The research describes systematic approach to the novel synthesis and formation of a potential organic-inorganic drug carriers. The poly(trimethylolpropane trimethacrylate) and polymer-silica composites based on SBA-3 or SBA-15 mesoporous silica were fabricated by the suspension-emulsion polymerization method in the form of small micrometric porous beads (specific surface area approx. 500 m2 /g).
Microporous and Mesoporous Materials 294 (2020) 109881 Contents lists available at ScienceDirect Microporous and Mesoporous Materials journal homepage: http://www.elsevier.com/locate/micromeso Polymer–mesoporous silica composites for drug release systems Agnieszka Kierys a, *, Radosław Zaleski b, Marta Grochowicz c, Marek Gorgol b, Andrzej Sienkiewicz a a Maria Curie-Sklodowska University, Faculty of Chemistry, Institute of Chemistry, M Curie-Sklodowska Sq 3, 20-031, Lublin, Poland Maria Curie-Sklodowska University, Institute of Physics, M Curie-Sklodowska Sq 1, 20-031, Lublin, Poland c Maria Curie-Skłodowska University, Faculty of Chemistry, Institute of Chemistry, 33 Gliniana Str., 20-614, Lublin, Poland b A R T I C L E I N F O A B S T R A C T Keywords: Polymer–mesoporous silica composites Mesoporous silica materials Diclofenac sodium SBA-15 SBA-3 Drug release The research describes systematic approach to the novel synthesis and formation of a potential organic-inorganic drug carriers The poly(trimethylolpropane trimethacrylate) and polymer-silica composites based on SBA-3 or SBA-15 mesoporous silica were fabricated by the suspension-emulsion polymerization method in the form of small micrometric porous beads (specific surface area approx 500 m2/g) The type of organic templates filling silica pores has proved to be crucial in the synthesis of the composites The introduction of diclofenac sodium via solvent diffusion method into the polymer and composites resulted in the solid drug dispersions The composites have greater effectiveness in the drug desorption (90% of the release) in comparison with the pure polymer (20% of the release after h) Both, however, suffer from the burst effect This downside can be overcome by func tionalization of the solid drug dispersions with (3-aminopropyl)triethoxysilane The functionalized solid drug dispersions not desorb the diclofenac sodium in an acidic medium (the desorption rate is less than 6% during h contact), which makes them attractive for oral multiparticulate formulations of modified release The pre sented solids were characterized with modern analytical methods and the relation between the material structure and desorption rate were discussed Introduction Mesoporous silica (MS) materials, synthesized by the application of various of surfactants as pore forming and structure directing agents, have gained interest due to their high specific surface area, large pore volume and tunable pore diameter The great advantage of these ma terials is their unique structural properties as well as the ease of their chemical and structural modification in a wide range The MS materials modified with various organic functional groups [1–10], nanoparticles (e.g Zn, Ag, Au, Pt, Fe, etc.) [11–13], hydrothermally [14] were pre pared and thoroughly investigated All these modifications were made in order to attain the highest effectiveness in a given application [15–22] Furthermore, the mesoporous silicas were also employed as a template to synthesise other materials such as CMK [23,24] It is no surprise that MS materials have attracted great attention in therapeutic (e.g designing and formation of different drug delivery systems [25–28]) as well as in diagnostic applications [29,30], especially that there are favourable reports concerning their mechanical and chemical stability and good biocompatibility [31,32] On the other hand, some in vitro and in vivo measures show that unfunctionalized mesoporous silicas, such as MCM-type and SBA-type materials, exhibit benign local biocompati bility but considerable systemic toxicity, e.g Ref [] However, this can be effectively mitigated by careful control of the particle size of silicas used in a formulation and by modification of neat silicas [34,35] Mesoporous silica materials were also successfully employed to fabricate MS-polymer composites [36,37] In their case the challenge is to obtain the composite with MS particles homogeneously dispersed within the polymer matrix since inorganic particles exhibit a strong tendency to agglomerate [37–39] Therefore, various methods for the synthesis of such composites are employed and the resulted materials are the objects of thorough studies From the data presented in the following review articles [37,40] it stems that MS-polymer materials are very attractive materials especially as carriers for drugs due to their complex pore system and chemical character The preparation of the MS-polymer composites in the form of microspheres makes it possible to apply them as drug carriers for oral multiparticulate matrix systems The * Corresponding author E-mail addresses: agnieszka.kierys@umcs.lublin.pl (A Kierys), radek@zaleski.umcs.pl (R Zaleski), mgrochowicz@umcs.lublin.pl (M Grochowicz), marek gorgol@umcs.lublin.pl (M Gorgol), andrzej.sienkiewicz@umcs.lublin.pl (A Sienkiewicz) https://doi.org/10.1016/j.micromeso.2019.109881 Received August 2019; Received in revised form 22 October 2019; Accepted November 2019 Available online November 2019 1387-1811/© 2019 The Authors Published by Elsevier Inc This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 strategy involving the permanent combining/embedding the silica par ticles in the polymer microspheres is very promising, since it makes possible to avoid the presence of the free nanoparticles of mesoporous silicas in the formulation As a result, it is to be expected that the toxicity of the mesoporous silicas has been mitigated Moreover, the diameter of the MS-polymer particles is within the micrometer range, thus it is un likely that they are able to cross the blood-brain barrier or penetrate cells Among different strategies of composites synthesis, the one involving the use of as-synthesized mesoporous silica materials as fillers seems to be very interesting The MS pores filled with the template molecules are inaccessible for the monomer during the MS-polymer synthesis Thus, they are free from the polymer phase in the composite Simultaneously, the template molecules have in its structure both hydrophobic groups and hydrophilic groups (since they are surface-active agents) Their presence in the system during the synthesis, should facilitate the mixing of MS particles with used reactants to obtain homogeneous dispersion of MS in the polymer matrix The aim of the present study was to determine how different assynthesized mesoporous silicas (used as additives/modifiers) affect the properties of the poly(trimethylolpropane trimethacrylate) resin ([41, 42], polyTRIM) in the context of using polymer–mesoporous silica composites as a specific drug carriers in oral multiparticulate controlled release systems The suspension-emulsion polymerization was chosen as a popular and relatively easy method for the synthesis of various, permanently porous polymer resins [43–45] SBA-3 and SBA-15 meso porous silicas synthesized under acidic conditions using octadecyl trimethylammonium bromide (C18TAB) and amphiphilic triblock copolymer - Pluronic P123, respectively, were selected as additives since they are widely known highly porous silicas, which were previously presented as promising drug carriers [46–49] Diclofenac sodium (DS), a non-steroidal anti-inflammatory drug (NSAID) with analgesic and anti pyretic properties was chosen as a model drug for this study The control over drug desorption rate, and especially the reduction of the burst release, is a very important issue in the case of water-soluble drugs This can be achieved by applying different drug carriers In particular, these with complex architecture are very promising and upcoming materials for drug delivery materials [7,50–52] The influence of mesoporous silicas on the polymerization process, the porosity of the resulted composites as well as the drug desorption rate and efficiency were examined The changes of the drug desorption kinetics after in situ fabrication of an amine-functionalized silica gel within solid dispersions were additionally explored The hybrid silica gel was employed not only to gain better control over the drug desorption, but also to minimize the possible toxicity of the composites in accor dance with favourable reports concerning cytotoxicity of the function alized silica [53,54] Positron annihilation lifetime spectroscopy (PALS) was employed to determine differences and changes in the porosity of materials during their processing, especially in the nanopore range and used without further thermal treatment The SBA-15As and SBA-3As after extraction in a Soxhlet apparatus (i.e 160 mL of methanol per 1.5 g of SBA-15As [59] and 160 mL of methanol and mL of 37% HCl (POCh, Poland) per 1.5 g of the SBA-3As [33]) were denoted as SBA-15EX and SBA-3EX, respectively Experimental The solid dispersions of diclofenac sodium (sodium-2-[(2,6-dichlorophenyl)amino] phenylacetate, DS; Caesar and Loretz, GmbH, Hilden, Germany) within PT and in the composites beads were prepared by the solvent diffusion method First, diclofenac sodium was dissolved in the mixture of ethanol (EtOH; POCh, Poland) and distilled water with the molar fraction of EtOH of 0.7 [60] Subsequently, the DS solution was added to the materials under study The amount of ethanolic DS solution was adjusted so that it can be fully absorbed by the swelling PT and CTs (2 g per g of dry beads) After conditioning step in closed containers at room temperature (3 h), the samples were dried at 80 � C under vacuum for h The samples with the drug were denoted by adding “D” suffix to their initial labels (e.g PTD, CT15-5D) 2.2 Preparation of polymer poly(TRIM) and polymer-mesoporous silica composites The microspheres of poly(TRIM) and polymer-mesoporous silica composites were synthesized via the suspension-emulsion polymeriza tion method Trimethylolpropane trimethacrylate (TRIM, Merck) alone was used to prepare the poly(TRIM), whereas the composites were ob tained with the TRIM monomer and two different contents of the assynthesized mesoporous silicas, i.e the MSAs to TRIM weight ratio was 5% or 25% In this procedure sodium dodecyl sulfate (SDS, Sigma Aldrich) was used as the surfactant and α,α0 -azobisisobutyronitrile (AIBN, Glentham Life Sciences Ltd) as the initiator Both reagents were analytical grade, obtained from Sigma Aldrich and used as received Toluene (POCh, Poland) and decan-1-ol (Fluka AG) at the vol/vol ratio 5.6 : 1.0 were used as pore-forming diluents, and the volume ratio of TRIM to toluene was : 1.5 The as-synthesized mesoporous silicas were added to the solution of TRIM, AIBN and pore-forming diluents, and sonicated for 10 in an ultrasonic bath and as a result the stable suspensions have been obtained (organic phases) Subsequently, the MSAs suspension with TRIM, AIBN and pore-forming agents were added while stirring to the aqueous solution of SDS (0.25% wt.) at 80 � C Polymerization was carried out at this conditions for 20 h The resulted polymer- MSAs materials were filtered, rinsed separately with distilled water, boiling acetone (POCh, Poland, 200 mL) and toluene (200 mL) Subsequently, the materials were thoroughly extracted in a Soxhlet apparatus first with pure methanol (160 mL of methanol per 1.5 g of the composite) for 24 h in the case of SBA-15As-TRIM [59], or with acidified methanol (160 mL of methanol and mL of 37% HCl (POCh, Poland) per 1.5 g of the composite) for 24 h in the case of SBA-3As-TRIM [33] Rinsing and extraction was performer due to complete removal of silica templating agent and unreacted chemicals from the polymer-MSAs composites The spherically shaped beads of composite (CTs) were ob tained for the weight ratio of SBA-15As to TRIM of both 5% and 25% On the other hand, the beads were formed only in the case of adding 5% of SBA-3As Introduction of larger amount of SBA-3As disrupted the polymerization process and the beads were not formed The final pure poly(TRIM) polymer was denoted as PT, whereas composites with 5% and 25% of SBA-15As were denoted as CT15-5 and CT15-25, respec tively The composite synthesized by the use of SBA-3As was labelled as CT3-5 Prior to their use, the PT and CTs beads were dried at 80 � C under vacuum for h 2.3 Preparation of diclofenac sodium solid dispersions 2.1 Preparation of as-synthesized mesoporous silicas (SBA-15As and SBA-3As) The synthesis procedure of the SBA-15As and SBA-3As mesoporous silicas was similar, i.e both materials were prepared under acidic con ditions using tetraethyl orthosilicate (TEOS, Acros Organics) as the silica source however different structure-directing agents were used SBA15As was prepared according to the well-known procedures using the amphiphilic triblock copolymer (Pluronic P123, BASF) [55,56] while octadecyltrimethylammonium bromide (C18TAB, Sigma-Aldrich) was used for the SBA-3As synthesis instead of widely used hexadecyl trimethylammonium bromide [57,58] The as-synthesized mesoporous silicas (MSAs; SBA-15As and SBA-3As) were filtered, thoroughly rinsed with distilled water (ca L), dried at 100 � C for h, ground in a mortar A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 2.4 Preparation of amine-functionalized diclofenac sodium solid dispersions microstructure of the materials under study Prior to the measurement the samples were sputtered with gold The parameters characterising the porosity of the initial samples and after the processing applied were determined by the measurements of nitrogen adsorption/desorption at 196 � C (LN2) using the ASAP 2420 (Micromeritics, Norcros, GA) ana lyser Prior to the experiment, the samples were dried overnight at 80 � C under vacuum The specific surface areas, SBET, were calculated using the standard Brunauer Emmett Teller (BET) equation [64], whereas the total pore volumes, Vp, were estimated from a single point on the adsorption isotherm at the relative pressure about 0.99 p/p0 The pore size distributions (PSDs) for all samples were determined from the adsorption and desorption branches of the N2 isotherm using the Bar rett Joyner Halenda (BJH) procedure [65] Additionally, the porosity was characterized by positron annihilation lifetime spectroscopy (PALS) The positron source (22Na, 0.4 MBq) was placed between two mm layers of a sample in the sealed chamber at the pressure of p < 10 Pa at room temperature The radiation from the positron creation inside the source and the positron annihilation inside the sample were collected by scintillation detectors equipped with BaF2 scintillators The signals form the detectors were registered by two digitizers (Agilent) with the sampling rate of GS/s triggered by the custom-made coincidence unit The program for the in-flight analysis of digitized impulses to obtain positron lifetime spectra was based on the algorithm developed by the Prague group [66] The time range of the digital spectrometer was set to μs The spectra with the total number of counts of 27 million were collected The continuous distributions of lifetimes were obtained with the use of the MELT program [67] The resolution curve was approximated by a Gaussian with FWHM of about 220 ps Two short-lived components originated from para-positronium (ca 140 ps) and unbound positrons (ca 390 ps) were ignored because they not provide a clear information about porosity Only the lifetime distributions of long-lived components (>1 ns), which originate from otho-positronium, served to calculate pore size distributions according to the procedure described in Ref [68] The Raman spectra of the samples were collected at room tempera ture using Raman microscope inVia Reflex from Renishaw (UK) which used a charge-coupled device (CCD) detector with a spectral resolution of cm Exciting radiation at 514 nm was provided by an Arỵ laser at the cross-section of dried samples The actual content of SiO2 in the composites was tested using ther mogravimetric measurements with the NETZSCH STA 449 F1 Jupiter® instrument by heating ~15 mg of sample under air flow from room temperature to 800 � C with the heating rate of 10 � The mea surement was repeated three times The measurements show that the SiO2 contents slightly differ between the composites, and it is about 0.4% in CT3-5 and in CT15-5 and CT15-25 is 1% The PTD, and CT15-25D solid dispersions of diclofenac sodium were additionally functionalized with 3-aminopropyl groups via in situ transformation of the mixture of (3-aminopropyl)triethoxysilane (APTES; Acros Organics) and TEOS introduced into them by the swelling method [61] The precursor’s mixture was prepared h prior to its use with the molar ratio APTES to TEOS, : It was introduced drop by drop to dry PTD and CT15-25D beads Both samples quickly imbibed the mixture of precursors The amount of the APTES and TEOS mixture was adjusted to be fully absorbed by samples (i.e no excess liquid was left outside the beads) The samples saturated with precursors (1.36 g per g of PTD and 1.41 g per g of CT15-25D) were exposed to the ammonia vapours (10 cm3 3.25 M NH3(aq) per g of precursors mixture) at autogenous pressure and room temperature for 72 h followed by drying at 80 � C under vacuum for h [62] The samples functionalized with 3-aminopropyl groups were denoted by adding “A” suffix to their labels, i.e PTDA and CT15-25DA 2.5 Analysis of actual diclofenac sodium contents The actual contents of diclofenac sodium in the samples, i.e nonfunctionalized and functionalized with 3-aminopropyl groups, was determined A portion of the PTD, CT3-5D, CT15-5D and CT15-25D beads was crushed and powdered in a mortar An accurately weighed 50 mg each of the powdered samples was immersed in 250 ml of phos phate buffer solution pH at 6.8 [63] The flask was shaken for h The amount of the drug dissolved was spectrophotometrically analysed at the wavelength of 276 nm The experiment was repeated three times As it follows from the measurement, the PTD sample contains 20.8% of diclofenac sodium, CT15-5D – 19.8%, CT15-25D – 19.2% and CT3-5D – 20.6% which in all materials corresponds to about (40 � 5) mg of drug in 200 mg of sample The actual contents of diclofenac sodium in the samples functional ized with 3-aminopropyl groups was calculated from the weight differ ences between PTD and PTDA or CT15-25D and CT15-25DA Prior to the functionalization, and after the process the PTD, PTDA, CT15-25D and CT15-25DA solid dispersions were thoroughly dried under vacuum and weighted The DS contents in PTDA and CT15-25DA was calculated from the mass of the introduced hybrid silica gel into the PTD and CT15-25D The PTDA sample contains 12.8% of diclofenac sodium and CT15-25DA – 11% 2.6 Release of diclofenac sodium The diclofenac sodium desorption was carried out to the phosphate buffer solution pH ¼ 6.8, under constant stirring at 170 rpm in a ther mostated bath at (37 � 0.5) � C Desorption profiles of DS were obtained by soaking 50 mg of the solid loaded with the drug in 225 mL of the buffer At predetermined time intervals, mL of the solution was taken out for an analysis of the DS concentration which was measured at the wavelength of 276 nm by using the UV/Vis spectrophotometer (Varian Cary 100 Bio) The DS release was also monitored after PTDA or CT1525DA exposure to 0.1 M hydrochloric acid for h under constant stirring at 170 rpm in a thermostated bath at (37 � 0.5) � C The samples initially exposed to an acidic environment were subsequently placed in a phos phate buffer at pH 6.8 under constant stirring at 170 rpm in a thermo stated bath at (37 � 0.5) � C Samples of the dissolution fluids were taken after the acidic-stage at predetermined time intervals and were analysed using the UV/Vis spectrophotometer Result and discussion 3.1 Physicochemical characterization of the investigated samples The polymer poly(TRIM) and mesoporous silica-polymer composites were synthesized via the suspension-emulsion polymerization method, therefore it was expected to obtain these materials in the form of microspheres The grains of pure PT are spherical in shape even though they are not entirely uniform in size (Fig 1a & 1a’) Their average diameter in a dry state was estimated to be (85 � 40) μm in diameter Introduction of MSAs into the reaction mixture influences not only the size of the final beads of CTs but also their shape SBA-3As and SBA-15As silicas are nonporous materials with silica channels filled with the template Simple rinsing of with water is not sufficient to completely remove the organic template from the MSAs materials Moreover amphiphilic character of the templating agent indicates that the surfactant molecules are not only present within its pores but also on the outer surface of the MSAs par ticles, giving rise to its moderately hydrophobic character It is clear that 2.7 Methods of characterization A scanning electron microscope (SEM, FEI Company, Quanta 3D FEG) working at 30 kV was used to investigate the morphology and A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 Fig SEM micrographs of representative beads of the polymer PT (a, a’) and composites CT3-5 (b, b’), CT15-5 (c, c’) and CT15-25 (d, d’) low solubility in water [69] As a result, the external surface of SBA-3As particles (after rinsing) is still covered with C18TAB molecules But unlike to the system with P123, C18TAB interferes much more with the polymer primary particles agglomeration into larger clusters called microspheres, contributing to an overall the unsuccessful formation of the CT3-25 composites The most probably it is related with C18TAB chemical character Even a small amount of C18TAB in the system (i.e CT3-5) results in poor building of SBA-3As into the polymer phase The representative SEM micrographs seem to confirm this assumption, since the spherical cavities (probably after SBA-3As particles) are clearly visible in the interior of crushed CT3-5 beads (Fig 4) Such cavities were not found in the other samples Although, SEM micrographs of representative beads confirm suc cessful embedding of SBA-15As (and to a lesser extent SBA-3As) within polymer matrix (Fig 1) it follows from thermogravimetric measure ments that the actual amount of SiO2 in the composites is very low (does not exceed 1% of the total mass of a composite) The significant differ ence between the amount of SBA-3As and SBA-15As used for the syn thesis and the SiO2 in the final composites is understandable, if one take into account that MSAs introduced into the system contain the template molecules which can constitute up to 60% their total mass [70] On the other hand, the low SiO2 content in CTs may be the result of the poor effectiveness to build MSAs in poly(TRIM) matrix Regardless of the low content of inorganic phase in the samples, it is clear that the MSAs presence in the system greatly influences the formation processes of composites This is confirmed by the LN2 and PALS results Both methods were employed to get insight into the porosity of investigated samples and to reveal its changes during the sample processing For all investigated materials in the dry state, the N2 adsorption- the presence in the reaction mixture of a disturbing agent, such as SBA15As particles of elongated morphology (Fig 2a) affects the polymeri zation process Nevertheless, regardless of the amount of SBA-15As in the system, the beads were obtained, but they are much less homoge neous in size in comparison with ones made of pure poly(TRIM) (Fig 1) It is known that, molecules of amphiphilic block copolymer P123 (used for the SBA-15As synthesis) contains one hydrophobic poly(pro pylene oxide) (PPO) and two hydrophilic poly(ethylene oxide) (PEO) regions arranged in a PEO PPO PEO triblock structure It seems that P123 molecules closely cover the surface of individual SBA-15As parti cles since after their introduction into the organic phase the stable sus pension is obtained Furthermore, P123 molecules seem to facilitate sticking microspheres consisting of poly(TRIM) (arising during poly merization process) to the SBA-15As surface As a result, SBA-15As particles closely adjoin to polymer phase and are integral part of com posite beads (Fig 3) It is worth to note, that milling of SBA-15As slightly affects its morphology and the large, elongated particles are clearly visible in the interior and on the surface of the composite beads (Fig 3) On the other hand, spheres were successfully formed only when the weight ratio of SBA-3As particles to TRIM was 5% The resulted CT3-5 beads are slightly smaller and have more spherical shape in compari son to the composites with SBA-15As (Fig 1) The large size of SBA-3As particles is not affected by milling (Fig 2b) Probably, their irregular shape and large size are responsible for the unsuccessful CT3-25 syn thesis However, the impact of the organic template different than P123 cannot be excluded It seems that the C18TAB surfactant of ionic char acter poorly works as an agent facilitating mixing of the SBA-3As and polymer phase, even at a small addition of it It was reported that among the alkyltrimethylammonium bromide series C18TAB has a relatively Fig SEM micrographs of as-synthesized mesoporous silicas SBA-15As (a) and SBA-3As (b) after milling in mortar before adding to the solution of TRIM, AIBN and pore-forming diluents A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 Fig SEM micrographs of beads (a) and the interior (b & c) of representative bead of the CT15-25 composite Fig SEM micrographs of the interior of representative bead of the polymer PT (a, a’) and composites CT15-5 (b, b’) and CT3-5 (c, c’) Fig The low-temperature nitrogen adsorption/desorption isotherms (a) and the pore size distributions determined by applying the BJH method to the desorption isotherms (b) and to the adsorption isotherms (c) of samples under study A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 desorption isotherms are similar in shape Type IV of the isotherms in dicates that all materials are mesoporous (Fig 5a) [71] Since in all cases, adsorption and desorption branches not overlap, hysteresis loops of type H2 arise They are extended along the whole pressure axis and are very similar in shape to each other The N2 isotherms of the composites with SBA-15As diverge slightly from these of PT and CT3-5 The corresponding PSDs computed from desorption branches of the isotherms are of bimodal character (Fig 5b) The peak centred at 3.8 nm is present in all curves, while it is hardly visible in the PSDs calculated from the adsorption branches (Fig 5c) Similar findings were presented before for TRIM-based materials [72–74] In addition to the first maximum, the second maximum appears in the PSD curves For the pure poly(TRIM) it is located at about 5.5 nm In the case of CTs, the second peak is shifted towards larger pores compared to PT (Table 1), but only for CT15-25 it exhibits much broader distribution compared to the pure polymer Interestingly, for PT, CT3-5 and CT15-5 a third peak of low intensity is also visible It is centred at about 24 nm for PT and CT3-5 and at about 43 nm for CT15-5 (Fig 5b) This peak is absent from the PSD curve for CT15-25 as well as all PSD curves calculated from adsorption branches of N2 isotherm (Fig 5b & c) Values of the parameters characterizing the porosity of PT, CT3-5 and CT15-5 obtained from the nitrogen sorption differ very slightly from each other (Table 1), mainly in the total pore volume The changes in the specific surface area should be interpreted with great caution There is no significant difference in SBET between PT and CTs (surpris ingly a decrease in SBET is observed in most CTs) The total pore volume increases by ca 25% in comparison to PT only in the CTs based on SBA15As These results are surprising since MSAs particles used for CTs syn thesis are highly porous after they are extracted alone (Table 1) In addition, it has previously been shown that polymerization of TRIM in the presence of preformed non-calcined MCM-41 particles leads not only to the composite whose SBET and Vp are much higher compared to the pure polymer, but also causes the structural reorganization of the polymer matrix towards a more loose structure [72] Similar changes (i e towards loosening of the structure) can be observed only in the case of the CT15-5 and CT15-25 composite Use of SBA-3As particles as addi tives not significantly influence the packing of the polymer particles (i.e nuclei and microspheres) [75] This hypothesis is also in line with the presented SEM micrographs (Fig 4c’) While discussing the lack of significant differences in the CTs porosity several possibilities should be considered First, as it follows from TG results the embedding efficiency of MSAs within polymer ma trix is very low As a result, the amount of SiO2 especially in CT3-5 and CT15-5 is too low to induce significant changes in the internal structure in comparison to PT On the other hand, it seems to be highly probable that the removal of the template from the silica channels of MSAs during extraction failed Although, the CT15-25 sample was extracted for 24 h, it seems that polymer species prevent the removal of template molecules by closing the pore entrances Such a situation can be explained by the polymer phase tightly adhesion to the silica particles (Fig 3) Other possibility is that the organic template is successfully removed from MSAs during extraction, but due to the MSAs presence the produced polymer phase is less porous However, the most probable situation is that the organic template is only partially removed from MSAs and simultaneously the polymer phase synthesized in the presence of MSAs is less porous Hence, the porosity of composites may be regarded as the sum of the porosity of the polymer and the emptied silica Information on the size of mesopores as well as smaller free volumes in the polymer and composites can be determined on the basis of PALS measurements (Fig 6) The mesopore sizes are smaller than these ob tained from LN2, which is quite common [43,76] The bimodal character of PSDs manifests only in PT and CT15-5, which is still an improvement in compatibility with LN2 The increase in the average size of mesopores (Dmeso) of all CTs compared with PT is similar (Table 2), while there is no significant changes in the total volume of mesopores (Vmeso), except CT15-25 This confirms the low impact of MSAs on the porosity of CTs Most likely there is almost no contribution from the porosity of MSAs and all changes origin from the polymer, where positronium formation prevails Thus, the PALS results reflect mostly the change in the polymer porosity (increase in the average pore size), while the increase in the total pore volume comes from the emptied pores inside MS Also in the range of micropores there are no significant changes Characteristic three peaks are visible in the polymer as well as in all composites (Fig 6) The differences are subtle and can be observed only in the average size of micropores (Table 2), which is slightly greater in CT3-5 and CT15-5 than in PT This indicates a slightly looser structure in these samples The newly synthesized materials were employed as carriers for diclofenac sodium which was introduced from the binary mixture of ethanol and water by swelling The representative SEM micrographs of the interior of PTD, CT3-5D, CT15-5D and CT15-25D (Fig 7) reveal slight changes after the drug introduction The DS is indistinguishable from the matrix in the SEM images, thus its location within the beads cannot be determined with this technique However, high homogeneity might indicate that the DS is highly dispersed within solid medium It appears that individual spherical species forming PTD microspheres are larger and more tightly packed, but large free volumes (macropores) appear between them Similar trend of structural changes is also observed in the case of CTs but it is less pronounced This effect seems to be connected to polymer swelling To confirm the presence of the drug and possible interactions of the components the Raman spectra were measured (Fig a-d) The most convenient range to detect differences between the pure DS and the solid drug dispersions is 1550–1630 cm 1, where the characteristic bands of DS appear (band broadening and shift), but no peaks from carriers are present (Fig a and c) In the selected regions, the three characteristic bands localized at 1578, 1587 and 1604 cm can be attributed to the asymmetric stretching vibration of O1C8O2, and to the stretching vi brations of dichlorophenyl (ring 1) and phenylacetate (ring 2) rings, respectively [77–79] They are also clearly visible in the PTD and CT15-25D solid dispersions confirming the successful introduction of DS into the PT and CT15-25 samples Simultaneously, shifting (moving towards higher wavenumbers) of these bands is observed Weak and very weak breathing vibrations of the ring and of the neat DS give rise to quite intense bands at 1073 and 1046 cm [80], respectively (Fig b and d) Although, these bands are slightly shifted, their pres ence is also clearly visible in the PTD and CT15-25D solid dispersions Moreover, the in-plane deformation vibrations of the CH groups of both DS rings give rise to Raman bands at 1159 and 1147 cm (bending vibrations) [80] They are also visible in Raman spectra of PTD and CT15-25D, but their shift towards higher wavenumbers is clearly visible Table Parameters characterizing the porosity of the composites from the lowtemperature N2 sorption.a Sample SBET (m2g Dp1 (nm) Dp2 (nm) SBA-3EX SBA-15EX 638 617 1.15 0.89 3.4 6.5/4.3* 9.4 – PT CT3-5 CT15-5 CT15-25 534 524 555 472 0.58 0.62 0.74 0.73 3.8 3.8 3.8 3.8 6.5 6.4 11.2 15.5 PDT CT3D CT5D CT25D 110 46 135 132 0.20 0.10 0.35 0.42 3.8 3.6 3.9 3.9 ~6.6 6.3 11.2 13.4 ) Vp (cm3g ) a SBET, the specific surface area; Vp, the total pore volume; Dpn, the pore diameter at the peak of PSD derived from the desorption branch of N2 isotherm; *the pore diameter at the peak of PSD derived from the adsorption branch of N2 isotherm (as it is recommended for this type of highly ordered mesoporous silicas) A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 Fig Pore size distributions in the polymer and composites determined from the PALS measurements PTD and CT15-25D, in samples functionalized with 3-aminopropyl groups the Raman bands indicating the presence of DS are visible only for PTDA The absence of the DS bands in the presented regions of the CT15-25DA spectra may indicate that the hybrid silica gel fabricated in the presence of DS effectively encapsulates the drug and plays the role of a shielding agent From the N2 sorption measurements (Table 1, Fig 9) it follows that introduction of drug molecules significantly alters the values of pa rameters characterising the porosity Although, samples prior the modification exhibit similar porosity characteristic, the solid drug dis persions significantly differs between each other (Table 1) This is quite surprising since the content of the drug is similar Thus, it can be ex pected that samples composition (i.e the presence of silica particles in CTs) influences both the swelling process as well as the way and the place of drug deposition after the solvent diffusion The decrease in the specific surface area and the total pore volumes is obvious, since drug molecules occupy free volumes in the carriers But it seems that DS introduced into PT and CT3-5 fills free volumes more effectively or it Table Average size of micropores (Dmicro < nm) and mesopores (Dmeso > nm), total volume of micropores (Vmicro) and mesopores (Vmeso) in the samples without DS and with DS determined from PALS spectra Sample Dmicro (nm) Vmicro (a.u.) Dmeso (nm) Vmeso (a.u.) PT CT3-5 CT15-5 CT15-25 0.76 0.82 0.80 0.74 1.1 1.2 1.1 1.2 3.4 4.2 4.0 4.3 2.1 1.9 2.0 1.4 PTD CT3-5D CT15-5D CT15-25D 0.46 0.44 0.46 0.46 2.0 2.1 1.8 1.7 5.0 3.3 5.8 7.2 0.5 0.2 0.6 0.6 only in the case of CT15-25D Taking into account that the deformations of the Raman spectra of the solid dispersions are observed, it may be assumed the presence of interactions between diclofenac sodium mole cules and other components of the systems [77,81] In contrast to the Fig SEM micrographs of the interior of representative bead of the solid dispersion of diclofenac sodium within polymer PTD (a, a’) and within composites CT3-5D (b, b’), CT15-5D (c, c’) and CT15-25D (d, d’) A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 Fig The Raman spectra of samples based on PT (a, b) and on the CT15-25 composite (c, d) Fig The N2 adsorption/desorption isotherms (a) and PSDs determined by applying the BJH method to the desorption isotherms (b) and to the adsorption iso therms (c) of solid dispersions under study creates restrictions for nitrogen molecules adsorption, and as a result the SBET and Vp in these samples are significantly smaller compared to the CT15-5D and CT15-25D Interestingly, the N2 isotherms are almost identical in shape to those of the materials free of drug, but the adsorption values are much lower for all matrices after the DS loading (Fig 9a) As a consequence, the pore size distributions are almost un changed except that the relative abundance of each pore size is lower (Fig 9b & c) A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 In order to get more information about the drug deposition place in the carriers, the PSDs obtained from the PALS measurements were analysed (Fig 10) The diversity of mesopore sizes is greater than in the case of the LN2 results The average diameter of mesopores (Dmeso, Table 2) increases after introducing DS in all composites except CT3-5D This in conjunction with lack of such shift in the LN2 results suggests either the appearance of closed pores or the decrease in their connec tivity [76] The decrease in the pore volume (Vmeso), which is larger than obtained from LN2 adsorption, points to the second reason The location of DS seems to proceed differently in CT3-5D, where almost all meso pores are filled, what is in agreement with LN2 adsorption The changes in the micropore range are quite straightforward Nearly all micropores are closed due to swelling and only spaces be tween polymer chains (Dmicro � 0.38 nm) remain available for positro nium The second peak at 0.50 nm is connected to DS, which forms clusters large enough to trap positronium (i.e at least several nano metres in size) The position of this peak is shifted towards larger sizes (0.56 nm) only in PTD indicating looser structure of the drug or smaller clusters of DS in the polymer This may suggest that either the polymer structure is altered in the composites (probably loosened) or DS is located in the vicinity of MSAs (possibly in its pores) If one considers the latter option then it may be assumed that the MSAs pores are at least partially emptied removal of the larger DS amounts from the carrier as compared to PTD The CT15-25D and PTD solid dispersions were additionally modified with amine-functionalized silica species (i.e hybrid silica gel) First, the mixture of APTES and TEOS was introduced into them by swelling It turns out that regardless of the matrix used, the solid dispersions maintain the ability to swell in the mixture of precursors, wherein the CT15-25D sample imbibes a little more of the precursor’s mixture Next, the amine-functionalized silica species were produced from precursors by the transformation in the presence of ammonia supplied in the vapour phase After formation of a new hybrid phase in PTD and CT1525D one can expect a huge drop of the values of parameters character izing the porosity similarly as it was reported elsewhere [82,83] Such direction of changes is obvious when one takes into account that the species derived from TEOS and APTES tend to form both a hybrid silica film as well as to fuse together forming larger lumps [84] In the case of these samples the DS release profiles are highly interesting and they differ significantly from the corresponding nonfunctionalized solid dispersions (Fig 11a) Firstly, it follows from the course of the drug release profiles in the phosphate buffer solution at 37 � C that the hybrid phase is responsible for successful reduction of degree of the burst release, wherein this effect is more pronounced for the PTDA sample Only ~16% of DS is desorbed within the first 30 from PTDA, with 45% release in h The initial release of the drug from CT15-25DA reaches ~37% and exceeds 78% in h PTDA and CT1525DA exhibit a lower efficiency of the drug desorption in comparison to PTA and CT15-25D, respectively In the case of CT15-25DA the DS amount released during 24 h decreases by about 10% in comparison to the CT15-25D, while less than 60% of DS is successfully desorbed from PTDA The drug desorption profiles in a phosphate buffer (pH¼6.8) change, if prior to the buffer-stage the PTDA or CT15-25DA samples are immersed in 0.1 M hydrochloric acid for h Firstly, the initial DS release from CT15-25DA is significantly lower and reaches about 7% The reduction of the burst release is even more pronounced in the case of PTDA Secondly, the acid-stage contributes to a lower efficiency of the drug desorption from both of samples In the case of CT15-25DA, only about 62% of DS is desorbed during 24 h, and 67% after 120 h, whereas from PTDA similar amount is desorbed after 24 h using the sequential pH in comparison to PTDA immersed only in pH 6.8 Extending the immersion time in the buffer up to 120 h does not affect the quantity of the DS desorbed It is obvious that amine-functionalized silica is responsible for the modification of the drug desorption from the investigated samples However, the amount and composition of the precursors’ mixture, from which hybrid silica was derived, are almost identical in PTDA and CT15- 3.2 Drug release The solid dispersions of diclofenac sodium non-functionalized and functionalized with 3-aminopropyl groups are in the form of micro spheres which can be regarded as discrete subunits The drug release profiles measured for them are presented in Fig 11 Fig 11 illustrates the influence of the MSAs silicas introduction on the drug desorption According to DS release profiles it follows that presence of the MSAs particles within polymer increases the efficiency of drug desorption The drug desorbs most effectively from CT15-5D and CT15-25D subunits, reaching about 90% after h, and it is at about 10% higher than from PTD However, both these samples suffer from prom inent burst release (about 15% higher than PTD), which manifests itself in leaching more than 75% of the drug within the first 30 It is clear that silica does not slow down the DS desorption at the initial stage (i.e just after immersion of the subunits within the buffer solution) The more effective desorption of DS from CT15-5D and CT15-25D is prob ably associated with easier diffusion of the buffer solution molecules into the interior of composite subunits The presence of large free vol umes and a more loose structure, together with more hydrophilic character of composites due to MSAs presence facilitate an effective Fig 10 Pore size distributions in the polymer and composites loaded with DS determined from the PALS measurements A Kierys et al Microporous and Mesoporous Materials 294 (2020) 109881 Fig 11 Diclofenac sodium release from the non-functionalized solid dispersions (PTD, CT3-15D, CT15-5D and CT15-25D) and functionalized with 3-aminopropyl groups solid dispersions (PTDA, CT3-5DA, CT15-5DA and CT15-25DA) measured in the phosphate buffer solution at 37 � C (a) Release profiles of diclofenac sodium using the sequential pH of 0.1 M HCl (data not shown) followed by pH¼6.8, phosphate buffer (b) In the figures, the lines are provided for convenience Due to the fact that the pure polymer as well as composites were in the form of small beads, they could be regarded as discrete subunits suitable to be the carriers of the diclofenac sodium Although, both kinds of carriers suffered from the drug burst release, the advantage of the composites was to provide the more effective drug desorption Whereas, the more compact structure of the pure polymer carrier caused that the large amount of drug was retained within it After additional modifi cation of the carriers with amine-functionalized silica species the burst release was significantly diminished, which resulted in gaining control over the drug desorption The composite after the modification turned out to be a better carrier than the modified polymer due to more effective desorption of the drug Taking into account that the crosslinked polymer microspheres are resistant to different pH of an envi ronment, they will most likely behave as non-disintegrating pellets, and their transport through the gastrointestinal tract will be without their digestion However, the in vitro evaluation of cytotoxicity of the MSpolymer composites is in progress and will be reported in due course 25DA Thus, it may be assumed that the differences in the drug release rate mainly result from different placement of this hybrid phase It is understandable if one take into account the differences in porosity and in composition of PTD and CT15-25D It seems that smaller pores/ channels in PTD are more effectively plugged by the hybrid silica fabricated; this, in turn, hinders free diffusion of the solvent molecules into the subunits As a result, desorption rate of DS is significantly slowed down The hybrid silica affects not only the rate, but also the efficiency of DS release reducing it significantly Taking into account the Raman results, it may be assumed that drug molecules are captured in part by the hybrid silica phase during its formation It seems, that mainly this fraction is able to be freely desorbed from PTDA, while desorption of DS molecules deeply embedded within PTD is restricted The peak at the PSD of CT15-25D is shifted towards larger pores compared to PTD It seems that the largest pores have not been totally plugged by the hybrid silica since the drug can easily desorb from this composite just after its immersion in the buffer solution Although, the hybrid silica is located in the subunits, the efficiency of drug release is relatively high Profiles of DS desorption using the sequential pH seem to confirm this conclusion It is likely that free volumes which ensure high efficiency of desorption of DS in a buffer pH 6.8 alone, also facilitate inflow of HCl into the CT1525DA microspheres As a result, part of DS molecules undergoes trans formation into a derivative of phenylacetic acid of a lower solubility Although, the total amount of the drug released in a buffer pH 6.8 after the acid-stage is lower in comparison to the sample immersed only in pH 6.8, it is still higher than from PTDA This indicate that the porosity of the carrier before modification with hybrid silica is a crucial factor which affects both the rate and the efficiency of DS release Authors contribution The manuscript was written through contributions of all authors All authors have given approval to the final version of the manuscript Declaration of competing interest There are no conflicts to declare Acknowledgement Conclusions The research leading to these results has received funding from the Polish National Science Centre [grant number 2018/02/X/ST5/00549] 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 Centre of Functional Nanomaterials) The polymer–mesoporous silica composites in the form of beads 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Grochowicz, J Goworek, Thinning down of polymer matrix by entrapping silica nanoparticles, Colloid Polym Sci 289 (2011) 751–758 12 ... subunits The drug release profiles measured for them are presented in Fig 11 Fig 11 illustrates the influence of the MSAs silicas introduction on the drug desorption According to DS release profiles... chosen as a model drug for this study The control over drug desorption rate, and especially the reduction of the burst release, is a very important issue in the case of water-soluble drugs This can... hybrid silica since the drug can easily desorb from this composite just after its immersion in the buffer solution Although, the hybrid silica is located in the subunits, the efficiency of drug release