CN117362228A - Roflumilast hydrate crystal and preparation method thereof - Google Patents
Roflumilast hydrate crystal and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 111
- 229960002586 roflumilast Drugs 0.000 title claims abstract description 34
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 25
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 17
- 238000001228 spectrum Methods 0.000 claims abstract description 9
- 230000005855 radiation Effects 0.000 claims abstract description 7
- 229910002483 Cu Ka Inorganic materials 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 239000000706 filtrate Substances 0.000 claims description 32
- 238000001914 filtration Methods 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 19
- 238000002425 crystallisation Methods 0.000 claims description 19
- 230000008025 crystallization Effects 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000011260 aqueous acid Substances 0.000 claims description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 230000004580 weight loss Effects 0.000 claims description 4
- 238000000862 absorption spectrum Methods 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 24
- 239000000843 powder Substances 0.000 description 24
- 239000007787 solid Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000007792 addition Methods 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000020832 chronic kidney disease Diseases 0.000 description 3
- 238000005538 encapsulation Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 229940113151 HIF prolyl hydroxylase inhibitor Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- 206010058116 Nephrogenic anaemia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- DQFAAIWCCHDCLO-UHFFFAOYSA-N acetonitrile;formic acid;hydrate Chemical compound O.CC#N.OC=O DQFAAIWCCHDCLO-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- -1 roflumilast carboxylate Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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 present invention provides a crystal of roflumilast hydrate and a preparation method thereof, wherein the crystal uses Cu-Ka radiation, and an X-ray powder diffraction spectrum expressed by a2 theta angle has diffraction peaks at 3.36+/-0.2 degrees, 6.49+/-0.2 degrees, 9.95+/-0.2 degrees, 11.80+/-0.2 degrees, 16.12+/-0.2 degrees and 19.05+/-0.2 degrees. The crystal has good chemical and physical stability under normal temperature, and can be used for preparation of preparation.
Description
Technical Field
The invention belongs to the technical field of novel crystal forms of medicines, and particularly relates to a roflumilast hydrate crystal (hereinafter sometimes simply referred to as an I-type crystal) and a preparation method thereof.
Background
Luo Shasi the English name is Roxadurtat, and the molecular formula is: c (C) 19 H 16 N 2 O 5 The molecular weight is: 352.34, cas number: 808118-40-3, the structural formula is shown as follows:
luo Shasi As a medicament, it is mainly used for treating anemia caused by chronic kidney disease (CKD, chronic kidney disease) in patients undergoing dialysis treatment, and is a medicament for treating renal anemia by using the low-molecular-weight hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) developed for the first time worldwide.
At present, various crystals are reported for roflumilast, and most of the crystals are prepared by using an organic solvent as a crystallization solvent, but most of the crystals prepared by using the organic solvent as the crystallization solvent have the problem of solvent residue encapsulation, and can possibly form solvates, so that the solvent residue exceeds the standard, and the use requirements of clinical application cannot be met. In addition, most Luo Shasi crystals have poor stability and the drug properties cannot meet the requirements.
Disclosure of Invention
The present invention has been made in view of the above problems occurring in the prior art, and an object of the present invention is to provide a novel crystal form of roflumilast and a preparation method thereof.
In one aspect, the present invention provides a crystal of roflumilast hydrate, characterized in that the crystal has diffraction peaks at 3.36±0.2°, 6.49±0.2°, 9.95±0.2°, 11.80±0.2°, 16.12±0.2° and 19.05±0.2° using Cu-Ka radiation and X-ray powder diffraction spectrum expressed in terms of 2θ angle.
Further, the above-mentioned crystals have diffraction peaks at 8.14.+ -. 0.2 °, 10.48.+ -. 0.2 °, 12.77.+ -. 0.2 °, 13.72.+ -. 0.2 °, 15.23.+ -. 0.2 °, 20.04.+ -. 0.2 °, 22.86.+ -. 0.2 °, 23.62.+ -. 0.2 °, 24.32.+ -. 0.2 °, 25.59.+ -. 0.2 °, 26.91.+ -. 0.2 °, 28.19.+ -. 0.2 ° using the X-ray powder diffraction spectrum expressed by 2. Theta. Angle using the Cu-Ka radiation.
Further, the mass percentage of the water of crystallization in the crystallization is 6.6% -7.6%.
Further, the infrared absorption spectrum of the above crystal was 3359cm -1 ，3110cm -1 ，1725cm -1 ，1754cm -1 ，1624cm -1 ，1536cm -1 ，1491cm -1 ，1351cm -1 ，1223cm -1 ，939cm -1 With an absorption peak.
Further, the above crystals showed a weight loss of 6.8% to 7.5% in TGA spectrum at 105 ℃.
In another aspect, the present invention also provides a method for preparing the above crystal, which is characterized by comprising:
adding roflumilast into an aqueous solution of inorganic weak base, dissolving and filtering;
adding acid or acid water solution into the filtrate obtained after filtration, adjusting the pH value of the filtrate until crystallization is separated out, and filtering to obtain the roflumilast hydrate crystal.
Further, in the above preparation method, the inorganic weak base is one or a combination of more selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
Further, in the above preparation method, the molar ratio of the inorganic weak base to the Luo Shasi is 1:1 to 50:1.
Further, in the above preparation method, an acid or an aqueous acid solution is added to the filtrate obtained after filtration, and the pH of the filtrate is adjusted to 5 to 7.
Further, in the above preparation method, adding an acid or an aqueous acid solution to the filtrate obtained after filtration, adjusting the pH of the filtrate until crystallization is precipitated, comprises:
dripping a preset amount of acid or an aqueous solution of the acid into the filtrate obtained after the filtration, and stirring at a preset temperature for a preset time after the dripping is finished to separate out crystals; wherein the preset amount is not lower than the molar equivalent of the inorganic weak base, the preset temperature is 0-70 ℃, and the preset time is 1-2 h.
Effects of the invention
The invention provides a novel crystal form of roflumilast, which has no problem of solvent residue encapsulation, has good stability and patentability, and has good application prospect in clinic.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of form I crystals of the present invention;
FIG. 2 is an X-ray powder diffraction pattern of one type of crystal (hereinafter referred to as form A crystal or form A) of the related art;
FIG. 3 is a TGA diagram of form I crystals of the present invention;
FIG. 4 is an infrared spectrum (IR chart) of the form I crystals of the present invention;
fig. 5 is an infrared spectrum (IR chart) of the crystal (form a) of comparative example 1.
Detailed Description
The following describes specific embodiments of the present invention in detail, but the embodiments of the present invention are not limited thereto.
The present invention provides a crystalline form I of roflumilast hydrate, which uses Cu-Ka radiation and has an X-ray powder diffraction spectrum expressed in terms of 2θ (Two-Theta, abbreviated as 2T) angle as shown in fig. 1. In fig. 1, 2θ is denoted by 2T. The form I crystals have characteristic diffraction peaks at the following positions: 3.36.+ -. 0.2 °, 6.49.+ -. 0.2 °, 9.95.+ -. 0.2 °, 11.80.+ -. 0.2 °, 16.12.+ -. 0.2 ° and 19.05.+ -. 0.2 °.
In the X-ray powder diffraction analysis, as shown in fig. 1, the form I crystals also had diffraction peaks at 8.14±0.2°, 10.48±0.2°, 12.77±0.2°, 13.72±0.2°, 15.23±0.2°, 20.04±0.2°, 22.86±0.2°, 23.62±0.2°, 24.32±0.2°, 25.59±0.2°, 26.91±0.2°, 28.19±0.2°.
The inventors have compared the above-mentioned form I crystals with all the existing crystals in the prior art, and have confirmed that the form I crystals of the present invention have a new crystal form, for example, the form of the form I crystals of the present invention has a larger deviation from the form of the form I crystals of the present invention of Luo Shasi, which was reported in the prior art, as compared with the form Luo Shasi of the related art, at the positions of 8.54±0.2 °, 11.51±0.2 °, 12.93±0.2 °, 19.05±0.2 °, 21.69±0.2 °, 23.02±0.2 °, 24.80±0.2 °, 25.83 ±0.2°, and 27.48±0.2°, which are different from the form of the form I crystals of the roflumistat hydrate of the present invention, as shown in fig. 2.
For the crystalline form I of the roflumilast hydrate of the present invention, moisture content was measured to be 6.6% to 7.6%. As shown in fig. 3, the form I crystals were subjected to thermogravimetric analysis to obtain: the weight loss rate of the I-type crystal at 105 ℃ is 6.8% -7.5%. The moisture content was substantially the same as that measured by the moisture meter described above. The two tests show that the water carried in the I-type crystal is crystal water, which is equivalent to 1.5 crystal water per roflumilast molecular band (theoretical value is 7.12%)
In some embodiments, as shown in fig. 4, in the infrared absorption spectrum, the form I crystals have the following characteristic absorption peaks: 3359cm -1 ，3110cm -1 ，1725cm -1 ，1754cm -1 ，1624cm -1 ，1536cm -1 ，1491cm -1 ，1351cm -1 ，1223cm -1 ，939cm -1 。
The inventors found in the study that: because Luo Shasi contains a carboxyl group in its molecule, the solubility in water is greatly increased after salifying with alkali, and the aqueous solution of salt is changed back to Luo Shasi he after being neutral or acidic by acid, thus completely avoiding the use of organic solvent for recrystallization and solving the problem of solvent residue of the product. In addition, because the molecular structure of the roflumilast contains an amide bond, the roflumilast is relatively sensitive to strong acid and strong alkali, and the cleavage of the amide bond is easy to generate, and therefore, the roflumilast can be dissolved in water by using inorganic weak base in salt formation.
Based on the above research results, the present invention also provides a preparation method of the type I crystal, which comprises: luo Shasi (solid powder or various crystals such as A-type crystals reported in the prior art) is added into an aqueous solution of an inorganic weak base, dissolved and filtered; adding acid or an aqueous solution of the acid into the filtrate obtained after the filtration, adjusting the pH value of the filtrate until crystallization is separated out, and filtering to obtain the I-type crystal of the roflumilast hydrate.
According to the preparation method of the I-type crystal of the roflumilast hydrate, the I-type crystal of the roflumilast hydrate can be obtained by adopting an inorganic weak base aqueous solution to dissolve the roflumilast and adjusting the pH value of the filtered filtrate until the crystal is separated out. The I-type crystal has good stability, can not generate crystal transformation after being stored for 6 months at the ambient temperature (such as 20-30 ℃), and has good drug property. In addition, the I-type crystal is precipitated from the water phase, compared with the prior art which adopts an organic solvent as a crystallization solvent, the method has the advantages that the problem of residual encapsulation of the organic solvent is avoided, the preparation method has good reproducibility, and the crystallization quality is not reduced before and after the crystallization.
Further, compared with the prior art that the roflumilast is dissolved by strong alkali for crystallization, the embodiment of the invention adopts the aqueous solution of inorganic weak alkali for crystallization, and can also avoid the problem that the amide bond in the roflumilast is easy to break under the strong alkali, so that the roflumilast is degraded. That is, in the embodiment of the present invention, the solution of roflumilast in water is achieved by using an inorganic weak base, and the subsequent pH adjustment by using an acid or an aqueous solution of an acid is achieved by converting Luo Shasi his inorganic weak base salt into Luo Shasi he and precipitating Luo Shasi his form I crystals. In this process, on the one hand, the use of organic solvents can be avoided, so that organic solvent residues can be avoided. On the other hand, the problem of amide bond cleavage in the roflumilast caused by strong alkali can be avoided.
In one embodiment, the inorganic weak base is one or more selected from the group consisting of ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
In one embodiment, the roflumilast is added into water, ammonia water is added into the mixture for stirring and dissolution, impurities are removed by filtration, then acid with molar equivalent of not less than ammonia water is added into the mixture to precipitate crystals, and the crystals are filtered, washed with water and dried under reduced pressure to obtain the I-type crystals of the roflumilast hydrate. The use of ammonia can reduce the amount of glowing residues compared to other weak inorganic bases, reducing the risk of the glowing residues of the final product exceeding the standard.
In one embodiment, the molar ratio of weak inorganic base to Luo Shasi is from 1:1 to 50:1.
In one embodiment, the dissolution temperature is 20 to 35 ℃.
In one embodiment, an acid or an aqueous acid solution is added to the filtrate obtained after filtration, and the pH of the filtrate is preferably adjusted to 5 to 7. It was found by research that the yield of form I crystals can be increased by adjusting the pH of the filtrate to 5 to 7. Further preferably, the pH of the filtrate is adjusted to 6 to 7.
In one embodiment, the step of adding an acid or an aqueous acid solution to the filtrate obtained after filtration, and adjusting the pH of the filtrate to precipitate crystals of form I of roflumilast hydrate comprises:
dripping a preset amount of acid or an aqueous solution of the acid into the filtrate obtained after the filtration, and stirring at a preset temperature for a preset time after the dripping is finished to separate out the I-type crystal of the Luo Shasi hydrate; wherein the preset amount of acid is not lower than the molar equivalent of the inorganic weak base, the preset temperature (i.e. the temperature at which crystals are precipitated) is 0-70 ℃, preferably 20-35 ℃, and the preset time is 1-2 hours.
In this embodiment, by using a drop-wise addition, the acid and the carboxylate of Luo Shasi can be brought into sufficient contact and Luo Shasi his form I crystals can be slowly precipitated, and the possibility of coating part of the roflumilast carboxylate in the form I crystals due to too rapid precipitation of the form I crystals by too rapid addition of the acid or aqueous acid solution can be avoided. In addition, by controlling the stirring temperature and stirring time, the acid or the aqueous solution of the acid and Luo Shasi carboxylate can be fully reacted at a proper temperature, so that the problem that byproducts are possibly generated due to too high temperature or too long time and the problem of insufficient reaction due to too short time are avoided.
In one embodiment, the form I crystals have an HPLC purity of not less than 99.5%.
The conditions for HPLC were: the chromatographic column adopts octadecylsilane chemically bonded silica gel as filler; acetonitrile-water-formic acid (volume ratio: 900:100:0.8) as mobile phase B, 0.08% formic acid aqueous solution as mobile phase A, gradient elution was performed according to the following Table 1, and the detection wavelength was 295nm; the column temperature was 40 ℃.
TABLE 1
| Time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0.0 | 70 | 30 |
| 32.0 | 60 | 40 |
| 37.0 | 60 | 40 |
| 47.0 | 40 | 60 |
| 50.0 | 30 | 70 |
| 52.0 | 0 | 100 |
| 57.0 | 0 | 100 |
| 57.1 | 70 | 30 |
| 67.0 | 70 | 30 |
In these embodiments, the above preparation method can be used to obtain high-purity I-type crystals, which can be directly applied to pharmaceutical preparations.
In one embodiment, the method further comprises: the obtained form I crystals are dried under reduced pressure under heating at a temperature of not more than 60 ℃. By drying at a temperature not exceeding 60 ℃, on the one hand, residual solvent water on the surface of the type I crystals can be removed and, on the other hand, excessive temperature can be prevented from causing changes in the crystals. The drying under reduced pressure is preferably carried out at 30 to 50 ℃.
In the embodiment of the present invention, the type of acid is not particularly limited in the neutralization with an acid, and any of a strong acid, a weak acid, an inorganic acid and an organic acid (the organic acid is a water-soluble acid) may be used, and the final pH after the neutralization of the acid may be controlled to 5 to 7. For example, examples of water-soluble organic acids may include, but are not limited to: formic acid, acetic acid, propionic acid, citric acid, methanesulfonic acid, and the like. The mineral acid may include, but is not limited to: hydrochloric acid, sulfuric acid, phosphoric acid, and the like.
The present invention will be described in more detail below by way of specific examples and comparative examples. The examples are only for illustrating the present invention, and the present invention is not limited thereto.
The equipment and operating conditions used in the examples and comparative examples are as follows:
x-ray powder diffractometer: bruker, germany, model: d8 Advance;
operating conditions: cuK alpha radiation, tube pressure of 40kV, tube flow of 30mA, graphite bent crystal monochromator, scanning speed of 2 DEG/min, step interval of 0.02 DEG and scanning range of 2 DEG-60 deg.
Infrared spectrometer: a perkin elmer Spectrum Two infrared spectrometer;
operating conditions: KBr pellet, scan range: 450-4000 cm -1 。
TGA: TA company, usa model: SDT Q60;
operating conditions: 10 ℃/min, test temperature range: 25-250 ℃.
Comparative example 1: luo Shasi preparation of his crystals (form A) (cf. WO2014014835A2 method VII)
5.0g of solid powder of roflumilast was added to a 100ml three-necked flask, 35ml of 90% methanol was added, and the mixture was sonicated for 5 seconds, and not completely dissolved. The slurry was stirred at 500rpm for a period of 4 days with the temperature maintained at 25℃and 50℃cycled (every 8 hours). Filtering, and drying under reduced pressure at 35 ℃ to constant weight to obtain 4.2g of product.
The obtained solid powder was analyzed under the above measurement conditions using the above-mentioned X-ray powder diffractometer and infrared spectrometer, respectively, and the X-ray powder diffractometer was shown in fig. 2, and the XRPD pattern expressed as 2θ angle had characteristic diffraction peaks at the angular positions of 8.54±0.2 °, 11.51±0.2 °, 12.93±0.2 °, 19.05±0.2 °, 21.69±0.2 °, 23.02±0.2 °, 24.80±0.2 °, 25.83 ±0.2°, and 27.48±0.2 ° in accordance with the peak values reported in WO2014014835 A2. The infrared spectrum is shown in FIG. 5, which shows that the infrared spectrum is 3359cm -1 ，3110cm -1 ，1725cm -1 ，1754cm -1 ，1624cm -1 ，1536cm -1 ，1491cm -1 ，1351cm -1 ，1223cm -1 ，939cm -1 There is a characteristic absorption peak.
Example 1: preparation of form I crystals of Luo Shasi He hydrate
5.0g Luo Shasi of the compound (crystal form A) is added into a 250ml three-mouth bottle, 100ml of purified water is added, 18ml of ammonia water is added, the mixture is heated to 30-35 ℃, stirred until the mixture is completely dissolved, and filtered; and (3) dropwise adding 40ml of glacial acetic acid to the filtrate until the pH value is 6, keeping the temperature and stirring for 1 hour after the dropwise addition, filtering, washing with water, and drying under reduced pressure at 35 ℃ until the weight is constant to obtain 5.0g of off-white solid powder. The purity was 99.93% by HPLC.
The obtained solid powder was analyzed under the above measurement conditions by using the above X-ray powder diffractometer and infrared spectrometer, respectively, and the X-ray powder diffractometer and IR spectrum thereof were as shown in FIG. 1 and FIG. 4, respectively, and were determined as type I crystals.
TGA analysis was performed under the above conditions for this type I crystal, and the resulting pattern is shown in fig. 3. As shown by thermogravimetric analysis, the weight loss at 105℃was about 7.24%. The water content of the form I crystals was determined to be 7.21% using a karl fischer moisture meter. The water contained in the form I crystals is illustrated as crystal water, not free water. The water of crystallization can be deduced from the water of crystallization to be 1.5 per molecule of the form I crystals.
Example 2: preparation of form I crystals of Luo Shasi He hydrate
5.0g Luo Shasi of the compound (crystal form A) is added into a 250ml three-mouth bottle, 100ml of purified water is added, 1ml of ammonia water is added, the mixture is heated to 30-35 ℃, stirred until the mixture is completely dissolved, and filtered; and (3) dropwise adding 0.5ml of formic acid to the filtrate until the pH value is 5, keeping the temperature and stirring for 2 hours after the dropwise addition, filtering, washing with water, and drying under reduced pressure at 35 ℃ until the weight is constant to obtain 5.1g of off-white solid powder. The purity was 99.89% by HPLC.
The resulting solid powder was analyzed in the same manner as in example 1, and the X-ray powder diffraction pattern and the IR pattern were substantially in accordance with fig. 1 and 4.
Example 3: preparation of form I crystals of Luo Shasi He hydrate
4.0g Luo Shasi he (form A) is added into a 250ml three-necked flask, 80ml of purified water is added, 10ml of potassium carbonate solution (containing 1.57g of potassium carbonate) is added, the temperature is controlled to 20-25 ℃, stirring is carried out until the solution is completely dissolved, and filtering is carried out; 45ml of 1N hydrochloric acid is added dropwise to the filtrate until the pH is 7, and after the completion of the dropwise addition, stirring is carried out for 2 hours, filtering, washing with water, and drying under reduced pressure at 35 ℃ until the weight is constant, 4.1g of pale white solid powder is obtained. The purity was 99.85% by HPLC.
The resulting solid powder was analyzed in the same manner as in example 1, and the X-ray powder diffraction pattern and the IR pattern were substantially in accordance with fig. 1 and 4.
Example 4: preparation of form I crystals of Luo Shasi He hydrate
5.0g Luo Shasi he (form A) is added into a 250ml three-necked flask, 100ml of purified water is added, 1ml of ammonia water is added, the mixture is heated to 25-30 ℃, stirred until the mixture is completely dissolved, and filtered; and (3) dropwise adding 8ml of 10% citric acid into the filtrate until the pH value is 7, keeping the temperature and stirring for 2 hours after the dropwise adding is finished, filtering, washing with water, and drying under reduced pressure at 35 ℃ until the weight is constant to obtain 5.2g of off-white solid powder. The purity was 99.95% by HPLC.
The resulting solid powder was analyzed in the same manner as in example 1, and the X-ray powder diffraction pattern and the IR pattern were substantially in accordance with fig. 1 and 4.
Example 5: preparation of form I crystals of Luo Shasi He hydrate
50.0g Luo Shasi he (crystal form A) is added into a 1000ml three-mouth bottle, 750ml of purified water is added, sodium bicarbonate aqueous solution (23.8 g sodium bicarbonate is prepared into 250 ml) is added in portions, the mixture is heated to 30-35 ℃, stirred until the mixture is completely dissolved, and filtered; methanesulfonic acid is added dropwise to the filtrate until the pH value is 6, the mixture is kept warm for 2 hours, filtered, washed with water and dried under reduced pressure at 35 ℃ until the weight is constant, and 51.6g of off-white solid powder is obtained. The purity was 99.88% by HPLC.
The resulting solid powder was analyzed in the same manner as in example 1, and the X-ray powder diffraction pattern and the IR pattern were substantially in accordance with fig. 1 and 4.
Example 6: preparation of form I crystals of Luo Shasi He hydrate
5.0g Luo Shasi (form A) is added into a 250ml three-necked flask, 100ml of purified water and 48ml of ammonia water are added, the mixture is stirred until the mixture is completely dissolved, the mixture is filtered, cooled to 0-2 ℃, acetic acid is added dropwise to the filtrate until the pH value is 6, the mixture is stirred for 2 hours after the dropwise addition, the mixture is filtered, washed with water, and dried under reduced pressure at 50 ℃ until the weight is constant, thus obtaining 5.1g of off-white solid powder. The purity was 99.91% by HPLC.
The resulting solid powder was analyzed in the same manner as in example 1, and the X-ray powder diffraction pattern and the IR pattern were substantially in accordance with fig. 1 and 4.
Example 7: preparation of form I crystals of Luo Shasi He hydrate
5.0g Luo Shasi of he (form A) is added into a 250ml three-necked flask, 100ml of purified water is added, then potassium bicarbonate aqueous solution (4.26 g potassium bicarbonate is prepared into 50 ml) is added, stirring is carried out until the mixture is completely dissolved, filtering is carried out, heating is carried out until the mixture is 68-70 ℃, acetic acid is dropwise added into the filtrate until the pH is 6, the mixture is completely added, the mixture is stirred for 1 hour under heat preservation, filtering and washing are carried out, and the mixture is dried under reduced pressure at 60 ℃ until the constant weight is obtained, thus obtaining 4.9g of off-white solid powder. The purity was 99.81% by HPLC.
The resulting solid powder was analyzed in the same manner as in example 1, and the X-ray powder diffraction pattern and the IR pattern were substantially in accordance with fig. 1 and 4.
Example 8: preparation of form I crystals of Luo Shasi He hydrate
5.0g Luo Shasi of (form A) is added into a 250ml three-necked flask, 80ml of purified water is added, then sodium carbonate aqueous solution (3.01 g sodium carbonate is prepared into 30 ml) is added, stirring is carried out until the mixture is completely dissolved, filtering is carried out, heating is carried out until the temperature reaches 38-40 ℃, acetic acid is dropwise added into the filtrate until the pH is 6, the dropwise addition is completed, the mixture is kept at the temperature for 2 hours, filtering and washing are carried out, and drying under reduced pressure at 35 ℃ until the weight reaches constant, thus obtaining 5.0g of off-white solid powder. The purity was 99.83% by HPLC.
The resulting solid powder was analyzed in the same manner as in example 1, and the X-ray powder diffraction pattern and the IR pattern were substantially in accordance with fig. 1 and 4.
Test example: stability investigation
The invention researches the chemical stability of Luo Shasi his I type crystal, about 100g of sample is prepared according to the method of example 1, the conditions of investigation are high temperature (60 ℃) and high humidity (92.5%) by the influence factor test, the total impurity content is measured in 0, 5 and 10 days, the total impurity content is measured in 0, 3 and 6 months by the long-term preservation test (25+/-2 ℃, sealing and shading). The results are shown in Table 2.
TABLE 2
As is clear from Table 2, the form I crystals can be stored for at least 10 days under high temperature and high humidity conditions, and have excellent stability. In long-term preservation experiments, the I-type crystal form can be preserved for at least more than 6 months under the conditions of room temperature, sealing and shading, which shows that the I-type crystal form has good stability and can be used for clinical application.
From the above, it is clear from the above examples and comparative examples that the form I crystals of the present invention can be obtained by dissolving roflumilast in an aqueous solution of an inorganic weak base and then adjusting the pH to crystallization by an acid or an aqueous solution of an acid. XRD analysis of the I-type crystal revealed that the I-type crystal was Luo Shasi as a new crystal form, and that the crystallinity was high. The I-type crystal is obtained by crystallization in a water phase, so that the problem of residual and wrapping of an organic solvent can not occur, and meanwhile, the obtained I-type crystal is 1.5 hydrate, the preparation process is simple, the reproducibility is good, the consumption of a crystallization solvent is reduced, and the production cost can be further reduced. In addition, the I-type crystal has good stability, can be stored for a long time at the ambient temperature, does not generate crystal transformation, and has good drug properties.
The foregoing has described exemplary embodiments of the invention, it being understood that any simple variations, modifications, or other equivalent arrangements which would not unduly obscure the invention may be made by those skilled in the art without departing from the spirit of the invention.
Claims (10)
1. A crystalline roflumilast hydrate, characterized by having diffraction peaks at 3.36±0.2°, 6.49±0.2°, 9.95±0.2°, 11.80±0.2°, 16.12±0.2° and 19.05±0.2° using Cu-Ka radiation in an X-ray powder diffraction spectrum expressed in terms of 2Θ angle.
2. The crystal according to claim 1, wherein the crystal further has diffraction peaks at 8.14±0.2°, 10.48±0.2°, 12.77±0.2°, 13.72±0.2°, 15.23±0.2°, 20.04±0.2°, 22.86±0.2°, 23.62±0.2°, 24.32±0.2°, 25.59±0.2°, 26.91±0.2°, 28.19±0.2° using Cu-Ka radiation and X-ray powder diffraction spectrum expressed in 2Θ angle.
3. The crystal according to claim 1, wherein the mass percentage of water of crystallization in the crystal is 6.6% to 7.6%.
4. The crystal according to claim 1, wherein the infrared absorption spectrum of the crystal is at 3359cm -1 ，3110cm -1 ，1725cm -1 ，1754cm -1 ，1624cm -1 ，1536cm -1 ，1491cm -1 ，1351cm -1 ，1223cm -1 ，939cm -1 With an absorption peak.
5. The crystal according to claim 1, characterized in that the crystal shows a weight loss in the TGA spectrum of 6.8% to 7.5% at 105 ℃.
6. A method for producing the crystal according to any one of claims 1 to 5, comprising:
adding roflumilast into an aqueous solution of inorganic weak base, dissolving and filtering;
adding acid or an aqueous solution of the acid into the filtrate obtained after the filtration, adjusting the pH value of the filtrate until crystallization is separated out, and filtering to obtain the crystal of the roflumilast hydrate.
7. The method of claim 6, wherein the inorganic weak base is selected from one or more of ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
8. The method according to claim 6, wherein the molar ratio of the weak inorganic base to Luo Shasi is from 1:1 to 50:1.
9. The method according to claim 6, wherein an acid or an aqueous acid solution is added to the filtrate obtained after filtration, and the pH of the filtrate is adjusted to 5 to 7.
10. The method according to claim 6, wherein adding an acid or an aqueous acid solution to the filtrate obtained after filtration, adjusting the pH of the filtrate to crystallize out, comprises:
dripping a preset amount of acid or an aqueous solution of the acid into the filtrate obtained after the filtration, and stirring at a preset temperature for a preset time after the dripping is finished to separate out crystals;
wherein the preset amount is not lower than the molar equivalent of the inorganic weak base, the preset temperature is 0-70 ℃, and the preset time is 1-2 h.
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