Quercetin-hexahydric alcohol eutectic and preparation method thereof

Abstract

The invention discloses a novel quercetin-hexahydric alcohol eutectic crystal and a preparation method thereof. These co-crystals have been developed as innovative pharmaceutical formulations. The invention encompasses methods for producing these eutectic materials and their use as biological enhancers of active pharmaceutical ingredients, phytochemicals, vitamins and minerals. The disclosed method for preparing quercetin-hexahydric alcohol co-crystals involves forming co-crystals by a kinetically controlled co-crystallization process, enhancing the bioavailability and efficacy of biologically active compounds.

Description

Cross-references to related applications

[0001] The embodiments herein claim priority to U.S. Provisional Application No. 63 / 517,659, filed August 4, 2023, entitled “QUERCETIN-HEXAHYDRIC ALCOHOL COCRYSTAL AND PROCESS FOR PREPARING THEREOF”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The subject matter of this invention generally relates to quercetin-hexane cocrystals. More specifically, the embodiments relate to, but are not limited to, solid quercetin as an active pharmaceutical ingredient, phytochemical, vitamin, and mineral bioenhancer, and methods for preparing quercetin-hexane cocrystals. Related technical descriptions

[0003] The topics discussed in the background section should not be assumed to be prior art simply because they are mentioned in the background section. Similarly, it should not be assumed that the problems mentioned in the background section or problems related to the topics in the background section were previously recognized in the prior art. The topics in the background section merely represent different methods, which may themselves be inventions.

[0004] Quercetin is a flavonoid compound found in many plants and foods, such as onions, moringa, apples, and berries. Quercetin is known for its anti-inflammatory and antioxidant properties. It has been widely used to treat cancer, cardiovascular disease, and diabetes. Previous research has shown the potential of quercetin as a bioenhancer. Its ability to enhance drug bioavailability through various pathways has been documented, such as inhibiting the P-glycoprotein efflux pump and inhibiting metabolic enzymes.

[0005] Despite these benefits, the low solubility of quercetin in water poses a significant challenge. Quercetin dihydrate is slightly soluble in aqueous buffer solutions. While quercetin is highly soluble in organic solvents such as ethanol (2 mg / ml) and dimethylformamide (30 mg / ml), this solubility property limits its application in the pharmaceutical and nutritional industries, where solubility in aqueous media is essential for better bioavailability.

[0006] Several methods for improving the solubility of quercetin have been documented. For example, steviol glycosides have been used to enhance the solubility of quercetin by forming complexes. In addition, quercetin cocrystals, including cocrystals formed with caffeine coformers, have been reported to increase the solubility of quercetin.

[0007] However, there is still a need for novel formulations that further improve the solubility and bioavailability of quercetin in aqueous media, thereby enhancing its application in the pharmaceutical and nutritional industries.

[0008] This invention addresses this need by developing a quercetin-hexahydrol cocrystal, which provides a method for improving the solubility and bioavailability of quercetin and enhancing the bioactivity of the bioactive compound.

[0009] Therefore, given the above circumstances, there has long been a need in this field to solve the described problem.

[0010] By comparing the described method with certain aspects of this disclosure, those skilled in the art will be able to clearly understand the further limitations and disadvantages of conventional and traditional methods, as illustrated in the remainder of this application and with reference to the accompanying drawings. Invention Overview

[0011] Quercetin-hexahydrol cocrystal and its preparation method are provided and shown and / or described in the accompanying drawings.

[0012] According to the embodiments shown herein, a method for preparing quercetin-hexane alcohol cocrystals as bioenhancers of bioactive compounds is provided. The method includes the step of forming a cocrystal from quercetin and hexane alcohol via a kinetically controlled cocrystallization method.

[0013] In one aspect, the kinetically controlled co-crystallization method includes the step of cooling a solution at a cooling rate of 10–20 °C / min to form a co-crystallization. In one aspect, the solution contains quercetin and hexahydrol, and the temperature prior to cooling is in the range of 40–70 °C.

[0014] In one aspect, the kinetically controlled co-crystallization method further includes a step of ripening the eutectic.

[0015] In one respect, the solution contains a solvent selected from the group consisting of methanol, ethanol, and combinations thereof.

[0016] In one respect, quercetin is preferably quercetin dihydrate.

[0017] In one respect, the diffusion coefficient of quercetin dihydrate in the solvent is preferably 5 × 10⁻⁶. -10 m 2 / s.

[0018] In one respect, hexahydrols are selected from the group consisting of straight-chain hexahydrols and cyclic hexahydrols.

[0019] In one respect, the hexahydrol is preferably sorbitol.

[0020] In one respect, the diffusion coefficient of the hexahydrol in the solvent is preferably 8 × 10⁻⁶. -10 m 2 / s.

[0021] In one respect, the molar ratio of quercetin to hexahydrol in the solution is in the range of 1:1.

[0022] In one respect, the kinetic constant (k) of the kinetically controlled co-crystallization method is in the range of 1 x 10⁻⁶. -16 - 1 x 10 -14 m 3 Within the range of / s.

[0023] In one aspect, the kinetic constant (k) of the kinetically controlled co-crystallization method is preferably 10. -15 m 3 / s.

[0024] In one respect, bioactive compounds are selected from the group consisting of active pharmaceutical ingredients, vitamins, natural bioactive substances, phytochemicals, minerals, and any combination thereof.

[0025] According to the embodiments shown herein, a quercetin-hexahydrol cocrystal is provided as a bioenhancer for bioactive compounds. The molar ratio of quercetin to hexahydrol in the cocrystal is in the range of 1:1.

[0026] In one respect, the quercetin-hexahydrol cocrystal is characterized by having at least one of the following XRPD peaks: 10.7, 12.4, 13.8, 13.9, 14.7, 16.2, 16.4, 17.7, 18.0, 19.3, 21.6, 23.8, 25.9, 27.2, 28.7, 29.8, 33.5, 35.8, 36.6 and 37.0 ±2-θ degrees [Cu Kα radiation (λ = 1.5406 Å)].

[0027] In one respect, the eutectic preferably exhibits thermogravimetric properties in the range of 338.58 - 342.2 °C.

[0028] In one respect, bioactive compounds are selected from the group consisting of active pharmaceutical ingredients, vitamins, natural bioactive substances, phytochemicals, minerals, and any combination thereof.

[0029] According to the embodiments shown herein, a pharmaceutical composition is provided comprising a quercetin-hexahydrol cocrystal and at least one pharmaceutically acceptable carrier.

[0030] In one respect, pharmaceutical compositions can be used to enhance the cell penetration and bioavailability of bioactive compounds.

[0031] In one respect, the pharmaceutical composition can be used to treat inflammation.

[0032] In one aspect, the present invention relates to the formation of cocrystals: cocrystals of quercetin and hexahydrol, wherein the hexahydrol may have a linear or cyclic structure. The cocrystals of quercetin dihydrate and hexahydrol are in a molar ratio of 1:1. In addition to cocrystal compositions, the present invention also describes pharmaceutical compositions comprising the cocrystals described in the foregoing aspects. Methods for administering treatment of conditions by applying cocrystals are described in the foregoing aspects. This multifaceted invention covers the identification and characterization of various cocrystal systems, and their application in improving the bioaccessibility of various active pharmaceutical ingredients, phytochemicals, vitamins, and minerals.

[0033] These features and advantages of the present disclosure can be understood by reading the following description of the disclosure and the accompanying drawings, in which like reference numerals refer to like parts. Brief description of the attached figures

[0034] The accompanying drawings illustrate implementations of the methods and other aspects of this disclosure. Those skilled in the art will understand that the element boundaries (e.g., boxes, groups of boxes, or other shapes) shown in the figures represent instances of such element boundaries. In some instances, one element may be designed as multiple elements, or multiple elements may be designed as one element. In some instances, an element shown as an internal component of one element may be implemented as an external component in another element, and vice versa. Furthermore, elements may not be drawn to scale.

[0035] Various embodiments will now be described with reference to the accompanying drawings, which are intended to illustrate rather than limit the scope of this disclosure, wherein similar reference numerals denote similar elements, and in the drawings:

[0036] Figure 1 A graphical representation of the X-ray powder diffraction (XRPD) patterns of quercetin and quercetin dihydrate according to one embodiment of the present invention is shown.

[0037] Figure 2 A graphical representation of the XRPD spectrum of a hexahydrol according to one embodiment of the present invention is shown.

[0038] Figure 3 The XRPD pattern of a quercetin-hexahydrol cocrystal according to one embodiment of the present invention is presented.

[0039] Figure 4 A DSC thermogram of a quercetin-hexahydrol cocrystal according to one embodiment of the present invention is shown, revealing its thermal stability and decomposition behavior.

[0040] Figure 5A graphical representation of the bioenhancing activity of a quercetin-hexahydrol cocrystal combined with resveratrol (a representative class of flavonoids) according to one embodiment of the present invention is shown.

[0041] Figure 6A A graphical representation of the bio-enhancing activity of quercetin-hexahydrol cocrystal combined with lutein (a representative class of carotenoids) according to one embodiment of the present invention is shown.

[0042] Figure 6B A graphical representation of the bioenhancing activity of quercetin-hexahydrol cocrystal combined with β-carotene (a representative class of carotenoids) according to one embodiment of the present invention is shown.

[0043] Figure 6C A graphical representation of the bioenhancing activity of quercetin-hexahydrol cocrystal combined with lycopene (a representative class of carotenoids) according to one embodiment of the present invention is shown.

[0044] Figure 7 A graphical representation of the bio-enhancing activity of quercetin-hexahydrol cocrystal combined with nicotine (a representative class of alkaloids) according to one embodiment of the present invention is shown.

[0045] Figure 8 A graphical representation of the bioenhancing activity of a quercetin-hexane cocrystal combined with glutathione (a representative class of amino acid derivatives) according to one embodiment of the present invention is shown.

[0046] Figure 9 A graphical representation of the bioenhancing activity of a quercetin-hexahydrol cocrystal combined with cannabidiol (a representative cannabinoid class) according to one embodiment of the present invention is shown.

[0047] Figure 10 A graphical representation of the bioenhancing activity of a quercetin-hexahydrol cocrystal combined with β-glucan (a representative class of glucans) according to one embodiment of the present invention is shown.

[0048] Figure 11 A graphical representation of the bio-enhancing activity of a quercetin-hexane cocrystal combined with a collagen tripeptide (a representative peptide class) according to one embodiment of the present invention is shown. Detailed Description of the Implementation Methods in this Document

[0049] This disclosure is best understood in conjunction with the detailed accompanying drawings and descriptions set forth herein. Various embodiments of the system and method have been discussed with reference to the drawings. However, it will be readily understood by those skilled in the art that the detailed description provided herein (including the drawings) is presented for illustrative purposes, and that the embodiments extend beyond those currently described. For example, the teachings and results presented in any particular application described may lead to a variety of alternative methods and may be implemented in any suitable manner.

[0050] The described implementation methods can be carried out manually, automatically, and / or in combination. The term "method" refers to the manner, means, technique, and procedure for accomplishing any task, including but not limited to those known to those skilled in the art, or those readily developed by those skilled in the art from existing methods, means, techniques, and procedures related to the implementation. Those skilled in the art will envision many other possible variations within the scope of the claimed subject matter.

[0051] This disclosure provides solid quercetin as a bioenhancer for active pharmaceutical ingredients, phytochemicals, vitamins, and minerals, and a method for its preparation. The low bioavailability of quercetin due to its limited solubility and absorption hinders its complete clinical translation. To address this challenge, this invention discloses the preparation of novel quercetin cocrystals, which can be synthesized by ball milling or solvent evaporation. Cocrystallization is a well-established technique for improving the physicochemical properties of active pharmaceutical ingredients, including solubility, stability, and dissolution rate. The quercetin-hexaol cocrystal was synthesized using a novel kinetically controlled cocrystallization method. Its physicochemical properties were comprehensively characterized using a variety of analytical techniques. The results showed that a novel solid phase with unique spectral characteristics was successfully formed compared to the individual components. The patentability of this invention lies in the significant bioenhancing activity of this solid quercetin. These novel cocrystals have been shown to enhance the bioactivity of a variety of biomolecules, including cannabinoids, flavonoids, peptides, alkaloids, dextran, carotenoids, and amino acid derivatives. This enhanced bioactivity is attributed to improved absorption and bioavailability when the co-formulated molecules are administered in combination with the quercetin cocrystal.

[0052] Therefore, the use of quercetin cocrystals may lead to reduced drug and / or nutrient-related toxicity, lower costs, and shorter durations of therapeutic interventions. Thus, this invention provides a promising solution to overcome the limitations of quercetin bioavailability, thereby unlocking its full therapeutic potential. The development of quercetin cocrystals represents a significant advancement in the fields of nutritional and pharmaceutical formulations, with the potential to enhance the efficacy of a variety of bioactive compounds.

[0053] The primary objective of this invention is to identify novel cocrystal formulations of quercetin bound to hexahydrol. The goal is to develop these quercetin-hexahydrol cocrystals to enhance the bioactivity of various active pharmaceutical ingredients, phytochemicals, vitamins, and minerals.

[0054] Another key objective of this invention is to synthesize and optimize the preparation methods of these quercetin cocrystals. Furthermore, this work aims to investigate and demonstrate that the bioavailability or cellular uptake of active pharmaceutical ingredients, phytochemicals, vitamins, and minerals is enhanced when administered together with quercetin-hexane cocrystal formulations.

[0055] The structures of quercetin dihydrate and hexahydrin are shown below: and

[0056] A eutectic is a unique crystalline material formed by the combination of two distinct molecular components—a host compound and a conformation. When these two components combine, they assemble into a unique crystallographic structure with specific properties distinct from those of the individual compounds. The conformation, often referred to as the "guest" molecule, interacts with the "host" compound to form this novel eutectic structure. Unlike typical salts, which have a neutral net charge and a balanced ion species, eutectics consist of neutral molecular entities. Therefore, the stoichiometric ratio of the compound to the conformation in a eutectic cannot be determined solely by considering charge balance. The molar ratio of the compound to the conformation in a eutectic can vary and can be greater than, less than, or equal to 1:1. This variable stoichiometry makes the precise molar composition of the eutectic difficult to predict and dependent on specific molecular interactions. The formation of this unique eutectic structure results in unique physicochemical properties that differ from those of a single starting material. This makes eutectics a valuable tool for modifying and enhancing the properties of compounds for a wide range of applications.

[0057] Cocrystals possess the ability to alter a wide range of physical and chemical properties of compounds. One of the main advantages of cocrystals is their potential to modify the solubility and dissolution rate of the host compound. Studies have shown that the formation of cocrystals can enhance the water solubility and dissolution kinetics of active compounds compared to their single form. This is particularly beneficial for improving the bioavailability of poorly soluble active pharmaceutical ingredients. In addition to enhanced solubility, cocrystals can also provide enhancements to other important properties. For example, they have been shown to enhance the stability of compounds under varying humidity conditions, preventing unwanted changes or degradation. To achieve these specific property alterations, researchers often experiment with multiple potential cocrystal molecules. By selecting the most suitable cocrystal, they can tune the cocrystal composition to optimize the desired physical, chemical, or biopharmaceutical properties of the final product. The versatility of cocrystals allows for the systematic exploration and tuning of compound properties, making them a valuable tool in formulation development and drug delivery applications.

[0058] Cocrystals have become a fascinating area of ​​research in pharmaceuticals, offering promising methods for enhancing the physicochemical properties of active pharmaceutical ingredients (APIs) without altering their chemical structure. The preparation of cocrystals involves assembling two or more distinct molecular or ionic components into a single crystal lattice, bound together by non-covalent interactions such as hydrogen bonding, π-π stacking, or halogen bonding. One of the main benefits of cocrystal formation is its ability to enhance the solubility and bioavailability of poorly soluble drugs. By incorporating a second component, called a coform, the crystal packing and physicochemical properties of the drug can be altered, thereby improving dissolution rates and oral absorption. Various cocrystal preparation strategies have been explored, including solution-based methods such as slow evaporation (thermodynamically controlled), antisolvent addition, and cold crystallization, as well as solid-state techniques such as grinding, kneading, and hot melt extrusion.

[0059] The precise composition of a eutectic, including the molar ratio between the conformation and the host compound (such as the active pharmaceutical ingredient or API), can be determined using single-crystal X-ray diffraction analysis. This analytical technique allows researchers to elucidate the crystallographic structure of the eutectic and accurately quantify the molar stoichiometry between the conformation and the compound. However, when single-crystal X-ray diffraction analysis may not be readily available, a commonly used alternative analytical method is solution-state proton nuclear magnetic resonance (SPMRI). 1 ¹H NMR spectroscopy. 1 HNMR can be used to confirm the composition of the cocrystal and identify the specific molar ratio between the conformation and the host compound. This solution-state NMR method provides a complementary analytical technique to the structural information obtained from X-ray diffraction. By utilizing these analytical methods, researchers can comprehensively characterize the composition of the cocrystal, including the precise molar ratio between the conformation and the host compound. This information is crucial for understanding structure-property relationships and optimizing cocrystal formulations for desired applications.

[0060] Verifying the formation of a eutectic requires comparing the solid-state analysis data of the eutectic product with those of the starting materials. The analytical response of a eutectic differs from that of a simple physical mixture of initial components. For example, X-ray powder diffraction (XRPD) can be used to compare patterns, as the XRPD pattern of the eutectic will differ from that of a physical mixture of starting materials. Single-crystal analysis can also be used to confirm the solid-state structure of the eutectic, where the compound and conformation occupy different positions within the crystal lattice. Furthermore, indexing can be employed to ensure the presence of a single phase in the eutectic product, rather than a multiphase mixture.

[0061] Characterizing eutectic crystals does not always require single-crystal structure determination. Various solid-state analysis methods can be used as alternatives, such as X-ray powder diffraction (XRPD), Raman spectroscopy, infrared spectroscopy, and solid-state analysis. 13 C10 NMR spectroscopy can be used to analyze the crystallographic and spectroscopic properties of eutectic crystals. Furthermore, eutectic crystals often exhibit unique thermal behavior compared to other forms of the same compound. This thermal behavior can be studied using techniques such as capillary melting point analysis, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). By employing this series of solid-state analytical methods, eutectic crystals can be identified and comprehensively characterized without relying solely on single-crystal structure determination.

[0062] A complete X-ray powder diffraction (XRPD) pattern obtained from a diffractometer can be used to characterize eutectics. However, a smaller subset of the XRPD data can also be sufficient for this purpose. For example, a set of one or more XRPD peaks can be used, and in some cases, even a single XRPD peak is sufficient to identify the eutectic. Similarly, a subset of spectra from other analytical techniques such as Raman spectroscopy, infrared spectroscopy, or solid-state NMR spectroscopy can be used alone or in combination with XRPD data to characterize eutectics. In these characterization examples, in addition to XRPD peak data, information about the guest and host components of the eutectic and their respective molar ratios can also be provided as part of the characterization process. The key point is that a complete XRPD pattern is not always necessary, and selective use of XRPD peaks or data from other analytical methods is effective for eutectic identification and characterization.

[0063] X-ray powder diffraction (XRPD) patterns are graphs displaying diffraction angles on the x-axis and intensity on the y-axis. The peaks observed in XRPD patterns are crucial for characterizing cocrystals. Pharmaceutical professionals often prefer to identify and label these peaks based on their position on the x-axis (representing diffraction angles) rather than focusing on peak intensity values ​​on the y-axis. This approach is more popular because sample orientation affects peak intensity, making it a less reliable parameter in cocrystal characterization. By focusing on peak position (°2θ) rather than peak intensity, cocrystal characterization becomes more robust and less susceptible to variations in sample orientation or preparation. This approach allows for more reliable and consistent identification and analysis of cocrystal samples.

[0064] Like any other measurement data, X-ray powder diffraction (XRPD) data exhibits a degree of variability. This variability can be observed not only in fluctuations in peak intensity but also in the position of the peaks along the x-axis (diffraction angle, °2θ). However, for eutectic characterization, this variability in peak position can generally be considered and interpreted. The variability in peak position can be attributed to several factors, including: Sample preparation: Even when processing the same crystalline material, preparing samples under different conditions (e.g., particle size, moisture content, solvent content, sample orientation) can result in slightly different diffraction patterns. Instrument parameters: Different X-ray diffractometers can be operated with different parameters, leading to minor differences in the obtained diffraction patterns, even when examining the same eutectic sample. Data processing software: Using different software packages to process X-ray data can also lead to observed variability in the results. Experts in the pharmaceutical field are well aware of the sources of these variabilities in XRPD data and address them as part of their expertise in eutectic characterization. Understanding and interpreting this variability is crucial for the reliable and consistent identification and analysis of eutectic samples.

[0065] Because numerous factors contribute to the variability of X-ray powder diffraction (XRPD) data, the common practice when describing peak positions in 2θ degrees (°2θ) is to use the term "about". This approach allows for approximations of data within a certain range, typically 0.1 or 0.2°2θ, depending on the specific circumstances. In the context of this document, all XRPD peak positions mentioned are reported with a variability of about 0.2°2θ. This level of variability is consistently applied throughout the document, regardless of whether the term "about" is explicitly used. The use of the qualifier "about" and the 0.2°2θ variability range acknowledges the inherent uncertainty and potential fluctuations in XRPD peak positions due to factors such as sample preparation, instrument parameters, and data processing methods. By interpreting this variability, XRPD data can be interpreted more accurately and appropriately for eutectic characterization.

[0066] Thermal analysis techniques are commonly used to characterize eutectics. Eutectics of the same compound often exhibit different melting temperatures, which aids in their identification. Thermal measurement techniques, such as differential scanning calorimetry (DSC), can also provide information about the purity of eutectic samples. A variety of thermal analysis methods can be employed for comprehensive characterization of eutectics, including melting point determination, DSC, and hot-stage microscopy. These thermal techniques can be used individually or in combination with other analytical methods, such as X-ray powder diffraction (XRPD), Raman spectroscopy, and infrared spectroscopy. By combining these thermal analyses with other analytical methods, eutectics can be effectively identified and analyzed. The different melting temperatures observed in thermal analysis, along with supplementary data from techniques such as XRPD and spectroscopy, provide a comprehensive characterization of eutectic samples. This multi-pronged approach, employing thermal analysis and other analytical methods, allows for a deep understanding and characterization of the physical and chemical properties of eutectics, enabling their accurate determination and analysis.

[0067] Similar to other analytical techniques, melting point analysis results can exhibit a degree of variability. Besides potential instrumental variability, other factors can also cause fluctuations in observed melting point measurements. The observed melting point of a eutectic sample can be affected by the presence of other eutectic or contaminant substances in the sample. These competing or conflicting properties in the sample can influence the measured melting point. To ensure accurate and reliable results, these sources of variability must be taken into account in melting point determinations. Factors such as sample purity, the presence of multiple eutectic forms, and instrumental limitations need to be carefully considered when interpreting melting point data. By recognizing and addressing these potential sources of variability, researchers and analysts can obtain more accurate and reliable melting point information for effectively characterizing eutectic samples.

[0068] In one embodiment of the present invention, a eutectic of quercetin dihydrate and hexahydrol (linear or cyclic structure) is disclosed, with a molar ratio of 1:1 and 2:1. The structure of the eutectic is... Figure 3 Overview in Chinese.

[0069] The XRPD spectrum of the quercetin dihydrate starting material used in this article is shown in [link to XRPD spectrum]. Figure 1 . Figure 1 A graphical representation 100 of X-ray powder diffraction (XRPD) patterns of quercetin and quercetin dihydrate according to an embodiment of the present invention is shown.

[0070] The spectrum shows diffraction peak characteristics in two forms. On the x-axis, the 2θ value represents the angle at which X-rays are diffracted by the lattice, while the y-axis represents the intensity of the diffracted X-rays, indicating the presence and concentration of specific crystal planes in the sample. The positions of the peaks correspond to specific interplanar spacings within the lattice, with each crystal form exhibiting a unique set of peaks. Specific peaks in the spectrum are attributed to the anhydrous form of quercetin, while other peaks indicate quercetin dihydrate, whose crystal structure contains water molecules. Quercetin dihydrate is a crystalline form of quercetin where each quercetin molecule contains two water molecules, resulting in unique diffraction peaks distinct from the anhydrous form.

[0071] Database references for quercetin indicate that its major peaks are located at 10.6°, 12.3°, 15.8°, 24.5°, and 27.9° 2θ, corresponding to its crystal structure. These peaks serve as a benchmark for identifying quercetin in samples. In contrast, quercetin dihydrate, due to the presence of water molecules, exhibits distinct peaks, thus differentiating it from its anhydrous form. By comparing this XRPD spectrum with the reference spectrum, including these specific peak positions of quercetin, the presence and purity of quercetin and quercetin dihydrate in the sample can be confirmed, providing further insights into the crystallization properties and stability of these compounds.

[0072] XRPD chromatogram of the hexahydrol starting material is shown below. Figure 2 . Figure 2 A graphical representation 200 of the XRPD spectrum of a hexahydrol according to an embodiment of the present invention is shown.

[0073] Its XRPD spectrum displays characteristic peaks, which helps in identifying and confirming its crystal structure. The main peaks of sorbitol XRPD spectra are referenced in the database. These peaks correspond to specific interplanar spacings in the sorbitol lattice. By comparing the XRPD spectrum of the sample with these reference peaks, the presence and purity of sorbitol can be confirmed, providing in-depth insights into its crystallization properties and stability.

[0074] By comparing XRPD spectra with reference spectra, including the specific peak positions of quercetin, quercetin dihydrate, and sorbitol, the presence and purity of these compounds in the sample can be confirmed, providing valuable insights into their crystallization properties and stability.

[0075] The XRPD pattern of the obtained eutectic is shown in [reference needed]. Figure 3 . Figure 3An XRPD spectrum 300 of a quercetin cocrystal according to an embodiment of the present invention is shown. The displayed XRPD spectrum reflects the crystal structure of the resulting compound during the preparation of the quercetin cocrystal. The spectrum shows a clear peak at a specific 2θ value, indicating the formation of the quercetin cocrystal. The sharp, well-defined peaks indicate high crystallinity. These peaks can be compared with reference spectra of quercetin and its cocrystal to confirm the successful formation of the desired cocrystal structure. This comparison helps identify unique crystal forms and verify the purity of the cocrystal.

[0076] Quercetin cocrystals can be characterized by their thermal properties. For example, Figure 4 This is the DSC thermogram of the quercetin eutectic, and under the conditions described herein, for Figure 4 The thermogram in the image was subjected to DSC, which showed an endotherm at approximately 155°C. The quercetin eutectic can be characterized by DSC alone, or in combination with XRPD diffraction patterns or one or more peaks described herein. Figure 4 A DSC thermogram 400 of a quercetin cocrystal according to an embodiment of the present invention is shown, revealing its thermal stability and decomposition behavior. The thermogram shows an onset temperature of 313.25°C, indicating the beginning of decomposition. A peak temperature, i.e., the temperature at which the maximum weight loss rate occurs, is 338.58°C, followed by a termination temperature of 345.74°C, marking the end of the decomposition process. Two significant weight loss events are observed: a minor loss of 0.142 mg (2.868%) and a major loss of 4.478 mg (90.428%), indicating initial moisture loss followed by significant decomposition of the quercetin cocrystal. This analysis is crucial for understanding the thermal properties of the cocrystal and its potential applications in various industries.

[0077] This invention also relates to pharmaceutical compositions comprising the cocrystals of the present invention. These compositions can be used to achieve the desired pharmacological effect by administration to patients in need, including for the treatment of other inflammatory conditions. In this invention, "patient" refers to a mammal, including humans, requiring treatment of a specific condition or disease, including but not limited to other inflammatory conditions. Therefore, this invention includes pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and the cocrystals of the present invention. A pharmaceutically acceptable carrier is any carrier that is relatively non-toxic and harmless to the patient at concentrations consistent with the effective activity of the active ingredient, such that any side effects attributable to the carrier do not diminish the beneficial effect of the active ingredient. A pharmaceutically effective amount of a compound refers to the amount that produces a result or exerts an effect on the specific condition being treated. The compounds of the cocrystals of the present invention can be administered with pharmaceutically acceptable carriers well known in the art, using any effective conventional dosage unit form, including immediate-release, sustained-release, and time-release formulations, orally, parenterally, topically, nasally, ophthalmologically, optically, sublingually, rectally, vaginally, etc.

[0078] For the kinetically controlled co-crystallization of the quercetin-hexahydride co-crystallization in this invention, the diffusion coefficient of quercetin dihydrate in ethanol is 5 × 10⁻⁶. -10 m 2 / s and the diffusion coefficient of the hexahydrol is 8 × 10⁻⁶. -10 m 2 / s. Using the classical nucleation theory equation, the nucleation rate (J) is: J = A × exp(-B / (ln S) 2 ), where A and B are system correlation constants (A = 10). 9 If B = 100, then J ≈ 10 5 nucleus / m 3 •s). Assuming a diffusion-restricted growth mechanism, the growth rate (G) is G = k × (C - C*) / C*, where k is the mass transfer coefficient, C is the bulk concentration, and C* is the equilibrium concentration. Assume k ≈ 10 -5 Given m / s, C ≈ 10C*, then G ≈ 10 -4 m / s. Combining nucleation and growth rates, the overall kinetic constant (k) of the quercetin-hexahydrol cocrystal is k = J × G 3 ≈ 10 -15 m 3 / s.

[0079] The equilibrium constant (Kd) for the dissolution of quercetin-hexane cocrystal represents the ratio of the concentrations of dissolved species at equilibrium. A higher Kd value indicates greater solubility and dissolution rate of the quercetin-hexane cocrystal under the experimental conditions (ethanol-water mixture, pH = 6-7, temperature = 40-50 °C, stirring speed = 600-800 rpm). With [quercetin]eq = 1.414 mol / L and [hexane]eq = 1.414 mol / L, the equilibrium constant (Kd) is calculated as Kd = [quercetin]eq × [hexane]eq. Therefore, the equilibrium constant (Kd) for the quercetin-hexane cocrystal is 2 mol / L.

[0080] Example

[0081] All chemicals were obtained from commercial sources and were used without further purification.

[0082] XRPD patterns were acquired using a PANalytical X'Pert PRO MPD diffractometer with Cu radiation from an Optix long-focus source as the incident beam. An elliptical graded multilayer mirror was used to focus Cu Kα X-rays through the sample and project them onto the detector. Prior to analysis, a silicon sample (NIST SRM 640d) was analyzed to verify that the observed Si 111 peak position was consistent with the NIST-certified position. The sample was sandwiched between 3 μm thick films and analyzed under transmission geometry. A beam blocker, a short anti-scattering extender, and an anti-scattering knife edge were used to minimize background from air. A Soler slit was used for both the incident and diffracted beams to minimize broadening caused by axial divergence. Diffraction patterns were acquired using a scan position-sensitive detector (X'Celerator) located 240 mm from the sample and DataCollector software v. 2.2b.

[0083] DSC analysis was performed using a TA Instruments 2920 and Q2000 differential scanning calorimeter. Temperature calibration was performed using NIST traceable indium. The sample was placed in an aluminum DSC pan, covered (T0C-Tzero crimped seal), and the weight was accurately recorded. The weighing aluminum pan configured as the sample pan was placed on the reference side of the sample cell. The data acquisition parameters and sample pan configuration for each thermogram are displayed in the image. The method code on the thermogram in each corresponding figure is an abbreviation for the onset temperature, termination temperature, and heating rate; for example, "-30-250-10" means "from -30 °C to 250 °C, at 10 °C / min".

[0084] Comparative Example 1: Preparation of Quercetin Cocrystal 1

[0085] Quercetin and hexahydrin solids were added to MEK, with an excess of quercetin dihydrate, resulting in undissolved solid residue. The mixture was stirred at room temperature for two days to obtain an opaque white suspension. The solid was collected by vacuum filtration and washed with MEK on the filter.

[0086] Comparative Example 2: Preparation of Quercetin Cocrystal 2

[0087] Quercetin dihydrate (45.0 mg) and hexahydrin (27.12 mg) were added to a clean vial at a 1:1 molar ratio. Ethanol (30 mL) was added under sonication to obtain a clear solution (hexahydrin can be used to accelerate dissolution). The vial was opened and covered with perforated aluminum foil to allow slow evaporation under ambient conditions. After approximately 6 weeks, the sample contained solids and a small amount of residual solvent. The solids were collected by vacuum filtration, yielding birefringent, grayish-white, rectangular, and irregularly shaped flakes.

[0088] Example 1: Preparation of quercetin cocrystal 3

[0089] The kinetically controlled quercetin-hexaol cocrystal formation procedure involves first preparing a saturated solution of quercetin and sorbitol in a suitable solvent such as ethanol, methanol, or a solvent mixture, with a molar ratio of 1:1. The solution is then heated to a temperature that ensures complete dissolution of the starting materials, typically between 40 and 50°C. A key step is the rapid cooling of the solution, usually achieved by immersing the reaction vessel in an ice bath, resulting in a cooling rate of approximately 10–20°C / min. This rapid cooling induces rapid supersaturation and promotes the nucleation and growth of the desired quercetin-hexaol cocrystal phase, rather than the nucleation and growth of individual starting material crystals. The cocrystal slurry is stirred or matured for a short time, typically 10–30 minutes, to ensure complete cocrystal formation. Finally, the cocrystal product is collected by vacuum filtration or centrifugation, washed with a small amount of cold solvent, and dried in a vacuum or desiccator to obtain the final product. Compared to other slower crystallization techniques, this kinetically controlled method typically yields finer and more uniform cocrystal particles.

[0090] In Comparative Examples 1-2 and Example 1, the final average crystal size was calculated using the provided data and the following formula:

[0091] in: L represents the average crystal size. C0 represents the initial concentration. C s Represents solubility concentration G represents the growth rate. n represents the index k represents the proportionality constant.

[0092] The conditions and corresponding crystal sizes for each co-crystallization method are shown in the table below:

[0093] These calculations illustrate the effect of the co-crystallization rate on the final crystal size, where the slower co-crystallization method produces significantly larger crystals compared to the faster method.

[0094] The relationship between particle size and bioavailability can be simulated using several equations from the pharmaceutical field. In Comparative Examples 1-2 and Example 1, the particle dissolution rate was calculated using the provided data and the Noyes-Whitney equation. This calculation helps illustrate how particle size affects the dissolution rate, and consequently, bioavailability and bioenhancing activity.

[0095] Noyes-Whitney equation:

[0096] in: Represents the dissolution rate D represents the diffusion coefficient. A represents the particle surface area. C s Represents saturated solubility C represents time t. Ontology Concentration of solute in solution h is the thickness of the diffusion layer.

[0097] in: A represents the particle surface area. R represents the crystal size.

[0098] The crystals formed through ultrafast co-crystallization have the smallest particle size (8.3 µm), resulting in the largest surface area and the fastest dissolution rate. This leads to the highest potential bioavailability, as the quercetin-sorbitol particles dissolve rapidly, enabling more efficient absorption in the gastrointestinal tract.

[0099] To compare the yields of quercetin cocrystals prepared by different methods (Comparative Examples 1-2 and Example 3), yields were calculated as the ratio of the mass of quercetin dihydrate in the resulting cocrystal to the initial mass of the starting material (quercetin dihydrate), and expressed as a percentage.

[0100] Yield analysis of quercetin-hexahydrol cocrystals prepared using different methods showed that Example 1 was the most efficient method, achieving a yield of 84.2%. This yield is significantly higher than the 71.1% yield observed in Comparative Example 1 and the 62.8% yield in Comparative Example 2. The superior yield of Example 1 can be attributed to the rapid cooling and kinetic control techniques employed, which enhance the efficiency of the cocrystallization method and result in a higher conversion of quercetin dihydrate to the desired cocrystal. This significant yield difference, compared to the slower and less efficient methods used in Comparative Examples 1 and 2, highlights the effectiveness of kinetic control methods in maximizing the production of high-quality quercetin cocrystals.

[0101] The effects of Comparative Examples 1-2 and Example 1 on ascorbic acid permeability in human intestinal epithelial cells (Caco-2 cell line) were investigated. The translocation of Caco-2 cells was determined using a modified method based on the work of Joshi G et al. [1]. Caco-2 cells from passages 10 to 20 were cultured in Transwell inserts (0.4 μm pore size, 1.13 cm² area). 2 The chambers were prepared and used for transport experiments 14-21 days after inoculation. Before the experiment, the chambers were washed twice with preheated transport medium (HBSS buffer containing 25 mM HEPES, pH 7.4) and equilibrated for 30 minutes.

[0102] The integrity of a monolayer was verified by monitoring the permeability of fluorescein, a marker of paracellular leakage. A permeability coefficient (Papp) of fluorescein less than 0.5 × 10⁻⁶ was considered acceptable. -6 At a speed of cm / s, a monolayer of cells was considered sufficiently dense for transport experiments. All transport studies were conducted at 37°C.

[0103] 0.5 ml of transfer buffer containing the test compound was added to the top side of the chamber, while 1.5 ml of transfer buffer was added to the outer side of the base of the chamber. After incubation for 6 hours, the concentration of the test compound in the transfer medium was diluted with acetonitrile (for dissolving the pigment), and the sample was immediately analyzed at OD 453 nm using a spectrophotometer.

[0104] The permeability coefficient (Papp) from the top side to the outer side of the substrate is calculated using the following equation:

[0105] in: dQ / dt is the change in the amount of compound in the outer compartment of the substrate over time (mg / min). A is the area of ​​a single layer of cells (1.13 cm²). 2 ) C0 is the initial concentration of the compound in the top-side chamber (0.4 mg / ml).

[0106] After 6 hours of incubation, the transfer study yielded the following data:

[0107] Trans-Cellular transport studies in Caco-2 cells showed that conjugating ascorbic acid with different forms of quercetin significantly enhanced its permeability. Ascorbic acid alone exhibited the lowest permeability. Addition of quercetin dihydrate provided a moderate enhancement. Greater enhancements were observed in quercetin cocrystals prepared by different methods, with the most significant enhancement achieved using the kinetically controlled cocrystallization method described in Example 3. This method significantly increased the permeability and transport of ascorbic acid, indicating a substantial improvement in its potential bioavailability compared to other forms. These findings support the superior performance and bioenhanced activity of quercetin cocrystals prepared via kinetically controlled methods.

[0108] To compare the stability of quercetin cocrystals prepared by different methods, we performed a series of tests. The initial concentration (C0) of quercetin in each sample was measured using high-performance liquid chromatography (HPLC). These samples were then stored under accelerated conditions (40°C and 75% relative humidity). At specific time intervals (1 week, 2 weeks, and 4 weeks), the concentration (C0) of quercetin in each sample was measured using HPLC. t The percentage of quercetin that has degraded over time was calculated using the following formula:

[0109] in: C0 is the initial concentration of quercetin dihydrate. C t The concentration of quercetin dihydrate at time t.

[0110] The results are summarized in the table below:

[0111] Example 1 exhibited excellent stability, with no significant degradation observed after 4 weeks. This indicates that the eutectic formed using the rapid cooling method is more stable under accelerated conditions compared to the eutectic obtained in Comparative Examples 1 and 2.

[0112] Figure 5 A graphical representation 500 shows the bioenhanced activity of quercetin cocrystals combined with resveratrol (a representative flavonoid class) according to an embodiment of the present invention. The graph shows the percentage of permeability of resveratrol alone and in combination with different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data reveal that the addition of quercetin cocrystals significantly enhances the permeability of resveratrol. Permeability of resveratrol increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystals. These results indicate that the bioavailability of resveratrol is significantly enhanced when combined with quercetin cocrystals.

[0113] Figure 6AA graphical representation 600A illustrates the bioenhanced activity of quercetin cocrystals bound to lutein (a representative carotenoid class) according to an embodiment of the present invention. The graph shows the percentage of permeability of lutein alone and bound to different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data indicate that the addition of quercetin cocrystals significantly enhances the permeability of lutein. The permeability of lutein increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystal. These results demonstrate that the bioavailability of lutein is significantly enhanced when bound to quercetin cocrystals.

[0114] Figure 6B A graphical representation 600B shows the bioenhanced activity of quercetin cocrystals combined with β-carotene (a representative class of carotenoids) according to an embodiment of the present invention. The graph shows the percentage of permeability of β-carotene alone and with different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data reveal that the addition of quercetin cocrystals significantly enhances the permeability of β-carotene. The permeability of β-carotene increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystal. These results indicate that the bioavailability of β-carotene is significantly enhanced when combined with quercetin cocrystals.

[0115] Figure 6C A graphical representation 600C shows the bioenhancing activity of quercetin cocrystals bound to lycopene (a representative class of carotenoids) according to an embodiment of the present invention. The graph shows the percentage of permeability of lycopene alone and bound to different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data indicate that the addition of quercetin cocrystals significantly enhances the permeability of lycopene. The permeability of lycopene increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystal. These results demonstrate that the bioavailability of lycopene is significantly improved when bound to quercetin cocrystals.

[0116] Figure 7 A graphical representation 700 shows the bioenhancing activity of quercetin cocrystals combined with nicotine (a representative alkaloid class) according to one embodiment of the present invention. The graph shows the percentage of permeability of nicotine alone and combined with different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data indicate that the addition of quercetin cocrystals significantly enhances the permeability of nicotine. Nicotine permeability increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystal. These results demonstrate that the bioavailability of nicotine is significantly improved when combined with quercetin cocrystals.

[0117] Figure 8 A graphical representation 800 shows the bioenhanced activity of quercetin cocrystals combined with glutathione (a representative class of amino acid derivatives) according to an embodiment of the present invention. The graph shows the percentage of permeability of glutathione alone and in combination with different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data indicate that the addition of quercetin cocrystals significantly enhances the permeability of glutathione. The permeability of glutathione also increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystal. These results demonstrate that the bioavailability of glutathione is significantly improved when combined with quercetin cocrystals.

[0118] Figure 9 A graphical representation 900 shows the bioenhancing activity of quercetin cocrystals combined with cannabidiol (a representative cannabinoid class) according to an embodiment of the present invention. The graph shows the percentage of permeability of CBD alone and in combination with different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data indicate that the addition of quercetin cocrystals significantly enhances the permeability of CBD. The permeability of CBD increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystals. These results demonstrate that the bioavailability of CBD is significantly improved when combined with quercetin cocrystals.

[0119] Figure 10 A graphical representation 1000 shows the bioenhanced activity of quercetin cocrystals combined with β-glucan (a representative class of glucans) according to one embodiment of the present invention. The graph shows the percentage of permeability of β-glucan alone and in combination with different concentrations of quercetin cocrystals (1%, 2%, 5%, and 10%). The data indicate that the addition of quercetin cocrystals significantly enhances the permeability of β-glucan. The permeability of β-glucan increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystal. These results demonstrate that the bioavailability of β-glucan is significantly improved when combined with quercetin cocrystals.

[0120] Figure 11 A graphical representation 1100 shows the bioenhanced activity of quercetin cocrystal bound to collagen tripeptide (a representative peptide) according to an embodiment of the present invention. The graph shows the percentage of permeability of collagen tripeptide alone and bound to different concentrations of quercetin cocrystal (1%, 2%, 5%, and 10%). The data indicate that the addition of quercetin cocrystal significantly enhances the permeability of collagen tripeptide. The permeability of collagen tripeptide increases with increasing quercetin cocrystal concentration, with the largest increase observed at 10% quercetin cocrystal. These results demonstrate that the bioavailability of collagen tripeptide is significantly improved when bound to quercetin cocrystal.

[0121] According to the embodiments shown herein, a method for preparing quercetin-hexane cocrystals as bioenhancers of bioactive compounds is provided. This method includes the step of forming a cocrystal from quercetin and hexane via a kinetically controlled cocrystallization method. In one implementation, the kinetically controlled cocrystallization method involves the rapid removal of a solvent containing quercetin and hexane under controlled temperature and humidity conditions. This technique utilizes an accelerated evaporation rate to induce rapid nucleation and crystallization, resulting in a high-quality cocrystal. Rapid solvent removal produces high supersaturation, driving molecules to rapidly align into a stable lattice. This method is particularly valuable in drug development due to its time efficiency, the potential to form metastable polymorphs with enhancing properties, and scalability for industrial applications. The main difference between the kinetically controlled cocrystallization method and conventional methods lies in its emphasis on accelerated kinetics and precise environmental control. In conventional methods, solvent evaporation occurs at a slower, more natural rate, often without strict control over temperature and humidity, which can lead to poor nucleation uniformity and the production of lower-quality crystals. In contrast, the kinetic-controlled method employs rapid solvent removal to quickly reach high supersaturation levels, driving rapid nucleation and crystallization. This rapid kinetics facilitates the formation of high-quality, defect-free cocrystals by reducing the time for free molecular movement and the potential formation of unwanted phases or amorphous materials. Furthermore, the controlled environment ensures the reproducibility and consistency of crystal formation, enhancing the purity and desired properties of the cocrystal. This method is particularly useful in the pharmaceutical field due to its high efficiency and ability to produce cocrystals with enhanced solubility and bioavailability.

[0122] In one embodiment, the kinetically controlled co-crystallization method includes the step of cooling the solution at a cooling rate of 10-20 °C / min to form a co-crystallization. In one aspect, the solution comprises quercetin and hexahydrol, and has a temperature in the range of 40-70 °C before cooling. In one embodiment, the kinetically controlled co-crystallization method further includes the step of ripening the co-crystallization. In one embodiment, the solution comprises a solvent selected from the group consisting of methanol, ethanol, and combinations thereof. In one embodiment, quercetin is preferably quercetin dihydrate. In one embodiment, the diffusion coefficient of quercetin dihydrate in the solvent is preferably 5 × 10⁻⁶. -10 m 2 / s. In one embodiment, the hexaol is selected from the group consisting of straight-chain hexaols and cyclic hexaols. In one embodiment, the hexaol is preferably sorbitol. In one embodiment, the diffusion coefficient of the hexaol in the solvent is preferably 8 × 10⁻⁶. -10 m 2 / s. In one embodiment, the molar ratio of quercetin to hexahydrol in the solution is in the range of 1:1. In one embodiment, the kinetic constant (k) of the kinetically controlled co-crystallization method is in the range of 1 × 10⁻⁶. -16 - 1 × 10 -14 m 3 Within the range of / s. In one embodiment, the kinetic constant (k) of the kinetically controlled co-crystallization method is preferably 10. -15 m 3 / s. In one embodiment, the bioactive compound is selected from the group consisting of active pharmaceutical ingredients, vitamins, natural bioactive substances, phytochemicals, minerals, and any combination thereof.

[0123] According to the embodiments shown herein, a quercetin-hexahydrol cocrystal is provided as a bio-enhancing agent for a bioactive compound. The molar ratio of quercetin to hexahydrol in this cocrystal is in the range of 1:1. In one embodiment, the quercetin-hexahydrol cocrystal is characterized by having at least one of the following XRPD peaks: 10.7, 12.4, 13.8, 13.9, 14.7, 16.2, 16.4, 17.7, 18.0, 19.3, 21.6, 23.8, 25.9, 27.2, 28.7, 29.8, 33.5, 35.8, 36.6, and 37.0 ± 2θ [Cu Kα radiation (λ = 1.5406 Å)]. In one embodiment, the cocrystal preferably exhibits thermogravimetric properties in the range of 338.58–342.2°C. In one embodiment, the bioactive compound is selected from the group consisting of active pharmaceutical ingredients, vitamins, natural bioactive substances, phytochemicals, minerals, and any combination thereof.

[0124] According to the embodiments shown herein, a pharmaceutical composition is provided comprising a quercetin-hexahydrol cocrystal and at least one pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition can be used to enhance the cellular permeability and bioavailability of a bioactive compound. In one embodiment, the pharmaceutical composition can be used to treat inflammation.

[0125] According to one embodiment of this invention, a method for preparing a quercetin-hexane cocrystal composition is provided. The method includes the step of combining quercetin and hexane in a solvent system comprising an ethanol-water mixture. The method includes the step of controlling the pH of the solvent system within the range of 6-7. The method includes the step of maintaining the temperature of the solvent system at 40-50 °C. The method includes the step of stirring the solvent system at a speed of 600-800 rpm. The method includes the step of bringing the system to equilibrium, whereby the equilibrium constant (Kd) of the quercetin-hexane cocrystal is in the range of 1.55-2 mol / L.

[0126] According to another embodiment of this invention, the present invention provides a method for kinetically controlled formation of a quercetin-hexane cocrystal. The method includes the step of preparing a saturated solution of quercetin and hexane in a suitable solvent. The molar ratio of quercetin to hexane is 1:1. The method includes the step of heating the solution to a temperature between 40 and 50 °C to ensure complete dissolution of the starting materials. The method includes the step of rapidly cooling the solution, such as by immersing the reaction vessel in an ice bath to achieve a cooling rate of 10–20 °C / min, thereby inducing rapid supersaturation and promoting the nucleation and growth of the quercetin-hexane cocrystal. The method includes the step of stirring or aging the cocrystal slurry for 10–30 minutes to ensure complete cocrystal formation. The method includes the steps of collecting the cocrystal product by vacuum filtration or centrifugation, washing the solid with a small amount of cold solvent, and drying the product in a vacuum or desiccator. In one embodiment, a suitable solvent is ethanol, methanol, or a mixture thereof.

[0127] According to another embodiment of this invention, the present invention provides a method for kinetically controlled formation of a quercetin-hexane cocrystal. The method includes the step of preparing a saturated solution of quercetin and hexane in a suitable solvent. The molar ratio of quercetin to hexane is 1:1. The method includes the step of heating the solution to a temperature between 50 and 70°C to ensure complete dissolution of the starting materials. The method includes the step of rapidly cooling the solution, such as by immersing the reaction vessel in an ice bath to achieve a cooling rate of 10-20°C / min, thereby inducing rapid supersaturation and promoting the nucleation and growth of the quercetin-hexane cocrystal. The method includes the step of stirring or aging the cocrystal slurry for 10-30 minutes to ensure complete cocrystal formation. The method includes the steps of collecting the cocrystal product by vacuum filtration or centrifugation, washing the solid with a small amount of cold solvent, and drying the product in a vacuum or desiccator. In one embodiment, a suitable solvent is ethanol, methanol, or a mixture thereof. In one embodiment, the diffusion coefficient of quercetin dihydrate in ethanol is 5 × 10⁻⁶. -10 m 2 / s, and the diffusion coefficient of the hexahydrol is 8 × 10⁻⁶. -10 m 2 / s. In one implementation, the nucleation rate (J) is approximately 10. 5 nucleus / m 3 •s, growth rate (G) is approximately 10 -4 The m / s ratio results in an overall kinetic constant (k) of approximately 10 for the formation of the quercetin-hexahydrol cocrystal. -15 m 3 / s.

[0128] Those skilled in the art will understand that the description of quercetin-hexahydrol cocrystal and its production method herein is for illustrative purposes and should not be construed as limiting the scope of this disclosure.

[0129] Those skilled in the art will understand that the methods shown and explained are examples and should not be considered limiting in any way. It should also be understood that variations or alternatives to the system elements, modules, and other features and functions disclosed above can be combined to create other different devices, systems, or applications.

[0130] Although this disclosure has been described with reference to certain embodiments, those skilled in the art will understand that various changes and substitutions can be made without departing from the scope of this disclosure. Furthermore, many modifications can be made to adapt particular situations or materials to the teachings of this disclosure without departing from its scope. Therefore, this disclosure is intended to be limited to the specific embodiments disclosed, but rather to include all embodiments falling within the scope of the appended claims.

Claims

1. A method for preparing a quercetin-hexahydrol cocrystal as a bio-enhancing agent of a bioactive compound, the method comprising forming a cocrystal from quercetin and hexahydrol by a kinetically controlled co-crystalization method.

2. The method according to claim 1, wherein, The kinetically controlled co-crystallization method involves forming a co-crystallization by cooling a solution containing quercetin and hexahydrol at a cooling rate of 10-20 °C / min, with the temperature prior to cooling in the range of 40-70 °C.

3. The method according to claim 2, further comprising the step of aging the eutectic.

4. The method according to claim 2, wherein, The solution contains a solvent selected from the group consisting of methanol, ethanol, and combinations thereof.

5. The method according to claim 4, wherein, Quercetin is preferably quercetin dihydrate.

6. The method according to claim 5, wherein, The preferred diffusion coefficient of quercetin dihydrate in a solvent is 5 × 10⁻⁶. -10 m 2 / s.

7. The method according to claim 2, wherein, Hexahydrols are selected from the group consisting of straight-chain hexahydrols and cyclic hexahydrols.

8. The method according to claim 4, wherein, The preferred hexahydrol is sorbitol.

9. The method according to claim 8, wherein, The diffusion coefficient of the hexahydrol in the solvent is preferably 8 × 10⁻⁶. -10 m 2 / s.

10. The method according to claim 2, wherein, The molar ratio of quercetin to hexahydrol in the solution is in the range of 1:

1.

11. The method according to claim 10, wherein, The kinetic constant (k) of the kinetically controlled co-crystallization method is in the range of 1 × 10⁻⁶. -16 - 1 × 10 -14 m 3 Within the range of / s.

12. The method according to claim 11, wherein, The kinetic constant (k) of the kinetically controlled co-crystallization method is preferably 10. -15 m 3 / s.

13. The method according to claim 1, wherein, Bioactive compounds are selected from the group consisting of active pharmaceutical ingredients, vitamins, natural bioactive substances, phytochemicals, minerals, and any combination thereof.

14. A quercetin-hexahydrol cocrystal as a bio-enhancing agent of a bioactive compound, wherein the molar ratio of quercetin to hexahydrol in the cocrystal is in the range of 1:

1.

15. The quercetin-hexahydrol cocrystal according to claim 14, characterized in that... It has at least one of the following XRPD peaks: 10.7, 12.4, 13.8, 13.9, 14.7, 16.2, 16.4, 17.7, 18.0, 19.3, 21.6, 23.8, 25.9, 27.2, 28.7, 29.8, 33.5, 35.8, 36.6 and 37.0 ±2θ degrees [Cu Kα radiation (λ = 1.5406 Å)].

16. The quercetin-hexahydrol cocrystal according to claim 15, wherein the cocrystal preferably exhibits thermogravimetric properties in the range of 338.58 - 342.2°C.

17. The quercetin-hexahydrol cocrystal according to claim 16, wherein, Bioactive compounds are selected from the group consisting of active pharmaceutical ingredients, vitamins, natural bioactive substances, phytochemicals, minerals, and any combination thereof.

18. A pharmaceutical composition comprising the quercetin-hexahydrol cocrystal according to claim 15 and at least one pharmaceutically acceptable carrier.

19. The pharmaceutical composition according to claim 18, which enhances the cell permeability and bioavailability of the bioactive compound.

20. The pharmaceutical composition according to claim 18, for treating inflammation.

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