Crystalline form of a voxel rotor, and method of manufacturing the same

Abstract

The present application relates to a crystalline form of a voxel-rotor salt, a crystalline form of a solvate of said compound, a method for preparing said crystalline form, and a pharmaceutical composition containing said crystalline form.

Description

Technology Field

[0001] The present invention relates to a crystalline form of a voxel rotor, a method for manufacturing the same, and a pharmaceutical composition containing said crystalline form. Background Technology

[0002] The voxeloteur has the IUPAC name 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazole-5-yl)pyridine-3-yl)methoxy)benzaldehyde or 2-hydroxy-6-[[2-(2-propane-2-ylpyrazole-3-yl)pyridine-3-yl]methoxy]benzaldehyde and has the chemical structure exemplified below:

[0003]

[0004] EP2797416B and EP3141542A (Licensed to Global Blood Therapeutics) describe the voxel rotor and its manufacture.

[0005] In Europe, orphan designation has been approved for voxeloteur for the treatment of sickle cell disease.

[0006] Information regarding the solid-state properties of drug substances is important. For example, different forms may have different solubility. Furthermore, the handling and stability of drug substances may vary depending on the solid form.

[0007] Polymorphism can be defined as the ability of a compound to crystallize into more than one distinct crystalline species, and different crystal arrangements of the same chemical composition are called polymorphs. Polymorphs of the same compound arise from differences in the internal arrangement of atoms and differ in free energy, resulting in different physical properties such as solubility, chemical stability, melting point, density, flow characteristics, hygroscopicity, and bioavailability. Compound voxels may exist in multiple polymorphic forms, many of which may not be desirable for producing pharmaceutically acceptable compositions. This may be due to various reasons, including a lack of stability, high hygroscopicity, low water solubility, and difficulty in handling.

[0008] definition

[0009] The term "approximately" or "roughly" means an acceptable error for a specific value as determined by a person skilled in the art, which depends in part on how the value is measured or determined. In a given embodiment, the term "approximately" or "roughly" means within 1, 2, 3, or 4 times the standard deviation. In a given embodiment, the term "approximately" or "roughly" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In a given embodiment, and with reference to the X-ray powder diffraction 2-θ peak, the term "approximately" or "roughly" means within ± 0.2° 2θ.

[0010] The term "ambient temperature" means one or more room temperatures between about 15°C and about 30°C, for example, between about 15°C and about 25°C.

[0011] The term "anti-solvent" refers to a first solvent that is added to a second solvent to reduce the solubility of a compound within the second solvent. The solubility can be reduced sufficiently from the combination of the first solvent and the second solvent for precipitation of the compound to occur.

[0012] The term "consisting of" is closed and excludes additional uncited elements or method steps in the claimed invention.

[0013] The term "essentially consisting of" is semi-closed and occupies an intermediate position between "consisting of" and "comprising." "Essentially consisting of" does not exclude additional uncited elements or method steps that do not substantially affect the essential characteristics(s) of the claimed invention.

[0014] The term “comprising” is inclusive and open-ended and does not exclude additional uncited elements or method steps in the claimed invention. This term is synonymous with “comprising but not limited thereto.” The term “comprising” includes three alternatives: (i) “comprising,” (ii) “consisting of,” and (iii) “essentially consisting of.”

[0015] The terms “crystalline” and related terms as used herein mean that, when used to describe a compound, substance, modifier, material, component, or product, said compound, substance, modifier, material, component, or product is substantially crystalline when determined by X-ray diffraction, unless otherwise specified. For example, see the literature [Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005)]; and the literature [The United States Pharmacopeia, 23rd ed., 1843-1844 (1995)].

[0016] The term "molecular complex" is used to refer to a crystalline material composed of two or more different components having a defined single-phase crystal structure. The components are held together by non-covalent bonds such as hydrogen bonds, ionic bonds, van der Waals interactions, and pi-pi interactions. The term "molecular complex" includes salts, cocrystals, and salt / cocrystal hybrids.

[0017] In one embodiment, the molecular complex is a co-crystal. Without being bound by theory, when the molecular complex is a co-crystal, the co-crystal is believed to exhibit improved physicochemical properties, such as crystallinity, solubility properties, and / or a modified melting point.

[0018] In this specification, the terms “polymorph,” “polymorphic form,” or related terms refer to a crystal form of one or more molecules of a voxel-rotor or a complex of these voxel-rotor molecules that may exist in two or more forms as a result of different arrangements or stereomorphisms of molecule(s) within the crystal lattice of the polymorph.

[0019] The term “pharmaceutical composition” is intended to include a pharmaceutically effective amount of the voxelrotor of the present invention and pharmaceutically acceptable excipients. As used herein, the term “pharmaceutical composition” includes pharmaceutical compositions such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injectable formulations.

[0020] The term "excipient" refers to a pharmaceutically acceptable organic or inorganic carrier material. Excipients may be natural or synthetic materials formulated with the active ingredient of a drug, included for bulking-up formulations containing a potent active ingredient (hence often referred to as "bulking agents," "fillers," or "diluents"), or to impart therapeutic enhancements to the active ingredient within the final dosage form, such as by promoting drug absorption or solubility. In addition to contributing to in vitro stability, such as preventing denaturation over the expected shelf life, excipients may also be useful in the manufacturing process to aid in the handling of the active ingredient, for example, by promoting powder fluidity or non-stick properties.

[0021] The term "patient" refers to an animal, preferably a patient, most preferably a human being that is the subject of treatment, observation, or experiment. Preferably, the patient has experienced and / or has experienced or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. Additionally, the patient may not have exhibited any symptoms of the disorder, disease, or condition to be treated and / or prevented, but has been considered by a physician, clinician, or other medical professional to be at risk of developing said disorder, disease, or condition.

[0022] The term "solvent" refers to a combination or aggregate formed by one or more molecules of a solute, e.g., a voxel, and one or more molecules of a solvent. One or more molecules of the solvent may be present in stoichiometric or non-stoichiometric amounts relative to one or more molecules of the solute.

[0023] The terms “treat,” “treating,” and “treatment” refer to the eradication or improvement of a disease or disorder, or one or more symptoms associated with a disease or disorder. In certain embodiments, the terms refer to minimizing the spread or exacerbation of a disease or disorder by administering one or more therapeutic agents to a patient having such disease or disorder. In some embodiments, the terms refer to administering the molecular complex provided herein, with or without other additional activators, after the onset of symptoms of the disease.

[0024] The term "one night" refers to the period between the end of one workday and the subsequent workday, indicating that a time frame of about 12 to about 18 hours has elapsed between the end of one procedure step and the start of the next procedure step. Brief explanation of the drawing

[0025] Certain aspects of the embodiments described in this specification may be more clearly understood by referring to the drawings, which are intended to illustrate, not limit, the invention. Figure 1 is a representative XRPD pattern of voxel-rotor hemipropylene glycol solvate. Figure 2 shows representative TGA thermograms and DSC thermograms of voxel-rotor hemipropylene glycol solvate. Figure 3 is a representative XRPD pattern of a voxel-hemi fumaric acid molecular complex. Figure 4 is a representative TGA temperature record and DSC temperature record of a voxel-rotor hemi-fumaric acid molecular complex. Figure 5 is a representative XRPD pattern of a voxel-hemisuccinic acid molecular complex. Figure 6 is a representative TGA temperature record and DSC temperature record of a voxel-rotor hemisuccinic acid molecular complex. Figure 7 is a speed mixer TMThis illustrates the method by which centrifugal force is applied to particles in a speedmixer. FIG. 7A is a top view illustrating the base plate and basket. The base plate rotates clockwise. Figure 7B is a side view of the base plate and basket. Fig. 7C is a top view along line A of Fig. 7B. The basket rotates counterclockwise. Specific details for implementing the invention

[0026] Voxelothor hemipropylene glycol solvate

[0027] It has been found that the voxeltor can be prepared in a well-defined and consistently reproducible form of propylene glycol solvate. Furthermore, a reliable and scalable method for producing this solvate form has been developed. The voxeltor polymorphs provided by the present invention may be useful as active ingredients in pharmaceutical formulations. In a specific embodiment, the crystalline solvate form is purifiable. In a specific embodiment, and depending on time, temperature, and humidity, the crystalline solvate form is stable. In a specific embodiment, the crystalline solvate form is easy to separate and handle. In a specific embodiment, the method for preparing the crystalline solvate form is scalable.

[0028] The crystalline forms described herein may be characterized using a number of methods known to those skilled in the art, including single-crystal X-ray diffraction, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy (including solution and solid-phase NMR). Chemical purity may be determined by standard analytical methods, such as thin-layer chromatography (TLC), gas chromatography, high-performance liquid chromatography (HPLC), and mass spectrometry (MS).

[0029] In one aspect, the present invention provides a crystalline form of a voxel, which is a crystalline voxel, a hemipropylene glycol solvate.

[0030] The molar ratio of voxelto to propylene glycol may be in the range of about 1 mole of voxelto : about 0.3 to about 1 mole of propylene glycol, for example, about 1 mole of voxelto : about 0.4 to about 0.7 moles of propylene glycol. In one embodiment, the molar ratio of voxelto to propylene glycol may be about 1 mole of voxelto : about 0.5 moles of propylene glycol.

[0031] Hemipropylene glycol solvate comprises one or more peaks selected from the group consisting of approximately 8.6, 8.8, 11.3, 12.6, 12.9, 14.5, 15.0, 15.5, 15.6, 16.0, 16.8, 17.1, 17.7, 18.0, 18.6, 19.1, 19.7, 20.2, 20.9, 22.8, 23.1, 23.7, 24.2, 25.1, 25.4, 25.9, 26.7, 27.2, 28.8, 30.3, 31.6, and 32.4 degrees 2-theta ± 0.2 degrees 2-theta (e.g., 1, 2, 3, 4, 5, It may have an X-ray powder diffraction pattern including 6, 7, 8, 9, or 10 peaks. In one embodiment, the solvate may substantially have an X-ray powder diffraction pattern as shown in FIG. 1.

[0032] The hemipropylene glycol solvate may have a DSC temperature record including an endothermic event having an onset temperature of about 92.0°C. In one embodiment, the solvate may have a DSC temperature record substantially as shown in FIG. 2.

[0033] The hemipropylene glycol solvate may have a TGA temperature history including a mass loss of about 10.2% when heated from approximately ambient temperature to about 200°C. In one embodiment, the solvate may have a TGA temperature history substantially as shown in FIG. 2.

[0034] The formed crystalline voxel-rotor hemipropylene glycol solvate may not have other polymorphic forms of the voxel-rotor or may not have them substantially. In a specified embodiment, the polymorphic purity of the solvate is 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, or higher. In a specified embodiment, the polymorphic purity of the solvate is 95% or more. In a specified embodiment, the polymorphic purity of the solvate is 96% or more. In a specified embodiment, the polymorphic purity of the solvate is 97% or more. In a specified embodiment, the polymorphic purity of the solvate is 98% or more. In a specified embodiment, the polymorphic purity of the solvate is 99% or more.

[0035] The crystalline voxel-rotor hemipropylene glycol solvate described above can be produced by a process comprising the step of reacting voxel-rotor with propylene glycol using low-energy ball milling or low-energy grinding.

[0036] Propylene glycol is present in an amount sufficient to form the desired solvate. The amount of propylene glycol is not particularly limited as long as there is enough propylene glycol to dissolve the voxeltor to form a solution, suspend the voxeltor, or wet the voxeltor. In one embodiment, the w / v ratio of voxeltor to propylene glycol may be in the range of about 1 mg of voxeltor : about 0.01 to about 1.5 μl of propylene glycol, e.g., about 1 mg of voxeltor : about 0.05 to about 1.0 μl of propylene glycol, e.g., about 1 mg of voxeltor : about 0.1 to about 0.75 μl of propylene glycol, e.g., about 1 mg of voxeltor : about 0.5 μl of propylene glycol.

[0037] When low-energy ball milling is used, the milling process can be controlled by various parameters including the milling speed, the length of the milling time, and / or the level at which the milling vessel is filled.

[0038] The milling speed may be approximately 50 rpm to approximately 1000 rpm. In one embodiment, the speed may be approximately 75 rpm to approximately 750 rpm. In another embodiment, the speed may be approximately 80 rpm to approximately 650 rpm. In one embodiment, the speed may be approximately 500 rpm.

[0039] Low-energy grinding involves shaking the material within a grinding vessel. Grinding occurs through impact and friction of the material within the vessel. This process can be controlled by various parameters, including the frequency at which grinding occurs, the length of the grinding time, and / or the level at which the vessel is filled.

[0040] The frequency at which grinding occurs may be about 1 Hz to about 100 Hz. In one embodiment, the frequency may be about 10 Hz to about 70 Hz. In another embodiment, the frequency may be about 20 Hz to about 50 Hz. In one embodiment, the frequency may be about 30 Hz.

[0041] Regardless of whether milling or grinding is used, a milling or grinding medium may be used to aid the reaction. In such cases, the incorporation of a hard, non-contaminating medium can further aid in the decomposition of particles that have aggregated, for example, as a result of the manufacturing process or during transport. Such decomposition of aggregates further enhances the reaction between voxelrotor and propylene glycol. The use of milling / grinding media is well known in the field of powder processing, and materials such as stabilized zirconia and other ceramics are suitable if the medium is sufficiently hard or if it is a ball bearing, for example, a stainless steel ball bearing.

[0042] Regardless of whether milling or grinding is used, the process can be improved by controlling the particle ratio, the size of the milling / grinding media, and other parameters familiar to skilled workers.

[0043] The length of the milling or grinding time may be about 1 minute to about 2 days, for example, about 10 minutes to about 5 hours, for example, about 20 minutes to 3 hours, for example, about 2 hours.

[0044] The voxeltor and propylene glycol may be contacted at a temperature below ambient temperature. Alternatively, the voxeltor may be contacted with propylene glycol at a temperature above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure at which the contacting step is performed. In one embodiment, the contacting step is performed at atmospheric pressure (i.e., 1.0135 x 10⁻⁶). 5 It is performed in Pa).

[0045] The voxel-rotor hemipropylene glycol solvate is recovered as a crystalline solid. The crystalline solvate can be recovered directly by filtration, gradient separation, or centrifugation. If desired, a portion of the propylene glycol can be evaporated before the recovery of the crystalline solid.

[0046] Alternatively, the voxeltor hemipropylene glycol solvate described above can be produced by a process comprising the step of forming a solvate by applying double asymmetric centrifugal force to a mixture of voxeltor and propylene glycol.

[0047] Propylene glycol is present in an amount sufficient to form the desired solvate. The amount of propylene glycol is not particularly limited as long as there is enough propylene glycol to dissolve the voxel rotor to form a solution, suspend the voxel rotor, or moisten the voxel rotor. In one embodiment, the w / v ratio of voxel rotor to propylene glycol may be in the range of about 1 mg of voxel rotor : about 0.01 to about 1.5 μl of propylene glycol, e.g., about 1 mg of voxel rotor : about 0.05 to about 1.0 μl of propylene glycol, e.g., about 1 mg of voxel rotor : about 0.1 to about 0.75 μl of propylene glycol, e.g., about 1 mg of voxel rotor : about 0.5 μl of propylene glycol.

[0048] The voxel-rotor hemipropylene glycol solvate is formed using double asymmetric centrifugal force. "Double asymmetric centrifugal force" means that two centrifugal forces, which are at a certain angle to each other, are applied to the particles simultaneously. To create an efficient mixing environment, the centrifugal forces preferably rotate in opposite directions. Hauschild’s Speedmixer™ (http: / / www.speedmixer.co.uk / index.php) utilizes this double rotation method in which the Speedmixer™ motor rotates the base plate of the mixing unit clockwise (see FIG. 7A) and the basket rotates counterclockwise (see FIG. 7B and FIG. 7C).

[0049] This process can be controlled by various parameters including the rotational speed at which the process occurs, the length of the processing time, the level at which the mixing vessel is filled, the use of the milling medium, and / or the temperature control of the components within the milling port.

[0050] The double asymmetric centrifugal force may be applied for a continuous period. "Continuous" means a period without interruption. The period may be from about 1 second to about 10 minutes, for example, from about 5 seconds to about 5 minutes, for example, from about 10 seconds to about 200 seconds, for example, 2 minutes.

[0051] Alternatively, the double asymmetric centrifugal force may be applied during an aggregate period. "Aggregate" means the sum or total of more than one period (e.g., 2, 3, 4, 5 or more times). The advantage of applying the centrifugal force in a stepwise manner is that excessive heating of the particles can be avoided. The double asymmetric centrifugal force may be applied during an aggregate period of about 1 second to about 20 minutes, e.g., about 30 seconds to about 15 minutes, e.g., about 10 seconds to about 10 minutes, e.g., 6 minutes. In one embodiment, the double asymmetric centrifugal force is applied in a stepwise manner with cooling periods between them. In another embodiment, the double asymmetric centrifugal force may be applied stepwise at one or more different speeds.

[0052] The speed of the dual asymmetric centrifugal force may be about 200 rpm to about 4000 rpm. In one embodiment, the speed may be about 300 rpm to about 3750 rpm, for example, about 500 rpm to about 3500 rpm. In one embodiment, the speed may be about 3500 rpm. In another embodiment, the speed may be about 2300 rpm.

[0053] The level at which the mixing vessel is filled is determined by various factors that will be obvious to those skilled in the art. These factors include the apparent density of the voxeltor and propylene glycol, the volume of the mixing vessel, and weight limits imposed on the mixer itself.

[0054] A milling medium as described above may be used to aid in the reaction. In a given embodiment, the double asymmetric centrifugal force may be applied in a stepwise manner, wherein the milling medium may be used for a portion of the period, but not for the entire period.

[0055] The voxel-rotor hemipropylene glycol solvate is recovered as a crystalline solid. The crystalline solvate can be recovered directly by filtration, gradient separation, or centrifugation. If desired, a portion of the propylene glycol can be evaporated before the recovery of the crystalline solid.

[0056] Even if the crystalline solvate is recovered, the separated solvate may be dried. Drying may be performed using known methods, for example, at a temperature in the range of about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, at ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline solvate may be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the solvate decomposes; thus, if the solvate is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0057] The crystalline voxelotherm hemipropylene glycol solvate described above can be prepared by a process comprising the following steps:

[0058] (a) a step of contacting a voxel rotor with a first solvent, wherein the first solvent is selected from the group consisting of tert-butylmethyl ether (TBME), isopropyl acetate, diethyl ether, 2-methyl tetrahydrofuran (2-methyl THF), and combinations thereof; and

[0059] (b) a step of adding propylene glycol to a solution or suspension of voxelrotor; and

[0060] (c) A step of recovering voxel-to-hemipropylene glycol solvate as a crystalline solid.

[0061] The amount of the first solvent is not particularly limited as long as there is sufficient solvent to dissolve the voxel rotor to form a solution or to suspend the voxel rotor. The w / v ratio of the voxel rotor to the first solvent may be in the range of about 1 mg of voxel rotor : about 1 to about 1000 μl of solvent, for example, about 1 mg of voxel rotor : about 1 to about 500 μl of solvent, for example, about 1 mg of voxel rotor : about 1 to about 150 μl of solvent, for example, about 1 mg of voxel rotor : about 1 to about 10 μl of solvent. In one embodiment, the w / v ratio of the voxel rotor to the first solvent may be about 1 mg of voxel rotor : about 4 μl of solvent.

[0062] The voxel rotor may be in contact with the first solvent at ambient temperature or below. In one embodiment, the contacting step may be performed at one or more temperatures in the range of about 0°C or higher to about 25°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 1°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 2°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 3°C ​​or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 4°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 5°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 20°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 15°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 10°C or lower. In one embodiment, the contacting step is performed at one or more temperatures in the range of about 0°C or higher to about 10°C or lower, for example, about 5°C. In one embodiment, the contacting step can be performed at approximately ambient temperature, for example, about 25°C.

[0063] Alternatively, the voxelrotor may be contacted with the solvent at a temperature above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure at which the contacting step is performed. In one embodiment, the contacting step is performed at atmospheric pressure (i.e., 1.0135 x 10⁻⁶). 5It is performed in Pa). In one embodiment, the contacting step may be performed at one or more temperatures in the range of about 40°C or higher to about 60°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 41°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 42°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 43°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 44°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 45°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 46°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 47°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 48°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 49°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 50°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 59°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 58°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 57°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 56°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 55°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 54°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 53°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 52°C or lower.In some embodiments, the contacting step is performed at one or more temperatures of about 51°C or lower. In one embodiment, the contacting step is performed at one or more temperatures in the range of about 45°C or higher to about 55°C or lower. In one embodiment, the contacting step is performed at a temperature of about 50°C.

[0064] The dissolution or suspension of the voxel rotor can be facilitated by the use of auxiliary means such as stirring, shaking, and / or ultrasonic treatment. Additional solvents may be added to assist in the dissolution or suspension of the voxel rotor.

[0065] The duration for which the mixture of the voxel rotor and the solvent is treated at a desired temperature is not particularly limited. In one embodiment, the duration may be about 1 minute to about 24 hours, for example, about 5 minutes.

[0066] In step (b), propylene glycol is added to the reaction mixture. The amount of propylene glycol is not particularly limited. In one embodiment, the w / v ratio of voxelator to propylene glycol may be in the range of about 1 mg voxelator : about 0.01 to about 1.5 μl of propylene glycol, e.g., about 1 mg voxelator : about 0.05 to about 1.0 μl of propylene glycol, e.g., about 1 mg voxelator : about 0.1 to about 0.75 μl of propylene glycol, e.g., about 1 mg voxelator : about 0.1 μl to about 0.4 μl of propylene glycol. This w / v ratio was calculated using the mass of voxelator initially dissolved or suspended in the first solvent, i.e., the amount of voxelator introduced into the process.

[0067] After adding propylene glycol, the reaction mixture can be treated for a certain period of time at ambient temperature or below in relation to the first solvent as described above.

[0068] Alternatively, the reaction mixture may be treated for a certain period of time at one or more temperatures above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture, in relation to the first solvent as described above.

[0069] The reaction mixture can be left as is for an additional period, for example, about 1 minute to about 24 hours, for example, about 1 hour.

[0070] Subsequently, the solution or suspension may be cooled so that the resulting solution or suspension has a temperature lower than that of the solution or suspension in step (b). The cooling rate may be about 0.05°C / min to about 2°C / min, e.g., about 0.1°C / min to about 1.5°C / min, e.g., about 0.1°C / min or 0.5°C / min. When the solution of voxeloteur and propylene glycol is cooled, the suspension may eventually be observed.

[0071] The solution or suspension may be cooled to ambient temperature or a temperature below ambient temperature. In one embodiment, the solution or suspension may be cooled to one or more temperatures in the range of about 0°C or higher to about 20°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 1°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 2°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 3°C ​​or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 4°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 5°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 15°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 14°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 13°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 12°C or lower. In some embodiments, the solution or suspension may be cooled to one or more temperatures of about 11°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 10°C or lower. In one embodiment, the solution or suspension is cooled to one or more temperatures in the range of about 5°C to about 10°C.

[0072] In a given embodiment, an antisolvent may be added to the solution or suspension after the solution or suspension has been cooled to one or more temperatures below ambient temperature as described above. The antisolvent may be pre-cooled to a suitable temperature before being added to the cooled solution or suspension. In one embodiment, the antisolvent is an alkane solvent, such as heptane. In one embodiment, the antisolvent is heptane, and it is added to the solution or suspension of voxelotherm hemipropylene glycol solvate at about 15°C. After adding the antisolvent, cooling may continue as described above.

[0073] In step (c), the voxel-rotor hemipropylene glycol solvate is recovered as a crystalline solid. The crystalline solvate can be recovered directly by filtration, gradient separation, or centrifugation. If desired, the suspension can be mobilized with an additional portion of solvent before the recovery of the crystalline solid. Alternatively, part or substantially all of the solvent can be evaporated before the recovery of the crystalline solid.

[0074] Even if the crystalline solvate is recovered, the separated solvate may be washed with a solvent (e.g., one or more of the solvents described above) and dried. Drying may be performed using known methods at a temperature, for example, in the range of about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline solvate may be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the solvate decomposes; thus, if the solvate is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0075] Steps (a) through (c) may be performed one or more times (e.g., 1, 2, 3, 4, or 5 times). If steps (a) through (c) are performed more than once (e.g., 2, 3, 4, or 5 times), step (a) may optionally be seeded with a crystalline voxel-hemipropylene glycol solvate (previously prepared and isolated by the method described herein).

[0076] Alternatively or additionally, if steps (a) through (c) are performed more than once (e.g., 2, 3, 4, or 5 times), the solution or suspension formed in step (b) may optionally be seeded with a crystalline voxel-hemipropylene glycol solvate (previously prepared and isolated by the method described herein).

[0077] The inventors assume that the crystalline voxel-hemipropylene glycol solvate described above can be produced by a process comprising the following steps:

[0078] (a) a step of providing a mixture of voxeloteur and propylene glycol; and

[0079] (b) a step of forming the voxel-rotor hemipropylene glycol solvate by feeding the mixture through an extruder.

[0080] The mixture is a blend of voxeltor and propylene glycol. The mixture can be prepared by mixing voxeltor and propylene glycol by any suitable means, for example using a tubular blender, for a suitable period, for example, about 30 minutes. It is desirable but not essential to prepare a homogeneous blend of voxeltor and propylene glycol.

[0081] Propylene glycol may be present in stoichiometric molar equivalents or excess molar equivalents relative to the voxeltor. In one embodiment, propylene glycol is present in stoichiometric amounts. The molar ratio of voxeltor to propylene glycol may be in the range of about 1 mol voxeltor : about 0.3 to about 1 mol propylene glycol, for example, about 1 mol voxeltor : about 0.4 to about 0.7 mol propylene glycol. In one embodiment, the molar ratio of voxeltor to propylene glycol may be about 1 mol voxeltor : about 0.5 mol propylene glycol.

[0082] No solvate is formed when the mixture is prepared. As the mixture is processed through an extruder, the voxel rotor and propylene glycol form a solvate.

[0083] The extruder typically comprises a rotary screw or screws within a stationary barrel having a die located at one end of the barrel. Solvation of the mixture is provided by the rotation of the screw(s) within the barrel along the entire length of the screw. The extruder may be divided into at least three sections: a feed section; a heating section; and a metering section. In the feed section, the mixture is fed into the extruder. The mixture may be added directly to the feed section with or without the need for a solvent. In the heating section, as the mixture traverses the section, the mixture is heated to a temperature that causes the voxel-rotor and propylene glycol solvate to form a voxel-rotor hemipropylene glycol solvate. A solvent may be optionally added to the heating section. After the heating section, there is an optional metering section, where the solvate may be extruded through the die into a specific shape, e.g., granules. The extruder may be a single-screw extruder, a twin-screw extruder, a multi-screw extruder, or an intermeshing screw extruder. In one embodiment, the extruder is a twin-screw extruder, for example, a co-rotating twin-screw extruder.

[0084] The mixture may be supplied into the supply section at any suitable speed. For example, the speed of the supply section may be about 1 rpm to about 100 rpm. In one embodiment, the speed may be about 5 rpm to about 80 rpm.

[0085] In a given embodiment, a solvent is added to the mixture when the mixture is fed into the feed section. Alternatively or additionally, as the mixture traverses the heating section, the solvent may be added one or more times (e.g., 1, 2, 3, 4, or 5 times) to one or more zones (e.g., 1, 2, 3, 4, or 5 zones) of the heating section. This may be advantageous in preventing the mixture from drying out as the material moves through the heating section.

[0086] The amount of solvent added is not particularly limited, provided that it is sufficient to moisten (i.e., "wet") the mixture but not so much that it makes the mixture too liquid.

[0087] The heating section may be heated to a single temperature along its length, or it may be divided into more than one (e.g., 2, 3, 4, or 5) zones, each of which may be heated independently of the other zones. As the voxeltor and propylene glycol exit the heating section, they are solvated to form a voxeltor hemipropylene glycol solvate, and as long as neither the voxeltor, propylene glycol, nor the solvate is substantially degraded or substantially decomposed, the temperature of the heating section or each of the zones is not particularly limited.

[0088] If the extruder includes a screw, the screw (or screws) may correspond to the heating section, that is, the screw (or screws) may also be the heating section.

[0089] The speed at which the screw (or screws) rotates may be any suitable speed. For example, the speed of the screw (or screws) may be about 1 rpm to about 500 rpm. In one embodiment, the speed may be about 5 rpm to about 400 rpm, e.g., about 10 rpm to about 100 rpm.

[0090] The voxel-based hemipropylene glycol solvate is recovered as a crystalline solid. The crystalline molecular complex can be recovered by simply collecting the crystalline product. If desired, some of the solvent (if present) can be evaporated before the recovery of the crystalline solid.

[0091] Even if the crystalline molecular complex is recovered, the separated molecular complex may be dried. Drying may be performed using known methods, for example, at a temperature in the range of about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, at ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline solvate may be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the solvate decomposes; thus, if the solvate is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0092] In another aspect, the present invention relates to a pharmaceutical composition comprising a crystalline voxel-hemipropylene glycol solvate as described herein and a pharmaceutically acceptable excipient.

[0093] In another aspect, the present invention relates to a method for treating a disease associated with oxygen deficiency in a patient, the method comprising the step of administering a therapeutically effective amount of a crystalline voxelotherm hemipropylene glycol solvate as described herein to the patient. The disease associated with oxygen deficiency may be sickle cell disease.

[0094] In another aspect, the present invention relates to a crystalline voxel-hemipropylene glycol solvate as described herein for use in treating diseases associated with oxygen deficiency. Diseases associated with oxygen deficiency may be sickle cell disease.

[0095] voxelothermophilic fumaric acid molecular complex

[0096] It has been found that voxelrotors can be prepared into well-defined, consistently reproducible fumaric acid molecular complexes. Furthermore, a reliable and scalable method for producing such molecular complexes has been developed. The voxelrotor molecular complexes provided by the present invention may be useful as active ingredients in pharmaceutical formulations. In a specific embodiment, the crystalline molecular complex is purifiable. In a specific embodiment, and depending on time, temperature, and humidity, the crystalline molecular complex is stable. In a specific embodiment, the crystalline molecular complex is easy to separate and handle. In a specific embodiment, the method for preparing the crystalline molecular complex is scalable.

[0097] The crystalline molecular complexes described herein may be characterized using a number of methods known to those skilled in the art, including single-crystal X-ray diffraction, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy (including solution and solid-phase NMR). Chemical purity may be determined by standard analytical methods, such as thin-layer chromatography (TLC), gas chromatography, high-performance liquid chromatography (HPLC), and mass spectrometry (MS).

[0098] In another aspect, the present invention provides a crystalline molecular complex of voxelothermia and fumaric acid. In one embodiment, the crystalline molecular complex is a voxelothermia hemi-fumaric acid molecular complex, for example, a voxelothermia hemi-fumaric acid cocrystal.

[0099] The molar ratio of voxeltor to fumaric acid may be in the range of about 1 mole of voxeltor : about 0.3 to about 1 mole of fumaric acid, for example, about 1 mole of voxeltor : about 0.4 to about 0.7 moles of fumaric acid. In one embodiment, the molar ratio of voxeltor to fumaric acid may be about 1 mole of voxeltor : about 0.5 moles of fumaric acid.

[0100] The hemi-fumaric acid molecular complex comprises one or more peaks selected from the group consisting of approximately 5.3, 6.9, 11.2, 12.5, 12.8, 13.4, 13.9, 14.2, 15.1, 15.9, 16.2, 17.3, 17.5, 17.8, 18.7, 19.4, 19.6, 20.3, 20.9, 21.2, 21.7, 22.3, 22.6, 23.1, 23.3, 24.1, 24.4, 24.8, 25.1, 25.8, 25.9, 26.4, and 27.7 degrees 2-theta ± 0.2 degrees 2-theta (e.g., 1, 2, 3, It may have an X-ray powder diffraction pattern including 4, 5, 6, 7, 8, 9, or 10 peaks. In one embodiment, the molecular complex may substantially have an X-ray powder diffraction pattern as shown in FIG. 3.

[0101] The hemi-fumaric acid molecular complex may have a DSC temperature record including an endothermic event having an onset temperature of about 131.7°C. In one embodiment, the molecular complex may have a DSC temperature record substantially as shown in FIG. 4.

[0102] The hemi-fumaric acid molecular complex can have a TGA temperature record with substantially no mass loss when heated from approximately ambient temperature to about 150°C. In one embodiment, the molecular complex can have a TGA temperature record substantially as shown in FIG. 4.

[0103] Thermal analysis of the hemi-fumaric acid molecular complex, based on TGA, shows that there is no loss of fumaric acid immediately after the melting of the solid. This indicates that there is a temperature window between the melting of the molecular complex (the DSC event at approximately 131.7°C) and the decomposition of the sample (at approximately 160°C based on TGA), where the liquid can cool and reform the molecular complex. This suggests that thermal methods (e.g., high-temperature melt extrusion) can be used to produce the molecular complex.

[0104] The formed crystalline voxelotherm hemi-fumaric acid molecular complex may not have other polymorphic forms of voxelotherm, or may not have them substantially. In a specific embodiment, the polymorphic purity of the molecular complex is 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, or higher. In a specific embodiment, the polymorphic purity of the molecular complex is 95% or more. In a specific embodiment, the polymorphic purity of the molecular complex is 96% or more. In a specific embodiment, the polymorphic purity of the molecular complex is 97% or more. In a specific embodiment, the polymorphic purity of the molecular complex is 98% or more. In a specific embodiment, the polymorphic purity of the molecular complex is 99% or more.

[0105] The crystalline voxelothermophilic fumaric acid molecular complex described above can be manufactured by a process comprising the following steps:

[0106] (a) a step of contacting a voxelotherm and fumaric acid with a first solvent, wherein the first solvent is selected from the group consisting of methanol and tert-butyl methyl ether (TMBE) and combinations thereof; and

[0107] (b) A step of recovering a voxel-hemi fumaric acid molecular complex as a crystalline solid.

[0108] Fumaric acid can be used as a solid or as a solution in a solvent (e.g., methanol and / or TBME).

[0109] In one embodiment, step (a) may include the following steps:

[0110] (a1) a step of contacting a voxel rotor with a first solvent, wherein the first solvent is selected from the group consisting of methanol and tert-butyl methyl ether (TMBE) and combinations thereof; and

[0111] (a2) A step of adding fumaric acid to a solution or suspension of voxeloteur.

[0112] In another embodiment, step (a) may include the following steps:

[0113] (a1') A step of contacting a solid mixture of voxelotherm and fumaric acid with a first solvent to form a solution or suspension, wherein the first solvent is selected from the group consisting of methanol and tert-butylmethyl ether (TMBE) and combinations thereof.

[0114] (a) If there is sufficient solvent to dissolve the voxeltor to form a solution or to suspend the voxeltor, and / or (b) to dissolve the fumaric acid to form a solution or to suspend the fumaric acid, the amount of the first solvent is not particularly limited. The w / v ratio of the voxeltor to the first solvent may be in the range of about 1 mg of voxeltor : about 1 to about 1000 μl of solvent, e.g., about 1 mg of voxeltor : about 1 to about 500 μl of solvent, e.g., about 1 mg of voxeltor : about 1 to about 150 μl of solvent, e.g., about 1 mg of voxeltor : about 1 to about 10 μl of solvent.

[0115] The voxel rotor may be in contact with the first solvent at ambient temperature or below. In one embodiment, the contacting step may be performed at one or more temperatures in the range of about 0°C or higher to about 25°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 1°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 2°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 3°C ​​or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 4°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 5°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 20°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 15°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 10°C or lower. In one embodiment, the contacting step is performed at one or more temperatures in the range of about 0°C or higher to about 10°C or lower, for example, about 5°C. In one embodiment, the contacting step can be performed at approximately ambient temperature, for example, about 25°C.

[0116] Alternatively, the voxelrotor may be contacted with the first solvent at a temperature above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure at which the contacting step is performed. In one embodiment, the contacting step is performed at atmospheric pressure (i.e., 1.0135 x 10⁻⁶). 5It is performed in Pa). In one embodiment, the contacting step may be performed at one or more temperatures in the range of about 40°C or higher to about 60°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 41°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 42°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 43°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 44°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 45°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 46°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 47°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 48°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 49°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 50°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 59°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 58°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 57°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 56°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 55°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 54°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 53°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 52°C or lower.In some embodiments, the contacting step is performed at one or more temperatures of about 51°C or lower. In one embodiment, the contacting step is performed at one or more temperatures in the range of about 45°C or higher to about 55°C or lower. In one embodiment, the contacting step is performed at a temperature of about 50°C.

[0117] The dissolution or suspension of the voxel rotor can be facilitated by the use of auxiliary means such as stirring, shaking, and / or ultrasonic treatment. Additional solvents may be added to assist in the dissolution or suspension of the voxel rotor.

[0118] The duration for which the mixture of the voxel rotor and the solvent is treated at a desired temperature is not particularly limited. In one embodiment, the duration may be about 1 minute to about 24 hours, for example, about 5 minutes.

[0119] When fumaric acid is added to the reaction as a solid, the w / v ratio of fumaric acid to the first solvent may be in the range of about 1 mg of fumaric acid : about 1 to about 1000 μl of solvent, for example, about 1 mg of fumaric acid : about 1 to about 500 μl of solvent, for example, about 1 mg of fumaric acid : about 1 to about 150 μl of solvent, for example, about 1 mg of fumaric acid : about 1 to about 20 μl of solvent.

[0120] When fumaric acid is introduced into the reaction as a solution in a solvent selected from methanol and / or TBME, the w / v ratio of fumaric acid to solvent may be in the range of about 1 mg fumaric acid : about 1 to about 1000 μl of solvent, e.g., about 1 mg fumaric acid : about 1 to about 500 μl of solvent, e.g., about 1 mg fumaric acid : about 1 to about 150 μl of solvent, e.g., about 1 mg fumaric acid : about 1 to about 25 μl of solvent. In this case, the solution of fumaric acid may be added to the solution / suspension of the voxelrotor.

[0121] When a solid mixture of voxelotherm and fumaric acid is brought into contact with methanol and / or MTBE, the w / v ratio of voxelotherm to solvent may be in the range of about 1 mg of voxelotherm: about 1 to about 1000 μl of solvent, e.g., about 1 mg of voxelotherm: about 1 to about 500 μl of solvent, e.g., about 1 mg of voxelotherm: about 1 to about 150 μl of solvent, e.g., about 1 mg of voxelotherm: about 1 to about 10 μl of solvent. In this case, the w / v of fumaric acid to solvent may be in the range of about 1 mg of fumaric acid : about 1 to about 1000 μl of solvent, for example, about 1 mg of fumaric acid : about 1 to about 500 μl of solvent, for example, about 1 mg of fumaric acid : about 1 to about 150 μl of solvent, for example, about 1 mg of fumaric acid : about 1 to about 20 μl of solvent.

[0122] The duration for which the mixture of voxeloteur, fumaric acid, and solvent is treated at a desired temperature is not particularly limited. In one embodiment, the duration may be about 1 minute to about 24 hours, for example, about 1 hour.

[0123] After the combination of voxeloteur, fumaric acid, and solvent, the reaction mixture can be treated for a certain period at ambient temperature or below as described above in relation to the first solvent.

[0124] Alternatively, the reaction mixture may be treated for a certain period of time at a temperature above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture, in relation to the first solvent as described above.

[0125] The reaction mixture can be left as is for an additional period, for example, about 1 minute to about 24 hours, for example, about 1 hour.

[0126] Subsequently, the solution or suspension may be cooled so that the resulting solution or suspension has a temperature lower than that of the solution or suspension of step (a), step (a2), or step (a1'). The cooling rate may be about 0.05°C / min to about 2°C / min, e.g., about 0.1°C / min to about 1.5°C / min, e.g., about 0.1°C / min or 0.5°C / min. When the solution of the reaction mixture is cooled, the suspension may eventually be observed.

[0127] The solution or suspension may be cooled to ambient temperature or a temperature below ambient temperature. In one embodiment, the solution or suspension may be cooled to one or more temperatures in the range of about 0°C or higher to about 20°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 1°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 2°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 3°C ​​or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 4°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 5°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 15°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 14°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 13°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 12°C or lower. In some embodiments, the solution or suspension may be cooled to one or more temperatures of about 11°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 10°C or lower. In one embodiment, the solution or suspension is cooled to one or more temperatures in the range of about 5°C to about 10°C, for example, about 5°C.

[0128] The reaction mixture may be left at a desired temperature for an additional period, for example, from about 1 minute to about 10 days. In one embodiment, the reaction mixture was left at a temperature below ambient temperature for about 7 days.

[0129] In step (b), the voxelothermophilic fumaric acid molecular complex is recovered as a crystalline solid. The crystalline molecular complex can be recovered directly by filtration, gradient separation, or centrifugation. If desired, the suspension may be used with an additional portion of solvent (e.g., methanol and / or TBME) before the recovery of the crystalline solid. Alternatively, part or substantially all of the solvent may be evaporated before the recovery of the crystalline solid.

[0130] Even if the crystalline molecular complex is recovered, the separated molecular complex may be washed with a solvent (e.g., one or more of the solvents described above) and dried. Drying may be performed using known methods at a temperature in the range of, for example, about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline molecular complex may be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the molecular complex decomposes; thus, if the molecular complex is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0131] Steps (a) → (b), (a1) → (a2) → (b), and (a1') → (b) may be performed one or more times (e.g., 1, 2, 3, 4, or 5 times). If steps (a) → (b), (a1) → (a2) → (b), and (a1') → (b) are performed more than once (e.g., 2, 3, 4, or 5 times), one or more of these steps may optionally, where appropriate, be seeded with a crystalline voxel-fumaric acid molecular complex (previously prepared and isolated by the method described herein).

[0132] The inventors assume that the crystalline voxel-rotor hemi-fumaric acid molecular complex described above can be manufactured by a process comprising the following steps:

[0133] (a) a step of providing a mixture of voxeloteur and fumaric acid; and

[0134] (b) a step of forming a voxel-rotor hemi-fumaric acid molecular complex by feeding the mixture through an extruder.

[0135] The mixture is a blend of voxelothermia and fumaric acid. The mixture can be prepared by mixing voxelothermia and fumaric acid by any suitable means, for example, using a tubular blender, for a suitable period, for example, about 30 minutes. It is desirable but not essential to prepare a homogeneous blend of voxelothermia and fumaric acid.

[0136] Fumaric acid may be present in stoichiometric molar equivalents or excess molar equivalents relative to the voxeltor. In one embodiment, fumaric acid is present in stoichiometric amounts. The molar ratio of voxeltor to fumaric acid may be in the range of about 1 mol of voxeltor : about 0.3 to about 1 mol of fumaric acid, for example, about 1 mol of voxeltor : about 0.4 to about 0.7 mol of fumaric acid. In one embodiment, the molar ratio of voxeltor to fumaric acid may be about 1 mol of voxeltor : about 0.5 mol of fumaric acid.

[0137] When preparing the mixture, molecular complexes are not formed. When the mixture is fed through an extruder, the voxel rotor and fumaric acid co-crystallize to form molecular complexes.

[0138] The extruder is as described above for the voxel rotor hemipropylene glycol solvate. A solvent may be used in the feed section and / or heating section.

[0139] The mixture may be supplied into the supply section at any suitable speed. For example, the speed of the supply section may be about 1 rpm to about 100 rpm. In one embodiment, the speed may be about 5 rpm to about 80 rpm.

[0140] In a given embodiment, a solvent is added to the mixture when the mixture is fed into the feed section. Alternatively or additionally, as the mixture traverses the heating section, the solvent may be added one or more times (e.g., 1, 2, 3, 4, or 5 times) to one or more zones (e.g., 1, 2, 3, 4, or 5 zones) of the heating section. This may be advantageous in preventing the mixture from drying out as the material moves through the heating section.

[0141] The amount of solvent added is not particularly limited, provided that it is sufficient to moisten (i.e., "wet") the mixture but not so much that it makes the mixture too liquid.

[0142] The heating section may be heated to a single temperature along its length, or it may be divided into more than one (e.g., 2, 3, 4, or 5) zones, each of which may be heated independently of the other zones. As the voxeloteur and fumaric acid exit the heating section, they co-crystallize to form a molecular complex, and if neither the voxeloteur, fumaric acid, nor the molecular complex is substantially degraded or substantially decomposed, the temperature of the heating section or each of the zones is not particularly limited.

[0143] If the extruder includes a screw, the screw (or screws) may correspond to the heating section, that is, the screw (or screws) may also be the heating section.

[0144] The speed at which the screw (or screws) rotates may be any suitable speed. For example, the speed of the screw (or screws) may be about 1 rpm to about 500 rpm. In one embodiment, the speed may be about 5 rpm to about 400 rpm, e.g., about 10 rpm to about 100 rpm.

[0145] The voxel-hemi fumaric acid molecular complex is recovered as a crystalline solid. The crystalline molecular complex can be recovered simply by collecting the crystalline product. If desired, a portion of the solvent (if present) can be evaporated prior to the recovery of the crystalline solid.

[0146] Even if the crystalline molecular complex is recovered, the separated molecular complex may be dried. Drying may be performed using known methods, for example, at a temperature in the range of about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, at ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline molecular complex may be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the molecular complex decomposes; thus, if the molecular complex is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0147] In another aspect, the present invention relates to a pharmaceutical composition comprising a crystalline voxel-hemi fumaric acid molecular complex as described herein and a pharmaceutically acceptable excipient.

[0148] In another aspect, the present invention relates to a method for treating a disease associated with oxygen deficiency in a patient, said method comprising the step of administering to said patient a therapeutically effective amount of a crystalline voxelothermophilic fumaric acid molecular complex as described herein. The disease associated with oxygen deficiency may be sickle cell disease.

[0149] In another aspect, the present invention relates to a crystalline voxelothermophilic fumaric acid molecular complex as described herein for use in treating diseases associated with oxygen deficiency. Diseases associated with oxygen deficiency may be sickle cell disease.

[0150] voxelothermophilic succinic acid molecular complex

[0151] It has been found that voxelrotors can be prepared into well-defined, consistently reproducible succinic acid molecular complexes. Furthermore, a reliable and scalable method for producing such molecular complexes has been developed. The voxelrotor molecular complexes provided by the present invention may be useful as active ingredients in pharmaceutical formulations. In a specific embodiment, the crystalline molecular complex is purifiable. In a specific embodiment, and depending on time, temperature, and humidity, the crystalline molecular complex is stable. In a specific embodiment, the crystalline molecular complex is easy to separate and handle. In a specific embodiment, the method for preparing the crystalline molecular complex is scalable.

[0152] The crystalline molecular complexes described herein may be characterized using a number of methods known to those skilled in the art, including single-crystal X-ray diffraction, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy, Raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy (including solution and solid-phase NMR). Chemical purity may be determined by standard analytical methods, such as thin-layer chromatography (TLC), gas chromatography, high-performance liquid chromatography (HPLC), and mass spectrometry (MS).

[0153] In another aspect, the present invention provides a crystalline molecular complex of voxelothermia and succinic acid. In one embodiment, the crystalline molecular complex is a voxelothermia-succinic acid molecular complex, for example, a voxelothermia-succinic acid cocrystal.

[0154] The molar ratio of voxelto to succinic acid may be in the range of about 1 mole of voxelto to about 0.3 to about 1 mole of succinic acid, for example, about 1 mole of voxelto to about 0.4 to about 0.7 moles of succinic acid. In one embodiment, the molar ratio of voxelto to succinic acid may be about 1 mole of voxelto to about 0.5 moles of succinic acid.

[0155] The hemisuccinic acid molecular complex may have an X-ray powder diffraction pattern comprising one or more peaks selected from the group consisting of about 8.2, 10.8, 11.5, 11.9, 15.2, 15.5, 16.3, 17.6, 18.2, 18.6, 20.0, 20.2, 20.7, 21.3, 21.8, 22.3, 23.1, 23.9, 24.4, 24.8, 25.2, 27.4, 27.9, and 29.9 degrees 2-theta ± 0.2 degrees 2-theta (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks). In one embodiment, the molecular complex may have an X-ray powder diffraction pattern substantially as shown in FIG. 5.

[0156] The hemisuccinic acid molecular complex may have a DSC temperature record including an endothermic event having an onset temperature of about 112.6°C. In one embodiment, the molecular complex may have a DSC temperature record substantially as shown in FIG. 6.

[0157] The hemisuccinic acid molecular complex can have a TGA temperature record with substantially no mass loss when heated from approximately ambient temperature to about 150°C. In one embodiment, the molecular complex can have a TGA temperature record substantially as shown in FIG. 6.

[0158] Thermal analysis of the hemisuccinic acid molecular complex, based on TGA, shows that there is no loss of succinic acid immediately after the melting of the solid. This indicates that there is a temperature window between the melting of the molecular complex (the DSC event at approximately 112.6°C) and the decomposition of the sample (at approximately 170°C based on TGA), where the liquid can cool and reform the molecular complex. This indicates that thermal methods (e.g., high-temperature melt extrusion) can be used to produce the molecular complex.

[0159] The formed crystalline voxel-rotor hemi-succinic acid molecular complex may not have other polymorphic forms of voxel-rotor or may not have them substantially. In a predetermined embodiment, the polymorphic purity of the molecular complex is 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, or higher. In a predetermined embodiment, the polymorphic purity of the molecular complex is 95% or more. In a predetermined embodiment, the polymorphic purity of the molecular complex is 96% or more. In a predetermined embodiment, the polymorphic purity of the molecular complex is 97% or more. In a predetermined embodiment, the polymorphic purity of the molecular complex is 98% or more. In a predetermined embodiment, the polymorphic purity of the molecular complex is 99% or more.

[0160] The voxel-rotor hemi-succinic acid molecular complex described above can be manufactured by a process comprising the step of reacting voxel-rotor with succinic acid using low-energy ball milling or low-energy grinding.

[0161] Succinic acid is present in sufficient amounts to form the desired molecular complex. The w / w ratio of voxelto to succinic acid may be in the range of about 1 mg of voxelto to about 0.1 to about 0.75 mg of succinic acid, e.g., about 1 mg of voxelto to about 0.5 mg of succinic acid, e.g., about 1 mg of voxelto to about 0.2 mg of succinic acid.

[0162] When low-energy ball milling is used, the milling process can be controlled by various parameters including the milling speed, the length of the milling time, and / or the level at which the milling vessel is filled.

[0163] The milling speed may be approximately 50 rpm to approximately 1000 rpm. In one embodiment, the speed may be approximately 75 rpm to approximately 750 rpm. In another embodiment, the speed may be approximately 80 rpm to approximately 650 rpm. In one embodiment, the speed may be approximately 500 rpm.

[0164] Low-energy grinding involves shaking the material within a grinding vessel. Grinding occurs through impact and friction of the material within the vessel. This process can be controlled by various parameters, including the frequency at which grinding occurs, the length of the grinding time, and / or the level at which the vessel is filled.

[0165] The frequency at which grinding occurs may be about 1 Hz to about 100 Hz. In one embodiment, the frequency may be about 10 Hz to about 70 Hz. In another embodiment, the frequency may be about 20 Hz to about 50 Hz. In one embodiment, the frequency may be about 30 Hz.

[0166] Regardless of whether milling or grinding is used, a milling or grinding medium may be used to aid the reaction. In such cases, the incorporation of a hard, non-contaminating medium can further aid in the decomposition of particles that have aggregated, for example, as a result of the manufacturing process or during transport. Such decomposition of aggregates further enhances the reaction between voxelrotor and succinic acid. The use of milling / grinding media is well known in the field of powder processing, and materials such as stabilized zirconia and other ceramics are suitable if the medium is sufficiently hard or if it is a ball bearing, for example, a stainless steel ball bearing.

[0167] Regardless of whether milling or grinding is used, the process can be improved by controlling the particle ratio, the size of the milling / grinding media, and other parameters familiar to skilled workers.

[0168] The length of the milling or grinding time may be about 1 minute to about 2 days, for example, about 2 minutes to about 5 hours, for example, about 20 minutes to 3 hours, for example, about 2 hours. The length of the milling or grinding time may be for a continuous or total period. "Continuous" and "total" are defined below.

[0169] The voxeltor and succinic acid may be contacted at a temperature below ambient temperature. Alternatively, the voxeltor may be contacted with succinic acid at a temperature above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure at which the contacting step is performed. In one embodiment, the contacting step is performed at atmospheric pressure (i.e., 1.0135 x 10⁻⁶). 5 It is performed in Pa).

[0170] The above process may be carried out in the presence of a solvent, such as methanol. The solvent may act to minimize particle welding. The addition of the solvent may be particularly helpful if the voxeltor and / or succinic acid being reacted are aggregated before use, in which case the solvent may help to break down the aggregates.

[0171] If there is enough solvent to dissolve, suspend, or moisten the voxelotherm and / or succinic acid, the amount of solvent is not particularly limited. The w / v ratio of voxelotherm to solvent may be in the range of about 1 mg of voxelotherm : about 0.01 to about 1.5 μl of solvent, e.g., about 1 mg of voxelotherm : about 0.05 to about 1.0 μl of solvent, e.g., about 1 mg of voxelotherm : about 0.1 to about 0.75 μl of solvent, e.g., about 1 mg of voxelotherm : about 0.5 μl of solvent. The solvent may be added all at once or added in more than one portion (e.g., 2, 3, 4, or 5 portions).

[0172] The voxelotherm and succinic acid may be brought into contact with a solvent at a temperature below ambient temperature. Alternatively, the voxelotherm may be brought into contact with a solvent at a temperature above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure at which the contacting step is performed. In one embodiment, the contacting step is performed at atmospheric pressure (i.e., 1.0135 x 10⁻⁶). 5 It is performed in Pa).

[0173] When milling or grinding time is applied over a total period, the presence or absence of a solvent may vary during each period. For example, the present method may include a first period in which the environment is dry (i.e., voxelrotor and succinic acid selectively react with the milling medium in the absence of a solvent), and a second period in which the environment becomes moist (i.e., wet) after the addition of a solvent.

[0174] The voxel-rotor hemi-succinic acid molecular complex is recovered as a crystalline solid. The crystalline molecular complex can be recovered directly by filtration, gradient separation, or centrifugation. If desired, a portion of the solvent may be evaporated prior to the recovery of the crystalline solid.

[0175] Alternatively, the voxelothermophilic acid molecular complex described above can be prepared by a process comprising the step of forming a solvate by applying a double asymmetric centrifugal force to a mixture of voxelothermophilic acid and succinic acid.

[0176] Succinic acid is present in an amount sufficient to form the desired molecular complex. The molar ratio of voxelto to succinic acid may be in the range of about 1 mole of voxelto to about 0.3 to about 1 mole of succinic acid, for example, about 1 mole of voxelto to about 0.4 to about 0.7 moles of succinic acid. In one embodiment, the molar ratio of voxelto to succinic acid may be about 1 mole of voxelto to about 0.5 moles of succinic acid.

[0177] The voxel-rotor hemi-succinic acid molecular complex is formed using double asymmetric centrifugal force. "Double asymmetric centrifugal force" means that two centrifugal forces, which are at a certain angle to each other, are applied to the particles simultaneously. To create an efficient mixing environment, the centrifugal forces preferably rotate in opposite directions. Hauschild's Speedmixer™ (http: / / www.speedmixer.co.uk / index.php) utilizes this double rotation method in which the Speedmixer™ motor rotates the base plate of the mixing unit clockwise (see FIG. 7A) and the basket rotates counterclockwise (see FIG. 7B and FIG. 7C).

[0178] This process can be controlled by various parameters including the rotational speed at which the process occurs, the length of the processing time, the level at which the mixing vessel is filled, the use of the milling medium, and / or the temperature control of the components within the milling port.

[0179] The double asymmetric centrifugal force may be applied for a continuous period. "Continuous" means a period without interruption. The period may be from about 1 second to about 10 minutes, for example, from about 5 seconds to about 5 minutes, for example, from about 10 seconds to about 200 seconds, for example, 2 minutes.

[0180] Alternatively, the dual asymmetric centrifugal force may be applied over a total period. "Total" means the sum or total of more than one period (e.g., 2, 3, 4, 5 or more times). The advantage of applying the centrifugal force in a stepwise manner is that excessive heating of the particles can be avoided. The dual asymmetric centrifugal force may be applied over a total period of about 1 second to about 20 minutes, e.g., about 30 seconds to about 15 minutes, e.g., about 10 seconds to about 10 minutes, e.g., 6 minutes. In one embodiment, the dual asymmetric centrifugal force is applied in a stepwise manner with cooling periods between them. In another embodiment, the dual asymmetric centrifugal force may be applied stepwise at one or more different speeds.

[0181] The speed of the dual asymmetric centrifugal force may be about 200 rpm to about 4000 rpm. In one embodiment, the speed may be about 300 rpm to about 3750 rpm, for example, about 500 rpm to about 3500 rpm. In one embodiment, the speed may be about 3500 rpm. In another embodiment, the speed may be about 2300 rpm.

[0182] The level at which the mixing vessel is filled is determined by various factors that will be obvious to those skilled in the art. These factors include the apparent densities of voxelothermia and succinic acid, the volume of the mixing vessel, and weight limitations imposed on the mixer itself.

[0183] A milling medium as described above may be used to aid in the reaction. In a given embodiment, the double asymmetric centrifugal force may be applied in a stepwise manner, wherein the milling medium may be used for a portion of the period, but not for the entire period.

[0184] The above process may be carried out in the presence of a solvent, such as methanol or TBME. The solvent may act to minimize particle fusion. The addition of the solvent may be particularly helpful if the voxel-rotor and / or succinic acid being reacted are aggregated before use, in which case the solvent may help to break down the aggregates.

[0185] When a double asymmetric centrifugal force is applied during the total period, the presence or absence of the solvent may change during each period. For example, the present method may include a first period in which the environment is dry (i.e., the voxelrotor and succinic acid selectively react with the milling medium in the absence of the solvent), and a second period in which the environment becomes moist (i.e., wet) after the addition of the solvent.

[0186] The voxel-rotor hemi-succinic acid molecular complex is recovered as a crystalline solid. The crystalline molecular complex can be recovered directly by filtration, gradient separation, or centrifugation. If desired, a portion of the solvent (if present) can be evaporated prior to the recovery of the crystalline solid.

[0187] Even if the crystalline molecular complex is recovered, the separated molecular complex may be dried. Drying may be performed using known methods, for example, at a temperature in the range of about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, at ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline molecular complex may be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the molecular complex decomposes; thus, if the molecular complex is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0188] The crystalline voxelothermophilic acid molecular complex described above can be manufactured by a process comprising the following steps:

[0189] (a) a step of contacting the voxelotherm and succinic acid with a solvent, wherein the solvent is tert-butyl methyl ether (TMBE); and

[0190] (b) A step of recovering a voxel-hemi-succinic acid molecular complex as a crystalline solid.

[0191] Succinic acid can be used as a solid or as a solution in a solvent (e.g., methanol and / or TBME).

[0192] In one embodiment, step (a) may include the following steps:

[0193] (a1) a step of contacting a voxel rotor with a solvent, wherein the solvent is tert-butyl methyl ether (TMBE); and

[0194] (a2) A step of adding succinic acid to a solution or suspension of voxel.

[0195] In another embodiment, step (a) may include the following steps:

[0196] (a1') A step of contacting a solid mixture of voxelotherm and succinic acid with a solvent to form a solution or suspension, wherein the solvent is tert-butyl methyl ether (TMBE).

[0197] (a) If there is sufficient solvent to dissolve the voxeltor to form a solution or to suspend the voxeltor, and / or (b) to dissolve the succinic acid to form a solution or to suspend the succinic acid, the amount of TBME is not particularly limited. The w / v ratio of voxeltor to TBME may be in the range of about 1 mg of voxeltor : about 1 to about 1000 μl of TBME, e.g., about 1 mg of voxeltor : about 1 to about 500 μl of TBME, e.g., about 1 mg of voxeltor : about 1 to about 150 μl of TBME, e.g., about 1 mg of voxeltor : about 1 to about 10 μl of TBME. In one embodiment, the w / v ratio of voxeltor to TBME may be about 1 mg of voxeltor : about 5 μl of TBME.

[0198] The voxel rotor may be in contact with the TBME at ambient temperature or below. In one embodiment, the contacting step may be performed at one or more temperatures in the range of about 0°C or higher to about 25°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 1°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 2°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 3°C ​​or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 4°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 5°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 20°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 15°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 10°C or lower. In one embodiment, the contacting step is performed at one or more temperatures in the range of about 0°C or higher to about 10°C or lower, for example, about 5°C. In one embodiment, the contacting step can be performed at approximately ambient temperature, for example, about 25°C.

[0199] Alternatively, the voxeltor can be contacted with TBME at a temperature above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure at which the contacting step is performed. In one embodiment, the contacting step is performed at atmospheric pressure (i.e., 1.0135 x 10⁻⁶). 5It is performed in Pa). In one embodiment, the contacting step may be performed at one or more temperatures in the range of about 40°C or higher to about 60°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 41°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 42°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 43°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 44°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 45°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 46°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 47°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 48°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 49°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 50°C or higher. In some embodiments, the contacting step is performed at one or more temperatures of about 59°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 58°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 57°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 56°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 55°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 54°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 53°C or lower. In some embodiments, the contacting step is performed at one or more temperatures of about 52°C or lower.In some embodiments, the contacting step is performed at one or more temperatures of about 51°C or lower. In one embodiment, the contacting step is performed at one or more temperatures in the range of about 45°C or higher to about 55°C or lower. In one embodiment, the contacting step is performed at a temperature of about 50°C.

[0200] The dissolution or suspension of the voxel rotor can be facilitated by the use of auxiliary means such as stirring, shaking, and / or ultrasonic treatment. Additional solvents may be added to assist in the dissolution or suspension of the voxel rotor.

[0201] The duration for which the mixture of voxelrotor and TBME is processed at a desired temperature is not particularly limited. In one embodiment, the duration may be about 1 minute to about 24 hours, for example, about 2 hours.

[0202] When succinic acid is added to the reaction as a solid, the w / v ratio of succinic acid to TBME may be in the range of about 1 mg of succinic acid : about 1 to about 1000 μl of TBME, for example, about 1 mg of succinic acid : about 1 to about 500 μl of TBME, for example, about 1 mg of succinic acid : about 1 to about 150 μl of TBME, for example, about 1 mg of succinic acid : about 1 to about 35 μl of TBME. In one embodiment, the w / v ratio of succinic acid to TBME may be about 1 mg of succinic acid : about 29 μl of solvent.

[0203] Succinic acid may be added to the reaction as a solution in methanol and / or TBME. In this case, the w / v ratio of succinic acid to TBME may be in the range of about 1 mg of succinic acid : about 1 to about 1000 μl of TBME, e.g., about 1 mg of succinic acid : about 1 to about 500 μl of TBME, e.g., about 1 mg of succinic acid : about 1 to about 150 μl of TBME, e.g., about 1 mg of succinic acid : about 1 to about 25 μl of TBME. In this case, the solution of succinic acid may be added to the solution / suspension of the voxelrotor.

[0204] When a solid mixture of voxelotherm and succinic acid comes into contact with MTBE, the w / v ratio of voxelotherm to TBME may be in the range of about 1 mg of voxelotherm to about 1 to about 1000 μl of TBME, for example, about 1 mg of voxelotherm to about 1 to about 500 μl of TBME, for example, about 1 mg of voxelotherm to about 150 μl of TBME, for example, about 1 mg of voxelotherm to about 1 to about 10 μl of TBME. In one embodiment, the w / v ratio of voxelotherm to TBME may be about 1 mg of voxelotherm to about 5 μl of TBME. In this case, the w / v ratio of succinic acid to TBME may be in the range of about 1 mg of succinic acid : about 1 to about 1000 μl of TBME, for example, about 1 mg of succinic acid : about 1 to about 500 μl of TBME, for example, about 1 mg of succinic acid : about 1 to about 150 μl of TBME, for example, about 1 mg of succinic acid : about 1 to about 35 μl of TBME. In one embodiment, the w / v ratio of succinic acid to TBME may be about 1 mg of succinic acid : about 29 μl of solvent.

[0205] The duration for which the mixture of voxelrotor, succinic acid, and solvent is treated at a desired temperature is not particularly limited. In one embodiment, the duration may be about 1 minute to about 24 hours, for example, about 1 hour.

[0206] After the combination of voxeloteur, succinic acid, and solvent, the reaction mixture can be treated for a certain period at ambient temperature or below as described above in relation to the first solvent.

[0207] Alternatively, the reaction mixture may be treated for a certain period of time at one or more temperatures above ambient temperature, i.e., above 30°C and below the boiling point of the reaction mixture, in relation to the first solvent as described above.

[0208] The reaction mixture can be left as is for an additional period, for example, about 1 minute to about 24 hours, for example, about 2 hours.

[0209] Subsequently, the solution or suspension may be cooled so that the resulting solution or suspension has a temperature lower than that of the solution or suspension of step (a), step (a2), or step (a1'). The cooling rate may be about 0.05°C / min to about 2°C / min, e.g., about 0.1°C / min to about 1.5°C / min, e.g., about 0.1°C / min or 0.5°C / min. When the solution of the reaction mixture is cooled, the suspension may eventually be observed.

[0210] The solution or suspension may be cooled to ambient temperature or a temperature below ambient temperature. In one embodiment, the solution or suspension may be cooled to one or more temperatures in the range of about 0°C or higher to about 20°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 1°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 2°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 3°C ​​or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 4°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 5°C or higher. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 15°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 14°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 13°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 12°C or lower. In some embodiments, the solution or suspension may be cooled to one or more temperatures of about 11°C or lower. In some embodiments, the solution or suspension is cooled to one or more temperatures of about 10°C or lower. In one embodiment, the solution or suspension is cooled to one or more temperatures in the range of about 5°C to about 10°C, for example, about 5°C.

[0211] The reaction mixture can be left at the desired temperature for an additional period, for example, from about 1 minute to about 10 days.

[0212] In step (b), the voxel-hemi-succinic acid molecular complex is recovered as a crystalline solid. The crystalline molecular complex can be recovered directly by filtration, gradient separation, or centrifugation. If desired, the suspension can be used with an additional portion of solvent (e.g., TBME) before the recovery of the crystalline solid. Alternatively, part or substantially all of the solvent can be evaporated before the recovery of the crystalline solid.

[0213] Even if the crystalline molecular complex is recovered, the separated molecular complex can be washed with a solvent (e.g., TBME) and dried. Drying can be performed using known methods at a temperature in the range of, for example, about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline molecular complex can be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the molecular complex decomposes; thus, if the molecular complex is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0214] Steps (a) → (b), (a1) → (a2) → (b), and (a1') → (b) may be performed one or more times (e.g., 1, 2, 3, 4, or 5 times). If steps (a) → (b), (a1) → (a2) → (b), and (a1') → (b) are performed more than once (e.g., 2, 3, 4, or 5 times), one or more of these steps may optionally, where appropriate, be seeded into a crystalline voxel-rotor succinic acid molecular complex (previously prepared and isolated by the method described herein).

[0215] The inventors assume that the crystalline voxel-hemisuccinic acid molecular complex described above can be manufactured by a process comprising the following steps:

[0216] (a) a step of providing a mixture of voxelotherm and succinic acid; and

[0217] (b) a step of forming a voxel-rotor hemi-succinic acid molecular complex by feeding the mixture through an extruder.

[0218] The mixture is a blend of voxelothermia and succinic acid. The mixture can be prepared by mixing voxelothermia and succinic acid by any suitable means, for example, using a tubular blender, for a suitable period, for example, about 30 minutes. It is desirable but not essential to prepare a homogeneous blend of voxelothermia and succinic acid.

[0219] Succinic acid may be present in stoichiometric molar equivalents or excess molar equivalents relative to the voxeltor. In one embodiment, succinic acid is present in stoichiometric amounts. The molar ratio of voxeltor to succinic acid may be in the range of about 1 mol of voxeltor : about 0.3 to about 1 mol of succinic acid, for example, about 1 mol of voxeltor : about 0.4 to about 0.7 mol of succinic acid. In one embodiment, the molar ratio of voxeltor to succinic acid may be about 1 mol of voxeltor : about 0.5 mol of succinic acid.

[0220] When preparing the mixture, molecular complexes are not formed. When the mixture is fed through an extruder, the voxel rotor and fumaric acid co-crystallize to form molecular complexes.

[0221] The extruder is as described above for the voxel rotor hemipropylene glycol solvate. A solvent may be used in the feed section and / or heating section.

[0222] The mixture may be supplied into the supply section at any suitable speed. For example, the speed of the supply section may be about 1 rpm to about 100 rpm. In one embodiment, the speed may be about 5 rpm to about 80 rpm.

[0223] In a given embodiment, a solvent is added to the mixture when the mixture is fed into the feed section. Alternatively or additionally, as the mixture traverses the heating section, the solvent may be added one or more times (e.g., 1, 2, 3, 4, or 5 times) to one or more zones (e.g., 1, 2, 3, 4, or 5 zones) of the heating section. This may be advantageous in preventing the mixture from drying out as the material moves through the heating section.

[0224] The amount of solvent added is not particularly limited, provided that sufficient solvent is added to moisten (i.e., "wet") the mixture, but not in an amount large enough to make the mixture too liquid. If the extruder is a twin-screw extruder, the w / v ratio of total solids (voxelotherm and succinic acid) to total added solvent may be in the range of about 1 g of total solids : about 0.1 to about 2 ml of total added solvent, e.g., about 1 g of total solids : about 0.5 ml to about 1.5 ml of total solvent, e.g., about 1 g of total solids : about 0.75 ml to about 1.25 ml of total solvent. In one embodiment, the w / v ratio of total solids (voxelotherm and succinic acid) to total solvent is about 1 g of total solids : about 1 ml of total solvent.

[0225] The heating section may be heated to a single temperature along its length, or it may be divided into more than one (e.g., 2, 3, 4, or 5) zones, each of which may be heated independently of the other zones. As the voxeloteur and succinic acid exit the heating section, they co-crystallize to form a molecular complex, and if neither the voxeloteur, succinic acid, nor the molecular complex is substantially degraded or substantially decomposed, the temperature of the heating section or each of the zones is not particularly limited.

[0226] If the extruder includes a screw, the screw (or screws) may correspond to the heating section, that is, the screw (or screws) may also be the heating section.

[0227] The speed at which the screw (or screws) rotates may be any suitable speed. For example, the speed of the screw (or screws) may be about 1 rpm to about 500 rpm. In one embodiment, the speed may be about 5 rpm to about 400 rpm, e.g., about 10 rpm to about 100 rpm.

[0228] The voxel-hemi-succinic acid molecular complex is recovered as a crystalline solid. The crystalline molecular complex can be recovered by simply collecting the crystalline product. If desired, a portion of the solvent (if present) can be evaporated prior to the recovery of the crystalline solid.

[0229] Even if the crystalline molecular complex is recovered, the separated molecular complex may be dried. Drying may be performed using known methods, for example, at a temperature in the range of about 10°C to about 60°C, for example, about 20°C to about 40°C, for example, at ambient temperature, under a vacuum (e.g., about 1 mbar to about 30 mbar) for about 1 hour to about 24 hours. Alternatively, the crystalline molecular complex may be allowed to dry naturally at ambient temperature, i.e., without the active application of a vacuum. It is desirable that the drying conditions be maintained below the point at which the molecular complex decomposes; thus, if the molecular complex is known to decompose within the temperature or pressure range given above, the drying conditions should be maintained below the decomposition temperature or under a vacuum.

[0230] In another aspect, the present invention relates to a pharmaceutical composition comprising a crystalline voxel-hemisuccinic acid molecular complex as described herein and a pharmaceutically acceptable excipient.

[0231] In another aspect, the present invention relates to a method for treating a disease associated with oxygen deficiency in a patient, said method comprising the step of administering to said patient a therapeutically effective amount of a crystalline voxelothermophilic acid molecular complex as described herein. The disease associated with oxygen deficiency may be sickle cell disease.

[0232] In another aspect, the present invention relates to a crystalline voxelothermophilic acid molecular complex as described herein for use in treating diseases associated with oxygen deficiency. Diseases associated with oxygen deficiency may be sickle cell disease.

[0233] Embodiments and / or optional features of the present invention are described above. Any aspect of the present invention may be combined with any other aspect of the present invention unless the context otherwise requires. Any embodiment or optional feature of any aspect may be combined with any aspect of the present invention, either alone or in combination, unless the context otherwise requires.

[0234] The present invention will now be further described with reference to the following examples, which are intended to be illustrative rather than limiting the scope of the invention.

[0235] Examples

[0236] 1. Details of the device and method

[0237] 1.1 X-ray Powder Diffraction (XRPD)

[0238] XRPD diffractograms were collected on a Bruker D8 diffractometer using a θ-2θ goniometer equipped with a GE monochromator and Cu Kα radiation (40 kV, 40 mA). The incident beam passed through a 2.0 mm diverging slit, followed by a 0.2 mm anti-scattering slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit, followed by a Lynxeye detector. The software used for data acquisition and analysis was Diffrac, respectively. Plus XRD Commander and Diffrac Plus It was EVA.

[0239] The sample was tested under ambient conditions as a flat plate specimen using the powder as obtained. The sample was prepared on a polished zero-background (510) silicon wafer by gently pressing it over a flat surface or packing it into a cut cavity. The sample was rotated on its own plane.

[0240] The details of the standard data collection method are as follows:

[0241] Angle range: 2 to 42° 2θ

[0242] Step size: 0.05° 2θ

[0243] Collection time: 0.5 s / step (Total collection time: 6.40 min)

[0244] 1.2 Differential Scanning Calorimetry (DSC)

[0245] DSC data were collected on a TA Instruments Q2000 equipped with a 50-position auto-sampler. Typically, 0.5 to 3 mg of each sample was heated in a pinhole aluminum pan from 25°C to 250°C at a rate of 10°C / min. A dry nitrogen purge of 50 ml / min was maintained over the samples.

[0246] Controlled temperature DSC was performed using a basic heating rate of 2℃ / min and a temperature control parameter of ±0.636℃ (amplitude) every 60 seconds (cycle).

[0247] The device control software was Advantage for Q Series and Thermal Advantage, and data was analyzed using Universal Analysis or TRIOS.

[0248] 1.3 Thermogravimetric Analysis (TGA)

[0249] 1.3.1 TA Instruments Q500

[0250] TGA data were collected using a TA Instruments Q500 TGA equipped with a 16-position auto-sampler. Typically, 5 to 10 mg of each sample was loaded onto a pre-emptively weighed aluminum DSC pan and heated from ambient temperature to 350°C at 10°C / min. A nitrogen purge of 60 ml / min was maintained over the samples.

[0251] The device control software was Advantage for Q Series and Thermal Advantage, and data was analyzed using Universal Analysis or TRIOS.

[0252] 1.3.2 TA Instruments Discovery TGA

[0253] TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position auto-sampler. Typically, 5 to 10 mg of each sample was loaded onto a pre-tared aluminum DSC pan and heated from ambient temperature to 350°C at 10°C / min. A nitrogen purge of 25 ml / min was maintained over the samples.

[0254] The device control software was TRIOS, and data was analyzed using TRIOS or Universal Analysis.

[0255] Voxelothor hemipropylene glycol solvate

[0256] Example 1

[0257] A voxel rotor (29 mg) was weighed and placed into an HPLC vial. The solid was moistened with propylene glycol (15 μl), and two 3 mm stainless steel grinding balls were added to the vial. The sample was ground in a planetary mill at 500 rpm for 2 hours. After grinding, the vial was left uncapped overnight to dry.

[0258] Example 2

[0259] A voxel-rotor (2.00 g) was dissolved in TBME (8.00 ml, 4 volumes) at 50°C. Propylene glycol (650 μl, 1.5 eq) was added to this solution, and then cooled to 5°C at a rate of 0.1°C / min. The resulting suspension was filtered under suction and dried.

[0260] Example 3

[0261] Voxelothor (29 mg) was dissolved in isopropyl acetate (150 μl, 5 volumes) at 50°C. Propylene glycol (0.5 eq, 12 μl) was added to the resulting solution and cooled to 5°C at 0.1°C / min. The resulting suspension was filtered under suction and dried.

[0262] Example 4

[0263] Voxelothor (29 mg) was dissolved in diethyl ether (150 μl, 5 volumes) at 50°C. Propylene glycol (0.5 eq, 12 μl) was added to the resulting solution and cooled to 5°C at 0.1°C / min. The resulting suspension was filtered under suction and dried.

[0264] Example 5

[0265] Voxelothor (29 mg) was dissolved in 2-methyl THF (150 μl, 5 volumes) at 50°C. Propylene glycol (0.5 eq, 12 μl) was added to the resulting solution and cooled to 5°C at 0.1°C / min. The resulting suspension was filtered under suction and dried.

[0266] Example 6

[0267] Voxelothor (5.0 g) was dissolved in TBME (20.0 ml, 4 volumes) and heated to 50°C. Propylene glycol (0.6 eq, 650 μl) was added to the resulting solution, cooled to 45°C, seeded with voxelothor hemipropylene glycol solvate (Example 2), and then cooled to 5°C at a rate of 0.5°C / min. At 15°C, heptane (20 ml) was added to the suspension. After cooling to 5°C, the resulting suspension was filtered under suction and dried. The isolated solid was dried under vacuum at room temperature for 1 hour.

[0268] Characterization of voxelotherm hemipropylene glycol solvate

[0269] Figure 1 shows a representative XRPD pattern of voxelotherm hemipropylene glycol solvate. The table below provides a list of XRPD peaks for this solvate:

[0270]

[0271] The voxel-rotor hemipropylene glycol solvate was also characterized by TGA and DSC analysis (see Fig. 2).

[0272] voxelothermophilic fumaric acid molecular complex

[0273] Example 7

[0274] Voxelloter (300 mg) was dissolved in methanol (1.5 ml, 5 volumes) at 50°C. A portion of the heated voxelloter solution (250 μl, approximately 50 mg) was added to a vial containing solid fumaric acid (18 mg, 1 eq), stirred at 50°C for 1 hour, and then cooled to 5°C at a rate of 0.1°C / min. After cooling, the resulting suspension was maintained at 5°C for 7 days, then filtered under suction and dried.

[0275] Example 8

[0276] A solid mixture of voxeloteur (1.00 g) and fumaric acid (173 mg, 0.5 eq) was dissolved in methanol (2.5 ml, 2.5 volume) at 50°C. The resulting solution was stirred at 50°C for 1 hour, then cooled to 5°C at a rate of 0.1°C / min. The resulting concentrated suspension was transferred onto filter paper and dried under ambient conditions.

[0277] Example 9

[0278] Voxelloter (1.00 g) was dissolved in TBME (4.00 ml, 4 volumes) at 50°C. Fumaric acid (0.6 eq, 210 mg in 4 ml of methanol) was added to this solution, cooled to 20°C, and then seeded with the voxelloter hemi-fumaric acid molecular complex (Example 8). The sample was further cooled to 5°C at a rate of 0.1°C / min. The resulting suspension was filtered under suction and dried.

[0279] Example 10

[0280] A solid mixture of voxelotherm (5.00 g) and fumaric acid (0.6 eq, 1035 mg) was dissolved in methanol (12.5 ml, 2.5 volume) and heated to 50°C. The resulting solution was cooled to 45°C, then seeded with a voxelotherm hemi-fumaric acid molecular complex (Example 8), and cooled to 5°C at a rate of 0.5°C / min. At 5°C, the resulting concentrated suspension was treated with TBME (5 ml) to extract the solid. After an additional 2 hours at 5°C, the suspension was filtered under suction and dried. The isolated solid was dried under vacuum at room temperature for 1 hour.

[0281] Characterization of voxelotherm hemi fumaric acid molecular complex

[0282] Figure 3 shows a representative XRPD pattern of a voxelothermophilic fumaric acid molecular complex. The table below provides a list of XRPD peaks for this molecular complex:

[0283]

[0284] The voxelothermophilic fumaric acid molecular complex was also characterized by TGA and DSC analysis (see Fig. 4).

[0285] voxelothermophilic succinic acid molecular complex

[0286] Example 11

[0287] Voxelothor (30 mg) and 0.5 eq succinic acid (6.1 mg) were weighed and placed into an HPLC vial. The solid was moistened with methanol (15 μl, 0.5 volume), and two 3 mm stainless steel grinding balls were added to the vial. The sample was ground in a planetary mill at 500 rpm for 2 hours. After grinding, the vial was left uncapped to dry the solid, and then analyzed by XRPD.

[0288] Example 12

[0289] A voxel rotor (1.00 g) and 0.5 eq succinic acid (175 mg) were weighed and placed into a 10 ml stainless steel grinding jar containing 7 mm stainless steel grinding balls. The solid mixture was ground in a retch mill at 30 Hz for 2 minutes to homogenize the solid, and then wetted with methanol (500 μl, 0.5 volume). The sample was further ground four times at 30 Hz for 30 minutes (total time 120 minutes).

[0290] Example 13

[0291] A solid mixture of voxelotherm (5.00 g) and succinic acid (0.5 eq, 875 mg) was suspended in TBME (25.0 ml, 5 volumes) and heated to 50°C. The resulting suspension was stirred at 50°C for 2 hours, and subsequently, the suspension was cooled to 5°C at a rate of 0.5°C / min. At 5°C, the suspension was filtered under suction and dried.

[0292] Characterization of the voxelothermophilic succinic acid molecular complex

[0293] Figure 5 shows a representative XRPD pattern of the voxelothermophilic acid molecular complex. The table below provides a list of XRPD peaks for this molecular complex:

[0294]

[0295] The voxelothermophilic acid molecular complex was also characterized by TGA and DSC analysis (see Fig. 6).

Claims

Claim 1 A crystalline form of voxelrotor, which is a crystalline voxelrotor hemisuccinic acid molecular complex having the X-ray powder diffraction pattern shown in the table below. Claim 2 delete Claim 3 delete Claim 4 A crystalline form of voxelotherm, which is a crystalline voxelotherm hemi-fumaric acid molecular complex having the X-ray powder diffraction pattern shown in the table below. Claim 5 delete Claim 6 delete Claim 7 A crystalline form of voxeltor, which is a crystalline voxeltor hemipropylene glycol solvate having the X-ray powder diffraction pattern shown in the table below. Claim 8 delete Claim 9 delete Claim 10 A pharmaceutical composition comprising a voxel-rotor and a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is intended for use in treating sickle cell disease, and the voxel-rotor is selected from the group consisting of (i) a crystalline form according to claim 1, (ii) a crystalline form according to claim 4, and (iii) a crystalline form according to claim 7. Claim 11 A pharmaceutical composition for use in treating sickle cell disease in a patient, comprising a therapeutically effective amount of voxelotherm, wherein the voxelotherm is selected from the group consisting of (i) a crystalline form according to claim 1, (ii) a crystalline form according to claim 4, and (iii) a crystalline form according to claim 7. Claim 12 delete Claim 13 A voxel rotor for use in treating diseases associated with oxygen deficiency, wherein the voxel rotor is selected from the group consisting of (i) a crystalline form according to claim 1, (ii) a crystalline form according to claim 4, and (iii) a crystalline form according to claim 7. Claim 14 In paragraph 13, a voxel rotor for use in treating the disease associated with the oxygen deficiency, which is sickle cell disease.

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