Economic Separations of Organic Acidic or Basic Enantiomeric Mixtures-A Protocol Suggestion.

In this review, we aim to present new concepts for the revisited separation of enantiomers from racemic compounds and a protocol worth to be followed in designing the preparation of pure enantiomers. We have taken into account not only the influence of the properties (eutectic composition) and characteristics of the reactants (racemic compound, resolving agent), but also the behavior of the resulting diastereomers and the different conditions (e.g., crystallization time, solvents used, solvate-forming compounds, achiral additives, etc.). The examples discussed are resolutions developed by our research team, through which we will try to illustrate the impact of all these considerations, presenting the methodological investigations interpreting recent discoveries and observations. Some special solid-state analytical and structural investigations assisting us in the elucidation and invention design of the resolution processes of some active pharmaceutical ingredients, such as Tetramisole, tofisopam, and Amlodipine, are also shown.

Enantiomeric separation of racemic amlodipine by sequential fractional crystallization through formation of diastereomeric salt solvates and co-crystals of solvate-like compounds with specific structure - A tandem resolution.

A new resolution method of racemic amlodipine has been developed. The racemic compound is reacted in a suitable solvent with 0.25-mol equivalent of (R,R)-tartaric acid. After the decomposition of the diastereomeric salt, the remaining racemic fraction is precipitated with half-equivalent of fumaric acid, and the pure amlodipine enantiomer is obtained. A quarter equivalent of the same resolving agent, (R,R)-tartaric acid has been also added to the mother liquor to obtain the other enantiomer. The advantage of this method is that both of the enantiomers of amlodipine could be obtained with high enantiomeric excess with the same resolving agent. The racemic excess can also be isolated and re-resolved. Achiral reagents (urea and thiourea) have been added to the resolving agent. These neutral additives are incorporated as co-crystals in the structure of the diastereomeric salts. The used solvate-former solvents and achiral additives are structurally similar, and their presence can enable the fractional separation of the diastereomers. In addition, the racemate, the enantiomers, and some intermediate salts with high diastereomeric excess obtained in the resolution process of amlodipine have been also subjected to thermal (DSC, TG/DTA-EGA-MS, and -FTIR), analytical (FTIR spectroscopic), and structural (XRD) comparisons, which indicate that the key-intermediate crystalline diastereomeric salts-as solvates and co-crystals-inherit a kind of structural similarity from their related additives-solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively.

Optical Resolution of Two Pharmaceutical Bases with Various Uses of Tartaric Acid Derivatives and Their Sodium Salts: Racemic Ephedrine and Chloramphenicol Base.

The optically active dibenzoyltartaric acid, tartaric acid, and its sodium salts were successfully applied to the optical resolution of (1R,2S)(1S,2R)-2-(methylamino)-1-phenylpropan-1-ol (EPH) and (1R,2R)(1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (AD) as resolving agents. It was observed that both compounds' resolution using a mixture of salts of quasi-racemic resolving agents showed a change in chiral recognition under the same conditions compared to the result of the use of the single enantiomeric resolving agent. The changes are followed by detailed analytical (XRD, FTIR, and DSC) studies. Meanwhile, the DASH indexing software package was also tested on powder XRD patterns of pure initial materials and intermediate salt samples of high diastereomeric excess.

Microstructural Distinction of Electrospun Nanofibrous Drug Delivery Systems Formulated with Different Excipients.

The electrospun nanofiber-based orally dissolving webs are promising candidates for rapid drug release, which is due to the high surface area to volume ratio of the fibers and the high amorphization efficacy of the fiber formation process. Although the latter is responsible for the physical and/or chemical instability of these systems. The primary aim of the present study was to elucidate how the addition of polysorbate 80 (PS80) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD) influenced the electrospinning process, the properties, and the behavior of the obtained nanofibers. In order to reveal any subtle changes attributable to the applied excipients, the prepared samples were subjected to several state of the art imaging and solid state characterization techniques at both macroscopic and microscopic levels. Atomic force microscopy (AFM) revealed the viscoelastic nature of the fibrous samples. At relatively low forces mostly elastic deformation was observed, while at higher loads plasticity predominated. The use of polysorbate led to about two times stiffer, less plastic fibers than the addition of cyclodextrin. The 1H-13C nuclear magnetic resonance (NMR) cross-polarization build-up curves pointed out that cyclodextrin acts as an inner, while polysorbate acts as an outer plasticizer and, due to its "liquid-like" behavior, can migrate in the polymer-matrix, which results in the less plastic behavior of this formulation. Positron annihilation lifetime spectroscopy (PALS) measurements also confirmed the enhanced mobility of the polysorbate and the molecular packing enhancer properties of the cyclodextrin. Solid-state methods suggested amorphous precipitation of the active ingredient in the course of the electrospinning process; furthermore, the nature of the amorphous systems was verified by NMR spectroscopy, which revealed that the use of the examined additives enabled the development of a molecularly dispersed systems of different homogeneities. An accelerated stability study was carried out to track physical state related changes of the incorporated drug and the polymeric carrier. Recrystallization of the active ingredient could not be observed, which indicated a large stress tolerance capacity, but time-dependent microstructural changes were seen in the presence of polysorbate. Raman mapping verified homogeneous drug distribution in the nanofibrous orally dissolving webs. The performed dissolution study indicated that the drug dissolution from the fibers was rapid and complete, but the formed stronger interaction in the case of the PVA-CD-MH system resulted in a little bit slower drug release, compared to the PS80 containing formulation. The results obviously show that the complex physicochemical characterization of the polymer-based fibrous delivery systems is of great impact since it enables the better understanding of material properties including the supramolecular interactions of multicomponent systems and consequently the rational design of drug-loaded nanocarriers of required stability.

Fast further purification of diastereomeric salts of a nonracemic acid by gas antisolvent fractionation.

A novel, green possibility of the further purification of the diastereomeric salt of 4-chloromandelic acid and 1-phenylethane-1-amine was developed. Gas antisolvent method using supercritical carbon dioxide was applied for the first time to precipitate the diastereomeric salts with increased purity followed by the supercritical fluid extraction of the dissolved diastereomers. The RR-salt can be purified to >99%, while fractionation-based purification of the SR-salt is limited to ~80%. The limiting initial diastereomeric excess correlates strongly with the atmospheric melting eutectic composition of the same salts, which suggests that despite the fast precipitation, the diastereomeric excess of the solid product is not kinetically determined. The efficiency of the diastereomeric enrichment is in the same range as that of the atmospheric reference experiments; however, technological advantages provided by the antisolvent precipitation method such as fast processing and dry product obtained suggest that this novel procedure is a promising alternative to the atmospheric methods.

Chitosan nanocoatings N-acylated with decanoic anhydride: Hydrophobic, hygroscopic and structural properties.

Thin (ca. 340 nm) chitosan coatings were deposited onto glass substrates via dip-coating, then modified with the methanol solution of decanoic anhydride (0.17-56 mM). NMR, FTIR and XPS measurements confirmed that the acylation degree increased from 18 % to 45 %, and at the highest degree, the whole layer was acylated homogeneously by the reagent molecules. The coating thickness increased (up to 60 %), and the refractive index decreased (from 1.541 to 1.532) due to the acylation, that was determined by UV-visible spectroscopy. The AFM did not reveal morphological changes, but wetting tests showed that the acylation rendered the coating hydrophobic (water contact angle increased from ca. 75° to 100°). The contact angle, however, decreased to 85° due to the development of a second molecular layer of the decanoic acid by-product at the highest (over 25 mM) reagent concentrations. XRD studies showed a self-assembling structuring of the alkyl-chains in the bulk phase, which occurred in the case of the highest degree of acylation. This also manifested itself in a significant decrease of the layer hygroscopicity: the swelling degree decreased from 40 % to 8 % in a saturated water atmosphere monitored by spectroscopic ellipsometry.

Barrier behaviour of partially N-acetylated chitosan layers in aqueous media.

Chitosan coatings of 353 ± 12 nm thickness were prepared on glass and zinc substrates by dip-coating method to study their barrier-behaviour. The coatings were chemically modified to increase their degree of acetylation (DA) from ca. 44 % up to ca. 98 % resulting a quasi-chitin coating. The effect of the acetylation reaction was studied by infrared spectroscopy, and the structural changes of the native and acetylated coatings were investigated by UV-Vis spectrophotometry and X-ray diffraction. The surface properties of the coated samples were characterized by wettability measurements - advancing water contact angle decreased from ca. 80° (native) to ca. 43° (fully acetylated) - and microscopic (SEM, AFM) studies. The barrier behaviour of the chitosan layer depending on the DA was evaluated by electrochemical impedance spectroscopy studies and with a special mesoporous silica - chitosan bilayer system by measuring the amount of dye (Rhodamine 6G) accumulated in the silica through the chitosan coating during an impregnation step. These methods showed significant decrease in the barrier-effect of the coatings with increasing DA (accumulation of approximately six times more dye and a reduction of charge transfer resistance by an order of magnitude), due to the structural and ionization changes in the coatings.

Understanding the pH Dependence of Supersaturation State-A Case Study of Telmisartan.

Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work aimed to investigate and better understand the pH dependence of supersaturation of telmisartan (TEL) at a molecular level and find a connection between the physicochemical properties of the active pharmaceutical ingredient (API) and the ability to form supersaturated solutions of the API. Therefore, the main focus of the work was the pH-dependent thermodynamic and kinetic solubility of the model API, TEL. Based on kinetic solubility results, TEL was observed to form a supersaturated solution only in the pH range 3-8. The experimental thermodynamic solubility-pH profile shows a slight deviation from the theoretical Henderson-Hasselbalch curve, which indicates the presence of zwitterionic aggregates in the solution. Based on pKa values and the refined solubility constants and distribution of macrospecies, the pH range where high supersaturation-capacity is observed is the same where the zwitterionic form of TEL is present. The existence of zwitterionic aggregation was confirmed experimentally in the pH range of 3 to 8 by mass spectrometry.

Biomass Related Highly Porous Metal Free Carbon for Gas Storage and Electrocatalytic Applications.

In this paper we report the synthesis of a N, S co-doped metal free carbon cryogel obtained from a marine biomass derived precursor using urea as nitrogen source. Natural carrageenan intrinsically contains S and inorganic salt. The latter also serves as an activating agent during the pyrolytic step. The overall 11.6 atomic % surface heteroatom concentration comprises 5% O, 4.6% N and 1% S. The purified and annealed final carbon (CA) has a hierarchical pore structure of micro-, meso- and macropores with an apparent surface area of 1070 m2/g. No further treatment was applied. The gas adsorption potential of the samples was probed with H2, CO2 and CH4, while the electrocatalytic properties were tested in an oxygen reduction reaction. The atmospheric CO2 and CH4 storage capacity at 0 °C in the low pressure range is very similar to that of HKUST-1, with the CO2/CH4 selectivity below 20 bar, even exceeding that of the MOF, indicating the potential of CA in biogas separation. The electrocatalytic behavior was assessed in an aqueous KOH medium. The observed specific gravimetric capacitance 377 F/g was exceeded only in B, N dual doped and/or graphene doped carbons from among metal free electrode materials. The CA electrode displays almost the same performance as a commercial 20 wt% Pt/C electrode. The oxygen reduction reaction (ORR) exhibits the 4-electron mechanism. The 500-cycle preliminary stability test showed only a slight increase of the surface charge.

A practical and efficient method for the resolution of 3-phospholene 1-oxides via coordination complex formation.

A simple, efficient, and economical method based on the combination of the exceptional behavior of o,o'-dibenzoyl- or o,o'-di-p-toluyl-(2R,3R)-tartaric acid in chiral recognition processes, and the coordination ability of calcium or magnesium ion was developed for the resolution of phospholene oxides 1. The calcium or magnesium salt of (-)-o,o'-dibenzoyl-(2R,3R)-tartaric acid 2,4-6 or calcium hydrogen (-)-o,o'-di-p-toluyl-(2R,3R)-tartrate 3 may form crystalline diastereomeric coordination complexes with the appropriate antipode of substituted 3-phospholene oxides 1 that makes possible efficient resolutions. Optically active phospholene oxides 1 were prepared directly by simply crystallization and digestion of the corresponding diastereomeric complexes so formed. Thermal behavior of the crystalline diastereomeric complexes was studied by simultaneous TG/DTA. The novel method may be of more general value in respect of the resolution of tertiary phosphine oxides.

Influence of Aqueous Solubility-Enhancing Excipients on the Microstructural Characteristics of Furosemide-Loaded Electrospun Nanofibers.

Electrospun nanofibers were prepared from furosemide-containing hydroxypropyl cellulose and poly(vinylpyrrolidone) aqueous solutions using different solubility enhancers. In one case, a solubilizer, triethanolamine, was applied, while in the other case a pH-modifier, sodium hydroxide, was applied. Scanning electron microscopy (SEM) was carried out for morphological characterization of the fibers. The SEM images indicated similar mean diameter size of the two fibrous formulations. However, in contrast to the NaOH-containing fibers of normal diameter distribution, the triethanolamine-containing fibers showed approximately normal diameter distribution, possibly due to their plasticizing effect and the consequent slightly ribbon-like morphology. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), powder X-ray diffraction (XRD) and positron annihilation lifetime spectroscopy (PALS) were applied for microstructural characterization. The FTIR measurements confirmed that furosemide salt was formed in both cases. There was no sign of any crystallinity based on the XRD measurements. However, the PALS highlighted the differences in the average o-Ps lifetime values and distributions of the furosemide-loaded fibrous formulations. The two types of electrospun nanofibrous formulations containing amorphous furosemide salt showed similar macrostructures but different microstructural characteristics depending on the type of solubility enhancers, which lead to altered storage stability.

Graphene Oxide Protected Copper Benzene-1,3,5-Tricarboxylate for Clean Energy Gas Adsorption.

Among microporous storage materials copper benzene-1,3,5-tricarboxylate (CuBTC MOF, Cu3(BTC)2 or HKUST-1) holds the greatest potential for clean energy gases. However, its usefulness is challenged by water vapor, either in the gas to be stored or in the environment. To determine the protection potential of graphene oxide (GO) HKUST1@GO composites containing 0-25% GO were synthesized and studied. In the highest concentration, GO was found to strongly affect HKUST-1 crystal growth in solvothermal conditions by increasing the pH of the reaction mixture. Otherwise, the GO content had practically no influence on the H2, CH4 and CO2 storage capacities, which were very similar to those from the findings of other groups. The water vapor resistance of a selected composite was compared to that of HKUST-1. Powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric (TG/DTG) and N2 adsorption techniques were used to monitor the changes in the crystal and pore structure. It was found that GO saves the copper-carboxyl coordination bonds by sacrificing the ester groups, formed during the solvothermal synthesis, between ethanol and the carboxyl groups on the GO sheets.

Effect of ultrasound-assisted crystallization in the diastereomeric salt resolution of tetramisole enantiomers in ternary system with O,O'-dibenzoyl-(2R,3R)-tartaric acid.

The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166°C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150°C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.

Plasticized drug-loaded melt electrospun polymer mats: characterization, thermal degradation, and release kinetics.

Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in the presence of plasticizers. This new method was found promising in the field of pharmaceutical formulation because it combines the advantages of melt extrusion and solvent-based electrospinning. Lowering of the process temperature was performed using plasticizers in order to avoid undesired thermal degradation. Carvedilol (CAR), a poorly water-soluble and thermal-sensitive model drug, was introduced into an amorphous methacrylate terpolymer matrix, Eudragit® E, suitable for fiber formation. Three plasticizers (triacetin, Tween® 80, and polyethylene glycol 1500) were tested, all of which lowered the process temperature effectively. Scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Raman microspectrometry investigations showed that crystalline CAR turned into an amorphous form during processing and preserved it for longer time. In vitro dissolution studies revealed ultrafast drug dissolution of the fibrous samples. According to the HPLC impurity tests, the reduced stability of CAR under conditions applied without plasticizer could be avoided using plasticizers, whereas storage tests also indicated the importance of optimizing the process parameters during MES.

Predicting final product properties of melt extruded solid dispersions from process parameters using Raman spectrometry.

Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity and glass-transition temperature in the case of melt-extruded pharmaceutical products. Tight correlation was shown between the results obtained by confocal Raman mapping and transmission Raman spectrometry, a PAT-compatible potential in-line analytical tool. Immediate-release spironolactone-Eudragit E solid dispersions were the model system, owing to the achievable amorphization and the heat-sensitivity of the drug compound. The deep investigation of the relationship between process parameters, residual drug crystallinity and degradation was performed using statistical tools and a factorial experimental design defining 54 different circumstances for the preparation of solid dispersions. From the examined factors, drug content (10, 20 and 30%), temperature (110, 130 and 150°C) and residence time (2.75, 11.00 and 24.75min) were found to have significant and considerable effect. By forming physically stable homogeneous dispersions, the originally very slow dissolution of the lipophilic and poorly water-soluble spironolactone was reasonably improved, making 3minute release possible in acidic medium.

Characterization of drug-cyclodextrin formulations using Raman mapping and multivariate curve resolution.

Raman chemical imaging was used in the characterization of drug-excipient interactions between a drug and different types of cyclodextrins. Detailed analysis was carried out regarding the interactions between the active ingredient (API) and the cyclodextrins and the heterogeneity of the samples was studied using multivariate curve resolution-alternating least squares algorithm. The amount of recrystallized pure API was also estimated using the same curve resolution method. The Raman mapping results were validated via scanning electron microscopy-energy dispersive X-ray spectroscopy and X-ray powder diffraction. Raman mapping was found to be suitable to detect traces of pure crystalline API below the detection limit of X-ray powder diffraction.