CN114539339A - Ruideciclovir oxalate and preparation method thereof - Google Patents
Ruideciclovir oxalate and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a Ruideciclovir oxalate and a preparation method thereof, belonging to the technical field of pharmaceutical chemicals. The crystal form of the Ruideciclovir oxalate provided by the invention has the advantages of good stability and high solubility, is beneficial to the research of pharmaceutical preparations, and meanwhile, the preparation method of the crystal form is simple, convenient to operate, mild in condition and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and relates to Ruidexiwei oxalate and a preparation method thereof.
Background
The Reidesciclovir is an antitoxic drug, and has a structural formula shown as the following formula:
four crystalline forms of the free base of Reidesciclovir (forms I, II, III, IV) and crystalline form I of its maleate salt are disclosed in patent application CN110636884A, with form II being the most stable form.
The solubility of the drug is an important factor influencing the absorption efficiency and bioavailability of the drug, and the physicochemical properties of the drug, such as solubility, stability and the like, can be improved by a salifying means, thereby having a key effect on further developing a drug dosage form.
The solubility of the crystal form of the free base of the Reidesciclovir is low, and the mixture of the crystal form II and the crystal form IV of the Reidesciclovir free base can be easily obtained in the production process, so that a solid form with higher solubility and better stability is needed to be searched.
Summary of The Invention
In a first aspect, the invention provides a crystalline form of ridciclovir oxalate.
According to the embodiment of the invention, the crystal forms of the Reidesciclovir oxalate are respectively named as a Reidesciclovir oxalate crystal form I, a Reidesciclovir oxalate crystal form II and a Reidesciclovir oxalate crystal form III.
The crystal form of the Ruideciclovir oxalate provided by the invention has the advantages of good stability, high solubility and the like.
The crystalline form I of the Ruideciclovir oxalate contains diffraction peaks with 2theta angles of 5.39, 7.28, 14.57, 16.57 and 19.93 degrees in an X-ray powder diffraction pattern.
In some embodiments, crystalline form I of rdisivir oxalate according to the present invention has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.39, 7.28, 8.29, 11.61, 14.57, 16.57, 19.93, and 24.97 degrees. In some embodiments, the crystalline form I of rdisivir oxalate comprises diffraction peaks at 2 Θ angles of 5.39, 7.28, 8.29, 8.71, 11.61, 14.57, 16.57, 19.93, 21.82, 22.27, 24.97, 25.96, 27.11, 28.25, and 29.62 degrees in an X-ray powder diffraction pattern. In some embodiments, the crystalline form I of rdisivir oxalate has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.39, 7.28, 8.29, 8.71, 11.61, 12.39, 14.57, 16.57, 17.45, 18.12, 18.78, 19.35, 19.93, 21.61, 21.82, 22.27, 22.92, 23.44, 24.97, 25.96, 27.11, 28.25, 29.25, 29.62, and 31.30 degrees.
In some embodiments, crystalline form I of ridciclovir oxalate has an X-ray powder diffraction pattern substantially as shown in figure 1.
The differential scanning calorimetry curve of the crystal form I of the Ruideciclovir oxalate has an endothermic peak at the temperature of 146-156 ℃. In some embodiments, the differential scanning calorimetry curve of crystalline form I of the ridciclovir oxalate described herein has an endothermic peak at 151 ℃. In some embodiments, the differential scanning calorimetry curve for crystalline form I of the ridciclovir oxalate described herein is substantially as shown in figure 2.
The thermogravimetric analysis curve of the crystal form I of the Ruideciclovir oxalate shows that the weight loss of the crystal form I is less than 1.0 percent in the temperature range of 30-160 ℃. In some embodiments, the crystalline form I of the ridciclovir oxalate has a thermogravimetric analysis curve showing that the crystalline form I loses 0.4% weight in the temperature range of 30 ℃ to 160 ℃. In some embodiments, the crystalline form I of rdciclovir oxalate has a thermogravimetric analysis curve substantially as shown in figure 3. The weight loss of the crystal form I of the Ruideciclovir oxalate is less than 1.0 percent, and the crystal form I can be considered as an anhydrous crystal form.
The crystal form II of the Ruideciclovir oxalate contains diffraction peaks with 2theta angles of 5.36 degrees, 8.89 degrees, 11.13 degrees, 16.14 degrees, 19.51 degrees and 24.98 degrees in an X-ray powder diffraction pattern.
The X-ray powder diffraction pattern of the crystal form II of the Rudexilvir oxalate comprises diffraction peaks with 2theta angles of 5.36 degrees, 8.89 degrees, 11.13 degrees, 14.16 degrees, 16.14 degrees, 19.51 degrees, 23.17 degrees and 24.98 degrees. In some embodiments, the crystalline form II of rdisivir oxalate has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.36, 8.04, 8.89, 11.13, 12.84, 13.19, 14.16, 15.25, 16.14, 17.31, 17.83, 19.51, 21.59, 23.17, and 24.98 degrees. In some embodiments, the crystalline form II of rdisivir oxalate has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.36, 8.04, 8.89, 9.81, 10.35, 11.13, 12.84, 13.19, 13.83, 14.16, 15.25, 16.14, 17.31, 17.83, 18.35, 18.60, 19.51, 20.39, 20.91, 21.59, 23.17, 24.98, 25.99, 26.98, 28.06, and 29.50 degrees.
In some embodiments, the crystalline form II of ridciclovir oxalate has an X-ray powder diffraction pattern substantially as shown in figure 4.
The differential scanning calorimetry curve of the crystal form II of the Ruideciclovir oxalate has an endothermic peak at the temperature of 147-157 ℃. In some embodiments, the differential scanning calorimetry curve of crystalline form II of the ridciclovir oxalate described herein has an endothermic peak at 152 ℃. In some embodiments, the differential scanning calorimetry curve for crystalline form II of the ridciclovir oxalate described herein is substantially as shown in figure 5.
The thermogravimetric analysis curve of the crystal form II of the Ruideciclovir oxalate shows that the weight loss of the crystal form II is less than 1.0 percent in the temperature range of 30-150 ℃. In some embodiments, the crystalline form II of the ridciclovir oxalate has a thermogravimetric analysis curve that shows that the crystalline form II loses 0.76% of weight in the temperature range of 30 ℃ to 150 ℃. In some embodiments, the crystalline form III of rdisivir oxalate has a thermogravimetric analysis curve substantially as shown in figure 6. The weight loss of the crystal form II of the Ruidexiwei oxalate is less than 1.0 percent, and the crystal form II can be considered as an anhydrous crystal form.
The crystal form III of the Ruideciclovir oxalate contains diffraction peaks with 2theta angles of 5.01, 16.35, 21.84, 24.14 and 26.46 degrees in an X-ray powder diffraction pattern.
The X-ray powder diffraction pattern of the crystal form III of the Rudesivir oxalate comprises diffraction peaks with 2theta angles of 5.01, 13.43, 16.35, 18.62, 21.84, 24.14, 25.37, 25.82 and 26.46 degrees. In some embodiments, the crystalline form III of rdisivir oxalate has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.01, 9.91, 13.43, 14.86, 16.35, 18.62, 19.79, 21.84, 24.14, 25.23, 25.37, 25.82, and 26.46 degrees. In some embodiments, the crystalline form III of rdisivir oxalate has an X-ray powder diffraction pattern comprising diffraction peaks at 2 Θ angles of 5.01, 9.91, 11.00, 11.78, 12.92, 13.43, 13.79, 14.40, 14.86, 16.35, 18.62, 19.79, 20.47, 21.84, 22.66, 23.66, 24.14, 25.23, 25.37, 25.82, 26.46, 26.91, 30.05, and 30.31 degrees.
In some embodiments, the crystalline form III of rdisivir oxalate has an X-ray powder diffraction pattern substantially as shown in figure 7.
The differential scanning calorimetry curve of the crystal form III of the Ruideciclovir oxalate has an endothermic peak at 81-91 ℃. In some embodiments, the differential scanning calorimetry curve of crystalline form III of the ridciclovir oxalate described herein has an endothermic peak at 86 ℃. In some embodiments, the differential scanning calorimetry curve for crystalline form III of the ridciclovir oxalate described herein is substantially as shown in figure 8.
The thermogravimetric analysis curve of the crystal form III of the Ruideciclovir oxalate shows that the weight loss of the crystal form III is less than 3.0 percent in the temperature range of 30-100 ℃. In some embodiments, the crystalline form III of the ridciclovir oxalate has a thermogravimetric analysis curve showing that the crystalline form III loses 2.17% weight in the temperature range of 30 ℃ to 100 ℃. In some embodiments, the crystalline form III of rdisivir oxalate has a thermogravimetric analysis curve substantially as shown in figure 9. The weight loss of the crystal form III of the Ruideciclovir oxalate is less than 3.0 percent, and the Ruideciclovir oxalate possibly contains residual solvent.
The crystal form II of the Ruidexiwei oxalate can be used for treating novel coronavirus infection and the like.
Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of crystalline form II of ridciclovir oxalate and a pharmaceutically acceptable adjuvant or excipient. A therapeutically effective amount of crystalline form II of the oxalate salt of reiciclovir is typically mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, which is prepared in a manner well known in the pharmaceutical art. The pharmaceutical composition or preparation can be used for resisting virus and treating diseases related to virus infection, such as new coronary pneumonia and the like.
The invention provides a pharmaceutical composition, which can contain at least 0.1-10% of the crystal form II based on the total weight of the composition. The present invention provides a pharmaceutical composition which may contain at least 0.1% to 5% of said crystalline form II by total weight of the composition. The invention provides a pharmaceutical composition which can contain at least 0.1-1% of the crystal form II based on the total weight of the composition. In some embodiments, the present invention provides a pharmaceutical composition comprising at least 0.1% to 0.5% of said crystalline form II, by total weight of the composition.
The pharmaceutical composition provided by the invention contains the Reidcvir, wherein at least 80% of the Reidcvir is the Reidcvir oxalate crystal form II. In some embodiments, a pharmaceutical composition comprises redciclovir wherein at least 90% by mass of the redciclovir is said redciclovir oxalate form II. In some embodiments, a pharmaceutical composition comprises redciclovir wherein at least 95% of the redciclovir is said redciclovir oxalate form II, by mass ratio. In some embodiments, a pharmaceutical composition comprises redciclovir wherein at least 99% of the redciclovir is said redciclovir oxalate form II, by mass ratio.
In some embodiments, the pharmaceutical composition has a purity of at least 80% for form II relative to redciclovir oxalate. In some embodiments, the purity of form II in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99% relative to reidecivir.
The pharmaceutical composition containing the Ruidexiwei oxalate crystal form II can be used for preparing pharmaceutical preparations for treating neocoronary pneumonia and the like. The pharmaceutical composition containing the Rudexilvir oxalate crystal form II can be used in a method for treating diseases such as novel coronavirus infection.
The crystal form II provided by the invention has good stability and solubility, is not easy to deliquesce under a high-humidity condition, is convenient for long-term storage and placement of the medicine, and can well avoid crystal transformation in the process of medicine storage and development, thereby avoiding the change of bioavailability and efficacy and having strong economic value.
In a second aspect of the invention, a preparation method of a crystal form of Rudexilvir oxalate is provided. The preparation method is simple, convenient to operate, mild in condition and suitable for industrial production.
The invention provides a preparation method of a crystal form I of Rudexilevir oxalate.
The preparation method of the Ruideciclovir oxalate crystal form I is simple, convenient to operate, mild in condition and suitable for industrial production.
A process for preparing crystalline form I of ridciclovir oxalate comprising: dissolving the Rudesavir in a good solvent, adding oxalic acid into the solution to react for a period of time, then slowly dropwise adding the poor solvent, stirring at room temperature until a solid is separated out, filtering and drying to obtain a Rudesavir oxalate crystal form I product.
The good solvent is alcohol. In some embodiments, the good solvent is methanol.
The poor solvent is ether. In some embodiments, the poor solvent is isopropyl ether.
The reaction temperature may be 20 ℃ to 80 ℃. In some embodiments, the reaction temperature is from 20 ℃ to 50 ℃. In some embodiments, the reaction temperature is from 20 ℃ to 40 ℃. In some embodiments, the reaction temperature is from 30 ℃ to 40 ℃. In some embodiments, the reaction temperature is 20 ℃. In some embodiments, the reaction temperature is 30 ℃. In some embodiments, the reaction temperature is 40 ℃. In some embodiments, the reaction temperature is 50 ℃.
The feeding molar ratio of the Reidesciclovir to the oxalic acid can be 1: 1-1: 3. In some embodiments, the ratio of the fed moles of the reed-solomon and oxalic acid is 1: 1. In some embodiments, the ratio of the reed-solomon to oxalic acid feed mole is 1: 2. In some embodiments, the ratio of the reed-solomon to oxalic acid feed mole is 1: 3.
The mass-volume ratio of the Reidesciclovir to the methanol can be 10 mg/mL-100 mg/mL. In some embodiments, the mass to volume ratio of the Reidesciclovir to methanol is 10 mg/mL. In some embodiments, the ratio of the mass to volume of the reed-solomon to methanol is 40 mg/mL. In some embodiments, the ratio of the mass to volume of the reed-solomon to methanol is 100 mg/mL.
The volume of the poor solvent can be 0.5 to 10 times of the volume of the good solvent. In some embodiments, the volume of poor solvent is 3 times the volume of good solvent. In some embodiments, the volume of poor solvent is 5 times the volume of good solvent. In some embodiments, the volume of poor solvent is 10 times the volume of good solvent.
The invention provides a preparation method of a crystal form II of Reidesciclovir oxalate.
The preparation method of the Ruideciclovir oxalate crystal form II is simple, convenient to operate, mild in condition and suitable for industrial production.
A process for preparing crystalline form II of ridciclovir oxalate comprising: dissolving the Reidesciclovir in an organic solvent 1, adding oxalic acid, suspending and pulping under a heating condition, filtering, and drying to obtain a Reidesciclovir oxalate crystal form II product.
The feeding molar ratio of the Reidesciclovir to the oxalic acid can be 1: 1-1: 3. In some embodiments, the ratio of the reed-solomon to oxalic acid feed mole is 1: 1. In some embodiments, the ratio of the reed-solomon to oxalic acid feed mole is 1: 2. In some embodiments, the ratio of the reed-solomon to oxalic acid feed mole is 1: 3.
The organic solvent 1 is a ketone. In some embodiments, the organic solvent 1 is acetone.
The mass-volume ratio of the Reidesciclovir to the organic solvent 1 can be 10 mg/mL-100 mg/mL. In some embodiments, the mass-to-volume ratio of the Reidesciclovir to the organic solvent 1 is from 10mg/mL to 80 mg/mL. In some embodiments, the mass-to-volume ratio of the Reidesciclovir to the organic solvent 1 is from 10mg/mL to 50 mg/mL. In some embodiments, the ratio of the mass to volume of the ridciclovir to the organic solvent 1 is 10mg/mL to 30 mg/mL. In some embodiments, the mass-to-volume ratio of the Reidesciclovir to the organic solvent 1 is from 30mg/mL to 50 mg/mL. In some embodiments, the ratio of the mass to volume of the ridciclovir to the organic solvent 1 is 50mg/mL to 80 mg/mL. In some embodiments, the mass-to-volume ratio of the Reidesciclovir to the organic solvent 1 is 80mg/mL to 100 mg/mL. In some embodiments, the mass to volume ratio of the Reidesciclovir to the organic solvent 1 is 10 mg/mL. In some embodiments, the mass to volume ratio of the Reidesciclovir to the organic solvent 1 is 30 mg/mL. In some embodiments, the mass to volume ratio of the Reidesciclovir to the organic solvent 1 is 50 mg/mL. In some embodiments, the mass to volume ratio of the Reidesciclovir to the organic solvent 1 is 80 mg/mL. In some embodiments, the mass to volume ratio of the Reidesciclovir to the organic solvent 1 is 100 mg/mL.
The pulping time can be 10-16 h. In some embodiments, the pulping time is from 10 hours to 14 hours. In some embodiments, the pulping time is from 10 hours to 12 hours. In some embodiments, the pulping time is from 12 hours to 14 hours. In some embodiments, the pulping time is from 14 hours to 16 hours. In some embodiments, the pulping time is 10 hours. In some embodiments, the pulping time is 12 hours. In some embodiments, the break time is 14 hours. In some embodiments, the break time is 16 h.
The pulping temperature can be 30-60 ℃. In some embodiments, the pulping temperature is from 30 ℃ to 50 ℃. In some embodiments, the pulping temperature is from 30 ℃ to 40 ℃. In some embodiments, the pulping temperature is from 40 ℃ to 50 ℃. In some embodiments, the pulping temperature is from 40 ℃ to 60 ℃. In some embodiments, the pulping temperature is from 50 ℃ to 60 ℃. In some embodiments, the pulping temperature is 30 ℃. In some embodiments, the pulping temperature is 40 ℃. In some embodiments, the pulping temperature is 50 ℃. In some embodiments, the suspension beating temperature is 60 ℃.
The invention provides a preparation method of a crystal form III of Ruideciclovir oxalate.
The preparation method of the crystal form III of the Ruidexiwei oxalate is simple, convenient to operate, mild in condition and suitable for industrial production.
A process for preparing crystalline form III of rdisivir oxalate comprising: adding the ridciclovir and oxalic acid into an organic solvent 2, suspending and pulping for a period of time at room temperature, filtering, and drying to obtain a crystal form III product of the ridciclovir oxalate.
The feeding molar ratio of the Reidesciclovir to the oxalic acid can be 1: 1-1: 3. In some embodiments, the ratio of the fed moles of the reed-solomon and oxalic acid is 1: 1.
The organic solvent 2 is alkane. In some embodiments, the organic solvent 2 is n-heptane.
The mass-volume ratio of the Reidesciclovir to the n-heptane can be 10 mg/mL-60 mg/mL. In some embodiments, the mass to volume ratio of the Reidesciclovir to n-heptane is 10 mg/mL. In some embodiments, the ratio of the mass to volume of the ridciclovir to the mass to volume of the n-heptane is 40 mg/mL. In some embodiments, the ratio of the mass to volume of the reed-solomon to n-heptane is 60 mg/mL.
The pulping time can be 24-48 h. In some embodiments, the pulping time is from 24 hours to 36 hours. In some embodiments, the pulping time is from 36h to 48 h. In some embodiments, the pulping time is 24 hours. In some embodiments, the pulping time is 36 hours. In some embodiments, the pulping time is 48 hours.
The preparation method can obtain the crystal form, and has convenient operation and mild conditions.
Definition of terms
"crystalline form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.
"amorphous" or "amorphous form" refers to a substance formed when particles (molecules, atoms, ions) of the substance are aperiodically arranged in three-dimensional space, characterized by a diffuse, non-peaked X-ray powder diffraction pattern. Amorphous is a particular physical form of solid material, with locally ordered structural features suggesting a myriad of connections to crystalline materials. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.
"good solvent" or "solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
"poor solvent" or "antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
"solvate" means having a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice, which may be water, 1, 4-dioxane, dimethyl carbonate, butyl formate, acetonitrile, isopropanol, ethylene glycol dimethyl ether, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.
Crystalline forms or amorphous forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.
Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.
Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program2O3) The energy difference therebetween varies with temperature. The melting peak height of the DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The melting peak has a tolerance of + -3 deg.C depending on the condition of the instrument used in the test.
Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be estimated that the crystal contains crystal water or a crystallization solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.
The term "substantially as shown in the figure" means that substantially pure certain "crystalline form" has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in its X-ray powder diffraction pattern that appear in the X-ray powder diffraction pattern given. When the content of a certain crystal form in a sample is gradually reduced, some diffraction peaks in an X-ray powder diffraction pattern of the sample, which are attributed to the crystal form, may be reduced due to the detection sensitivity of an instrument.
In the context of the present invention, the diffraction angle 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (. degree.).
The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not ascribe to background noise.
In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may differ by 1%, 2%, or 5%. When used to approximate the 2theta (also known as 2theta or diffraction peak) value used to describe the X-ray powder diffraction peak, approximately means that there may be a +/-0.2 unit or +/-0.1 unit or +/-0.05 unit difference in the 2theta value.
The term "room temperature" means a temperature of about 20 ℃ to 35 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.
In some embodiments, the solubility of resisitivir in a good solvent is greater than in an anti-solvent; in some embodiments, the difference in solubility of the good solvent and the anti-solvent for the sample is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%; in some embodiments, the good solvent has greater solubility for reidesavir than the anti-solvent, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
In the context of the present invention, positive dropping means dropping a good solvent into an anti-solvent, and anti-dropping means dropping an anti-solvent into a good solvent.
In the present invention, mg/mL means mg/mL, h means hour, g means g, mL means mL, DEG C means centigrade, mL/min means mL/min, and RH means relative humidity.
Drawings
Figure 1 shows an XRPD spectrum of crystalline form I of rdisivir oxalate with 2 θ angle in degrees (°) on the abscissa and relative intensity counts (intensity (counts)) on the ordinate;
FIG. 2 shows a DSC spectrum of crystalline form I of Redcisvir oxalate with temperature on the abscissa and Heat Flow (Heat Flow) on the ordinate and Watt/gram (W/g) on the ordinate;
FIG. 3 shows a TGA spectrum of crystalline form I of Redcisvir oxalate with temperature on the abscissa and Weight loss in degrees C on the ordinate (Weight,%);
figure 4 shows an XRPD spectrum of crystalline form II of rdisivir oxalate with 2 θ angle in degrees (°) on the abscissa and relative intensity counts (intensity (counts)) on the ordinate;
FIG. 5 shows a DSC spectrum of crystalline form II of Redcisvir oxalate with temperature on the abscissa and Heat Flow (Heat Flow) on the ordinate and Watt/gram (W/g) on the ordinate;
figure 6 shows a TGA spectrum of crystalline form II of ridciclovir oxalate with temperature on the abscissa and Weight loss in units deg.c on the ordinate (Weight,%);
figure 7 shows an XRPD spectrum of crystalline form III of rdisivir oxalate with 2 θ angle in degrees (°) on the abscissa and relative intensity counts (intensity (counts)) on the ordinate;
FIG. 8 shows a DSC spectrum of crystalline form III of Redcisvir oxalate with temperature on the abscissa and Heat Flow (Heat Flow) on the ordinate and Watt/gram (W/g) on the ordinate;
figure 9 shows a TGA spectrum of crystalline form III of ridciclovir oxalate with temperature on the abscissa and Weight loss in units deg.c on the ordinate (Weight,%);
figure 10 shows the results of a 15 day effect factor experiment for crystalline form II of rdisivir oxalate with 2Theta angle (2Theta), units (°), and relative intensity counts (intensity (counts)) on the abscissa.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the invention are either commercially available or can be prepared by the methods described herein.
Example 1: preparation of crystalline form I of Reidesciclovir oxalate
Dissolving 60.0mg of Darisvir in 1mL of methanol in an amorphous form, adding 9.0mg of anhydrous oxalic acid, reacting at 50 ℃ for 12h, cooling to room temperature, slowly dropwise adding 5mL of isopropyl ether, and continuously stirring until solid is separated out. Filtering and drying to obtain 52.4mg of white solid product, which is detected as oxalate crystal form I, and the XRPD, DSC and TGA spectrums thereof are respectively basically consistent with that of figure 1, figure 2 and figure 3.
1H NMR(CD3OD)δ7.93(s,1H),7.35(t,J＝7.9Hz,2H),7.18(t,J＝8.7Hz,3H),6.91(d,J＝4.5Hz,1H),6.83(d,J＝4.5Hz,1H),6.03(dd,J＝13.0,10.2Hz,1H),4.64(d,J＝4.8Hz,1H),4.30–4.20(m,2H),4.13–4.04(m,1H),3.95(dd,J＝10.9,5.8Hz,2H),1.41(dq,J＝12.1,6.0Hz,1H),1.29–1.18(m,7H),0.79(t,J＝7.4Hz,6H)。
Example 2: preparation of crystalline form II of Ruideciclovir oxalate
Amorphous 40.0mg of Reidesciclovir is dissolved in 0.5mL of acetone, 6.0mg of anhydrous oxalic acid is added, the mixture is stirred for 16 hours at 30 ℃, filtered and dried to obtain a white solid product 32.2mg, the white solid product is detected as oxalate crystal form II, and XRPD, DSC and TGA spectrums of the white solid product are respectively basically consistent with those of figure 4, figure 5 and figure 6.
1H NMR(CD3OD)δ7.93(s,1H),7.35(t,J＝7.8Hz,2H),7.18(t,J＝9.1Hz,3H),6.91(d,J＝4.5Hz,1H),6.84(d,J＝4.5Hz,1H),6.04(dd,J＝12.9,10.2Hz,1H),4.64(d,J＝4.9Hz,1H),4.30–4.19(m,2H),4.10(dd,J＝11.4,5.4Hz,1H),3.96(dd,J＝10.9,5.8Hz,2H),1.41(dd,J＝12.3,6.2Hz,1H),1.30–1.16(m,7H),0.79(t,J＝7.4Hz,6H)。
Example 2: preparation of crystalline form II of Ruideciclovir oxalate
600mg of Reidesciclovir is amorphous dissolved in 20mL of acetone, 90mg of anhydrous oxalic acid is added, stirring is carried out for 12h at 50 ℃, filtering and drying are carried out, 627mg of white solid product is obtained, the white solid product is detected as oxalate crystal form II, and XRPD, DSC and TGA spectrums of the white solid product are respectively basically consistent with those in figure 4, figure 5 and figure 6.
1H NMR(CD3OD)δ7.93(s,1H),7.35(t,J＝7.8Hz,2H),7.18(t,J＝9.1Hz,3H),6.91(d,J＝4.5Hz,1H),6.84(d,J＝4.5Hz,1H),6.04(dd,J＝12.9,10.2Hz,1H),4.64(d,J＝4.9Hz,1H),4.30–4.19(m,2H),4.10(dd,J＝11.4,5.4Hz,1H),3.96(dd,J＝10.9,5.8Hz,2H),1.41(dd,J＝12.3,6.2Hz,1H),1.30–1.16(m,7H),0.79(t,J＝7.4Hz,6H)。
Example 3: preparation of crystalline form III of Ruideciclovir oxalate
Suspending and pulping 30.0mg of amorphous Ruidexiwei and 4.5mg of anhydrous oxalic acid in 1mL of n-heptane at room temperature for 48h, filtering, and drying to obtain 25.5mg of a white solid product, wherein the white solid product is detected as oxalate crystal form III, and XRPD, DSC and TGA spectrums of the white solid product are respectively basically consistent with those of figure 7, figure 8 and figure 9.
1H NMR(CD3OD)δ7.93(s,1H),7.35(t,J＝7.9Hz,2H),7.18(t,J＝8.5Hz,3H),6.91(d,J＝4.5Hz,1H),6.84(d,J＝4.5Hz,1H),6.04(dd,J＝12.9,10.2Hz,1H),4.65(d,J＝4.9Hz,1H),4.31–4.20(m,2H),4.14–4.05(m,1H),1.42(dt,J＝12.4,6.2Hz,1H),1.29–1.18(m,7H),0.80(t,J＝7.4Hz,6H)。
Example 4: test for influence factor
According to the guiding principle of the stability test of the pharmaceutical preparation, influence factor experiments including a high temperature test, a high humidity test and a strong light irradiation test are carried out on the crystal form II of the Rudexilvir oxalate, and the influence on the stability of the crystal form is investigated.
High-temperature test: taking a proper amount of a Ruidexiwei oxalate crystal form II sample respectively, flatly placing the samples in weighing bottles, placing the samples in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5%, then taking about 100mg of the samples in 5, 10 and 15 days respectively, and testing the crystal form condition of the samples by adopting X-ray powder diffraction (XRPD), wherein the results are shown in Table 1, and an XRPD contrast diagram is shown in FIG. 10 (0 day, 15 days of high humidity and 15 days of high temperature and 15 days of illumination from bottom to top in sequence).
High humidity test: taking a proper amount of a Ruidexiwei oxalate crystal form II sample respectively, flatly placing the samples in weighing bottles, placing the samples in a constant temperature and humidity box with the temperature of 25 ℃ and RH of 92.5 +/-5 percent, taking about 100mg of the samples in 5 days, 10 days and 15 days respectively, and testing the crystal form condition of the samples by X-ray powder diffraction (XRPD), wherein the results are shown in Table 1.
And (3) illumination test: taking a proper amount of a sample of the crystal form II of the oxalate of the Reidesciclovir respectively, flatly spreading the sample into a weighing bottle, placing the sample in a constant temperature and humidity box (25 ℃, RH 60% +/-5%) with visible light 4500Lux +/-500 Lux (VIS) and ultraviolet light 1.7W X h/m2(UV), taking about 100mg of the sample respectively at 5 days, 10 days and 15 days, and testing the crystal form condition by X-ray powder diffraction (XRPD), wherein the results are shown in Table 1.
Table 1: stability test results of crystalline form II of Ruideciclovir oxalate
As a result: the crystal form II of the Ruidexiwei oxalate is not changed after being placed for 15 days under the test conditions of high temperature, high humidity and illumination influence factors, and has good stability.
Example 5: solubility test
Solubility contrast studies of Reidesciclovir oxalate with the free base:
preparing a saturated solution from the crystal form II of the Rudexiliwei oxalate and the crystal form II + the crystal form IV of the Rudexiliwei free base in the patent CN110636884A by using purified water respectively, balancing the saturated solution at 37 ℃ for 4 hours, filtering the solution by using a water system filter membrane, detecting the filtrate by using a High Performance Liquid Chromatography (HPLC), calculating the solubility of a sample, performing parallel measurement on each batch of samples twice, and taking an average value, wherein the solubility measurement result is shown in Table 2.
Table 2: results of solubility measurement
| Type of salt | Solubility (mg/mL) |
| Crystalline forms II + IV of the free base of Rudexilvir | 0.012 |
| Crystalline form II of Reidesciclovir oxalate | 0.180 |
The result shows that the solubility of the crystal form II of the Ruidexilvir oxalate is improved by nearly 15 times compared with the free alkali mixed crystal II + IV after the crystal form II of the Ruidexilvir oxalate is balanced in pure water at 37 ℃ for 4 hours.
Instrument parameters, test conditions and characterization results
Instrument information:
1) x-ray powder diffraction analyzer (XRPD) -PANalytical;
2) differential Scanning Calorimeter (DSC) -TA Q2000;
3) thermogravimetric analyzer (TGA) - -TA Q500;
the test method comprises the following steps:
1) XRPD method
2) DSC method
The DSC process parameters were as follows:
30-300℃，10℃/min；N2(50mL/min)；
3) TGA process
The TGA process parameters are as follows:
30-300℃，10℃/min；N2(60mL/min)。
while the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017184668A1 (en) * | 2016-04-20 | 2017-10-26 | Gilead Sciences, Inc. | Methods for treating flaviviridae virus infections |
| CN110636884A (en) * | 2017-05-01 | 2019-12-31 | 吉利德科学公司 | (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7 Crystalline form of -2-ethylbutyl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017184668A1 (en) * | 2016-04-20 | 2017-10-26 | Gilead Sciences, Inc. | Methods for treating flaviviridae virus infections |
| CN110636884A (en) * | 2017-05-01 | 2019-12-31 | 吉利德科学公司 | (S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7 Crystalline form of -2-ethylbutyl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid |
Non-Patent Citations (1)
| Title |
|---|
| 弋东旭等: "药物共晶研究进展及应用", 中国抗生素杂志, vol. 36, no. 8, 31 December 2011 (2011-12-31), pages 561 - 565 * |
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