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This technical paper delves into the creation and application of an enhanced mathematical model for semi crystalline thermoplastics based on the Pressure-Volume-Temperature (PVT) Two Domain Tait Equation. The model is designed to incorporate the impact of the cooling rate on the specific volume of the material. This is achieved by utilizing Flash differential scanning calorimetry (fDSC) measurements, thereby ensuring a direct correlation to the actual behavior of the material in reality. The practical application of the model in the context of injection molding simulation was also considered. This was done by integrating the mathematical model into the Moldflow software via the Solver API. The paper underscores the discontinuity issue inherent in the traditional Tait equation with cooling rates and proposes a solution that guarantees a correct transition from the liquid to the solid phase, even at high cooling rates and pressures. The results demonstrated a realistic PVT curve across a wide range of cooling rates and high pressures. The model was put to the test using a 3D tetrahedron meshed calculation model in the injection molding simulation. This study marks a significant step forward in the simulation of injection molding processes, as it successfully bridges the gap between real material properties and simplified simulation, paving the way for more accurate and efficient simulations in the future. [ABSTRACT FROM AUTHOR]

This paper presents the performance of an airblowing heater controller used with UHMW sheet material. Temperature control is implemented within the range of 80°C to 110°C to achieve the re-crystallization temperature of the UHMW sheet material. A PID controller was applied, and its performance was analyzed by varying the temperature set point (SET VALUE), the fan's flow capacity, and the use of dual heaters to heat both surfaces of the UHMW sheet simultaneously. This paper also examines the effects of auto-tuning and selftuning PID methods on control performance. The test results indicate that balancing the fan's flow capacity and the heat generation of the heater unit is the dominant factor in PID controller performance. In addition, with the use of double heaters, the material's energy accumulation becomes the main factor, causing a slower PID controller response in reaching the target temperature. Implementing self-tuning PID constants yielded better controller performance compared to the auto-tuning method. [ABSTRACT FROM AUTHOR]

The objective of this paper is to rapidly and accurately quantify the content of the dominant crystal form of Sinomenine hydrochloride (SH) and to evaluate the respective characteristics of Raman spectroscopy and Fourier transform near infrared spectroscopy techniques for rapid quantification of crystalline substances. In this study, we performed an adulterated gradient quantification based on two new crystalline forms of SH prepared in the laboratory in combination with commercially available products. And established 86 samples containing 66 batches of ternary and 20 batches of binary mixtures. We quantified SH possessing polycrystalline forms based on two kinds of spectroscopy techniques combined with chemometric methods. In the process of establishing the partial least squares quantitative model, according to the experimental design thought, we used the ensemble preprocessing method to screen the optimal preprocessing method for the spectral data of crystal samples. Then we optimized four variable selection methods by single factor investigation. Finally, after completing the PLSR model, we found that the regression models established for both Raman spectra (RMSEP = 0.00672) and FT-NIR spectra (RMSEP = 0.00533) have a high ability to rapidly quantify the crystals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diclofenac (DIC) is a nonsteroidal anti-inflammatory drug with poor tabletability and water solubility. In the present study, a new diclofenac-picolinamide cocrystal (DIC-PIC) was prepared to simultaneously improve its tabletability and solubility. The cocrystal was characterized using multiple techniques, such as X-ray diffraction, thermal methods and spectral analyses. The tabletability of DIC-PIC was significantly improved over DIC, which is attributed to the larger bonding area between crystals due to the higher plasticity of DIC-PIC, demonstrated by the lower in-die mean yield pressure, P y,i , of DIC-PIC (59.5 ± 0.6 MPa) than DIC (86.6 ± 1.4 MPa). The higher plasticity of DIC-PIC is consistent with the existence of a slip plane (001) in its crystal structure. The solubility of DIC-PIC is significantly higher than that of DIC (112 times higher in water and 22 times higher in pH = 6.8 buffer solution). Hence, the simultaneous improvement in tabletability and solubility of DIC-PIC overcomes two main barriers in developing DIC tablets, which makes it a promising candidate for developing a DIC tablet with improved performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Investigating the formation mechanism and effective manipulation of multi-component crystal polymorphs is crucial for facilitating industrial drug development. Herein, five novel Osimertinib-caffeic acid forms were first strategically tailored by varying solvent selection. Theoretical analysis demonstrated this polymorphism is correlated with multiple hydrogen bond donors-acceptors within multi-component system, which provides manipulation space for reconfiguration of intermolecular interactions and structural competition, while solvent further induced or involved in hydrogen-bonded rearrangements. Molecular dynamics simulation and solvent characterization revealed strong solute-solvent interaction and hydrogen bond donor propensity promoted the generation of hydrate. Small molecular size or large cavity of crystal facilitated solvent entry, resulting in the generation of channel-type solvates. Higher solvation free energy implied faster reaction rate and poorer solvent removal ability for solvates. Thermal analysis confirmed removal of the solvent occupying crystal channels for precursor solvates led to polymorph formation while maintaining the structure. Properties assessments revealed multi-component crystals significantly enhanced the physicochemical properties of Osimertinib. Polymorphs and hydrate exhibited remarkable distinctions in solubility, dissolution rate and physical stability. Nanoindentation and tableting tests confirmed distinct mechanical properties of different forms. Overall, this exploration has the potential to reshape the landscape of multi-component crystal polymorph development, paving the way for manipulating intermolecular interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Enhancing the aqueous solubility via amorphization of crystalline poor glass-forming drugs represents a challenge, particularly when drug dosing is high. In such scenarios, there is often a need for high polymer loadings, leading to an increase in the dosage form mass and less patient acceptability. This work investigated the role that polymer type and after-melt cooling rate had upon the amorphicity of solid dispersions (SDs) containing high levels of naproxen and three commonly used polymeric excipients: Eudragit® EPO, Kollidon® VA64, and Soluplus®. Using a combination of thermogravimetry, conventional and fast-scan DSC, oscillatory rheology, in silico Hansen solubility parameter computation, FTIR, and PXRD, we have shown that amorphicity could be affected by the cooling rate with the specific polymer type and amount playing a significant role in the degree of this impact. The amorphous drug content, evident at higher cooling rates, was found to be dependent on drug-polymer interaction and polymer melt viscosity. Higher polymer concentration and faster cooling produced less melt crystallization upon cooling, which was attributed to a shift in nucleation to lower temperatures where it could be inhibited by polymer matrix viscosity. Amorphous drug content, which contained drug nuclei, was evidenced by cold crystallization upon reheating. After 4 weeks of 'gentle' storage, cold crystallization increased if nucleation was the dominant process, whereas cold crystallization decreased if crystal growth prevailed. Storage at elevated temperature and humidity resulted in the absence of cold crystallization, and increased melt crystallisation. Thus, faster cooling could serve as an additional tool to improve amorphous yield and stability of high drug-loaded SDs, however, intermolecular polymer-drug interaction, melt viscosity of the drug-polymer matrix, and storage conditions are of critical importance to achieve this goal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

This paper presents an innovative approach that utilizes self-synthesized homopolymers of polyvinylpyrrolidone (PVP) with different architectures as effective matrices for inhibiting the crystallization of naproxen (NAP). We have thoroughly investigated amorphous solid dispersions containing NAP and (i) self-synthesized linear PVP, (ii) self-synthesized three-armed star-shaped PVP, and (iii) self-synthesized linear PVP with a mass (M n ) corresponding to the length of one arm of the star polymer, as well as (iv) commercial linear PVP K30 as a reference. Differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy studies, as well as molecular dynamics simulations were conducted to gain comprehensive insights into the thermal and structural properties, as well as intermolecular interactions in the NAP-PVP systems. The main purpose of all experiments was to assess the impact of macromolecule structure (topology, molecular weight) on the kinetics of the crystallization of NAP - a drug that is very difficult to vitrify. Our studies clearly showed that the most effective matrix in inhibiting the NAP crystallization is linear, self-synthesized PVP with higher molecular weight (M n ) similar to that of the commercial PVP K30, but lower, strictly controlled dispersity. We also found that crystallization of API proceeds at a similar pace for the binary mixture composed of a star-shaped PVP and linear polymer with M n corresponding to M n of one arm of the star-shaped macromolecule in the vicinity of the T g . The obtained data highlight the key role of polymer structure in designing new pharmaceutical formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diacylglycerol (DAG) is a novel functional structural lipid, but its application in base oils remains underexplored. This research investigated the effect of three liquid oils (groundnut oil, corn oil, and flaxseed oil), with varying polyunsaturated fatty acid (PUFA) (39.60, 69.50, and 77.65 %) and DAG content (0.00, 40.00, 80.00 %), on the crystallization behaviors of palm-based oil. DAG (40.00 %), obtained through enzymatic glycerolysis and molecular distillation, was found to stabilize the binary system with good compatibility and fine crystal structure. "Liquid" DAG played a dual role: diluting solid lipids, and promoting crystallization. Increasing DAG content led to larger crystalline domain size, while higher PUFA content accelerated crystallization and increased crystal orderliness, though decreasing crystal density. These results demonstrated the clear influence of PUFA and DAG content on palm-based oil crystallization. This knowledge can guide the utilization of different unsaturated DAGs for tailored fat crystallization in food application., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Herein, we develop novel O/W and W/O emulsion gels based on soybean protein isolate nanoparticles, xanthan gum, and crystalline fat to enhance 3D printability and achieve an effective alternative to butter. Palm mid fraction can self-assemble to form a fat crystal network, thus improving the structural strength of emulsion gels. Different emulsion gels are obtained by adjusting the sequence of crystallization and emulsification. The increased viscoelastic modulus of O/W emulsion gel is attributed to the tighter network structure between emulsion droplets. W/O emulsion gels exhibit better freeze-thaw stability due to the presence of fat crystal networks at the oil-water interface and the continuous phase. W/O emulsion gels with 60 wt% oil phase fractions had minimal print deformation rate. Both W/O and O/W emulsion gels significantly improve the hardness, gumminess, and chewiness of baked cakes. These findings provide new strategies for designing emulsion gels utilized in 3D printing and fat replacement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pirfenidone (PFD) is one of the first-line drugs for treating idiopathic pulmonary fibrosis, while directly delivering PFD to lung showed better efficiency. However, PFD is a non-glass former and easily precipitates into larger-sized crystals that are undesirable for pulmonary delivery. Hence, the fabrication of PFD particles with pulmonary delivery efficiency remains challenging. Herein, a series of particles were prepared by spray freeze drying a PFD and leucine mixed solution. The sub-ambient behavior of the mixed solution was evaluated via a differential scanning calorimeter. The effects of the PFD/leucine mass ratio and freezing temperature on the particle morphology, size, crystal polymorphism, molecular structure and in vitro aerosol performance were investigated. Shortening the lifetime of the droplet and adding proper amounts of leucine are the keys to decreasing the PFD crystal size and improving its dispersity. The optimal sample is SF -80 D-P 95 L 5 -2, with high FPF and eFPF values of ∼ 65.97 % and ∼ 27.86 %, and owing to its high drug loading (95 %), the FPD and eFPD are extremely high at ∼ 6.27 mg and ∼ 2.65 mg, respectively, equivalent to ∼ 6.27 mg and ∼ 2.65 mg PFD deposited in the lungs and alveoli, respectively, when 10 mg dry powder is inhaled. This work provides a potential strategy for tuning the precipitation behavior of PFD microcrystals with high pulmonary drug delivery efficiency., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Broparestrol has been used as a drug to treat acne in the form of a mixture of its two stereoisomers. Although it has been withdrawn from the market, the binary system is rich in polymorphism and understanding the phase behaviour of the binary system involving the E- and Z-isomers is challenging. Physical mixtures do not immediately give rise to equilibrium phase behaviour, whereas recrystallization often leads to metastable phases and the appearance of stable phases can take years. A new polymorph of E-broparestrol has been found crystallizing in a monoclinic unit cell, space group P2 1 /c, with lattice parameters a = 5.6079(4) Å, b = 16.1206(10) Å, c = 20.250 (1) Å, β = 100.569(4)°, V cell  = 1799.6(2) Å 3 , and Z = 4. This polymorph, I E , is stable at high temperatures, whereas the published form, II E , is stable at room temperature. In the case of Z-broparestrol polymorphism has been observed too; however, it has so far only occurred within the binary phase diagram, and it has not been possible to isolate the new polymorph of Z-broparestrol, II Z . Through the phase behaviour in the binary system, it could be determined that the new Z polymorph, II Z , behaves monotropically in relation to the known triclinic polymorph of the Z-isomer, I Z . Nothing is known about its structure, and it is therefore not clear yet whether II Z may possess a stable domain under pressure. A stable temperature-composition phase diagram of the binary system containing E- and Z-broparestrol is proposed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.-Ll. Tamarit reports financial support was provided by Spanish ministry of science and innovation. J.-Ll. Tamarit reports financial support was provided by Government of Catalonia. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polyoxylglycerides-based solid mixtures, commercially known as Gelucire®, are excipients commonly used for bioavailability improvement of poorly water-soluble drugs. However, their effect on solutions containing hydrophobic drugs above crystalline solubility has not yet been explored. The goal of this study was to investigate the impact of a mix of two commercial Gelucire® with high HLB values (Gelucire®50/13 and Gelucire®48/16) on the amorphous solubility and crystallization from supersaturated solutions of ketoprofen, used as model drug. The results evidenced a strong interaction between Gelucire® components and the drug-rich nanodroplets generated upon liquid-liquid phase separation. This led to two important consequences: on one hand, the drug amorphous solubility was decreased, together with the amorphous-to-crystalline solubility ratio; on the other hand, the enlargement and coalescence of the drug-rich droplets were prevented. This stabilizing effect towards the drug-rich phase was comparable to, or even stronger than, that obtained with traditional amorphous polymers (PVP or HPMC) and contributed to inhibiting drug crystallization. Notably, the impact of Gelucire® on drug crystallization from the supersaturated state depended on its micellar behaviour: the monomeric form (below 50 μg/mL) accelerated the formation of crystals, whereas pre-micellar aggregates (50-500 μg/mL) and solubilizing micelles (above 500 μg/mL) inhibited drug crystallization. These findings will contribute to a better understanding of the behaviour of supersaturated drug solutions in the presence of Gelucire® and will facilitate the rational design of supersaturating drug delivery systems containing these excipients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this work, the effect of storage time on the fat crystallization, rheological and whipping characteristics of emulsions was studied and the static destabilization mechanism during storage was explored. As the storage time prolonged, peak melting temperature and onset of melting temperature increased while both the crystallization temperature and crystallization rate increased. Crystal birefringence was more pronounced at the oil/water interface accompanied by the desorption of interfacial proteins from fat droplets. The droplet size (d 4,3 ) began to increase significantly (p < 0.05) from the 5th month. The viscosity and the elastic modulus increased from 505.2 mPa·s to 908.4 mPa·s, and from 23.53 Pa to 51.38 Pa, respectively, as storing from 1st to 7th month. The whipping time decreased while the partial coalescence rate increased from 50.84 % to 65.34 %. The whipped cream at the 3rd month exhibited a smooth surface, whereas a rough surface and lost gloss was observed at the 7th month., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Crystallization degrades the physicochemical properties of honey and reduces consumer acceptance. To address this issue, radiofrequency was developed to investigate the decrystallization efficiency and quality impact mechanism of rape honey. The results showed that radiofrequency significantly decreased the number and size of crystals, leading to shortening the decrystallization time to less than 10 min. The response surface optimization methodology further indicated that the highest decrystallization rate (98.72 ± 0.34 %) and lower 5-Hydroxymethylfurfural (2.45 ± 0.12 mg/kg) contents were obtained. Furthermore, radiofrequency changed the honey from a pseudoplastic into a Newtonian fluid efficiently due to the volumetric heating feature. It is worth noting that the inactivation of glucose oxidase reduced the antibacterial capacity, while the increase in total phenolic and flavonoid contents improved the antioxidant capacity of rape honey. In summary, current findings indicated that radiofrequency is a potential alternative decrystallization technology for water baths., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Cocrystals easily undergo solution-mediated phase transformation at the surface of dissolving cocrystals during dissolution, which significantly deteriorates the solubility advantage of cocrystals. Here, a new scenario for the phase transformation of liquiritigenin (LQ) cocrystals in which the boundary of phase transformation diffuses along the surface to the bulk of the cocrystal was identified. Additionally, depending on the rate of supersaturation generation, phase transformation processes to the anhydrate and hydrate of LQ compete during cocrystal dissolution. The liquiritigenin-nicotinamide (LQ-NIC) cocrystal yielded a higher supersaturation rate, causing the nucleation kinetics to dominate the recrystallization process and the formation of a metastable form of LQ. However, in the liquiritigenin-isoniazid (LQ-INZ) cocrystal, the low supersaturation rate leading to recrystallization was controlled by thermodynamics and the subsequent formation of monohydrates of LQ (less soluble). As a result, in plain buffer, a multistep pathway for phase transformation of the LQ-NIC cocrystal was observed, in which the cocrystal was firstly converted into the anhydrate LQ (metastable form) and subsequently transformed into LQ·H 2 O. A one-step phase transformation was observed for the LQ-INZ cocrystal, where the cocrystal was directly converted to LQ·H 2 O. In a buffer containing the Eudragit E100 (E100) additive, for the LQ-NIC cocrystal, the dissolution performance was improved, which can presumably be attributed to the solubilization effect of E100 on the anhydrate and the inhibitory effect on the transformation of the anhydrate to the monohydrate. However, for the LQ-INZ cocrystal, a negligible improvement in drug concentration was observed in the presence of E100 because of the slight effects of E100 on the solubility of LQ·H 2 O. These findings provide valuable insights into the phase transformation pathways of cocrystals at the solid-liquid interface and the effects of additives on the dissolution behavior of cocrystals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Andrographolide (AG) is a diterpene lactone with significant anti-inflammatory and antitumor activities. However, the poor water solubility limits its clinical application. An andrographolide-salicylic acid (AG-SLA) nano-cocrystal delivery system was rapidly developed using hummer acoustic resonance (HAR) technology in this research. The formulation of the AG-SLA nano-cocrystal suspension and the process parameters for HAR technology were optimized in a high-throughput manner, with SDS-Tween 80 as the optimal composite stabilizer. Nano-cocrystal suspension of AG-SLA with an average particle size of 190 nm were successfully prepared, and then the optimal formulation were tenfold scaled up. Freeze-drying was adopted to solidify the nano-cocrystal and improve its stability. Various analytical techniques were used to characterize the particle size and solid state of the nano-cocrystals. The high-energy input from the HAR instrument induced partial amorphization of the nano-cocrystals, as confirmed by PXRD and DSC analyses. Saturation solubility experiments demonstrated that the solubility in pH 1.2 hydrochloric acid buffer and pH 6.8 phosphate buffer increased by 5.74 times and 6.82 times, respectively, compared to raw AG. In vitro dissolution tests indicated that the cumulative release over 120 min in pH 1.2 hydrochloric acid buffer and pH 6.8 phosphate buffer increased by 1.60 times and 1.88 times, respectively, compared to raw AG., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cocrystallization has emerged as a promising formulation strategy for modulating transdermal drug absorption by enhancing solubility and permeability. However, challenges related to cocrystal dissociation in the semi-solid state need to be addressed to mitigate regulatory concerns before the widespread implementation of topical cocrystal products in clinical practice. This study aimed to develop oil-based topical formulations incorporating cocrystals with distinct thermodynamic stabilities, followed by investigating the roles of different structurally similar coformers and oily vehicles on their physicochemical properties. Three pharmaceutical cocrystals of poorly water-soluble flufenamic acid (FFA) were synthesized with isomeric pyridine carboxamides in a 1:1 stoichiometry via rapid solvent removal. These included the reported flufenamic acid-nicotinamide cocrystal (FFA-NIC), the long-elusive flufenamic acid-isonicotinamide cocrystal (FFA-IST) and flufenamic acid-picolinamide cocrystal (FFA-PIC). The resulting cocrystals, which exhibited different hydrogen bonding patterns, were characterized using powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, and structural analysis through single crystal X-ray diffraction. The cocrystals were further formulated in a series of oleaginous and absorption bases, including liquid paraffin, Vaseline, lanolin, and theobroma oil, for topical delivery. The cocrystal dissociation, content uniformity, and in vitro membrane diffusion were assessed. Notably, although all FFA cocrystals exhibited thermodynamic instability in aqueous solution, a significantly reduced propensity for cocrystal dissociation was observed in the ointment bases. Integrated computational analyses of packing efficiency and interaction energy revealed that the thermodynamic stability of cocrystals followed a descending order of FFA-NIC > FFA-PIC > FFA-IST. Compared with raw FFA, FFA-IST and FFA-PIC, which had larger positive ΔV non-H and ΔE cocryst , achieved superior cumulative diffusion of FFA from Vaseline, with a 4.3-fold (p = 0.0003) and 3.3-fold (p = 0.0029) increase at 6 h in a Franz diffusion cell model, respectively. The diffusion of all FFA cocrystals mainly followed the Higuchi kinetic model and was positively correlated with the intrinsic dissolution rate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This survey provides a comprehensive analysis of solid form screens for 476 new chemical entities (NCEs) conducted at Pharmaron from 2016 to 2023. The findings from this survey reveal notable trends in polymorphism, salt formation, crystallization behavior and molecular weight (MW) distribution of the NCEs evaluated. Most solid form screens were conducted to select the preferred solid form for Investigational New Drug (IND) enabling projects, others were for candidate selection or late-stage development. Comparison to published historical data was made to show changes in occurrence of counterions/co-formers for salts/co-crystals, polymorphs, and the distribution of MWs over time. Increased complexity in the solid-form landscape and selection of the development form are discussed, including challenges in crystallization and selection of lead forms. The distribution of types of crystal forms and the observation of emerging and disappearing polymorphs are presented. These results highlight the evolving challenges and considerations in solid form screening and form selection and offer insights for future pharmaceutical development and crystallization strategies., Competing Interests: Declaration of competing interest Pharmaron is a Contract Resource Organization and performs work at the request of the international biotech and pharmaceutical companies (sponsors) under a fee-for-service work contract. All authors are employed by Pharmaron, Inc. All rights and privileges are assigned to the companies who contract the work. The dataset is a collection of solid form data from the projects’ reports; no chemical structure or specific project information are disclosed. The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Mechanical perturbations of drug during solid pharmaceutical processing like milling can often generate crystal disorder posing serious implications to drug's stability. While physical changes like amorphization, recrystallization, polymorphism of the disordered drugs are extensively studied and reported in the literature, the propensities and inter-dependencies of recrystallization and degradation of disordered drugs have seldom received deep attention. Previous investigations from our lab have explored some of these interplays, aiming to develop predictive stability models. As a follow-up, the implication of crystal disorder on the oxidative instability of Olanzapine (OLA) during accelerated storage is investigated in this work. Cryo-milling OLA at varied time intervals generated different extents of crystal disorder. The milled samples were characterized using calorimetry and infrared (IR) spectroscopy to examine the physical state, while their degradation was evaluated using ultra-performance liquid chromatographic methods. An X-ray amorphous OLA sample was generated by melt-cooling, and used as an amorphous reference. The crystallinity of the cryo-milled samples was quantified using a partial least square regression model based on ATR-FTIR spectroscopic data. The cryo-milled samples were exposed to different accelerated stability conditions along with crystalline (unmilled) and quench cooled (amorphous) samples, serving as controls. At periodic intervals, samples were removed from the stability storage, and analyzed using ATR-FTIR and UPLC methods to quantify the crystallinity- and degradation extents. A positive relation was witnessed between the initial degree of crystallinity and degradation kinetics of the disordered OLA samples during stability storage indicating a strong dependency of degradation on the disorder contents for such disordered solids. The results obtained in this study can potentially explain consequences of inter-batch variations of drugs during stability storage, in addition to enabling de-risking strategies towards eliminating solid drug instabilities in product development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Biopharmaceutical drugs, including proteins, peptides, and antibodies, are renowned for their high specificity and efficacy, fundamentally transforming disease treatment paradigms. However, their structural complexity presents challenges for their formulation and delivery. Protein crystals, characterized by high purity, high stability and a porous structure for biopharmaceutical drug encapsulation, providing a potential avenue for formulating and delivering biopharmaceutical drugs. There is increasing interest in engineering protein crystals to delivery biopharmaceutical drugs for biomedical applications. This review summarizes the recent advances in biopharmaceutical drug delivery and phototherapy using protein crystals. First, we evaluate the advantages of using protein crystals for biopharmaceutical drugs delivery. Next, we outline the strategies for in vitro and in vivo crystallization to prepare protein crystals. Importantly, the review highlights the advanced applications of protein crystals in biopharmaceutical drug delivery, tumor phototherapy, and other optical fields. Finally, it provides insights into future perspectives of biopharmaceutical drug delivery using protein crystals. This comprehensive review aims to provide effective insights into design of protein crystals to simplify biopharmaceutical drug delivery and improve disease treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The purpose of this study was twofold: to identify the growth mechanisms of amorphous nanoparticles in solution and during the drying process at high temperatures, and to guide the process condition and stabilizer selection for amorphous nanoparticle formulations. In contrast to nanocrystals that are mostly mechanically robust, amorphous nanoparticles tend to undergo deformation under stress. As a result, development of a stable formulation and evaluation of the drying process for re-dispersible amorphous nanoparticles present considerable challenges. Although amorphous nanoparticles have stability issues, they have several pros in terms of production, high monodispersity, and diverse applications in drug delivery. In this study, amorphous nanoparticles were prepared via liquid-liquid phase separation, and their growth mechanisms were investigated both in solution and during the drying process. In solution, particles were found to be susceptible to flocculation, crystallization, coalescence, and Ostwald ripening, with coalescence being a preliminary step providing the driving force for Ostwald ripening. However, during the heat drying process, coalescence and crystallization were found to be the primary mechanisms for particle growth, with Ostwald ripening being negligible due to reduced molecular mobility. The glass transition temperature (T g ) of these amorphous nanoparticles was found to be a crucial factor both in solution and during the drying process. At temperatures < T g , particles remained in a rigid, glassy state thereby inhibiting coalescence, whereas at or above T g , particles transition from glassy to rubbery state, making them more susceptible to deformation and coalescence. The mechanistic understanding of particle growth from this study can also be extended to the stabilization of other types of soft nanoparticles., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Na Li reports financial support was provided by Dane O. Kildsig Center of Pharmaceutical Processing Research. Na Li reports financial support was provided by International Pharmaceuticals Excipients Council of the Americas. Paroma Chakravarty reports a relationship with Genentech Inc that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Low concentration polymer additives can significantly alter crystal growth kinetics of molecular liquids and glasses. However, the effect of polymer concentration on nucleation kinetics remains poorly understood. Based on an experimentally determined first nucleation time (time to form the first critical nucleus, t 0 ), we show that the polymer overlap concentration, c*, where polymer coils in the molecular liquid start to overlap with each other, is a critical polymer concentration for efficient inhibition of crystallization of a molecular liquid. The value of t 0 is approximately equal to that of the neat molecular liquid when the polymer concentration, c, is below c*, but increases significantly when c > c*. This finding is relevant for effective polymer screening and performance prediction of engineered multicomponent amorphous materials, particularly pharmaceutical amorphous solid dispersions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. All rights reserved.)

This study investigates the compatibility of excipients with the model system SDI-X and their role in the induced crystallization of the amorphous compound-X in tablet formulations. We aimed to establish a straightforward and practical screening approach for evaluating excipient-induced crystallization of SDI in tablet matrices. Three methodologies-binary powder mixture, binary compact, and bilayer tablets-were employed to qualitatively and quantitatively evaluate the recrystallization of SDI-X with various excipients under accelerated storage conditions. The results demonstrated that binary compacts, providing direct physical contact between SDI-X and excipients, are superior in reflecting realistic drug-excipient contact within pharmaceutical tablets, enabling a more accurate assessment of excipient-induced crystallization for SDI-X. In contrast, the broadly used conventional binary blends can significantly underestimate this risk due to insufficient proximity. In addition, the bilayer tablets further confirmed that crystallization initiates at the contact surface between SDI-X and the excipients. The study highlighted that not only hygroscopicity but also the type of excipient and its physical contact with SDI-X significantly influence the recrystallization extent and rate of SDI-X. Interestingly, less hygroscopic diluents such as mannitol and lactose induced much higher levels of crystallization of SDIs, contrary to expectations based on moisture content alone. This suggests that the excipient type and contact surface are more critical in inducing recrystallization than just the level of moisture. The findings emphasize the need for careful excipient selection, study design, and sample preparation to enable appropriate assessments of SDI-excipient compatibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Despite being recognized as a promising technique for treating high salinity water, membrane distillation (MD) has been plagued by the scaling of sparingly soluble salts. The growth of crystals can not only create additional resistance to evaporating water at the feed-membrane interface, but also alter the hydrophobic network to bridge the feed and distillate (i.e., result in the phenomenon of wetting). When recognizing the uncertain behaviors of calcium sulfate (CaSO 4 ) scaling in MD, this study was motivated to ascertain whether the crystal-membrane interactions could be dependent on the variation in crystalline morphology. In particular, optical coherence tomography (OCT) was employed to characterize the scaling-induced wetting via a direct-observation-through-the-membrane (DOTM) mode, which mitigated the effects of developing an external scaling layer on resolving the crystal-membrane interactions. The improved in-situ characterization suggests that the crystalline morphology of CaSO 4 could be effectively regulated by varying the stoichiometry of crystallizing ions; the richness of calcium in the aqueous environment for crystallization would be in favor of weakening the crystal-membrane interactions. The stoichiometry-dependent growth of CaSO 4 crystals can be exploited to develop an effective strategy for preventing the hydrophobic network from being wetted or irreversibly damaged., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Although physical stability can be a critical issue during the development of amorphous solid dispersions (ASDs), there are no established protocols to predict/detect their physical stability. In this study, we have prepared fenofibrate ASDs using two representative manufacturing methods, hot-melt extrusion and spray-drying, to investigate their physical stability for one year. Intentionally unstable ASDs were designed to compare the detection power of each evaluation method, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and dissolution study. Each method did not provide the same judgment results on physical stability in some cases because of their different evaluation principles and sensitivity, which has been well-comprehended only for one-component glass. This study revealed that the detection powers of each evaluation method significantly depended on the manufacturing methods. DSC was an effective method to detect a small amount of crystals for both types of ASDs in a quantitative manner. Although the sensitivity of XRPD was always lower compared to that of DSC, interpretation of the data was the easiest. SEM was very effective for observing the crystallization of the small amount of drug for hot-melt extruded products, as the drug crystal vividly appeared on the large grains. The dissolution performance of spray-dried products could change even without any indication of physical change including crystallization. The advantage/disadvantage and complemental roles of each evaluation method are discussed for deeper understanding on the physical stability data of ASDs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Formulating active pharmaceutical ingredients (APIs) as co-crystals requires a thorough understanding of co-crystallization behavior under different process conditions. This study employs two forms of coherent Raman microscopy, narrowband coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) with spectral focusing, to study co-crystallization via liquid-assisted ball milling. Indomethacin and nicotinamide served as the model API and co-former, and the results were compared with established analytical methods. Narrowband CARS, with univariate peak position analysis, was useful to visualize co-crystal formation, but suffered some degree of signal mixing that affected component identification. Hyperspectral SRS imaging, combined with classical least squares multivariate analysis, separated the different components with high confidence and proved to be a robust and rapid tool to qualitatively and quantitatively image co-crystallization. The coherent Raman imaging results explained divergent co-crystallization endpoints obtained with the conventional solid-state analysis methods. CARS and SRS microscopies also revealed the presence of otherwise undetected trace forms. Finally, we also demonstrated the dramatic reversal of partial co-crystal formation during milling, depending on ethanol content. Overall, the study demonstrates the added value coherent Raman microscopy can provide for analysis of co-crystallization processes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The rapid and efficient cocrystal screening, based on solution-mediated phase transformation (SMPT), was applied to the screening of cocrystals between ketoconazole (KTZ) and nine aliphatic dicarboxylic acids. Cocrystals formed successfully, in minutes, with a change of suspension characteristics, either a cake formation or the formation of large particles. Bulk cocrystals were characterized by powder X-ray diffraction, thermal analysis, and Raman spectroscopy. Single crystals were grown, and molecular structures were determined. Three previously reported cocrystals were reproduced, and six new cocrystals were discovered, including one that was reported as a failure in literature by solution or grinding method. Two hydrogen-bonded motifs are observed in these nine cocrystals: Most cocrystals form hydrogen bonded discrete tetramer with two KTZ and two acids molecules; while two cocrystals form infinite chain. This study demonstrated the high efficacy of cocrystal generation using the slurry screening method. It should be fully utilized in future cocrystal screening., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

For a pair of hydrated and anhydrous crystals, the hydrate is more stable than the anhydrate when the water activity is above the critical water activity (a wc ). Conventional methods to determine a wc are based on either hydrate-anhydrate competitive slurries at different a w or solubilities measured at different temperatures. However, these methods are typically resource-intensive and time-consuming. Here, we present simple and complementary solution- and solid-based methods and illustrate them using carbamazepine and theophylline. In the solution-based method, a wc can be predicted using intrinsic dissolution rate (IDR) ratio or solubility ratio of the hydrate-anhydrate pair measured at a known water activity. In the solid-based method, a wc is predicted as a function of temperature from the dehydration temperature and enthalpy obtained by differential scanning calorimetry (DSC) near a water activity of unity. For carbamazepine and theophylline, the methods yielded a wc values in good agreement with those from the conventional methods. By incorporating a wc as an additional variable, the hydrate-anhydrate relationship is categorized into four classes based on their dehydration temperature (T d ) and enthalpy (ΔH d ) in analogy with the monotropy/enantiotropy classification for crystal polymorphs. In Class 1 (ΔH d < 0 and T d ≥ 373 K), no a wc exists. In Class 2 (ΔH d >0andT d ≥373K), a wc always exists under conventional crystallization conditions. In Class 3 (ΔH d <0andT d <373K), a wc exists when T>T d . In Class 4 (ΔH d >0andT d <373K), a wc exists only when Td . The hydrate-anhydrate pairs of carbamazepine and theophylline belong to Class 4., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The particulate properties of α-lactose monohydrate (αLMH), an excipient and carrier for pharmaceuticals, is important for the design, formulation and performance of a wide range of drug products. Here an integrated multi-scale workflow provides a detailed molecular and inter-molecular (synthonic) analysis of its crystal morphology, surface chemistry and surface energy. Predicted morphologies are validated in 3D through X-ray diffraction (XCT) contrast tomography. Interestingly, from aqueous solution the fastest growth is found to lie along the b-axis, i.e. the longest unit cell dimension of the αLMH crystal structure reflecting the greater opportunities for solvation on the prism compared to the capping faces leading to the former's slower relative growth rates. The tomahawk morphology reflects the presence of β-lactose which asymmetrically binds to the capping surfaces creating a polar morphology. The crystal lattice energy is dominated by van der Waals interactions (between lactose molecules) with electrostatic interactions contributing the remainder. Predicted total surface energies are in good agreement with those measured at high surface coverage by inverse gas chromatography, albeit their dispersive contributions are found to be higher than those measured. The calculated surface energies of crystal habit surfaces are not found to be significantly different between different crystal surfaces, consistent with αLMH's known homogeneous binding to drug molecules when formulated. Surface energies for different morphologies reveals that crystals with the elongated crystal morphologies have lower surface energies compared to those with a triangular or tomahawk morphologies, correlating well with literature data that the surface energies of the lactose carriers are inversely proportional to their aerosol dispersion performance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Molecular conformational diversity plays a crucial role in both polymorphic nucleation and cocrystal formation during the cocrystallization process. However, the relationship between molecular conformation and cocrystallization polymorphism is not well-explored. Herein, the impact of molecular conformational landscapes on cocrystallization outcomes was investigated using tizanidine (TZND) as model compound. Four coformers, namely maleic acid (MA), salicylic acid (SA), p-hydroxybenzoic acid (pHBA), and heptanedioic acid (HDA), were employed and five salt forms were developed for the first time. Compared with TZND, all five salts showed significantly improved water solubility and dissolution rate. The cocrystallization behavior of TZND varied with each coformer: MA exhibited solvent-dependent polymorphism, while SA, pHBA, and HDA showed solvent-independent monomorphism. Crystal structure and conformational analyses revealed the conformational variation of TZND across different cocrystallization outcomes. Molecular dynamics simulations and quantum chemical calculations demonstrated that the interplay between solvent effects and coformer interactions determines the dominant conformations of TZND. The cocrystallization nucleation process was also examined, and the molecular mechanism that explains both polymorphism and monomorphism in the cocrystallization of TZND was proposed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Developing co-amorphous systems is a promising strategy to improve the water solubility of poorly water-soluble drugs. Most of the studies focused on the initial dissolution rate of the fresh co-amorphous systems, and only physical stability was investigated after storage. However, the maintenance of the enhanced dissolution rate of co-amorphous systems after storage is necessary for further product development. The maintenance of amorphous forms after storage does not always mean the maintenance of the dissolution rate. In this study, indomethacin, arginine, tryptophan, and phenylalanine were used as the model drug and the co-formers to prepare co-amorphous systems and then stored under dry condition and RH 60 ± 5 % condition. No recrystallization was observed after the storage for 40 d and 80 d. Interestingly, both intrinsic dissolution rate (IDR) decrease and unexpected increase after storage were confirmed. The further mixing of IND and the co-former at a molecular level and the moisture changes of the co-amorphous systems during storage were supposed to play important roles in the aging. This study reminds us that the possible dissolution changes (both dissolution decrease and increase) of co-amorphous systems during storage should be carefully considered, though these samples maintained amorphous forms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A new cocrystalline form of metronidazole (MET) with propyl gallate (PRO), referred to as MET-PRO, has been successfully synthesized and characterized. Structural characterization reveals that MET and PRO are present in a 1:1 ratio within the cocrystal lattice, with one water molecule equivalent incorporated into the structure. This arrangement facilitates the formation of MET-PRO heterodimers and multiple stable units, collectively constructing a three-dimensional supramolecular network. The solubility and permeability of the current cocrystal, along with the parent drug MET, are evaluated under physiological pH conditions. Experimental findings reveal that MET within the cocrystal exhibits a 1.54-2.37 folds increase in solubility and approximately a threefold improvement in permeability compared to its standalone form. Intriguingly, these concurrent enhancements in the physicochemical properties of MET lead to augmented antibacterial activity in vitro, evidenced by a reduction in minimum inhibitory concentration. Even more intriguingly, the enhanced physicochemical properties observed in vitro for the current cocrystal translate into tangible pharmacokinetic benefits in vivo, characterized by prolonged half-life and enhanced bioavailability. Consequently, this research not only introduces a fresh crystal structure for antibacterial medication but also presents approach for optimizing drug properties across in vitro and in vivo settings, while concurrently bolstering the antibacterial effectiveness of MET through pharmaceutical cocrystallization techniques., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bi Qingqing reports financial support was provided by Qingdao Key Health Discipline Development Fund. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The choice of drug content is a critical factor as far as the solid dispersion is concerned. This investigation aims to build the relationship between the drug content, intermolecular hydrogen bonding and the crystalline of the carbamazepine-polyvinyl pyrrolidone solid dispersion. In this work, the microstructural changes of solid dispersions were investigated using experimental characterization combined with molecular simulation. Experimental investigations demonstrated that increasing the drug content enhances the intermolecular hydrogen bonding between drugs, resulting in the crystalline phase of the drug emerged in the solid dispersion. This negatively affects the solubility and stability of solid dispersions. Molecular simulations were then used to analyze the changes of intermolecular hydrogen bonding at different drug content in the system. It revealed a tenfold increase in drug-drug hydrogen bonding concentration as drug content elevated from 10% to 50%, while the drug-excipient hydrogen bonding concentration decreased by 45%. The correlation analysis proves the significant relationships among the drug content, intermolecular hydrogen bonding, and crystallinity of solid dispersion. Using polynomial fitting analysis, the quantitative relationships between the drug content and crystalline properties were investigated. This study will offer valuable insights into the impact of drug content on the performance of solid dispersion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Amorphous solid dispersions enhance the dissolution and oral bioavailability of poorly water-soluble drugs. However, the link between polymer properties and formulation performance has not been fully clarified yet. We studied the effect of hydroxypropyl cellulose (HPC) polymers molecular weight (M w ) on the storage stability, dissolution kinetics and supersaturation stability of spray-dried amorphous glibenclamide (GLB) formulations. The solid-state stability of amorphous GLB during storage was significantly enhanced by both the 40 kDa (HPC-SSL) and 84 kDa (HPC-L) polymers, regardless of M w differences. In contrast, HPC-SSL maintained significantly higher aqueous drug concentrations during dissolution, compared to HPC-L (its higher M w analogue). Dedicated dissolution experiments, in situ optical microscopy and solid-state characterization revealed that aqueous drug concentrations were determined by the interplay between crystallization inhibition, drug ionization, wetting and solubilization effects: (1) HPC prevents surface nucleation, hence inhibiting crystallization, (2) intestinal colloids (bile salts and phospholipids) increase supersaturated drug concentrations via wetting and solubilization effects and (3) pH and drug ionization severely impact the degree of supersaturation. The better performance of the lower M w HPC-SSL was due to its superior inhibition of surface crystallization during dissolution. These insights into the molecular mechanisms of dissolution and crystallization of amorphous solids provide foundation for rational formulation development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zahari Vinarov reports financial support was provided by Bulgarian National Science Fund. Vladimir Petkov reports equipment, drugs, or supplies was provided by European Union. Slavka Tcholakova reports financial support was provided by European Union. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Creatinine is the end product of the catabolism of creatine and creatine phosphate. Creatine phosphate serves as a reservoir of high-energy phosphate, especially in skeletal and cardiac muscle. Besides typical known changes in serum and urinary creatinine concentrations, rare cases associated with changes in serum and urinary creatine levels have been described in the literature in humans. These cases are mostly linked to an excessive intake of creatine ethyl ester or creatine monohydrate, often resulting in increased urine creatinine concentrations. In addition, it is known that at such elevated creatinine concentrations, creatinine crystallisation may occur in the urine. Analysis of crystals and urinary concrements, often of heterogenous chemical composition, may provide diagnostic and therapeutic hints to the benefit of the patient. The aim of the present work was to analyze urine crystals of unclear composition with microscopic and spectroscopic techniques. On routine microscopic analysis of urine, a preliminary suspicion of uric acid or creatinine crystals was expressed. The crystals were of a cuboid shape and showed polarization effects in microscopy. The dried urine sample was whitish-orange in colour, odourless and dissolved well in water. Protein concentration in dry weight (DW) urine was about 0.3 mg/mg. The measured zinc content in the studied sample was approximately 660 µg/g DW sample and copper content was approximately 64 µg/g DW sample. A lead signal of around 10 µg/g DW sample was also observed. UV-Vis analysis showed a maximum creatine peak around 220 nm, compatible with the spectrum of creatinine with a maximum peak of 230 nm. Using HPLC technique, an extreme high ratio of creatine to creatinine of about 38 was measured, which led to the conclusion of the occurrence of rare creatine crystals in urine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The poly(L-lactic acid) (PLLA)/ZnO composite membrane with cluster assemblies microstructure was constructed by a combination of non-solvent induced phase separation (NIPS) and the Breath-Figure method. In this novel method, the controllable diffusion rate between solvent and non-solvent was introduced to the system by adjusting the non-solvent solubility parameters. The humidity was adjusted to control non-solvent solubility parameters in the Breath-Figure method, which avoids the instantaneous phase separation induced by direct coagulation of water droplets. Hydrophobic modified ZnO nanoparticles were used as heterogeneous nucleation points to induce PLLA crystallization and formation of micro-nano structures. Controlling molecular chain growth with crystal nuclei as templates and constructing cluster assemblies microscopic morphology at 99 % humidity, and the size of the cluster decreases gradually from 10 μm to 3 μm as the nanoparticles content increased up to 5 wt%. The surface water contact angle could reach 153.8° with cluster morphology. In addition, the porous structure formed by the polymer-lean phase could increase the porosity to 93.1 % and exhibit an excellent oil absorption capacity up to 12.64 g/g. It is foreseeable that porous PLLA/ZnO composite membranes have potential applications as biodegradable oil-water separation materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anhydrous milk fat (AMF) is a flavorful, but particularly complex fat containing a wide variety of fatty acids (FAs) and triglycerides (TGs), resulting in an extended melting range of -40 °C to 40 °C. The functionality of this fat can be steered by the addition of sucrose esters (SEs). In this study, the crystallization behavior of AMF in the presence of a stearic-palmitic SE was assessed. Samples were cooled at 1 °C/min (slow cooling) or 20 °C/min (fast cooling) to 0 °C, 20 °C or 25 °C and kept isothermal for one hour. At each of these temperatures, AMF was found to crystallize via different polymorphic pathways and chain length structures, as studied by wide- and small-angle X-ray scattering. The addition of the SE (0.5 wt%) accelerated nucleation and allowed crystallization to start at higher temperatures. Polymorphic transitions were accelerated, but not changed. For fast-cooled samples, ultra-small-angle X-ray scattering provided insights into the mesoscale behavior of the crystal nanoplatelets (CNPs). It was observed that CNPs formed at 20 °C were smaller than those at 25 °C. The addition of the SE did not change the size nor the shape of CNPs. Polarized light microscopy (PLM) and cryo-scanning electron microscopy (cryo-SEM) gave insight into the microstructure of the networks. Addition of the SE resulted in more fine and dense fat crystal networks at 0 °C and 20 °C. At 25 °C, large separate floc structures were encountered, with and without the addition of the SE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Here, we investigated the complexation of short chain amylose (SCAs) and palmitic acid (PA), serving as polymeric building blocks that alter the selectivity and directionality of particle growth. This alteration affects the shape anisotropy of the particles, broadening their applications due to the increased surface area. By modifying the concentration of PA, we were able to make spherical, macaron, and disc-shaped particles, demonstrating that PA acts as a structure-directing agent. We further illustrated the lateral and longitudinal stacking kinetics between PA-SCA inclusion complexes during self-assembly, leading to anisotropy. Transmission electron microscope (TEM) and scanning electron microscope (SEM) revealed the structural difference between the initial and final morphologies of palmitic acid-short chain amylose particles (PA-SCAPs) compared to those of short-chain amylose particle (SCAPs). The presence of PA-SCA inclusion complex in the anisotropic particles was confirmed using nuclear magnetic resonance (NMR) and powder x-ray diffraction (XRD) analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Biominerals, as complex organic-inorganic nanocomposites synthesized by organisms, exhibit unique properties across various scales. This study investigates the role of soluble organic molecules, specifically acidic polysaccharides such as N-carboxymethyl chitosan (CMC) and chondroitin 6-sulfate (ChS), in regulating the formation of calcium carbonate mesocrystals. Using a precipitation method, the effects of these polymers on the morphology, size, and polymorphism of mesocrystals were evaluated. The findings reveal that the interactions between calcium carbonate and the polymers dictate the morphology of primary nanoparticles, which subsequently assemble into spherical or rod-shaped mesocrystals. Carboxylated polymers were found to stabilize the vaterite phase, while sulfated polymers favored calcite formation. By fine-tuning the polymer quantities, addition rate, and mixing technique, the size and aspect ratio of the mesocrystals can be precisely controlled, enabling targeted morphogenesis. This strategy not only advances the design of tailored mesocrystals but also deepens our understanding of nonclassical crystallization processes mediated by soluble organic biomacromolecules., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Enhancing the ductility of polylactide (PLA) through toughening modification to expand the application range of PLA aligns with the requirements of green development. In this study, eco-friendly bio-based plastic polyamide 11 (PA11) was chosen to modify poly(l-lactide) (PLLA). PA11 and poly(d-lactide) (PDLA) were grafted onto the main chain of ADR via simple reactive processing and utilized as reactive compatibilizers to improve toughening efficiency of PA11. The successful preparation of the graft copolymer was confirmed through 1 H NMR, FT-IR and DSC, and a detailed investigation was conducted on how the composition and concentration of the compatibilizer influence the mechanical properties, phase morphology, crystallization, and nucleation behaviors of PLLA/PA11 blends. Elongation at break of the 5 % PDLA/PA11 graft copolymers toughed PLLA was as high as 222 % at 30 % PA11 content, which was 17 times greater than the PLLA toughened by pristine PA11 without compromising the strength. PLLA and PA11 were immiscible binary blends with PA11 droplet/PLLA matrix phase separated morphologies in the molten state. Based on the calculation of interfacial tension, the grafted copolymer would be mainly distributed at the interface between the two phases. The dispersion of PA11 droplet in PLLA matrix was improved since the interfacial interaction force was enhanced through in-situ reaction. The increase of the nucleation site and decrease of the spherulites size were worked synergistically by stereocomplex (SC) crystallites and PA11. Under the impact of reducing the size of the dispersed phase and spherulites, the toughness of blends was enhanced. This study provided valuable insights into the control of PLLA immiscible blend morphology and elucidated the relationship between the size of dispersed phase and spherulites and the ultimate mechanical performance of bio-based PLA materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nucleation is a fundamental process that determines the structure, morphology, and properties of crystalline materials, and is difficult to control because it is unpredictable. Here, we demonstrate a new method to control the protein crystal nucleation using a magnetic force, where we manipulate the movement and coalescence of nucleation precursors by adding paramagnetic salt into the crystallization solution to constrain the number and position of nucleation. We found that protein nucleation could be significantly affected by the magnetic force that the gradient magnetic fields generate. When the magnetization force is sufficiently enough, nucleation can be confined to the crystallization solution with no interface contact; therefore, only one crystal nucleus appears, which results in noncontact suspension growth of a single crystal in the crystallization solution system. Under these situations, the nucleation rate significantly decreases due to the coalescence of the dense liquid phase, and the crystal growth rate also decreases due to the suppression of convection, which increases the crystal quality. Our findings provide a new method for the noncontact control of crystal nucleation and demonstrate that externally applied physical environments can be used to affect the liquid-liquid phase separation process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microbial fuel cell (MFC) and subsequent struvite crystallization are available low-carbon environmental- friendly techniques for resource utilization of waste activated sludge (WAS). In this study, low temperature thermo-alkaline pretreatment (LTTAP) was innovatively proposed for enhancing MFC electricity generation and subsequent struvite crystallization from WAS. The results indicated that LTTAP at 75 °C and pH 10 not only substantially shortened the start-up time of MFC to 3-4 days, but also significantly increased maximum power density to 5.38 W/m 3 . Moreover, thermo-alkaline pretreated WAS effectively exhibited stable and high output voltage over long period, compared to unpretreated WAS. Furthermore, pretreated WAS can provide an effective pH buffering function for MFC operation. In addition, about 90 % of phosphate in the pretreated WAS supernatant was recovered by struvite crystallization. The findings herein provided a new route for enhancing electricity production and nutrient recovery from WAS, which can realize the full-scale applicationof WAS resource utilization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Celecoxib, a selective COX-2 inhibitor non-steroidal anti-inflammatory drug (NSAID), exhibits analgesic and anti-inflammatory properties similar to piperine, the secondary metabolite of Piper nigrum L. Unfortunately, celecoxib has a low compressibility and low dissolution rate in aqueous medium. This study aimed to prepare a cocrystal of celecoxib and piperine to enhance the dissolution rate and compressibility properties of celecoxib. The cocrystal was synthesized using the seeding method and thoroughly characterized using Powder X-ray diffraction (XRD), differential scanning calorimetry (DSC), infrared spectrophotometry, and single-crystal X-ray diffraction techniques. The complete change in PXRD, decrease in melting point in DSC measurements, and shift in the NH stretching band in the FT-IR spectrum suggested the formation of cocrystals phase. Single-crystal XRD confirmed the formation of an equimolar ratio of cocrystals of celecoxib and piperine. The intrinsic dissolution test was conducted to confirm the impact on the cocrystal to dissolution, and it showed a slight increase compared to intact celecoxib. To assess the physico-mechanical properties, the cocrystal powders were compressed into tablets with varying forces. The results demonstrated a significant improvement in compressibility compared with intact celecoxib owing to the slip plane in the crystal lattice of the cocrystal. In conclusion, our novel celecoxib-piperine cocrystal exhibited distinct physicochemical characteristics compared to intact celecoxib, showing enhanced dissolution rate and compressibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)