Preparation of orodispersible tablets of bosentan using xylitol and menthol as dissolution enhancers.

Bosentan is a drug used to treat pulmonary hypertension via dual endothelial receptor antagonism. Bosentan has a restricted oral bioavailability, a problem that's mostly due to poor solubility and hepatic metabolism. It is extensively used for the elderly and children who require a friendly dosage form like orodispersible tablets. So, the goal of this research work was to hasten the dissolution rate of bosentan to produce an orodispersible tablet with immediate drug release. Bosentan was exposed to ethanol-assisted kneading with a rise of xylitol or menthol concentrations (1:1 and 1:2 molar ratio of bosentan with excipient). In addition to observing the dissolution behavior, the resulting dry products were investigated using Fourier transform infrared spectroscopy (FTIR), differential thermal analysis (DTA), and X-ray diffraction (XRD). The FTIR reflected possible hydrogen bonding with xylitol and menthol. DSC studies reflected a reduction in the enthalpy and Tm. These results with XRD data reflected partial co-amorphization in the case of xylitol and eutaxia in the case of menthol. These modifications were related to an accelerated dissolving rate. The developed systems were fabricated as orodispersible tablets which exhibited immediate release of bosentan. Thus, the current study offered simple co-processing for the preparation of orodispersible bosentan tablets.

Xylitol binding to the M1 site of glucose isomerase induces a conformational change in the substrate binding channel.

Glucose isomerase (GI) is extensively used in the food industry for production of high-fructose corn syrup and for the production of biofuels and other renewable chemicals. Structure-based studies on GI inhibitors are important for improving its efficiency in industrial applications. Here, we report the subatomic crystal structure of Streptomyces rubiginosus GI (SruGI) complexed with its inhibitor, xylitol, at 0.99 Å resolution. Electron density map and temperature factor analysis showed partial binding of xylitol to the M1 metal binding site of SruGI, providing two different conformations of the metal binding site and the substrate binding channel. The xylitol molecule induced a conformational change in the M2 metal ion-interacting Asp255 residue, which subsequently led to a conformational change in the side chain of Asp181 residue. This led to the positional shift of Pro25 by 1.71 Å and side chain rotation of Phe26 by 21°, where located on the neighboring protomer in tetrameric SruGI. The conformation change of these two residues affect the size of the substrate-binding channel of GI. Therefore, xylitol binding to M1 site of SruGI induces not only a conformational changes of the metal-binding site, but also conformational change of substrate-binding channel of the tetrameric SruGI. These results expand our knowledge about the mechanism underlying the inhibitory effect of xylitol on GI.

A natural deep eutectic solvent - protonated L-proline-xylitol - based stationary phase for gas chromatography.

The paper presents a new kind of stationary phase for gas chromatography based on deep eutectic solvents (DES) in the form of a mixture of L-proline (protonated with hydrochloric acid) as a hydrogen bond acceptor (HBA) and xylitol as a hydrogen bond donor (HBD) in a molar ratio of HBA:HBD 5:1. DES immobilized on a silanized chromatographic support was tested by gas chromatography (GC) in order to determine its resolving power for volatile organic compounds. Studies have demonstrated the suitability of this type of DES as a stationary phase for GC. The Rohrschneider-McReynolds constants were determined for the synthesized DES, revealing that it is a polar stationary phase (Σ(ΔI) = 1717). The selectivity of DES is influenced by the presence of hydroxyl groups in the xylitol structure capable of forming hydrogen bonds of a donor nature and the proton acceptor properties of the protonated L-proline structure. The presence of additional interactions is brought about by the presence of the carboxyl group. As a result, the retention of alcohols is several times higher (200-670%) than the expected value based on their boiling points. A significant increase in retention (400-970%) was also found for pyridine derivatives. The developed DES stationary phase is characterized by very good repeatability of retention and stability (up to 140°C). The efficiency of the prepared columns (6300-11300 theoretical plates/m) and the selectivity of the DES stationary phase are competitive with the commercial products.

Rotamers in Crystal Structures of Xylitol, D-Arabitol and L-Arabitol.

Rotamers are stereoisomers produced by rotation (twisting) about σ bonds and are often rapidly interconverting at room temperature. Xylitol-massively produced sweetener-(2R,3r,4S)-pentane-1,2,3,4,5-pentol) forms rotamers from the linear conformer by rotation of a xylitol fragment around the C2-C3 bond (rotamer 1) or the C3-C4 bond (rotamer 2). The rotamers form two distinguishable structures. Small differences in geometry of rotamers of the main carbon chain were confirmed by theoretical calculations; however, they were beyond the capabilities of the X-ray powder diffraction technique due to the almost identical unit cell parameters. In the case of rotamers of similar compounds, the rotations occurred mostly within hydroxyl groups likewise rotations in L-arabitol and D-arabitol, which are discussed in this work. Our results, supported by theoretical calculations, showed that energetic differences are slightly higher for rotamers with rotations within hydroxyl groups instead of a carbon chain.

Production and Digestibility Studies of ß-Galactosyl Xylitol Derivatives Using Heterogeneous Catalysts of LacA ß-Galactosidase from Lactobacillus Plantarum WCFS1.

The synthesis of ß-galactosyl xylitol derivatives using immobilized LacA ß-galactosidase from Lactobacillus plantarum WCFS1 is presented. These compounds have the potential to replace traditional sugars by their properties as sweetener and taking the advantages of a low digestibility. The enzyme was immobilized on different supports, obtaining immobilized preparations with different activity and stability. The immobilization on agarose-IDA-Zn-CHO in the presence of galactose allowed for the conserving of 78% of the offered activity. This preparation was 3.8 times more stable than soluble. Since the enzyme has polyhistidine tags, this support allowed the immobilization, purification and stabilization in one step. The immobilized preparation was used in synthesis obtaining two main products and a total of around 68 g/L of ß-galactosyl xylitol derivatives and improving the synthesis/hydrolysis ratio by around 30% compared to that of the soluble enzyme. The catalyst was recycled 10 times, preserving an activity higher than 50%. The in vitro intestinal digestibility of the main ß-galactosyl xylitol derivatives was lower than that of lactose, being around 6 and 15% for the galacto-xylitol derivatives compared to 55% of lactose after 120 min of digestion. The optimal amount immobilized constitutes a very useful tool to synthetize ß-galactosyl xylitol derivatives since it can be used as a catalyst with high yield and being recycled for at least 10 more cycles.

Xylitol as a Hydrophilization Moiety for a Biocatalytically Synthesized Ibuprofen Prodrug.

Biocatalyzed synthesis can be exploited to produce high-value products, such as prodrugs. The replacement of chemical approaches with biocatalytic processes is advantageous in terms of environmental prevention, embracing the principles of green chemistry. In this work, we propose the covalent attachment of xylitol to ibuprofen to produce an IBU-xylitol ester prodrug. Xylitol was chosen as a hydrophilizer for the final prodrug, enhancing the water solubility of ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) extensively used as an analgesic, anti-inflammatory, and antipyretic. Despite being the third-most-prescribed medicine in the world, the aqueous solubility of ibuprofen is just 21 mg/L. This poor water solubility greatly limits the bioavailability of ibuprofen. We aimed to functionalize ibuprofen with xylitol using the reusable immobilized N435 biocatalyst. Instead of a biphasic media, we proposed a monophasic reaction environment. The characterization of the IBU-xylitol ester was performed by 1H, 13C-NMR, DEPT, COSY, HMQC, HMBC, FTIR, and MS spectroscopy. Preliminary in vitro tests showed that this enzymatically synthesized prodrug of ibuprofen reduced the expression of the interleukin 8 genes in human bronchial epithelial cells (IB3-1) from cystic fibrosis (CF) patients.

Propanediol (and) Caprylic Acid (and) Xylitol as a New Single Topical Active Ingredient against Acne: In Vitro and In Vivo Efficacy Assays.

In addition to dermatological complications, acne can affect the quality of life of individuals in numerous ways, such as employment, social habits and body dissatisfaction. According to our expertise, caprylic acid and propanediol would not have a direct action on Cutibacterium acnes. Despite this, we investigated the existence of a synergistic effect among xylitol, caprylic acid and propanediol as a mixture of compounds representing a single topical active ingredient that could benefit the treatment against acne. In vitro and in vivo assays were performed to challenge and to prove the efficacy of propanediol, xylitol and caprylic acid (PXCA) against acne. PXCA had its MIC challenged against C. acnes (formerly Propionibacterium acnes) and Staphylococcus aureus, resulting in concentrations of 0.125% and 0.25%, respectively, and it also developed antimicrobial activity against C. acnes (time-kill test). PXCA was able to reduce the 5-alpha reductase expression in 24% (p < 0.01) in comparison with the testosterone group. By the end of 28 days of treatment, the compound reduced the skin oiliness, porphyrin amount and the quantity of inflammatory lesions in participants. According to the dermatologist evaluation, PXCA improved the skin's general appearance, acne presence and size.

Confectionery Xylitol Gum-Containing Tablets for Medical Application and the Sintering Effect on Gum Tablets.

Confectionery ingredients are expected to enhance the medication adherence of pediatric patients taking bitter-tasting drugs when adequate pediatric medicines are not available in practical settings. Gum is a familiar confectionery, and several drug-loaded gums are on the market as medicated chewing gums. In this study, medical gum tablets composed of confectionery xylitol gum and a drug (ibuprofen or acetaminophen) were prepared and evaluated for the purpose of potential hospital applications. The effect of the sintering process, a heating treatment, on the physical properties of the solid materials was also examined. The sintering process markedly improved the hardness of the gum tablets. The sintering temperature and time affected the hardness of both ibuprofen- and acetaminophen-loaded gum tablets, whereas heat treatment around the melting point of ibuprofen or xylitol and longer heat treatment resulted in failure of the preparation or a reduction in hardness. The sintered gum tablets exhibited a delayed drug release profile in artificial saliva after an in vitro chewing test. The current results provide basic and useful information about the preparation of gum-containing tablets in future clinical settings.

Ultrasound-assisted enzymatic synthesis of xylitol fatty acid esters in solvent-free conditions.

A commercial immobilized lipase was successfully used for the synthesis of five xylityl acyl esters by means of the esterification of free fatty acids (caprylic, capric, lauric and myristic, respectively) with xylitol under solvent-free conditions. Ultrasound-assistance was shown to be a key tool to overcome the handicap imposed by both the mutual immiscibility of fatty acids and xylitol substrates, and the semisolid character of the initial reaction mixtures. In such semisolid systems, ultrasonic irradiation may enable the transport of substrate molecules to the enzyme catalytic-site, leading to the efficient synthesis of xylityl fatty ester (e.g. up to 95% yield after 90 min at 40 °C), with xylityl monoacyl ester and xylitol diacyl ester appearing as the main products (greater than 96%), assessed by HPLC and NMR analyses. The separation of products was carried out by heating and simple centrifugation of the reaction medium, which was possible due to different densities of the resulting fractions.

Room-Temperature Structure of Xylitol-Bound Glucose Isomerase by Serial Crystallography: Xylitol Binding in the M1 Site Induces Release of Metal Bound in the M2 Site.

Glucose isomerase (GI) is an important enzyme that is widely used in industrial applications, such as in the production of high-fructose corn syrup or bioethanol. Studying inhibitor effects on GI is important to deciphering GI-specific molecular functions, as well as potential industrial applications. Analysis of the existing xylitol-bound GI structure revealed low metal occupancy at the M2 site; however, it remains unknown why this phenomenon occurs. This study reports the room-temperature structures of native and xylitol-bound GI from Streptomyces rubiginosus (SruGI) determined by serial millisecond crystallography. The M1 site of native SruGI exhibits distorted octahedral coordination; however, xylitol binding results in the M1 site exhibit geometrically stable octahedral coordination. This change results in the rearrangement of metal-binding residues for the M1 and M2 sites, the latter of which previously displayed distorted metal coordination, resulting in unstable coordination of Mg2+ at the M2 site and possibly explaining the inducement of low metal-binding affinity. These results enhance the understanding of the configuration of the xylitol-bound state of SruGI and provide insights into its future industrial application.

Effect of stevia, xylitol, and corn syrup in the development of velvet tamarind (Dialium indum L.) chewy candy.

The research aimed to study the effect of stevia, xylitol, and corn syrup on the physical, physicochemical, and sensory properties of velvet tamarind chewy candy (VTCC). The content of sweeteners was optimized using stevia (5.5-6%), xylitol (5.5-6%), and corn syrup (7.5-8.5%) by mixture design (d-optimal) with 3 centerpoints and response surface methodology (RSM). The sweeteners in optimized VTCC consisted of velvet tamarind powder (40.5%), water (40%), stevia (6%), xylitol (6%), and corn syrup (7.5%) which provided the approximation error between prediction and observation values: of color (a* and b*), hardness, adhesiveness, gumminess, bioactive activities, and sensory properties within the range of 0.07-9.69%. The optimized VTCC using stevia and xylitol can reduce the sugar content by up to 60%. The sensory preference scores of VTCC from consumer acceptance were slightly like (6.1-6.9) which indicated that the VTCC with stevia and xylitol can provide satisfaction in all evaluated attributes and can be applied to this concept to create fruit chewy candy using stevia and xylitol.

Optimization of activated charcoal detoxification and concentration of chestnut shell hydrolysate for xylitol production.

OBJECTIVES: To increase xylose concentration of the chestnut shell hemicellulosic hydrolysate with an acceptable phenolic compound level in order to enhance xylitol production by Candida tropicalis M43. RESULTS: The xylose concentration and total phenolic compound concentration of the hydrolysate were obtained as 33.68 g/L and 77.38 mg gallic acid equivalent/L, respectively by optimization of detoxification parameters and concentration level (60 °C, 115 min contact time, 5.942% (w/v) dosage of activated charcoal, 120 strokes/min shaking rate and 0.2 volume ratio). Xylitol production was achieved in the hydrolysate by using Candida tropicalis M43. The maximum xylitol concentration was 6.30 g/L and productivity, yield and percentage of substrate conversion were calculated as 0.11 g/L h, 19.13% and 97.79%, respectively. In addition, the chestnut shell hydrolysate fortified with xylose and the maximum xylitol concentration increased to 18.08 g/L in the hydrolysate-based medium containing 80 g/L xylose. CONCLUSIONS: Optimizing detoxification conditions with concentration level was found to be useful for enhancing xylitol production. In addition, fortification of the hydrolysate caused a three fold increase in maximum xylitol concentration.

Production of bio-xylitol from D-xylose by an engineered Pichia pastoris expressing a recombinant xylose reductase did not require any auxiliary substrate as electron donor.

BACKGROUND: Xylitol is a five-carbon sugar alcohol that has numerous beneficial health properties. It has almost the same sweetness as sucrose but has lower energy value compared to the sucrose. Metabolism of xylitol is insulin independent and thus it is an ideal sweetener for diabetics. It is widely used in food products, oral and personal care, and animal nutrition as well. Here we present a two-stage strategy to produce bio-xylitol from D-xylose using a recombinant Pichia pastoris expressing a heterologous xylose reductase gene. The recombinant P. pastoris cells were first generated by a low-cost, standard procedure. The cells were then used as a catalyst to make the bio-xylitol from D-xylose. RESULTS: Pichia pastoris expressing XYL1 from P. stipitis and gdh from B. subtilis demonstrated that the biotransformation was very efficient with as high as 80% (w/w) conversion within two hours. The whole cells could be re-used for multiple rounds of catalysis without loss of activity. Also, the cells could directly transform D-xylose in a non-detoxified hemicelluloses hydrolysate to xylitol at 70% (w/w) yield. CONCLUSIONS: We demonstrated here that the recombinant P. pastoris expressing xylose reductase could transform D-xylose, either in pure form or in crude hemicelluloses hydrolysate, to bio-xylitol very efficiently. This biocatalytic reaction happened without the external addition of any NAD(P)H, NAD(P)+, and auxiliary substrate as an electron donor. Our experimental design & findings reported here are not limited to the conversion of D-xylose to xylitol only but can be used with other many oxidoreductase reactions also, such as ketone reductases/alcohol dehydrogenases and amino acid dehydrogenases, which are widely used for the synthesis of high-value chemicals and pharmaceutical intermediates.

Development of a purification process via crystallization of xylitol produced for bioprocess using a hemicellulosic hydrolysate from the cashew apple bagasse as feedstock.

Xylitol was biotechnologically produced by Kluyveromyces marxianus ATCC36907 using the hemicellulosic hydrolysate of the cashew apple bagasse (CABHH). Sequentially, the present study investigated the recovery and purification of xylitol evaluating different antisolvents [ethanol, isopropanol and the ionic liquid 2-hydroxyl-ethylammonium acetate (2-HEAA)], their proportion in the medium (10-90% v/v), and their cooling rate (VC 0.25-0.50 °C/min). These processes were contrasted with the crystallization process of commercial xylitol. This study is the first to assess xylitol crystallization using a protic ionic liquid. The hydrolysate obtained from a mild treatment with sulfuric acid contained mainly glucose and xylose at concentrations of 15.7 g/L and 11.9 g/L, respectively. With this bioprocess, a maximum xylitol production of 4.5 g/L was achieved. The performance of the investigated antisolvents was similar in all conditions evaluated in the crystallization process of the commercial xylitol, with no significant difference in yields. For the crystallization processes of the produced xylitol, the best conditions were: 50% (v/v) isopropanol as antisolvent, cooling rate of 0.5 °C/min, with a secondary nucleation of yield and purity of 69.7% and 84.8%, respectively. Under the same linear cooling rate, using ethanol, isopropanol or the protic ionic liquid 2-hydroxyl-ethylammonium acetate (2-HEAA), crystallization did not occur, probably due to the presence of carbohydrates not metabolized by the yeast in the broth, which influences the solubility curve of xylitol. With the results of this work, a possible economical and environmentally friendly process of recovery and purification of xylitol from CABHH could be proposed.

Melt milling as manufacturing method for solid crystalline suspensions.

Production of submicron particles (0.1-1 µm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long-term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility.

Catalytic Deoxygenation of Xylitol to Renewable Chemicals: Advances on Catalyst Design and Mechanistic Studies.

Xylitol is commonly known as one of the top platform intermediates for biomass conversion. Catalytic deoxygenation of xylitol provides an atomic and energetic efficient way to produce a variety of renewable chemicals including ethylene glycol, 1,2-propanediol, lactic acid and 1,4-anhydroxylitol. Despite a few initial attempts in converting xylitol into those products, improving catalyst selectivity towards C-O and C-C cleavage reactions remains a grand challenge in this area. To our best knowledge, there is lack of comprehensive review to summarize the most recent advances on catalyst design and mechanisms in deoxygenation of xylitol, offering important perspective into future development of xylitol transformation technologies. Therefore, in this mini-review, we have critically discussed the conversion routes involved in xylitol deoxygenation over solid catalyst materials, the nanostructures of supported metal catalysts for C-H, C-C and C-O bond cleavage reactions, and mechanistic investigation for xylitol conversion. The outcome of this work provides new insights into rational design of effective deoxygenation catalyst materials for upgrading of xylitol and future process development in converting hemicellulosic biomass.

The effect of osmotic dehydration conditions on the calcium content in plant matrice.

Osmotic dehydration is used as a pre-treatment before drying. This process can also be used as a method of modulation of the sensory values of plant components and fortifying them with selected components. The aim of this study was to examine the effect of osmotic dehydration as a method of pumpkin flesh 'Melon Yellow' (Cucurbita maxima) fortification with calcium. The studies showed for the first time that by selecting the appropriate process conditions it is possible to significantly increase the level of calcium in plant matrice. The highest calcium content was found in the pumpkin pulp dehydrated in 50% xylitol and inulin solutions with a calcium carbonate (5%), where the process was conducted for 120 min at 30 °C (1,380.4 and 1,328.4 mg Ca/100 g). Therefore, study has shown an innovative application of the osmotic dehydration process for the design of food with health-promoting properties, including for those at risk of osteoporosis.

A Novel Formulation of Glucose-Sparing Peritoneal Dialysis Solutions with l-Carnitine Improves Biocompatibility on Human Mesothelial Cells.

The main reason why peritoneal dialysis (PD) still has limited use in the management of patients with end-stage renal disease (ESRD) lies in the fact that the currently used glucose-based PD solutions are not completely biocompatible and determine, over time, the degeneration of the peritoneal membrane (PM) and consequent loss of ultrafiltration (UF). Here we evaluated the biocompatibility of a novel formulation of dialytic solutions, in which a substantial amount of glucose is replaced by two osmometabolic agents, xylitol and l-carnitine. The effect of this novel formulation on cell viability, the integrity of the mesothelial barrier and secretion of pro-inflammatory cytokines was evaluated on human mesothelial cells grown on cell culture inserts and exposed to the PD solution only at the apical side, mimicking the condition of a PD dwell. The results were compared to those obtained after exposure to a panel of dialytic solutions commonly used in clinical practice. We report here compelling evidence that this novel formulation shows better performance in terms of higher cell viability, better preservation of the integrity of the mesothelial layer and reduced release of pro-inflammatory cytokines. This new formulation could represent a step forward towards obtaining PD solutions with high biocompatibility.

Efficient Synthesis of Sugar Alcohols under Mild Conditions Using a Novel Sugar-Selective Hydrogenation Catalyst Based on Ruthenium Valence Regulation.

Sugar alcohols are the prominent alternatives of sugars in food, medical, and health industries. The ruthenium supported on multiwalled carbon nanotubes (Ru/MWCNTs) catalysts were prepared based on the Ru valence regulation strategy and applied for selective sugar hydrogenation to prepare various sugar alcohols including xylitol, arabinitol, sorbitol, mannitol, and galactitol for the first time, with high selectivity (>99.0%) and yield (>98.0%) under mild conditions (≤110 °C, 3.0 MPa H2 pressure). The hydrogenation reaction of xylose was further optimized and under mild conditions (100 °C, 3.0 MPa H2 pressure, and 500 rpm), which were lower than ever reported for high efficient synthesis of xylitol, 99.8% xylose conversion and 99.0% xylitol yield were achieved after 120 min of reaction.

Effect of pH on xylitol production by Candida species from a prairie cordgrass hydrolysate.

Using hydrolysates of the North American prairie grass prairie cordgrass buffered at pH 4.5, 5.0, 5.5 or 6.0, xylitol production, xylitol yield, cell biomass production and productivity were investigated for three strains of yeast Candida. Of the three strains, the highest xylitol concentration of 20.19 g xylitol (g xylose consumed)-1 and yield of 0.89 g xylitol (g xylose consumed)-1 were produced by Candida mogi ATCC 18364 when grown for 120 h at 30° C on the pH 5.5-buffered hydrolysate-containing medium. The highest biomass level being 7.7 g cells (kg biomass)-1 was observed to be synthesized by Candida guilliermondii ATCC 201935 after 120 h of growth at 30° C on a pH 5.5-buffered hydrolysate-containing medium. The highest xylitol specific productivity of 0.73 g xylitol (g cells h)-1 was determined for C. guilliermondii ATCC 20216 after 120 h of growth at 30°C on a pH 5.0-buffered hydrolysate-containing medium. Xylitol production and yield by the three Candida strains was higher on prairie cordgrass than what was previously observed for the same strains after 120 h at 30° C when another North American prairie grass big bluestem served as the plant biomass hydrolysate indicating that prairie cordgrass may be a superior plant biomass substrate.