Biomaterials 21 (2000) 2073}2079

Morphology of and release behavior from porouspolyurethane microspheres

Esmaiel Jabbari*, Maziar KhakpourLaboratory of Biomaterials and Controlled Delivery Systems for Biologically Active Agents, School of Biomedical Engineering,

Amir-Kabir University of Technology, Hafez Ave. No. 424, Tehran 15914, Iran

Received 20 September 1999; accepted 6 April 2000

Abstract

A novel biomaterial application of porous microspheres is for sustained delivery of biologically active agents. Recent studies havepointed out the importance of biomaterial porosity in promoting biocompatibility and controlling release rate of active agents. Theobjective of this research was to investigate the e!ect of chain-extending agent on the porosity and release behavior of polyurethane(PU) microspheres prepared using a two-step suspension polycondensation method with methylene diphenyl diisocyanate (MDI) asthe isocyanate, polyethylene glycol (PEG400) as the diol, and 1,4-butanediol as the chain-extending agent. Chain-extending agent wasused to increase the ratio of hard to soft segments of the PU network, and its e!ect on microsphere morphology was studied withscanning electron microscopy. According to the results, porosity was signi"cantly a!ected by the amount of chain-extending agent.The pore size decreased as the concentration of chain-extending agent increased from zero to 50 mole%. With further increase ofchain-extending agent to 60 and 67%, PU chains became sti!er and formation of pores was inhibited. Therefore, pore morphologywas signi"cantly a!ected by variations in the amount of chain-extending agent. The release behavior of microspheres was investigatedwith diazinon as the active agent. After an initial burst, corresponding to 3% of the incorporated amount of active agent, the releaserate was zero order. ( 2000 Elsevier Science Ltd. All rights reserved.

Keywords: Polyurethane microspheres; Suspension polycondensation; Morphology; Pore size; Chain-extending agent

1. Introduction

Polyurethanes are used extensively in the medical "eldas intravascular devices [1,2], uretral stents [3], for men-iscal reconstruction [4}6], cartilage and bone repair[7}10], and as vehicles for sustained delivery of bio-logically active agents. Polyurethanes have excellentmechanical properties, high elongation capacity, goodabrasion resistance, high #exibility and hardness, andgood biocompatibility [1]. Recent studies have pointedout the importance of porosity of the arti"cial material,more speci"cally, pore size distribution and structure,in promoting biocompatibility and biodegradability[11}19].

A novel application of porous biomaterials is for sus-tained and targeted delivery of biologically active agentssuch as drug molecules, nutrients, or growth factors

*Corresponding author. Tel./fax:#98-21-649-5655.E-mail address: ejabari@cic.aku.ac.ir (E. Jabbari).

[20}23]. In particular, porous microspheres are usedextensively in biomedical and pharmaceutical "elds asvehicles for sustained delivery of active agents [24,25].Polymeric microspheres can be prepared by physical aswell as chemical methods. The structure of microspheresprepared by physical methods such as phase separation,solvent evaporation, and spray drying is studied exten-sively by many researchers [26}28].

Polymeric microspheres can be prepared by a varietyof chemical methods [29}31]. These methods includeemulsion [32], suspension [33], semi-suspension [34],precipitation [35], dispersion [30,31], interfacial polym-erization [36}42], and suspension polycondensation[31]. In the method of suspension polycondensation, twomonomers that are dissolved in the suspended oil phase,which also contains the active agent, polymerize by con-densation reaction to form a polymeric matrix. Thismethod of incorporation results in dissolution or homo-geneous distribution of the active agent in the polymermatrix. In most applications, an isocyanate monomerreacts with a diol in the suspended oil phase to form

0142-9612/00/$ - see front matter ( 2000 Elsevier Science Ltd. All rights reserved.PII: S 0 1 4 2 - 9 6 1 2 ( 0 0 ) 0 0 1 3 5 - 6

a polyurethane microsphere. Most of the work onpreparation and properties of microspheres preparedby suspension polycondensation is in patentedform [43}46]. More speci"cally, little work is doneon characterization of porous structure of these micro-spheres. Previous work [47] indicates that thechemical nature of the monomers has a signi"cant e!ecton pore morphology and release behavior of these micro-spheres.

The objective of this work was to investigate the e!ectof chain extending agent on porous structure and releasebehavior of polyurethane microspheres prepared usinga two-step suspension polycondensation method withMDI as the isocyanate, PEG400 as the diol, and 1,4-butanediol as the chain-extending agent.

2. Materials and methods

2.1. Materials

4,4@-Methylene bisphenyl isocyanate (MDI) with func-tionality of 2.2 and equivalent weight of 113.6, polyethy-lene glycol 400 (PEG400) with hydroxyl number of 280.5and equivalent weight of 200, and 1,4-butanediol (BD) asa chain-extending agent with hydroxyl number of 1245and an equivalent weight of 45.06 were obtained fromMerck Chemical Co., Germany. The composition ofisocyanate used was 60% w/w difunctional MDI, 30%w/w trifunctional isocyanates, and 10% w/w otherdifunctional isocyanates. The purity of 1,4-butanediolused was higher than 98%, as reported by the supplier.Polyvinyl pyrrolidone (PVP), as a suspension stabilizer,with MM

vof 24 000 g/mol was obtained from Aldrich

Chemical Co. Technical grade diazinon, o,o-diethyl-o-(2-isopropyl-6-methyl-4-pyromedinyl) phosphoro thioate,was purchased from Ciba-Geigy Co. and it was used asa model active agent to study the release behavior of themicrospheres. All chemicals were used as received with-out further puri"cation.

2.2. Preparation of PU microspheres

PU aqueous suspension was prepared in two stepsincluding prepolymer formation and polycondensation.To prepare the prepolymer, 9.6 g MDI with8.45]10~2 mol isocyanate groups was mixed in a beakerwith 8.45 g PEG400 with 4.22]10~2mol hydroxylgroups and 1.90 g BD with 4.23]10~2mol hydroxylgroups, in stoichiometric ratio. For release studies, 1.8 gdiazinon was added to the prepolymer mixture to geta 10% w/w concentration of the active agent in thedispersed phase. The mixture was allowed to react par-tially for approximately 3 min at ambient conditions inorder to convert most of the PEG400 and BD to isocyan-ate}polyol oligomers.

In the next step, the prepolymer was added dropwiseto the aqueous phase in a reaction vessel equipped witha homogenizer (DIAX 600, Heidolph). The homogenizerconsisted of a rotor and a static mixer. Shaft diameterwas 10.0mm, width of stator slot was 1.0mm, width ofstator cutting blade was 1.0mm. Homogenization con-tinued for 45min while the reaction proceeded [48].After the completion of polycondensation reaction,microspheres were "ltered, washed twice with distilledwater to remove the suspending agent and allowed to dryfor at least 24 h at ambient conditions.

2.3. Microsphere characterization

The completion of polycondensation reaction wascon"rmed by Fourier transform infrared spectroscopy(FTIR) in the attenuated total re#ection (ATR) mode.The microspheres, in a dry powder form, were sprinkledon a ATR crystal and spectra were recorded usinga Bruker IFS88 spectrometer. A strong absorption bandwith peak location at 2272 cm~1, due to N"C"Ostretching vibration of the isocyanate groups, was used toidentify MDI. The absorption band between 1000 and1300 cm~1, due to stretching vibration of C"O"Cstretching vibration, was used to identify PEG400.A strong absorption band with peak location at3400 cm~1, due to stretching vibration of N}H group ofurethane linkages, and the absorption band between1650 and 1700 cm~1, due to stretching vibration of C}Ogroup of urethane linkages, were used to identify the PU,after the reaction had taken place.

The average diameter of microspheres was determinedwith an optical microscope (Euromex). A drop of thesuspension was placed on a microscope slide, dilutedwith distilled water, and examined at a magni"cation of1650. Samples of the microspheres were selected at ran-dom from di!erent locations on the glass slide anddiameter of 100 particles was measured. The samplingprocedure was repeated three times and the averagevalue was reported as the diameter of microspheres. Thestructure of porous polyurethane microspheres wasstudied with SEM. A drop of the suspension was placedon a double stick tape which was a$xed to a SEMmount. After drying, the sample was sputter coated withgold and examined with Leica Cambridge S360 SEM atan accelerating voltage of 10 keV.

2.4. Release measurements

The release behavior of microspheres was studied withultraviolet (UV) spectroscopy using diazinon as themodel active agent. For calibration, solutions of diazinonin distilled water with concentrations ranging from 2 to40ppm were prepared and their absorption was mea-sured at 246 nm with a Milton Roy Spectronic 601 spec-trophotometer. The calibration line was linear with slope

2074 E. Jabbari, M. Khakpour / Biomaterials 21 (2000) 2073}2079

Fig. 1. ATR-FTIR absorption spectrum of the PU powder prepared by suspension polycondensation of MDI and PEG400 with 1,4-butanediol as thechain-extending agent.

of 44.07 ppm per absorption unit. For release studies,three 1.0 g samples of dried PU powder containing10%w/w diazinon, from the same polymerization experi-ment, were dispersed in 1500ml of distilled water. Thesuspensions were stirred gently while temperature waskept constant at 253C. At a given time, a sample wastaken from each suspension, centrifuged for 10min at5000 rpm to separate the microspheres, and the absorp-tion of each aqueous phase was measured. The concen-tration of diazinon in each aqueous phase was obtainedfrom the calibration curve using the measured absorp-tions. The average value was reported and the highestand lowest concentrations were used as error bars foreach concentration measured.

3. Results and discussion

3.1. Polycondensation reactions

The oil phase suspended in the continuous aqueousphase contained MDI, PEG400, BD, and the activeagent, diazinon. Water could also di!use into the oilphase and participate in the polycondensation reaction.The following reactions could occur in the oil phase [49]:

O"C"N}R}N"C"O#HO}R@}OH

P}[}C(O)N(H)}R}N(H)C(O)O}R@}O}]n}, (1)

}RN"C"O#HOHP}[RN(H)COOH]

P}RNH2#CO

2, (2)

}RNH2#}R@N"C"OP}RN(H)C(O)N(H)R@}, (3)

}RN"C"O#R@N(H)C(O)ORA

P}RN(H)C(O)N(R@)C(O)ORA}, (4)

}RN"C"O#R@N(H)C(O)N(H)RA

P}RN(H)C(O)N(R@)C(O)N(H)RA}. (5)

In the "rst reaction, isocyanate groups react with hy-droxyl groups of PEG400 or BD to form the PU chains.In the second reaction, isocyanate groups react withwater di!used from the aqueous phase to form an aminoacid group which is unstable and dissociates into a chainwith amine end-group and carbon dioxide. The extent ofcarbon dioxide formation by this reaction contributessigni"cantly to the porosity of microspheres. In the thirdreaction, a chain with amine end-group reacts with anisocyanate end-group to form a urea linkage. In thefourth reaction, an isocyanate end-group reacts witha urethane NH group to form an allophanate. In the "fthreaction, an isocyanate end-group reacts with a urea NHto form a biuret. Reactions (4) and (5) cause interconnec-tion and crosslinking of PU chains. The functionality ofMDI, which was 2.2, also contributed to the extent ofcrosslinking and network formation.

The completion of polycondensation reaction betweenMDI and polyol was con"rmed by ATR-FTIR. TheFTIR spectra of the prepared PU microspheres is shownin Fig. 1. The absence of absorption band due to isocyan-ate groups and the presence of urethane absorption bandin the spectrum of PU microspheres clearly indicatedthat the reaction reached completion after 45min. Fromthe absorption bands in the IR spectra, it was not pos-sible to di!erentiate between urethane and urea linkagesin the chemical structure of microspheres.

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Fig. 2. SEM micrograph of a microsphere prepared by suspensionpolycondensation without chain-extending agent at magni"cation of2660. The homogenization speed was 13 500 rpm. The emulsi"er wasPVP with concentration of 1% w/w of the aqueous phase. Typical poresize was 950 nm, as marked in the micrograph.

Fig. 3. SEM micrograph of a microsphere prepared by suspensionpolycondensation with 50 mol% of the PEG400 diol substituted withchain-extending agent, 1,4-butanediol, at magni"cation of 3650. Thehomogenization speed was 13 500 rpm. The stabilizer was PVP withconcentration of 1%w/w of the aqueous phase. Typical pore size was600nm, as marked in the micrograph.

Fig. 4. SEM micrograph of a microsphere prepared by suspensionpolycondensation with 60 mol% of the PEG400 diol substituted withchain-extending agent, 1,4-butanediol, at magni"cation of 800. Thehomogenization speed was 13 500 rpm. The stabilizer was PVP withconcentration of 1%w/w of the aqueous phase.

3.2. Microsphere morphology

The morphology of PU microspheres was investigatedwith SEM. Chain-extending agent, BD, was used to in-crease the ratio of hard to soft segments of the PU chainswhich also increased the viscosity of the prepolymer. Italso increased the density and hardness of the micro-spheres. Fig. 2 shows an SEM picture of a microsphereprepared without BD at homogenization speed of13 500 rpm and 1% w/w PVP stabilizer, at 2660magni"-cation. Figs. 3}5 show SEM pictures of microspheresprepared with 50, 60, and 67% by mol of PEG400 polyolsubstituted with BD at 3650, 800, and 1400magni"ca-tion, respectively, with the same homogenization speedand stabilizer concentration. According to these "gures,microspheres with no BD and 50% BD were porouswhereas microspheres with 60 and 67% BD were non-porous. As the amount of BD increased from zero to50%, the number of pores decreased and the typical porediameter decreased from 950 to 600nm. Typical porediameter was obtained by inspecting visually the dia-meter of at least 20 pores on the surface of the micro-spheres. Due to uncertainty in the resolution of SEM, thereported pore diameters should be considered as relativeand not as absolute values. As the amount of BD in-creased to 60 and 67%, no pores were observed on thesurface of microspheres, as shown in Figs. 4 and 5. Withthe substitution of BD for PEG400, due to increase in theratio of hard to soft segments, micro-viscosity of thereacting polymer chains increased which lowered thedi!usivity of carbon dioxide. Therefore, as evidenced byFigs. 2 and 3, the number and size of the pores decreasedwith increase in the amount of BD. With further increaseof chain-extending agent to 60 and 67%, the PU chains

became sti!er and the di!usion coe$cient decreased suchthat the formation of pores was inhibited. Also as thechains became sti!er, solubility of monomers in thecrosslinked PU chains decreased and partial phase separ-ation and collapse of the microsphere structure tookplace. Figs. 6 and 7 show the microspheres with no BDand 67% BD, respectively, at 7000 magni"cation.According to Fig. 6, when chain-extending agent was notused, PU chains were #exible, solubility of monomers inthe polymer was higher, probability of phase separationwas lower, and the particle surface was smooth. On theother hand, according to Fig. 7, when high concentration

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Fig. 5. SEM micrograph of a microsphere prepared by suspensionpolycondensation with 67 mol% of the PEG400 diol substituted withchain-extending agent, 1,4-butanediol, at magni"cation of 1400. Thehomogenization speed was 13 500 rpm. The stabilizer was PVP withconcentration of 1% w/w of the aqueous phase.

Fig. 6. SEM micrograph showing the surface of a microsphere pre-pared by suspension polycondensation without chain-extending agentat magni"cation of 7000. The homogenization speed was 13 500 rpm.The stabilizer was PVP with concentration of 1% w/w of the aqueousphase.

Fig. 7. SEM micrograph showing the surface of a microsphere pre-pared by suspension polycondensation with 67% by mole of thePEG400 diol substituted with chain-extending agent, 1,4-butanediol, atmagni"cation of 7000. The homogenization speed was 13 500 rpm. Thestabilizer was PVP with concentration of 1% w/w of the aqueous phase.

Fig. 8. Release of diazinon versus time from microspheres prepared bysuspension polycondensation with 50 mole% of the PEG400 diol sub-stituted with chain-extending agent, 1,4-butanediol. The homogeniz-ation speed was 13 500 rpm. The stabilizer was PVP with concentrationof 1% w/w of the aqueous phase. Temperature was kept constant at253C. Release was measured with ultraviolet spectroscopy ata wavelength of 246nm.

of chain-extending agent was used, PU chains weresti!er, solubility of monomers in the polymer was lower,probability of phase separation was higher, and the par-ticle surface was rough. Therefore, the number andsize of the pores formed during the polycondensationreaction depended strongly on the microstructure of PUchains.

3.3. Release behavior

Fig. 8 shows the release of diazinon versus time. Theconcentrations in this "gure are the average of three

measurements. The error bars shown in Fig. 8 are thehighest and lowest values of the measured concentrationsfor each time. About 3% of the active agent was releasedfrom the microspheres initially at zero time due to surfaceabsorption. After the initial burst, release was linear withtime with slope of 0.017 ppm/h. After 480 h, 18% ofdiazinon was released from the microspheres. By assum-ing a constant release of 0.017 ppm/h and extrapolatingto 100% release, these microspheres could release theactive agent for up to 100 days.

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4. Conclusions

Porous polyurethane microspheres were prepared bya two-step suspension polycondensation method with4,4@-methylene bisphenyl isocyanate, polyethylene glycol400, and 1,4-butanediol (BD) as the chain-extendingagent using a homogenizer. As the amount of chain-extending agent increased from zero to 50% by mol, thenumber of pores decreased and the typical pore diameterdecreased from 950 to 600nm. With further increase ofchain-extending agent to 60 and 67%, the microspheresbecame non-porous. Therefore, the porosity of micro-spheres depended on the amount of chain-extendingagent. The release behavior of PU microspheres contain-ing 50% by mol chain-extending agent was investigatedwith diazinon. About 3% of the active agent was releasedfrom the microspheres initially at zero time. After theinitial burst, the release rate was zero order.

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