CN113173881B - Crystal form of hydroxyl-niatone and preparation method and application thereof - Google Patents
Crystal form of hydroxyl-niatone and preparation method and application thereof Download PDFInfo
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- CN113173881B CN113173881B CN202110287773.2A CN202110287773A CN113173881B CN 113173881 B CN113173881 B CN 113173881B CN 202110287773 A CN202110287773 A CN 202110287773A CN 113173881 B CN113173881 B CN 113173881B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a novel crystal form of oxycodone, a preparation method and application thereof, in particular to a novel crystal form of oxycodone with better stability, oral exposure and bioavailability.
Description
Technical Field
The invention relates to a novel crystal form of hydroxyl-nitone, a preparation method and application thereof, belonging to the field of pharmaceutical chemistry.
Background
Fibrosis is a very widespread disease that can occur in a variety of organs, with the major pathological changes being fibrous connective tissue augmentation within the organ tissue, parenchymal cell depletion, with continued progression leading to destruction of the organ structure and functional decline until organ failure. Once fibrosis occurs, organ function is greatly compromised.
Hepatic fibrosis is a pathophysiological process and is a common pathological basis in the progress of chronic liver diseases. Various pathogenic factors cause degeneration and necrosis of liver cells and abnormal proliferation of connective tissues. If the damaging factors in the course of liver repair are not removed for a long period of time, the long-lasting fibrosis process will eventually lead to the development of cirrhosis.
Hepatic fibrosis can be caused by various chronic diseases, such as chronic viral hepatitis, chronic alcoholism, cholestasis, congenital enzyme-deficient metabolic disorder diseases, long-term exposure to poisons and medicines, and the like. At present, fewer drugs can be used for treating hepatic fibrosis, so that the requirements on safe and effective related drugs exist.
Nicotine (Hydronidone) is a drug for treating hepatic fibrosis, is coded by F351 in research and development, and currently, the II-phase clinical research in China evaluates the curative effect and safety of treating hepatic fibrosis of patients with chronic hepatitis B. The chemical name of the hydroxyl-niadone is N- (4-hydroxyphenyl) -5-methyl-2-pyridone, and the chemical formula is as follows:
various methods exist in the art for preparing the oxycodone compounds.
N-substituted 2 (1H) pyridinone derivatives or pharmaceutically acceptable salts thereof for use in the treatment of various fibrotic diseases, such as liver fibrosis, are disclosed in CN100358872C, wherein a preferred compound is F351 (hydroxyanisolone). In the preparation of this compound, the final product is obtained by recrystallization using ethanol as a solvent.
CN101723883A relates to a synthesis method of hydroxyl-niadone, wherein final products are obtained by concentrating mother liquor (using ethanol as a solvent), adding ethanol into tetrahydrofuran and adding ethanol into dichloromethane respectively.
CN 1076988498A, CN 1076988499A, WO2018028508A1 and WO2018028506A1 respectively disclose a preparation method of hydroxyanisolone, wherein after obtaining a crude product of hydroxyanisolone, the crude product is firstly pulped and filtered by a mixed solvent of ethanol and ethyl acetate; dissolving the obtained filter cake in boiling water, decoloring, cooling, crystallizing, drying and the like to obtain a white crystalline solid.
CN111004173A describes a process for preparing hydroxyanisolone, wherein N- (4-methoxyphenyl) -5-methyl-2-pyridone is heated under reflux with sulfuric acid, thereby obtaining hydroxyanisolone through demethylation; after the first preparation of the hydroxyl-ketone sulfate, the coarse product of hydroxyl-ketone is obtained through the neutralization of sodium carbonate or sodium bicarbonate, then the white crystalline solid wet product is obtained through the processes of pulping, refining and decoloring in water, and the finished product is obtained after the white crystalline solid wet product is dried.
However, the hydroxyanisolone obtained by the above preparation method has problems of low solubility (especially water solubility) and dissolution rate, and they show different pharmacokinetic characteristics, thereby making bioavailability unsatisfactory; and the stability is also poor. These factors influence the application properties of the oxycodone in the drug-forming process. However, since the crystalline form of the drug and its physicochemical properties, such as solubility, dissolution rate, melting point, bioavailability, stability, etc., are unpredictable, there remains a need in the art to find a suitable crystalline form of oxycodone that can help meet the needs of the formulation.
Disclosure of Invention
Therefore, the object of the present invention is to provide a crystalline form of oxycodone which is more suitable for pharmaceutical use, in particular with better oral exposure and higher bioavailability, and the preparation and use thereof, thus overcoming the drawbacks of the prior art and being superior to the products obtained in the prior art in terms of pharmaceutical properties.
According to the present invention, the above object is solved by a novel form of hydroxyl-nitrone (r) (r code F351), having the chemical name N- (4-hydroxyphenyl) -5-methyl-2-pyridone and having the following chemical formula:
according to one aspect of the present invention, the present invention relates to a form B of oxycodone having an X-ray powder diffraction pattern comprising one or more of the diffraction peaks at the following 2 θ angles measured using CuK α radiation: 24.46 ° ± 0.2 °, 27.88 ° ± 0.2 °, 30.18 ° ± 0.2 °, 34.44 ° ± 0.2 ° and 43.48 ° ± 0.2 °.
According to one aspect of the present invention, the present invention relates to a form B of oxycodone having an X-ray powder diffraction pattern comprising one or more of the diffraction peaks at the following 2 θ angles measured using CuK α radiation: 8.76 degrees +/-0.2 degrees, 12.24 degrees +/-0.2 degrees, 12.94 degrees +/-0.2 degrees, 14.56 degrees +/-0.2 degrees, 15.30 degrees +/-0.2 degrees, 18.00 degrees +/-0.2 degrees, 22.66 degrees +/-0.2 degrees, 26.04 degrees +/-0.2 degrees, 27.88 degrees +/-0.2 degrees and 29.48 degrees +/-0.2 degrees.
According to one aspect of the present invention, the present invention relates to form B of oxycodone having an X-ray powder diffraction pattern comprising one or more of the following diffraction peaks at the 2 Θ angles measured using CuK α radiation: 8.76 degrees +/-0.2 degrees, 12.24 degrees +/-0.2 degrees, 12.94 degrees +/-0.2 degrees, 14.56 degrees +/-0.2 degrees, 15.30 degrees +/-0.2 degrees, 16.54 degrees +/-0.2 degrees, 17.54 degrees +/-0.2 degrees, 18.00 degrees +/-0.2 degrees, 19.58 degrees +/-0.2 degrees, 24.46 degrees +/-0.2 degrees, 27.88 degrees +/-0.2 degrees, 30.18 degrees +/-0.2 degrees, 34.44 degrees +/-0.2 degrees and 43.48 degrees +/-0.2 degrees.
According to one aspect of the present invention, the present invention relates to form B of oxycodone having an X-ray powder diffraction pattern comprising one or more of the following diffraction peaks at the 2 Θ angles measured using CuK α radiation: 16.54 degrees +/-0.2 degrees, 17.54 degrees +/-0.2 degrees, 24.46 degrees +/-0.2 degrees, 27.34 degrees +/-0.2 degrees, 27.88 degrees +/-0.2 degrees, 28.34 degrees +/-0.2 degrees, 30.18 degrees +/-0.2 degrees, 32.89 degrees +/-0.2 degrees, 34.44 degrees +/-0.2 degrees, 43.48 degrees +/-0.2 degrees, 44.12 degrees +/-0.2 degrees, 45.42 degrees +/-0.2 degrees, 46.40 degrees +/-0.2 degrees, 47.26 degrees +/-0.2 degrees and 47.50 degrees +/-0.2 degrees.
According to one aspect of the present invention, the present invention relates to a form B of oxycodone having an X-ray powder diffraction pattern comprising one or more of the diffraction peaks at the following 2 θ angles measured using CuK α radiation: 8.76 ° ± 0.2 °, 12.24 ° ± 0.2 °, 12.94 ° ± 0.2 °, 14.56 ° ± 0.2 °, 15.30 ° ± 0.2 °, 16.54 ° ± 0.2 °, 17.54 ° ± 0.2 °, 18.00 ° ± 0.2 °, 19.56 ° ± 0.2 °, 22.66 ° ± 0.2 °, 24.46 ° ± 0.2 °, 26.04 ° ± 0.2 °, 26.40 ° ± 0.2 °, 27.34 ° ± 0.2 °, 27.88 ° ± 0.2 °, 28 ° ± 0.2 °, 29.48 ° ± 0.2 °, 30.18 ° ± 0.2 °, 32.89 ° ± 0.2 °, 34.44 ° ± 0.2 °, 43.48 ° ± 0.2 °, 44.12 ° ± 0.2.42 ° ± 0.40 ° ± 0.2 °, 47 ° ± 0.2 ° and 26.50 ° ± 2 °.
According to one aspect of the present invention, the present invention relates to a form B of oxycodone having an X-ray powder diffraction pattern substantially as shown in figure 2.
According to one aspect of the present invention, the present invention also provides a process for preparing a crystalline form of oxycodone according to the present invention. According to the invention, the method comprises: the method comprises the steps of completely dissolving the hydroxyl-niacinamide in a solvent by heating, and then crystallizing the hydroxyl-niacinamide out by cooling the solution, wherein the solvent comprises an organic solvent or water, preferably ethyl acetate or ethanol. According to one embodiment of the invention, said lowering comprises lowering from the heating temperature to ambient temperature, preferably to room temperature, more preferably to 0 ℃; and optionally cooled with an ice water bath. According to one embodiment of the invention, the cooling rate is 1-5 ℃/min, preferably 2-3 ℃/min, most preferably about 2 ℃/min.
According to one aspect of the invention, the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form B1 according to the invention and pharmaceutically acceptable excipients. According to one aspect of the invention, the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form B2 according to the invention and pharmaceutically acceptable excipients.
According to an embodiment of the present invention, in the pharmaceutical composition of the present invention, the pharmaceutical excipient comprises: one, two or more excipients or carriers.
According to one embodiment of the present invention, the pharmaceutical composition according to the present invention may be prepared in various formulation forms including: solution, syrup, suspension, emulsion, injection, powder, granule, capsule, tablet, coated tablet or pill, microcapsule, pellet, cyclodextrin clathrate, sustained release, controlled release, delayed release dosage form, etc.
According to one aspect of the present invention, the present invention also provides the use of a crystalline form of oxycodone according to the present invention for the preparation of a medicament for the treatment of fibrosis, preferably liver fibrosis related diseases.
According to one embodiment of the invention, the compounds of the invention can also be used in combination with other active substances for the treatment of fibrosis, including, for example, interferon-alpha, interferon-beta, interferon-gamma, corticosteroids and the like.
To avoid any ambiguity, where the term "crystalline form" is referred to herein individually, the skilled person will understand that said "crystalline form" comprises at least crystalline form B of oxycodone and that crystalline form B comprises at least crystalline forms B1 and B2 obtained under different solvent conditions.
It will also be appreciated by those skilled in the art that aspects described above and one, two or more features included in each embodiment may be recombined independently of each other to arrive at further embodiments falling within the scope of the invention.
Advantageous effects
Compared with the solid form of the hydroxyl-niadone in the prior art, the novel crystal form of the hydroxyl-niadone and the preparation method thereof provided by the invention have the following advantages: the stability of the form B (B1 and B2) of the oxycodone according to the present invention is superior to that of the amorphous form thereof, and the oral exposure and oral bioavailability of the drug obtained by the crystalline form are superior to those of the drug obtained by the amorphous form thereof. In addition, the preparation method can obtain the high-purity hydroxynicol crystal form B in a simple, convenient, good-reproducibility and high-yield manner, thus being beneficial to industrial production and having better application value.
Terms definition and interpretation
Definitions of terms recited in the specification and claims of this application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions set forth in tables, definitions of specific compounds in the examples, and the like, may be combined with one another in any combination and permutation, unless otherwise stated. The definitions and compound structures of such combinations and combinations are intended to fall within the scope of the present specification.
Where the specification and claims recite "about" a value, that value is included by itself, as well as values within a range around the value that is acceptable in the art, such as values within the range of ± 15% of the value, values within the range of ± 10% of the value, values within the range of ± 5% of the value, and the like.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human, which includes one or more of the following: (1) prevention of diseases: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed disease pathology or symptomatology; (2) inhibition of diseases: for example, inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or condition) in an individual who is experiencing or presenting the pathology or condition of the disease, disorder or condition; (3) relieving the disease: for example, relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or presenting with the pathology or symptomatology of the disease, disorder or condition.
The term "pharmaceutically acceptable" means that the prescribed components or active ingredients do not unduly adversely affect the health of the general therapeutic target.
The term "pharmaceutically acceptable excipient or carrier" means one or more compatible solid or liquid fillers or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and between the compounds of the present invention without significantly diminishing the pharmaceutical efficacy of the compounds. Examples of pharmaceutically acceptable excipients or carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, wetting agents (e.g. sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
Drawings
Fig. 1 is a stacked graph of curves of XRPD spectra measured immediately after the crystalline form of F351 obtained in different solvents according to the present invention, wherein (1) F351 EtOH-0d corresponds to the result of crystalline form B2 of F351 obtained by recrystallization in ethanol in example 3; (2) F351 EA-0d corresponds to the result of form B1 of F351 obtained by recrystallization from ethyl acetate in example 2; and (3) F351 AS-0d corresponds to the results obtained for amorphous F351 in example 1; as can be seen from the stacked figures, the crystal forms B1 and B2 are the same crystal form;
fig. 2 is an XRPD spectrum of form B1 of hydroxyanisolone obtained in example 2;
FIG. 3 is an XRPD spectrum of amorphous form A obtained by cooling a melt of oxycodone in example 1;
FIG. 4 is a DSC spectrum of amorphous form A obtained in example 1;
figure 5 is a DSC profile of form B1 obtained in example 2;
fig. 6 is a DSC profile of form B2 obtained in example 3.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the techniques realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise specified, the reagents used in the following examples are all commercially available products or can be prepared by known methods.
Test method
After obtaining the samples, the obtained samples were measured respectively by the following methods:
1. sample processing
The matrix sample or working fluid (standard curve/quality control related sample, etc.) is taken out and then put to room temperature, and vortex and mix evenly (blank sample can be centrifuged before use as required). 47.5. Mu.L of plasma as a blank medium was taken, 2.5. Mu.L of working solution (standard curve/quality control-related sample, etc.) was added thereto, and vortexed and mixed. The resulting mixture was added to 1000. Mu.L of an internal standard working solution (for blank, no internal standard was added but the same volume of acetonitrile was added), vortexed, and then centrifuged at 14,000rpm for 15 minutes. 50 μ L of the supernatant was taken, 150 μ L of ultrapure water was added thereto to the corresponding 96-well sample plate, and vortexed to mix well. And carrying out LC-MS/MS sample injection analysis on the obtained solution.
2. Preparation of stock solution
F-351 stock solution: a10 mg F351 control was weighed precisely, placed in a brown glass scintillation vial, dissolved by adding 100. Mu.L acetonitrile or other appropriate solvent, mixed well to prepare a 100mg/ml stock solution, and stored at 4 ℃ for further use.
Propranolol (Propranolol) stock (internal standard): the 10mg Napolor reference IS precisely weighed and placed in a glass scintillation vial, 100 mul of acetonitrile or other proper amount of solvent IS added to dissolve the Napolor reference, and the mixture IS uniformly mixed to prepare 100mg/ml internal standard Stock solution (IS Stock) which IS stored for standby at 4 ℃.
3. Preparation of test solutions
Preparing an internal standard working solution: 20 mul of propranolol internal standard stock solution is sucked and diluted by acetonitrile to obtain internal standard working solution with the concentration of 20 ng/mL.
Preparing a mobile phase solution:
mobile phase A: 1ml of formic acid is sucked into a liquid chromatography bottle, and is mixed with 1000ml of ultrapure water to prepare 0.1% formic acid aqueous solution.
And (3) mobile phase B: sucking 1ml formic acid into a liquid chromatography bottle, adding 1000ml acetonitrile, mixing uniformly, and preparing into 0.1% formic acid acetonitrile solution.
Preparing a needle washing solution:
weak washing liquid: and (3) sucking 500ml of methanol into a liquid chromatography bottle, adding 500ml of water, and uniformly mixing to prepare a 50% methanol water solution as a weak needle washing solution.
Strong washing liquid: according to a volume ratio V: V: V = 1.
4. Preparation of standard curve working solution and standard curve sample
Mu.l of F-351 stock solution was taken and diluted with 240. Mu.l of 50% acetonitrile aqueous solution to a standard curve working solution having a concentration of 400. Mu.g/mL.
Then, 400. Mu.g/mL of the working solution for the standard curve was diluted with 50% acetonitrile aqueous solution to 200, 100, 20, 10, 2, 1, and 0.2. Mu.g/mL of the working solution for the standard curve in the following order, as shown in Table 1.
Adding 2.5 μ L of standard curve working solution into 47.5 μ L of blank matrix to obtain standard curve sample with concentration of 20000, 10000, 5000, 1000, 500, 100, 50, and 10ng/mL.
TABLE 1
5. Preparation of quality control working solution and quality control sample
32 mu.l of F-351 stock solution is taken and diluted into quality control working solution with the concentration of 320 mu g/mL by 50 percent acetonitrile aqueous solution. Then 320 mu g/mL of quality control working solution is taken and diluted into the quality control working solution with the concentration of 80 and 0.6 mu g/mL by 50 percent acetonitrile aqueous solution in turn. Adding 2.5 μ L of quality control working solution into 47.5 μ L of blank matrix to obtain quality control sample with concentration of 16000, 4000, and 30ng/mL.
6. The measurement of the samples was carried out by liquid chromatography mass spectrometry (LC-30 AD ultra performance liquid chromatography system from Shimadzu and TQ 5500Plus mass spectrometer from applied biosystems USA) using the following conditions:
6.1 chromatographic conditions
A chromatographic column: ACQUITY
BEH C18 1.7μm(2.1*50mm)
Flow rate: 500 mu L/min
Column temperature: 40 deg.C
Sample introduction amount: 1 μ L
Autosampler temperature: 4 deg.C
The eluent gradient formulation is shown in table 2 below:
table 2: eluent gradient
6.2. Mass spectrometer conditions:
scanning mode: positive ion multi-reaction monitoring mode
An ion source: electrospray ion source
Ion source voltage (IS): 5500V
Ion source Temperature (TEM): 550 deg.C
Resolution of Q1: unit
Resolution of Q3: unit
Atomizing Gas (Gas 1): 55psi
Air curtain gas (CUR): 35psi
Collision gas (CAD): 8
Auxiliary heating Gas (Gas 2): 55psi;
wherein the atomizing gas, the air curtain gas, the collision gas and the auxiliary heating gas are all nitrogen.
In tests directed to form B of the present invention and propranolol, the mass spectrometry conditions also differ as described in table 3 below:
table 3: testing the Mass Spectrometry conditions of the crystalline form of the invention and Propranolol
Powder diffraction method of X-ray
Sample preparation: appropriate amount of sample was placed in the recess of the XRPD sample pan and after the sample was spread flat the powder sample was pressed flat with another glass plate.
And (3) testing conditions are as follows: the samples were scanned using a Shimadzu XRD-6000 instrument according to the following parameters: the ray source is a Cu-K alpha target
The operating voltage of the light tube is 40kV, and the current is 30mA; the 2 theta values for the sample scan range were from 5 deg. to 50 deg.. The scanning speed was 5deg/min.
Examples
Example 1 (preparation of amorphous Nidone A)
About 11g of F351 was placed in a 50mL ceramic crucible. The crucible was then placed in a muffle furnace. The muffle furnace was set to a temperature of 190 ℃ and heated within about 40min until the contents were completely melted. An iron plate was prepared in advance and placed in an ice-water bath at a constant temperature. After the F351 in the crucible was completely melted, it was poured into the iron pan to obtain 10.5g of a pale yellow transparent block-shaped solid, which was numbered amorphous a. It was used directly in subsequent experiments.
Example 2 (recrystallization from ethyl acetate to obtain form B1)
10g of F351 was placed in a 500ml single-necked bottle, and 300ml of ethyl acetate was added thereto. The mixture was heated to reflux to give a suspension, during which stirring was continued for 30min. The temperature of the obtained solution is reduced to room temperature (the temperature reduction speed is about 2 ℃/min), and solid is gradually separated out in the process. It was filtered and dried in vacuo to obtain 8g of white powder, numbered as form B1, which was used directly in the subsequent experiments.
Example 3 (recrystallization from ethanol to obtain form B2)
10g of F351 was placed in a 500ml single-necked bottle, and 50ml of ethanol was added thereto. The mixture was heated to reflux and the solids were all dissolved to obtain a clear solution, during which stirring was carried out and stirring was continued for 30min after obtaining a clear solution. The temperature of the obtained solution is reduced to room temperature (the temperature reduction speed is about 2 ℃/min), and solid is gradually separated out in the process. It was filtered and dried in vacuo to give 7.7g of white powder, which was numbered as form B2 and used directly in subsequent experiments.
Example 4 (measurement by sample DSC)
Approximately 1mg of sample was weighed into a 40. Mu.l standard aluminum crucible, capped (perforated), compacted and placed in a Mettler DSC apparatus for measurement. The test temperature range is 30-300 ℃, and the heating rate is 20 ℃/min. The results are given in Table 4 below.
TABLE 4 DSC test results
For the spectra of the DSC test, please additionally see fig. 4-6.
Example 5 (moisture absorption measurement)
Under the circulation of 0% -95% -0% Relative Humidity (RH), weighing about 10mg of sample to carry out the moisture absorption/desorption characteristic test under the condition of 25 ℃, and the parameters are as follows:
| is provided with | Parameter(s) |
| Temperature of |
25℃ |
| Equilibrium condition | dm/dt:0.01％/min |
| Humidity range, RH (%) | 0％～95％～0％RH |
| Measurement step Length, RH (%) | 5％RH |
| Amount of sample | ～10mg |
Moisture absorption grading:
| moisture absorption grading | Moisture adsorption standard |
| Deliquescence | Absorb sufficient water to form liquid |
| Very hygroscopic | W％≧15％ |
| Is hygroscopic | 2％≦W％≦15％ |
| Slightly hygroscopic | 0.2％≦W％≦2％ |
| Not prone to absorb moisture | W％<0.2％ |
"*": DVS results of amorphous A in Table 5-1 under 25. + -. 1 ℃ and 80. + -. 2% RH conditions (European Pharmacopeia 10.0)
TABLE 5-2 DVS results for form B2
As can be seen from the DVS test results, amorphous a is slightly hygroscopic, whereas form B2 according to the invention is not hygroscopic.
Example 6 (stability test)
0.5g of the active ingredient and impurity content of the amorphous form a and the crystalline forms B1 and B2 of the present invention were measured, respectively, and structural analysis of impurities was performed, and XRPD measurement was also performed to obtain relevant data.
In addition, 1.0g of the amorphous form a and the crystalline forms B1, B2 of the present invention were placed in an environment with a relative humidity of 92.5% and a temperature of 45 ℃, respectively, and the content of active ingredients and impurities were measured on days 10, 30, 60, and 90, respectively, and structural analysis of impurities was performed while XRPD measurement was also performed to obtain relevant data.
In addition, 1.0g of the amorphous form a and the crystalline forms B1, B2 of the present invention were left at-10 ℃ for 10 days, the contents of active ingredients and impurities were measured, and structural analysis of impurities was performed while XRPD measurement was also performed, to obtain relevant data.
The results of the above tests are summarized in table 6 below.
TABLE 6 stability test results
* In table 6 above, the intermediates generally include: 2-hydroxy-5-methyl-pyridine; the largest single hetero occurs usually as N- (4-hydroxyphenyl) -5-methyl-2-pyridone.
As can be seen from table 6 above, both amorphous form a and crystalline forms B1 and B2 according to the present invention have good stability, maintaining very low levels in total impurities after long-term storage under various temperature and humidity conditions; the total impurities do not exceed 0.08% even after 60 days storage at 45 ℃ and 92.5% relative humidity, thus confirming the long-term stability of amorphous form a and crystalline forms B1, B2 according to the invention.
Example 7 (oral bioavailability)
Samples of amorphous form a, form B1 and form B2 according to the invention were first prepared as test articles, the basic parameters of which are shown in table 7 below:
table 7: partial physicochemical parameters of the test article
Preparing the above materials into intragastric administration solution, wherein the intragastric administration solution adopts 0.5% sodium cellulose water solution as solvent; the concentration of the prepared gastric lavage administration solution is 10 mg/mL -1 。
Selecting 9 male SD rats, dividing into 3 groups, each group comprising 3 male SD rats, and making into intragastric administration groups 1-3 with dosage of 100 mg/kg -1 Dosage of (i.e., 10 mL. Kg) -1 Volumetric dose) was administered at a concentration of 10 mg/mL -1 The gavage administration solution of (1).
The above administration information can be summarized as shown in table 8 below:
table 8: dosing regimens
Before and after administration to the animals respectively,0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8 hours, and plasma samples were collected from the animals in the gavage group. Separating plasma from the collected blood sample, and adding dipotassium ethylenediaminetetraacetate (EDTA-K) 2 ) Can be used as anticoagulant.
The following table 9 is the results obtained after measurement and calculation of the active compounds in the plasma samples of rats treated by various administration modes:
table 9: pharmacokinetic parameters of rat plasma samples
From the above results, it can be seen that the forms B1 and B2 according to the present invention have the following advantages in terms of pharmacokinetics: the oral exposure and the oral bioavailability of the medicines of the crystal forms B1 and B2 are higher than those of amorphous forms.
In summary, the embodiments of the present invention have been described. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (13)
1. Form B of oxycodone having an X-ray powder diffraction pattern substantially as shown in figure 2.
2. A process for preparing a crystalline form of oxycodone according to claim 1, the process comprising: completely dissolving the hydroxyl-niacinamide in a solvent by heating, and then cooling the solution to separate out the hydroxyl-niacinamide crystals, wherein the solvent is ethyl acetate or ethanol.
3. The method of claim 2, wherein the reducing comprises reducing from a heating temperature to an ambient temperature; and optionally cooled with an ice water bath.
4. The method of claim 3, wherein the reducing comprises reducing from a heating temperature to a room temperature.
5. The method of claim 3, wherein the reducing comprises reducing from the heating temperature to 0 ℃.
6. The method of claim 3, wherein the cooling rate is 1-5 ℃/min.
7. The method of claim 3, wherein the cooling rate is 2 to 3 ℃/min.
8. The method of claim 3, wherein the cooling rate is 2 ℃/min.
9. A pharmaceutical composition comprising a therapeutically effective amount of form B of oxycodone according to claim 1 and a pharmaceutically acceptable excipient.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical excipient comprises one, two or more excipients or carriers.
11. The pharmaceutical composition according to claim 9 or 10, in the form of: solution, syrup, suspension, emulsion, injection, powder, granule, capsule, tablet, coated tablet or pill, microcapsule, pellet, cyclodextrin clathrate, sustained release, controlled release, and delayed release dosage form.
12. Use of crystalline form B of oxycodone according to claim 1 for preparing a medicament for treating a fibrosis-related disease.
13. The use of claim 12, wherein the fibrosis is liver fibrosis.
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| CA2545813C (en) * | 2003-11-14 | 2011-01-04 | Shanghai Genomics, Inc. | The derivatives of pyridone and use thereof |
| CN101723883B (en) * | 2008-10-24 | 2013-06-05 | 上海睿星基因技术有限公司 | Method for preparing oxycodone |
| JP7474495B2 (en) * | 2019-07-22 | 2024-04-25 | 協立化学産業株式会社 | Composition for liquid crystal sealant and use thereof |
| CN111004173A (en) * | 2019-12-31 | 2020-04-14 | 北京康蒂尼药业有限公司 | Preparation method of hydroxyl-niatone |
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