Adsorption and Release Properties of Drug Delivery System Naproxen-SBA-15: Effect of Surface Polarity, Sodium/Acid Drug Form and pH.

Mesoporous silica SBA-15 was prepared via sol-gel synthesis and functionalized with different types of organosilanes containing various organic functional groups: (3-aminopropyl)triethoxysilane (SBA-15-NH2), (3-mercaptopropyl)triethoxysilane (SBA-15-SH), triethoxymethylsilane (SBA-15-CH3), triethoxyphenylsilane (SBA-15-Ph), and (3-isocynatopropyl)triethoxysilane (SBA-15-NCO). The prepared materials were investigated as drug delivery systems for naproxen. As model drugs, naproxen acid (HNAP) and its sodium salt (NaNAP) were used. Mentioned medicaments belong to the group of non-steroidal anti-inflammatory drugs (NSAIDs). The prepared materials were characterized by different analytical methods such as transmission electron microscopy (TEM), infrared spectroscopy (IR), nitrogen adsorption/desorption analysis (N2), thermogravimetric analysis (TG), 1H, 13C and 23Na solid-state nuclear magnetic resonance spectroscopy (1H, 13C and 23Na ss-NMR). The abovementioned analytical techniques confirmed the successful grafting of functional groups to the SBA-15 surface and the adsorption of drugs after the impregnation process. The BET area values decreased from 927 m2 g-1 for SBA-15 to 408 m2 g-1 for SBA-15-NCO. After drug encapsulation, a more significant decrease in surface area was observed due to the filling of pores with drug molecules, while the most significant decrease was observed for the SBA-15-NH2 material (115 m2 g-1 for NaNAP and 101 m2 g-1 for HNAP). By combining TG and nitrogen adsorption results, the occurrence of functional groups and the affinity of drugs to the carriers' surface were calculated. The dominant factor was the volume of functional groups and intermolecular interactions. The highest drug affinity values were observed for phenyl and amine-modified materials (SBA-15-Ph = 1.379 µmol m-2 mmol-1 for NaNAP, 1.761 µmol m-2 mmol-1 for HNAP and SBA-15-NH2 = 1.343 µmol m-2 mmol-1 for NaNAP, 1.302 µmol m-2 mmol-1 for HNAP) due to the formation of hydrogen bonds and π-π interactions, respectively. Drug release properties and kinetic studies were performed at t = 37 °C (normal human body temperature) in different media with pH = 2 as simulated human gastric fluid and pH = 7.4, which simulated a physiological environment. Determination of drug release quantity was performed with UV-VIS spectroscopy. The surface polarity, pH and naproxen form influenced the total released amount of drug. In general, naproxen sodium salt has a higher solubility than its acid form, thus significantly affecting drug release from surface-modified SBA-15 materials. Different pH conditions involved surface protonation and formation/disruption of intermolecular interactions, influencing both the release rate and the total released amount of naproxen. Different kinetic models, zero-order, first-order, Higuchi and Hixson-Crowell models, were used to fit the drug release data. According to the obtained experimental results, the drug release rates and mechanisms were determined.

Rational Design of Self-Emulsifying Pellet Formulation of Thymol: Technology Development Guided by Molecular-Level Structure Characterization and Ex Vivo Testing.

The growing need for processing natural lipophilic and often volatile substances such as thymol, a promising candidate for topical treatment of intestinal mucosa, led us to the utilization of solid-state nuclear magnetic resonance (ss-NMR) spectroscopy for the rational design of enteric pellets with a thymol self-emulsifying system (SES). The SES (triacylglycerol, Labrasol®, and propylene glycol) provided a stable o/w emulsion with particle size between 1 and 7 µm. The ex vivo experiment confirmed the SES mucosal permeation and thymol delivery to enterocytes. Pellets W90 (MCC, Neusilin®US2, chitosan) were prepared using distilled water (90 g) by the M1−M3 extrusion/spheronisation methods varying in steps number and/or cumulative time. The pellets (705−740 µm) showed mostly comparable properties­zero friability, low intraparticular porosity (0−0.71%), and relatively high density (1.43−1.45%). They exhibited similar thymol release for 6 h (burst effect in 15th min ca. 60%), but its content increased (30−39.6 mg/g) with a shorter process time. The M3-W90 fluid-bed coated pellets (Eudragit®L) prevented undesirable thymol release in stomach conditions (<10% for 3 h). A detailed, ss-NMR investigation revealed structural differences across samples prepared by M1−M3 methods concerning system stability and internal interactions. The suggested formulation and methodology are promising for other lipophilic volatiles in treating intestinal diseases.

Enantiotropy of Simvastatin as a Result of Weakened Interactions in the Crystal Lattice: Entropy-Driven Double Transitions and the Transient Modulated Phase as Seen by Solid-State NMR Spectroscopy.

In crystalline molecular solids, in the absence of strong intermolecular interactions, entropy-driven processes play a key role in the formation of dynamically modulated transient phases. Specifically, in crystalline simvastatin, the observed fully reversible enantiotropic behavior is associated with multiple order-disorder transitions: upon cooling, the dynamically disordered high-temperature polymorphic Form I is transformed to the completely ordered low-temperature polymorphic Form III via the intermediate (transient) modulated phase II. This behavior is associated with a significant reduction in the kinetic energy of the rotating and flipping ester substituents, as well as a decrease in structural ordering into two distinct positions. In transient phase II, the conventional three-dimensional structure is modulated by periodic distortions caused by cooperative conformation exchange of the ester substituent between the two states, which is enabled by weakened hydrogen bonding. Based on solid-state NMR data analysis, the mechanism of the enantiotropic phase transition and the presence of the transient modulated phase are documented.

Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution.

At present, the risk of generic substitutions in warfarin tablets is still being discussed. The aim of this study was to assess whether API interactions with commonly used excipients may affect the safety of generic replacement of warfarin sodium tablets. These interactions were observed during an accelerated stability study, and the effect of the warfarin solid phase (crystalline/amorphous form) as well as the API particle size distribution was studied. Commercial tablets and prepared tablets containing crystalline warfarin or amorphous warfarin were used. In addition, binary mixtures of warfarin with various excipients were prepared. The structural changes before and after the stability study were monitored by dissolution test in different media, solid-state NMR spectroscopy and Raman microscopy. During the stability study, the conversion of the sodium in warfarin to its acid form was demonstrated by some excipients (e.g., calcium phosphate). This change in the solid phase of warfarin leads to significant changes in dissolution, especially with the different particle sizes of the APIs in the tablet. Thus, the choice of suitable excipients and particle sizes are critical factors influencing the safety of generic warfarin sodium tablets.

Ultrasonic Pretreatment as a Tool for the Preparation of Low-Defect Zeolite Mordenite.

The effects of the ultrasonic (US) pretreatment of synthesis gel for the preparation of mordenite zeolite were studied in comparison with the classical stirring method. Even though the US pretreatment was performed before the hydrothermal crystallization, it significantly affected the properties of the obtained mordenite crystals. The US-assisted procedure resulted in a material with improved textural characteristics, in particular, the micropore volume accessible for nitrogen molecules in the as-made form. On the other hand, mordenite prepared with the classical stirring method demonstrated comparable sorption properties only after a postsynthetic treatment. Moreover, in the case of US-pretreated mordenite, altered crystal shape and more homogeneous morphology were observed. 29Si magic-angle spinning nuclear magnetic resonance (MAS NMR) demonstrated that the US pretreatment introduced structural changes on the atomic level, resulting in fewer defects (reflected in the number of silanol groups) and less pore blockage (affected by Na+ cations) for the as-made sample.

Transferring Lithium Ions in the Nanochannels of Flexible Metal-Organic Frameworks Featuring Superchaotropic Metallacarborane Guests: Mechanism of Ionic Conductivity at Atomic Resolution.

Metal-organic frameworks (MOFs), owing to their unique architecture, attract consistent attention in the design of high-performance Li battery materials. Here, we report a new category of ion-conducting crystalline materials for all-solid-state electrolytes based on an MIL53(Al) framework featuring a superchaotropic metallacarborane (Li+CoD-) salt and present the first quantitative data on Li+ ion sites, local dynamics, chemical exchange, and the formation of charge-transfer pathways. We used multinuclear solid-state nuclear magnetic resonance (ss-NMR) spectroscopy to examine the mechanism of ionic conductivity at atomic resolution and to elucidate order-disorder processes, framework-ion interactions, and framework breathing during the loading of Li+CoD- species and transfer of Li+ ions. In this way, the MIL53(Al)@LiCoD framework was found to adopt an open-pore conformation accompanied by a minor fraction of narrow-pore channels. The inserted Li+ ions have two states (free and bound), which both exhibit extensive motions. Both types of Li+ ions form mutually communicating chains, which are large enough to enable efficient long-range charge transfer and macroscopic conductivity. The superchaotropic anions undergo high-amplitude uniaxial rotation motions supporting the transfer of Li+ cations along them, while the fluctuations of MOF aromatic linkers support the penetration of Li+ through the channel walls. Our findings provide a detailed atomic-resolution insight into the mechanism of ionic conductivity and thus have significant implications for the design of the next generation of energy-related materials.

Cytotoxicity study and influence of SBA-15 surface polarity and pH on adsorption and release properties of anticancer agent pemetrexed.

Mesoporous material SBA-15 was functionalized with different polar and nonpolar groups: 3-aminopropyl, (SBA-15-NH2), 3-isocyanatopropyl (SBA-15-NCO), 3-mercaptopropyl (SBA-15-SH), methyl (SBA-15-CH3) and phenyl (SBA-15-Ph). The resulting surface grafted materials were investigated as matrices for controlled drug delivery. Anticancer agent, pemetrexed (disodium pemetrexed heptahydrate) was selected as a model drug and loaded in the unmodified and functionalized SBA-15 materials. Materials were characterized by elemental analysis, infrared spectroscopy, transmission electron microscopy, nitrogen adsorption/desorption analysis, small angle X-ray scattering, powder X-ray diffraction, solid state NMR spectroscopy and thermogravimetry. It was shown that surface modification has an impact on both encapsulated drug amount and release properties. Release experiments were performed into two media with different pH: simulated body fluid (pH = 7.4) and simulated gastric fluid (pH = 2). In general, the effect of pH was reflected by the lower release of pemetrexed under acidic conditions (pH = 2) compared to slightly alkaline saline environment (pH = 7.4). The release rate of pemetrexed from propylamine-, propylisocyanate- and phenyl-modified SBA-15 was found to be effectively controlled by intermolecular interactions as compared to that from pure SBA-15, SBA-15-SH, and SBA-15-CH3, that evidenced a steady and similar release. The highest release was observed for methyl-functionalized material whose hydrophobic surface accelerates the pemetrexed release. The data obtained from release studies were fitted using various kinetic models to determine the pemetrexed release mechanism and its release rate. The best correlations were found for Korsmeyer-Peppas and Higuchi models. Moreover, the theoretical three-parameter model for drug release kinetic was applied to calculate the strength of drug-support interactions. The in vitro cell study was performed on SKBR3 cancer cells and obtained results demonstrated that the modification of the mesoporous silica material by grafted polar/nonpolar groups may significantly affect the compatibility of this material with cells, drug release from this material and subsequent biological activity of PEM.

Interaction Pathways and Structure-Chemical Transformations of Alginate Gels in Physiological Environments.

The remarkably diverse affinity of alginate (ALG) macromolecules for polyvalent metal ions makes cross-linked alginate gels an outstanding biomaterial. Surprisingly, however, very little is known about their interactions and structural transformations in physiological environments. To bridge this gap, we prepared a set of ALG gels cross-linked by various ions and monitored their structural changes at different media simulating gastric and intestinal fluids and cellular environments. For these studies, we used multinuclear solid-state NMR (ss-NMR) spectroscopy, which revealed a range of competitive ion-exchange and interconversion reactions, the rate of which strongly depended on the nature of the cross-linking metal ions. Depending on the environment, ALG chains adopted different forms, such as acidic (hydro)gels stabilized by strong hydrogen bonds, and/or weakly cross-linked Na/H-gels. Simultaneously, the exchanged polyvalent ions extensively interacted with the environment even forming in some cases insoluble phosphate microdomains directly deposited in the ALG bead matrix. The extent of the transformations and incorporation of secondary phases into the alginate beads followed the size and electronegativity of the cross-linking ions. Overall, the applied combination of various macroscopic and biological tests with multinuclear ss-NMR revealed a complex pathway of alginate beads transformations in physiological environments.

Tubes for detection of cholinesterase inhibitors-Unique effects of Neusilin on the stability of butyrylcholinesterase-impregnated carriers.

Detection tubes are small devices for the colorimetric enzymatic detection of cholinesterase inhibitors such as sarin, soman, VX nerve agents and substances denoted as Novichok. These detectors contain carriers in the form of pellets with immobilized cholinesterase, substrate and detection reagent. Their advantages are portability, sensitivity and simplicity, enabling fast detection of such compounds from air and water in case of a terrorist attack or war. In general, maintaining the stability of an enzyme for a longer time is very problematic; therefore, its further enhancement is required for safety and financial reasons. In this study, the stability of our patented carriers in the form of pellets with immobilized butyrylcholinesterase containing an increasing amount of the unique sorbent Neusilin® US2 was evaluated. The samples containing Neusilin maintained the stability of the immobilized enzyme for a longer time even at higher temperature and humidity than the currently commercially used carrier without Neusilin, allowing improved detection of nerve agents.

Waste Brick Dust as Potential Sorbent of Lead and Cesium from Contaminated Water.

Adsorption properties of waste brick dust (WBD) were studied by the removing of PbII and CsI from an aqueous system. For adsorption experiments, 0.1 M and 0.5 M aqueous solutions of Cs+ and Pb2+ and two WBD (Libochovice-LB, and Tyn nad Vltavou-TN) in the fraction below 125 µm were used. The structural and surface properties of WBD were characterized by X-ray diffraction (XRD) in combination with solid-state nuclear magnetic resonance (NMR), supplemented by scanning electron microscopy (SEM), specific surface area (SBET), total pore volume and zero point of charge (pHZPC). LB was a more amorphous material showing a better adsorption condition than that of TN. The adsorption process indicated better results for Pb2+, due to the inner-sphere surface complexation in all Pb2+ systems, supported by the formation of insoluble Pb(OH)2 precipitation on the sorbent surface. A weak adsorption of Cs+ on WBD corresponded to the non-Langmuir adsorption run followed by the outer-sphere surface complexation. The leachability of Pb2+ from saturated WBDs varied from 0.001% to 0.3%, while in the case of Cs+, 4% to 12% of the initial amount was leached. Both LB and TN met the standards for PbII adsorption, yet completely failed for any CsI removal from water systems.

Highly Soluble Drugs Directly Granulated by Water Dispersions of Insoluble Eudragit® Polymers as a Part of Hypromellose K100M Matrix Systems.

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

Structure and Dynamics of Alginate Gels Cross-Linked by Polyvalent Ions Probed via Solid State NMR Spectroscopy.

Alginate gels are an outstanding biomaterial widely applicable in tissue engineering, medicine, and pharmacy for cell transplantation, wound healing and efficient bioactive agent delivery, respectively. This contribution provides new and comprehensive insight into the atomic-resolution structure and dynamics of polyvalent ion-cross-linked alginate gels in microbead formulations. By applying various advanced solid-state NMR (ssNMR) spectroscopy techniques, we verified the homogeneous distribution of the cross-linking ions in the alginate gels and the high degree of ion exchange. We also established that the two-component character of the alginate gels arises from the concentration fluctuations of residual water molecules that are preferentially localized along polymer chains containing abundant mannuronic acid (M) residues. These hydrated M-rich blocks tend to self-aggregate into subnanometer domains. The resulting coexistence of two types of alginate chains differing in segmental dynamics was revealed by 1H-13C dipolar profile analysis, which indicated that the average fluctuation angles of the stiff and mobile alginate segments were about 5-9° or 30°, respectively. Next, the 13C CP/MAS NMR spectra indicated that the alginate polymer microstructure was strongly dependent on the type of cross-linking ion. The polymer chain regularity was determined to systematically decrease as the cross-linking ion radius decreased. Consistent with the 1H-1H correlation spectra, regular structures were found for the gels cross-linked by relatively large alkaline earth cations (Ba2+, Sr2+, or Ca2+), whereas the alginate chains cross-linked by bivalent transition metal ions (Zn2+) and trivalent metal cations (Al3+) exhibited significant irregularities. Notably, however, the observed disordering of the alginate chains was exclusively attributed to the M residues, whereas the structurally well-defined gels all contained guluronic acid (G) residues. Therefore, a key role of the units in M-rich blocks as mediators promoting the self-assembly of alginate chains was experimentally confirmed. Finally, combining 2D 27Al 3Q/MAS NMR spectroscopy with density functional theory (DFT) calculations provided previously unreported insight into the structure of the Al3+ cross-linking centers. Notably, even with a low residual amount of water, these cross-linking units adopt exclusively 6-fold octahedral coordination and exhibit significant motion, which considerably reduces quadrupolar coupling constants. Thus, the experimental strategy presented in this study provides a new perspective on cross-linked alginate structure and dynamics for which high-quality diffraction data at the atomic resolution level are inherently unavailable.

Exploring the Molecular-Level Architecture of the Active Compounds in Liquisolid Drug Delivery Systems Based on Mesoporous Silica Particles: Old Tricks for New Challenges.

A general, easy-to-implement strategy for mapping the structure of organic phases integrated in mesoporous silica drug delivery devices is presented. The approach based on a few straightforward solid-state NMR techniques has no limitations regarding concentrations of the active compounds and enables straightforward discrimination of various organic phases. This way, among a range of typical arrangements of the active compounds and solvent molecules, a unique, previously unknown organogel phase of the self-assembled tapentadol in glucofurol as a solvent was unveiled and clearly identified. Subsequently, with an aid of 2D 1H-1H MAS NMR and high-level quantum-chemical calculations this uncommon low-molecular-weight organogel phase, existing exclusively in the porous system of the silica carrier, was described in detail. The optimized model revealed the tendency of tapentadol molecules to form hydrophobic arrangements through -OH···π interactions combined with π-π stacking occurring in the core of API aggregates, thus precluding the formation of hydrogen bonds with the solvent. Overall, the proposed experimental approach allows for clear discrimination of a variety of local structures of active compounds loaded in mesoporous silica drug delivery devices in reasonably short time being applicable for advancement of novel drug delivery systems in pharmaceutical industry.

Interface Induced Growth and Transformation of Polymer-Conjugated Proto-Crystalline Phases in Aluminosilicate Hybrids: A Multiple-Quantum (23)Na-(23)Na MAS NMR Correlation Spectroscopy Study.

Nanostructured materials typically offer enhanced physicochemical properties because of their large interfacial area. In this contribution, we present a comprehensive structural characterization of aluminosilicate hybrids with polymer-conjugated nanosized zeolites specifically grown at the organic-inorganic interface. The inorganic amorphous Al-O-Si framework is formed by alkali-activated low-temperature transformation of metakaoline, whereas simultaneous copolymerization of organic comonomers creates a secondary epoxide network covalently bound to the aluminosilicate matrix. This secondary epoxide phase not only enhances the mechanical integrity of the resulting hybrids but also introduces additional binding sites accessible for compensating negative charge on the aluminosilicate framework. This way, the polymer network initiates growth and subsequent transformation of protocrystalline short-range ordered zeolite domains that are located at the organic-inorganic interface. By applying an experimental approach based on 2D (23)Na-(23)Na double-quantum (DQ) MAS NMR spectroscopy, we discovered multiple sodium binding sites in these protocrystalline domains, in which immobilized Na(+) ions form pairs or small clusters. It is further demonstrated that these sites, the local geometry of which allows for the pairing of sodium ions, are preferentially occupied by Pb(2+) ions during the ion exchange. The proposed synthesis protocol thus allows for the preparation of a novel type of geopolymer hybrids with polymer-conjugated zeolite phases suitable for capturing and storage of metal cations. The demonstrated (23)Na-(23)Na DQ MAS NMR combined with DFT calculations represents a suitable approach for understanding the role of Na(+) ions in aluminositicate solids and related inorganic-organic hybrids, particularly their specific arrangement and clustering at interfacial areas.

Molecular-Level Control of Ciclopirox Olamine Release from Poly(ethylene oxide)-Based Mucoadhesive Buccal Films: Exploration of Structure-Property Relationships with Solid-State NMR.

Mucoadhesive buccal films (MBFs) provide an innovative way to facilitate the efficient site-specific delivery of active compounds while simultaneously separating the lesions from the environment of the oral cavity. The structural diversity of these complex multicomponent and mostly multiphase systems as well as an experimental strategy for their structural characterization at molecular scale with atomic resolution were demonstrated using MBFs of ciclopirox olamine (CPX) in a poly(ethylene oxide) (PEO) matrix as a case study. A detailed description of each component of the CPX/PEO films was followed by an analysis of the relationships between each component and the physicochemical properties of the MBFs. Two distinct MBFs were identified by solid-state NMR spectroscopy: (i) at low API (active pharmaceutical ingredient) loading, a nanoheterogeneous solid solution of CPX molecularly dispersed in an amorphous PEO matrix was created; and (ii) at high API loading, a pseudoco-crystalline system containing CPX-2-aminoethanol nanocrystals incorporated into the interlamellar space of a crystalline PEO matrix was revealed. These structural differences were found to be closely related to the mechanical and physicochemical properties of the prepared MBFs. At low API loading, the polymer chains of PEO provided sufficient quantities of binding sites to stabilize the CPX that was molecularly dispersed in the highly amorphous semiflexible polymer matrix. Consequently, the resulting MBFs were soft, with low tensile strength, plasticity, and swelling index, supporting rapid drug release. At high CPX content, however, the active compounds and the polymer chains simultaneously cocrystallized, leaving the CPX to form nanocrystals grown directly inside the spherulites of PEO. Interfacial polymer-drug interactions were thus responsible not only for the considerably enhanced plasticity of the system but also for the exclusive crystallization of CPX in the thermodynamically most stable polymorphic form, Form I, which exhibited reduced dissolution kinetics. The bioavailability of CPX olamine formulated as PEO-based MBFs can thus be effectively controlled by inducing the complete dispersion and/or microsegregation and nanocrystallization of CPX olamine in the polymer matrix. Solid-state NMR spectroscopy is an efficient tool for exploring structure-property relationships in these complex pharmaceutical solids.

Location of Framework Al Atoms in the Channels of ZSM-5: Effect of the (Hydrothermal) Synthesis.

(27) Al 3Q MAS NMR and UV/Vis spectroscopy with bare Co(II) ions as probes of Al pairs in the zeolite framework were employed to analyze the location of framework Al atoms in the channel system of zeolite ZSM-5. Furthermore, the effect of Na(+) ions together with tetrapropylammonium cation (TPA(+)) in the ZSM-5 synthesis gel on the location of Al in the channel system was investigated. Zeolites prepared using exclusively TPA(+) as a structure-directing agent (i.e., in the absence of Na(+) ions) led to 55-90% of Al atoms located at the channel intersection, regardless the presence or absence of Al pairs [Al-O-(Si-O)2 -Al sequences in one ring] in the zeolite framework. The presence of Na(+) ions in the synthesis gel did not modify the Al location at the channel intersection (55-95% of Al atoms) and led only to changes in i) the distribution of framework Al atoms between Al pairs (decrease) and single isolated Al atoms (increase), and ii) the siting of Al in distinguishable framework tetrahedral sites.

Structure of framework aluminum Lewis sites and perturbed aluminum atoms in zeolites as determined by 27Al{1H} REDOR (3Q) MAS NMR spectroscopy and DFT/molecular mechanics.

Zeolites are highly important heterogeneous catalysts. Besides Brønsted SiOHAl acid sites, also framework AlFR Lewis acid sites are often found in their H-forms. The formation of AlFR Lewis sites in zeolites is a key issue regarding their selectivity in acid-catalyzed reactions. The local structures of AlFR Lewis sites in dehydrated zeolites and their precursors--"perturbed" AlFR atoms in hydrated zeolites--were studied by high-resolution MAS NMR and FTIR spectroscopy and DFT/MM calculations. Perturbed framework Al atoms correspond to (SiO)3AlOH groups and are characterized by a broad (27)Al NMR resonance (δi = 59-62 ppm, CQ = 5 MHz, and η = 0.3-0.4) with a shoulder at 40 ppm in the (27)Al MAS NMR spectrum. Dehydroxylation of (SiO)3AlOH occurs at mild temperatures and leads to the formation of AlFR Lewis sites tricoordinated to the zeolite framework. Al atoms of these (SiO)3Al Lewis sites exhibit an extremely broad (27)Al NMR resonance (δi ≈ 67 ppm, CQ ≈ 20 MHz, and η ≈ 0.1).

In vitro dissolution study of acetylsalicylic acid solid dispersions. Tunable drug release allowed by the choice of polymer matrix.

Due to their high versatility and diverse excipient options, solid dispersions (SDs) are an elegant choice for the formulation of active pharmaceutical ingredients with inconvenient solubility. Four distinct types of polymers with different physicochemical properties [polyvinylpyrrolidone, poly[N-(2-hydroxypropyl)-metacrylamide], poly(2-ethyl-2-oxazoline), and polyethylene glycol] and variable molecular weights were compared to investigate the influence of the polymer matrix on drug release. To probe the extent of intercomponent interactions, acetylsalicylic acid (ASA) was used as a model active substance. Controlled drug release was demonstrated for all four types of polymer-ASA SDs created by the freeze-drying method. While the polyethylene glycol-ASA SD exhibited an increased dissolution rate, the other polymer-ASA systems exhibited significantly reduced drug dissolution kinetics compared to free ASA. Furthermore, in contrast to physical mixtures, the prepared SDs all exhibited zero-order dissolution kinetics for ASA. The dissolution rate was strongly dependent on the molecular weight of the polymer. These results demonstrate that the type of SD may be controlled by the chemical constitutions of the polymers and that appropriate selection of the molecular weight of the polymer matrix enables finely tuned drug release over a wide range of dissolution rates.

Structural insight into the physical stability of amorphous Simvastatin dispersed in pHPMA: enhanced dynamics and local clustering as evidenced by solid-state NMR and Raman spectroscopy.

New drug formulations are sought for poorly water-soluble substances because there is a risk of compromised bioavailability if such substances are administered orally. Such active pharmaceutical ingredients can be reformulated as solid dispersions with suitable water-soluble polymers. In this contribution, formulation of a novel and physically stable dispersion of Simvastatin in poly(2-hydroxypropyl) methacrylamide (pHPMA) is demonstrated. Due to the limited water sorption of pHPMA and a high Tg, the prepared dispersion is more suited for oral administration and storage compared with neat amorphous Simvastatin. Surprisingly, the rate of global reorientation and the internal motion of Simvastatin molecules were enhanced and exhibited dynamical heterogeneities when incorporated into the pHPMA matrix. As revealed by solid-state nuclear magnetic resonance combined with Raman spectroscopy exploiting the fluorescence phenomenon the mobility of the ester and lactone components increased considerably, whereas the naphthalene ring remained rigid. Furthermore, the solid dispersion was found to be nano-heterogeneous with nanometer-sized Simvastatin domains. The presence of these clusters had no impact on the dynamics of the rigid pHPMA chains. Thus, the diffusion of Simvastatin molecules through the glassy pHPMA walls and the subsequent transformation of the clusters into larger crystallites were prevented. No crystallization was detected for more than two years.

Structural diversity of solid dispersions of acetylsalicylic acid as seen by solid-state NMR.

Solid dispersions of active pharmaceutical ingredients are of increasing interest due to their versatile use. In the present study polyvinylpyrrolidone (PVP), poly[N-(2-hydroxypropyl)-metacrylamide] (pHPMA), poly(2-ethyl-2-oxazoline) (PEOx), and polyethylene glycol (PEG), each in three Mw, were used to demonstrate structural diversity of solid dispersions. Acetylsalicylic acid (ASA) was used as a model drug. Four distinct types of the solid dispersions of ASA were created using a freeze-drying method: (i) crystalline solid dispersions containing nanocrystalline ASA in a crystalline PEG matrix; (ii) amorphous glass suspensions with large ASA crystallites embedded in amorphous pHPMA; (iii) solid solutions with molecularly dispersed ASA in rigid amorphous PVP; and (iv) nanoheterogeneous solid solutions/suspensions containing nanosized ASA clusters dispersed in a semiflexible matrix of PEOx. The obtained structural data confirmed that the type of solid dispersion can be primarily controlled by the chemical constitutions of the applied polymers, while the molecular weight of the polymers had no detectable impact. The molecular structure of the prepared dispersions was characterized using solid-state NMR, wide-angle X-ray scattering (WAXS), and differential scanning calorimetry (DSC). By applying various (1)H-(13)C and (1)H-(1)H correlation experiments combined with T1((1)H) and T1ρ((1)H) relaxation data, the extent of the molecular mixing was determined over a wide range of distances, from intimate intermolecular contacts (0.1-0.5 nm) up to the phase-separated nanodomains reaching ca. 500 nm. Hydrogen-bond interactions between ASA and polymers were probed by the analysis of (13)C and (15)N CP/MAS NMR spectra combined with the measurements of (1)H-(15)N dipolar profiles. Overall potentialities and limitations of individual experimental techniques were thoroughly evaluated.