ORIGINAL PAPER

Structure and properties of polycaprolactone/ibuprofenrods prepared by melt extrusion for implantable drugdelivery

G. V. Salmoria1,2 • F. Sibilia2,3 • V. G. Henschel1,2 •

S. Fare3 • M. C. Tanzi3

Received: 3 August 2016 / Revised: 27 February 2017 /Accepted: 21 March 2017

� Springer-Verlag Berlin Heidelberg 2017

Abstract In this study, the structure and properties of polycaprolactone/ibuprofen(PCL/IBP) rods prepared by melt extrusion were investigated by infrared spec-

troscopy, X-ray diffraction, scanning electron microscopy, flexural tests, dynamic

mechanical analysis and drug release analysis. The crystallinity values for the PCL/

IBP rods were lower than that for the pure PCL rods. The PCL/IBP rods had higher

values for the flexural modulus compared with the pure PCL rods prepared using the

same processing temperature, suggesting that ibuprofen has a hardening effect when

dispersion in a PCL matrix. Rods prepared at a processing temperature of 130 �Chad the highest flexural modulus and glass transition temperature, probably due to

better drug dispersion in the PCL matrix at lower temperature. The surfaces of PCL/

IBP rods prepared at 150 �C had small particles and molten drug was deposited onthe surface. This is probably due to the low melt temperature of ibuprofen and thus

at high temperatures the ibuprofen phase migrates from the PLC matrix to the rod

surface. The PCL/IBP rods prepared using different processing temperatures pro-

vided different drug release behaviors, with fast or slow drug release depending on

the ibuprofen distribution. This feature is of great interest in relation to producing

implantable drug delivery rods for acute inflammatory crisis or therapeutic treat-

ments via controlled release.

Electronic supplementary material The online version of this article (doi:10.1007/s00289-017-1999-x)contains supplementary material, which is available to authorized users.

& G. V. Salmoriagean.salmoria@ufsc.br

1 CIMJECT Laboratory, Department of Mechanical Engineering, Federal University of Santa

Catarina, Florianópolis, SC 88040-900, Brazil

2 Biomechanics Engineering Laboratory, University Hospital (HU), Federal University of Santa

Catarina, Florianópolis, SC 88040-900, Brazil

3 Laboratorio di Biomateriali, Politecnico di Milano, Via Golgi 39, 20133 Milan, LO, Italy

123

Polym. Bull.

DOI 10.1007/s00289-017-1999-x

http://dx.doi.org/10.1007/s00289-017-1999-xhttp://crossmark.crossref.org/dialog/?doi=10.1007/s00289-017-1999-x&domain=pdfhttp://crossmark.crossref.org/dialog/?doi=10.1007/s00289-017-1999-x&domain=pdf

Keywords Extruded rods � Polycaprolactone/ibuprofen � Drug delivery

Introduction

In recent years the melt extrusion (ME) process has found widespread application as

a viable drug delivery option in the drug development process. It is mainly used to

improve the dissolution of insoluble drugs and to obtain controlled-release

formulations and homogeneous mixtures. During the melt extrusion of a drug

within a polymer binary mixture the drug can remain molecularly dispersed within

the polymer or it can be present as an amorphous or crystalline phase [1, 2]. Hot-

melt extrusion offers some advantages, including ease of use and lack of residual

solvents, decreasing the environmental hazards and costs, and it allows continuous

processing [1–6]. Implantable medical devices are widely used in the pharmaceu-

tical field and these are generally prepared by melt extrusion. Considering the local

delivery and controlled-release profiles, these implants could be used as

implantable drug carriers and functional materials in medical devices [7–9].

Ibuprofen, obtained from isobutyl-phenyl-propanoic acid, is a nonsteroidal anti-

inflammatory drug used to treat fever, mild-to-moderate pain after surgery, painful

menstruation, osteoarthritis, dental pain, headaches and pain from kidney stones

[10–13]. It is also effective in cases of inflammatory diseases, such as juvenile

idiopathic arthritis and rheumatoid arthritis. In addition, it has been given to patients

with pericarditis and patent ductus arteriosus. Ibuprofen is an inhibitor of

cyclooxygenase, an enzyme involved in prostaglandin synthesis via the arachidonic

acid pathway. Its pharmacological effects are believed to be due to the inhibition of

cyclooxygenase-2 (COX-2), which decreases the synthesis of prostaglandins

involved in mediating inflammation, pain, fever, and swelling. Antipyretic effects

may be due to action on the hypothalamus, resulting in an increased peripheral

blood flow, vasodilation, and subsequent heat dissipation [11–13]. Inhibition of

COX-1 is thought to cause some of the side effects of ibuprofen including

gastrointestinal ulceration. The toxic effects of ibuprofen can be severe at doses

above 400 mg/kg or 3200 mg per day [11].

Polyesters are polymers used in biomedical implants and drug delivery systems

with a biodegradable character [13–15]. The best-known examples are polycapro-

lactone (PCL), poly-lactic acid (PLA) and copolymers of lactic acid and glycolic

acid [4, 7, 13–15]. Preliminary, the production of PCL/IBU tubes presented

interesting mechanical properties and ibuprofen release profile for nerve regener-

ation [16]. The general use of an implantable drug delivery system based on a

polycaprolactone matrix can reduce the risk of ibuprofen overdose compared to oral

administration. In this study, the structure and properties of polycaprolactone/

ibuprofen rods prepared by melt extrusion for general drug delivery use were

investigated employing infrared spectroscopy, X-ray diffraction, scanning electron

microscopy, flexural tests, dynamic mechanical analysis and drug release analysis.

The structure and properties of the rods were correlated with the processing

temperature.

Polym. Bull.

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Experimental

Materials

In this study poly(e-caprolactone) reference 440744 (Sigma-Aldrich) was used. Itwas acquired in the form of pellets with 3 mm of diameter and average molecular

weight (Mn) in the range of 70,000–90,000 g/mol, determined by the GPC

technique. The polydispersity value was\2. The ibuprofen (IBP) was obtained fromPharmanostra (São Paulo, Brazil) and it had the appearance of a white crystalline

powder with a density of 1.175 g/cm3. The ibuprofen melt temperature was

determined by DSC as 77.4 �C.

Melt extrusion process

The extrusion equipment used was an Axplastic mono-screw extruder (model LAB

AX-14) with an L/D ratio of 20. The extruder was instrumented with an extrusion

die for small-diameter rods (diameter 5 mm). The three different zones of the

extruder barrel were pre-set to the same processing temperature. A composed

cooling system with cold air (10 �C) and chill ceramic plate (15 �C) was used forthe downstream processing of extrudates. Figure 1 shows a diagram of the extrusion

system used in the preparation of the PCL/IBP rods. The pure PCL was processed

using the intermediate values for the extrusion parameters (i.e., melt temperature of

140 �C and screw speed of 50 rpm). The processing conditions used in thefabrication of the PCL/IBP rods with 10% of ibuprofen content are shown in

Table 1.

Fig. 1 Diagram of extrusion system

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Scanning electron microscopy (SEM)

Philips XL 30 and JEOL JSM-6390LV scanning electronic microscopes were used in

the microstructural analysis. For fracture analysis, the samples were mechanically

fractured in liquid nitrogen (cryogenic fracture). Prior to the analysis by SEM, all

samples were coated with a thin layer of gold in a sputter diode D2 sputtering system.

X-ray diffraction and Fourier transform infrared (FTIR) analysis

X-ray diffraction analysis was carried out on a Philips X’Pert diffractometer. The

scan was obtained at 2h = 5�–40� directly from the surface of the sample rodpositioned horizontally. The specimen crystallinity was determined by the area

measurement method. Fourier transform infrared spectra of the pure material and

the rods were obtained using a Perkin-Elmer Frontier MIR/NIR spectrophotometer

in attenuated total reflectance (ATR) mode scanning from 4000 to 450 cm-1.

Mechanical analysis

A DMAQ800 analyzer (TA instruments) with a single cantilever clamp was used for

mechanical tests carried out on rods with 2.2 mm diameter and 30.0 mm length. A

force rate of 2 N/min from 0 to 18 N was applied in the quasi-static tests. Dynamic

mechanic analysis (DMA) was conducted to obtain the values for the storage modulus

(E0), loss modulus (E00) and tan delta (d) at a frequency of 1 Hz within the temperaturerange of -80 to 80 �C, using a heating rate of 3 �C/min and strain of 0.3%.

Recovery of ibuprofen incorporated in the rods

Rod segments obtained from three different portions of the total material produced

under each condition were collected. Each piece was weighed and cut into smaller

pieces to increase the surface area in contact with the solvent added (10 mL of

methanol; in triplicate). Samples were kept in an ultrasonic bath for 2 h and then

analyzed by UV–vis spectrophotometry, at kmax of 269 nm, on a Hitachi 2010double-beam UV–visible spectrophotometer.

Drug-release test

Specimenswith knownmasswere placed in sealedvialswith 20 mLofphosphate buffer

solution (pH = 7.4) and 0.01 M cetyltrimethyl ammonium bromide (to maintain sink

Table 1 Processing conditions used in the production of the PCL/IBP rods

Factors Low Inter-mediate High

Temperature (�C) 130 140 150Screw speed (rpm) 50 50 50

Drug content (%) 10 10 10

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solubilization conditions). The vials were shaken horizontally in a Dubnoff bath (Faalk,

Brazil)maintained at a temperature of 37.0 ± 0.5 �Cat a rate of 60 rev/min tominimizethe boundary effect. Total buffer solutionswere collected periodically (at predetermined

time intervals). After suitable dilutionwith the buffer solution, the total drug releasewas

determined, based on a previously obtained calibration curve (five dilutions of

0.050–0.40 mg/mL), using UV–vis spectrophotometry, at kmax of 269 nm, on a Hitachi2010 double-beam UV–visible spectrophotometer.

Results and discussion

Figure 2 shows the cryogenic fracture surfaces of the PCL/ibuprofen rods and

ibuprofen particles. Measurements revealed an average value for the diameter of the

PCL/IBP rods of 2.2 (±0.2) mm. The cryogenic fracture surface morphologies of

the PCL/IBP rods showed similar brittle characteristics. The fracture surface of

PCL/IBU rod prepared at 130 �C shows the distribution of ibuprofen particles intothe PCL matrix (Fig. 2a–c). The ibuprofen particles present at fracture surface have

smaller average size (50 lm) than the pure ibuprofen particles (200 lm, Fig. 2f)used, suggesting the partial dissolution of ibuprofen into PCL matrix. The PCL/IBU

rod processed at 150 �C presents the lower quantity of ibuprofen particles at thefracture surface (Fig. 2g–i).

Fig. 2 Images of cryogenic fracture surfaces of PCL/ibuprofen rods extruded using different processtemperatures: 130 �C (a–c), 140 �C (d, e) and 150 �C (g–i), and of ibuprofen particles (f)

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The images in Fig. 3 shows the surfaces of the PCL/IBP rods where low surface

irregularities can be observed. The PCL/IBP rods presented small particles and

molten drug deposited on the surface, particularly in the case of PCL/IBP rods

prepared using 150 �C (Fig. 3c), probably due to the low melt temperature of theibuprofen which leads to migration of the ibuprofen phase from the PLC matrix to

the surface of the extrude rods. The growth of ibuprofen particles can be

significantly affected by the presence of polymer matrix. This phenomenon was also

observed in other studies with ibuprofen and polymers [16, 17]. The use of the EDS

technique confirmed the presence of small particles of ibuprofen on the surfaces of

the PCL/IBP rods, using the composition analysis to compare the oxygen contents

of the ibuprofen particles and the PCL matrix (Fig. 3d).

Figure 4 shows the X-ray diffractograms for the pure PCL and PCL/IBP rods

prepared at 140 �C. The diffractogram for pure PCL shows two peaks (at 2h 21.6�and 23.8�). These peaks are indexed to the (110) and (200) planes of anorthorhombic crystalline structure, respectively [18, 19]. The diffractograms of the

PCL/IBP rods prepared using different temperatures showed the same peaks at 2h21.6� and 23.8�. Peaks related to the crystalline phase of ibuprofen at 11.9�, 16.5�,19.3� and 22.5� [20] were not detected, due to the fact of ibuprofen was the minorcomponent (10 wt.%) and it was present as kinetically stabilized amorphous phase

[21].

Fig. 3 Scanning electronic micrographs of the surface of PCL/ibuprofen rods prepared applyingprocessing temperatures of 130 �C (a), 140 �C (b) and 150 �C (c) and EDS results for carbon and oxygencontents in ibuprofen particles and PCL matrix (d)

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The crystallinity values for the pure PCL and PCL/IBP rods are shown in

Table 2. It can be observed that the crystallinity values for the PCL/IBP rods are

lower than that for the pure PCL rod, probably due to interaction of the drug with

the polymer chains and the processing conditions. According to Pant [22] and

collaborators, the occurrence of this phenomenon is verified by the interaction of

components at the molecular level, which suggests the partial dissolution of

ibuprofen in the PCL matrix. Lower processing temperatures led to a decrease in the

crystallinity of the PCL/IBP rods, probably due to a rapid solidification and better

dispersion of ibuprofen in the PCL matrix.

Figure 5 shows the FTIR spectra for the ibuprofen (a), pure PCL (b) and PCL/

IBP rods (c–e) prepared using different processing temperatures. The pure PCL

shows peaks at 2940, 2863, 1721, 1294, 1164, 1157 and 717 cm-1 related to CH2asymmetric stretching, CH2 symmetric stretching, C=O carbonyl stretching, C–O

stretching in the crystalline phase, asymmetric C–O–C stretching, C–O stretching in

the amorphous phase and CH2 rocking, respectively (Fig. 5b) [23, 24]. The peaks

present in the ibuprofen spectrum at 2955, 1721 and 1240 cm-1 are assigned to

asymmetric CH3 stretching, C=O stretching and C–O stretching, respectively

(Fig. 5a) [25], while the peaks at 668 and 580 cm-1 are related to the aromatic ring

Fig. 4 Diffractograms of pure PCL and PCL/IBP rods produced using a processing temperature of140 �C

Table 2 Crystallinity by X-raydiffraction to pure PCL and

PCL/IBP rods prepared with

different extrusion temperatures

Samples Crystallinity (%)

Pure PCL 140 �C 56 ± 2PCL/IBP 130 �C 48 ± 2PCL/IBP 140 �C 50 ± 2PCL/IBP 150 �C 51 ± 3

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vibration in the ibuprofen structure. The main peaks in the FTIR spectra for the

PCL/IBP rods (Fig. 5c–e) were the same as those observed in the spectra for the

PCL rods and the peaks at 668 and 580 cm-1 are related to the aromatic group in the

ibuprofen structure, verifying the presence of the drug. The interpretation on the

intermolecular interaction was from the peaks related to PCL, the main component

(90 wt.%). The C=O stretching peak of PCL (1721 cm-1) overlapped too much with

that of IBU (1721 cm-1). However, the dislocation of the C=O stretching peak of

PCL to 1713 cm-1, suggested the existence of intermolecular interactions between

IBU and PCL. The appearance of a broad band from 3300 to 3100 cm-1,

corresponding to O–H bending, can be related to interactions between PCL and

ibuprofen by hydrogen bonds [26]. Also can be noted the displacement of the PCL

peaks 2940 and 2863 cm-1 corresponding to the stretching of CH2 groups in PCL/

IBU rods spectra.

DSC measurements were performed to characterize the thermal behavior the

ibuprofen, PCL and PCL/IBU rods. The DSC thermograms are presented in Fig. 6.

At ambient temperature, Ibuprofen is a white crystal. Under heating (at 10 �C/min),this crystalline form melts at 78.8 �C, which gives rise to an endothermic peak onthe DSC thermogram. This melting temperature is typical of the racemic mixture

[27]. The melting enthalpy is 99 J/g, in agreement with the value previously

reported [27, 28]. PCL showed a melting process located between 53 and 57 �Cwith a Tm = 56.3 �C, related to a crystalline phase, in agreement with the valuespreviously reported [29]. In all PCL/IBU rods, only an endothermic peak between

52 and 57 �C was observed, that is probably due to the melting of the crystallinephase of PCL matrix. The melting temperature of the PCL/IBU rods was found to

slightly decrease with the presence of ibuprofen (Table 3). The endothermic peak

Fig. 5 FTIR-ATR spectra for ibuprofen (a), pure PCL (b) and PCL/IBP rods prepared at processingtemperatures of 130 �C (c), 140 �C (d) and 150 �C (e)

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related to the melting of crystalline phase of ibuprofen was not detected. Previous

investigation showed that when ibuprofen is quenched faster than 20 �C/min,crystallization is avoided [27]. This ibuprofen behavior can explain the absence of

an endothermic peak related to the ibuprofen melting on DSC thermograms of PCL/

IBU rods fabricated by hot melt extrusion. Campbell and collaborators demon-

strated that ibuprofen was well dispersed and distributed throughout the PCL/clay

composite matrix. The glass transition of pure PCL increased by up to 16 �C foribuprofen composites. It was attributed to the constrained mobility of PCL chains

intercalated between the composites components and to the tethering of PCL chains

by hydrogen bonding with those. As a consequence, PCL crystallization was

inhibited. The fraction of PCL that was crystalline decreased by 15% on addition of

ibuprofen and nanoclay [30].

The DSC crystallinity calculated from the enthalpy of melting of 100%

crystalline PCL [29], for the pure PCL and PCL/IBP rods are shown in Table 3. It

can be observed that the DSC crystallinity values for the PCL/IBP rods are slightly

Fig. 6 DSC thermograms for ibuprofen (a), pure PCL (b) and PCL/IBP rods prepared at processingtemperatures of 130 �C (c), 140 �C (d) and 150 �C (e)

Table 3 Melting temperature and DSC crystallinity to pure PCL and PCL/IBP rods prepared withdifferent extrusion temperatures

Samples Melting temperature (�C) Crystallinitya (%)

Pure PCL 140 �C 56.3 62 ± 2PCL/IBP 130 �C 55.5 55 ± 2PCL/IBP 140 �C 55.7 58 ± 2PCL/IBP 150 �C 56.2 61 ± 2a Crystallinity values based in the enthalpy of melting of 100% crystalline PCL, 142.0 J/g [29]

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lower than that for the pure PCL rod, probably due to interaction of the drug with

the polymer chains and the processing conditions. Lower processing temperatures

(130 �C) led to a decrease in the crystallinity of the PCL/IBP rods, probably due to abetter dispersion of ibuprofen in the PCL matrix and faster solidification when

compared to PCL/IBU rod fabricated using higher processing temperature (150 �C).The flexural modulus for the PCL/IBP rods prepared at different processing

temperatures are shown in Table 4. The PCL/IBP rods fabricated at 140 �C hadhigher flexural modulus values compared with the pure PCL rods prepared using the

same processing temperature, suggesting that dispersion of the ibuprofen in the PCL

matrix has a hardening effect (Fig. 7). PCL/IBP rods prepared at 130 �C had thehighest flexural modulus value, probably due to better drug dispersion in the PCL

matrix at lower temperature.

Figure 8 shows the curves for the storage modulus (E0) as a function oftemperature for the PCL/IBP rods prepared using different processing conditions.

The storage modulus for the PCL/IBP rods decreased with the DMA test

temperature, particularly at temperatures close to -50 �C, which relates to thePCL glass transition temperature. The rods prepared using a higher processing

temperature had a lower storage modulus value, indicating the effect of temperature

Table 4 Flexural modulus forpure PCL and PCL/IBP rods

prepared by melt extrusion

Specimen Flexural modulus (MPa)

Pure PCL 140 �C 221 ± 36PCL/IBP 130 �C 257 ± 30PCL/IBP 140 �C 244 ± 27PCL/IBP 150 �C 230 ± 33

Fig. 7 Stress versus strain curves obtained in flexural test for PCL/IBP rods produced using differentmelt temperatures: 130 �C (a), 140 �C (b) and 150 �C (c), and pure PCL (d)

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on the ibuprofen dispersion which, in turn, influences the mechanical properties of

the PCL/IBP rods.

The determination of the maximum value for the loss tangent as a function of

temperature (Fig. 9) allowed the glass transition temperature (Tg) to be determined

for the PCL/IBP rods prepared using different processing temperatures. The PCL/

IBP rods had higher Tg values compared with the pure PCL rods (Table 5),

indicating that the dispersion of the ibuprofen in the PCL matrix had a hardening

Fig. 8 Storage modulus (E0) as a function of temperature for PCL/IBP rods produced using differentmelt temperatures: 130 �C (a), 140 �C (b) and 150 �C (c), and pure PCL (d)

Fig. 9 Values for loss tangent (tand) as a function of temperature for PCL/IBP rods prepared usingdifferent processing temperatures: 130 �C (a), 140 �C (b), 150 �C (c) and pure PCL (d)

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effect. Rods prepared using a processing temperature of 130 �C had the highestglass transition temperature, suggesting a greater dispersion of ibuprofen in the PCL

matrix. Similar effect was found by Campbell and collaborators on the glass

transition of ibuprofen composites [30].

The recovery of the ibuprofen incorporated into the rods showed an average of

96% (±1%) incorporation of the drug, presenting no significant differences in

relation to the processing temperature, which indicates that although there was drug

loss this was constant, contributing to the process reproducibility. The drug release

curves for PCL/IBP rods prepared applying different processing conditions are

shown in Fig. 10. The rods produced at a higher processing temperature (150 �C)showed a rapid release during the first 3 days and a release of 80% of ibuprofen

during the first 30 days due to the drug distribution mainly at the rod surface. In

previous study about the production thin wall tubes of PCL/IBU, we found a high

rate of ibuprofen release, adequate for nerve regeneration [16].

On the other hand, PCL/IBU rods produced at a lower processing temperature

(130 �C) showed only 10% of ibuprofen release during the first 30 days, showing acontrolled release of the dispersed ibuprofen from the polymeric matrix by

diffusion/erosion mechanism. The ibuprofen dissolution and initial burst effect

observed to the rods prepared at 150 �C, were retarded by the better dispersion of

Table 5 Tg values for purePCL and PCL/ibuprofen rods

obtained from the maximum loss

tangent in DMA

Sample Tg (�C)

Pure PCL 140 �C -40 ± 2PCL/IBP 130 �C -35 ± 2PCL/IBP 140 �C -36 ± 3PCL/IBP 150 �C -38 ± 2

Fig. 10 Ibuprofen release as a function of time for rods prepared applying different processingtemperatures: 130 �C (a), 140 �C (b) and 150 �C (c)

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ibuprofen into the PCL matrix of rods prepared 130 �C. Terebetski and Michniak-Kohn suggested that induction of intermolecular interactions between ibuprofen and

cellulose polymers were effective at inhibiting nucleation and maintaining

prolonged drug release [31]. Del Valle and collaborators showed a moderator

effect of PCL over ibuprofen release. Polymer-ibuprofen blends presenting a rapid

release could have the release delayed by the addition of polycaprolactone to the

mixture [32].

The PCL/IBP rods prepared at different processing temperatures provided varied

drug release behaviors (fast to slow release), which is of interest with regard to

producing implantable drug delivery rods for acute inflammatory crisis or

therapeutic treatments.

Conclusions

It has been demonstrated that the fabrication of PCL/IBU rods is possible, and it can

be done by hot melt extrusion with efficiency. PCL/IBP rods showed small particles

of ibuprofen deposited on the surface, especially in the case of PCL/IBP rods

prepared at 150 �C. The crystallinity values for the PCL/IBP rods were lower thanthat for the pure PCL rod, probably due to interaction of the drug with the polymer

chains. The rods prepared using 130 �C as the processing temperature had thehighest flexural modulus, probably due to better drug dispersion in the PCL matrix

at lower temperature. The rods prepared using a higher processing temperature had

a lower storage modulus value, indicating that the temperature had an effect on the

ibuprofen dispersion which, in turn, influenced the mechanical properties of the

PCL/IBP rods, as observed in the quasi-static tests.

Rods produced at a processing temperature of 150 �C showed a fast ibuprofenrelease during the first 30 days. The rods produced using the lowest processing

temperature (130 �C) showed a slower ibuprofen release, indicating greaterdispersion of the ibuprofen in the PCL matrix. The PCL/IBP rods prepared using

different processing temperatures showed different drug release behaviors, with fast

or slow drug release depending on the ibuprofen distribution. This is of interest with

regard to producing implantable drug delivery rods for acute inflammatory crisis or

therapeutic treatments applying controlled release.

Acknowledgements The authors would like to thank PRONEX/FAPESC, CNPQ and FINEP forfinancial support and the Center of Microscopy-UFSC for the micrographics.

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Structure and properties of polycaprolactone/ibuprofen rods prepared by melt extrusion for implantable drug deliveryAbstractIntroductionExperimentalMaterialsMelt extrusion processScanning electron microscopy (SEM)X-ray diffraction and Fourier transform infrared (FTIR) analysisMechanical analysisRecovery of ibuprofen incorporated in the rodsDrug-release test

Results and discussionConclusionsAcknowledgementsReferences