEMA (poly-ethylmethacrylate) in the finalproduct (lower than 8% in every case) indicate a high reac-tivity of these carbohydrates with EMA.

Hydroxypropylstarch copolymers (THSEMA) are char-acterized by larger % GE and % G values than starch ones(TSEMA), which indicates a higher reactivity of THS com-pared with TS, as expected [12,29]. So the presence of thehydroxypropyl group in the starch molecule favours thegraft copolymerization. This can be attributed to the factthat the presence of side groups into the starch structureweakens the attractive interaction between polymerchains [30,31] as well as the presence of more availablesites, allowing the graft of polymethacrylic chains [32].

Combining the grafting yields (% GE and % G), the per-centage of grafted PEMA (60–70%) in the graft copolymersis higher than the percentage of carbohydrate (30–40%)(see Table 1), proving the hydrophobic character of thesynthesized copolymers in agreement with Echeverríaet al. [12] and Marinich et al. [29] using other starches.

3.2. Spectroscopy characterization

3.2.1. IR spectroscopyInfrared spectroscopy confirms the change of chemical

structure of the copolymers. With the aim to compare,Fig. 1 shows an example of the infrared spectra of ODand FD-THSEMA and their original carbohydrate. Infraredspectra of copolymers show a band of stretching vibrationat 1750–1735 cm�1 of carbonyl group (C@O) from esteraliphatic that confirms that EMA is grafted in the glucosemoiety. Also, the absence of typical stress (@CAH) and

omopolymer and copolymer composition. Values in brackets represent the

n composition (%)

Copolymer composition (%)

olymer (%) Grafted PEMA (%) Polysaccharide (%)

.83) 55.60 (2.62) 37.40 (0.21)

.54) 58.31 (1.66) 34.19 (1.88)

.71) 67.76 (0.84) 31.74 (0.13)

.71) 68.61 (0.12) 29.89 (0.83)

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

0.55

0.60

0.65

0.70

0.75

500 10001500 2000 2500 3000 35004000

C=O

C=O

st OH

st OH

st OH

C=C-H

C-O

FD-THSEMA

OD-THSEMA

THS

Wavenumber (cm-1)

Abso

rban

ce

Fig. 1. Infrared spectra of tapioca hydroxypropylstarch (THS) and copolymers OD-THSEMA and FD-THSEMA.


flexion (C@C) bands of a, b unsatured carbonyl compoundsat 3040–3010 cm�1 and 1690–1635 cm�1 proves the ab-sence of EMA without grafting. Moreover, the copolymersshow the four bands with typical ‘‘saw”, ‘‘stone” or ‘‘grind”shape, so characteristics of stress vibration from ester(CAO) at 1270, 1240, 1200, 1150 cm�1. The other bandsare present not only in THS raw material IR but also in thegrafted THSEMA copolymer IR, as expected. Finally, it is pos-

190 180 170 160 150 140 130 120 110 100 90

176177 ppm 8090100

H

2

CH2-O-CH7

6

3

4

5

OH

OHO

O

HHS4

HS1

C=O

Pyridine-d5

HS1

Fig. 2. 13C NMR spectru

sible to appreciate the relative decrease in intensity of thestretching OAH band (3500–3400 cm�1) from the glucopyr-anose rings in the copolymers compared to the raw starch.

3.2.2. NMR spectroscopy13C NMR spectroscopy confirms the results obtained by

IR spectroscopy. Fig. 2 shows the 13C NMR spectrum of FD-THSEMA, where the peaks attributed to the carbons of the

80 70 60 50 40 30 20 10 ppm

6070 ppm

(CH2)βOCH2

S3,2,5

HS6,7

2-CH-CH398

OH |

1

O

S8

HS4 HS8,3,2,5

HS6,7

OCH2

(CH2)β (CH2)α

CH3

Cα

DMSO-d6

O

C-O-CH2-CH3

CH3

CH2-C ß α

HS9

m of FD-THSEMA.

05

1015202530354045

WEI

GH

T %

<38 38-45 45-63 63-90 90-125

125-180

180-250

250-355

355-500

>500

Mesh size (μm)

TS OD-TSEMA FD-TSEMA

0

5

10

15

20

25

30

35

40

WEI

GH

T %

<38 38-45 45-63 63-90 90-125

125-180

180-250

250-355

355-500

>500

Mesh size (μm)

THS OD-THSEMA FD-THSEMA

(a)

(b)

Fig. 4. Particle size distribution of materials: (a) TS and TSEMA copoly-mers; (b) THS and THSEMA copolymers.


glucose unit and those described in the literature for PEMAcan be distinguished [33]. In addition to the typical signalsattributed to C in hexapyranoses from native starch (HS1 toHS6) [16], the peaks C7, C8 and C9 corresponding to thehydroxypropyl groups (HS7 to HS9) at 20, 65 and 78 ppmare found. The peak at 178 ppm corresponds to the car-bonyl group of PEMA and, the lack of bands at 100–140 ppm of olefinic carbon atoms (CAC@C) proves the ab-sence of EMA without grafting.

In agreement with Newman et al. [34], the spectra for ourproducts do not differ from those of other sources of starch[12,29]. Also, the drying methods do not affect to the chem-ical structure of the copolymers and so, no differences arefound by spectroscopic analysis (IR and NMR) [35–37].

3.2.3. X-ray diffractionIn agreement with other authors [17,38], is clear to see

in XRD pattern of TS (Fig. 3) two peaks at (2h) about 15�and 23� and unresolved doublets at 17� and 18�.

Concerning the two types of carbohydrates, TS and THS,the patterns show the same typical feature, according toother authors in studies with native and acid-modified tap-ioca starch [16,17,38], or dialdehyde tapioca starch [39]. Kim[40] reported a different behaviour for the hydroxypropylpotato starch. Thus, the influence of the carbohydrate back-bone is prevalent in the XRD patterns in our case.

As expected, the decrease of the diffraction peaks on thecopolymers confirms that the graft reaction leads to amor-phization of the structure [29,41]. The bands at diffractionangles 12� and 15� were already present in the startingmaterials but with low intensity. After amorphization, ahigher display of the mentioned two bands could be ob-served. The presence of the new PEMA chains grafted inthe carbohydrate backbone makes difficult the effectivepacking of the copolymer chains.

3.3. Powder and particle characterization

3.3.1. Particle size analysisThe particle size distribution of the carbohydrates and

graft copolymers obtained after the sieving process are

2-Theta Scale

0

1000

2000

3000

4000

10 20 30 40 50

THS

TS

OD-THSEMA

Lin

(Cou

nts)

Fig. 3. X-ray diffractograms of carbohydrates and copolymer OD-THSEMA.

shown in Fig. 4. Both carbohydrates present similar parti-cle sizes and skewness and kurtosis coefficients (Table 2).Rao and Tattiyakul [42] also observed left-skewed size dis-tribution to hydrated native tapioca starch.

By comparison of micro-particle size distribution ofgraft copolymer samples respect to pure TS and THS, wecan appreciate larger mean particle sizes for graft copoly-mers (Table 2), especially for THSEMA derivatives. Themilling process of the TSEMA copolymers could explaintheir lower particle sizes. The particle size distribution aswell as the kurtosis and skewness coefficients (Table 2), re-veal in agreement with Marinich et al. [29], a broader andmore symmetric distribution for copolymers, especially forTHSEMA products, with skewness coefficients close tozero. The negative values obtained for kurtosis coefficientin the case of THSEMA copolymers indicate a platicurticdistribution, meanwhile TSEMA have a leptokurticdistribution.

Furthermore, in contrast to other works [13,29], no dif-ferences are found between drying methods results.

3.3.2. Scanning electron microscopy (SEM)The surface of the products obtained from the graft

copolymerization onto starch can be seen in Fig. 5. Nativetapioca starch granules (Fig. 5a) mostly exhibit roundshape with a truncated area and smooth surface with ob-servable slight pores or fissures [43–45]. Kim [40] found

Table 2Physical and technological properties of the carbohydrates and copolymers: mean particle size (lm), skewness and kurtosis coefficients, apparent particledensity (g/cm3), moisture content (%) and flow rate (g/s). Values in brackets represent the standard deviation.

Polymer Mean particlesize (lm)

Skewnesscoefficient

Kurtosiscoefficient

Apparent particledensity (g/cm3)

Moisturecontent (%)

Flow rate(g/s)

TS 74 (75) 4.40 24.62 1.505 (0.002) 5.98 (0.05) –OD-TSEMA 138 (141) 1.60 2.19 1.228 (0.001) 2.01 (0.04) 9.5FD-TSEMA 125 (121) 2.10 4.58 1.225 (0.002) 1.98 (0.04) –THS 78 (69) 4.31 24.75 1.486 (0.002) 4.05 (0.06) –OD-THSEMA 346 (203) �0.12 �1.27 1.229 (0.003) 1.97 (0.08) 11.1FD-THSEMA 377 (214) �0.35 �1.36 1.225 (0.001) 1.99 (0.08) –


a rougher particle surface of hydroxypropylstarch of patataas long as increase the substitution degree. However,Fig. 5b reveals no change in the appearance of the THSgranules. This might be due to the low substitution degree,in according to the X-ray diffraction results.

The particles, after copolymerization, show more irreg-ular morphology and it is possible to see important aggre-gation of granules of various size (Fig. 5c and d), especiallyto THSEMA [12]. Extensive heat and moisture during dry-ing could produce a slight gelatinization of the surface ofthe granule and cause the granules adhere together to formaggregates [34]. Furthermore, microphotographs of indi-vidual particles show morphological differences amongcopolymers. So, TSEMA particles (Fig. 5e and f) have brokenfaces probably due to the milling process carried out afterdrying, whereas THSEMA particles (Fig. 5g and h) havemore regular and rounded shape. Although Schoch andMaywald [46] pointed out the possibility of distinguishthe drying method of pregelatinized starches by SEM, thiscan be seen only with milled particles, with rough struc-ture for FD product.

3.3.3. Apparent particle densityAs can be seen in Table 2, apparent particle density val-

ues are statistically lower for copolymers respect to thecarbohydrates (p < 0.05), due to the EMA component. Inaddition, when a grafting reaction takes place polymerchains wrap the carbohydrate’s backbone, increasing thefree volume of the total product and consequently decreas-ing its density [11]. Also, it is possible to appreciate a goodhomogeneity in the measure (SD < 0.003%). Finally, nodifference (p > 0.05) is found between drying methods orcarbohydrate nature results.

3.3.4. IR balance moisture determinationThe moisture content values of carbohydrates and graft

copolymers are shown in Table 2. The lower moisture con-tent of THS respect to TS (p < 0.05) is a consequence of thelower hydrophility of the THS as it reveals an increment inthe carbon–hydrogen ratio respect to the hydroxyl groups.The extent of hydratation also depends on the accessibilityof the hydroxypropyl groups in the starch to the water[34]. However, in agreement with Bravo et al. [47] andMarinich et al. [29], the addition of an important amountof hydrophobic polymer, as the EMA, to the carbohydratesgives statistically fewer hydrophilic products (p < 0.05),with a moisture content about 2%, for all of them. No dif-

ferences (p > 0.05) are found between drying methods orcarbohydrate nature results.

3.3.5. Flow propertiesAccording to Bos et al. [15] and Atichokudomchai and

Varavinit [16], native tapioca starch has poor flow proper-ties (Table 2). The small size of particles for TH and THScould explain these results.

The copolymers have poor flow properties, with betterflow for OD copolymers, although only OD-THSEMA hasfree flow. Different authors [48,49] have pointed out theincreasing friction and cohesion properties for rough parti-cles, which could explain the better flow of OD-copolymersrespect to the FD products, which have a rough structure.

3.4. Compression behaviour

Data from Heckel treatment are compiled in Table 3.From the tablet-in-die method, relative density values(Da or total densification, D0 or densification by die filling,Db or densification by particle rearrangement and frag-mentation) were obtained. The tendency of the materialto total deformation and fast elastic deformation could alsobe evaluated from the mean yield pressures Kd and Kef,respectively. The ability of the material to deform plasti-cally was shown by Kp, obtained using the ejected-tabletmethod. Ket has been regarded as a constant describingthe tendency of the material to deform elastically andwas obtained from the two methods mentioned above[50]. The higher the mean yield pressure values (K) thesmaller the tendency to deform by one or anothermechanism.

According with Marinich et al. [29], higher Db and smal-ler D0 values are observed for original carbohydrates com-pared to copolymers. The predominance of small particlesin the formers that promotes the presence of mechanicaland electrostatic forces could prevent the packing of theirparticles in the bulk state [50].

The similar particle characteristics of OD and FD-TSEMAare in agreement with its similar densification values. Thesame behaviour is possible to see in THSEMA. Moreover,the lightly higher Db values observed for THSEMA copoly-mers compared with the corresponding TSEMA derivativesmight be explained by the broader particle size distribu-tion detected for the THSEMA products (Table 2 andFig. 4). Pospèch and Schneider [51] have pointed out thatin powders with wide size distribution, smaller particles

Fig. 5. Microphotographs corresponding to: (a) TS; (b) THS; (c) FD-TSEMA; (d) FD-THSEMA; and individual micro-particles of (e) OD-TSEMA; (f) FD-TSEMA;(g) OD-THSEMA; (h) FD-THSEMA.


can be partly accommodates in the voids among largerones.

Additionally, the Kd values obtained for the copolymersfit well with those of some widely used commercial directcompression excipients. The best agreement is found forFD copolymers, who exhibit similar values as Avicel PH�

101 [52,53] (microcrystalline cellulose) which is known

to deform easily by plastic flow. Also, the new macromol-ecules exhibit lower total elastic deformation (Ket) thanStarch 1500� and Avicel PH-101�, used as direct compres-sion excipients [52].

On the other hand, TSEMA copolymers show bettercompression properties than THSEMA ones, being moreplastic and less elastic. The small particle size of TSEMA

Table 4Main compression parameters for the carbohydrates and copolymers. Values in brackets represent the standard deviation (n = 4).

Materials P (MPa) R Fe (N) Wf (J) We (J) Wan (J) Pl (%)

TS 150.13 (4.00) 0.537 (0.007) 1742.9 (53.1) 8.1 (0.8) 0.3 (0.1) 13.3 (0.5) 97.6 (0.3)OD-TSEMA 81.83 (3.11) 0.665 (0.026) 301.9 (41.5) 2.3 (0.3) 0.4 (0.0) 9.7 (0.2) 96.2 (0.2)FD-TSEMA 58.56 (0.87) 0.588 (0.013) 304.9 (18.5) 2.6 (0.1) 0.2 (0.0) 8.2 (0.1) 97.1 (0.2)THS 157.62 (4.14) 0.593 (0.007) 2275.0 (349.4) 5.7 (0.2) 0.4 (0.0) 11.7 (0.1) 96.3 (0.3)OD-THSEMA 88.81 (1.35) 0.466 (0.005) 713.2 (4.8) 5.6 (0.3) 0.2 (0.0) 11.9 (0.3) 98.1 (0.1)FD-THSEMA 72.36 (0.61) 0.480 (0.002) 621.8 (7.5) 5.0 (0.1) 0.2 (0.0) 10.8 (0.1) 97.9 (0.2)

P, maximum applied upper punch pressure; R, lubrication ratio; Fe, maximum ejection force; Wf, Juslin’s friction work; We, expansion work; Wan, Juslin’sapparent net work; Pl, plasticity.

Table 3Typical parameters from Heckel treatment for the different materials under study. Values in brackets represent the standard deviation (n = 4).

Materials Tablet-in-die methoda Ejected-tablet methodb Both methods

Da D0 Db Kd (Mpa) Kef (MPa) Kp (MPa) Ket (MPa)

TS 0.461 (0.003) 0.166 (0.006) 0.295 (0.005) 112.3 (7.2) 450.0 (91.3) 119.1 1977.5OD-TSEMA 0.440 (0.004) 0.251 (0.002) 0.189 (0.004) 123.5 (9.4) 787.2 (237.7) 140.9 1000.6FD-TSEMA 0.386 (0.002) 0.240 (0.008) 0.146 (0.009) 99.5 (7.6) 1766.1 (946.2) 104.2 2199.7THS 0.436 (0.005) 0.161 (0.005) 0.276 (0.010) 132.8 (0.9) 968.4 (265.2) 133.3 34723.3OD-THSEMA 0.406 (0.007) 0.214 (0.005) 0.192 (0.002) 118.3 (5.4) 892.7 (196.9) 147.1 605.2FD-THSEMA 0.397 (0.004) 0.214 (0.002) 0.183 (0.004) 106.6 (3.7) 551.1 (85.2) 120.5 927.6

Da, total densification; D0, densification due to die filling; Db, densification due to particle rearrangement and fragmentation; Kd, mean yield pressure of totaldeformation; Kef, mean yield pressure of fast elastic deformation; Kp, mean yield pressure of plastic deformation; Ket, mean yield pressure of total elasticdeformation.

a Correlation coefficients of tablet-in-die method: compression (0.996–0.999) and decompression (0.805–0.988) phases.b Correlation coefficients of ejected-tablet method (0.967–0.996).


(and therefore the higher interparticle surface expose),and the shape of TSEMA particle (more prone to plasticflow), could explain these results. Paronen and Juslin[50] also indicated that the shape of particles affects thetendency of the starches to deform plastically. Similarbehaviour is found for FD products related to OD ones[29], probably associated to the rough surface of theseproducts [13].

3.5. Preparation of tablets

In order to obtain a deeper understanding of the com-pression physics, various parameters involved in compres-sion have been determined. These typical compressionterms [54,55] are summarised in Table 4.

As can be seen in Table 4, graft copolymers requiremarkedly lower applied pressure (P) (p < 0.05) for tabletspreparation. Also, in agreement with the different plasticdeformation values (Table 3) obtained using Heckel equa-tion, the maximum applied pressure are larger for OD thanFD derivatives.

The lubrication ratio values (R) obtained for all products(0.4–0.6) do not fulfil the requirements proposed byBolhuis and Lerk [56] for direct compression excipients.Significant differences (p < 0.05) are found among copoly-mers, showing THSEMA lower R values, in agreement withits higher particle aggregation behaviour. In any case, dueto the low values observed for this parameter, it will benecessary the addition of a lubricant in the use of thecopolymers as tablet excipients.

Despite of the poor R measures, only copolymer tabletshave ejection force values (Fe) lower than 750 N, which is

the limit for direct compression excipients [56]. Also, thecopolymer tablets are characterized by lower values of fric-tion work (Wf), but no significant differences (p > 0.05) arefound related to the drying method used.

Respecting to the expansion work (We), the larger val-ues obtained by THS tablets do not agree with the ten-dency to fast elastic deformation (Kef) noticed in Heckelcompression cycles (Table 3). This could be attributed tothe different measuring conditions: Kef values (with higherSD) are obtained from a linear phase of Heckel compres-sion cycles [52], while the expansion work takes into ac-count the whole process of elastic expansion duringdecompression.

Only TS shows a higher value of apparent net work(Wan) than the corresponding copolymers (p < 0.05). Also,THSEMA is characterized by higher values of Wan than TSE-MA derivatives (p < 0.05). Similar behaviour is found re-lated to the drying method used; FD copolymers showlower values, in agreement with Kp data in Heckel analysis(Table 3).

On the other hand, plasticity behaviour (Pl) is similar forall products (96–98%), due to the plastic character of thesematerials. Only significant differences are found betweenFD and OD-TSEMA (p < 0.05), due to the higher expansionwork of the last one.

3.6. Standard physical test of tablets

Results from the physical test of tablets obtained fromthe different products are compiled in Table 5.

All tablets fulfil the guidelines specified in EuropeanPharmacopoeia [23] related to weight uniformity test.

Table 5Tablet test results for the carbohydrates and copolymers: average weight, thickness, diameter, crushing force (CF), friability (F), disintegration time (DT). Valuesin brackets represent the standard deviation.

Materials Average weight (mg) Thickness (mm) Diameter (mm) CF (N) F (%) DT (min)

TS 498 (4) 3.672 (0.022) 12.125 (0.038) 74 (16) 6.85 <1OD-TSEMA 496 (2) 5.043 (0.006) 12.245 (0.022) 76 (4) 2.48 >30FD-TSEMA 499 (2) 5.512 (0.012) 12.202 (0.022) 71 (4) 4.12 >30THS 491 (13) 3.668 (0.022) 12.184 (0.050) 71 (12) 5.42 5OD-THSEMA 501 (1) 5.591 (0.004) 12.325 (0.014) 73 (9) 4.74 >30FD-THSEMA 500 (2) 5.761 (0.008) 12.300 (0.013) 72 (7) 5.01 >30


The copolymer tablets display higher thickness anddiameter than the raw materials tablets, probably due totheir greater axial and radial expansion. The crushing forcetest confirms the values of 70–80 N for all tablets.

The main advantages of the copolymers compared tothe commercial raw materials are the friability and disinte-gration time values, having copolymer tablets lower fria-bility than carbohydrates and larger disintegration times(over 30 min). These parameters are similar to those foundfor Preflo�, modified starches used as commercial directcompression diluents for sustained release tablets [3]. Also,the synthesized copolymers display better disintegrationtimes than tapioca starch derivatives studied by Atichoku-domchai and Varavinit [16]. Those data demonstrate thatthe copolymers recorded in this paper could be used ascompressed non-disintegrating matrix tablets.

3.7. Mercury porosimetry measurements

In order to evaluate the microstructure of the matrices,their pore size distribution was measured by mercuryintrusion–extrusion porosimetry (Table 6).

Copolymers tablets display larger porosities than theraw materials, according to the higher thickness (Table5), and lower mean pore diameters.

The drying methods affected the porosity and meanpore diameter. Thus, there is a big difference between ODand FD copolymers, with higher porosities and lower meanand median pore diameters for FD copolymers than thoseobtained from OD derivatives. Again, these results are con-sistent with the higher thickness for FD copolymers.

According to IUPAC guidelines definitions, the systemsunder study would contain mesopores and macropores[57]. The pore size distribution profiles are unimodal inall cases and show a similar behaviour among them, as

Table 6Parameters characterizing the porous structure of materials, calculated bymercury intrusion–extrusion porosimetry. Values in brackets represent thestandard deviation (n = 2).

Materials Porosity (%) Mean porediameter (nm)

Median porediameter (nm)

TS 21.70 (0.63) 62.5 (8.4) 1687.7 (8.6)OD-TSEMA 28.10 (0.13) 47.0 (2.5) 1416.6 (10.3)FD-TSEMA 38.11 (0.08) 45.9 (3.8) 1357.1 (42.1)THS 21.23 (0.71) 65.9 (14.3) 1735.9 (102.5)OD-THSEMA 37.94 (0.59) 64.5 (2.7) 2352.0 (77.1)FD-THSEMA 40.95 (0.23) 63.0 (1.3) 2091.5 (19.9)

has been previously recorded for other acrylic-basedcopolymers [13,29,58].

4. Conclusions

It can be concluded that grafting of EMA on carbohy-drate backbone causes important modifications on thephysicochemical and technological properties of tapiocaand hydroxypropyl tapioca starches. The reaction yieldsobtained when grafting EMA on tapioca starch andhydroxypropyl tapioca starch are high (over 93%) and exhi-bit low relative standard deviation values, which confirmthe reproducibility of the synthesis.

The copolymer composition was accurately estimated,with 30–40% of carbohydrate and 60–70% of ethyl methac-rylate. The incorporation of ethyl methacrylate chains isconfirmed by infrared and NMR spectroscopies. Graft copo-lymerization induces physical and chemical changes likelower crystallinity and density, higher hydrophobicityand bigger irregular size of particles.

One of the technological improvements of the newcopolymers related to commercial raw materials is thatthe adequate crushing strength of TSEMA and THSEMA tab-lets was achieved with lower compression force and lowerejection force than for raw commercial starches. On theother hand, the total deformation and the total elastic defor-mation values for the new macromolecules are similar andlower, respectively, compared to those of some widely usedcommercial direct compression excipients. Also, it isremarkable the high disintegration time values observed,similar to Preflo�, a commercial direct compression diluentfor sustained released tablets. These qualities make themgood candidates for their use as excipients in matrix tabletsobtained by direct compression and, with a potential use incontrolled release, which is being investigated.

Acknowledgements

This work has been supported by a FPU grant from theSpanish Government and is part of a project (MAT2004-01599) from Spanish Ministry of Science and Technology.

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