Single-crystal-to-single-crystal translation of a helical supramolecular polymer to a helical covalent polymer.

Polymers possessing helical conformation in the solid state are in high demand. We report a helical peptide-polymer via the topochemical ene-azide cycloaddition (TEAC) polymerization. The molecules of the designed Gly-Phe-based dipeptide, decorated with ene and azide, assemble in its crystals as ß-sheets and as supramolecular helices in two mutually perpendicular directions. While the NH…O H-bonding facilitates ß-sheet-like stacking along one direction, weak CH…N H-bonding between the azide-nitrogen and vinylic-hydrogen of molecules belonging to the adjacent stacks arranges them in a head-to-tail manner as supramolecular helices. In the crystal lattice, the azide and alkene of adjacent molecules in the supramolecular helix are suitably preorganized for their TEAC reaction. The dipeptide underwent regio- and stereospecific polymerization upon mild heating in a single-crystal-to-single-crystal fashion, yielding a triazoline-linked helical covalent polymer that could be characterized by single-crystal X-ray diffraction studies. Upon heating, the triazoline-linked polymer undergoes denitrogenation to aziridine-linked polymer, as evidenced by differential scanning calorimetry, thermogravimetric analysis, and solid-state NMR analyses.

Large Local Internal Stress in an Elastically Bent Molecular Crystal Revealed by Raman Shifts.

The structural dynamics involved in the mechanical flexibility of molecular crystals and the internal stress in such flexible materials remain obscure. Here, the study reports an elastically bending lipidated molecular crystal that shows systematic shifts in characteristic vibrational frequencies across the bent crystal region - revealing the nature of structural changes during bending and the local internal stress distribution. The blueshifts in the bond stretching modes (such as C═O and C-H modes) in the inner arc region and redshifts in the outer arc region of the bent crystals observed via micro-Raman mapping are counterintuitive to the bending models based on intermolecular hydrogen bonds. Correlating these shifts with the trends observed from high-pressure Raman studies on the crystal reveals the local stress difference between the inner arc and outer arc regions of the bent crystal to be ≈2 GPa, more than an order of magnitude higher than the previously proposed value in elastically bending crystals. High local internal stress can have direct ramifications on the properties of molecular piezoelectric energy harvesters, actuators, semiconductors, and flexible optoelectronic materials.

Cross-Linking CdSO4-Type Nets with Hexafluorosilicate Anions to Form an Ultramicroporous Material for Efficient C2H2/CO2 and C2H2/C2H4 Separation.

A 44.610.8 topology hybrid ultramicroporous material (HUM), {[Cu1.5F(SiF6)(L)2.5]·G}n, (L = 4,4'-bisimidazolylbiphenyl, G = guest molecules), 1, formed by cross-linking interpenetrated 3D four-connected CdSO4-type nets with hexafluorosilicate anions is synthesized and evaluated in the context of gas sorption and separation herein. 1 is the first HUM functionalized with two different types of fluorinated sites (SiF6 2- and F- anions) lining along the pore surface. The optimal pore size (≈5 Å) combining mixed and high-density electronegative fluorinated sites enable 1 to preferentially adsorb C2H2 over CO2 and C2H4 by hydrogen bonding interactions with a high C2H2 isosteric heat of adsorption (Qst) of ≈42.3 kJ mol-1 at zero loading. The pronounced discriminatory sorption behaviors lead to excellent separation performance for C2H2/CO2 and C2H2/C2H4 that surpasses many well-known sorbents. Dynamic breakthrough experiments are conducted to confirm the practical separation capability of 1, which reveal an impressive separation factor of 6.1 for equimolar C2H2/CO2 mixture. Furthermore, molecular simulation and density functional theory (DFT) calculations validate the strong binding of C2H2 stems from the chelating fix of C2H2 between SiF6 2- anion and coordinated F- anion.

Crystal Engineering Under Residual Solvent Evaporation: A Journey Into Crystallization Chronicles of Soluble Acenes.

In the pursuit of achieving high-performance and high-throughput organic transistors, this study highlights two critical aspects: designing new soluble acenes and optimizing their solution processing. A fundamental understanding of the crystallization mechanism inherent to these customized soluble acenes, as they undergo a transformation during the evaporation of residual solvent, is deemed essential. Here, the pathway to crafting ideal solution processing conditions is elucidated, meticulously tailored to the molecular structure of soluble acenes when blended with polymers. Employing a comprehensive array of analytical and computational methodologies, this investigation delves directly into the intricate interplay between processing parameters and crystallization mechanisms, firmly rooted in the domains of thermodynamics and kinetics. Notably, a delicate equilibrium where the optimal weight of residual solvent harmoniously aligns is uncovered with the specific attributes of soluble acene molecules, exerting influence over vertical phase separation with the blended polymer and the crystallization process of soluble acenes at the surface. Consequently, transistors showcasing remarkable field-effect mobility exceeding 8 cm2 V-1 s-1 are successfully developed. These findings provide invaluable guidance for navigating the path toward determining optimal solution processing conditions across a diverse array of soluble acene/polymer blend systems, all achieved through the strategic application of crystal and residual solvent engineering.

Ultrahigh Degree of Cationic Disorder, Configurational Entropy in New Type of High-Entropy Pseudobrookite Phase.

High-entropy ceramics exhibit various excellent properties owing to their high configurational entropy, which is caused by multi-principal elements sharing one lattice site. The configurational entropy will further increase significantly if multi-principal elements randomly share two different lattice sites. For this purpose, pseudobrookite phase containing two cationic lattice sites (A and B sites) is selected, and corresponding high-entropy pseudobrookite (M2+ 0.4M3+ 1.2)Ti1.4O5 is synthesized. Herein, the distribution of the 2-valent and 3-valent cations in the A and B sites are analysed in depth. The distance between the A and B sites in the crystal structure models which are constructed by the Rietveld analysis is calculated and defined as distance d. Meanwhile, the atomic column positions in the STEM images are quantified by a model-based mathematical algorithm, and the corresponding distance d are calculated. By comparing the distance d, it is determine that the 2-valent and 3-valent cations are jointly and disorderly distributed in the A and B sites in high-entropy (M2+ 0.4M3+ 1.2)Ti1.4O5. The density functional theory (DFT) simulations also demonstrate that this type of crystal structure is more thermodynamically stable. The higher degree of cationic disorder leads to a higher configurational entropy in high-entropy (M2+ 0.4M3+ 1.2)Ti1.4O5, and endows high-entropy (M2+ 0.4M3+ 1.2)Ti1.4O5 with very low thermal conductivity (1.187-1.249 W m-1 K-1).

Gas Release as an Efficient Strategy to Tune Mechanical Properties and Thermoresponsiveness of Dynamic Molecular Crystals.

Dynamic molecular crystals combining multiple and finely tunable functionalities are attracting and an increasing attention due to their potential applications in a broad range of fields as efficient energy transducers and stimuli-responsive materials. In this context, a multicomponent organic salt, piperazinium trifluoroacetate (PZTFA), endowed with an unusual multidimensional responsive landscape is reported. Crystals of the salt undergo smooth plastic deformation under mechanical stress and thermo-induced jumping. Furthermore, via controlled crystal bending and release of trifluoroacetic acid from the lattice, which is anticipated from the design of the material, both the mechanical response and the thermoresponsive behavior are efficiently tuned while partially preserving the crystallinity of the system. In particular, mechanical deformation hampers guest release and hence the macroscopic jumping effect, while trifluoroacetic acid release stiffens the crystals. These complex adaptive responses establish a new crystal engineering strategy to gain further control over dynamic organic crystals.

Polymorphism-driven Distinct Nanomechanical, Optical, Photophysical, and Conducting Properties in a Benzothiophene-quinoline.

Polymorphic forms of organic conjugated small molecules, with their unique molecular shapes, packing arrangements, and interaction patterns, provide an excellent opportunity to uncover how their microstructures influence their observable properties. Ethyl-2-(1-benzothiophene-2-yl)quinoline-4-carboxylate (BZQ) exists as dimorphs with distinct crystal habits - blocks (BZB) and needles (BZN). The crystal forms differ in their molecular arrangements - BZB has a slip-stacked column-like structure in contrast to a zig-zag crystal packing with limited π-overlap in BZN. The BZB crystals characterized by extended π-stacking along [100] demonstrated semiconductor behavior, whereas the BZN, with its zig-zag crystal packing and limited stacking characteristics, was reckoned as an insulator. Monotropically related crystal forms also differ in their nanomechanical properties, with BZB crystals being considerably softer than BZN crystals. This discrepancy in mechanical behavior can be attributed to the distinct molecular arrangements adopted by each crystal form, resulting in unique mechanisms to relieve the strain generated during nanoindentation experiments. Waveguiding experiments on the acicular crystals of BZN revealed the passive waveguiding properties. Excitation of these crystals using a 532 nm laser confirmed the propagation of elastically scattered photons (green) and the subsequent generation of inelastically scattered (orange) photons by the crystals. Further, the dimorphs display dissimilar photoluminescence properties; they are both blue-emissive, but BZN displays twice the quantum yield of BZB. The study underscores the integral role of polymorphism in modulating the mechanical, photophysical, and conducting properties of functional molecular materials. Importantly, our findings reveal the existence of light-emitting crystal polymorphs with varying electric conductivity, a relatively scarce phenomenon in the literature.

Dynamic Luminescence Vapochromism of Pyridinium-Based Organic Salts.

Organic vapochromic materials which undergo a drastic change in their photophysical properties upon exposure to vapors or gases are attracting growing scientific attention because of their low price and wide range of possible applications. In this work, luminescence vapochromism of carbazole-pyridinium-based organic salts with a general structure of (CzPy)X (CzPy+=2,3-di(9H-carbazol-9-yl)pyridinium ion; X=Cl, Br or I) is reported. It was found that (CzPy)X compounds form J-aggregates, which rearranged back to monomeric form upon exposure to methanol, ethanol, acetone, and water vapors. In contrast, acetonitrile was found to promote the J-aggregation in (CzPy)X compounds by occupying the voids in their crystal lattice and pushing cations closer together. It was further demonstrated that the efficiency of J-aggregation in (CzPy)X compounds depends on the size of the anion, which was employed to realize dynamic luminescence vapochromism, with vapochromic response times ranging from a couple of minutes in (CzPy)Cl to more than an hour in (CzPy)I. In addition, (CzPy)X compounds exhibited high melting points of about 250 °C and excellent thermal stability. (CzPy)Cl and (CzPy)Br have also shown good photoluminescence quantum yields at room temperature in a solid state.

Leveraging Halogen Interactions for a Supramolecular Nanotube.

We demonstrate the formation of supramolecular nanotubes from molecular triangles in a single crystal by balancing the hydrogen bonds and halogen interactions between individual macrocycles. Thereby, we template the supramolecular nanotube growth by intermolecular interactions encoded directly in the macrocycles instead of those provided by the crystallization solvent. Ultimately, we show that replacing bromines for iodines in the macrocycle is necessary to achieve this supramolecular organization by enhancing the strength of the halogen interactions and concomitant reduction of the detrimental hydrogen bonds. We investigated the nature and the interplay of the individual intermolecular interactions by analysis of the experimental single crystal data and quantum chemical calculations. This work enriches the available toolbox of supramolecular interactions and will aid and abet the development of rationally-designed materials with a long-range 1D tubular organization.

Transition Behaviors of Isostructural Hydrogen-Bonded Frameworks Composed of Naphthalene, Quinoxaline, and Pyrazinopyrazine Derivatives.

A series of isostructural reticular frameworks with systematic differences on chemical structures allows us to disclose correlations between specific structural factors and properties, providing insights for designing novel porous materials. However, even slight differences in the molecular structure often lead to non-isostructural polymorphic frameworks particularly in the case of hydrogen-bonded organic frameworks (HOFs) because the structures of HOFs are based on a subtle balance of reversible interactions. In this study, we found that three simple analogues of tetracarboxylic acids with naphthalene, quinoxaline, and pyrazinopyrazine cores (NT, QX, and PP, respectively) yielded isostructural solvated HOFs (NT-1, QX-1, and PP-1, respectively), where hydrogen-bonded sql-networked sheets were slip-stacked with closely similar manners. More importantly, these isostructural HOFs underwent structural transformations in different manners upon removal of the guest solvents. Comparison of the crystal structures of the HOFs before and after the transformation revealed that intermolecular interactions of the core significantly affected on rearrangements of hydrogen bonds in the transformation. The results suggest the potential to control the properties and functions of isostructural HOFs by elements in the core.

Investigating the Mechanism of Triboluminescence: Insights from Structural and Electrostatic Characterization of Copper Thiocyanate Complexes.

Triboluminescence is a phenomenon in which light is generated through mechanical stress; it has emerging applications in stress-sensing devices. Although the prevailing mechanistic model indicates that light emits from charge separation and recombination in fracture planes arising from polar structures, its application in designing triboluminescent materials remains limited owing to numerous exceptions. This study provides insights into the essential requirements for triboluminescence by investigating the structural and electrostatic properties of fractured crystals of copper thiocyanate complexes. The examined fracture plane indicated that charge pairs (which are essential for light emission) form when intermolecular interactions are disrupted during fracturing. On the basis of the nature of these charges, we successfully suppressed triboluminescence by inhibiting the formation of intermolecular interactions disrupted in the examined complexes. Furthermore, we induced its re-emergence by creating an alternative fracture plane through controlled manipulation of the molecular network. This demonstrative deactivation and reactivation of triboluminescence underscores the critical role of intermolecular disruption in generating charge pairs, a prerequisite for triboluminescence.

Symmetry-Breaking and Symmetry-Retaining Morphological Evolution of the Single Crystals of Cyclodextrin Metal-Organic Frameworks.

The morphological symmetry-retaining and symmetry-breaking of single crystals of the γ-cyclodextrin metal-organic framework have been achieved via introducing lower symmetric ß-cyclodextrins and α-cyclodextrins, respectively. ß-cyclodextrins led to a morphological evolution with retained symmetry from cubic to rhombic dodecahedra, while α-cyclodextrins resulted in the original cubic crystal missing a vertex angle presenting symmetry-breaking behavior. The crystal structures of rhombic dodecahedra and angle-deficient crystals were confirmed through X-ray crystallography, and the mechanisms underlying the morphological transformation evolution were further analyzed. Our work not only provides a rare case realizing two different paths of morphological evolution in one system, but also encourages future efforts towards the evolution of artificial crystal systems in a natural way.

Perfect Polar Alignment of Parallel Beloamphiphile Layers: Improved Structural Design Bias Realized in Ferroelectric Crystals of the Novel "Methoxyphenyl Series of Acetophenone Azines".

An improved design is described for ferroelectric crystals and implemented with the "methoxyphenyl series" of acetophenone azines, (MeO-Ph, Y)-azines with Y=F (1), Cl (2), Br (3), or I (4). The crystal structures of these azines exhibit polar stacking of parallel beloamphiphile monolayers (PBAMs). Azines 1, 3, and 4 form true racemates whereas chloroazine 2 crystallizes as a kryptoracemate. Azines 1-4 are helical because of the N-N bond conformation. In true racemates the molecules of opposite helicity (M and P) are enantiomers A(M) and A*(P) while in kryptoracemates they are diastereomers A(M) and B*(P). The stacking mode of PBAMs is influenced by halogen bonding, with 2-4 showcasing a kink due to directional interlayer halogen bonding, whereas fluoroazine 1 demonstrates ideal polar stacking by avoiding it. Notably, (MeO-Ph, Y)-azines display a stronger bias for dipole parallel alignment, attributed to the linearity of the biphenyl moiety as compared to the phenoxy series of (PhO, Y)-azines with their non-linear Ph-O-Ph moiety. The crystals of 1-4 all feature planar biphenyls and this synthon facilitates their crystallization through potent triple T-contacts and enhances their nonlinear optical (NLO) performance by increasing conjugation length and affecting favorable chromophore conformations in the solids.

Controllable Structural Transformation of Non-Porous Propyl-Malonate Hexakis[60]fullerene by Chloroform Uptake/Release.

The design of dynamic structures with high recognition host-guest materials capable to host selectively small volatile molecules is an emergent field of research with both fundamental and applied implications. The challenge of exploring novel materials with advanced functionalities has led to the development of dynamic crystalline structures promoted by soft interactions. Here, a new pure organic dynamic framework based on hexakis[60]fullerene that are held together by weak van der Waals interactions is described. This crystalline structure is capable of absorbing and releasing chloroform, through internal structural reorganization. This research provides new insight into the design of organic molecular crystals for selective adsorption applications.

Electrostatic Surface Potentials and Chalcogen-Bonding Motifs of Substituted 2,1,3-Benzoselenadiazoles Probed via 77Se Solid-State NMR Spectroscopy.

Chalcogen bonds (ChB) are moderately strong, directional, and specific non-covalent interactions that have garnered substantial interest over the last decades. Specifically, the presence of two σ-holes offers great potential for crystal engineering, catalysis, biochemistry, and molecular sensing. However, ChB applications are currently hampered by a lack of methods to characterize and control chalcogen bonds. Here, we report on the influence of various substituents (halogens, cyano, and methyl groups) on the observed self-complementary ChB networks of 2,1,3-benzoselenadiazoles. From molecular electrostatic potential calculations, we show that the electrostatic surface potentials (ESP) of the σ-holes on selenium are largely influenced by the electron-withdrawing character of these substituents. Structural analyses via X-ray diffraction reveal a variety of ChB geometries and binding modes that are rationalized via the computed ESP maps, although the structure of 5,6-dimethyl-2,1,3-benzoselenadiazole also demonstrates the influence of steric interactions. 77Se solid-state magic-angle spinning NMR spectroscopy, in particular the analysis of the selenium chemical shift tensors, is found to be an effective probe able to characterize both structural and electrostatic features of these self-complementary ChB systems. We find a positive correlation between the value of the ESP maxima at the σ-holes and the experimentally measured 77Se isotropic chemical shift, while the skew of the chemical shift tensor is established as a metric which is reflective of the ChB binding motif.

Optimizing Drug Development: Harnessing the Sustainability of Pharmaceutical Cocrystals.

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.

Analysis of the Dissolution Behavior of Theophylline and Its Cocrystal Using ATR-FTIR Spectroscopic Imaging.

Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging is a powerful tool to visualize the distribution of components, and it has been used to analyze drug release from tablets. In this work, ATR-FTIR spectroscopic imaging was applied for observing the dissolution of molecular crystals from tablet compacts. The IR spectra provided chemically specific information about the transformation of crystal structures during the dissolution experiments. Theophylline (TPL) anhydrate and its cocrystals were used as model systems of molecular crystals. The IR spectra during the dissolution of TPL revealed information about the crystal structure of TPL, which transformed from anhydrate to monohydrate in water. During a dissolution test of a model cocrystal system, it was suggested that an active pharmaceutical ingredient (API) and a coformer were dissolved in water simultaneously. The IR spectra that were acquired during the dissolution of a cocrystal tablet showed new spectral bands attributed to the API after 5 min. This suggested that the precipitation of API was observed during the dissolution experiment. Measurements from ATR-FTIR spectroscopic imaging can visualize the drug release from the tablet and determine the transformation of molecular crystals during their dissolution. These results will have an impact on clarifying the dissolution mechanism of molecular crystals.

Repurposing of Antifungal Drug Flucytosine/Flucytosine Cocrystals for Anticancer Activity against Prostate Cancer Targeting Apoptosis and Inflammatory Signaling Pathways.

This study aimed to repurpose the antifungal drug flucytosine (FCN) for anticancer activity together with cocrystals of nutraceutical coformers sinapic acid (SNP) and syringic acid (SYA). The cocrystal screening experiments with SNP resulted in three cocrystal hydrate forms in which two are polymorphs, namely, FCN-SNP F-I and FCN-SNP F-II, and the third one with different stoichiometry in the asymmetric unit (1:2:1 ratio of FCN:SNP:H2O, FCN-SNP F-III). Cocrystallization with SYA resulted in two hydrated cocrystal polymorphs, namely, FCN-SYA F-I and FCN-SYA F-II. All the cocrystal polymorphs were obtained concomitantly during the slow evaporation method, and one of the polymorphs of each system was produced in bulk by the slurry method. The interaction energy and lattice energies of all cocrystal polymorphs were established using solid-state DFT calculations, and the outcomes correlated with the experimental results. Further, the in vitro cytotoxic activity of the cocrystals was determined against DU145 prostate cancer and the results showed that the FCN-based cocrystals (FCN-SNP F-III and FCN-SYA F-I) have excellent growth inhibitory activity at lower concentrations compared with parent FCN molecules. The prepared cocrystals induce apoptosis by generating oxidative stress and causing nuclear damage in prostate cancer cells. The Western blot analysis also depicted that the cocrystals downregulate the inflammatory markers such as NLRP3 and caspase-1 and upregulate the intrinsic apoptosis signaling pathway marker proteins, such as Bax, p53, and caspase-3. These findings suggest that the antifungal drug FCN can be repurposed for anticancer activity.

A Perspective on the Permeability of Cocrystals/Organic Salts of Oral Drugs.

According to the BCS classification system, the differentiation of drugs is based on two essential parameters of solubility and permeability, meaning the latter is as pivotal as the former in creating marketable pharmaceutical products. Nevertheless, the indispensable role of permeability in pharmaceutical cocrystal profiles has not been sufficiently cherished, which can be most probably attributed to two principal reasons. First, responsibility may be on more user-friendly in vitro measurement procedures for solubility compared to permeability, implying the permeability measurement process seems unexpectedly difficult for researchers, whereas they have a complete understanding of solubility concepts and experiments. Besides, it may be ascribed to the undeniable attraction of introducing new crystal-based structures which mostly leaves the importance of improving the function of existing multicomponents behind. Bringing in new crystalline entities, to rephrase it, researchers have a fairly better chance of achieving high-class publications. Although the Food and Drug Administration (FDA) has provided a golden opportunity for pharmaceutical cocrystals to straightforwardly enter the market by simply considering them as derivatives of the existing active pharmaceutical ingredients, inattention to assessing and scaling up permeability which is intimately linked with solubility has resulted in limited numbers of them in the global pharmaceutical market. Casting a glance at the future, it is apprehended that further development in the field of permeability of pharmaceutical cocrystals and organic salts requires a meticulous perception of achievements to date and potentials to come. Thence, this perspective scrutinizes the pathway of permeation assessment making researchers confront their fear upfront through mapping the simplest way of permeability measurement for multicomponents of oral drugs.

Multicomponent Amorphous Solid Forms of Telmisartan: Insights into Mechanochemical Activation and Physicochemical Attributes.

The present work aims to explore the new solid forms of telmisartan (TEL) with alpha-ketoglutaric acid (KGA) and glutamic acid (GA) as potential coformers using mechanochemical approach and their role in augmentation in physicochemical parameters over pure crystalline TEL. Mechanochemical synthesis was performed using 1:1 stoichiometric ratio of TEL and the selected coformers in the presence of catalytic amount of ethanol for 1 h. The ground product was characterized by PXRD, DSC, and FTIR. The new solid forms were evaluated for apparent solubility, intrinsic dissolution, and physical stability. Preliminary characterization revealed the amorphization of the mechanochemical product as an alternate outcome of cocrystallization screening. Mechanistic understanding of the amorphous phase highlights the formation of amorphous-mediated cocrystallization that involves three steps, viz., molecular recognition, intermediate amorphous phase, and product nucleation. The solubility curves of both multicomponent amorphous solid forms (TEL-KGA and TEL-GA) showed the spring-parachute effect and revealed significant augmentation in apparent solubility (8-10-folds), and intrinsic dissolution release (6-9-folds) as compared to the pure drug. Besides, surface anisotropy and differential elemental distributions in intrinsic dissolution compacts of both solid forms were confirmed by FESEM and EDX mapping. Therefore, amorphous phases prepared from mechanochemical synthesis can serve as a potential solid form for the investigation of a cocrystal through amorphous-mediated cocrystallization. This has greater implications in solubility kinetics wherein the rapid precipitation of the amorphous phase can be prevented by the metastable cocrystal phase and contribute to the significant augmentation in the physicochemical parameters.