New co-crystals of dexamethasone

Abstract

The present invention relates to a co-crystal of dexamethasone (DEX) and a benzenediol, the co-crystal consisting of a 1:1 molar ratio of DEX and a benzenediol. The benzenediol can be catechol (CAT) or resorcinol (RES). The co-crystal of DEX and a benzenediol is formed by milling crystalline DEX with crystalline benzenediol combined in a 1:1 molar ratio. The milling can be performed at room temperature. The co-crystal can be heat annealed or exposed to moisture to enhance co-crystal formation. The DEX-CAT or DEX-RES co-crystal can be included in a medicament for the treatment of allergy, asthma, rhinitis, cancer, diabetes, anemia, ulcer, and viral infection. The DEX-benzenediol co-crystal can be screened to provide particles in the range of 10 to 45 pm, which can be used for intranasal administration, with improved dissolution properties.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 365,396, filed May 26, 2022, which is incorporated herein by reference in its entirety, including any forms, figures or drawings. Technical Field

[0003] This invention belongs to the field of pharmaceutical crystal forms. Specifically, this invention relates to a novel eutectic of dexamethasone. Background Technology

[0004] Recent advances in cocrystallization have greatly motivated its application in modifying the physicochemical properties of pharmaceuticals, including not only solubility, dissolution rate, and bioavailability, but also manufacturability, luminescence, and sensory properties. Early cocrystallization screening and preparation methods can be broadly categorized into two types: solution-based crystallization and solid-state crystallization. The former offers advantages in the pharmaceutical industry due to its ease of scalability and control over key properties (e.g., size, morphology, and polymorphism). However, the thermodynamics and kinetics of cocrystallization processes exhibit interesting interactions in different solvent systems, leading to unpredictable results. Inconsistent solubility of cocrystallization formations also increases the tendency for poorly soluble formations to precipitate from solution before their concentration reaches the unstable region for spontaneous cocrystallization. Solid-state cocrystallization, such as neat grinding, can counteract solvent effects, and the apparent equilibrium achieved under specific conditions often conforms to the experimental conditions used, but not to thermodynamic equilibrium. Therefore, it is a useful alternative for discovering hidden metastable cocrystallizations that are unavailable through solution crystallization.

[0005] As a kinetic process, the mechanochemical reaction is induced by a sufficient energy input exceeding the relative strength of the supramolecular interactions responsible for assembling the crystalline matrix. The molecular diffusion process involving co-crystallization via mechanochemistry can be mediated by one of three high-energy transition intermediates with enhanced molecular mobility: (i) a vapor phase, (ii) a liquid eutectic phase, and (iii) an amorphous phase. For fine milling, the formation of amorphous intermediates is the most common mechanism, especially when limited mass transfer occurs. For example, 60 minutes of milling yields only 60% phenazine and diconic acid eutectic, with the remainder remaining an amorphous mixture. Similarly, co-milling carbamazepine and saccharin at low temperatures results in the formation of an amorphous phase, which subsequently transforms into a eutectic during storage at room temperature. The transformation efficiency strongly depends on the annealing temperature and humidity. These findings are significant, particularly when eutectic screening involves high glass transition temperatures (T0). gWhen co-forming products of glass-forming ability (GFA), the complete conversion to a stable eutectic state may take days, months or even years depending on storage conditions, because there is a risk that reactants may be trapped in an undesirable amorphous state.

[0006] Dexamethasone (DEX), 9-fluoro-11β,17,21-trihydroxy-16α-methylpregn-1,4-diene-3,20-dione, is a commonly used synthetic glucocorticoid used to treat a variety of acute and chronic inflammatory conditions, including allergic states, skin diseases, ophthalmic diseases, rheumatic diseases, and neurological disorders. It is considered by the World Health Organization (WHO) to be one of the drugs that can reduce mortality in critically ill or severely ill patients infected with COVID-19. However, DEX is poorly soluble in water, with a solubility of approximately 90 mg / L at 25°C, exhibiting poor solubility. No known DEX cocrystals exist. Confirmation of complementary cocrystal formation is generally considered the rate-limiting step for successful cocrystal formation. Supramolecular chemistry studies have shown that most active pharmaceutical ingredients possess polar groups rich in predictable interactions beneficial to cocrystal formation, primarily R2. 2 (8) Hydrogen-bonded synthons. DEX is characterized by hydroxyl groups and is not a single part that imparts sufficiently strong or general interactions to facilitate co-crystallization. Summary of the Invention

[0007] The implementation scheme involves a dexamethasone (DEX) and hydroquinone cocrystal composed of DEX and hydroquinone in a 1:1 molar ratio. The hydroquinone can be catechol (CAT) or resorcinol (RES). The DEX and hydroquinone cocrystal can have a particle size of less than 63 μm, for example, 10-45 μm.

[0008] Another embodiment relates to a method for preparing a DEX-hydroquinone cocrystal, wherein crystalline DEX and crystalline hydroquinone are combined in a 1:1 molar ratio to form a DEX+hydroquinone mixture, which is then milled to form a DEX-hydroquinone cocrystal. Mixing and milling can be performed at room temperature. The resulting DEX-hydroquinone cocrystal can be heat-annealed and / or exposed to moisture. The DEX-hydroquinone cocrystal can be screened. The screened DEX-hydroquinone cocrystal can have particles smaller than 63 μm, for example, 10-45 μm.

[0009] Other implementation schemes involve drugs comprising DEX-hydroquinone cocrystals. These drugs can be used to treat allergies, asthma, rhinitis, cancer, diabetes, anemia, ulcers, and viral infections. The drugs can be administered intranasally. Attached Figure Description

[0010] Figure 1 The chemical structure of the DEX and hydroquinone and pyrogallol co-formed products used for eutectic according to the implementation scheme is shown.

[0011] Figure 2A The temperature-composition phase diagram of the DEX-CAT eutectic system is shown, representing a 1:1 stoichiometric ratio.

[0012] Figure 2B The temperature-composition phase diagram of the DEX-RES eutectic system is shown, representing a 1:1 stoichiometric ratio.

[0013] Figure 3 This shows the PXRD pattern of a 1:1 physical mixture of DEX and hydroquinone (HYQ), pyrogallol (HXQ), pyrogallol (PYR), and pyrogallol (PHL) formed by fine milling, and the components therein.

[0014] Figure 4 The PXRD pattern and Rietveld refinement simulation diagram of the 1:1 DEX-hydroxybenzene eutectic system of catechol (CAT) and resorcinol (RES) according to the embodiment of the present invention, obtained by fine grinding after annealing, are shown.

[0015] Figure 5 The DEX-hydroquinone eutectic system, DEX-CAT and DEX-RES eutectic system according to the embodiment are shown by PXRD after one month of storage at 25°C / 75% relative humidity.

[0016] Figure 6 DSC curves of the DEX-hydroquinone eutectic system according to the embodiment are shown after annealing relative to their starting materials.

[0017] Figure 7 The TGA diagram shows the combination of the DEX-hydroquinone eutectic system according to the implementation scheme compared to the starting materials.

[0018] Figure 8A DSC curves of DEX-CAT according to one implementation scheme are shown at different grinding stages.

[0019] Figure 8B DSC curves of DEX-RES according to one implementation scheme are shown at different grinding periods.

[0020] Figure 9A The thermal analysis of quenched and cooled DEX-CAT is shown by DSC heating / cooling / heating plots, which indicate the conversion efficiency from the eutectic phase to the eutectic phase at different annealing temperatures.

[0021] Figure 9BThe thermal analysis of quenched and cooled DEX-RES is shown by DSC heating / cooling / heating plots, which show the conversion efficiency from the eutectic phase to the eutectic phase at different annealing temperatures.

[0022] Figure 10 The least-squares superposition (RMS = 0.0845) of the six pairs of quaternary carbon atoms showing the structures of DEX-CAT (dark) and DEX-RES (bright) yields another pair of DEX(-x, 1 / 2+y, 1-z) and CAT(-x, -1 / 2+y, 1-z) molecules for better comparison with the asymmetric units of DEX-RES.

[0023] Figure 11 The crystal structure of a 1×1×2 unit cell showing the DEX-CAT eutectic system along the b-axis without hydrogen atoms is used to clearly show the intermolecular hydrogen bonding between (DEX-CAT), (DEX-DEX), and (CAT-CAT).

[0024] Figure 12 Crystal structure of a 1×1×1 unit cell of the DEX-RES eutectic system along the b-axis without hydrogen atoms, used to clearly show the intermolecular hydrogen bonding between (DEX-RES), (DEX-DEX), and (RES-RES).

[0025] Figure 13 The FTIR spectra of the DEX-hydroquinone eutectic after annealing and the FTIR spectra of the starting material are shown.

[0026] Figure 14A Displays a filtered DEX SEM image with a magnification of 5000x.

[0027] Figure 14B Displays a filtered SEM image of DEX-CAT at 5000x magnification.

[0028] Figure 14C Displays a filtered SEM image of DEX-RES at 5000x magnification.

[0029] Figure 15 This is a composite plot showing the dissolution curves of DEX, DEX eutectic (DEX-CAT, DEX-RES), and physical mixtures of DEX and hydroquinone (DEX+CAT, DEX+RES) with particle sizes smaller than 63 μm in simulated nasal drops (n=3) at pH 5.5.

[0030] Figure 16Bar graph showing NGI dispersion data for spray-dried DEX-RES formulations (n=3), where S1-S7 represent impactor levels 1-7 with upper aerodynamic cutoff diameters in parentheses, and MOC is the micropore collector in the NGI. Detailed Implementation

[0031] In embodiments of the invention, a cocrystal containing dexamethasone (DEX) is formed by mechanochemical milling. The DEX cocrystal exhibits improved pharmaceutical properties through OH···OH isosynthetics, which are energy-inferior compared to other isosynthetics. The DEX cocrystal is identified by detecting structurally similar polyphenolic substances that differ in the position and number of hydroxyl groups on the benzene ring. Coformations tested include catechol (CAT), resorcinol (RES), hydroquinone (HYQ), pyrogallol (HXQ), phlorogallol (PHL), and pyrogallol (PYR). Figure 1 As shown. Although not all co-formations are on the GRAS list, many have been reported to have antioxidant and anti-inflammatory effects, and they potentially synergize with DEX through co-crystallization. In one embodiment, RES derivatives have demonstrated a wide range of pharmaceutical uses, including the treatment of inflammation (such as allergies, asthma, and rhinitis), cancer, diabetes, anemia, ulcers, and viral infections. RES exerts its anti-allergic effect by blocking histamine release. Ongoing analysis of unique supramolecular interactions reveals patterns used to design co-crystallizations of DEX with other phenolic compounds, including traditional Chinese medicines as polyphenols and flavonoids exhibiting chemical structures similar to the model co-formations.

[0032] In the implementation, the eutectic comprises one or more co-formations with the following structures:

[0033]

[0034] Wherein, R1, R2, R3, R4, and R5 are independently H, OH, CO2H, NH2, or SH, and at least two of R1, R2, R3, R4, and R5 are not H. The eutectic is formed with a DEX to co-formed product molar ratio of m:n, where m is 1, 2, 3, or 4, and n is 0.5, 1, 2, 3, or 4, for example, where m is 1 and n is 0.5, 1, or 2. The co-formed product is selected from hydroquinone, pyrogallol, tetraphenylbenzene, and pentahydroxybenzene, such as, but not limited to, catechol or resorcinol. Figure 2A and 2BAs shown, in the hydroquinone and phloroglucinol co-formations, when obtained by mechanochemical milling, phase-pure DEX-CAT and DEX-RES eutectics form in a 1:1 stoichiometric ratio, although this is not the case with other tested methods, including solvent evaporation and melt crystallization. The localized maximum melting temperature of each eutectic form at 0.5 DEX molar fraction can be observed in the temperature composition diagrams of DEX-CAT and DEX-RES, confirming their 1:1 stoichiometry. Figure 3 As shown, other potential eutectics tested only resulted in simple physical mixtures. Anhydrous DEX eutectics were obtained as polycrystalline free-flowing powders with micron-scale particle sizes. Figure 4 As shown, the PXRD spectrum of this eutectic sample exhibits some unique diffraction peaks (DEX-CAT: 2θ = 10.56°, 14.12°, 15.34°, 15.87°, 17.54°, 17.89°, 18.53°, 21.51°; DEX-RES: 2θ = 10.53°, 15.36°, 15.85°, 17.50°, 17.91°, 18.61°, 2...). The characteristic peaks corresponding to DEX (2θ = 12.56°, 13.64°, 14.57°, 15.10°, 16.22°, 17.84°), CAT (2θ = 10.09°, 16.36°, 20.12°), and RES (2θ = 16.88°, 18.22°, 19.29°, 20.08°, 20.40°) are not present, unlike the simulated PXRD. Figure 1 Notably, the resulting DEX-CAT and DEX-RES eutectics exhibit highly similar PXRD patterns with various shared characteristic diffraction peaks. For example, as... Figure 4 As indicated by the asterisk (*), a dense doublet is clearly observed in the 2θ range of approximately 15.4° to 15.9°, followed by another, weaker doublet at higher angles, i.e., 2θ = ~17.5° to ~17.9°. The presence of similar peaks at 2θ in PXRD suggests that DEX-CAT and DEX-RES share a very similar molecular scaffold for their isomorphic properties. Regarding solid-state stability, as... Figure 5 As shown in Table 1, under high humidity conditions (25°C / 75% relative humidity), the eutectics maintained their physicochemical stability for one month.

[0035] Table 1. Drug detection of DEX-hydroquinone eutectic system before and after storage at 25℃ / 75% relative humidity on days 0, 7 and 30.

[0036]

[0037]

[0038] Table 2 presents the thermal properties of the eutectic, where the DEX eutectic DEX-RES (133.8 °C) melts at a higher temperature compared to DEX-CAT (128.4 °C). This may reflect the slightly higher packing efficiency achieved through RES, leading to stronger interactions in DEX-RES at dynamic equilibrium. Figure 6 As shown, both eutectic states exhibit melting endotherm between that of DEX (273.2℃) and the eutectic (CAT: 104.9℃; RES: 109.3℃), ruling out the possibility of eutectic formation. The non-hygroscopic state of both eutectic states is supported by TGA data, such as... Figure 7 As shown, TGA data reveal a seemingly insignificant weight loss step prior to melting. Specifically, an unusual decrease in lattice strength is observed during co-crystallization. The molar enthalpy of fusion (ΔH) of DEX-CAT is also shown. f The sum of the molar enthalpies of melting of its individual components [ΔH] f(DEX) +ΔH f(CAT) Low to 60%, while DEX-RES' ΔH f Ratio ΔH f(DEX) +ΔH f(RES) Low to 70%. This is related to ΔH. f The vast majority of organic compounds that are located between or above their corresponding counterparts form a eutectic contrast.

[0039] Table 2. Melting temperature and heat of fusion of DEX, polyphenol co-formations and various DEX eutectic systems (n=3).

[0040]

[0041] In embodiments of the invention, metastable eutectics are synthesized via a single preparation method: mechanochemical milling. Efforts at co-crystallization through slow evaporation result in phase separation into individual components due to the inconsistent solubility of the eutectic formations in the solvent system. Attempts at rapid evaporation and melt crystallization preferentially form a mixture of amorphous phases. Due to its complex structure and molecular weight greater than 300 g / mol, DEX appears to possess high glass-forming ability, readily transforming into its amorphous state under kinetic conditions, especially when subjected to mechanical treatment, i.e., kinetic processes.

[0042] When eutectic synthesis is not achievable via solvent-mediated methods, solid-state cocrystallization, such as contact molding and milling, is useful for minimizing the complex effects of solubility and solvent competition. During milling, mechanical stress is applied to fracture the DEX crystals, promoting molecular diffusion across the crystal surface. Mechanochemical cocrystallization generates activation energies with low affinity between DEX and CAT / RES sufficient to overcome the kinetic barriers to transcendental eutectic synthesis. This self-assembly process in the solid phase is stabilized by a weak hydrogen-bonded network.

[0043] like Figure 8A and 8B As shown, the effect of grinding time on lattice strength was investigated. The DSC curve of the DEX eutectic obtained immediately after 3 minutes of grinding showed a glass transition temperature of approximately 75 °C (T0). g Following this, recrystallization and the melting of the recrystallized eutectic occurred. Further grinding for 10, 20, and 30 minutes continued to reveal the recrystallized eutectic, suggesting an equilibrium structure was reached within 3 minutes. Therefore, at temperatures far below T... g Co-milling of the binary mixture at room temperature kinetically traps DEX and hydroquinone molecules in a highly unstable, partially co-amorphous state, which then transforms into a eutectic state during storage via a moisture-promoted process. Eutectic formation during mechanically activated storage is known to be mediated by the amorphous phase and dependent on annealing conditions (i.e., temperature and humidity). Evaluation of DEX eutectic from supercooled melts at different annealing temperatures (30, 60, 80, and 100 °C) during DSC hot-cold-hot cycling indicates that energy input during hot annealing at 60 °C and 80 °C induces disordered molecular orientation to complete the recrystallization of DEX-CAT, resulting in the highest crystallinity and ΔH. f (kJ / mol) phase-pure DEX eutectic, such as Figure 9A As shown. Based on structural similarity, similar trends were observed in DEX-RES, such as... Figure 9B As shown. Annealing temperatures deviating from the optimal value have an inhibitory effect on phase transformation. When annealing occurs near room temperature (30°C)—below the sample's T... gAt temperatures above a certain point, a short-range disordered eutectic solid is formed in a high-energy state. Due to its more defective and less molecularly mobile state compared to its supercooled liquid counterpart, the recrystallization process is inhibited. This results in several melting endothermic peaks observed in the DEX-CAT DSC curve, while almost no complete peak of DEX-RES is detected, indicating that the eutectic phase is dominant. High annealing temperatures (100°C) close to the melting initiation point of DEX eutectic lead to similar results. To accelerate the phase transition at room temperature, the ground samples were equilibrated at 75% relative humidity using a saturated sodium chloride solution in a desiccator. Storage can lead to a phase transition from eutectic to eutectic. It is speculated that the hygroscopic eutectic undergoes a continuous phase in moisture-promoted co-crystallization, i.e., adsorbing moisture from the atmosphere and then locally reorganizing the adsorbate into a thermodynamically stable geometry. This is achievable due to the strong plasticizing effect of water, which lowers the temperature of the eutectic phase. g This increases the eutectic rate by improving molecular mobility and complementarity in the solid state. Successful transformation to a eutectic is only possible under optimal annealing conditions, such as elevated temperature and humidity that are typically mismatched with normal storage conditions.

[0044] The three-dimensional molecular structures and spatial arrangements of the two DEXs are shown in Rietveld refinement of their X-ray powder diffraction patterns. The crystals prepared by fine grinding are submicron in size and exhibit weak diffraction, making them unsuitable for single-crystal X-ray diffraction analysis. The crystal structures obtained from the Rietveld refinement of their corresponding PXRD data confirm that DEX-CAT and DEX-RES employ similar crystal packing, such as... Figure 10 As shown, the crystal stacking driving force is dominated by intermolecular hydrogen bonding. DEX-CAT and DEX-RES crystallize in the non-centrosymmetric monoclinic P21 space group. The asymmetric unit of DEX-CAT consists of one DEX molecule and one CAT molecule, while the asymmetric unit of DEX-RES consists of two pairs of crystallographically independent DEX and RES molecules. In a homogeneous DEX crystal structure, the compound crystallizes in the orthorhombic P212121 space group, with intramolecular hydrogen bonding in the α-hydroxy ketone group and intermolecular hydrogen bonding between the tertiary hydroxyl group and the cyclic ketone oxygen of the adjacent molecule, and between the secondary hydroxyl group and the alcohol oxygen of the adjacent α-keto alcohol. In addition to the intermolecular hydrogen bonding between the tertiary hydroxyl group and the cyclic ketone oxygen in the DEX molecule, the DEX-CAT and DEX-RES lattices are also stabilized by OH···O hydrogen bonding between the O5 atom on the hydroxyl group of the α-keto alcohol group (acceptor) in DEX and the phenolic hydroxyl group of CAT or RES (donor), forming OH···OH hybrid atoms with hydrogen bond lengths of [missing information]. and like Figure 11 and 12As shown. It was observed that both CAT and RES molecules simultaneously form homo- and hetero-homogeneous intermolecular hydrogen bonds, resulting in unique hydrogen-bonded interlayers between DEX molecules that block intermolecular interactions in the original DEX stack. This may allow for different drug properties (e.g., solubility and dissolution rate) relative to the parent DEX. Selected crystallographic data and structural refinement results are shown in Table 3 below.

[0045] Table 3. Selected crystallographic data and structure refinement results for DEX-CAT and DEX-RES.

[0046]

[0047] Figure 13 The FTIR spectra shown in Table 4 below reveal the OH stretching vibrations reflecting changes in the molecular environment during co-crystallization. DEX-CAT and DEX-RES exhibit these vibrations in the range of 3200 to 3700 cm⁻¹. -1 The new broad absorption peaks between these peaks are attributed to phenol OH stretching (DEX-CAT: 3466, 3201 cm⁻¹). -1 DEX-RES: 3470, 3260cm -1 The wavelength of phenol OH stretching ranges from 3472 cm⁻¹. -1 A decrease in (DEX) frequency to a lower frequency indicates that the OH group is involved in the intermolecular hydrogen bond network without proton transfer. For the original CAT, an intramolecular OH···O hydrogen bond is formed between the two hydroxyl groups in a six-membered ring, one acting as a hydrogen donor or bonding group (OH). b Another acts as an acceptor or free group (OH). f Intramolecular hydrogen bonds are relatively weaker than intermolecular hydrogen bonds. During mechanochemical co-crystallization, these bonds break to form an "open" structure; CAT in DEX co-crystallization exists only in the homodimer, where OH... b It bonds to another CAT molecule, and OH f A hydrogen atom is provided to form an intermolecular hydrogen bond with the oxygen atom O5 in the hydroxyl group of DEX. This is reflected in 3555 cm⁻¹. -1 The additional shoulder that appears is unrecognizable in the starting material, and at a lower frequency, namely 3201cm. -1 A new broadband band appears. DEX-RES exhibits vibrational characteristics similar to DEX-CAT. In inert solvents, the intramolecular hydrogen bonding of CAT is enhanced due to interactions with bases such as DEX. This enhancement is consistent with the more difficult-to-achieve intramolecular bond breaking, which may explain why solvent evaporation does not produce a phase-pure DEX-CAT eutectic.

[0048] Table 4. Key features in the FTIR spectra of DEX, polyphenol co-formations, and each DEX eutectic system.

[0049]

[0050] Due to its potential applications in various therapeutic areas, DEX has been formulated into a variety of dosage forms. In addition to the most common oral and topical routes of administration, the development of intranasal DEX dry powder has received increasing attention for the treatment of allergic rhinitis and neuroinflammation caused by Covid-19 via nasal-to-brain delivery, aiming to achieve rapid onset of action and reduce off-target side effects. However, rapid drug elimination via mucosal clearance and the low fluid volume available for dissolution pose significant challenges to delivering this poorly water-soluble drug into the human nasal cavity. Intranasal DEX sodium phosphate has shown good in vivo biodistribution and rapid onset of action compared to intravenous administration.

[0051] According to established intranasal dry powder formulation dissolution protocols, the solubility of finely milled DEX-CAT and DEX-RES in simulated nasal solution (SNF) at pH 5.5 is superior to that of pristine DEX and physical mixtures of DEX with various hydroquinones (DEX+CAT, DEX+RES). Micronized powders only allow for sufficient nasal deposition if the particle size falls within the 10 to 45 μm range. To ensure successful intranasal deposition and minimize the impact of particle size on the initial surface-specific dissolution rate, only a fraction of the pristine DEX and DEX cocrystals are screened to provide a particle size below 63 μm. Figures 14A to 14C At 120 minutes, the release of the DEX-CAT and DEX-RES eutectic in SNF was 2.4 times faster than that of the original DEX, as... Figure 15 As shown, the p-value for DEX versus DEX-CAT is 0.006, and the p-value for DEX versus DEX-RES is 0.004. These two cocrystals exhibit a 3-fold faster dissolution rate compared to the original DEX (p-value for DEX versus DEX-CAT = 0.085, p-value for DEX versus DEX-RES = 0.051), indicating that these cocrystals have the ability to improve the bioavailability of DEX via intranasal delivery. The intrinsic dissolution rate (IDR) is determined by the following formula: IDR = (dm / dt) 最大 / A, where (dm / dt) 最大 is the slope of the initial linear region of the cumulative dissolution curve until 10% of the drug is dissolved, and A is the specific surface area of ​​the dissolved sample. The volume size distribution of screened samples exhibiting similar particle morphology was evaluated using laser diffraction. D for all formulations 50The diameters range from 1.52 to 24.87 μm (Table 5). Therefore, the IDR ratio of DEX eutectic to DEX can be estimated by the ratio of slope to the spherical assumption, which is 76.86 (DEX-CAT) and 48.29 (DEX-RES), indicating that the dissolution rate of DEX eutectic in SNF is significantly faster than that of pristine DEX.

[0052] Table 5. Volume distribution of DEX and each DEX eutectic system as measured by laser diffraction (n=3).

[0053]

[0054] *DEX-CAT and DEX-RES are manufactured through precision grinding.

[0055] In addition to intranasal administration, the development of DEX cocrystal dry powder inhalers for targeted lung delivery may also benefit the relief of relapses and established chronic lung diseases, such as allergic asthma and chronic obstructive pulmonary disease. Particles with an aerodynamic diameter of 1 to 5 μm are considered effective for deep lung delivery (Malcolmson and Emblton, 1998). Commercially available excipient-based DPIs have reportedly produced 10–50% FPF at different flow rates (Demoly et al., 2014). In one embodiment, DEX cocrystal dry powder inhalers (DPIs) for lung delivery can be formed by spray drying, a well-established particle engineering technique used in the pharmaceutical industry. DEX cocrystal DPIs contain DEX and co-formed compounds (RES) in a 1:1 molar ratio, eliminating the need for excipients used in the development of inhalable formulations. Co-formed compounds are pharmaceutically recognized antiseptics and disinfectants used to treat various skin conditions and infections. NGI data show that the spray-dried eutectic formulation prepared under optimized processing parameters exhibits satisfactory aerosol performance at an inhalation flow rate of 90 L / min, with an MMAD of 2.96 ± 0.49 μm and an FPF of 35.43 ± 4.97% wt / wt, which is comparable to the performance of commercial products, as shown in Table 6 below. Figure 16 The paper presents NGI dispersion data for the spray-dried eutectic formulation, which shows that 30.26% of the aerosol powder is deposited in grades 3–6, with aerodynamic diameters ranging from 3.61 to 0.76 μm.

[0056] Table 6. Aerodynamic size distribution (MMAD, GSD, and FPF) of spray-dried DEX-RES formulations at a 1:1 molar ratio under selected processing parameters. Methanol was used as the model solvent.

[0057]

[0058] Materials and methods

[0059] method:

[0060] Material

[0061] DEX (≥99%) was obtained from Yick Vic Chemicals & Pharmaceuticals Limited (Hong Kong, China). Hydroquinone and pyrogallol co-formations: catechol (CAT), resorcinol (RES), hydroquinone (HYQ), pyrogallol (HXQ), pyrogallol (PHL), and pyrogallol (PYR) were purchased from Sigma-Aldrich (St. Louis, MO, USA) and Alfa Aesar (Ward Hill, MA, USA). Potassium bromide (KBr) used for FTIR analysis was obtained from J&K Scientific Co., Ltd., China. Sodium chloride (NaCl), potassium chloride (KCl), and calcium chloride (CaCl2) used to prepare nasal swabs were obtained from VWR BDH Chemicals (VWR International SAS, France). Analytical grade ethanol and methanol were obtained from VWR BDH Chemicals (VWR International SAS, France) and Merck KGaA (Darmstadt, Germany). The water is purified using the Thermolyne NANOpure Diamond Analytical ultrapure water system (Barnstead, Thermo Fisher Scientific, Waltham, MA, USA).

[0062] Preparation of DEX eutectic for nasal inhalation

[0063] The co-crystallization of DEX with hydroquinone (CAT, RES, and HYQ) and pyrogallol coforms (HXQ, PHL, and PYG) was examined using fine grinding, solution evaporation, and melt crystallization. For the fine grinding method, equimolar amounts (0.597 mmol) of DEX (234.3 mg) and hydroquinone (65.7 mg) were mixed and ground in a mortar and pestle at ambient temperature for approximately 15 minutes. Throughout the grinding process, the powder was frequently scraped from the mortar and pestle and remixed. Particle size variation was minimized by passing the sample through a standard test sieve (VWR International, New York, USA) with a diameter of 63 μm prior to solid-state characterization. For the solution evaporation method, equimolar amounts (0.597 mmol) of DEX (234.3 mg) and coforms (65.7 mg) were dissolved in a beaker containing 100 mL of ethanol and then sonicated until a homogeneous solution was obtained. The solution was sealed with a perforated sealing film to allow slow evaporation in a fume hood for 72 hours. The solvent was rapidly removed under vacuum using a rotary evaporator (Buchi, Germany), with the rotating flask immersed in a 60°C water bath at a rotation speed of 60 rpm. The product was dried in a 60°C oven for 3 hours to remove residual solvent and gently ground into a fine powder for further analysis. For the melt crystallization method, a 1:1 molar ratio physical mixture of DEX and co-formants was heated at 10°C / min using a differential scanning calorimeter until a melt was formed. The molten mixture was then cooled to the specified annealing temperature at a cooling rate of 10°C / min. The mixture was held at the annealing temperature until the crystallization process was complete, for a maximum of 24 hours. All obtained products were stored in sealed containers.

[0064] Preparation of spray-dried DEX eutectic powder for oral inhalation

[0065] The inhalable DEX cocrystal formulation for pulmonary delivery comprises an equimolar amount (0.597 mmol) of DEX (234.3 mg) and hydroquinone (65.7 mg) in a methanol solution, which is spray-dried using a Büchi B-290 spray dryer equipped with a standard two-fluid nozzle, a glass chamber, and a high-performance cyclone separator for collecting small particles (Büchi Labortechnik, Flawil, Switzerland). The spray dryer is equipped with a Buchi B-296 dehumidifier and a B-295 inert loop, with a nozzle tip diameter of 0.7 mm and nitrogen as the atomizing gas. The formulation is prepared according to the processing parameters listed in Table 6 above, with a fixed inhalation rate of 100% (approximately 35 m). 3 The output temperature is approximately 44°C ( / h).

[0066] Powder X-ray diffraction (PXRD) and crystal structure determination

[0067] The polycrystalline eutectic of DEX was characterized by X-ray diffraction. Measurements were performed on a Rigaku SmartLab 9kW diffractometer with a copper rotating anode (K alpha1). K alpha2 The X-ray was rated at 200 mA / 45 kV at room temperature with a step size of 0.02 degrees 2θ. A Bragg Brentano CBO incident X-ray optics system was used, with a 5.0-degree parallel Soller slit, a 1 / 2-degree incident slit, a 1.0 x 10.0 mm length-limiting slit, a 5.0-degree receiving parallel slit, a 1 / 2-degree first receiving slit, and a 0.3 mm second receiving slit. Diffraction signals were filtered using a Kβ nickel filter, and diffraction data were collected in one-dimensional mode using a HyPix-3000 detector.

[0068] Possible unit cell parameters were obtained using N-TREOR09 based on diffraction patterns. Unit cells with reasonable volumes were used for further analysis. Space group determination was performed by detecting the extinction group. The three-dimensional atomic coordinates of individual components CAT (Brown, C., Acta Crystallographica 1966, 21(1), 170-4), RES (Bacon, G. et al., Zeitschrift für Kristallographie-Crystalline Materials 1973, 138(1-6), 19-40) and DEX (Raynor et al., Acta Crystallogr.Sect.Sect.E:Struct.Rep.Online 2007, 63(6), o2791-3) were used as the initial model for the simulated annealing procedure in the EXPO2014 program suite. Ten simulated annealings were performed to achieve a consistent convergent structural model, resulting in ten structural schemes in each annealing. The structure with the lowest cost function was used for Rietveld refinement. All non-hydrogen atoms were isotropically refined. Geometric constraints were imposed on the DEX, CAT, and RES molecules based on the reported crystal structures of the individual compounds, but not on the α-hydroxy ketone group in DEX. Hydrogen atoms were included in idealized positions.

[0069] Thermal analysis

[0070] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves were generated using a TA DSC 250 differential scanning calorimeter (TA Instruments, Newcastle, DE, USA) and a TGA Q5000 thermogravimetric analyzer (TA Company, Newcastle, DE, USA), respectively. For DSC experiments, pure indium was used for routine calibration of enthalpy and cell constant. Accurately weighed samples (~3 mg) were encased in Tzero aluminum sealed pans (TA Instruments, Newcastle, DE, USA), with a cap featuring pinhole ventilation if desired, and heated from 50 °C to 300 °C at a scan rate of 10 °C / min. In TGA experiments, each sample (5–7 mg) was placed on an open pan and heated from 50 °C to 300 °C at a rate of 10 °C / min. Nitrogen was used as the purge gas in both DSC and TGA analyses at a rate of 20 mL / min. TA Trios software was used for data analysis.

[0071] Fourier transform infrared spectroscopy (FTIR)

[0072] Fourier transform infrared spectra were obtained using a Fourier transform spectrophotometer (Spectrum Two, PerkinElmer Instruments, USA) in KBr diffuse reflectance mode. Scans were performed at 4000 cm⁻¹. -1 up to 400cm -1 The range is measured, with intervals of 0.5cm. -1 A total of 32 scans were collected for each sample, with a resolution of 4 cm⁻¹. -1 .

[0073] Scanning electron microscope (SEM)

[0074] The particle morphology of the samples was observed using a field emission scanning electron microscope (Hitachi S-4800FEG, Hitachi, Tokyo, Japan). The powder was sprayed onto a carbon tape mounted on a SEM holder. Any sample not adhering to the tape was removed using compressed air. The powder was coated with a gold-palladium alloy of approximately 11 nm in two cycles (60 seconds each) using a sputtering coating machine (Bal-Tec SCD 005 sputtering coating machine, Bal-Tec GmbH, Schalksmühle, Germany) to create a conductive layer and avoid overheating.

[0075] High-performance liquid chromatography (HPLC)

[0076] The concentration of DEX was quantified by HPLC (Agilent 1200 series, Agilent Technologies, USA) equipped with a diode array detector and an Agilent Zorbax Eclipse Plus C18 column (5 μm, 250 mm × 4.6 mm) under isocratic conditions at 239 nm. The mobile phase consisted of a mixture of methanol and water (65:35, v / v). 30 μL aliquots of each sample solution were injected into the column at a flow rate of 1 mL / min. The retention time of DEX was found to be 8.3 min.

[0077] Particle size distribution measurement by laser diffraction

[0078] The particle size and size distribution of the powder were determined using a Mastersizer 3000 laser diffraction apparatus with an Aero S dry powder dispenser (Malvern Instruments Ltd, Worcestershire, UK). Prior to analysis, both the pristine DEX and DEX eutectic powders were screened to diameters less than 63 micrometers to control for particle size variation. The particle size distribution was calculated from the light scattering patterns using Mie theory. The particle size distribution was determined at 10% (D...) of the volume distribution. 10 ), 50% (D 50 ), 90% (D 90 The granularity at () was automatically calculated using Mastersizer 3000 software based on Fraunhofer theory. The span was calculated as (D) 90 -D 10 ) / D 50 All samples were measured in triplicate.

[0079] In vitro drug release studies for nasal delivery

[0080] 1.5 mg of raw DEX powder and an equimolar amount of screened DEX eutectic powder were separately poured into jacketed beakers containing 50 mL of simulated nasal solution (pH 5.5, 8.77 g NaCl, 2.98 g KCl, 0.59 g CaCl2, and distilled water to 1000 mL) and incubated at 37 ± 0.5 °C in an immersion state for 240 minutes. The solutions were stirred at 50 rpm on a magnetic stirrer. The dissolution medium and temperature were selected to simulate physiological conditions within the nasal cavity. 35,36 At specified time points of 5, 10, 15, 20, 30, 45, 60, 90, and 120 minutes, 1 mL of dissolution medium was withdrawn and replaced with an equal volume of fresh medium. The sample solution was filtered through a 0.45 μm nylon syringe filter, and the drug concentration was determined by HPLC. The intrinsic dissolution rate (IDR) was determined by the following formula: IDR = (dm / dt) 最大 / A, where (dm / dt)最大 is the slope of the initial linear region of the cumulative dissolution curve until 10% of the drug is dissolved, and A is the specific surface area of ​​the dissolved sample. The following assumptions were made: (i) spherical particles, (ii) constant particle size, and (iii) a constant number of particles during the initial stage of the dissolution experiment in the immersion state. Using these assumptions, particle size distribution data collected by laser diffraction were used to determine the particle surface area (SA). 颗粒 The total number of particles undergoing dissolution (n) is calculated by V. 体积 / V 颗粒 Calculate, where V 颗粒 V is the volume of each primary particle. 体积 This is the volume of the compound added to the dissolution medium. Therefore, the total surface area of ​​all particles added to the dissolution medium is expressed by nSA. 颗粒 Calculations are performed. Finally, the specific surface area (A, m²) can be obtained, defined as the total surface area of ​​the material per unit mass. 2 / g).

[0081] In vitro aerosol performance evaluation for lung delivery

[0082] The in vitro aerosol performance of spray-dried DEX-RES powder formulations was evaluated using a next-generation impactor (NGI, Copley, Nottingham, UK). A thin layer of silicone grease (Slipicone; DC Products, Waverley, VIC, Australia) coated on the impactor platform minimized particle bounce. Approximately 3 mg of spray-dried DEX-RES eutectic powder was loaded into No. 3 hydroxypropyl methylcellulose capsules (Capsugel, West Ryde, NSW, Australia), which were then subjected to... (Novartis, Hong Kong) Nebulization was performed at a flow rate of 90 L / min for 2.7 seconds. DEX and RES were rinsed with precise amounts of methanol at all stages. The solution was then filtered through a 0.45 μm nylon syringe filter and analyzed by HPLC. The recovered dose, fine particle fraction (FPF), median mass aerodynamic diameter (MMAD), and geometric standard deviation (GSD) were calculated. FPF is the mass fraction of particles <5 μm relative to the recovered dose. The recovered dose was defined as the sum of the powder masses detected on all components.

[0083] Stability Study

[0084] Raw DEX powder and DEX cocrystal powder were stored at 25°C / 75% relative humidity for one month. Samples were collected before and after storage for PXRD analysis. Drug determination of the DEX-hydroquinone cocrystal system at days 0, 7, and 30 after storage was performed by HPLC at 25°C / 75% relative humidity.

[0085] Statistical analysis

[0086] A two-sample t-test was used for data analysis. A p-value less than 0.05 was considered statistically significant.

[0087] All publications mentioned or referenced herein, including all accompanying drawings and tables, are incorporated in their entirety by reference, without departing from the explicit teachings of this specification. It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and various modifications or variations based on these embodiments and implementations are to be suggested to those skilled in the art and will be included within the spirit and scope of this application and the appended claims. Furthermore, any element or limitation of any invention or implementation thereof disclosed herein may be combined with any and / or all other elements or limitations disclosed herein (alone or in any combination) or any other invention or implementation thereof, and all such combinations are conceived within the scope of this invention and are not limited thereto.

[0088] References

[0089] Wong et al., SN; Chen, YCS; Xuan, B.; Sun, CC; Chow, SF

[0090] Sun,CC,Cocrystallization for successful drug delivery.Expertopinion on drug delivery 2013,10(2),201-213.

[0091] Chow, SF; Shi, L.; Ng, WW; Leung, KHY; Nagapudi, K.; Sun, CC; Chow, AH, Kinetic entrapment of a hidden curcumin cocrystal with phloroglucinol. Crystalgrowth&design 2014, 14(10), 5079-5089.

[0092] Hasa,D.;Jones,W.,Screening for new pharmaceutical solid forms usingmechanochemistry:A practical guide.Advanced drug delivery reviews 2017,117,147-161.

[0093] Loya,J.D.;Li,S.J.;Unruh,D.K.;Hutchins,K.M.,Mechanochemistry as a ToolforCrystallizing Inaccessible Solids from Viscous Liquid Components.CrystalGrowth&Design2021.

[0094] Trask,A.V.;van de Streek,J.;Motherwell,W.S.;Jones,W.,Achievingpolymorphicand stoichiometric diversity in cocrystal formation:Importance ofsolid-state grinding,powderX-ray structure determination,and seeding.Crystalgrowth&design 2005,5(6),2233-2241.

[0095] am Ende,D.J.;Anderson,S.R.;Salan,J.S.,Development and scale-up ofcocrystalsusing resonant acoustic mixing.Organic Process Research&Development2014,18(2),331-341.

[0096] Boldyreva,E.,Mechanochemistry of inorganic and organic systems:whatis similar,what is different?Chem.Soc.Rev.2013,42(18),7719-7738.

[0097] T.;Jones,W.,Application of mechanochemistry in the synthesisand discoveryof new pharmaceutical forms:co-crystals,salts and coordinationcompounds.In PharmaceuticalSalts and Co-crystals,2011;pp 154-187.

[0098] Friscic,T.;Jones,W.,Recent advances in understanding the mechanism ofcocrystalformation via grinding.Cryst.Growth Des.2009,9(3),1621-1637.

[0099] Lien Nguyen,K.; T.;Day,G.M.;Gladden,L.F.;Jones,W.,Terahertztime-domain spectroscopy and the quantitative monitoring of mechanochemicalcocrystalformation.Nature Materials 2007,6(3),206-209.

[0100] Jayasankar,A.;Somwangthanaroj,A.;Shao,Z.J.;Rodríguez-Hornedo,N.,Cocrystalformation during cogrinding and storage is mediated by amorphousphase.Pharm.Res.2006,23(10),2381-2392.

[0101] Willart,J.;Descamps,M.,Solid state amorphization of pharmaceuticals.MolecularPharmaceutics 2008,5(6),905-920.

[0102] Descamps,M.;Willart,J.,Perspectives on the amorphisation / millingrelationship inpharmaceutical materials.Advanced Drug Delivery Reviews 2016,100,51-66.

[0103] MERCK&CO.,I. package insert.https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2004 / 11664slr062_decadron_lbl.pdf.

[0104] Ledford,H.,Coronavirus breakthrough:dexamethasone is first drug shownto save lives.Nature 2020,582(7813),469-470.

[0105] Group,T.R.C.,Dexamethasone in hospitalized patients with Covid-19—preliminaryreport.The New England journal of medicine 2020.

[0106] Corticosteroids for COVID-19:living guidance,2 September 2020;WorldHealthOrganization:2020.

[0107] National Center for Biotechnology Information.PubChem CompoundDatabase.CID 5743.https: / / pubchem.ncbi.nlm.nih.gov / compound / 5743.

[0108] Allen,F.H.;Motherwell,W.D.S.;Raithby,P.R.;Shields,G.P.;Taylor,R.,Systematic analysis of the probabilities of formation of bimolecularhydrogen-bonded ringmotifs in organic crystal structures.New J.Chem.1999,23(1),25-34.

[0109] Desiraju,G.R.,Supramolecular synthons in crystal engineering—a neworganicsynthesis.Angewandte Chemie International Edition in English 1995,34(21),2311-2327.

[0110] Wang,J.-R.;Yu,Q.;Dai,W.;Mei,X.,Drug–drug co-crystallization presentsa newopportunity for the development of stable vitamins.Chem.Commun.2016,52(17),3572-3575.

[0111] Cambridge Crystallographic Data Center.Cambridge,U.K.www.ccdc.cam.ac.uk.

[0112] Goud,N.R.;Babu,N.J.;Nangia,A.,Sulfonamide-Pyridine-N-oxideCocrystals.Crystal growth&design 2011,11(5),1930-1939.

[0113] Wong,S.N.;Hu,S.;Ng,W.W.;Xu,X.;Lai,K.L.;Lee,W.Y.T.;Chow,A.H.L.;Sun,C.C.;Chow,S.F.,Cocrystallization of curcumin with benzenediolsandbenzenetriols via rapid solvent removal.Crystal Growth&Design 2018,18(9),5534-5546.

[0114] Durairaj,R.B.,Resorcinol:chemistry,technology andapplications.Springer Science&Business Media:2005.

[0115] Altomare,A.;Giacovazzo,C.;Guagliardi,A.;Moliterni,A.G.;Rizzi,R.;Werner,P.-E.,New techniques for indexing:N-TREOR inEXPO.J.Appl.Crystallogr.2000,33(4),1180-1186.

[0116] Brown,C.,The crystal structure of catechol.Acta Crystallographica1966,21(1),170-174.

[0117] Bacon,G.;Jude,R.,Neutron-diffraction studies of salicylic acid andαresorcinol.Zeitschrift für Kristallographie-Crystalline Materials 1973,138(1-6),19-40.

[0118] Raynor,J.W.;Minor,W.;Chruszcz,M.,Dexamethasone at 119 K.ActaCrystallogr.Sect.Sect.E:Struct.Rep.Online 2007,63(6),o2791-o2793.

[0119] A. Altomare, CC, C. Giacovazzo, A. Moliterni, R. Rizzi, N. Corriero and A. Falcicchio, EXPO2014. J. Appl. Cryst. 2013, (46), 1231-1235.

[0120] Kürti, L.;Gáspár, R.;Márki, Kápolna, E.;Bocsik, A.;Veszelka, S.;Bartos, C.;Ambrus, R.;Vastag, M.;Deli, M.A., In vitro and in vivo characterization of meloxicam nanoparticles designed for nasal administration. European Journal of Pharmaceutical Sciences 2013, 50(1), 86-92.

[0121] Mohamad,SA;Badawi,AM;Mansour,HF,Insulin fast-dissolving filmfor intranasal delivery via olfactory region,a promising approach for thetreatment of anosmia inCOVID-19 patients:Design,in-vitro characterization andclinical evaluation.Int.J.Pharm.2021,601,120600.

[0122] Bartos, C.;Pallagi, E.;Szabó-Révész, P.;Ambrus, R.;Katona, G.;Kiss, T.;Rahimi, M.;Csóka, I.,Formulation of levodopa containing dry powder for nasal delivery applying the quality-by-design approach. European Journal of Pharmaceutical Sciences 2018, 123, 475-483.

[0123] Jug,M.;Hafner,A.; J.;Kregar,M.L.; I.; B.; J.,An overview of in vitro dissolution / release methodsfornovel mucosal drug delivery systems.J.Pharm.Biomed.Anal.2018,147,350-366.

[0124] Jug,M.;Hafner,A.; J.;Lusina Kregar,M.; I.; B.; J.,In vitro dissolution / release methods formucosal deliverysystems.ADMET and DMPK 2017,5(3),173-182.

[0125] Nayak,A.;Pedireddi,V.,Rational analysis of melting point behavior ofco-crystals of4-nitrophenol with some aza-compounds.Crystal Growth&Design2016,16(10),5966-5975.

[0126] Berman,P.;Meiri,N.;Colnago,L.A.;Moraes,T.B.;Linder,C.;Levi,O.;Parmet,Y.;Saunders,M.;Wiesman,Z.,Study of liquid-phase molecular packinginteractionsand morphology of fatty acid methyl esters(biodiesel).Biotechnology for Biofuels 2015,8(1),1-16.

[0127] Boese,R.;Kirchner,M.T.;Dunitz,J.D.;Filippini,G.;Gavezzotti,A.,Solid-StateBehaviour of the Dichlorobenzenes:Actual,Semi-Virtual and VirtualCrystallography.Helv.Chim.Acta 2001,84(6),1561-1577.

[0128] Wang,F.-Y.;Zhang,Q.;Zhang,Z.;Gong,X.;Wang,J.-R.;Mei,X.,Solid-statecharacterization and solubility enhancement of apremilast drug–drugcocrystals.CrystEngComm2018,20(39),5945-5948.

[0129] Weng,J.;Wong,S.N.;Xu,X.;Xuan,B.;Wang,C.;Chen,R.;Sun,C.C.;Lakerveld,R.;Kwok,P.C.L.;Chow,S.F.,Cocrystal engineering of itraconazole withsubericacid via rotary evaporation and spray drying.Crystal Growth&Design2019,19(5),2736-2745.

[0130] Xuan,B.;Wong,S.N.;Zhang,Y.;Weng,J.;Tong,H.H.;Wang,C.;Sun,C.C.;Chow,S.F.,Extended release of highly water-soluble isoniazid attainedthroughcocrystallization with curcumin.Crystal Growth&Design 2020,20(3),1951-1960.

[0131] Alhalaweh,A.;Alzghoul,A.;Kaialy,W.;Mahlin,D.; C.A.,Computationalpredictions of glass-forming ability and crystallizationtendency of drug molecules.Molecularpharmaceutics 2014,11(9),3123-3132.

[0132] Baird,J.A.;Van Eerdenbrugh,B.;Taylor,L.S.,A classification system toassess thecrystallization tendency of organic molecules from undercooledmelts.J.Pharm.Sci.2010,99(9),3787-3806.

[0133] Mahlin,D.; C.A.,Early drug development predictions of glass-formingability and physical stability of drugs.European Journal ofPharmaceutical Sciences 2013,49(2),323-332.

[0134] Chattoraj,S.;Bhugra,C.;Telang,C.;Zhong,L.;Wang,Z.;Sun,C.C.,Originoftwo modes of non-isothermal crystallization of glasses produced bymilling.Pharm.Res.2012,29(4),1020-1032.

[0135] Mithu,M.S.H.;Ross,S.A.;Hurt,A.P.;Douroumis,D.,Effect ofmechanochemicalgrinding conditions on the formation of pharmaceuticalcocrystals and co-amorphous solid formsof ketoconazole–Dicarboxylicacid.Journal of Drug Delivery Science and Technology 2021,63,102508.

[0136] Hu,Y.;Gniado,K.;Erxleben,A.;McArdle,P.,Mechanochemical reactionofsulfathiazole with carboxylic acids:Formation of a cocrystal,a salt,andcoamorphous solids.Crystal growth&design 2014,14(2),803-813.

[0137] Haneef,J.;Chadha,R.,Drug-drug multicomponent solid forms:cocrystal,coamorphousand eutectic of three poorly soluble antihypertensive drugs usingmechanochemical approach.AAPS PharmSciTech 2017,18(6),2279-2290.

[0138] Aljohani,M.;MacFhionnghaile,P.;McArdle,P.;Erxleben,A.,Investigationof theformation of drug-drug cocrystals and coamorphous systems of theantidiabetic drug gliclazide.Int.J.Pharm.2019,561,35-42.

[0139] Jayasankar,A.;Good,D.J.;Rodríguez-Hornedo,N.,Mechanisms by whichmoisturegenerates cocrystals.Molecular pharmaceutics 2007,4(3),360-372.

[0140] Wong,S.N.;Chan,S.W.S.;Peng,X.;Xuan,B.;Lee,H.W.;Tong,H.H.;Chow,S.F.,Effects of the Glass-Forming Ability and Annealing ConditionsonCocrystallization Behaviors via Rapid Solvent Removal:A Case Study ofVoriconazole.Pharmaceutics 2020,12(12),1209.

[0141] Pekar,K.B.;Lefton,J.B.;McConville,C.A.;Burleson,J.;Sethio,D.;Kraka,E.;Runcevski,T.,Mechanosynthesis of a Coamorphous Formulation of Creatinewith CitricAcid and Humidity-Mediated Transformation into a Cocrystal.CrystalGrowth&Design 2021,21(2),1297-1306.

[0142] Wu,W.;Wang,Y.; K.;Grohganz,H.;Rades,T.,TransformationsbetweenCo-Amorphous and Co-Crystal Systems and Their Influence on theFormation and PhysicalStability of Co-Amorphous Systems.Molecularpharmaceutics 2019,16(3),1294-1304.

[0143] Seefeldt,K.;Miller,J.;Alvarez-Nunez,F.;Rodríguez-Hornedo,N.,Crystallizationpathways and kinetics of carbamazepine–nicotinamide cocrystalsfrom the amorphous state by insitu thermomicroscopy,spectroscopy,andcalorimetry studies.J.Pharm.Sci.2007,96(5),1147-1158.

[0144] Kjaergaard,H.G.;Howard,D.L.;Schofield,D.P.;Robinson,T.W.;Ishiuchi,S.-i.;Fujii,M.,OH-and CH-stretching overtone spectra of catechol.The Journal ofPhysicalChemistry A 2002,106(2),258-266.

[0145] Grieco,C.;Hanes,A.T.;Blancafort,L.;Kohler,B.,Effects of intra-andintermolecular hydrogen bonding on O–H bond photodissociation pathways ofa catecholderivative.The Journal of Physical Chemistry A 2019,123(25),5356-5366.

[0146] Varfolomeev,M.A.;Abaidullina,D.I.;Gainutdinova,A.Z.;Solomonov,B.N.,FTIR study of H-bonds cooperativity in complexes of 1,2-dihydroxybenzene withprotonacceptors in aprotic solvents:Influence of the intramolecular hydrogenbond.SpectrochimicaActa Part A:Molecular and Biomolecular Spectroscopy 2010,77(5),965-972.

[0147] Nodilo,L.;Ugrina,I.; D.; D.; Brala,C.; M.; I.; J.; V.; M.,A Dry PowderPlatformfor Nose-to-Brain Delivery of Dexamethasone:Formulation Development andNasalDeposition Studies.Pharmaceutics 2021,13(6),795.

[0148] Pérez-Osorio,I.N.;Espinosa,A.;Velázquez,M.G.;Padilla,P.;Bárcena,B.;Fragoso,G.;Jung-Cook,H.;Besedovsky,H.;Meneses,G.;Conde,E.L.S.,Nose-to-braindelivery of dexamethasone:biodistribution studies inmice.J.Pharmacol.Exp.Ther.2021,378(3),244-250.

[0149] Johnson,RM;Vinetz,JM,Dexamethasone in the management of covid-19.British Medical Journal Publishing Group:2020:Vol.

[0150] Schipper,NG;Verhoef,J.Merkus,FW,The nasal mucociliary clearance:relevance to nasal drug delivery.Pharm.Res.1991,8(7),807-814.

[0151] Forbes,B.; Drug Delivery 2020, 17(2), 127-132.

[0152] Fasiolo,LT;Manniello,MDTratta,E.Buttini,F.Rossi,A.Sonvico,F.Bortolotti,F.Russo,P.Colombo,G.,Opportunity and challenges of nasalpowders:Drug formulation and delivery.European Journal of PharmaceuticalSciences 2018,113,2-17.

[0153] Noyes,AA;Whitney,WR,The rate of solution of solid substances in their ownsolutions.Journal of the American Chemical Society 1897,19(12),930-934.

[0154] Demoly,P.,Hagedoorn,P.,de Boer,A.H.,Frijlink,H.W.,2014.The clinicalrelevance ofdry powder inhaler performance for drug delivery.Respiratorymedicine 108,1195-1203.

[0155] Malcolmson,R.J.,Embleton,J.K.,1998.Dry powder formulations for pulmonarydelivery.Pharmaceutical Science&Technology Today 1,394-398.

Claims

1. A dexamethasone eutectic comprising dexamethasone and at least one co-formulation, wherein, The co-formed product contains multiple hydrogen-bonded functional groups; in: The co-formulated product is catechol or resorcinol; The molar ratio of dexamethasone to co-formulation is 1:1; The PXRD pattern of the eutectic formed by dexamethasone and catechol showed the following diffraction peaks: 2θ = 10.56°, 14.12°, 15.34°, 15.87°, 17.54°, 17.89°, 18.53°, 21.51°; The PXRD pattern of the eutectic formed by dexamethasone and resorcinol showed the following diffraction peaks: 2θ = 10.53°, 15.36°, 15.85°, 17.50°, 17.91°, 18.61°, 21.51°.

2. The eutectic according to claim 1, wherein, The eutectic is a polycrystalline free-flowing powder with micron-sized particles.

3. A method for preparing a eutectic of dexamethasone and co-formations, comprising: Provide a mixture of dexamethasone and at least one hydroquinone; and Mechanochemical treatment of the mixture to form the eutectic; in: The hydroquinone is catechol or resorcinol; In the mixture, the molar ratio of dexamethasone to hydroquinone is 1:1; The PXRD pattern of the eutectic formed by dexamethasone and catechol showed the following diffraction peaks: 2θ = 10.56°, 14.12°, 15.34°, 15.87°, 17.54°, 17.89°, 18.53°, 21.51°; The PXRD pattern of the eutectic formed by dexamethasone and resorcinol showed the following diffraction peaks: 2θ = 10.53°, 15.36°, 15.85°, 17.50°, 17.91°, 18.61°, 21.51°.

4. The method according to claim 3, wherein, The mechanochemical treatment includes grinding the mixture.

5. The method according to claim 3, further comprising heat-annealed dexamethasone-hydroquinone eutectic.

6. The method according to claim 5, wherein, The heat annealing is performed in a temperature range of 30°C to 100°C.

7. The method according to claim 5, wherein, The heat annealing is performed in a temperature range of 60°C to 80°C.

8. The method of claim 3, further comprising exposing the eutectic to moisture.

9. The method according to claim 5, wherein, The heat annealing was carried out at 25°C and a relative humidity of 75%.

10. The method of claim 3, further comprising screening the eutectic to produce particles with a size in the range of 10-45 micrometers.

11. A drug comprising a cocrystal of dexamethasone and hydroquinone in a 1:1 molar ratio of dexamethasone to hydroquinone; in: The hydroquinone is catechol or resorcinol; The PXRD pattern of the eutectic formed by dexamethasone and catechol showed the following diffraction peaks: 2θ = 10.56°, 14.12°, 15.34°, 15.87°, 17.54°, 17.89°, 18.53°, 21.51°; The PXRD pattern of the eutectic formed by dexamethasone and resorcinol showed the following diffraction peaks: 2θ = 10.53°, 15.36°, 15.85°, 17.50°, 17.91°, 18.61°, 21.51°.

12. The medicament according to claim 11, wherein, The drug is a preparation for intranasal administration.

13. The medicament according to claim 11, wherein, The drug is a formulation for inhalation and administration to the lungs.

14. The medicament according to claim 11, wherein, The drug contains at least one component used to treat at least one of the following: allergies, asthma, rhinitis, cancer, diabetes, anemia, ulcers, and viral infections.

Images