Structural Elucidation of Poloxamer 237 and Poloxamer 237/Praziquantel Solid Dispersions: Impact of Poly(Vinylpyrrolidone) over Drug Recrystallization and Dissolution.

Praziquantel (PZQ) is the recommended, effective, and safe treatment against all forms of schistosomiasis. Solid dispersions (SDs) in water-soluble polymers have been reported to increase solubility and bioavailability of poorly water-soluble drugs like PZQ, generally due to the amorphous form stabilization. In this work, poloxamer (PLX) 237 and poly(vinylpyrrolidone) (PVP) K30 were evaluated as potential carriers to revert PZQ crystallization. Binary and ternary SDs were prepared by the solvent evaporation method. PZQ solubility increased similarly with PLX either as binary physical mixtures or SDs. Such unpredicted data correlated well with crystalline PZQ and PLX as detected by solid-state NMR (ssNMR) and differential scanning calorimetry in those samples. Ternary PVP/PLX/PZQ SDs showed both ssNMR broad and narrow superimposed signals, thus revealing the presence of amorphous and crystalline PZQ, respectively, and exhibited the highest PZQ dissolution efficiency (up to 82% at 180 min). SDs with PVP provided a promising way to enhance solubility and dissolution rate of PZQ since PLX alone did not prevent recrystallization of amorphous PZQ. Based on ssNMR data, novel evidences on PLX structure and molecular dynamics were also obtained. As shown for the first time using ssNMR, propylene glycol and ethylene glycol constitute the PLX amorphous and crystalline components, respectively.

Unexpected solvent impact in the crystallinity of praziquantel/poly(vinylpyrrolidone) formulations. A solubility, DSC and solid-state NMR study.

The saturation solubility of PVP:PZQ physical mixtures (PMs) and solid dispersions (SDs) prepared from ethanol (E/E) or ethanol/water (E/W) by the solvent evaporation method at 1:1, 2:1 and 3:1 ratio (w/w) was determined. The presence of PVP improves the solubility of PZQ (0.31±0.01mg/mL). A maximum of 1.29±0.03mg/mL of PZQ in solution was achieved for the 3:1 SD (E/E). The amount of PZQ in solution depends on the amount of polymer and on the preparation method. Solid-state NMR (ssNMR) and DSC were used to understand this behavior. Results show that PMs are a mixture of crystalline PZQ with the polymer, while SDs show different degrees of drug amorphization depending on the solvent used. For E/W SDs, PZQ exists in amorphous and crystalline states, with no clear correlation between the amount of crystalline PZQ and the amount of PVP. For E/E SDs, formulations with a higher percentage of PZQ are amorphous with the components miscible in domains larger than 3nm ((1)H ssNMR relaxation measurements). Albeit its higher saturation solubility, the 3:1 E/E PVP:PZQ sample has a significant crystalline content, probably due to the water introduced by the polymer. High PVP content and small crystal size account for this result.

Elucidating the guest-host interactions and complex formation of praziquantel and cyclodextrin derivatives by (13)C and (15)N solid-state NMR spectroscopy.

Praziquantel is the drug of choice to treat several parasitic infections including the neglected tropical disease schistosomiasis. Due to its low aqueous solubility, cyclodextrins have been tested as potential host candidates to prepare praziquantel inclusion complexes with improved solubility. For the first time, the interactions of praziquantel with ß-cyclodextrin and ß-cyclodextrin derivatives (methyl-ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) were investigated using high resolution solid-state NMR spectroscopy. The results of this work confirmed that solid-state NMR experiments provided structural characterization, demonstrating the formation of inclusion complexes most probably with PZQ adopting an anti conformation, also the most likely in amorphous raw PZQ. Further information on the interaction of praziquantel with methyl-ß-cyclodextrin was obtained from proton rotating-frame relaxation time measurements, sensitive to kilohertz-regime motions but modulated by spin-diffusion. Evidences were presented in all cases for praziquantel complexation through the aromatic ring. In addition, 1:2 drug:carrier molar ratio appears to be the most probable and therefore suitable stoichiometry to improve pharmaceutical formulations of this antischistosomal drug.

First solid-state NMR spectroscopy evaluation of complexes of benznidazole with cyclodextrin derivatives.

Complexation of benznidazole (BZL), a drug of choice for the treatment of Chagas'neglected disease, with cyclodextrin (CD) derivatives was analyzed by solid-state NMR. (13)C cross polarization/magic angle spinning spectra were recorded from BZL and from BZL:ß-CD, BZL:methyl ß-CD and BZL:hydroxypropyl ß-CD complexes, which were obtained by the solvent evaporation technique. No significant evidence was obtained on BZL inclusion complexes involving either ß-CD or hydroxypropyl ß-CD. Conversely, BZL:methyl ß-CD displayed BZL resonances characteristic of an amorphous drug and data analysis confirmed the presence of stable BZL:methyl ß-CD inclusion complexes, with benzene encapsulated into the host cavity. Further evidences on complex structure and dynamics were obtained from proton and carbon spin-lattice relaxation times in the rotating frame. These data are consistent with a common guest-host spin reservoir. The BZL interaction with methyl ß-CD provided a route to stabilize amorphous BZL. Physical mixtures with identical BZL and CD compositions were also studied for comparison.

(13)C and (15)N solid-state NMR studies on albendazole and cyclodextrin albendazole complexes.

(13)C and (15)N solid-state nuclear magnetic resonance (NMR) spectra were recorded from albendazole (ABZ) and from ABZ:ß-cyclodextrin, ABZ:methyl-ß-cyclodextrin, ABZ:hydroxypropyl-ß-cyclodextrin and ABZ:citrate-ß-cyclodextrin, which were prepared by the spray-drying technique. ABZ signals were typical of a crystalline solid for the pure drug and of an amorphous compound obtained from ABZ:cyclodextrin samples. Relevant spectral differences were correlated with chemical interaction between ABZ and cyclodextrins. The number and type of complexes revealed a strong dependence on the cyclodextrin group substituent. Solid-state NMR data were consistent with the presence of stable inclusion complexes.

New thermoresistant polymorph from CO2 recrystallization of minocycline hydrochloride.

PURPOSE: To prepare and thoroughly characterize a new polymorph of the broad-spectrum antibiotic minocycline from its hydrochloride dehydrate salts. METHODS: The new minocycline hydrochloride polymorph was prepared by means of the antisolvent effect caused by carbon dioxide. Minocycline recrystallized as a red crystalline hydrochloride salt, starting from solutions or suspensions containing CO2 and ethanol under defined conditions of temperature, pressure and composition. RESULTS: This novel polymorph (ß-minocycline) revealed characteristic PXRD and FTIR patterns and a high melting point (of 247 ºC) compared to the initial minocycline hydrochloride hydrates (α-minocycline). Upon dissolution the new polymorph showed full anti-microbial activity. Solid-state NMR and DSC studies evidenced the higher chemical stability and crystalline homogeneity of ß-minocycline compared to the commercial chlorohydrate powders. Molecular structures of both minocyclines present relevant differences as shown by multinuclear solid-state NMR. CONCLUSIONS: This work describes a new crystalline structure of minocycline and evidences the ability of ethanol-CO2 system in removing water molecules from the crystalline structure of this API, at modest pressure, temperature and relatively short time (2 h), while controlling the crystal habit. This process has therefore the potential to become a consistent alternative towards the control of the solid form of APIs.

A stable amorphous statin: solid-state NMR and dielectric studies on dynamic heterogeneity of simvastatin.

Statins have been widely used as cholesterol-lowering agents. However, low aqueous solubility of crystalline statins and, consequently, reduced biovailability require seeking for alternative forms and formulations to ensure an accurate therapeutic window. The objective of the present study was to evaluate the stability of amorphous simvastatin by probing molecular dynamics using two nondestructive techniques: solid-state NMR and dielectric relaxation spectroscopy. Glassy simvastatin was obtained by the melt quench technique. (13)C cross-polarization/magic-angle-spinning (CP/MAS) NMR spectra and (1)H MAS NMR spectra were obtained from 293 K up to 333 K (Tg ≈ 302 K). The (13)C spin-lattice relaxation times in the rotating frame, T1ρ, were measured as a function of temperature, and the correlation time and activation energy data obtained for local motions in different frequency scales revealed strong dynamic heterogeneity, which appears to be essential for the stability of the amorphous form of simvastatin. In addition, the (1)H MAS measurements presented evidence for mobility of the hydrogen atoms in hydroxyl groups which was assigned to noncooperative secondary relaxations. The complex dielectric permittivity of simvastatin was monitored in isochronal mode at five frequencies (from 0.1 to 1000 kHz), by carrying out a heating/cooling cycle allowing to obtain simvastatin in the supercooled and glassy states. The results showed that no dipolar moment was lost due to immobilization, thus confirming that no crystallization had taken place. Complementarily, the present study focused on the thermal stability of simvastatin using thermogravimetric analysis while the thermal events were followed up by differential scanning calorimetry and dielectric relaxation spectroscopy. Overall, the results confirm that the simvastatin in the glass form reveals a potential use in the solid phase formulation on the pharmaceutical industry.

Molecular dynamics of amorphous gentiobiose studied by solid-state NMR.

A solid-state NMR (SSNMR) study is reported on the effect of temperature on the molecular mobility of amorphous gentiobiose, which is complemented with data obtained from crystalline samples. (13)C cross-polarization/magic-angle-spinning (CPMAS) spectra and (1)H MAS spectra were obtained for gentiobiose at natural abundance, in the amorphous state, from 293 K up to the glass transformation region (T(g) = 359 K). Two well-defined molecular mobility regimes were observed, corresponding to different motional modes. NMR results on molecular dynamics are discussed and compared with those obtained by thermally stimulated depolarization currents (TSDC) and dielectric relaxation spectroscopy (DRS). SSNMR spectra presented evidence for a new polymorphic form of gentiobiose, not yet reported in the literature, which is obtained by slow heating of the amorphous solid up to 364 K inside the NMR zirconia rotor.

Molecular mobility studies on the amorphous state of disaccharides. I-thermally stimulated currents and differential scanning calorimetry.

The relaxational processes in amorphous solid gentiobiose and cellobiose are studied by thermally stimulated depolarization currents (TSDC) in the temperature region from 108K up to 423K. The slow molecular mobility was characterized in the crystal and in the glassy state. The features of different motional components of the secondary relaxation have been monitored as a function of time as the glass structurally relaxes on aging. It is concluded that some modes of motion of this mobility are aging independent, while others are affected by aging. The value of the steepness index or fragility (T(g)-normalized temperature dependence of the relaxation time) was obtained by differential scanning calorimetry (DSC) from the analysis of the scanning rate dependency of T(g).

Effect of curing protocol on the polymerization of dual-cured resin cements.

OBJECTIVES: The purpose of this study was to evaluate how curing protocol affects the extent of polymerization of dual-cured resin cements. METHODS: Four commercial resin cements were used (DuoLink, Panavia F 2.0, Variolink II and Enforce). The extent of polymerization of the resin cements cured under different conditions was measured using a (1)H Stray-Field MRI method, which also enabled to probe molecular mobility in the kHz frequency range. RESULTS: Resin cements show well distinct behaviours concerning chemical cure. Immediate photo-activation appears to be the best choice for higher filler loaded resin cements (Panavia F 2.0 and Variolink). A photo-activation delay (5 min) did not induce any significant difference in the extent of polymerization of all cements. SIGNIFICANCE: The extent of polymerization of dual-cured resin cements considerably changed among products under various curing protocols. Clinicians should optimize the materials choice taking into account the curing characteristics of the cements.

Sodium complexes containing 2-iminopyrrolyl ligands: the influence of steric hindrance in the formation of coordination polymers.

Iminopyrrolyl complexes of sodium were prepared from the reaction of 2-arylformiminopyrrole ligand precursors (aryl = C(6)H(5) (I); 2,6-Me(2)C(6)H(3) (II); 2,4,6-Me(3)C(6)H(2) (III); 2,6-(i)Pr(2)C(6)H(3) (IV)) with one equivalent of sodium hydride. The resulting corresponding compounds 1-4, [{Na(mu(2):kappa(2)N,N'-iminopyrrolyl)}(2n)(OEt(2))(2x)] (n > or = 1; x = 0 or 1), were obtained in moderate to high yields and were characterised by NMR spectroscopy, high resolution mass spectrometry and X-ray diffraction, when suitable crystals were obtained. The X-ray structure of compound 1 (n >> 1; x = 0) reveals the formation of a coordination polymer with repeating units consisting of dimers that contain two iminopyrrolyl ligands chelating two sodium atoms, where both pyrrolyl rings exhibit bridging sigma + sigma coordination to the Na atoms within the dimer; the self-assembling of the polymer is established by additional pi-bonds (eta(5)-coordination) of each of the pyrrolyl rings to the sodium atoms of the adjacent dimer units. Conversely, the structure of complex D(IV) (n = x = 1) shows it as one of such dimers capped by two diethyl ether molecules, each coordinated to the sodium atoms (n = 2; x = 1). DFT calculations indicate that the differences between the structures 1-4 of arise from the increasing bulkiness imposed by the corresponding substituents of the iminic aryl groups.

One-step self-etching adhesive polymerization: influence of a self-curing activator.

OBJECTIVES: The objectives of this work were to study the spatially resolved extent of photopolymerization and the final volumetric contraction of the self-etching adhesive Xeno IV (Dentsply/Caulk, Milford, DE, USA) in association with the self-curing agent Aurora (Dentsply/Caulk, Milford, DE, USA), using (1)H Stray-Field magnetic resonance imaging ((1)H STRAFI-MRI). METHODS: One-dimensional (1)H STRAFI-MRI images (projections along an axis, profiles) were acquired from the adhesive with and without Aurora, before and after solvent removal. Specimens were observed after the irradiation period recommended by the manufacturers and new profiles were recorded. Extent of polymerization and volumetric contraction were obtained by subtracting the profile of the cured adhesive from the profile of the liquid; the profiles were previously normalized using an external reference signal and the highest magnetization intensity recorded from the cured adhesive, respectively. Data were obtained in the presence of oxygen. Solvent evaporation was measured by gravimetry. RESULTS: High volumetric contraction was observed for Xeno IV and Xeno IV and Aurora mixture mainly related to solvent evaporation. A drying period favourably influenced the extent of photopolymerization of Xeno IV, which did not increase in the presence of Aurora. CONCLUSIONS: The incorporation of Aurora reduced the extent of polymerization of the one-step adhesive, probably due to the increase in the solvent content of the mixture. It may be that enhancing solvent evaporation is important in order to reach a higher extent of polymerization during the bonding procedure.

The role of aluminium and silicon in the setting chemistry of glass ionomer cements.

A model of the setting chemistry of glass-ionomer cements (GICs) is proposed based on 27Al and 29Si solid state nuclear magnetic resonance spectroscopy data on three GICs. All the precursor glasses are found to contain three aluminium species viz.: four, five and six-coordinate aluminium environments as well as four-bridging silicate tetrahedra. Upon cement formation, Al3+ ions in the glass are leached out from the surface layer of the glass. On entering the cement matrix, these ions adopt six-coordination and crosslink the polymer chains as part of the setting reaction. The remaining four-coordinate aluminium is distributed between two species: one in the inert core of the glass particles; and a second, less concentrated, in the surface layer of the glass particles, modified by the curing reactions. There is some evidence for residual five and six coordinate aluminium species in the final cement in some of the systems. In the case of the silicate tetrahedra, the curing reactions result in a decrease in the number of aluminium atoms in the second coordination sphere, with a subsequent recondensation of silicate network of the glass.

Multinuclear magnetic resonance studies on the chemical interaction of a self-etching adhesive with radicular and coronal human dentin.

This study presents evidence at molecular level for the chemical interaction between human dentin from different tooth regions and a monomer with phosphate groups, incorporated in the formulation of a simplified adhesive system. Because dentin was observed as a powder, previous verification was obtained for an eventual collagen denaturation due to the grinding process. The presence of chemical bonds involving coronal (CD) or radicular dentin (RD) was investigated using multinuclear magnetic resonance (MR) techniques. Narrow signals were identified in the carbon magic angle spinning (MAS) spectra of CD and RD treated with the adhesive, which were assigned to methylenic groups in methacryloyloxydecyl dihydrogen phosphate (MDP) bound to hydroxyapatite Ca2+; 1H spectra of the adhesive components and treated dentin, in ethanol, support this conclusion. (31)P MAS spectra obtained from both dentin regions present additional shielding and broadening effects subsequent to application and photopolymerization of the adhesive, which were higher for CD. Multinuclear MR studies provided evidence for the interaction of the adhesive with dentin, which involves hydroxyapatite and is stronger for CD than for RD, but no direct proof was obtained on bonding to collagen.

Novel light-cured resins and composites with improved physicochemical properties.

OBJECTIVES: The aim of this study was to determine the effect of two new diluent agents (Bis-GMA analogues), at different dilution levels and filler contents on relevant physicochemical properties of several novel resins and composites containing Bis-GMA as matrix. Composites using TEGDMA as diluent were used as control. METHODS: Twenty formulations were prepared combining three monomer mixtures (Bis-GMA/TEGDMA, Bis-GMA/CH(3) Bis-GMA and Bis-GMA/CF(3) Bis-GMA), at three dilution levels (85/15, 10/90, 0/100) and two percentages of filler loading (silanated barium aluminosilicate glass): 0%, 10%, 35%. Preliminary rheological testing was performed in order to obtain the viscosity of the resin samples. Resins and composites were then inserted into molds and light-cured (500mW/cm(2)). The properties evaluated were: (1) homogeneity of curing (HC), using FTIR or Vickers microindentor, (2) microhardness, by a Vickers microindentor, (3) depths of cure and oxygen inhibitor effect (OIE), quantified by scraping, (4) water contact angle on the materials surface, (5) water sorption and solubility, performed by the Oysaed-Ruyter method and (6) scanning electron microscopy analysis of the specimens surfaces. Data were analyzed by ANOVA and Student-Newman-Keuls tests (p<0.05). RESULTS: Materials with CH(3) Bis-GMA and CF(3) Bis-GMA exhibited less hydrophilicity, water sorption and solubility. Bis-GMA dilution induced an increase in depth of cure and promoted a higher OIE, particularly when the diluent was TEGDMA. Filler loading reduced the OIE and increased hydrophobicity of the resins. SIGNIFICANCE: CH(3) Bis-GMA may be considered as good candidate to be used as diluent because when replacing TEGDMA-induced lower hydrolytic degradation and increase in HC.

Structural and spatially resolved studies on the hardening of a commercial resin-modified glass-ionomer cement.

A commercial photopolymerizable resin-modified glass-ionomer (Fuji II LC) was studied using a variety of nuclear magnetic resonance (NMR) techniques. (1)H and (19)F stray-field imaging (STRAFI) enabled to follow the acid-base reaction kinetics in self-cured (SC) samples. Gelation and maturation processes with 25 min and 40 h average time constants, respectively, were distinguished. In self- & photo-cured (SPC) samples, two processes were also observed, which occurred with 2 s and 47 s average time constants. (1)H, (27)Al and (29)Si magic angle spinning (MAS) NMR, (13)C cross-polarization (CP)/MAS NMR and (27)Al multiple quanta (MQ)MAS NMR spectroscopy were used to obtain structural information on the glass and cements that were either SC or SPC. The presence of methacrylate groups was identified in the solid component. Unreacted hydroxyl ethylmethacrylate (HEMA) was detected in self-cured cement. (27)Al data showed that approximately 28% and 20% of Al is leached out from glass particles in SC and SPC samples, respectively. The upfield shift detected in (29)Si MAS NMR spectra of the cements is consistent with a decrease in the number of Al species in the second coordination sphere of the silicon structures. Scanning electron microscopy (SEM) showed existence of 3D shrinkage of the cement matrix in photo-cured cements.

Evaluation of two Bis-GMA analogues as potential monomer diluents to improve the mechanical properties of light-cured composite resins.

OBJECTIVES: The aim of this study was to investigate the influence of new diluent agents, diluent ratio and filler content, on relevant mechanical properties of several novel composite resins containing Bis-GMA as resin matrices, and to compare these with the properties of composites based on TEGDMA, a conventionally used diluent. METHODS: Two Bis-GMA analogues were synthesized and 20 experimental composite resins were prepared combining three monomer mixtures (Bis-GMA/TEGDMA, Bis-GMA/CH3 Bis-GMA and Bis-GMA/CF3 Bis-GMA), at three dilution rates (85/15, 10/90, 0/100) and three levels of hybrid filler content (barium aluminosilicate glass): 0, 10 and 35%. Flexural strength (FS), modulus of elasticity (ME) and microhardness (VHN) of the composites were evaluated. Five specimens of each material were prepared for each mechanical test, light-cured over 120 s and stored in water at 37 degrees C for 1 week. Three-point bending test was used for FS measurement and VHN was quantified by using a Vickers microindentor. Data were analyzed by ANOVA and Student-Newman-Keuls tests (P<0.05). RESULTS: Materials with CH3 Bis-GMA showed an enhanced VHN. Mean FS was higher for matrices containing TEGDMA. Overall, dilution favored FS and VHN but not ME. Filler loading specially improved ME and VHN. SIGNIFICANCE: Results correlate with an increase in the extent of polymerization due to the higher flexibility of the less viscous comonomer starting system and the hydrophobic character of the Bis-GMA analogues.

Spatially resolved photopolymerization kinetics and oxygen inhibition in dental adhesives.

A comparative study of three commercial dental adhesives was performed by (1)H nuclear magnetic resonance spectroscopy and Stray-Field magnetic resonance imaging. Spectroscopic evidence was found for the presence of solvent and unreacted methacrylate groups in photopolymerized adhesives. Spatially resolved photopolymerization kinetics and volumetric contraction (solvent evaporation and polymerization shrinkage) were obtained without solvent removal and in the presence of oxygen from the atmosphere. The oxygen and solvent inhibitor effects in the photopolymerization were found to be higher for water/ethanol based adhesives. However, was one of these adhesives that exhibited less spatially dependent irradiation time to start vitrification, higher concentration and a more uniform spatial distribution of rigid domains at the end of the photopolymerization.

Stray-field imaging and multinuclear magnetic resonance spectroscopy studies on the setting of a commercial glass-ionomer cement.

A commercial glass-ionomer (Fuji II) was studied using different NMR techniques. 1H and 19F stray-field imaging (STRAFI) were used to monitor the curing kinetics of the cement and two processes were distinguished: the gelation and maturation phases. Characterization of the aluminium and silicon species present in the glass component and cement was performed by conventional 27Al and 29Si MAS and two-dimensional 27Al triple quantum MAS NMR (MQMAS) techniques. Quantification of the aluminium in the glass component and in the cement indicates the leaching of about 32% of the 4-coordinate aluminium, about 100% of the 5-coordinate aluminium and about 41% of the 6-coordinate aluminium, during the setting reaction. It is also shown that the 5-coordinate aluminium is only present in the surface layer created by the acid attack during the cement formation process. In the cement, silicon maintains species with four bridging oxygens after the leaching of tetrahedral (4-coordinate) aluminium. The silicon analysis correlates well with the aluminium determinations.

Low viscosity dimethacrylate comonomer compositions [Bis-GMA and CH3Bis-GMA] for novel dental composites; analysis of the network by stray-field MRI, solid-state NMR and DSC & FTIR.

The effect of dilution of 2,2-bis (4-(2-hydroxy-3-methacryloxyprop-1-oxy) phenyl) propane (Bis-GMA) with 2,2-bis(4-(2-methacryloxyprop-1-oxy)phenyl) propane (CH3Bis-GMA) on extent of polymerization (Ep) was investigated by FTIR and NMR. The results correlate well with Ep values of the system and its flexibility probed by Tg (obtained by DSC). Spatially resolved photopolymerization kinetics and polymerization shrinkage (PS, i.e. volumetric polymerization contraction) was also studied by stray-field imaging (STRAFI-MRI). PS was obtained in the presence of oxygen from the atmosphere as the total volumetric contraction. All the results were compared with those obtained for the Bis-GMA/TEGDMA (triethylene glycol dimethacrylate) system. Use of Bis-GMA mixed with hydrophobic low viscosity CH3Bis-GMA comonomer, as a substitute for the commonly used TEGDMA, resulted in improving significantly properties such as PS, water sorption and Ep, thereby reducing the unreacted double bond concentration.