Effect of silica precursor transformation on diclofenac sodium release

Abstract

The present paper describes the preparation of a new type of ternary composite where pure silica gel or polysilsesquioxane was deposited on a polymer carrier loaded with a high dose of diclofenac sodium. The silica species were prepared by in situ gelation of the precursors, tetraethoxysilane (TEOS) or ethyltriethoxysilane (ETEOS), in the presence of an acidic catalyst in the vapour phase. The conducted studies (low temperature nitrogen sorption, XRD, SEM, EDX) reveal that the introduction of drug molecules, as well as silica species, significantly changes the internal structure of the host material. The total porosity of the ternary composites strongly depends on the type of applied silica precursor. Additionally, it is shown that the exposure of the TEOS-saturated or ETEOS-saturated solid dispersion of drug within the polymer to acid vapors is sufficient to cause the irreversible transformation of diclofenac sodium into sodium chloride and a derivative of phenylacetic acid. Furthermore, TEOS prevents the transformation of the drug into its acidic form more effectively than the ETEOS precursor. Finally, the in vitro release of the drug is demonstrated, which clearly indicates that after the embedding both of the silica species, the rate of drug release is modified and the degree of initial drug delivery is successfully diminished. The obtained data are analyzed using different kinetics models to give insight into the possibility of prolonged release of a drug and the probable mechanism of drug release from the investigated samples.

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Introduction

Polymer resins which have a permanent well-developed porous structure even in the dry state arouse great interest in the scientific community as well as in industry. These materials can be used in a variety of medical, chemical or biological applications, such as carriers for drugs, immobilization of enzymes, as supports for catalysts, in nuclear imaging and cell culturing chromatographic separation media, solid phase reagents, adsorbents, ion exchangers, etc.^1–4 Since their use is determined by the presence of functional groups, an enormous amount of effort has been directed towards the incorporation of a variety of functional monomers into the polymer network.^5–8 Moreover, because of the fact that the polymer resins possess a permanent porous structure, they make it possible to additionally modify their properties by the incorporation of different organic or inorganic components to improve, for instance, their catalytic activity or their ability to chelate different heavy metal atoms, amongst other things.^9–14 What is more, modified microspheres can be used for the improved isolation of protein p53 from cell lysates, and in consequence, they open new possibilities for the detection of human cancer biomarkers.¹⁵ The highly developed internal pore structure of the polymer beads also makes it possible to introduce an appropriate amount of drug through the dispersion, usually by solvent evaporation or melt mixing.¹⁶ Alternatively, the drug can be complexed with the counter ions of an ion-exchange resin.¹⁷ Therefore, polymer resins exhibit notable potential in the formulation of an oral multiparticulate controlled drug release dosage.^17,18 Since such a system consists of a multiplicity of small discrete units (whose size is within the range from 0.5 to 1.5 mm), it is obvious that the functionality of the entire dose depends on the subunits exhibiting the desired characteristics.¹⁹ Thus, an effective approach to control drug release from such a polymer carrier is to control the infiltration of the release medium; this in turn, may be controlled by the selection of the composition and the porosity of the polymer matrix. On the other hand, the porous polymer beads may be simultaneously regarded as the carrier and as a micro-reaction system, ensuring the specific microenvironment where different chemical reactions take place.¹⁰ As was previously presented, the in situ gelling of a silica precursor under mild conditions within polymer beads loaded with a drug causes the latter to become encapsulated and separated from the external environment by the characteristic type of the silica gel-barrier. Consequently, the diffusion and desorption of the drug are significantly limited, especially at the beginning of the release.^20,21 Thus, polymer-supported composites are promising systems for modified drug release and exhibit notable potential in the formulation of a multiparticulate modified drug release dosage.

In this study, a novel system based on an acrylic porous polymer support containing a large amount of drug and silica species dispersed into the polymer matrix has been developed. The polymeric support selected for this study is Amberlite XAD7HP, a commercially available, food-grade macroporous resin which possesses a well-developed permanently porous structure and is of moderately polar character.^22,23 The drug chosen for this study is diclofenac sodium (DS), a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties which reduces pain in the long-term treatment of degenerative diseases.²⁴ TEOS (tetraethoxysilane) and ETEOS (ethyltriethoxysilane) were chosen as silica precursors. It was assumed that TEOS, a precursor of SiO₂, might be applicable for the effective encapsulation of the embedded drug. Additionally, ETEOS, a precursor of polyethylsilsesquioxane (which is composed of a repeat unit C₂H₅–SiO_1.5, where a single silicon atom is attached to C₂H₅– unit in a network of up to three siloxane bonds^25–27), was considered as an encapsulating agent for comparative purposes. The silica species were fabricated using a sol–gel method by transformation of the silica precursors introduced into the polymeric matrix with the embedded drug. To initiate the transformation of both of the silica precursors, a vapor mixture of water and hydrochloric acid of the desired composition was used at ambient temperature. These unusual and mild conditions of synthesis make it possible to embed nanoparticles with specific structure parameters.^21,28 Here, it should be emphasized that the transformation of ETEOS in the presence of vapours of water and acid catalyst is reported for the first time.

The aim of this study is to present a sol–gel method involving the presence of catalyst vapours, in the field of development of ternary polymer–drug–silica composites which might possibly be used in modified release systems. Thus, one of the major issues of our approach is to identify the factors influencing the drug release from these nanocomposites. Therefore, the project provides not only the first results pertaining to the structural differences of subunits, i.e. polymer carrier with embedded drug as well as polymer–drug–silica particles, but it also presents the impact of the applied vapor mixture of water and hydrochloric acid on the embedded diclofenac sodium. Furthermore, the study involves the in vitro examination of the drug release rate from these solid forms in order to determine the kinetic model and the mechanism of drug release. At this point, it should be mentioned that there are no studies on formulations consisting of polymer–drug–silica subunits where pure silica gel and polysilsesquioxane are deposited from the vapor phase on the polymer carrier with a high dose of drug.

Experimental

Materials

Diclofenac sodium (sodium-2-[(2,6-dichloro-phenyl)amino]phenylacetate, DS) was generously supplied by Caesar and Loretz, GmbH, Hilden, Germany. Amberlite XAD7HP, a food-grade macroporous resin, was supplied by ROHM & HAAS (now Dow Chemical Co.) in the form of porous beads (fraction with diameter range from 0.57 to 0.71 mm) and used as a polymeric drug carrier. Prior to their use, the XAD7HP beads were rinsed with distilled water, according to the manufacturer’s suggestion, and dried at 80 °C. Tetraethoxysilane (TEOS, 98%) and ethyltriethoxysilane (ETEOS, 98%), serving as the silica sources, were supplied by Sigma-Aldrich and used as received.

Preparation of diclofenac sodium-loaded composites

The scheme of the synthesis of the ternary composites is depicted in Fig. 1. Initially, dry XAD7HP beads were wetted, drop by drop, with an alcoholic solution of diclofenac sodium, which was freshly prepared by dissolving diclofenac sodium in anhydrous ethanol (50 mg ml⁻¹). The diclofenac sodium solution was fully absorbed during the process of polymer bead swelling. Next, the drug-loaded beads were left for 3 h at room temperature. Following the evaporation of the solvent at 55 °C for 12 h, the procedure of drug loading was repeated 3 times, to achieve a high drug content within the polymer carrier. The final solid dispersion of drug within the XAD7HP beads was labeled as P-DS. Next, the P-DS beads were saturated with TEOS (1.7 g per 1 g P-DS) or ETEOS (1.3 g per 1 g P-DS), respectively. The amount of both precursors was adjusted in such a way that the P-DS beads would stick to each other, whilst at the same time preserving a loosely packed structure.²⁹ Afterwards, the P-DS beads saturated with TEOS or ETEOS were exposed to the vapors of a 2 M HCl solution (10 cm³ per 1 g of P-DS saturated with precursor) at autogenous pressure and room temperature for 1 day to initiate silica precursor hydrolysis and condensation. The solid products were dried at 55 °C for 18 h and were labeled as P-DS-T and P-DS-ET, respectively. This ‘vapour’ method prevents drug loss during transformation of the silica precursors, since the processing doesn’t take place in aqueous solution. The theoretical amount of the introduced drug was calculated on the basis of the mass balance before and after the loading of the diclofenac sodium and silica species. Moreover, it was assumed that after transformation of the precursors, the SiO₂ and C₂H₅–SiO_1.5 are deposited within the P-DS-T and P-DS-ET, respectively. The theoretical drug loading efficiency ranges from 203 mg g⁻¹ for P-DS to 136 mg g⁻¹ for P-DS-T and 132 mg g⁻¹ for P-DS-ET, taking into account the mass of the total carrier system. However, the actual content of diclofenac sodium ranges from 203 mg g⁻¹ for P-DS to 63 mg g⁻¹ for P-DS-T and 38 mg g⁻¹ for P-DS-ET, taking into account the mass of the total carrier system. Detailed information concerning analysis of actual diclofenac sodium content in the investigated samples, as well as drug release kinetics, are given in the ESI.†

Fig. 1 Scheme for the synthesis of the ternary composites.

Release studies

The dissolution test was carried out in a Ph Eur. Apparatus 1 (Erweka, Germany), called a basket apparatus,³⁰ to avoid any possibility for capsule floating that could lead to extra measures needing to be taken. For the test, 900 ml of phosphate buffer at pH 6.8 maintained at 37 ± 0.5 °C was used as a dissolution medium. Each gelatin capsule, filled with a 200 mg portion of the investigated beads, was placed in one of the six vessels of the basket apparatus. The stirrer was turned on to 100 rpm rotation speed. At appropriate intervals, 2 ml of solution was collected and an equivalent amount of phosphate buffer at pH 6.8 (2 ml) was added to the vessel with the dissolution medium. Following the dilution, each of the drawn solutions was analyzed spectrophotometrically at 276 nm (Omega UV-VIS, Thermo Scientific, England). The amount of the released substance was calculated by reference to a Beer’s plot based on a calibration curve. Statistical analysis was carried out using GraphPad Prism Software Version 5.0. The data obtained were subjected to statistical analysis using one-way ANOVA and a “p” value of <0.05 was considered as statistically significant. Additionally, disintegration tests of the gelatin capsules have been conducted using a disintegration apparatus (PTZ-Auto 02, Pharma Test, Hainburg, Germany). The procedure was followed as in USP37-NF32 regarding “〈701〉 Disintegration”.³¹ On the basis of this experiment, it may be concluded that gelatin capsules filled with the investigated samples disintegrate within the first 1.5 minutes. Hence, it may be assumed that the release profiles of diclofenac sodium are not heavily affected by the gelatin capsules.

Characterisation

The investigated materials were viewed in a Quanta scanning electron microscope (SEM; FEI Quanta 3D FEG), equipped with energy dispersive X-ray spectrometer (EDX), working at 10 kV. The parameters characterizing the porosity (the specific surface area, S_BET, the total pore volume, V_p, and the pore size, D_p) of the samples (XAD7HP, P-DS, P-DS-T and P-DS-ET) were determined by the measurements of nitrogen adsorption–desorption at −196 °C, using a volumetric adsorption analyzer, ASAP 2420 V2.09 (Micromeritics, Norcross, GA, USA). The pore size distributions (PSDs) were determined from the desorption branch of the nitrogen isotherm using the BJH procedure.³² The structural differences between the investigated materials were determined using X-ray powder diffraction. The XRD analysis was performed on powdered samples using a high-power X-ray diffractometer (Empyrean, PANalytical). The diffraction patterns were recorded in the 2θ range of 6° to 60° at room temperature using Cu Kα radiation at a scanning speed of 1 min⁻¹ and a step of 0.02°.

Results and discussion

On the basis of the previous results, it might be expected that the interior of the investigated sample beads possesses a complex character since in their synthesis the porous XAD7HP was employed as a polymer matrix.^20,21,29,33 Thus, SEM micrographs were collected to reveal possible changes during processing of the polymer matrix (Fig. 2). Amberlite XAD7HP possesses a permanent porous structure in the dry state and can be considered as a system of continuous free volumes of different size (ESI SI1a†). As a consequence, a permanent network of pores gives easy access of solvent molecules into the interior of the beads, which fill the pore volume as well as swell the polymer matrix.

Fig. 2 SEM micrographs of representative beads of the pure polymer Amberlite XAD7HP (a), P-DS (b) and ternary composites P-DS-T (c) and P-DS-ET (d) (see other magnifications in the ESI†).

Recently, the swelling of XAD7HP, which occurs rapidly, was presented as an easy and efficient method to introduce inorganic nanoparticles and inorganic oxides,^11,29,34 ionic liquids³⁵ and also drug molecules^3,20,21 into the polymer interior. There, it was shown that this polymer matrix is able to undergo many cycles of swelling and deswelling without mechanical damage,^11,21 which is highly desired from the view of their possible technological applications. Thus, the immersion of the resins in the alcoholic diclofenac sodium solution and drying were repeated until the matrix reached a large amount of drug loading.

This procedure does not cause mechanical damage to the polymer beads, but only leads to the increase of their size (Fig. 2b). It can be assumed that, following the introduction of drug solution and the removal of ethanol, the internal pore network deforms and rearranges, but preserves the three-dimensional structure. Although the drug precipitation during the evaporation of the solvent is considered to take place within the interior of the polymer beads,³⁶ the drug species are indistinguishable from the polymer in the SEM images (ESI SI1b†). It is understood that after the introduction of the drug, as well as in situ transformation of the silica precursors within the polymer carrier, the porosity of the samples changes and affects the release of the embedded active substance. Hence, the pore structure of the pure polymer, drug-loaded polymer and ternary composites in the dry state was investigated using low-temperature nitrogen sorption porosimetry (Fig. 3).

Fig. 3 Nitrogen adsorption (solid symbols) and desorption (open symbols) isotherms at −196 °C (a) and pore size distributions (b) of the investigated samples.

For the pure matrix (Fig. 3a), the isotherms are of type IV, which is typical for a mesoporous structure. An up-step appearing in the desorption branch at p/p₀ of 0.40–0.50 along with another one, a steep rise in the N₂ adsorption isotherm at high relative pressures ranging from 0.70 to 0.80, indicate the presence of two mesopore groups. Indeed, they are visible in the corresponding PSD curve (Fig. 3b).

Nevertheless, at this point, it should be emphasized that the adsorption and desorption isotherms differ in shape; thus, it may be assumed that the step on the desorption isotherm is associated with the entrance size (or neck size) of the pores because their size controls the N₂ desorption process. The distribution of the smaller pores (pore openings) is relatively narrow with the peak centered at 3.8 nm, while the group of larger ones, with the peak of the PSD centered at 9.4 nm, exhibits a broader size distribution. After the introduction of diclofenac sodium into the polymer matrix, the shape of the N₂ isotherms changes and displays a IV type isotherm and a type H3 hysteresis loop. Moreover, the corresponding PSD curves, calculated from the desorption branch of the isotherm (Fig. 3b), exhibit a broad distribution with the peak centered at 33.0 nm. These changes prove that the internal structure of the polymer support is significantly rearranged after the precipitation of the drug. The significant lowering of the specific surface area suggests the successful introduction of drug molecules into the XAD7HP beads (Table 1). On the other hand, the introduction of the drug strongly increases the pore volume of the P-DS. However, this is reasonable if the likely mechanism of the swelling of porous polymer is taken into account and irreversible swelling is assumed.

Table 1 The parameters characterizing the porosity of the samples obtained from the low temperature N₂ sorption^a

Sample	SBET (m^2 g^−1)	Vp (cm^3 g^−1)	Dp (nm)
a SBET, the specific surface area; Vp, the total pore volume; Dp, the pore diameter at the peak of the PSD derived from the desorption branch of the N2 isotherm.
XAD7HP	458	0.56	3.8; 9.4
P-DS	208	0.72	33.0
P-DS-T	147	0.54	32.5
P-DS-ET	69	0.31	36.4

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The ternary composites have been prepared by the introduction of the silica or polyethylsilsesquioxane species into the solid dispersion of diclofenac sodium within the polymer. It is expected that the introduction of particles of different chemical character will significantly change the internal structure of the P-DS, including porosity, as well influencing the release profiles of the drug molecules.

Although the P-DS beads contain a high dosage of drug, they still exhibit the ability to swell in applied precursors. The exposure of the P-DS saturated with TEOS or ETEOS to the catalyst vapours results in the transformation of the precursors and, in consequence, the silica gel or polyethylsilsesquioxane are produced in situ within beads of the P-DS. The average size of the ternary composite beads decreases in comparison to P-DS (Fig. 2c and d). This is associated with the development of silica species within the P-DS beads. The silica network shrinks during condensation and, in consequence, it causes shrinkage of the whole composite bead. The SEM micrographs in ESI SI1c and SI1d† reveal that the modification of the P-DS containing a high dosage of drug through the introduction of the solid nanoparticles only slightly influences its internal structure. Thus, it may be assumed that species which are formed as a result of hydrolysis and condensation of the silica precursors are indistinguishable from the polymer species in the SEM images. Thus, the SEM images give only a general view of the internal topography of the investigated samples.

The shape of the nitrogen adsorption–desorption isotherms of both ternary composites is similar to the shape of the P-DS isotherms (Fig. 3a). However, the N₂ adsorption decreases in comparison to P-DS. Furthermore, the presence of silica and polyethylsilsesquioxane species marginally influences the size of the mesopores. After the deposition of silica nanoparticles, the specific surface area, S_BET, of the resulting P-DS-T decreases by about 26%, while the pore volume decreases to 75% compared to the P-DS solid dispersion. The decrease in both of the parameter values characterizing porosity is more pronounced in the case of P-DS-ET (Table 1). The decrease in the specific surface area and the pore volume of P-DS-T and P-DS-ET results from the formation of the additional species within the P-DS beads, which most probably causes clogging and spatial restrictions inside their pore network.

A possible explanation of the differences between the porosity of the ternary composites should be sought in the properties of materials produced through sol–gel processing of tetraethoxysilane and ethyltriethoxysilane in the presence of vapours of water and a catalyst. Numerous studies dealing with the sol–gel process of alkoxide precursors reveal that it is a highly complex process and any modification of the process conditions (i.e. silica gel precursor, organic additives, pH, temperature, precursor-to-solvent ratio, aging environment and time) makes it possible to achieve a wide range of materials of different structure and morphology.^37–39 However, when it takes place in the porous polymer support in the presence of vapours of water and catalyst, the mechanism of the tetraethoxysilane and ethyltriethoxysilane gelation has not been satisfactorily recognized, even though the synthesis of composite materials under such conditions has been previously presented.^21,28 On the other hand, the possibility of the synthesis of highly ordered mesoporous silica films in the presence of vapors, both the catalyst and TEOS or only the vapor of TEOS, has also been previously reported.^40,41 Therefore, it may be assumed that the gelation of the precursors introduced into P-DS, when the acidic catalyst is in the vapour phase, is a two-step process, similarly to their gelation in the liquid phase. Furthermore, it is likely that the gelation of TEOS under the applied conditions also results in the formation of silica gel whose external surface is highly developed. A small concentration of Q⁴ sites suggests its high hydroxylation.^21,28 As a consequence, it may be assumed that the condensation of silica species in P-DS-T is not complete, or the silica gel can hold a lot of water, making a dense pore clogging mass. The formation of such pore filling in the solid dispersion prevents N₂ adsorption, which manifests itself in the drop in S_BET.

A much more difficult task is to describe the nature of the material obtained as a result of ethyltriethoxysilane gelation in the presence of HCl vapour. Ideally, the ETEOS would polymerize to a highly cross-linked polymer network, analogous to a silica gel network. Such an insoluble hybrid polymer in the form of a membrane or coating might potentially be considered as an element of the polymer–drug system which controls the release of the drug. However, it is known that cyclization reactions play an important role in the silsesquioxane polymerization process, giving rise to soluble crystalline polyhedral oligomers, amorphous oligomers and polymers.⁴²

The further investigation of the nature of this hybrid material is not only highly interesting but also essential. This, however, remains out of the main scope of this work, and will be discussed elsewhere. Nevertheless, the significant decrease in the parameters characterizing the porosity of P-DS-ET (Table 1) proves that the employed strategy yields an amorphous material which clogs pores and effectively prevents N₂ adsorption, probably due to the incomplete polymerization of monomers under the applied conditions. This problem may be solved by the longer exposure of TEOS-saturated or ETEOS-saturated drug-loaded polymer beads to the water and hydrochloric acid vapours.

It may be expected that the acidic environment of the synthesis of the ternary composites will cause the transformation of the diclofenac sodium into sodium chloride and the acid form of diclofenac. Indeed, detailed examination of the SEM micrographs shows the presence of crystals on the external surface of certain P-DS-T and P-DS-ET beads. The presented SEM image (ESI SI2a†), along with the qualitative chemical analysis of the selected beads given in ESI SI2b,† indicate the presence of Na and Cl atoms (resulting from the presence of sodium chloride) at the surface of certain P-DS-T and P-DS-ET beads. Silicon and oxygen atoms confirm the presence of silica gel within the composites. Accordingly, the difference between the theoretical and actual content of diclofenac sodium in P-DS, P-DS-T and P-DS-ET was calculated. The theoretical amount of the introduced diclofenac sodium was calculated on the basis of the mass balance before and after loading of the polymer support by the diclofenac sodium and silica species.

The actual content of the diclofenac sodium was determined by the leaching of the drug from the powdered samples into phosphate buffer at pH 6.8 for 2 h. On the basis of Fig. 4, it may be concluded that the P-DS-T and P-DS-ET composites differ significantly with regard to the actual content of diclofenac sodium. Therefore, it may be assumed that exposure of the TEOS-saturated or ETEOS-saturated P-DS beads to acid vapors is sufficient to cause an irreversible transformation of diclofenac sodium into sodium chloride and a derivative of phenylacetic acid, which is poorly soluble in the used buffer solution.

Fig. 4 Content of molecular form of the drug embedded in the investigated samples – the diclofenac sodium (grey) and the acidic form of diclofenac (dotted).

Such a transformation of the drug is highly probable, since it is a salt of a weak organic acid which performs the function of a base in the reaction with vapors of the strong acid. These conclusions are consistent with previous studies.⁴³

Although the intramolecular cyclization of diclofenac sodium under acidic conditions was postulated,⁴⁴ the succeeding studies conducted by Frutos et al. did not confirm this hypothesis, and the lactamic structure of the compound hasn’t been verified.⁴³ Similarly to our findings, it was shown that diclofenac sodium undergoes chemical structure modification once it has been treated with an acidic solution. As a consequence, the substance loses Na⁺ in acidic solutions and gives rise to a compound with rather low water solubility.⁴³ From the analysis of Fig. 3 it may also be concluded that the TEOS prevents the transformation of the drug into its acidic form more effectively than the ETEOS precursor. Hence, the content of diclofenac sodium within the P-DS-T composite is about 5 mg higher than in P-DS-ET, which represents about 17% of the total drug content. Also, from the analysis of the XRD patterns (Fig. 5c and d), it may be concluded that sodium chloride exists in both of the ternary composites. Sharp diffraction peaks at 2θ = 31.7°, 45.4° and 56.4°, indicating the presence of NaCl salt, are of lower intensity for P-DS-T. This suggests a smaller quantity of NaCl and higher content of diclofenac in the form of its sodium salt in comparison with the P-DS-ET sample.

Fig. 5 XRD patterns of XAD7HP (a), P-DS (b), P-DS-ET (c) and P-DS-T (d).

Additionally, the X-ray diffraction analysis gives an insight into the macrostructure of the investigated materials, because it makes it possible to examine the long-range order, produced as a consequence of very short-range interactions. Therefore, the XRD analysis reveals the effect of the applied processing of XAD7HP on its internal structure (Fig. 5). The broad peaks centered at about 2θ = 7°, 14° and 41° indicate the amorphous nature of the XAD7HP polymer. Similar results were also demonstrated for pure PMMA polymer.⁴⁵ On the basis of the XRD pattern for P-DS, it may be said that the precipitation of diclofenac sodium significantly rearranges the internal structure of the polymer. Moreover, peaks in the XRD pattern for P-DS, which, however, are barely visible, may attest to the crystalline nature of the embedded drug.

Nevertheless, their intensity is low, hence it may be expected that the drug exists partially as an amorphous nanodispersion within the polymer network, whereas drug crystals occupy the pore interior. In situ formation of the species from the TEOS and ETEOS precursors within the P-DS beads causes further changes in the internal structure. However, as may be assumed on the basis of the XRD analysis, during in situ polymerization of the ETEOS monomer, the internal structure of P-DS surely undergoes an internal rearrangement, which, however, only slightly influences the XRD spectrum of P-DS-ET. On the contrary, the resulting structure of the P-DS-ET composite differs significantly from the pure XAD7HP. However, the introduction of silica gel results in significant modification and rearrangement within the P-DS beads, the final structure converges to that of XAD7HP and, in consequence, the broad peaks which seem to have origins in the polymer matrix are clearly visible. In the case of both ternary composites, the appearance of the additional very broad peak at about 22° is associated with the presence of the amorphous silica species within the interior of the beads.⁴⁶

Taking into consideration the release profiles of diclofenac sodium in comparison to the total mass of drug introduced into the investigated samples (Fig. 6), it may be noticed that a maximum of ∼96% of diclofenac sodium is released from P-DS, whereas the efficiency of the drug desorption from the ternary P-DS-T and P-DS-ET composites is much lower and after 24 hours reaches 44.2 and 32%, respectively. The analysis of the desorption curves for P-DS-T and P-DS-ET, and especially their segments after 7 h, which are rising, indicate that the release of the drug is not complete. Thus, it may be said that the remaining portion of the drug in P-DS-T and P-DS-ET, which did not desorb within 24 hours in the phosphate buffer at pH 6.8, is in the poorly soluble acidic form of diclofenac. It is reasonable to assume that with the increase of the ionic strength of the release medium, the solubility of the acidic form of diclofenac also increases. Therefore, the amount of the released drug is slightly higher (only about 3%) than the amount of diclofenac sodium determined by its leaching within 2 h (the procedure is given in the Experimental part).

Fig. 6 The release profiles of drug in comparison with the total mass of drug introduced into the investigated samples for pure DS (▲), P-DS (●), P-DS-T (♦) and P-DS-ET (■). In the figure, the lines are added for convenience.

The observed tendency may continue up to the point of reaching a saturated solution by the used release medium. Therefore, the presented ternary system might potentially be considered as a system which ensures drug release over a prolonged period of time.

Diclofenac sodium release was further carried out in order to better understand the influence of silica and polysilsesquioxane species on drug transport. A comparison of the diclofenac sodium release profiles for the investigated composites is provided in Fig. 7. Moreover, the obtained drug release data were analyzed by zero order, first order, Higuchi and Hixson–Crowell models so as to determine the possibility of prolonged drug release and the Korsmeyer–Peppas model in order to explain the mechanism of drug release from the samples.

Fig. 7 Diclofenac sodium release kinetics from P-DS (●) P-DS-T (♦) and P-DS-ET (■) samples. Inset, the DS release within the first hour. In the figure, the lines are provided for convenience.

The release rate constants calculated from the slope of the appropriate plots for different models and the coefficients of determination (R²) are collected in Table S1 (see ESI†). The most suitable kinetic models for describing the release mechanism of the drug (i.e. these presenting the best fitting model, taking into account the value of the coefficient of determination) from the investigated materials are discussed below.

As follows from the desorption curves, the pure diclofenac sodium is completely released within the first 30 minutes. If the polymer support alone is used to control the release of the introduced drug, 43% of the drug is released in the first 15 minutes, with 91% released in 7 h. The most probable explanation for the observed initial fast desorption of the soluble drug is the good ability of the XAD7HP pore network to swell and to expand in the buffer solution at the temperature of 37 °C. As a consequence, the drug molecules are easily released, which points to the limitation of the applicability of XAD7HP as a single polymer carrier for the system of extended release of high doses of soluble drugs. A similar effect of fast initial desorption was also previously observed for this polymer carrier.^20,21 The in vitro release profiles (Fig. 7) clearly demonstrate that the rate of diclofenac sodium release is significantly modified by the embedding of the silica species into P-DS. First, in both silica-loaded systems (P-DS-T and P-DS-ET), the degree of burst release is successfully diminished (Fig. 7, the inset). The change in the initial drug desorption for silica-enriched systems can be interpreted in terms of the restricted swelling of such composite carriers and thus the limited inflow of the release medium into their interior. This unusual behavior of the system appears because the silica species may be regarded as a reinforcing agent which prevents the easy expansion of the carrier in the buffer solution.

From the analysis of the parameters collected in Table S1,† it follows that the release profile of diclofenac sodium from P-DS may be satisfactorily explained by the Korsmeyer model (the so-called power law). Also, the P-DS-T sample presents an acceptable fitting to the power law. Nonetheless, the derivation of the power law for slab geometry assumes constant diffusivity and constant dimensions of the device during drug release,⁴⁷ whereas in the case of the investigated P-DS and P-DS-T composites, their swelling to some extent in the buffer solution should be considered. Moreover, the value of release exponent ‘n’ (indicative of the mechanism of drug release) lies below 0.43, which is beyond the limits of the power law for spheres. A similar value of ‘n’ was reported for matrices made of agar and polyacrylamide-grafted agar with enclosed 5-amino salicylic acid (a drug used in the treatment of inflammatory colitis).⁴⁸ The low value of the exponent ‘n’ may indicate a diffusion-controlled drug release mechanism from the P-DS sample. Moreover, an apparent square root of time release kinetics can result from the superposition of various effects, and is not necessarily based on a simple drug diffusion-control.⁴⁷ Thus, it should be emphasized that the power law gives only limited insight into the exact release mechanism of the drug, since several simultaneous processes take place according to this model. On the other hand, the higher value of the exponent ‘n’ for P-DS-T, compared to P-DS, may indicate that the release seemed to be predominantly diffusion-controlled. This may be associated with the silica nanoparticles which restrict the swelling of the P-DS-T system in the buffer solution. The release profile of diclofenac sodium from the P-DS-T composite may be also explained by first order model, where the determination coefficient (R²) equals 0.94. This suggests that the rate of release of the diclofenac sodium depends on the concentration of drug in the sample, as well as the fact that the dissolution phenomena of a solid particle in a liquid media involves a surface action.⁴⁹ This model is used to explain the drug release following its dissolution in pharmaceutical dosage forms, such as those containing water-soluble drugs in porous matrices.⁵⁰ Therefore, it may be expected that the change in the rate of diclofenac sodium release rate for P-DS-T can be interpreted in terms of the chemical character of the composite network. It may be assumed that the incorporation of the silica nanoparticles into P-DS causes the changes in the chemical nature of the carrier, and, as a consequence, the release rate strongly depends on the specific interaction between the diclofenac sodium molecules and the components of the P-DS-T composite. The influence of the silica gel introduction on the drug release rate of the polymer–silica composite has already been studied and presented in the literature.^51–53 It has been shown that the presence of silica nanoparticles reduces the rate of drug release from XAD7HP-based composites, and this reduction is related to the conditions of the transformation of the silica source.^21,53

For the P-DS-ET sample, the mechanism of drug release cannot be predicted unambiguously, since the applied kinetic models do not present an acceptable fitting (R² < 0.9). However, from Table S1,† it follows that a high value of R² occurs in the case of the power law and the Higuchi model. In the power law, the value of the exponent ‘n’ providing the type of release mechanism is 0.482, which indicates anomalous behaviour or non-Fickian transport, indicating a coupling of the diffusion and erosion mechanisms. The Higuchi model describes drug release as a diffusion process based on Fick’s law, which depends on the square root of time. This relation can be used to describe the drug dissolution from several types of modified release pharmaceutical dosage forms.⁴⁹ An important advantage of the classical Higuchi equation is its simplicity; therefore, it is often used to analyze experimental drug release data. However, the assumptions of the Higuchi derivation should carefully be taken into account and the information obtained should be viewed with caution.^47,49 Thus, taking into account the parameters for the P-DS-ET composite (Table S1†), only a rough idea of the underlying release mechanism may be assumed. The presence of the ethyl groups attached to the silicon atoms in the polysilsesquioxane species decreases the hydrophobicity of the system to a lesser extent than the silica nanoparticles in P-DS-T. As a result, the specific interactions of diclofenac sodium and silica are weaker; thus, they affect the rate of the drug desorption to a lesser extent. Moreover, it is probable that polysilsesquioxane species influence the swelling of P-DS-ET as well as its wettability. It appears that for this ternary composite, the mechanism of diclofenac sodium release is of a character which combines swelling, diffusion and erosion simultaneously.⁴⁹ The difficulty with the clear description of the release mechanism of diclofenac sodium is probably related to the complex internal structure and composition of the investigated samples. At this point, it should be mentioned that the transformation of the salt into the acidic form of diclofenac and its possible slow release may also affect the mechanism of drug desorption from the P-DS-T and P-DS-ET composites.

Conclusions

The present paper has demonstrated the preparation of a new type of ternary composite in which pure silica gel and polysilsesquioxane are deposited from the vapor phase on the polymer carrier loaded with a high dose of the drug. The conducted studies have revealed that the crosslinked polymer matrix is able to undergo many cycles of swelling and deswelling, with each of the delivery cycles increasing the drug content within the polymer carrier. Obviously, the internal structure of the polymer carrier is significantly rearranged after the precipitation of the drug. Additionally, TEOS and ETEOS gelation in the presence of an acidic catalyst in the vapour phase has been demonstrated as an efficient method of introducing the silica and polysilsesquioxane species into the solid dispersion of the drug within the polymer. Their introduction significantly alters the internal structure of the solid dispersion, and, in consequence, the porosity of the host material. Both the internal structure and the total porosity of the ternary composites strongly depend on the type of silica precursor. In the case of the composite obtained from ETEOS gelation, the tremendous decrease in the porosity parameters clearly indicates that the employed strategy yields an amorphous material which clogs pores and effectively prevents N₂ adsorption, probably due to the incomplete polymerization of monomers under the applied vapour conditions. Moreover, the XRD pattern suggests a significant rearrangement of the internal structure of the polymer, due to in situ polymerization of the ETEOS monomers.

In the course of the present study, it has been revealed that exposure of the TEOS-saturated or ETEOS-saturated solid dispersion of the drug within the polymer to acid vapors is sufficient to cause the irreversible transformation of diclofenac sodium into sodium chloride and a derivative of phenylacetic acid that is poorly soluble in the used buffer solution. Furthermore, it turns out that the TEOS prevents the transformation of the drug into its acidic form more effectively than the ETEOS precursor. Accordingly, taking into consideration the release profiles of diclofenac sodium in comparison to the total mass of drug initially introduced into the investigated samples, it may be noticed that the drug is not effectively leached out from the ternary composites within 24 h. Hence, it should be emphasized that the conditions of silica precursor hydrolysis and condensation have to be carefully matched, taking into account the chemical nature of the embedded drug. Nevertheless, the analysis of the in vitro release profiles clearly demonstrates that the rate of diclofenac sodium release is significantly modified after the embedding of the silica species into the solid dispersion. Moreover, the degree of burst release is successfully diminished in the case of both of the silica-loaded systems. The changes in the initial drug desorption for the ternary composites might be interpreted in terms of the restricted swelling of such composite carriers, causing the limited inflow of the release medium into their interior. This takes place since the silica species may be regarded as the reinforcing agent which prevents the easy expansion of the carrier under the applied conditions. It is considered that the gelation of the silica precursor in the vapor phase of the acidic catalyst is generally relevant in the field of modified release systems. The successful synthesis of polymer–drug–silica composites indicates that it might be applicable to other polymer-based systems, and, as a methodology, it opens new perspectives for the fabrication of modified release systems.

Acknowledgements

The research was carried out with the equipment purchased thanks to the financial support of the European Regional Development Fund in the framework of the Polish Innovation Economy Operational Program (Contract No. POIG.02.01.00-06-024/09 Center of Functional Nanomaterials).

References

1. B. N. Kolarz, A. W. Trochimczuk, D. Jermakowicz-Bartkowiak, J. Jezierska and W. Apostoluk, React. Funct. Polym., 2002, 52, 53–60.
2. J. K. Oh, R. Drumright, D. J. Siegwart and K. Matyjaszewski, Prog. Polym. Sci., 2008, 33, 448–477.
3. J. Li and H. A. Chase, Nat. Prod. Rep., 2010, 27, 1493–1510.
4. M. Maciejewska and D. Kolodynska, Mater. Chem. Phys., 2015, 149, 43–50.
5. D. Horák, B. Rittich and A. Španová, in Aqueous Polymer Dispersions, ed. K. Tauer, Springer, Berlin Heidelberg, 2004, vol. 124, ch. 16, pp. 77–81.
6. M. Grochowicz, A. Bartnicki and B. Gawdzik, J. Appl. Polym. Sci., 2008, 107, 3718–3726.
7. H. J. Naghash and F. Shafie, Polym. Sci., Ser. B, 2013, 55, 620–633.
8. R. Zaleski, M. Maciejewska and M. Puzio, J. Phys. Chem. C, 2015, 119, 11636–11645.
9. A. Denizli, B. Salih and E. Piskin, J. Appl. Polym. Sci., 1997, 65, 2085–2093.
10. P. Hodge, Chem. Soc. Rev., 1997, 26, 417–424.
11. T. M. Suzuki, J. O. Bomani, H. Matsunaga and T. Yokoyama, React. Funct. Polym., 2000, 43, 165–172.
12. T. Balaji and H. Matsunaga, Anal. Sci., 2002, 18, 1345–1349.
13. M. S. Hosseini, A. Hosseini-Bandegharaei, H. Raissi and F. Belador, J. Hazard. Mater., 2009, 169, 52–57.
14. Z. Chen, S. Deng, H. Wei, B. Wang, J. Huang and G. Yu, ACS Appl. Mater. Interfaces, 2013, 5, 6937–6945.
15. J. Koubková, P. Müller, H. Hlídková, Z. Plichta, V. Proks, B. Vojtěšek and D. Horák, New Biotechnol., 2014, 31, 482–491.
16. E. Karavas, M. Georgarakis, A. Docoslis and D. Bikiaris, Int. J. Pharm., 2007, 340, 76–83.
17. S. H. Jeong and K. Park, Int. J. Pharm., 2008, 353, 195–204.
18. X. Guo, R.-K. Chang and M. A. Hussain, J. Pharm. Sci., 2009, 98, 3886–3902.
19. C. Tuleu, C. Andrieux, P. Boy and J. C. Chaumeil, Int. J. Pharm., 1999, 180, 123–131.
20. A. Kierys, M. Rawski and J. Goworek, Microporous Mesoporous Mater., 2014, 193, 40–46.
21. A. Kierys, ACS Appl. Mater. Interfaces, 2014, 6, 14369–14376.
22. M. Scordino, A. Di Mauro, A. Passerini and E. Maccarone, J. Agric. Food Chem., 2003, 51, 6998–7004.
23. E. M. Silva, D. R. Pompeu, Y. Larondelle and H. Rogez, Sep. Purif. Technol., 2007, 53, 274–280.
24. R. Kasperek, H. Trębacz, Ł. Zimmer and E. Poleszak, Acta Poloniae Pharmaceutica–Drug Research, 2014, 71, 439–449.
25. R. H. Baney, M. Itoh, A. Sakakibara and T. Suzuki, Chem. Rev., 1995, 95, 1409–1430.
26. D. A. Loy, B. M. Baugher, C. R. Baugher, D. A. Schneider and K. Rahimian, Chem. Mater., 2000, 12, 3624–3632.
27. A. Miniewicz, J. Girones, P. Karpinski, B. Mossety-Leszczak, H. Galina and M. Dutkiewicz, J. Mater. Chem. C, 2014, 2, 432–440.
28. I. Halasz, A. Kierys and J. Goworek, J. Colloid Interface Sci., 2015, 441, 65–70.
29. A. Kierys, M. Dziadosz and J. Goworek, J. Colloid Interface Sci., 2010, 349, 361–365.
30. Council of Europe, European Pharmacopoeia, Council of Europe, Strasbourg, 8th edn, 2014, p. 288.
31. The Polish Pharmaceutical Society, Polish pharmacopoeia, The Polish Pharmaceutical Society, Warsaw, 2014, p. 387.
32. E. P. Barrett, L. G. Joyner and P. P. Halenda, J. Am. Chem. Soc., 1951, 73, 373–380.
33. R. Zaleski, A. Kierys, M. Dziadosz, J. Goworek and I. Halasz, RSC Adv., 2012, 2, 3729–3734.
34. R. Navarro, I. Saucedo, A. Nunez, M. Avila and E. Guibal, React. Funct. Polym., 2008, 68, 557–571.
35. R. Navarro, I. Saucedo, C. Gonzalez and E. Guibal, Chem. Eng. J., 2012, 185, 226–235.
36. F. Forni, G. Coppi, V. Iannuccelli, M. A. Vandelli and M. T. Bernabei, J. Pharm. Sci., 1989, 78, 25–27.
37. C. Gerardin, J. Reboul, M. Bonne and B. Lebeau, Chem. Soc. Rev., 2013, 42, 4217–4255.
38. S. K. Natarajan and S. Selvaraj, RSC Adv., 2014, 4, 14328–14334.
39. A.-M. Putz, S. Cecilia, C. Ianăşi, Z. Dudás, K. Székely, J. Plocek, P. Sfârloagă, L. Săcărescu and L. Almásy, J. Porous Mater., 2015, 22, 321–331.
40. S. Tanaka, N. Nishiyama, Y. Oku, Y. Egashira and K. Ueyama, J. Am. Chem. Soc., 2004, 126, 4854–4858.
41. N. Nishiyama, S. Tanaka, Y. Egashira, Y. Oku and K. Ueyama, Chem. Mater., 2003, 15, 1006–1011.
42. C. Sanchez, G. J. d. A. A. Soler-Illia, F. Ribot, T. Lalot, C. R. Mayer and V. Cabuil, Chem. Mater., 2001, 13, 3061–3083.
43. M. E. Palomo, M. P. Ballesteros and P. Frutos, J. Pharm. Biomed. Anal., 1999, 21, 83–94.
44. I. Rácz, in Pharmazie in unserer Zeit, ed. R. Herzog, J. Wiley & Sons, Chichester, 1990, pp. 352–386.
45. A. Sil, R. Sharma and S. Ray, Surf. Coat. Technol., 2015, 271, 201–206.
46. X. Chen, J. Jiang, F. Yan, S. Tian and K. Li, RSC Adv., 2014, 4, 8703–8710.
47. J. Siepmann and N. A. Peppas, Adv. Drug Delivery Rev., 2001, 48, 139–157.
48. G. U. Rani, A. K. Konreddy, S. Mishra and G. Sen, Int. J. Biol. Macromol., 2014, 65, 375–382.
49. P. Costa and J. M. Sousa Lobo, Eur. J. Pharm. Sci., 2001, 13, 123–133.
50. N. V. Mulye and S. J. Turco, Drug Dev. Ind. Pharm., 1995, 21, 943–953.
51. P. Du and P. Liu, Langmuir, 2014, 30, 3060–3068.
52. M. Prokopowicz, J. Żegliński, A. Gandhi, W. Sawicki and S. A. M. Tofail, Colloids Surf., B, 2012, 93, 249–259.
53. S. H. Cypes, W. M. Saltzman and E. P. Giannelis, J. Controlled Release, 2003, 90, 163–169.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra15064g

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