CN108440381A - A kind of Apremilast novel crystal forms H and preparation method thereof - Google Patents
A kind of Apremilast novel crystal forms H and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The present invention relates to field of pharmaceutical chemistry technology, and in particular to a kind of Apremilast novel crystal forms H and preparation method thereof.Crystal form H of the present invention, it is characterized in that：A. only there are one endothermic peak between differential scanning calorimetric analysis is shown in 100 ~ 180 DEG C, endothermic peak top value is 156 ± 3 DEG C；B. its X ray powder diffraction pattern has following characteristics peak in 2 θ ± 0.2：7.980、14.494、14.723、15.081、17.317、18.261、19.147、20.362、21.809、23.138、23.505、25.057；C. its X ray powder diffraction pattern 2 θ ± 0.2 be 8.443,15.482 at without characteristic peak.The present invention provides a kind of Apremilast novel crystal forms H of high dissolution.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to a kind of Apremilast novel crystal forms H and preparation method thereof.
Background technology
Apremilast（The entitled Apremilast of English）, chemical name is S- (+) -2- [1- (3- ethyoxyl -4- methoxies
Base phenyl) -2- methanesulfonyl-ethyls] -4- acetyl-amino isoindoline -1,3- diketone；Molecular formula is C22H24N2O7S,
No. CAS is 608141-41-9, is a kind of small molecule selective PDE enzyme（PDE4）Inhibitor, by Celgene biologies
Technology company researchs and develops, and FDA is obtained in March, 2014 and is ratified for treating psoriatic arthritis, curative for effect.Its structural formula is such as
Under：
It is well known that polymorph in pharmaceuticals is an important factor for influencing drug quality, physicochemical property, biological utilisation to drug
Degree, related preparations quality etc. all have a major impact, such phenomenon receives the concern of pharmacy worker at present, it is clear that at
For one of content indispensable in drug research and drug quality control.Common solid drugs crystal form discriminatory analysis technology
Have：X-ray powder diffraction, X-ray single crystal diffraction, differential scanning calorimetry, thermogravimetry, infra-red sepectrometry, Raman spectrum
Method and nuclear magnetic resonance method etc..
Being currently known Apremilast, there are many crystal forms：Patent CN105111127A disclose Apremilast it is amorphous and its system
Preparation Method；Patent CN102702070A discloses seven kinds of crystal forms of Apremilast A, B, C, D, E, F, G；Patent CN105461610A is public
Apremilast crystal form I is opened；Patent CN104761484A discloses Apremilast crystal form II；Patent CN106008315A is disclosed
Apremilast crystal form S；Patent CN104892486A discloses Apremilast crystal form B+.Pass through comparative study, it is believed that Apremilast
Crystal form F and crystal form S is same crystal form, and Apremilast crystal form II and crystal form B+ is same crystal form.
The different crystal forms of drug can significantly affect its solvability, to influence its dissolution and absorption in vivo, into
And influence the bioavilability of drug, Clinical efficacy and safety etc..Under normal circumstances, the solubility of medicine crystal in water and
Solution rate sequence is hydrate ＜ anhydride ＜ organic solvates.In the 12 of Apremilast disclosed above in crystal form,
Crystal form I is hydrate, and solvability is weaker；Crystal form C, D, E, G are respectively toluene, dichloromethane, acetonitrile, ethyl acetate solvent
Change crystal form, these organic solvent crystal forms have preferable solvability, but unsuitable medicinal, especially toluene, dichloromethane, second
Nitrile belongs to that the two class solvents used should be limited；Only crystal form A, B, F/S, II/B+ and it is amorphous be non-solvated crystal form.
Polymorph in pharmaceuticals can be divided into instability mode, metastable type, three kinds of stable crystal form, wherein stable type by its stability
It is best to learn stability, but dissolution rate and solvability are minimum, poor bioavailability, and instability mode is then just on the contrary, dissolution
Rate is too fast and stability is poor.Both types are not suitable for clinical application.Metastable type is molten because its property is stablized relatively
Solution ability is preferably applied to preparation research by more relatively.It is amorphous to belong in 7 kinds of above-mentioned non-solvated crystal forms
Instability mode, crystal form A, B, F/S, II/B+ belong to stable type.
Therefore, there is certain defect in the Apremilast crystal form being currently known, exploitation is a kind of to be prepared in terms of dissolution properties
Simple for process, solvability is stronger, and stable type is relatively preferable, and non-solvated crystal form still has important value.
Invention content
The present invention provides the preparation methods of Apremilast novel crystal forms H and crystal form H a kind of.
The technical scheme is that：
A kind of formula（I）Shown in Apremilast crystal form H
Formula（I）
It is characterized in that：
A. only there are one endothermic peak between differential scanning calorimetric analysis is shown in 100 ~ 180 DEG C, endothermic peak top value is 156 ± 3
℃。
B. its X-ray powder diffraction figure has following characteristics peak in 2 θ ± 0.2：7.980、14.494、14.723、
15.081、17.317、18.261、19.147、20.362、21.809、23.138、23.505、25.057。
C. its X-ray powder diffraction figure 2 θ ± 0.2 be 8.443,15.482 at without characteristic peak.
Preferably, Apremilast crystal form H of the present invention, differential scanning calorimetry（DSC）Analysis shows that Apremilast is brilliant
For type H only there are one endothermic peak between 100 ~ 180 DEG C, endothermic peak top value is 156 ± 3 DEG C.
Preferably, the X-ray powder diffraction figure of Apremilast crystal form H（XRPD）There is following characteristic feature in 2 θ ± 0.2
Absorption peak：
Differential scanning calorimetry（DSC）Analysis shows that Apremilast crystal form H between 100 ~ 180 DEG C only there are one endothermic peak,
Endothermic peak top value is 156 ± 3 DEG C.
Thermal weight loss（TGA）Analysis shows that Apremilast crystal form H is unsolvated, the crystallization water or recrystallisation solvent are not contained.
The present invention also provides the preparation method of Apremilast crystal form H as described above, the specific steps are：By Apremilast
In 40 DEG C ~ 80 DEG C solvents after complete dissolved clarification, system temperature is reduced to -20 DEG C ~ 50 DEG C, at this temperature precipitation or crystal seed naturally
Crystal form H crystal, 1 ~ 3h of growing the grain is precipitated in induction, and filtering is dried to constant weight in air dry oven to obtain the final product.
Specifically, the solvent be methanol, ethyl alcohol, isopropanol, acetone etc. single solvent or above-mentioned solvent and water it is mixed
Bonding solvent.
Solvent for use amount is 5 ~ 50 times, preferably 10 ~ 30 times of Apremilast amount（Volume mass ratio, ml/g）.
After Apremilast in a solvent dissolved clarification, system rate of temperature fall is 5 ~ 120 DEG C/h, optional in certain embodiments
Select instantaneous temperature reduction.
Advantageous effect：Apremilast crystal form H is that a kind of solvability is stronger, and stability is relatively preferable, belongs to non-solvated
Crystal form, provide more more options for the exploitation of new pharmaceutical preparation.
Description of the drawings
Fig. 1 is the differential scanning calorimetry figure of Apremilast crystal form H；
Fig. 2 is the X-ray powder diffraction figure of Apremilast crystal form H；
Fig. 3 is the thermogravimetric analysis figure of Apremilast crystal form H；
Fig. 4 is the rate of dissolution curve of each crystal form of Apremilast in water.
Specific embodiment
In order to make those skilled in the art be better understood from technical scheme of the present invention, some realities are disclosed further below
Applying example, the present invention is described in further detail.
Unless otherwise instructed, embodiment operates under room temperature, condition of normal pressure.
Unless otherwise instructed, the Apremilast raw material used in embodiment can be that the Apremilast of relevant report is non-solvated
Any one in crystal form, can be from purchasing on the market.
Embodiment 1：The preparation of crystal form H
Apremilast 5.0g, absolute ethyl alcohol 150ml are put into 250ml there-necked flasks, 78 DEG C of reflux dissolved clarifications are persistently heated with stirring to,
Stir speed (S.S.) 200r/min.Start cooling system to 10 DEG C, 10 DEG C/h of rate of temperature fall after reflux 10min, and supports at this temperature
Brilliant 2h, filtering, by solid in 50 DEG C of forced air dryings to constant weight.The molar yield of the technique is 90.5%, and measuring its HPLC purity is
99.96%.X-ray powder diffraction and differential scanning calorimetric analysis are the result shows that the solid is Apremilast crystal form H.
Embodiment 2：The preparation of crystal form H
By Apremilast 5.0g, acetone 130ml, purified water 130ml is put into 500ml there-necked flasks, is persistently heated with stirring to 50 DEG C
Dissolved clarification, stir speed (S.S.) 300r/min.Continue constant temperature after dissolved clarification and stirs 10min.Cooling system is to 5 DEG C afterwards, and 30 DEG C of rate of temperature fall/
H, and growing the grain 3h at this temperature, filtering, by solid in 50 DEG C of forced air dryings to constant weight.The molar yield of the technique is 72.1%,
It is 99.95% to measure its HPLC purity.X-ray powder diffraction and differential scanning calorimetric analysis are the result shows that the solid is A Pusi
Special crystal form H.
Embodiment 3：The preparation of crystal form H
Apremilast 5.0g, isopropanol 300ml are put into 500ml there-necked flasks, 75 DEG C of dissolved clarifications, stirring speed are persistently heated with stirring to
Rate is 300r/min.Continue constant temperature after dissolved clarification and stirs 10min.System is cooled down to 50 DEG C with the rate of temperature fall of 5 DEG C/h afterwards, is then added
The solid form for entering the H containing crystal form induces crystallization as crystal seed, and continues growing the grain 3h at this temperature, filtering, by solid in 50 DEG C
Forced air drying is to constant weight.The molar yield of the technique is 81.0%, and it is 99.96% to measure its HPLC purity.X-ray powder diffraction
And differential scanning calorimetric analysis is the result shows that the solid is Apremilast crystal form H.
Embodiment 4：The preparation of crystal form H
Apremilast 5.0g, acetone 35ml are put into 100ml there-necked flasks, are persistently heated with stirring to 40 DEG C of dissolved clarifications, stir speed (S.S.) is
200r/min.Continue constant temperature after dissolved clarification and stirs 10min.Extremely -20 DEG C of cooling system temperature afterwards, 120 DEG C/h of cooling rate.And-
Growing the grain 2h at 20 DEG C, filtering, by solid in 50 DEG C of forced air dryings to constant weight.The molar yield of the technique is 63.8%, measures it
HPLC purity is 99.97%.X-ray powder diffraction and differential scanning calorimetric analysis are the result shows that the solid is Apremilast crystal form
H。
Embodiment 5：The preparation of crystal form H
Apremilast 5.0g, methanol 120ml are put into 100ml there-necked flasks, are persistently heated with stirring to 60 DEG C of dissolved clarifications, stir speed (S.S.) is
200r/min.Continue constant temperature after dissolved clarification and stirs 10min.System is cooled down to 20 DEG C with the rate of temperature fall of 5 DEG C/h afterwards, is then added and contains
The solid form of crystal form H induces crystallization as crystal seed, and continues growing the grain 3h at this temperature, filtering, by solid in 50 DEG C of air blast
It dries to constant weight.The molar yield of the technique is 73.3%, and it is 99.97% to measure its HPLC purity.X-ray powder diffraction and difference
Show scanning thermometric analysis the result shows that the solid is Apremilast crystal form H.
Test example 1：Non-solvated crystal form solubility experiment
Determine the dissolubility of crystal form A, B, F, II and crystal form H in purified water.
According to《Chinese Pharmacopoeia》Solubility test requires contrived experiment to measure in 2010 editions two notes on the use.
Sample is smashed, a certain amount of purified water is added in 25 DEG C ± 2 DEG C, every 5min strength shaking 30s, is used
Ultraviolet-visible spectrophotometry measures dissolving situation.
The solubility of each non-solvated crystal form of Apremilast in water is as shown in the table.
The rate of dissolution of each non-solvated crystal form of Apremilast is as shown in Figure 4.
Claims (6)
1. a kind of formula（I）Shown in Apremilast crystal form H, characterized in that
A. only there are one endothermic peak between differential scanning calorimetric analysis is shown in 100 ~ 180 DEG C, endothermic peak top value is 156 ± 3
℃；
B. its X-ray powder diffraction figure has following characteristics peak in 2 θ ± 0.2：7.980、14.494、14.723、15.081、
17.317、18.261、19.147、20.362、21.809、23.138、23.505、25.057；
C. its X-ray powder diffraction figure 2 θ ± 0.2 be 8.443,15.482 at without characteristic peak.
2. Apremilast crystal form H according to claim 1, characterized in that have differential scanning calorimetry as shown in Figure 1
Figure.
3. Apremilast crystal form H according to claim 1 or 2, it is characterised in that have X-ray powder as shown in Figure 2
Diffraction pattern.
4. according to claim 1 ~ 3 any one of them Apremilast crystal form H, it is characterized in that thermal weight loss（TGA）Analysis shows that should
Crystal form is unsolvated, does not contain the crystallization water or recrystallisation solvent, as shown in Figure 3.
5. the preparation method of Apremilast crystal form H described in claim 1, characterized in that include the following steps：
By Apremilast in 40 DEG C ~ 80 DEG C solvents after complete dissolved clarification, system temperature is reduced to -20 DEG C ~ 50 DEG C, at this temperature
Naturally it is precipitated or crystal form H crystal, 1 ~ 3h of growing the grain is precipitated in crystal seed induction, filtering is dried in air dry oven to constant weight to obtain the final product, institute
State the mixed solvent that solvent is selected from methanol, ethyl alcohol, isopropanol, acetone one kind or itself and water, solvent for use amount and Apremilast amount
Volume mass ratio be 5 ~ 50 times.
6. the preparation method of Apremilast crystal form H according to claim 6, characterized in that solvent for use amount and Apremilast
The volume mass ratio of amount is 10 ~ 30 times.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2021000934A1 (en) * | 2019-07-04 | 2021-01-07 | 南京明德新药研发有限公司 | Crystal form of benzimidazole-2-one compound, solvate thereof, crystal form of solvate thereof, and preparation method therefor |
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Application publication date: 20180824 |