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Keywords:

  • Miniemulsion;
  • Nanoparticles;
  • Natural polyol;
  • Polymerization;
  • Polyurethane

Abstracts

  1. Top of page
  2. Abstracts
  3. 1 Introduction
  4. 2 Materials and methods
  5. 3 Results and discussion
  6. 4 Conclusions
  7. References

The development of colloidal delivery systems from degradable polyurethanes (PU) has attracted increasing interest as the highly variable synthetic chemistry of PU may be exploited to generate polymers having properties ranging from very soft elastomers to very rigid plastics. In this work, the synthesis of PU nanoparticles using isophorone diisocyanate, castor oil, and poly(ϵ-caprolactone) as monomers and containing high amounts of vegetable oils as açaí oil and crodamol GTCCwas studied. The effect of surfactants Tween 80 and sodium dodecyl sulfate (SDS) and of poly(ethylene glycol) molar masses 400, 600, and 1000 g/mol on the stability, size, and nanoparticle morphology was evaluated. Stable dispersions with sizes between 50–70 nm and 170–250 nm were achieved when, respectively, SDS and Tween 80 were used as surfactant. The polyol type used in the step polymerization in miniemulsion had a major effect on the molar mass of the resulting PU nanoparticles. The effect of poly(ethylene glycol) molar masses was more pronounced when Castor oil and Tween 80 were employed. Increasing the molar mass of PEG increased the average particle size and the molar mass of the PU. Finally, a strong reduction of the molar mass of the PU nanoparticles was observed in degradation assays when those were maintained during 30 days at 37°C and pH 7.0.

Practical applications: Using natural renewable oil as polyol to obtain polyurethane nanoparticles combined with incorporation of other vegetable oil therein showed good results in terms of molar mass and nanoparticle size. The simple and straightforward procedure to prepare polyurethane nanoparticles containing vegetable oils by step polymerization in miniemulsion contributes to improve the application range of these polymers.

Abbreviations
DLS

dynamic light scattering

FTIR

Fourier transform IR spectroscopy

GPC

gel permeation chromatography

IPDI

isophorone diisocyanate

PCL

poly(ϵ-caprolactone)

PEG

poly(ethylene glycol)

PU

polyurethane

SDS

sodium dodecyl sulfate

SEM

scanning electron microscope

TEM

transmission electron microscopy

THF

tetrahydrofuran

Tween 80

polysorbate 80

1 Introduction

  1. Top of page
  2. Abstracts
  3. 1 Introduction
  4. 2 Materials and methods
  5. 3 Results and discussion
  6. 4 Conclusions
  7. References

The development of polyurethanes (PU) has drawn much attention in the last decades due to their excellent physical properties [1-5] ranging from very soft elastomers to very rigid plastics [4, 6-10]. The highly variable synthetic chemistry of PU with several different monomers and oligomers that could be employed in its synthesis helps to explain the vast field of application of PUs, including medical and pharmaceutical [3, 4, 8-10]. Depending on the application, it is necessary to obtain PU particles that can be synthesized using several techniques such as prepolymer method [11], suspension [12], miniemulsion [9, 14, 15], and interfacial polymerization[13]. Miniemulsion polymerization is a straightforward technique to synthesize PU nanoparticles, as it can be performed in just one-step and it is not necessary to use organic solvents. To obtain these nanoparticles, a miniemulsion, that is defined as a colloidal dispersion of relatively stable droplets with a size range from 50 to 500 nm, must be formed prior to polymerization by means of high shear achieved, e.g., by ultrasonication [16, 17]. The kinetic stability of such direct miniemulsion is attained preventing droplet coalescence by the use of a surfactant that stabilizes the particles electrostatically or sterically, and avoiding molecular diffusion degradation, also known as Ostwald ripening, by the addition of a co-stabilizer [18, 19]. After obtaining the miniemulsion, the temperature of the reaction medium is raised and the polymerization proceeds resulting in a stable dispersion of PU nanoparticles in water.

When PU nanoparticles are prepared by direct oil in water miniemulsion polymerization two reaction paths may occur, the first one is the step polymerization of isocyanate with the polyol to form urethane and the second one is the reaction between hydroxyl groups from water and isocyanate to form urea with CO2 release. This second reaction route results in a loss of stoichiometry, as well as to the formation of polymers with a lower molar mass [20, 21]. In order to reduce the reaction with water and urea formation the use of a slowly reacting diisocyanate, as isophorone diisocyanate (IPDI), is advised for the synthesis of PU via direct miniemulsion polymerization [9, 15, 22]. The polymerization mechanism also allows the modification and functionalization of the surface of the nanoparticles during PU synthesis. Poly(ethylene glycol) (PEG) is a hydrophilic polymer that can be attached to the surface of the nanoparticles by the reaction of one of its terminal hydroxyl with the isocyanate group. PEGylation not only provides a higher stability to the polymer particles, but can also prolong the circulatory time of the nanoparticles as PEG chains present low immunogenicity [23, 24].

Poly(ϵ-caprolactone) (PCL) has been attracting interest since PCL is one the most frequently used monomers for the soft segments of degradable PUs, usually enhancing crystallinity and elastomeric mechanical properties [1]. During the degradation the aliphatic ester linkages of the PCL can be hydrolyzed and its degradation product, 6-hydroxy hexanoic acid, is a non-toxic metabolic [1, 25]. Castor oil, extracted from seeds of the castor plant (Ricinuscommunis), is an interesting alternative as polyol for the preparation of PU nanoparticles since it is a common and relatively pure natural TAG that contains hydroxyl groups [26]. In addition, the use of this TAG as monomer in this step polymerization favors the incorporation in PU nanoparticles of high amounts of other natural TAGs with interesting properties for applications in pharmaceutical, cosmetic, and textile industries, as shown in a previous work [9]. Crodamol GTCC is a TAG of saturated medium chain length fatty acids (caprylic and caproic) obtained from coconut oil that is used in pharmaceutical and personal care applications. Açaí (Euterpeoleracea) pulp oil is a TAG rich in mono and PUFA with moistening, skin regeneration, and anti-bacterial properties [27].

This work involves the preparation of degradable PU nanoparticles using isophoronediisocyanate (IPDI) and different polyols: castor oil and poly(ϵ-caprolactone) (PCL) via step polymerization in miniemulsion. Poly(ethylene glycol) of different molar masses (PEG400, PEG600, and PEG1000) was also added to the reaction medium to impart particle stability and improve the bioavailability of the polymeric nanoparticles. In addition, other TAGs, as Crodamol GTCC and açaí oil, were incorporated into the PU nanoparticles. Finally, the reduction of the molar mass of PU nanoparticles was evaluated at 37°C and pH 7.0 during 30 days.

2 Materials and methods

  1. Top of page
  2. Abstracts
  3. 1 Introduction
  4. 2 Materials and methods
  5. 3 Results and discussion
  6. 4 Conclusions
  7. References

2.1 Materials

Isophorone diisocyanate (IPDI, 98%, Mw 222 g/mol) and polycaprolactone with molar mass 530 g/mol (PCL530), as well as poly(ethylene glycol) with nominal molar masses of 400 g/mol (PEG400), 600 g/mol (PEG600), and 1000 g/mol (PEG1000), were purchased from Sigma. Cyclohexane (97%) was purchased from Alfa Aesar. Castor oil (100%, Mw 928 g/mol) was purchased from Linfar, Crodamol GTCC, a fully saturated triglyceride obtained from coconut oil used as hydrophobic agent was purchased from Alfa Aesar, and açaí oil, an unsaturated triglyceride, was donated by Beraca. Surfactants polysorbate 80 (Tween 80) and sodium dodecyl sulfate (SDS) were obtained from Aldrich Chemicals Ltd. Tetrahydrofuran (THF) was used as solvent in the molar mass analyses. The buffer solution was prepared using NaOH (0.1 molar) and potassium dihydrogen phosphate (0.1 molar) purchased from Sigma. The chemicals were used as received without further purification. Figure 1 shows the molecular structure of the vegetable oils with the average composition of the main fatty acid chains that compose the TAGs.

image

Figure 1. Molecular structure of the vegetable oils with the average composition of the main fatty acid chains that compose the TAGs.

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2.2 Step polymerization in miniemulsion

PU nanoparticles were prepared by step polymerization in miniemulsion using IPDI as diisocyanate and varying the polyol type as shown in Table 1. In all reactions the IPDI and polyol (NCO:OH) molar ratio was 1.5. The amount and type of vegetable oil varied in the formulations according to the type of polyol employed (Castor oil or PCL). Crodamol GTCC and açaí oil can be used to solubilize hydrophobic drugs into the polymer particles and the latter also has antimicotic and cicatrization properties [28, 29]. Therefore, PU nanoparticles could act as nanocarriers for applications in dermatology, medicine, etc. [30, 31]. Besides that, these vegetable oils act as co-stabilizer preventing the molecular diffusion degradation, or Ostwald ripening, of the monomer droplets [18, 19].

Table 1. Miniemulsion polymerizations
Monomers (NCO:OH)Aqueous phaseVegetable oil
IPDI:Castor oilWater/Tween 80Açaí oil
IPDI:Castor oilWater/Tween 80/PEG400Açaí oil
IPDI:Castor oilWater/Tween 80/PEG600Açaí oil
IPDI:Castor oilWater/Tween 80/PEG1000Açaí oil
IPDI:PCLWater/SDS/PEG400Crodamol oil
IPDI:PCLWater/SDS/PEG600Crodamol oil
IPDI:PCLWater/SDS/PEG1000Crodamol oil
2.2.1 Reactions with castor oil/PEG

The organic phase was prepared with IPDI and castor oil in a 1.5 molar ratio (NCO:OH), Açaí oil (50 wt% in relation to the monomers) and, when used, 10 wt% of PEG (in relation to monomers). The aqueous phase, corresponding to 80 wt% of the reaction medium, was prepared with DDI water (distilled and deionized) and 20 wt% of surfactant Tween 80 relative to the monomers. Both phases were mixed and kept under magnetic stirring for 5 min. The miniemulsion was prepared by sonication of the previous emulsion in an ice bath for 120 s at 70% amplitude with an ultrasonic probe (Fisher-Scientific – Ultrasonic Dismembrator 500, 400 W). Polymerizations were conducted at constant temperature 70°C during 3 h in a jacketed reactor (50 mL).

2.2.2 Reactions with PCL/PEG

The aqueous phase was prepared with 10 wt% of surfactant SDS relative to the monomers, and 10 wt% PEG in relation to monomers. The organic phase was prepared by dissolving IPDI and PCL530 in a 1.5 molar ratio (NCO:OH), and Crodamol oil (20 wt% in relation to the organic phase) in 2 mL of cyclohexane. In sequence the organic phase was allowed to pre-react under magnetic stirring for 30 min at 40°C. The aqueous phase was then added slowly to the organic phase under magnetic stirring and the miniemulsification and further reaction steps were similar to those described for reactions with castor oil.

2.3 Polymer characterization

Fourier transform IR spectroscopy (FTIR) in the attenuated total reflectance (ATR) mode was used to verify the completion of the step polymerization. The absorption band with peak location at 2272 cm−1, due to N[DOUBLE BOND]C[DOUBLE BOND]O stretching vibration of the isocyanate groups, was used to identify IPDI. The absorption band with peak location between 1680 and 1650 cm−1 of N[BOND]H urea group and absorption band between 1740 and 1700 cm−1 to stretching vibration of C[DOUBLE BOND]O urethane group, were used to identify the PU.

The molar mass of PU nanoparticles was determined by gel permeation chromatography (GPC) using a High Performance Liquid Chromatograph (HPLC, model LC-20A, Shimadzu) equipped with a RID-10A detector in THF at 35°C. GPC analyses were carried out by injecting 20 µL of a 0.5 wt% polymer solution previously filtered through a Teflon-filter with mesh of size 450 nm. A column set was employed consisting of three 300 × 8 mm2 columns in series (GPC-801, GPC-804, and GPC-807). Molar mass distributions and average molar masses were calculated based on polystyrene standards between 580 and 3 800 000 g/mol.

Dynamic light scattering (DLS, Zetasizer Nano S, from Malvern) was used to measure the intensity average diameter of PU nanoparticles. Samples were prepared by latexes dilution (1:10), measurements were performed at 25°C and the values are reported as an average of two measurements. Scanning electron microscopy (SEM – JSM-6510LV-LGS) and transmission electron microscopy (TEM 100 kV – JEM-1011) were used to investigate nanoparticle morphology. For TEM and SEM analyses samples were first diluted in deionized water (1:10). In sequence, for SEM, several drops of the nanoparticle suspension were placed on a cover glass slide, allowed to dry, sputter-coated with gold (Ernest Fullam) for 30 s, and analyzed at 22 kV. For TEM several drops of the diluted nanoparticle suspension were placed on a carbon-coated copper grid, dried overnight and analyzed at 80 kV.

2.4 Degradation experiments

For degradation assays 5 mL PU nanoparticles dispersions were placed into a vial containing 15 mL buffer solution (pH 7.0), and then incubated in an oven at 37°C. Each sample was taken out in a regular interval 3, 7, 10, 15, and 30 days for molar mass analyses and in 3, 7, 10, 15, 20, 25, 30 days for pH and particle size measurements.

3 Results and discussion

  1. Top of page
  2. Abstracts
  3. 1 Introduction
  4. 2 Materials and methods
  5. 3 Results and discussion
  6. 4 Conclusions
  7. References

PU formation in the miniemulsion polymerizations is clearly indicated by FTIR results (Fig. 2). The characteristic carbonyl stretching was observed at 1750–1740 cm−1, indicating the presence of a urethane linkage. The absorption band of urea groups ([BOND]NH) were observed between peak locations at 1600–1640 cm−1. The absence of absorbance at 2270 cm−1 (N[DOUBLE BOND]C[DOUBLE BOND]O stretching vibration) indicates that all isocyanate groups were consumed during the reaction. Presence of ester carbonyl at 1735 cm−1 was noted when PCL was used as polyol. Stretching vibrations were observed at 1330 cm−1 due to castor oil used as polyol. The double bond in the polyol moieties was observed as a medium intensity peak at 1635 cm−1. The PEG absorption band was also confirmed at 1115 cm−1 and 1010 cm−1.

image

Figure 2. Fourier transform IR (FTIR) spectra of PU synthesized by step polymerization in miniemulsion using PCL/PEG400 and castor oil/PEG400 as polyol.

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By the FTIR spectra it was possible to determine the urethane/urea ratio using the respective peak areas (urea at 1600–1640 cm−1 and urethane at 1750–1740 cm−1). Results showed that using PCL/PEG400 as monomers the urethane/urea ratio was 1.6 and using castor oil/PEG400 the urethane/urea ratio was 1.4. This information suggests that during the polymerization the NCO groups reacted preferentially with OH groups from PCL, castor oil, and PEG400 rather than OH from water increasing the urethane content compared to the urea formed through the reaction with water.

3.1 Effect of the molar mass of PEG

The effect of the molar mass of PEG on the molar mass and size of PU nanoparticles prepared by miniemulsion polymerization is presented in Table 2.

Table 2. Molar masses and average particles diameter of PU nanoparticles prepared by miniemulsion polymerization
PolyolSurfactantMa) (g/mol)Dp b)(nm)/PdIb)Mwb) (g/mol)Mnc) (g/mol)
  • a)

    Molar masses of the polyols.

  • b)

    Intensity average particle diameter (Dp) and Polydispersity index (PdI) measured by dynamic light scattering.

  • c)

    Weight (Mw) and number (Mn) average molar masses of the polymers measured by GPC.

Castor oilTween 80928179/0.25389995753
Castor oil/PEG400Tween 80928/400197/0.24011 1786861
Castor oil/PEG600Tween 80928/600206/0.19313 1236412
Castor oil/PEG1000Tween 80928/1000225/0.22117 2977574
PCL/PEG400SDS530/40053/0.28158732514
PCL/PEG600SDS530/60061/0.18364363188
PCL/PEG1000SDS530/100065/0.16768154317

According to molar mass results reported in Table 2 the same tendency was observed for the reactions using PEG400, PEG600, and PEG1000 associated with castor oil or PCL as polyols. It may be observed that increasing PEG molar mass resulted in an increase of the weight average molar mass of PU from 5873 to 6815 g/mol, respectively, for PEG400 and PEG1000 using PCL as polyol and from 11178 to 17297 g/mol, respectively for PEG400 and PEG1000 using castor oil as polyol. These results indicate that increasing the molar mass of PEG leads to an increase of the molar mass of PU. This effect can be attributed to the size of the repeated units of PEG in the PU chains. Due to the presence of two hydroxyl groups at each extremity of the PEG chains, PEG molecules can be incorporated to the PU chain as a polyol. It is also interesting to note that the presence of PEG acting as co-monomer also resulted in an enhancement of the molar mass when compared to the reaction using only castor oil without PEG, as a result of the higher reactivity of the primary hydroxyl of PEG when compared to the secondary hydroxyl of castor oil [32].

Two different surfactant types were used in this work resulting in different particle sizes and polydispersities due the difference in the colloidal stability associated with the surfactant type and molar concentration [9, 13, 16]. As shown in Table 2, when SDS was used as surfactant it was possible to obtain nanoparticles with size up to 65 nm and when Tween 80 was used as surfactant was possible to obtain nanoparticles with size between 179 and 225 nm using castor oil and castor oil/PEG1000 as polyol, respectively. The results are an effect of several factors as the higher molar concentration of SDS, as the molar mass of SDS (288 g/mol) is lower than the molar mass of Tween 80 (1310 g/mol), the higher mobility of SDS molecules in the aqueous phase and the higher efficiency of the electrostatic stability promoted by the anionic SDS when compared to the steric stability provided by Tween 80.

The introduction of PEG also affected Dp and PdI and in general the increase of the molar mass of PEG led to the formation of larger PU nanoparticles. For both polyols, PCL and castor oil, when PEG molar mass was increased from 400 to 1000 g/mol the size of PU nanoparticles increased, from 53 to 65 nm for PCL/PEG and from 197 to 225 nm for castor oil/PEG. The effect of PEG molar mass could be attributed to the steric stability promoted by the PEG chains attached to the particle surface. The higher concentration of PEG chains, the higher stability of the particles and the lower particle size. In all reactions, the same amount in grams of PEG was used, it means that the lower PEG molar mass, the higher the molar concentration of PEG employed. Therefore, it would be expected a higher reaction rate between the hydroxyl of PEG of lower molecular weight and the isocyanate group resulting in a higher surface coverage of the particles.

SEM and TEM images of PU nanoparticles shown in Fig. 3 indicate that PU nanoparticles present a broad particle size distribution, as already observed by the PdI results obtained by DLS (PdI higher than 0.1 indicate a broad distribution).

image

Figure 3. (a) SEM image of PU nanoparticles prepared with PCL/PEG600 and (b) TEM image of PU nanoparticles prepared with castor oil/PEG400 as polyol.

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3.2 Degradation assay

The weight average molar mass of PU nanoparticles during the degradation assays at 37°C and pH 7.0 was determined by GPC and the results are shown in Fig. 4. Molar mass decreased rapidly during the first 15 days and after 30 days the molar mass of PU nanoparticles prepared with castor oil/PEG1000, castor oil/PEG400, and PCL/PEG400 decreased respectively 68% (to 5492 g/mol), 77% (to 2574 g/mol), and 84% (to 923 g/mol) in relation to the initial weight average molar mass values reported in Table 2. This fast decrease of the molar mass, compared with literature results of the degradation of poly(ϵ-caprolactone)–poly(ethylene glycol)–poly(ϵ-caprolactone)-based polyurethane copolymer chips [33], can be attributed to the higher superficial area PU nanoparticles that combined with the hydrophilicity provided by the PEG segments enhances water uptake and, thus, favors hydrolysis. This hypothesis is reinforced by the increase of the size of PU nanoparticles in the beginning of degradation time observed in this work (Fig. 3 upper right inset). Leimann et al. [34] studying the hydrolysis of poly(hydroxybutyrate-co-hydroxyvalerate) nano- and microparticles, also observed a strong decrease of the molar mass of the former, while the latter, due to their much lower superficial area, exhibited only a minor decrease.

image

Figure 4. PU weight average molar mass (Mw) and PU particle size (upper right inset) during the degradation assay at 37°C: castor oil/PEG1000 (▪), castor oil/PEG400 (●), and PCL/PEG400 (▴).

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4 Conclusions

  1. Top of page
  2. Abstracts
  3. 1 Introduction
  4. 2 Materials and methods
  5. 3 Results and discussion
  6. 4 Conclusions
  7. References

Results obtained in this work show that PU nanoparticles with the incorporation of high amounts of vegetable oils (açaí oil and crodamol GTCC) can be efficiently prepared by miniemulsion polymerization using isophorone diisocyanate and different polyols, as castor oil and PCL. Poly(ethylene glycol) of different molar masses (PEG400, PEG600, and PEG1000) was also added to the reaction medium. The molar mass of PU nanoparticles was strongly influenced by the polyol type and the molar mass of poly(ethylene glycol). When PEG molar mass was increased from castor oil/PEG400 to castor oil/PEG1000 and from PCL/PEG400 to PCL/PEG1000 the PU molar mass was enhanced from 11 178 to 17 297 g/mol and from 5873 to 6815 g/mol, respectively. Due to the high superficial area combined with the hydrophilicity provided by the PEG chains, the molar mass of the PU nanoparticles decreased rapidly during degradation assays at 37°C and pH 7.0.

The authors thank the financial support from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) and Laboratório Central de Microscopia Eletrônica (LCME) of Federal University of Santa Catarina for TEM analyses, and Departament of Chemistry of Wayne State University for SEM analyses.

The authors have declared no conflict of interest.

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  3. 1 Introduction
  4. 2 Materials and methods
  5. 3 Results and discussion
  6. 4 Conclusions
  7. References
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