International Journal of Polymer Science

International Journal of Polymer Science / 2016 / Article
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Recent Advances in Cellulose-Based Materials: Synthesis, Characterization, and Their Applications

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Research Article | Open Access

Volume 2016 |Article ID 2634104 |

Claudia Alicia Castillo-Miranda, Ana Beatriz Morales-Cepeda, Carlos Fernando Castro-Guerrero, Homero Salas-Papayanopolos, Hugo Alberto Velasco-Ocejo, Jorge Alberto González-Sánchez, Ulises Paramo-Garcia, Hugo De Alva-Salazar, "Deposition of Ibuprofen Crystals on Hydroxypropyl Cellulose/Polyacrylamide Gel: Experimental and Mathematic Modeling Releasing", International Journal of Polymer Science, vol. 2016, Article ID 2634104, 8 pages, 2016.

Deposition of Ibuprofen Crystals on Hydroxypropyl Cellulose/Polyacrylamide Gel: Experimental and Mathematic Modeling Releasing

Academic Editor: Ming-Guo Ma
Received12 May 2016
Revised28 Aug 2016
Accepted06 Sep 2016
Published11 Oct 2016


The crystallization of nonsteroidal anti-inflammatory drug [2-(4-isobutyl-phenyl) propionic acid] ibuprofen (IBP) on a hydroxypropyl cellulose (HPC) and polyacrylamide (PAAm) gel was studied as well as the release kinetics of the drug. The IBP was crystallized on the gel surface of HPC/PAAm. It had a prismatic shape and the growth was made in an aqueous medium; the crystallinity grade of the gels HPC/PAAm and HPC/PAAm-IBU increased to 68% and to 58%, respectively. The release of IBP is performed by two means: by a non-Fickian diffusion process and by relaxation of the chains of the gel; without regard to temperature and the diffusion media, this correlates with the lower critical solution temperature (LCST) of the proposed gel. This polymer matrix provides an option for releasing nonsteroidal anti-inflammatory drugs in a temperature range of 35–39°C. Korsmeyer and Peppas mathematical model was simulated for data releases, statistically significant at 95% confidence level.

1. Introduction

Gels represent a major group of biomaterials; they are considered intelligent systems, as they have a swelling response depending upon selective environmental conditions such as pH, temperature, ionic strength, and electric and magnetic field [1, 2]. Within the gels we find hydrogels, which are synthesized using water as reacting medium. To achieve selective medium, responsive hydrogels have been synthesized from various homopolymers and copolymers, with recent wider applicability, as monomers combine to provide good mechanical properties, along with other monomers that give gels a hydrophilic material nature, as well as a selective response to environmental conditions.

In recent years, there has been an increased interest in hydrogels, and they have been extensively studied as drug delivery systems that allow the release of the right amount of the active ingredient, at the appropriate time and at specific sites within the body. Previous studies of the HPC/PAAm gels have been performed; the phase behavior has been studied, and it was found that the LCST and UCST (upper critical solution temperature) depend on the amount of HPC. The gel described in this paper has a LCST of 38.3°C and an UCST of 29.1°C [3].

Several authors reported the simulation of drug releases from delivery system using hydroxypropyl methylcellulose (HPMC) [4] to elucidate the mass transport and possibility to predict the effect of design parameters tablets.

This research demonstrates that ibuprofen is crystallized on a HPC/PAAm gel and then released. Crystallization is due to the ability of IBP to form the crystals on diamond shape and to stack on the gel due to the solvent and to the LCST and UCST of the gels. The nonsteroidal anti-inflammatory drug (NSAID) release kinetics was studied in two media, buffer saline and ethanol-water system. The mathematical models were used to find a correlation with experimental data.

2. Experimental

2.1. Materials

In this paper we used hydroxypropyl cellulose (HPC) with average molecular weight (Mw) of ~80,000 g/mol, acrylamide (AAm, purity 97%), methylenebisacrylamide (MBAm, purity 99%), tetramethylethylenediamine (TEMED, purity 99%), ibuprofen (IBP), ammonium persulfate (APS, purity 98%), and divinyl sulfone (DVS, purity 97%), all of which were purchased from Sigma-Aldrich. Deionized (DI) water and phosphate buffered solution (PBS) at pH 7.38 were supplied by Hycel.

2.2. Synthesis of Hydrogels

The synthesis of HPC/PAAm hydrogels was synthesized according to the method of Castro et al. [3] at a ratio of 25/75 wt%. The reaction was carried out in a four-necked flask with a temperature control at °C and an inert nitrogen atmosphere. The solution consisted of 90% deionized water and 10% of reagents in the desired amount to work. At the beginning, 1 g of HPC was diluted in 20 mL of DI water, and the mixture was allowed to stir at room temperature for about 15 hours to achieve a homogeneous solution. Then, the reactor was purged with nitrogen and 3 g of AAm was added. Thus, 0.06 g of APS was dissolved with 0.003 g of MBAm in a vial containing 8 mL of DI water, and in another vial containing the same amount of water 0.06 g of TEMED was dissolved; both vials were stirred for 20 minutes. Once well dissolved, the content of first vial was injected in the reactor, then 0.3 mL of DVS was added, and finally the second vial was injected in the reactor. The polymerization was done for 1 hour at 40°C in an inert atmosphere and with constant stirring at pH 7. After the reaction, the solution was poured in a petri dish, and it was allowed to dry at 40°C in an oven with vacuum for one week. Once dried, the resulting films were washed with DI water in order to remove the nonreacted substances and then they were left to dry again.

2.3. Deposition of IBP

The deposition of IBP on the gel was carried out according to the method of Risbud et al. [5]. The NSAID was loaded into the samples by inserting them into an aqueous solution of the drug at a concentration of 5 mg/mL of IBP at room temperature for 48 hours. After this time, the excess of solution was removed from the gels, then frozen at −10°C for 48 hours, and finally allowed to stand at room temperature for constant weight.

2.4. Drug Release

Once the samples were loaded with the drug, we proceeded to perform the release studies. These studies were done with the dried gel after the incorporation of the NSAID. All of the release experiments were carried out in a heating bath at a controlled temperature (35, 37, and 39°C) with electromagnetic vibrations (80 cycles/min) using as release means PBS at pH 7.4 and ethanol-water solution (50 : 50) at pH 7. The release kinetics was measured by taking samples at different intervals of time and determining the drug concentration by UV spectroscopy at wavelengths of 261 nm for samples released in PBS and 255 nm in samples released from ethanol-water solution using a UV-Vis spectrophotometer, Perkin-Elmer (model Lambda 10).

2.5. Kinetic Study of the Release of IBP

Release profiles (concentration of drug released versus time) were calculated using absorbance data. The nature of NSAID diffusion from the gels was determined to indicate what model it fits.

Mathematical models proposed by Higuchi [6] and Korsmeyer and Peppas [7] are among the most widely used to analyze and describe the mechanism by which the release process occurs. Higuchi proposed a mathematical model widely used to describe the empirical process of the drug delivery, which complies with Fick’s law and is represented as follows:where is the released fraction of IBP in a time interval and is the constant release rate.

The mathematical model proposed by Korsmeyer and Peppas is linear for values equal to . This model attempts to explain release mechanisms where erosion and/or dissolution of the matrix occurs and is a generalized form of Higuchi equation (1) [8], which is expressed aswhere is the release rate constant which incorporates structural and geometric features of the delivery system and is an exponent that indicates the mechanism by which drug release occurs. The exponent value provides information on drug’s kinetics release; so if is equal to 0.5, the drug release occurs through a diffusion phenomenon, Fickian (Higuchi mathematical model) type; if the value of falls between 0.5 and 1, it indicates that the drug release is caused by a non-Fickian mechanism or anomalous diffusion, and when equals 1, the mechanism of drug release depends on the process of relaxation of the polymer chains [1].

Equation (2) described the first 60% of the release behavior of hypothetical distribution. Later, Korsmeyer and Peppas [7] described an empirical equation, for three Fickian diffusional cases. The case II of the Peppas equations for Fickian and anomalous release was used in this study:

2.6. Characterization of Gels

The samples were characterized using Fourier Transform Infrared (FTIR) spectroscopy in a Perkin-Elmer device (model Spectrum One) in attenuated total reflectance (ATR) mode using the frequency range 4000–600 cm−1. Thermal properties were carried out using Differential Scanning Calorimetry (DSC) in a Perkin-Elmer device model Pyris 1. The sample was heated from 0°C to 200°C at a rate of 10°C/min, under a nitrogen atmosphere. Micrographs of the samples were prepared in a Scanning Electronic Microscope (SEM) JEOL model JSM-5900 using a size of sample 1 cm2; the gels were sputtered with a gold layer. The samples were analyzed with energy dispersive X-ray spectroscopy (EDX), using the EDX instrumentation attached to the SEM, with a Bruker Analyzer operating at 133 eV. X-ray diffraction of the samples was performed with a Bruker AXS D8 Advance diffractometer using CuKα radiation; the samples were cut into squares with sides of 0.5 cm.

Degree of crystallinity was calculated according toThe degree of crystallinity of the gels was calculated by Peak Height method. For cellulosic materials, the apparent crystallinity is calculated from the height ratio between the intensity of the crystalline peak (22–24° in 2θ) and the intensity of the noncrystalline material (18° in 2θ).

3. Results and Discussion

3.1. Infrared Spectroscopy

The infrared spectrum of the synthesized xerogel HPC/PAAm is shown in Figure 1(c). At 3338 cm−1, a broad peak attributable to the strong symmetric stretching NH of the PAAm can be seen and the peak at 3182 cm−1 is another one of high intensity corresponding to the stretch OH in the HPC [8]. Moreover, the peak at 2929 cm−1 of asymmetrical stretching of the CH3 groups in HPC is observed as well as the peak at 2867 cm−1 due to the symmetric stretching band of CH2 in the cellulosic derivative [9]. At 1653 cm−1, there is a very strong peak attributed to the stretching of carbonyl bond (C=O) in PAAm, with a little peak at 1602 cm−1 which is not so strong due to the bending NH group of the PAAm. The absorption band at 1450 cm−1 corresponds to the asymmetric CH2 (deformation band of the PAAm and HPC). The next peak is the 1408 cm−1 attributed to CH2 out of plane symmetrical bending. The absorption band at 1271 cm−1 was assigned to a CN vibration of PAAm. At 1123 cm−1, there is a medium peak attributed to COC stretching and crosslinking reactions.

The spectrum of pure IBP and the gel is shown in (a) and (b) in Figure 1. The spectrum (b), in addition to the previously described bands of the gel HPC/PAAm, shows the characteristic peak of the IBP at 1719 cm−1, attributed to the stretching of the carbonyl group C=O (typical of the carboxyl function COOH) [10]. The peaks at 3080 cm−1 and 770–735 cm−1 also indicate that the structure of IBP is present on the sample and that there is an orthosubstitution in the aromatic ring of IBP.

3.2. Thermal Analysis

De Brabander et al. [10] showed that ethyl cellulose compatible with IBP has a glass transition temperature () of about 70 to 80°C, depending on the amount of cellulose derivative. In Figure 2, the results of DSC analysis are shown. In the curve corresponding to IBP, there is a peak around 77°C, which is characteristic of the active ingredient and corresponds to the melting point of IBP [11]. The curve of the gel with IBP has a peak at 75°C; this shows that there is a polymer-drug interaction. When there is single in a composite of two compounds that has its own , then the system is fully miscible [12]. According to the literature, at 75-76°C of temperature, the IBP is prismatic and irregular in shape [13].

3.3. Morphology and Structure

The yellowish appearance in the xerogel (Figure 3(a)) is conferred by PAAm and the swollen gel looks transparent, due to the water incorporated in the matrix.

In Figure 4, SEM micrographs of the sample HPC/PAAm are showed at different magnifications (100x and 500x). The pure gel has a smooth and uniform surface without the presence of agglomerates. The uniformity presented by the film indicates that there is no phase separation between the HPC and PAAm. There are pores of 6 μm in diameter; the formation of channels that facilitate migration of solvent is also present.

Figure 5 corresponds to samples containing pure IBP. The images show a surface with many features, with cuts in different directions and a few shiny white spots that stand out. The sample was compressed and formed a tablet; no crystals are seen.

In Figure 6 are shown SEM micrographs at 100x and 500x of the HPC/PAAm films with IBP incorporated. A surface with rugged relief is seen in the images; this is due to the inclusion of clusters of various shapes and sizes homogeneously distributed throughout the film; these clusters correspond to crystals of IBP. This corroborates the incorporation of the drug and the existence of a drug-polymer interaction, which was also observed by FTIR spectra and DSC calorimetry. The clusters are shaped in some cases as a diamond with a length of 101.8 μm and they grow vertically with 60 μm, assuming that ibuprofen is adhered to the surface in an average area of 9003 μm2 (Figure 6(a)). Like other authors, induction to crystallization temperature is observed near 40°C, where there is presence of growth of the crystals in the shape of circles, squares, or diamonds [14]. The time of formation of the crystals indicates that, after one hour, the crystals have sizes of 100 μm, and they extend from the bottom plane of the gel substrate to the top.

The HPC/PAAm gels are negative thermosensitive; because the quantity of polyacrylamide has an influence on the LCST [1518], PAAm changes the LCST of HPC, a polymer that is known to have this property [19].

Figure 7 shows an EDX analysis of the HPC/PAAm pure polymer. The spectrum shows the presence of carbon, oxygen, sodium, and sulfur; no nitrogen was detected with the EDX. The quantitative analysis gave, in atomic percentages (at.%), C 51.74 at.%, O 38 at.%, S 9.43 at.%, and Na 0.83 at.%. Figure 8 shows an EDX analysis performed on the polymer after absorbing ibuprofen. The analysis detected the presence of nitrogen, but no sodium was detected on the polymer. The composition of the sample with ibuprofen was C 56.92 at.%, O 26.16 at.%, N 16.11 at.%, and S 0.81 at.%. Interestingly, sulfur was detected on both samples; APS and DVS both contain sulfur, so this is the source of S in the samples; the ratio C/S is higher on the sample containing ibuprofen than on the sample of the polymer without the NSAID; this difference is attributed to the presence of IBP that elevated the content of carbon relative to sulfur.

3.4. Drug Release

In the PBS solution, more IBP is released than in the ethanol-water solution, about 1.17 mg/mL at 35°C and 0.58 mg/mL at 39°C in PBS, while in ethanol-water the maximum is 0.45 mg/mL at 39°C and the minimum is 0.23 mg/mL at 37°C. This suggests that the kinetics of crystallization of ibuprofen on the gel surface is preferred in PBS than in an ethanol-water solution, as various authors state that it depends on temperature, and temperatures below 40°C promote supersaturation of ibuprofen [14].

In order to determine the drug release kinetic model describing the dissolution profile, Matlab software was used. The simulation of the drug release of ibuprofen in buffer solution (PBS) and ethanol-water solution (EWS) was done using the mathematic models: zero, first, Higuchi, and Korsmeyer-Peppas. ANOVA results are summarized in Tables 1 and 2 for zero, first, and Higuchi models and those for Korsmeyer-Peppas model for both solvents are in Table 3. The -values are not statistically significant (Tables 2 and 3). The confidence level is low around 80%; this demonstrates that the release of IBU is not “zero” and “first order.” According to the results of the kinetics of IBP, values ​​are lower than 0.5; this corresponds to the ranges described by the Higuchi model, indicating the existence of several simultaneous processes in the diffusion phenomenon of ibuprofen [20].

Zero orderFirst orderHiguchi


Zero orderFirst orderHiguchi

350.69242.331 × 10−240.36791.4299 × 10−60.85791.2814 × 10−22
370.635856.841 × 10−160.39987.4200 × 10−90.806011.083 × 10−24
390.544939.202 × 10−130.3087067.685 × 10−70.71682.060 × 10−19

SolventTemperature (°C)


Ethanol-water350.793161.3162 × 10−18
Ethanol-water370.8238014.9406 × 10−26
Ethanol-water390.7455486.6297 × 10−21

In the first stage of this diffusional process, described by zero, first, and Higuchi, for Fickian diffusion is >0.5.

Cylindrical samples were used, and , for the Korsmeyer-Peppas model. The Korsmeyer-Peppas simulation was correlated by ANOVA results for both solvents of IBU medium. From the calculated , it can be inferred that the parameters and the interactions considered in the experimental design are statistically significant at 95% confidence level. The contribution of Korsmeyer-Peppas simulation is shown in Figure 9; in this figure, the Korsmeyer-Peppas contribution is shown as an isotherm. It can be observed from Table 3 that the parameter is the most significant factor with 37°C for both solvents. The best solvent to release the IBP is the buffer solution. Using the simulation, the release of ibuprofen at the first 50 minutes is clearly demonstrated. The mathematical model of Korsmeyer-Peppas is the best correlation between the minimum diffusional exponents.

If we try to correlate the observations from the SEM micrographs, where IBP clusters are seen, there is a threshold of dispersed percolation, and the critical percolation probability is preferred at 39°C in an ethanol-water solution. The buffer solution releases IBP in smaller quantities without diffusion restriction by polymeric chain relaxation or erosion.

3.5. XRD

Figure 10 shows the powder diffractograms of the pure polymer and of the polymer with IBP. The result for pure HPC/PAAm, shown in Figure 10(a), is very similar to HPC with a molar substitution (MS) of 4 [21], with reflections of 2θ at 7° and 21°; the material of the diffractogram has a low degree of crystallinity, as it shows an amorphous halo diffraction pattern [22], and the sample is noisy, with the peak at 40° being broad and having noise. The diffractogram of the HPC/PAAm gel is shown in Figure 10(b); the intensity of the peak at 21° is increased and the sample looks less amorphous; however, the peaks of IBP are not seen on the diffractogram, and this indicates that there is a reduction in crystallinity or a change in crystal size because there is a higher quantity of polymers [4, 2325].

The crystallization grades of the samples were calculated for the HPC/PAAm gel, having 68% of crystallinity, and the sample HPC/PAAm-IBP has 58% of crystallinity; the results are according to reports in literature [23, 24].

4. Conclusions

IBP was incorporated into HPC/PAAm films and the release kinetics was measured. The incorporation of the NSAID was verified with FTIR. The spectra showed that the IBP peaks are present on the films after the incorporation of the drug; this observation was confirmed with the DSC thermograms, which showed a peak at 75–77°C consistent with the presence of IBP on the polymer. The peak showed by DSC suggested that IBP crystals had a prismatic shape [13] and that there is a polymer-drug interaction. The SEM micrographs showed the presence of IBP crystals on the surface of the polymer, corroborating the results of FTIR and DSC. EDX indicated a change in the ratio C/S in the samples, suggesting the incorporation of a molecule having carbon and no sulfur, as the molecule of ibuprofen. There is a change in the size of the crystals of IBP during the process of incorporation of the NSAID to the polymer, as indicated by XRD.

The HPC/PAAm gel is able to release the IBP that was incorporated in the polymer. The polymer was able to release 1.1 mg/mL of IBP at 35°C in PBS; the kinetics of the drug release is a non-Fickian phenomenon. In this case, the NSAID is released by a diffusion phenomenon and by viscoelastic relaxation of the polymer during the simultaneous swelling process [1].

Competing Interests

The authors declare that there is no conflict of interests regarding the publication of this article.


C. Castillo-Miranda and H. Velasco-Ocejo would like to thank SEP and CONACYT (no. 572436) for the scholarship for graduate studies. The authors are grateful to Mr. D. Pozas Zepeda (University of Colima, Faculty of Science) and R. Morán (National Autonomous University of Mexico, Campus IER Cuernavaca) for the SEM images. The article was published with the support of PRODEP.


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Copyright © 2016 Claudia Alicia Castillo-Miranda et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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