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In order to balance the contradiction between safety and performance of energetic compounds, a novel approach known as cocrystallization has been widely utilized. In this work, a novel cocrystal of 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX) and ammonium perchlorate (AP) was successfully synthesized and characterized. The SEM images, PXRD spectra, and FT-IR spectrum confirmed the varied crystal structure of the cocrystal in comparison to the raw materials. In addition, the density of the cocrystal was measured to be 1.90 g.cm−3, and the detonation velocity and detonation pressure were calculated to be (8.53) km.s−1 and (35.21) GPa, respectively. [ABSTRACT FROM AUTHOR]

To overcome the poor solubility, permeability, and bioavailability of the plant isoflavone daidzein (DAI), a novel salt of DAI with anhydrous piperazine (PIP) was obtained based on cocrystallization strategy. The new salt DAI-PIP was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, and optical microscopy. The results showed that the maximum apparent solubility (Smax) of DAI-PIP increased by 7.27-fold and 1000-fold compared to DAI in pH 6.8 buffer and water, respectively. The peak apparent permeability coefficient (Papp) of DAI-PIP in the Caco-2 cell model was 30.57 ± 1.08 × 10-6 cm/s, which was 34.08% higher than that of DAI. Additionally, compared to DAI, the maximum plasma concentration (Cmax) value of DAI-PIP in beagle dogs was approximately 4.3 times higher, and the area under the concentration-time curve (AUC0-24) was approximately 2.4 times higher. This study provides a new strategy to enhance the dissolution performance and bioavailability of flavonoid drugs, laying a foundation for expanding their clinical applications. [ABSTRACT FROM AUTHOR]

Waxes find use as processing aids in filled compounds and polyethylene‐based masterbatches. In such applications, the thermal and physical property changes they impart to the polymer matrix are important. Therefore, this study details results obtained for blends prepared by mixing a Fischer–Tropsch (F–T) wax with a high‐flow linear low‐density polyethylene (LLDPE). The melting and crystallization behavior are studied using hot‐stage polarized optical microscopy (POM) and differential scanning calorimetry (DSC). The calorimetry results are consistent with partial cocrystallization of the two components. The melting and crystallization exo‐ and endotherms for the wax‐ and LLDPE‐rich phases remained separate. However, they change in shape and shift toward higher‐ and lower temperature ranges, respectively. It is found that increasing the wax content delays the crystallization, decreases the overall crystallinity, and reduces the size of the crystallites of the polyethylene‐rich phase. Rotational viscosity is measured at 170 °C in the Newtonian shear‐rate range. The variation of the zero‐shear viscosity with blend composition is consistent with the assumption of a homogeneous melt in which the chains are in an entangled state. Therefore, it is concluded that the wax and LLDPE are, in effect, miscible in the melt and partially compatible in the solid state. [ABSTRACT FROM AUTHOR]

Benzotrifuroxan (BTF) is a powerful energetic material (EM) with high density that can be used both as a primary and a secondary explosive. However, high mechanical sensitivity limits its application prospects. To actualize its potential, cocrystallization was introduced into BTF-based EMs for insensitivity improvement in the current work. A novel cocrystal explosive composed of BTF and a non-energetic molecule (2-Nitroaniline (ONA)) was prepared with a molar ratio of 1:1. The possible mechanism of cocrystal formation was studied by the analysis and characterization of its crystal structure, and the crystal structure, thermal decomposition, and energetic properties were investigated. The results indicate that the formation of the BTF/ONA cocrystal is mainly attributed to the strong interactions of the hydrogen bonds formed between the hydrogen on the amino group in the ONA molecule and the oxygen and nitrogen atoms in BTF. The impact sensitivity of BTF/ONA is obviously reduced, with the drop height of 50% explosion probability (H50) increasing from 56.0 to 90.0 cm. The calculated detonation velocity and detonation pressure of the BTF/ONA cocrystal are 7115.26 m/s and 20.51 GPa, respectively. The decomposition peak temperature of the BTF/ONA cocrystal (191.1 °C) decreases by about 90.9 °C compared to BTF (282.0 °C). This suggests that cocrystallization could effectively reduce its impact sensitivity and produce an explosive with excellent comprehensive properties. [ABSTRACT FROM AUTHOR]

Single-crystal X-ray diffraction analysis has emerged as the most reliable method for determining the structures of organic molecules. However, numerous analytes, such as liquid organic molecules, pose challenges in crystallization, making their structures directly elusive via X-ray crystallography methods. Herein, we introduced the rapid cocrystallization of a macrocycle named phenanthrene[2]arene (PTA, host) with 15 liquid organic molecules (guests). The guest liquid organic molecules were successively cocrystallized with the aid of the PTA host. Moreover, the chemical structures of the liquid organic molecules could be determined through single-crystal X-ray diffraction analysis. PTA exhibited high adaptivity and was capable of encapsulating liquid organic molecules without forming covalent bonds or strong directional interactions. The results revealed that the adaptive crystals of PTA exhibited excellent cocrystallization capacity. Weak noncovalent interactions between the host and guest molecules were crucial for organizing the guests in an ordered pattern. [ABSTRACT FROM AUTHOR]

Abstract Waxes find use as processing aids in filled compounds and polyethylene‐based masterbatches. In such applications, the thermal and physical property changes they impart to the polymer matrix are important. Therefore, this study details results obtained for blends prepared by mixing a Fischer–Tropsch (F–T) wax with a high‐flow linear low‐density polyethylene (LLDPE). The melting and crystallization behavior are studied using hot‐stage polarized optical microscopy (POM) and differential scanning calorimetry (DSC). The calorimetry results are consistent with partial cocrystallization of the two components. The melting and crystallization exo‐ and endotherms for the wax‐ and LLDPE‐rich phases remained separate. However, they change in shape and shift toward higher‐ and lower temperature ranges, respectively. It is found that increasing the wax content delays the crystallization, decreases the overall crystallinity, and reduces the size of the crystallites of the polyethylene‐rich phase. Rotational viscosity is measured at 170 °C in the Newtonian shear‐rate range. The variation of the zero‐shear viscosity with blend composition is consistent with the assumption of a homogeneous melt in which the chains are in an entangled state. Therefore, it is concluded that the wax and LLDPE are, in effect, miscible in the melt and partially compatible in the solid state.

Carbamazepine (CBZ), a widely used antiepileptic drug, is known for its therapeutic efficacy but exhibits suboptimal physicochemical characteristics, including limited bioavailability, low solubility, and poor dissolution rates. In recent years, cocrystallization has emerged as a promising approach to improve these properties and enhance the overall performance of CBZ. This review paper presents a comprehensive exploration of the advances in CBZ cocrystals, focusing on their role in enhancing bioavailability, solubility/dissolution rates, morphology, and stability compared to raw CBZ. It delves into the in‐depth examination of computational techniques, such as molecular modelling and crystal structure prediction, that play a pivotal role in the rational design and prediction of CBZ cocrystals, thereby expediting the development process. Additionally, the morphological attributes of CBZ cocrystals are discussed, shedding light on how the unique crystal structures affect their physical properties. Stability is another critical aspect addressed in this review, encompassing thermal, physical, and chemical stability. The thermal behavior of CBZ cocrystals is analyzed through differential scanning calorimetry (DSC), and their crystal structures are characterized by techniques such as X‐ray diffraction (XRD) and Fourier‐transform infrared spectroscopy (FTIR). These analyses reveal the stability and structural changes of CBZ cocrystals under various conditions, providing valuable insights for formulation and storage. In summary, this comprehensive review paper amalgamates the latest advancements in CBZ cocrystals, demonstrating their capacity to significantly improve bioavailability, solubility, dissolution rates, and stability. [ABSTRACT FROM AUTHOR]

Recycled paper has become increasingly used as a raw material in the paper industry. However, hornification limits its application. Herein, the effect of recycling on the mechanical properties and microstructure of khasi pine pulp was systematically studied. The mechanical properties deteriorated and water retention value decreased after recycling. X-ray diffraction and Fourier-transform infrared spectroscopy revealed that cellulose crystallinity increased and partial cocrystallization occurred on cellulose microfibrils. Through the analysis of the morphology of secondary fibers by FQA, the loss of fine fibers caused by each reuse was found. Using the filtration method to prepare the recycled paper reduced the loss of fine fibers and improved the mechanical properties, with the tensile strength of a sample prepared using a sand core filter unit for five cycles (8.37 MPa) being like that of a sample prepared using a paper machine after one cycle. The investigation of the internal structure of the paper showed that the retained fine fibers were bonded between the long fibers, promoting the bonding between the fibers. Fine fibers improve the curling and twisting of fibers to some extent, especially in the first three recycling cycles. The hornification phenomenon of recycled paper was studied from the viewpoint of the fiber components, which is important to promote the development and application prospect of recycled paper. [ABSTRACT FROM AUTHOR]

It is challenging to enhance the stress‐free two‐way shape memory (stress‐free TWSM) effect to obtain a wide range of response temperatures. Herein, a polycaprolactone (PCL)/poly(ω‐pentadecalactone) (PPDL) is photocured under UV light irradiation in the solvent of 1,1,2‐trichloroethane (TCA), to obtain a series of cross‐linked polyesters (CPES). Controlling solvent content (SC) which is removed after the polymerization allows the yielded CPES to perform a regulatable thermodynamic and stress‐free TWSM properties. High SC is beneficial to reduce the degree of chain overlap (C/C*) of PPDL chain segments in the PCL‐based CPES network, then causes the cocrystallization of PCL and PPDL and yielding an additional melting‐transitions (Tm). An enhanced stress‐free TWSM is obtained in high SC samples (CPES‐15‐90), reflected in the attainment of a wide range of response temperature, which means a wider service temperature. The enhancement is reflected in higher reversible strain of high SC samples compared with the samples prepared with low SC when varying high trigger temperature (Thigh). Even at high Thigh, the high SC sample still has reversible strain. Therefore, controlling SC strategy for photocuring copolyester not only provides a new preparation approach for high‐performance shape memory (SM) polymers, but also offers new condensed polymer structure to explore. [ABSTRACT FROM AUTHOR]

Cocrystallization drug/coformer and drug/drug stands as a promising method to enhance the physicochemical properties and to improve the antibacterial activity of active pharmaceutical ingredients (API). In this study the combinations metronidazole/maleic acid and metronidazole/paracetamol were prepared in the molar ratio of 1:1 via the liquidassisted grinding technique and characterized by differential scanning calorimetry (DSC), powder X-ray diffraction and scanning electron microscopy. The thermal analysis revealed the existence of an endothermic peak at the temperature of 144.93°C for the combination MTZ-MA and 130.5°C for the binary mixture MTZ-PCA. The PXRD showed the apparition of new peaks which demonstrate the formation of a novel crystalline phase. The SEM microscopy supported the results obtained through DSC and PXRD analysis. The antibacterial activity of the two combinations drug/coformer and drug/drug and the pure antibacterial agent was evaluated against aerobic and anaerobic bacterial strains. As a result, the two combinations displayed a synergistic effect. This phenomenon yields a significantly stronger therapeutic impact compared to the effect expected for the parent component. [ABSTRACT FROM AUTHOR]

Benzotrifuroxan (BTF) is a powerful energetic material (EM) with high density that can be used both as a primary and a secondary explosive. However, high mechanical sensitivity limits its application prospects. To actualize its potential, cocrystallization was introduced into BTF-based EMs for insensitivity improvement in the current work. A novel cocrystal explosive composed of BTF and a non-energetic molecule (2-Nitroaniline (ONA)) was prepared with a molar ratio of 1:1. The possible mechanism of cocrystal formation was studied by the analysis and characterization of its crystal structure, and the crystal structure, thermal decomposition, and energetic properties were investigated. The results indicate that the formation of the BTF/ONA cocrystal is mainly attributed to the strong interactions of the hydrogen bonds formed between the hydrogen on the amino group in the ONA molecule and the oxygen and nitrogen atoms in BTF. The impact sensitivity of BTF/ONA is obviously reduced, with the drop height of 50% explosion probability (H50) increasing from 56.0 to 90.0 cm. The calculated detonation velocity and detonation pressure of the BTF/ONA cocrystal are 7115.26 m/s and 20.51 GPa, respectively. The decomposition peak temperature of the BTF/ONA cocrystal (191.1 °C) decreases by about 90.9 °C compared to BTF (282.0 °C). This suggests that cocrystallization could effectively reduce its impact sensitivity and produce an explosive with excellent comprehensive properties.

Purpose: To synthesize and characterize new cocrystals of berberine chloride (BCl) for potential pharmaceutical tablet formulation. Methods: Solutions of BCl with each of three selected cocrystal formers, catechol (CAT), resorcinol (RES), and hydroquinone (HYQ) were slowly evaporated at room temperature to obtain crystals. Crystal structures were solved using single crystal X-ray diffraction. Bulk powders were characterized by powder X-ray diffraction, thermogravimetric-differential scanning calorimetry, FTIR, dynamic moisture sorption, and dissolution (both intrinsic and powder). Results: Single crystal structures confirmed the formation of cocrystals with all three coformers, which revealed various intermolecular interactions that stabilized crystal lattices, including O–H···Cl− hydrogen bonds. All three cocrystals exhibited better stability against high humidity (up to 95% relative humidity) at 25 ℃ and higher intrinsic and powder dissolution rates than BCl. Conclusion: The enhanced pharmaceutical properties of all three cocrystals, as compared to BCl, further contribute to the existing evidence that confirms the beneficial role of cocrystallization in facilitating drug development. These new cocrystals expand the structure landscape of BCl solid forms, which is important for future analysis to establish a reliable relationship between crystal structure and pharmaceutical properties. [ABSTRACT FROM AUTHOR]

Background: Cocrystallization by solvent evaporation was used to enhance the dissolution, physicochemical properties, and bioavailability of nimodipine (NMD). Here, we aimed to develop NMD cocrystals with improved solubility and dissolution. Thereafter, our objective was to check the changes in brain tissue concentrations before and after the cocrystal formation of NMD. Methods: A 32-factor design was used for product optimization by determining the desirability function. Differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy were used to confirm the formation of cocrystals. Results: The saturation solubility study of NMD:SA cocrystals resulted in 9.52 mg/ml, which is 128-fold higher than that of pure NMD (0.074 mg/ml). In vitro dissolution and permeability studies showed an improvement in the percentage of drug release and permeability of NMD from cocrystals as compared to pristine NMD. An in vivo study of oral bioavailability in Wistar rats demonstrated higher plasma and brain tissue concentrations of NMD in the cocrystal form than in the conventional oral suspension. Discussions: The findings of this study showed a positive correlation between nimodipine solubility, improvement in dissolution, and its effect on brain tissue concentration in Wistar rats. The improved solubility of nimodipine may lead to increased dissolution rates, which can enhance its bioavailability and therapeutic efficacy in the treatment of cerebral vasospasms. [ABSTRACT FROM AUTHOR]

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Single-crystal X-ray diffraction analysis has emerged as the most reliable method for determining the structures of organic molecules. However, numerous analytes, such as liquid organic molecules, pose challenges in crystallization, making their structures directly elusive via X-ray crystallography methods. Herein, we introduced the rapid cocrystallization of a macrocycle named phenanthrene[2]arene (PTA, host) with 15 liquid organic molecules (guests). The guest liquid organic molecules were successively cocrystallized with the aid of the PTA host. Moreover, the chemical structures of the liquid organic molecules could be determined through single-crystal X-ray diffraction analysis. PTA exhibited high adaptivity and was capable of encapsulating liquid organic molecules without forming covalent bonds or strong directional interactions. The results revealed that the adaptive crystals of PTA exhibited excellent cocrystallization capacity. Weak noncovalent interactions between the host and guest molecules were crucial for organizing the guests in an ordered pattern.

The formation of cocrystallization in two various conjugated components may endow the newly formed conjugated cocrystals with multiple functionalities and improved charge transport properties. However, compared to conjugated small molecules, this strategy is rather limitedly realized in conjugated polymers. Herein, a simple meniscus-assisted solution printing (MASP) strategy is utilized to achieve the cocrystallization in the blends of two conjugated polymers, i.e., poly(3-hexylthiophene) (P3HT) and poly(3-octylthiophene) (P3OT), and the cocrystalline structures are correlated closely to their charge mobilities. The P3HT/P3OT blends phase separate and crystallize individually in their drop-cast thin films. When subjecting the P3HT/P3OT blended solution to MASP, the confined solvent evaporation between two nearly parallel plates triggers them to cocrystallize progressively when accelerating the moving lower plate. The cocrystallization kinetics and the changes in P3HT/P3OT molecular structures are elucidated. Finally, these different crystalline structures of P3HT/P3OT blends are applied in organic field-effect transistors, imparting the cocrystallization-enhanced charge transport than respective P3HT and P3OT crystal domains. Such MASP method can be extended to craft cocrystals of other conjugated polymer blends for their diverse optoelectronic applications. [ABSTRACT FROM AUTHOR]

The chemotherapeutic agent known as 5-fluorouracil (5-FU) is an artificial fluoropyrimidine antimetabolite that has been widely used for its antineoplastic properties. Cocrystals of 5-fluorouracil (5-FU) with five different Schiff bases (benzylidene-urea (BU), benzylidene-aniline (BA), salicylidene-aniline (SA), salicylidene-phenylhydrazine (SPH), and para-hydroxy benzylideneaniline (HBA)) are reported in this study. The newly synthesized cocrystals were analyzed by FTIR and PXRD. In this study, we investigated the antitumor efficacy of 5-FU derivatives in SW480 colon cancer cells via MTT assay at varying dose concentrations. Molecular docking was performed to predict the binding mechanism of TS with various 5-FU complexes. FTIR revealed the presence of respective functional groups in the prepared cocrystals. The frequencies (v) of N-H (3220.24 cm−1) and carbonyl groups (1662.38 cm−1) in the spectrum of 5-FU shifted considerably in all derivative cocrystal new interactions. There was a noticeable transformation in the PXRD peak of 5-FU at 2θ = 28.37° in all derivatives. The novelty of the present study lies in the fact that 5-FU-BA showed an anticancer potential IC50 (6.4731) far higher than that of 5-FU (12.116), almost comparable to that of the reference drug doxorubicin (3.3159), against SW480 cancel cell lines, followed by 5-Fu-HBA (10.2174). The inhibition rates of 5-FU-BA and 5-FU-HBA were highest among the derivatives (99.85% and 99.37%, respectively) in comparison with doxorubicin (97.103%). The results revealed that the synthesized 5-FU cocrystals have promising antitumor efficacy compared with previously reported 5-FU and 5-FU. The activities of the cocrystals were rationalized by a molecular modeling approach to envisage binding modes with the target cancer protein. [ABSTRACT FROM AUTHOR]

Pyruvic acid is an organic compound used in various fields (e.g., the pharmaceutical, cosmetic, food, and chemical industries) and subject to constantly growing demand. Pyruvic acid is liquid at room temperature, rendering manipulation less straightforward. Furthermore, in the liquid phase, pyruvic acid is air-sensitive. We here present a multi-component crystal engineering strategy to render pyruvic acid solid under ambient conditions, focusing on cocrystallization and salt formation. Out of 73 screened cocrystal and salt formers, eight were found to form novel crystalline forms with pyruvic acid. Four of these were studied in detail, with pyruvic acid stable in a solid phase at temperatures up to 120 °C. These results illustrate the effectiveness of cocrystallization as a tool to convert unstable liquid compounds into stable crystalline solid forms. [ABSTRACT FROM AUTHOR]

This study describes the preparation, characterization, and influence of the enantiopure vs. racemic coformer on the physico-chemical properties of a pharmaceutical cocrystal. For that purpose, two new 1:1 cocrystals, namely lidocaine:dl-menthol and lidocaine:d-menthol, were prepared. The menthol racemate-based cocrystal was evaluated by means of X-ray diffraction, infrared spectroscopy, Raman, thermal analysis, and solubility experiments. The results were exhaustively compared with the first menthol-based pharmaceutical cocrystal, i.e., lidocaine:l-menthol, discovered in our group 12 years ago. Furthermore, the stable lidocaine/dl-menthol phase diagram has been screened, thoroughly evaluated, and compared to the enantiopure phase diagram. Thus, it has been proven that the racemic vs. enantiopure coformer leads to increased solubility and improved dissolution of lidocaine due to the low stable form induced by menthol molecular disorder in the lidocaine:dl-menthol cocrystal. To date, the 1:1 lidocaine:dl-menthol cocrystal is the third menthol-based pharmaceutical cocrystal, after the 1:1 lidocaine:l-menthol and the 1:2 lopinavir:l-menthol cocrystals reported in 2010 and 2022, respectively. Overall, this study shows promising potential for designing new materials with both improved characteristics and functional properties in the fields of pharmaceutical sciences and crystal engineering. [ABSTRACT FROM AUTHOR]

The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

Melt-cast explosive 2,4-dinitroanisole (DNAN) crystal and its cocrystals DNAN/1,3-dinitrobenzene (DNB) and DNAN/2-nitroaniline (NA) were used to identify the effects of cocrystallization on the crystal structure, non-covalent interactions, and melting points of the DNAN crystal through density functional theory and molecular dynamics. The components DNB and NA with subtle structure variations between the nitro group and amino group can significantly affect the non-covalent interactions, especially the π-π stacking and H-bonds, which can lead to different crystal stacking styles. The melting points of the DNAN crystal are decreased through the cocrystallization, which expands the utilization of the DNAN-based melt cast explosives. Our study deciphers the effects caused by the cocrystallization on the structure and properties of melt cast explosives and may help to design and optimize novel melt-cast explosives. [ABSTRACT FROM AUTHOR]

The cocrystallization of the earlier described carboxy-containing iron(II) clathrochelate (I) with 2-hydroxypyridine and 2-aminopyridine affords two new crystalline products: the salt and cocrystal of this complex, respectively, formed by the acid–pyridine two-point heterosynthone, which is often met in multicomponent crystals of aromatic acids and ortho-substituted pyridines. The neutral nature of the cocrystallization product with 2-hydroxypyridine violates the rule of pKa, which is fulfilled in the case of 2-aminopyridine, because of the equilibrium shift in the crystalline phase toward the keto form of 2-hydroxypyridine: pyridone-2. According to the X-ray diffraction (XRD) data, complex I in the salt and cocrystal exists in the low-spin state and undergoes no temperature-induced transition in a temperature range of 100–298 K. [ABSTRACT FROM AUTHOR]

The application of a computational screening methodology based on the calculation of intermolecular interaction energies has guided the discovery of new multicomponent solid forms of the oral antiviral Adefovir Dipivoxyl. Three new cocrystals with resorcinol, orcinol and hydroquinone have been synthesized and thoroughly characterized. They show improved dissolution profiles with respect to the single solid form, particularly the cocrystals of orcinol and resorcinol, which have 3.2- and 2-fold faster dissolution rates at stomach conditions (pH 1.5). Moreover, dynamic dissolution experiments that simultaneously mimic both the pH variation along the gastrointestinal tract and the partition into biological membranes show that, in addition to the faster initial dissolution, Adefovir Dipivoxyl also penetrates faster into the organic membranes in the form of resorcinol and orcinol cocrystals. [ABSTRACT FROM AUTHOR]

Cross‐fractionation characterization (CFC) between temperature rising elution fractionation (TREF) and gel permeation chromatography (GPC) is a technique developed to determine the bivariate molecular weight and chemical composition distribution (MWDxCCD), a unique and detailed microstructural fingerprint of polyolefin. Like other crystallization‐based characterization techniques, CFC may suffer from cocrystallization effects during analysis, which can mislead the interpretation of polymer microstructures. However, cocrystallization phenomena during CFC analysis are not investigated, especially for industrial polymers. In this study, the cocrystallization effect during CFC analysis is systematically investigated using two series of binary blends based on four individual polyethylene samples. These individual samples have distinct microstructural characteristics, representing polyethylene produced using different polymerization processes and catalytic systems. The effects of microstructural characteristics and blending ratio on cocrystallization level are examined. When the CFC profiles of individual components do not overlap, a high level of cocrystallization can be observed. Furthermore, the behavior of how the blending ratio affects cocrystallization depends on the characteristics of CFC profiles of individual component and their interactions. The level of cocrystallization in binary blends increases with the weight fraction of the component having microstructures eluted in the cocrystallization temperature range. [ABSTRACT FROM AUTHOR]

[Display omitted] In the past several decades, the field of cocrystal engineering has developed into a vital research topic in supramolecular chemistry, holding the foremost scope in crystal engineering, medicinal chemistry, materials chemistry, and the pharmaceutical industry. The medium of cocrystallization has been through the classic non-covalent interactions. However, cocrystallization through sigma hole (σ-hole)-based modern interactions is a breakthrough in crystal engineering. This σ-hole mediated non-covalent interaction uniquely contributes to supramolecular chemistry through different subgroups viz halogen bonding (XB), chalcogen bonding (ChB), pnictogen bonding (PnB), and tetrel bonding (TB). Despite much potential, chalcogen bonding, pnictogen bonding, and tetrel bonding are yet at an infancy stage compared to halogen bonding. Hence, we attempted to address the great potential of these non-covalent interactions (intra- and inter-molecular) and enlighten the ChB, PnB, and TB, as their outstanding contribution to the supramolecular domain needs to be communicated. Through this account, we promote these cooperative σ-hole-based interaction synthons as attractive toolboxes in supramolecular chemistry by addressing the strength and directionality of σ-hole potential, the role of steric hindrance, different modes of characterizations, application in distinct fields, etc. We hope this work will be the medium of a new direction in advancing σ-hole-assisted interactions in different research areas. Also, chalcogen, pnictogen, and tetrel bonding could get out of the shadow of halogen bonding and get their recognition in supramolecular chemistry. [ABSTRACT FROM AUTHOR]

Crystal engineering provides a unique approach to modulating the physicochemical properties of forming active drug molecules so nowadays pharmaceutical companies and researchers have shown interest in designing and building cocrystals. Creating new crystalline solid structures with altered physicochemical properties such as solubility, bioavailability, tabletability, melting point, stability, and so on. The intermolecular interactions of molecules in the crystal lattice are used to investigate these properties. Numbers of methods for crystallizing the drug are summarised and analyzed, pointing to the advantages and disadvantages that have been highlighted in the literature. This literature review discusses in detail the different types of cocrystals, their mechanisms, methods of cocrystals, applications of cocrystals, and their characterization. The main purpose of this article is to look at what has changed in this field in the last ten years and show what could be learned from better research on cocrystal formation and how it can be used. [ABSTRACT FROM AUTHOR]

Crystallization is one of the largest and most economical bulk purification techniques used in industry today. There has been an increase in demand for enantiomerically pure compound production for research, organic synthesis, pharmaceutical drug production, and other applications. Even after asymmetric synthesis, chiral purification will always be necessary. The focus of this review is on recent advances in chiral crystallization for the purification of enantiomers. A comprehensive discussion of three techniques and their mechanisms is provided, namely: attrition‐enhanced deracemization, cocrystallization, and inorganic ionic cocrystallization. Several examples of attrition‐enhanced deracemization are discussed. The key advantage of this technique is that it eliminates enantiomeric waste and can be used to produce enantiomeric excesses of greater than 99% from racemic mixtures. Chiral cocrystallization is examined, with over 60 cocrystallizing compounds, as an excellent means for enantiomeric enrichment. Selective chiral inclusion complexation was shown to be a novel approach for the formation of cocrystals. Chiral inorganic ionic cocrystallization is a new technique involving the formation of cocrystals between chiral ligands and certain metal salts in order to produce conglomerate crystal behavior in otherwise racemic compounds. [ABSTRACT FROM AUTHOR]

Crystalline metal oxide nanosheets show exceptional catalytic performance owing to the large surface‐to‐volume ratio and quantum confinement effect. However, it is still a challenge to develop a facile and general method to synthesize metal oxide nanosheets. Herein, we report a cocrystallization induced spatial self‐confinement approach to synthesize metal oxide nanosheets. Taking the synthesis of SnO2 as an example, the solvent evaporation from KCl and SnCl2 solution induces the cocrystallization of KCl and K2SnCl6, and the obtained composite with encapsulated K2SnCl6 can be in situ converted into SnO2 nanosheets confined in KCl matrix, after water washing to remove KCl, porous SnO2 nanosheets can be obtained. Notably, a series of metal oxide nanosheets can be obtained through this general and efficient green route. In particular, porous CeO2/SnO2 nanosheets with improved surface O− species and abundant oxygen vacancies exhibit superior gas sensing performance to 3‐hydroxy‐2‐butanone. [ABSTRACT FROM AUTHOR]

In the niche area of energetic materials, a balance between energy and safety is extremely important. To address this "energy–safety contradiction", energetic cocrystals have been introduced. The investigation of the synthesis methods, characteristics, and efficacy of energetic cocrystals is of the utmost importance for optimizing their design and development. This review covers (i) various synthesis methods for energetic cocrystals; (ii) discusses their characteristics such as structural properties, detonation performance, sensitivity analysis, thermal properties, and morphology mapping, along with other properties such as oxygen balance, solubility, and fluorescence; and (iii) performance with respect to energy contents (detonation velocity and pressure) and sensitivity. This is followed by concluding remarks together with future perspectives. [ABSTRACT FROM AUTHOR]

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.)

Abstract Background Cocrystallization process involved the understanding of interaction at molecular level between two molecules in context to their crystal packing and designing of new solids having improved physicochemical as well as pharmaceutical properties. In the present research, an attempt to increase the aqueous solubility and dissolution rate of a poorly aqueous soluble drug fenofibrate (FB) by formulation and evaluation of its cocrystals with benzoic acid (BZ) as a coformer was carried out. Results The drug and coformer were cocrystallized by using the solvent drop grinding method. For prediction of cocrystals formation, CSD (Cambridge Structure Database) software was utilized. Fourier transformation infrared spectroscopy (FTIR), X-ray diffraction (XRD) and differential scanning calorimetry (DSC) techniques were used for analysis of cocrystals. Albino rats were procured from institution as per IAEC guidelines for in vivo anti-hyperlipidaemic studies. The in vitro dissolution profile of cocrystals, pure drug, their physical mixture and marketed formulation was found to be 89%, 39%, 47% and 61%, respectively. Conclusions An enhanced anti-hyperlipidaemic activity of cocrystals was found compared to pure drug. The FB: BZ cocrystals also compared to the pure drug showed better dissolution profile and improved in vivo anti-hyperlipidaemic activity in rats. The study proved that cocrystals can promise to improve in vitro dissolution rate of poorly aqueous soluble drugs, which in turn can lead to better in vivo activities.

The chemotherapeutic agent known as 5-fluorouracil (5-FU) is an artificial fluoropyrimidine antimetabolite that has been widely used for its antineoplastic properties. Cocrystals of 5-fluorouracil (5-FU) with five different Schiff bases (benzylidene-urea (BU), benzylidene-aniline (BA), salicylidene-aniline (SA), salicylidene-phenylhydrazine (SPH), and para-hydroxy benzylideneaniline (HBA)) are reported in this study. The newly synthesized cocrystals were analyzed by FTIR and PXRD. In this study, we investigated the antitumor efficacy of 5-FU derivatives in SW480 colon cancer cells via MTT assay at varying dose concentrations. Molecular docking was performed to predict the binding mechanism of TS with various 5-FU complexes. FTIR revealed the presence of respective functional groups in the prepared cocrystals. The frequencies (v) of N-H (3220.24 cm−1) and carbonyl groups (1662.38 cm−1) in the spectrum of 5-FU shifted considerably in all derivative cocrystal new interactions. There was a noticeable transformation in the PXRD peak of 5-FU at 2θ = 28.37° in all derivatives. The novelty of the present study lies in the fact that 5-FU-BA showed an anticancer potential IC50 (6.4731) far higher than that of 5-FU (12.116), almost comparable to that of the reference drug doxorubicin (3.3159), against SW480 cancel cell lines, followed by 5-Fu-HBA (10.2174). The inhibition rates of 5-FU-BA and 5-FU-HBA were highest among the derivatives (99.85% and 99.37%, respectively) in comparison with doxorubicin (97.103%). The results revealed that the synthesized 5-FU cocrystals have promising antitumor efficacy compared with previously reported 5-FU and 5-FU. The activities of the cocrystals were rationalized by a molecular modeling approach to envisage binding modes with the target cancer protein.

Pyruvic acid is an organic compound used in various fields (e.g., the pharmaceutical, cosmetic, food, and chemical industries) and subject to constantly growing demand. Pyruvic acid is liquid at room temperature, rendering manipulation less straightforward. Furthermore, in the liquid phase, pyruvic acid is air-sensitive. We here present a multi-component crystal engineering strategy to render pyruvic acid solid under ambient conditions, focusing on cocrystallization and salt formation. Out of 73 screened cocrystal and salt formers, eight were found to form novel crystalline forms with pyruvic acid. Four of these were studied in detail, with pyruvic acid stable in a solid phase at temperatures up to 120 °C. These results illustrate the effectiveness of cocrystallization as a tool to convert unstable liquid compounds into stable crystalline solid forms.

The interactions and morphology of molecules in a polymer blend influence the physical properties of the blend. However, little is known about the influence of molecular interaction and morphology on the thermal and mechanical properties of LLDPE/wax blends. Although cooling rate can be used to investigate blends' thermal and mechanical properties, it is inadequate to determine interactions between the molecules in the LLDPE/wax blends. However, since the morphology is related to the thermal and mechanical properties of polymer blends and could be related to the cooling rate, LLDPE/wax samples prepared by melt mixing were cooled at different rates. The thermal and mechanical properties of the LLDPE/wax blends were modelled through molecular dynamic simulations. The modelled transitions were compared to experimentally determined mechanical relaxations of LLDPE/wax blends to investigate the effect of wax addition on the blend crystallinity. The crystallization behaviour of the blends was studied by differential scanning calorimetry, dynamic mechanical behaviour by dynamic mechanical analysis, and differences in crystallinity by X-ray diffraction. There were no significant differences between the results for the slow- and quench-cooled samples, confirming the rapid crystallization of both the LLDPE and the wax. Experiments and molecular dynamics simulations confirmed the cocrystallization of wax with LLDPE. [ABSTRACT FROM AUTHOR]

The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1 H -indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF- β 1-induced epithelial-mesenchymal transition (EMT). 6-Ethynyl-1 H -indole derivative 55 is a potent and selective PAK4 inhibitor (K i = 10.2 nmol/L), which effectively inhibits lung metastasis in A549 or B16-BL6 cells. [Display omitted] [ABSTRACT FROM AUTHOR]

It is impossible to optimize a process for a target drug product with the desired profile without a proper understanding of the interplay among the material attributes, the process parameters, and the attributes of the drug product. There is a particular need to bridge the micro- and mesoscale events that occur during this process. Here, we propose a molecular engineering methodology for the continuous cocrystallization process, based on Raman spectra measured experimentally with a probe and from quantum mechanical calculations. Using molecular dynamics simulations, the theoretical Raman spectra were calculated from first principles for local mixture structures under an external shear force at various temperatures. A proof of concept is developed to build the process design space from the computed data. We show that the determined process design space provides valuable insight for optimizing the cocrystallization process at the nanoscale, where experimental measurements are difficult and/or inapplicable. The results suggest that our method may be used to target cocrystallization processes at the molecular scale for improved pharmaceutical synthesis. [ABSTRACT FROM AUTHOR]

Abstract Background Cocrystallization is one of the crystal engineering strategies used to alter the physicochemical properties of drugs that are poorly water-soluble. Gliclazide (GLZ), an antidiabetic drug, belongs to Biopharmaceutical Classification System class-II (low solubility and high permeability) and has low bioavailability, resulting in poor therapeutic effects in patients. Therefore, to impart better solubility and bioavailability of GLZ, the study was carried out by preparing GLZ cocrystals using liquid-assisted grinding method with three coformers [3,5-dinitrosalicylic acid (DNS), 2,6-pyridine dicarboxylic acid (PDA), and L-proline (LPN)], and these were characterized using Differential Scanning Colorimetry (DSC), Powder X-ray diffraction (PXRD), Fourier Transform Infra-red spectroscopy (FTIR), and Raman spectral studies. Further, Scanning electron microscopy (SEM) analysis, accelerated stability, solubility, in vitro dissolution studies, and in vivo pharmacokinetic studies were performed in male Wistar rats. Results DSC and PXRD analysis confirmed the formation of the GLZ cocrystals. Hydrogen bonding between pure GLZ and its coformers was demonstrated based on FTIR and Raman analysis. SEM data showed morphological images for GLZ cocrystals differed from those of pure GLZ. In comparison with pure GLZ, these GLZ cocrystals have greatly improved solubility, in vitro dissolution, and in vivo profiles. Among the three, GLZ–DNS cocrystals outperformed the pure drug in terms of solubility (6.3 times), degradation (1.5 times), and relative bioavailability (1.8 times). Conclusion Hence, cocrystallization of GLZ leads to improved physicochemical properties of poorly soluble drug gliclazide.

Co-crystallization (CCs) is a less studied phenomenon related to its applicability and reliability as it is directly related to the generation of newer multicomponent solids like co-crystals (CS), eutectic, salts or solid solutions etc. having improved physicochemical properties compared to their pure components. Further, the design and structural aspects of these multicomponent systems remain hindered compared to other techniques such as nanotechnology or solid dispersion. CC is a newer technique to modify the physicochemical as well as pharmaceutical characteristics of various drugs having issues like solubility, stability, etc. without altering or hindering their pharmacological activities. For drug delivery purpose, CC process has numerous advantages over nanotechnology and solid dispersion drug delivery techniques. CCs can modify the physicochemical properties of active pharmaceutical ingredients (API) have issues like sensitivity toward environmental hazards like temperature, moisture, or photostability issues. The availability of large numbers of conformers makes this technique favorable for the researchers in designing CS of newer and older. Although, solid dispersion and nanotechnology techniques are being utilized to a larger extent still there are some drawbacks of these techniques like stability, toxicological factors and protection from environmental factors need to be considered, while the CCs process drastically modifies the various pharmaceutical parameters without altering the pharmacological properties of API's. Salts, design of CS, their methods of preparation, and their application in various fields with special emphasis on their applicability in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

A significant difference in behavior of ZrIV ions during their cocrystallization and sorption binding to hydroxyapatite (HAP) is demonstrated. When the concentration of doping ions exceeds 10−4 mol L−1, a chemical reaction with the formation of amorphous zirconium phosphate and complete dissolution of the sorbent occurs in the system rather than sorption. According to the X-ray diffraction and transmission electron microscopy (TEM) data, a similar reaction is also possible at lower concentrations of zirconium ions. The effect of doping ions on the morphology and structure of HAP is significantly lower for the cocrystallization introduction of Zr. In addition, according to high-resolution TEM data, doping ions can uniformly be distributed over the carrier surface or volume. Therefore, this method of binding method can be recommended for the preparation of a target HAP-Zr complex. [ABSTRACT FROM AUTHOR]

Abstract Background Increasing hydrophilicity of poorly water-soluble drugs is a major challenge in drug discovery and development. Cocrystallization is one of the techniques to enhance the hydrophilicity of such drugs. Carvedilol (CAR), a nonselective beta/alpha1 blocker, used in the treatment of mild to moderate congestive heart failure and hypertension, is classified under BCS class II with poor aqueous solubility and high permeability. Present work is an attempt to improve the solubility of CAR by preparing cocrystals using hydrochlorothiazide (HCT), a diuretic drug, as coformer. CAR-HCT (2:0.5) cocrystals were prepared by slurry conversion method and were characterized by DSC, PXRD, FTIR, Raman, and SEM analysis. The solubility, stability, and dissolution (in vitro) studies were conducted for the cocrystals. Results The formation of CAR-HCT cocrystals was confirmed based on melting point, DSC thermograms, PXRD data, FTIR and Raman spectra, and finally by SEM micrographs. The solubility of the prepared cocrystals was significantly enhanced (7.3 times), and the dissolution (in vitro) was improved by 2.7 times as compared to pure drug CAR. Further, these cocrystals were also found to be stable for 3 months (90 days). Conclusion It may be inferred that the drug–drug (CAR-HCT) cocrystallization enhances the solubility and dissolution rate of carvedilol significantly. Further, by combining HCT as coformer could well be beneficial pharmacologically too.

The present study discusses comparative structural features of fourteen multicomponent solids of two non-steroidal anti-inflammatory drugs, Niflumic and Mefenamic acids, with amine and pyridine-based coformers. All the solids were structurally characterized through PXRD, SCXRD, DSC, and the monophasic nature of some of the solids was established through Rietveld refinement. The solid forms include salt, cocrystal, hydrate, and solvate. Except for two, all the solids reported here showed relatively higher solubility compared to the acids. The difference in pKa and similarity in structural features of both the molecules enabled us to study the effect of ΔpKa on crystallization outcome systematically. The structures of all the solids are described through acid-pyridine synthon perspective.

The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products. [ABSTRACT FROM AUTHOR]

Abstract Background The cocrystallization process in pharmaceuticals has gained widespread attention as a recent method of modifying physicochemical properties without altering the pharmacological characteristics of drugs. Cocrystallization provides a couple of benefits like it can be employed for a large number of APIs (acidic, basic, ionizable, or non-ionizable), and secondly, the availability of a large number of potential coformers increases the possibility of the cocrystals (CCs) that can be synthesized for an API. The main objective of this study was to investigate the effects of cocrystallization on drugs having poor aqueous solubility. Results Aspirin (AN) and benzoic acid (BZ) were cocrystallized by using the solvent evaporation technique. CSD (Cambridge Structure Database) software and ∆pKa value method were used for the selection of the drug and coformer and for prediction of CC formation. The analysis of CCs was performed using DSC (differential scanning calorimetry), FT-IR (Fourier transformation infra-red spectroscopy) and XRD (X-ray diffraction) techniques. In vivo anti-inflammatory studies were conducted on 24 Wistar rats divided into four groups. Conclusions Here, in this study, in vitro dissolution studies revealed an improved solubility profile of CCs compared to pure drug and marketed formulation viz. 87%, 31% and 60% respectively. The in vivo anti-inflammatory studies exhibited improved anti-inflammatory activity compared to pure drug. So, on the basis of outcomes of this study, we concluded that cocrystallization process have a direct impact on the improvement of physicochemical characteristics of APIs having issues like solubility or stability without any modification and alteration of their pharmacological actions.

The pharmacokinetics profile of active pharmaceutical ingredients (APIs) in the solid pharmaceutical dosage forms is largely dependent on the solid-state characteristics of the chemicals to understand the physicochemical properties by particle size, size distribution, surface area, solubility, stability, porosity, thermal properties, etc. The formation of salts, solvates, and polymorphs are the conventional strategies for altering the solid characteristics of pharmaceutical compounds, but they have their own limitations. Cocrystallization approach was established as an alternative method for tuning the solubility, permeability, and processability of APIs by introducing another compatible molecule/s into the crystal structure without affecting its therapeutic efficacy to successfully develop the formulation with the desired pharmacokinetic profile. In the present review, we have grossly focused on cocrystallization, particularly at different stages of development, from design to production. Furthermore, we have also discussed regulatory guidelines for pharmaceutical industries and challenges associated with the design, development and production of pharmaceutical cocrystals with commercially available cocrystal-based products.

To overcome the poor solubility, permeability, and bioavailability of the plant isoflavone daidzein (DAI), a novel salt of DAI with anhydrous piperazine (PIP) was obtained based on cocrystallization strategy. The new salt DAI-PIP was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, and optical microscopy. The results showed that the maximum apparent solubility (S max ) of DAI-PIP increased by 7.27-fold and 1000-fold compared to DAI in pH 6.8 buffer and water, respectively. The peak apparent permeability coefficient (P app ) of DAI-PIP in the Caco-2 cell model was 30.57 ± 1.08 × 10 -6  cm/s, which was 34.08% higher than that of DAI. Additionally, compared to DAI, the maximum plasma concentration (C max ) value of DAI-PIP in beagle dogs was approximately 4.3 times higher, and the area under the concentration-time curve (AUC 0-24 ) was approximately 2.4 times higher. This study provides a new strategy to enhance the dissolution performance and bioavailability of flavonoid drugs, laying a foundation for expanding their clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Meng, Qiu, Lu, He and Zhao.)

Dacarbazine (DTIC) is a widely prescribed oncolytic agent to treat advanced malignant melanomas. Nevertheless, the drug is known for exhibiting low and pH-dependent solubility, in addition to being photosensitive. These features imply the formation of the inactive photodegradation product 2-azahypoxanthine (2-AZA) during pharmaceutical manufacturing and even drug administration. We have focused on developing novel DTIC salt/cocrystal forms with enhanced solubility and dissolution behaviors to overcome or minimize this undesirable biopharmaceutical profile. By cocrystallization techniques, two salts, two cocrystals, and one salt-cocrystal have been successfully prepared through reactions with aliphatic carboxylic acids. A detailed structural study of these new multicomponent crystals was conducted using X-ray diffraction (SCXRD, PXRD), spectroscopic (FT-IR and 1 H NMR), and thermal (TG and DSC) analyses. Most DTIC crystal forms reported display substantial enhancements in solubility (up to 19-fold), with faster intrinsic dissolution rates (from 1.3 to 22-fold), contributing positively to reducing the photodegradation of DTIC in solution. These findings reinforce the potential of these new solid forms to enhance the limited DTIC biopharmaceutical profile.

Environmental impacts of the industrial revolution necessitate adoption of sustainable practices in all areas of development. The pharmaceutical industry faces increasing pressure to minimize its ecological footprint due to its significant contribution to environmental pollution. Over the past two decades, pharmaceutical cocrystals have received immense popularity due to their ability to optimize the critical attributes of active pharmaceutical ingredients and presented an avenue to bring improved drug products to the market. This review explores the potential of pharmaceutical cocrystals as an ecofriendly alternative to traditional solid forms, offering a sustainable approach to drug development. From reducing the number of required doses to improving the stability of actives, from eliminating synthetic operations to using pharmaceutically approved chemicals, from the use of continuous and solvent-free manufacturing methods to leveraging published data on the safety and toxicology, the cocrystallization approach contributes to sustainability of drug development. The latest trends suggest a promising role of pharmaceutical cocrystals in bringing novel and improved medicines to the market, which has been further fuelled by the recent guidance from the major regulatory agencies.

Melt-cast explosive 2,4-dinitroanisole (DNAN) crystal and its cocrystals DNAN/1,3-dinitrobenzene (DNB) and DNAN/2-nitroaniline (NA) were used to identify the effects of cocrystallization on the crystal structure, non-covalent interactions, and melting points of the DNAN crystal through density functional theory and molecular dynamics. The components DNB and NA with subtle structure variations between the nitro group and amino group can significantly affect the non-covalent interactions, especially the π-π stacking and H-bonds, which can lead to different crystal stacking styles. The melting points of the DNAN crystal are decreased through the cocrystallization, which expands the utilization of the DNAN-based melt cast explosives. Our study deciphers the effects caused by the cocrystallization on the structure and properties of melt cast explosives and may help to design and optimize novel melt-cast explosives.