A Widespread Radical-Mediated Glycolysis Pathway.

Glycyl radical enzymes (GREs) catalyze mechanistically diverse radical-mediated reactions, playing important roles in the metabolism of anaerobic bacteria. The model bacterium Escherichia coli MG1655 contains two GREs of unknown function, YbiW and PflD, which are widespread among human intestinal bacteria. Here, we report that YbiW and PflD catalyze ring-opening C-O cleavage of 1,5-anhydroglucitol-6-phosphate (AG6P) and 1,5-anhydromannitol-6-phosphate (AM6P), respectively. The product of both enzymes, 1-deoxy-fructose-6-phosphate (DF6P), is then cleaved by the aldolases FsaA or FsaB to form glyceraldehyde-3-phosphate (G3P) and hydroxyacetone (HA), which are then reduced by the NADH-dependent dehydrogenase GldA to form 1,2-propanediol (1,2-PDO). Crystal structures of YbiW and PflD in complex with their substrates provided insights into the mechanism of radical-mediated C-O cleavage. This "anhydroglycolysis" pathway enables anaerobic growth of E. coli on 1,5-anhydroglucitol (AG) and 1,5-anhydromannitol (AM), and we probe the feasibility of harnessing this pathway for the production of 1,2-PDO, a highly demanded chiral chemical feedstock, from inexpensive starch. Discovery of the anhydroglycolysis pathway expands the known catalytic repertoire of GREs, clarifies the hitherto unknown physiological functions of the well-studied enzymes FsaA, FsaB, and GldA, and demonstrates how enzyme discovery efforts can cast light on prevalent yet overlooked metabolites in the microbiome.

A Triptycene-Based Layered/Flower-Like 2D Conductive Metal-Organic Framework with 3D Extension as an Electrode for Efficient Li Storage.

2D metal-organic frameworks (2D MOFs) with π conjugation have attracted widespread attention in the field of lithium storage due to their unique electron transfer units and structural characteristics. However, the periodic 2D planar extension structure hides some active sites, which is not conducive to the utilization of its structural advantages. In this work, a series of triptycene-based 2D conductive MOFs (M-DBH, M = Ni, Mn, and Co) with 3D extension structures are constructed by coordinating 9,10-dihydro-9,10-[1,2]benzenoanthracene-2,3,6,7,14,15-hexaol with metal ions to explore their potential applications in lithium-ion and lithium-sulfur batteries. This is the first study in which 2D conductive MOFs with the 3D extended molecule are used as electrode materials for lithium storage. The designed material generates rich active sites through staggered stacking layers and shows excellent performance in lithium-ion and lithium-sulfur batteries. The capacity retention rate of Ni-DBH can reach over 70% after 500 cycles at 0.2 C in lithium-ion batteries, while the capacity of S@Mn-DBH exceeds 305 mAh g-1 after 480 cycles at 0.5 C in lithium-sulfur batteries. Compared with the materials with 2D planar extended structures, the M-DBH electrodes with 3D extended structures in this work exhibit better performance in terms of cycle time and lithium storage capacity.

Low-Temperature Flexibility of Chiral Organic Crystals with Highly Efficient Second-Harmonic Generation.

Flexible crystals with unique mechanical properties have presented enormous applications in optoelectronics, soft robotics and sensors. However, there have been no reports of low-temperature-resistant flexible crystals with second-order nonlinear optical properties (NLO). Here, we report the flexible chiral Schiff-base crystals capable of efficient second harmonic generation (SHG). Both enantiomers and racemic modifications of these crystals are mechanically flexible in two directions at both room temperature and at -196 °C, although their mechanical responses differ. The enantiomers display SHG with an intensity of up to 12 times that of potassium dihydrogenphosphate (KDP) when pumped at 980 nm, and they also have high laser-induced damage thresholds (LDT). Even when bent, the crystals retain strong second harmonic generation, although with a different intensity distribution depending on the polarization, compared to when they are straight. This work describes the first instance of flexible organic crystal with NLO properties and lays the foundation for the development of mechanically flexible organic NLO materials.

Effects of Different Flotation Agents on the Nucleation and Growth of Potassium Chloride.

The flotation agent is an important collector in the production of potassium chloride and is brought into the crystallization stage with the reflux of the mother liquor. Octadecylamine Hydrochloride (ODA), 1-Dodecylamine Hydrochloride (DAH) and Sodium 1-dodecanesulfonate (SDS) were selected to study their effect on the nucleation of potassium chloride. Focused Beam Reflectance Measurement was used to collect the nucleation-induced periods of KCl in the presence of flotation agents at different supersaturations. Then, empirical equations, classical nucleation theory and growth mechanism equations were employed for data analysis. It was found that the presence of flotation agents increased the nucleation sequence m, and m(ODA) > m(SDS) > m(DAH) > m(H2O). In addition, the interfacial energy data obtained using classical nucleation theory suggest that the flotation agents used in our paper promoted the homogeneous nucleation of KCl (reduced from 5.3934 mJ·m-2 to 5.1434 mJ·m-2) and inhibited the heterogeneous nucleation of KCl (increased from 2.8054 mJ·m-2 to 3.6004 mJ·m-2). This investigation also revealed that the growth of potassium chloride was consistent with the 2D nucleation-mediated growth mechanism, and the addition of flotation agent did not change the growth mechanism of potassium chloride. Finally, the particle size distribution results were exactly consistent with the order of nucleation order m. The study of nucleation kinetics and growth mechanisms of different flotation agents on potassium chloride can provide guidance for optimizing the production process of potassium chloride and developing new flotation agents.

Insoluble Salt of Memantine with a Unique Fluorescence Phenomenon.

Alzheimer's disease is a chronic disease, and the long-term treatment of chronic diseases has always been a concern. Memantine (Mem) is approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimer's disease. In this study, reactions of memantine (Mem) with pamoic acid (Pam) were carried out to form insoluble salts (Mem-Pam). Four polymorphic forms (Forms I-IV) of Mem-Pam were successfully obtained through polymorphic screening, which were systematically characterized by X-ray powder diffraction (PXRD), thermal analysis (TGA and DSC), single-crystal X-ray diffraction (SXRD), and solid-state fluorescence. Compared with the hydrochloride form, the dissolution and release rates of these four forms are lower. The presence of pamoic acid reduces the release rate of memantine and makes it possible to achieve a sustained release of the drug. Interestingly, because of the presence of memantine, each polymorphic solid crystal of Mem-Pam has unique fluorescence emission. Therefore, memantine and pamoic acid have a synergistic effect on the fluorescence performance and can be expected to be used for real-time monitoring in continuous and controlled release drug delivery systems. In addition, the polymorphic solid crystals also exhibit reversible mechanochromic luminescence under the fumigation of acetonitrile vapor, which has a guiding role in the fluorescence design and synthesis of Pam substances and is expected to be used for information security, visual inspection of organic substances, etc.

Insight into the Nucleation Mechanism of p-Methoxybenzoic Acid in Ethanol-Water System from Metastable Zone Width.

The metastable zone width (MSZW) of p-methoxybenzoic acid (PMBA) in an ethanol-water system was measured using the polythermal method. The nucleation order m obtained by the Nývlt's model indicates the nucleation of PMBA following a progressive nucleation mechanism at low saturation temperature (m = 3.18-7.50) and an instantaneous nucleation mechanism at high saturation temperature (m = 1.46-2.55). Then, combined with the metastable zone experiment and the Sangwal model, we found that the MSZW and the interfacial energy reached the maximum when the mass fraction of ethanol was 0.8, which resulted in the smallest crystal product size. Meanwhile, the maximum rcrit and ΔGcrit obtained based on the modified Sangwal model indicating the PMBA needs to overcome a higher nucleation barrier in the ethanol mass fraction of 0.8. Finally, we proposed a preferential strategy for adjusting MSZW by correlating the interfacial energy with the change in ethanol mass fraction, saturation temperature, and cooling rate, respectively.

Biocompatible Nano-Cocrystal Engineering for Targeted Herbicide Delivery: Enhancing Efficacy through Stimuli-Responsive Release and Reduced Environmental Losses.

In addressing the critical challenges posed by the misuse and inefficiency of traditional pesticides, we introduce a Nano-Cocrystal material composed of the herbicide clopyralid and coformer phenazine. Developed through synergistic supramolecular self-assembly and mechanochemical nanotechnology, this Nano-Cocrystal significantly enhances pesticide performance. It exhibits a marked improvement in stability, with reductions in hygroscopicity and volatility by approximately 38%. Moreover, it intelligently modulates release according to environmental factors, such as temperature, pH, and soil inorganic salts, demonstrating decreased solubility by up to four times and improved wettability and adhesion on leaf surfaces. Importantly, the herbicidal activity surpasses that of pure clopyralid, increasing suppression rates of Medicago sativa L. and Oxalis corniculata L. by up to 27% at the highest dosage. This Nano-Cocrystal also shows enhanced crop safety and reduced genotoxicity compared to conventional formulations. Offering a blend of simplicity, cost-effectiveness, and robust stability, our findings contribute a sustainable solution to agricultural practices, favoring the safety of nontarget organisms.

Optimization of green spherical agglomeration process based on response surface methodology for preparation of high-performance spherical particles.

Spherical agglomeration (SA) is a processing technique that enhances the physical properties of particles, reduces the number of unit operations in pharmaceutical manufacturing, and improves process efficiency. However, one of the limitations of SA is its high nonlinearity, which makes scalability a challenge. This prospective study was designed to realize the optimization of SA process parameters of aspirin, the world's first and most widely used nonsteroidal anti-inflammatory drug, by developing a green SA model through response surface methodology. First, Plackett-Burman experiments were conducted to identify the key operating variables affecting SA, and Sustainability Index (STI) was defined to evaluate the effects of these operating variables on the SA and the energy input to the environment during the post-processing process. Furthermore, the effects of three independent variables on mean size, yield, and STI were investigated based on Box-Behnken design. A second-order regression equation with response values was developed to optimize the above three objectives. As a result, the spherical products were obtained with excellent powder properties, including anti-caking property, filtration property, and tableting performance compared to the raw materials. This work provides an experimental and modelling basis for the further application of this environmentally-friendly SA technology.

Fabrication of targeted and pH responsive lysozyme-hyaluronan nanoparticles for 5-fluorouracil and curcumin co-delivery in colorectal cancer therapy.

Green nanotechnology is considered a promising method to construct functional materials with significant anticancer activity, while overcoming the shortcomings of traditional synthesis process complexity and high organic solvents consumption. Thus, in this study, we report for the first time the rational design and green synthesis of functionalized 5-fluorouracil and curcumin co-loaded lysozyme-hyaluronan composite colloidal nanoparticles (5-Fu/Cur@LHNPs) for better targeted colorectal cancer therapy with minimized side effects. The functionalized 5-Fu/Cur@LHNPs exhibit stabilized particle size (126.1 nm) with excellent homogeneity (PDI = 0.1), favorable colloidal stabilities, and excellent re-dispersibility. In vitro cell experiments illustrate that the cellular uptake of 5-Fu/Cur@LHNPs was significantly improved and further promoted a higher apoptosis ratio of HCT-116 cells. Compared with the control group, the 5-Fu/Cur@LHNPs formulation group achieved effective inhibition (60.1 %) of colorectal tumor growth. The alcohol-free self-assembly method to construct 5-Fu/Cur@LHNPs is simple and safe for a translational chemotherapy drug, also to promote more robust delivery systems for treating colorectal cancer.

Uncovering the mechanism of Tenofovir amibufenamide fumarate punch sticking by combining direct compression experiment and computational simulation.

Punch sticking during tablet manufacturing is a prevalent issue for many active pharmaceutical ingredients (APIs) encountered by the pharmaceutical industry. Tenofovir amibufenamide fumarate (TMF), a heavyweight drug for the treatment of hepatitis B, was selected as a model drug due to its tendency to punch sticking during tablet compression. In this study, the cause of sticking was explored by investigating crystal habits, excipients and structure characteristics. The difference in sticking of three crystal habits can be visually represented through direct compression experiments on powdered samples and analysis of crystal surfaces. The excipients play a direct role in decreasing the probability of sticking, and the extent of sticking can be assessed by measuring the tensile strength of the tablet. Additionally, the plasticity index was utilized to theoretically analyze the potential enhancements of four excipients. These experimental results indicate that the block-shaped crystals have superior ability of anti-sticking and that suitable excipients can significantly improve the sticking situation of TMF. Ultimately, the phenomenon of punch sticking was additionally examined through computational calculations, focusing on the mechanical characteristics of TMF molecules and intermolecular interactions. The strategy of combining experiments and simulation calculations has broader significance for the study of drug production.

Highly efficient in crystallo energy transduction of light to work.

Various mechanical effects have been reported with molecular materials, yet organic crystals capable of multiple dynamic effects are rare, and at present, their performance is worse than some of the common actuators. Here, we report a confluence of different mechanical effects across three polymorphs of an organic crystal that can efficiently convert light into work. Upon photodimerization, acicular crystals of polymorph I display output work densities of about 0.06-3.94 kJ m-3, comparable to ceramic piezoelectric actuators. Prismatic crystals of the same form exhibit very high work densities of about 1.5-28.5 kJ m-3, values that are comparable to thermal actuators. Moreover, while crystals of polymorph II roll under the same conditions, crystals of polymorph III are not photochemically reactive; however, they are mechanically flexible. The results demonstrate that multiple and possibly combined mechanical effects can be anticipated even for a simple organic crystal.

Preparation of tenofovir amibufenamide fumarate spherical particles to improve tableting performance and sticking propensity by designing a spherical crystallization process.

Tenofovir amibufenamide fumarate (TMF) is the first oral drug developed in Asia for the treatment of adult patients with chronic viral hepatitis B, however, further applications are limited by poor tableting performance and high sticking propensity. In this work, the spherulitic growth process of TMF has been designed and explored with the help of molecular dynamics simulation and process analysis technologies (ATR-FTIR, FBRM and EasyViewer). The spherical particles with high bulk density, good flowability and uniform particle size distribution are prepared by a simple quenching process. More importantly, experimental results show that spherical particles have higher average tensile strength (100.8% increase), higher plastic deformability and lower amount of punch sticking (87.4% decrease in 30 tablets) compared to the commercial powder products. These contributions not only shed light on the design principle of drug spherulitic growth processes, but also provide guidance for the manufacture of high-quality tablet products.

Mechanosynthesis of magnolol multicomponent crystalline solids for improved natural antibiotics and customizable release profiles.

Antibiotic is one of the most important discoveries in human and animal medicine. However, the inefficient use of antibiotics has caused widespread and persistent contamination of ecosystems, setting off microbial resistance storms. Magnolol is a botanical antibiotic, but poor physicochemical properties result in low bioavailability. Increasing solubility of magnolol can help to reduce the doses of medications to patients, minimize bothersome side effects. In this work, three novel multicomponent crystalline solids were synthesized from magnolol and isomeric coformers by mechanochemistry. It was found that the multicomponent crystalline solids achieved the customizable release profile of magnolol by manipulating the substituent positions of the isomers and complexation. Antibacterial activity test showed that bioactivity on two bacteria was considerably improved by designed MGN multicomponent crystals. In addition, the coformers controlled the dissolution behavior and further stabilized the improvement according to the variable statistical analysis. In conclusion, the properties of antibiotic multicomponent solids can be manipulated through the coformers. This provides an effective strategy for managing the release of drugs to meet individual biological differences and diverse therapeutic needs.

Systematic study on lysozyme-hyaluronan complexes: Multi-spectroscopic characterization and molecular dynamics simulation.

This study systematically investigated the complexation mechanism of lysozyme (LYS) and hyaluronan (HA) as well as their complex-formation process using multi-spectroscopy combined with molecular dynamics simulation. Overall, the results demonstrated that electrostatic interaction provides the primary self-assembly driving forces for LYS-HA complex formation. Circular dichroism spectroscopy revealed that the LYS-HA complexes formation primarily alters the α-helix and ß-sheet structures of LYS. Fluorescence spectroscopy yielded an entropy of 0.12 kJ/mol·K and enthalpy of -44.46 kJ/mol for LYS-HA complexes. Molecular dynamics simulation indicated that the amino acid residues of ARG114 in LYS and 4ZB4 in HA contributed most significantly. HT-29 and HCT-116 cell experiments demonstrated that LYS-HA complexes possess excellent biocompatibility. Furthermore, LYS-HA complexes were found to be potentially useful the efficient encapsulation of several insoluble drugs and bioactives. These findings provide new insight into the binding mechanism between LYS and HA, and prove indispensable to promoting the potential application of LYS-HA complexes as bioactive compound delivery systems, emulsion stabilizers, or foaming agents in the food industry.

Structural origins of two-dimensional elastic bending in a nonaromatic organic molecular crystal.

Mechanically flexible crystals are generally obtained based on weak interactions in the aromatic systems. Here, we reported the remarkable 2D elastic bending behaviors in a nonaromatic organic molecular crystal. The strong hydrogen bonding interactions are also verified to play a crucial role in the reversible bending.

Quantitative analysis of low content polymorphic impurities in canagliflozin tablets by PXRD, NIR, ATR-FITR and Raman solid-state analysis techniques combined with stoichiometry.

Canagliflozin (CFZ) was a commercially new class of anti-diabetic drug, which had various anhydrate crystal forms and two hydrate crystal forms (Canagliflozin hemihydrate (Hemi-CFZ) and Canagliflozin monohydrate (Mono-CFZ) crystal form). Commercially available CFZ tablets' active pharmaceutical ingredient (API) was Hemi-CFZ, which was easy conversion to CFZ or Mono-CFZ under the influence of temperature, pressure, humidity and other factors in tablets processing, storage, and transportation, thus affected bioavailability and efficacy of tablets. Therefore, quantitative analysis low content of CFZ and Mono-CFZ in tablets was essential to control tablets' quality. The main objective of this study was to examine the feasibility of Powder X-ray Diffraction (PXRD), Near Infrared Spectroscopy (NIR), Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) and Raman for quantitative analysis the low content of CFZ or Mono-CFZ in ternary mixtures. PLSR calibration models for low content of CFZ and Mono-CFZ were established by the solid analysis techniques of PXRD, NIR, ATR-FTIR and Raman combined with various pretreatments (such as Multiplicative Scatter Correction (MSC), Standard Normal Variate (SNV), Savitzky-Golay First Derivative (SG1st), Savitzky-Golay Second Derivative (SG2nd) and Wavelet Transform (WT)), and the correction models were verified. However, compared with PXRD, ATR-FTIR and Raman, NIR due to its water sensitivity was the most suitable for the quantitative analysis low content of CFZ or Mono-CFZ in tablets. Partial Least Squares Regression (PLSR) model for quantitative analysis low content of CFZ in tablets was as follow: Y = 0.0480 + 0.9928 X, R2 = 0.9986, LOD = 0.1596 %, LOQ = 0.4838 %, SG1st + WT pretreated. And that of Mono-CFZ were Y = 0.0050 + 0.9996 X, R2 = 0.9996, LOD = 0.0164 %, LOQ = 0.0498 %, MSC + WT pretreated and Y = 0.0051 + 0.9996 X, R2 = 0.9996, LOD = 0.0167 %, LOQ = 0.0505 %, SNV + WT pretreated, respectively. That can be used for quantitative analysis of impurity crystal content in drug production to ensure drug quality.

Effects of the molecular weight of hyaluronan on the conformation and release kinetics of self-assembled 5-fluorouracil-loaded lysozyme-hyaluronan colloidal nanoparticles.

Lysozyme (LYS) and hyaluronan with low (HA1: 3 kDa), medium (HA2: 120 kDa), and high (HA3: 1200 kDa) molecular weights were used to fabricate lysozyme-hyaluronan colloidal nanoparticles using a green self-assembly method. Fourier transform infrared spectroscopy indicated that hydrogen bonding, hydrophobic and electrostatic interactions promoted the formation of the colloidal nanoparticles. The hydrophobic area of prepared colloidal nanoparticles was quantified using a pyrene fluorescent probe, and the results showed that the LYS-HA3 nanoparticles had the strongest hydrophobic capacity. Furthermore, 5-fluorouracil (5-Fu) was used to evaluate encapsulation performance, demonstrating that the LYS-HA3 nanoparticles had the highest encapsulation ability (>90 %). All prepared 5-Fu-loaded lysozyme-hyaluronan (5-Fu@LYS-HA) colloidal nanoparticles exhibited excellent long-term storage stability at 4 °C for 60 days. Cellular uptake and in vitro release results indicated that the LYS-HA2 nanoparticles exhibited the highest cellular uptake efficiency, and the LYS-HA3 nanoparticles had the best slow-release effect, while the release process was mainly controlled by the combination of Fickian diffusion and structural relaxation, respectively. This study demonstrates the influence of molecular weight on the conformational and structural properties of colloidal nanoparticles, which has implications for the design of insoluble drug self-assembly systems.

Asparagine endopeptidase-targeted Ultrasound-responsive Nanobubbles Alleviate Tau Cleavage and Amyloid-ß Deposition in an Alzheimer's Disease Model.

Inhibition of asparagine endopeptidase (AEP) has been implied to be effective for treating tau- and amyloid-beta-mediated neurodegenerative diseases, although a method for targeted intracerebral delivery of AEP inhibitors has not yet been achieved. Here, we fabricated ultrasound-responsive nanobubbles (NBs) to load AEP inhibitor RR-11a, and modified the NB surface with either AEP recognizable peptide AAN or pro-transendothelial transversal motif RGD, i.e. NB(11a)-A and NB(11a)-R, for AEP-targeted treatment of Alzheimer's disease (AD). The developed NBs were uniform, small in size (50.1 ± 1.5 nm), with strong echogenicity and high drug loading efficiency (∼91.97%). When intravenously co-injected in the APP/PS1 mouse model, NB(11a)-R could adhere to endothelial cells and enhance transient opening of the blood-brain barrier (BBB) upon focused ultrasound oscillations, allowing the rest NBs/localized released RR-11a molecules to enter the brain, and then NB(11a)-A could selectively bind with the impaired neurons and deposit RR-11a molecules at the AD lesion. As a result, co-administration of NB(11a)-A and NB(11a)-R significantly promoted accumulation of RR-11a in the mouse brain, and substantially alleviated both tau cleavage and amyloid plaques deposition in the hippocampus. Most strikingly, the cognitive ability of the AD model mice was dramatically improved, achieving a level close to the normal mice. Overall, this unique AEP-targeted nanobubble design provides an efficient intracerebral drug delivery strategy and significantly enhances treatment efficacy of AD. STATEMENT OF SIGNIFICANCE: Asparagine endopeptidase (AEP) is an innovative therapeutic target simultaneously involved in Aß and tau-mediated Alzheimer's disease (AD) pathology, but targeted delivery of AEP inhibitors has not been achieved yet. Here we developed an efficient strategy to deliver AEP inhibitor RR-11a towards impaired neurons. We fabricated RR-11a-loaded ultrasound-responsive nanobubbles (NBs) and modified the NB surface with RGD peptide to promote BBB crossing upon focused ultrasound oscillations, or with AAN peptide to increase binding of NBs on the neurons. Our results indicated that, co-administration of the NB(11a)-A and NB(11a)-R significantly enhanced accumulation of RR-11a molecules at the AD lesion, alleviated both tau cleavage and amyloid plaques deposition in the hippocampus, and consequently restored cognitive function of the AD model mice.

Ultrasound-assisted solution crystallization of fotagliptin benzoate: Process intensification and crystal product optimization.

The ultrasound-assisted crystallization process has promising potentials for improving process efficiency and modifying crystalline product properties. In this work, the crystallization process of fotagliptin benzoate methanol solvate (FBMS) was investigated to improve powder properties and downstream desolvation/drying performance. The direct cooling/antisolvent crystallization process was conducted and then optimized with the assistance of ultrasonic irradiation and seeding strategy. Direct cooling/antisolvent crystallization and seeding crystallization processes resulted in needle-like crystals which are undesirable for downstream processing. In contrast, the ultrasound-assisted crystallization process produced rod-like crystals and reduced the crystal size to facilitate the desolvation of FBMS. The metastable zone width (MSZW), induction time, crystal size, morphology, and process yield were studied comprehensively. The results showed that both the seeding and ultrasound-assisted crystallization process (without seeds) can improve the process yield and the ultrasound could effectively reduce the crystal size, narrow the MSZW, and shorten the induction time. Through comparing the drying dynamics of the FBMS, the small rod-shaped crystals with a mean size of 9.6 µm produced by ultrasonic irradiation can be completely desolvated within 20 h, while the desolvation time of long needle crystals with an average size of about 157 µm obtained by direct cooling/antisolvent crystallization and seeding crystallization processes is more than 80 h. Thus the crystal size and morphology were found to be the key factors affecting the desolvation kinetics and the smaller size produced by using ultrasound can benefit the intensification of the drying process. Overall, the ultrasound-assisted crystallization showed a full improvement including crystal properties and process efficiency during the preparation of fotagliptin benzoate desolvated crystals.

Use of additives to regulate solute aggregation and direct conformational polymorph nucleation of pimelic acid.

Understanding the nucleation pathway and achieving regulation to produce the desired crystals are mutually beneficial. The authors previously proposed a nucleation pathway of conformational polymorphs in which solvation and solute self-assembly could affect the result of the conformational rearrangement and further nucleation outcomes. Based on this, herein α,ω-alkanedi-carb-oxy-lic acids (DAn, where n represents the number of carbon atoms in the molecule, n = 2-6, 8-11) were designed as homologous additives to interfere with the self-assembly of pimelic acid (DA7) to further induce the form II compound, which differs from form I only in conformation. Interestingly, longer-chain additives (DA6-11) have a stronger form II-inducing ability than short-chain ones (DA2-4). In addition, an apparent gradient of the degree of interference with solute self-assembly, consistent with form II-inducing ability, was detected by infrared and nuclear magnetic resonance spectroscopy. The calculated molecular electrostatic potential charges also clearly indicate that additive-solute electrostatic interactions gradually increase with increasing carbon chain length of the additives, reaching a maximum value with DA6-11. This novel use of additives demonstrates a direct link between solute aggregation and conformational polymorph nucleation.