PVP/Clay/Vanadium Oxide Nanocomposites Development and Characterization for Potential Use as Controlled Drug Release Matrix in Diabetes’ Treatment

Research in drug release field, nowadays, focuses on more efficient systems for better release of the drug and wider timespan of action, granting several benefits to the patient’s organism and to the industry. The present work aims on developing a matrix of polymer nanocomposite based on Polyvinylpyrrolidone (PVP), bentonite clay and two different vanadium oxides, via spray drying technique. The goal is to achieve a long and steady release of metformin hydrochloride in future formulations with this drug. Since either the nanocomposites or metformin hydrochloride is highly hydrophilic, it is most suited for a future formulation of tablets. For now, the nanocomposites obtained were characterized through Nuclear Magnetic Resonance (NMR), Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), Thermogravimetric Analysis (TGA) and Fourier Transform Infrared Spectroscopy (FTIR). The SEM and XRD analysis portrayed a very amorphous and homogenized material. TGA and FTIR proved the insertion of the nanoparticles, thus granting to the new material a slightly higher thermal resistance. The NMR analysis, using T1H parameters, is key for determining the formulations would behave better for extending the resistance of the nanocomposite’s matrix with the drug in later dissolution of tablets.


Introduction
Nanostructured materials are part of a class of hybrid materials [1] that have characteristics that differentiate them from the composites due mainly to the greater aspect ratio that the nanometric particles have, providing a greater surface area. Because of this, the proportions of these fillers are smaller than those used in the production of micrometric composites, generating materials with different density and strength than those of the materials commonly used [2] [3] [4]. When one of the phases composing the nanostructured material is a polymer, it is said that this is a polymer nanocomposite, in which the dispersion of the nanoparticle in the polymer matrix is the main factor for determining the final properties of the material [5] [6]. The production of polymeric nanocomposites is possible with almost all types of polymers with the proper methods [1]. Lately, the use of hybrid nanomaterials for drug release has been very intense, due to the characteristics of the new materials and the relative simplicity that these systems can be prepared and employed [7].
For several years, research in the field of drug formulation focused on the search for systems that would make the release of these drugs prolonged after being given. The motives, among others, that have led to the formulation of sustained drug delivery systems are based on the desire to obtain highly water soluble compounds capable of releasing slowly, targeting such compounds to the target tissues or cells, to achieve adequate release rates at given reduce the number of daily administrations and improve reliability while minimizing side effects. As with immediate release formulations, oral administration is the primary form of delivery of sustained release drugs to the body as well. Due to the easy availability, there are better adjustment of the doses administered, better acceptance by patients and cost-efficient production, among other reasons [7] [8] [9] [10] [11]. Among these systems, especially those that do controlled diffusion and dissolution, those of hydrophilic matrices stand out. Some important characteristics of these matrices include the fact that they are of simple formulation, of easy and inexpensive production, besides their excellent in vitro-in vivo correlation. Another important feature and advantage is the possibility of associating high molecular weight hydrophilic drugs with hydrophilic polymer matrices, which are the most widely used controlled release systems in a few years more recently [12] [13] [14] [15]. However, these systems are also subject to problems. One of the major problems of formulating such systems is achieving an adequate rate of drug release so that drug concentrations in the blood remain within the therapeutic range and that this occurs within the desired time. Equally worrying in the case of hydrophilic matrices, when it comes to drugs with low solubility in water, low dissolution is a real problem. In order to overcome the hydrophilic polymer barrier and to make the drug more soluble in the solvent, it is possible to use molecular engineering in the nanocomposite formulation, so that the availability of the drug is greater, compensating for its naturally low solubility [10]  clay is used as a functional excipient in tablets due to its ability to form gels at low concentrations by swelling in water, and it is also used as a binder and disintegrate. For these reasons, bentonite is often employed to produce nanostructured microparticles [24]- [30].
Some metallic oxides are known to be used for treating diabetes, as well as for other diseases like cancer, parasitosis, and so on. Among them, vanadium oxides are the most utilized for treating diabetes; since it presents important characteristics for controlling that condition, such as inhibiting lipolysis process, lowering the glucose levels in the blood stream, and stimulating insulin secretion [15] [31] [32].
To produce such kind of nanostructured microparticles for controlled drug release, the spray-drying technique appears as an interesting alternative to achieve homogeneously dispersed materials. Specially for further production of tablets, which are a more convenient means of administration. With good dosage precision, ease to be manufactured, product stability when compared to liquids and inviolability compared to capsules. Tablets are preferably manufactured by direct compression given their simplicity, continuous nature and financial advan- The spray-drying is a very efficient method for producing powders, granules, agglomerates or crystals from a liquid phase, which may come from solutions,

Materials
For this work, the following reagents and products were used to produce the dif-

PVP Analysis
PVP was received as a donation from UFRJ department of pharmacy. PVP sample and the nanocomposites obtained with it were evaluated through Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, scanning electron microscopy and low field nuclear magnetic resonance.

Preparation of the Nanocomposites
The nanocomposites were prepared via solution using Mili-Q grade purified water as the solvent. The tests for the blends consisted of solutions with final 5 g of the mixture of polyvinylpyrrolidone K-30, sodium bentonite clay, vanadium pentoxide and vanadium (IV) oxide sulphate hydrate. So that the clay and the vanadium oxides were presented in proportions of, respectively, 2%, 0.1%, 0.1% of the final mass intended for these blends. This data will be better detailed in the example of Table 1. It shows how one of the formulations was done, but for the others studied, it was just a matter of adjusting the mass of PVP accordingly, in order to reach final mass of 5 g. Using Erlenmeyers to separately disperse the nanoparticles and polymer in Mili-Q water. These mixtures were stirred for 4 hours in Erlenmeyer with magnetic stirring.
In a more advanced phase of this study, at the same time, in another Erlenmeyer, were dissolved in 100 ml of Mili-Q water, 5 g of metformin hydrochloride. It had also undergone magnetic stirring for 4 hours separately. After this initial time, all the Erlenmeyers were poured into a Beaker under magnetic stirring for another 1 hour, in order to promote a good interaction between the components before undergoing the spray dryer treatment.
The spray-dryer parameters were configured considering the glass transition temperatures and/or melting point of each component of the nanocomposite, so as not to scorch the material, being only enough to evaporate all the solvent. These parameters were: peristaltic pump flow of 0.5 L/h, inlet temperature 125˚C, outlet temperature 89˚C, spray nozzle 1 mm, compressed air flow 30 L/h. After collecting all the powdered material, it proceeded to analysis.

1) Thermogravimetric analysis
The analyses of the samples were made to evaluate the thermal stability of the obtained nanocomposites. They occurred in an inert nitrogen atmosphere with a constant heating rate of 10˚C/min, the heating range was 0˚C to 700˚C, the sample masses were approximately 8 mg. The analysis was obtained with an accuracy of ±2˚C.

2) Fourier transform infrared spectroscopy
Samples behavior was verified in the intermediary portion of infrared spectrum. Aiming to observe the spectrum bands variations due to the dispersion/interaction between clay nanoparticles and the polymeric matrix. Conditions applied were: 20 scannings with 4 cm −1 resolution, throughout all the spectrum from 4000 cm −1 to 400 cm −1 .

3) X-rays diffraction analysis
The nanocomposites samples obtained, as well as the pristine polymer, were evaluated through x-ray diffraction analysis as powdered samples. These analyses were executed with CuKα (α = 1.5418 Å) radiation emission, at room temperature in 30 kV and 15 mA, with 2θ varying from 2 to 60 degrees and scanning speed at 0.05˚/s.

4) Scanning electron microscopy
Analysis of scanning electron microscopy were conducted to study the morphology of the microparticles containing nanocomposites, observing their distribution, uniformity, porosity resulting from the spray-drying technique. The scanning electron microscope was equipped with field emission. Increases of up to 200,000 times were performed with 10 kV of voltage, and the ideal increase in visualization of the particle morphology stabilized around 5000 times. The samples were covered with gold, to allow the analysis of the polymeric materials.

5) NMR characterization in the time domain
NMR was employed to study characteristics such as fluidity or stiffness and how the interaction with the nanoparticles interferes with the polymer. For the determination of mean spin-lattice relaxation times (T 1 H) of the hydrogen nuclei, were used the inversion-recovery pulse sequence (p180˚x -τ -p90˚x) with pulse duration of 90˚ of 7.5 μs, logarithmic time list between the pulses 0.01 -5000 ms, 40 points, 4 scans, 1 s of recycle delay and 2% gain of the receiver.

Thermogravimetric Analysis
Six compositions of the nanocomposites were compared regarding their thermal resistance, and their maximum degradation temperatures had a very similar degradation behavior in all compositions. There was a seventh composition of PVP with V 2 O 5 , but unfortunately that data was lost. Nevertheless, the values were around the average of these portrayed as in Table 2.  Figure 1 shows the thermal degrading events of the nanocomposite of PVP and 2% bentonite clay by thermal gravimetric analysis.
From the TGA curves ( Figure 1) and the data in Table 2, it is possible to conclude that, although the insertion of these nanoparticles in the system makes it slightly more thermally resistant, all the compositions had a very similar thermal behavior. Figure 2 shows the FTIR spectra of the nanocomposites.

Fourier Transform Infrared Spectroscopy
From the analysis of the infrared spectra of all nanocomposite's formulations produced, it was observed that the bands, from 500 to 1750 cm −1 , refer to the polymer and the nanoparticles were detected. The slight disturbances in higher wavelengths refer most likely to residual water, due to hygroscopicity. Corroborating the behavior observed in the TGA in relation to uniformity between the systems. Figure 3 shows the profiles of the nanocomposites diffractograms in comparison to each other.

X-Ray Diffraction Analysis
The analysis of the diffractograms revealed that these materials are predominantly amorphous in all compositions, both for the nanocomposites without drug and for the same with the addition of drug. The different insertion of either sodium bentonite and/or the vanadium oxides into the PVP matrix gave rise to a very low diffraction peak around 2.5˚ in 2θ, varying very little among the nanocomposites' compositions, indicating the formation of mixed nanocomposites containing exfoliated part and intercalated part of clay. In all materials, including the pure polymer, the presence of diffraction peaks occurs around 12.5˚ and 22˚.   That pattern of both exfoliated and intercalated material is most welcome for future compositions that will have the drug inserted, since that morphology is intended for controlled release scenarios. Crystalline materials tend to be those of stronger molecular stability, making it less prone for anchoring of new substances such as an external drug. Figure 4 and Figure 5 show the Scanning Electron Microscopies of PVP in different magnifications and treatments. Figure 6 refers to the PVP system with 2% sodium bentonite.

Scanning Electron Microscopy
The micrographs of Figure 4 and Figure 5 represent PVP in different magnifications and treatments. In these first two SEM images, the pure PVP K-30 is shown, with no treatment beyond the gold coating required for microscopy. It is noted that there is an extreme disorganization of the microparticles, with completely irregular shapes and sizes. The second image ( Figure 5) is a projection of the same field of Figure 4, but with the same magnification practiced in the third image (5000×) (Figure 6). In this way, it is observed that the treatment by     Although all compositions with the vanadium oxides were unable to be scanned, due to technical difficulties of the microscope, luckily enough, there was opportunity to make such of the drug alone, and of it inserted on this nanocomposite. It is stated in the experimental part, as described in Table 1.
Micrographs of the nanocomposite matrix with the drug show that it coated the surface of the microparticles, which is a very interesting and important fact for the study in question. There is a noticeable difference in the relaxation times of for T 1.1 H and T 1.2 H. In  Still, it is also desirable that the peak of relaxation has a wider base, so that it will mean that there are regions of the material that will release controllably the ensnared drug at different and continuous moments through the extended release process. For these cases, the formulations with both vanadium oxides, with or without sodium bentonite, are the most desirable to pursue [43].

Conclusion
Thermogravimetric analysis showed that the nanocomposites in all the formulations presented similar resistance to thermal degradation among the different samples. The infrared spectroscopy, intended to evaluate the insertion of the drug in the nanocomposite chains in later readings, displayed very similar behavior for the samples analyzed. X-ray diffractograms of the nanocomposites revealed that the material is predominantly amorphous, as expected. Scanning electron microscopy showed that, not only after treating the samples via spray-dryer, the PVP microparticles had a more uniform, consistent and defined appearance, especially in the nanocomposites, but also with the insertion of metformin hydrochloride in the system has altered the morphological aspect of materials,