CN113603673A - Duloxetine hydrochloride crystal form, preparation method and application thereof - Google Patents
Duloxetine hydrochloride crystal form, preparation method and application thereof Download PDFInfo
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- CN113603673A CN113603673A CN202011276223.2A CN202011276223A CN113603673A CN 113603673 A CN113603673 A CN 113603673A CN 202011276223 A CN202011276223 A CN 202011276223A CN 113603673 A CN113603673 A CN 113603673A
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- 229960002496 duloxetine hydrochloride Drugs 0.000 title claims abstract description 137
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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 discloses a duloxetine hydrochloride crystal form D, and a preparation method and application thereof. The duloxetine hydrochloride crystal form D has low hygroscopicity, is easy for industrial production and subsequent preparation operation, has stable and reliable quality and better patent medicine prospect.
Description
Technical Field
The invention relates to a duloxetine hydrochloride crystal form, a preparation method and application thereof.
Background
Duloxetine Hydrochloride (Duloxetine Hydrochloride), chemical name: (+) - (S) -N-methyl-gamma- (1-naphthyloxy) -2-thienylpropylamine hydrochloride having the CAS number: 136434-34-9, developed by Eli Lilly corporation, USA, 8 and 12 months 2004, and approved for marketing by the US and European Union, respectively, under the trade name Cymbalta (Xin Baida). Duloxetine hydrochloride is a 5-hydroxytryptamine and norepinephrine reuptake inhibitor (SSNRI) which inhibits the reuptake of neurons for 5-hydroxytryptamine and norepinephrine, thereby increasing the concentration of these two central neurotransmitters in the brain and spinal cord, and is useful for treating certain mood disorders such as depression and anxiety and relieving central pain such as diabetic peripheral neuropathic pain and female fibromyalgia. The structure is as follows:
duloxetine hydrochloride structural formula
US5362886 (application date: 1993.10.12, Applicant: Eli Lilly and Company) is a compound synthesis patent which discloses only the preparation of compounds.
US2006/0270859A1 (application date: 2006.11.30, Applicant: Santiago Ini) discloses polymorphic forms of duloxetine hydrochloride comprising form B and an amorphous form, wherein form B has characteristic diffraction peaks at 2 θ values of 11.1, 12.1, 14.9, 21.6, 24.2. The applicant repeated the preparation of duloxetine hydrochloride of US5362886 and designated it as form a, which has characteristic diffraction peaks at 2 theta values of 9.6, 13.9, 18.1, 18.9, 20.9, 23.4. The method adopts a decompression spin-drying method to remove the water-containing reaction solvent, and consumes time and energy.
WO2007119114 (application date: 2006.12.12, applicant: Medichem, s.a.) discloses duloxetine hydrochloride acetone solvates characterized by diffraction peaks at 5.5, 10.5, 12.2, 16.6,17.9, 18.2, 18.8, 21.1, 22.1, 23.9, 24.5, 24.8, 25.7, 27.7. The acetone solvate can be changed into a crystal form A under the condition of refluxing or heating in methanol, and has thermal instability.
CN101448815A (application date: 2007.5.23, applicant: twatt pharmaceutical industry limited) discloses duloxetine hydrochloride form C having characteristic diffraction peaks at 2 θ values of 10.5, 16.7, 23.9, 24.8, and 27.7, a weight loss on TGA spectrum of 9%, and is actually duloxetine hydrochloride acetone solvate. The patent discloses that duloxetine hydrochloride form C can be converted into form A under a dry condition, which indicates that the form C is unstable and is not beneficial to preparation production.
CN101631783A (application date: 2007.6.21, applicant: Jianfeng International Inc., Chongqing saint Huaxi pharmaceutical industry Co., Ltd.) discloses a duloxetine hydrochloride crystal form I, which has characteristic diffraction peaks at 2 theta values of 9.52, 13.82, 17.98, 18.77, 20.78, 23.24, 24.41, 26.35 and 27.86, a melting point of 158-. The preparation method of the crystal form comprises the steps of firstly putting duloxetine oxalate into ethyl acetate and a water system, adding ammonia water to completely dissolve the duloxetine oxalate, obtaining free duloxetine in an ethyl acetate layer, then adopting reaction crystallization to dissolve the duloxetine in a heterocyclic compound or nitrile compound solution, and then adding the solution into an organic solvent containing HCl to crystallize, wherein the preparation process is complicated, and the yield is low (lower than 70%).
CN101595099B (application date: 2007.6.21, applicant: Jianfeng International Inc., Chongqing san Huaxi pharmaceutical Co., Ltd.) discloses a duloxetine hydrochloride crystal form II having characteristic diffraction peaks at 2 theta values of 11.02, 11.99, 13.94, 14.78, 16.19, 16.87, 18.0, 18.8, 19.77, 20.84, 21.44, 22.16, 23.12, 24.12, 26.34, 26.76, 27.0, 27.45, 29.24, 29.58, 29.92, 30.4, 32.2, 32.82 and 34.18 and a melting point of 154-. The crystal form patent is granted. The preparation method of the crystal form comprises the steps of firstly putting duloxetine oxalate into an ethyl acetate and water system, adding ammonia water to completely dissolve the duloxetine oxalate, obtaining free duloxetine in an ethyl acetate layer, then adopting reaction crystallization to dissolve the duloxetine in an aromatic hydrocarbon solution, and then adding the solution into an organic solvent containing HCl for crystallization, wherein the preparation process is complicated, and the yield is low (lower than 70%).
CN101627026A (application date: 2007.6.21, applicant: Jianfeng International Inc., Chongqing san Huaxi pharmaceutical industry Co., Ltd.) discloses a duloxetine hydrochloride crystal form III, which has characteristic diffraction peaks at 2 theta values of 11.95, 21.44, 22.12, 23.08 and 24.06 and a melting point of 160.6 ℃. The preparation method of the crystal form comprises the steps of firstly putting duloxetine oxalate into an ethyl acetate and water system, adding ammonia water to completely dissolve the duloxetine oxalate, obtaining free duloxetine in an ethyl acetate layer, then adopting reaction crystallization to dissolve the duloxetine in hydrochloric ether solution, and then adding the solution into an organic solvent containing HCl to crystallize, wherein the preparation process is complicated, and the problem of low yield (lower than 70%) also exists.
CN101522189A (application date: 2007.7.3, applicant: Raiboxcel laboratories, Inc.) discloses a duloxetine hydrochloride form having characteristic diffraction peaks at 2 theta values of 9.74, 14.02, 18.20, 19.02, 21.00, 22.28, 23.28, 23.48 and 24.64, also named form I, which is prepared by dissolving duloxetine hydrochloride in absolute ethanol and then adding at least one of an aliphatic ether, an aliphatic hydrocarbon, an aromatic hydrocarbon or an aliphatic ester for crystallization, and also has the problem of low yield (less than 75%).
WO2007093439 (application date: 2007.2.16, applicant: KRKA) discloses duloxetine hydrochloride crystal form A having characteristic diffraction peaks at 2 theta values of 9.6, 13.9, 18.0, 18.8, 19.2, 20.8, 27.4 and 27.9, and a single endothermic peak at 170 ℃ on a DSC spectrum; the crystal form T has characteristic diffraction peaks at 12.0, 14.8, 19.8, 21.3, 21.6, 22.1, 22.4, 23.1 and 24.1, and a DSC spectrum thereof has a solid-solid conversion peak of the crystal form T converted to the crystal form A at 130 ℃ and a single endothermic melting peak of the crystal form A at 170 ℃. The preparation method of the crystal form A is that duloxetine hydrochloride is dissolved in water, alcohols, esters, ketones, acetonitrile, nitromethane, 1, 2-dimethoxyethane or a mixed solvent of the solvents or an aqueous solution of the solvents, the mixture is heated to reflux temperature, and then the mixture is slowly crystallized for 1 to 6 days under the condition of refrigeration to obtain the crystal form A, and the preparation process is time-consuming and tedious. The preparation method of the crystal form T is that duloxetine hydrochloride is dissolved in 1, 4-dioxane, or a mixed solvent of 1, 4-dioxane and water, or a mixed solvent of 1, 4-dioxane and methanol, heated to a reflux temperature, and cooled to obtain the crystal form A, wherein the crystal form A is unstable when heated and can be converted into the crystal form A.
CN103626735A (application date: 2014.3.12, applicant: Shi Jia Zhong pharmaceutical technology (Shijiazhuang) Co., Ltd.) discloses a duloxetine hydrochloride alpha crystal form having characteristic diffraction peaks at 2 theta values of 12.3, 18.3, 18.9, 21.2 and 24.6. The patent also discloses a preparation method of the alpha crystal form, which is to dissolve a duloxetine hydrochloride raw material in a mixed solvent of a soluble solvent and an insoluble solvent, and then add the insoluble solvent in a proper proportion for crystallization, so that the dosage of the solvent is large, and the operation is inconvenient.
Polymorphism is the phenomenon that the same drug molecule exists in different crystal forms due to different crystal arrangement and filling modes. Because of the obvious difference of physicochemical properties of different polymorphic forms of the same medicine, such as solubility, dissolution rate, bioavailability, stability, fluidity, compression resistance and other mechanical properties, the properties have certain influence on the application of the medicine. Therefore, it is necessary to improve various properties of duloxetine hydrochloride through the intensive research on the crystal form of duloxetine hydrochloride and the related preparation method.
Disclosure of Invention
The invention aims to overcome the defects that a preparation method of a duloxetine hydrochloride crystal form in the prior art is complex in operation and poor in hygroscopicity, and provides a duloxetine hydrochloride crystal form and a preparation method thereof. The duloxetine hydrochloride crystal form has low hygroscopicity, is easy for industrial production and subsequent preparation operation, has stable and reliable quality and better patent medicine prospect.
The invention provides a duloxetine hydrochloride crystal form D, which has an X-ray powder diffraction pattern expressed by a 2 theta angle and has characteristic diffraction peaks at 9.8 +/-0.2 degrees, 10.9 +/-0.2 degrees, 13.6 +/-0.2 degrees, 16.4 +/-0.2 degrees, 18.4 +/-0.2 degrees, 22.0 +/-0.2 degrees, 24.9 +/-0.2 degrees and 27.6 +/-0.2 degrees.
In one embodiment, the form D of duloxetine hydrochloride has characteristic diffraction peaks at 5.4 ± 0.2 °, 9.8 ± 0.2 °, 10.9 ± 0.2 °, 13.6 ± 0.2 °, 14.7 ± 0.2 °, 16.4 ± 0.2 °, 17.3 ± 0.2 °,17.9 ± 0.2 °, 18.4 ± 0.2 °, 19.8 ± 0.2 °, 20.1 ± 0.2 °, 22.0 ± 0.2 °, 22.6 ± 0.2 °, 23.4 ± 0.2 °, 24.0 ± 0.2 °, 24.9 ± 0.2 ° and 27.6 ± 0.2 ° in an X-ray powder diffraction pattern, expressed in terms of 2 Θ angle.
In one embodiment, the duloxetine hydrochloride form D has an X-ray powder diffraction pattern with peak widths and peak heights relative intensities expressed in degrees 2 Θ as shown in table 1:
TABLE 1
In one embodiment, the duloxetine hydrochloride form D has an X-ray powder diffraction pattern expressed in terms of 2 Θ angles substantially as shown in figure 1.
In one embodiment, the duloxetine hydrochloride form D has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak at 167.03 ± 5 ℃.
In one embodiment, the duloxetine hydrochloride form D has a Differential Scanning Calorimetry (DSC) curve substantially as shown in figure 2.
In one embodiment, the duloxetine hydrochloride form D has a thermogravimetric analysis (TGA) curve substantially as shown in figure 3.
The invention also provides a preparation method of the duloxetine hydrochloride crystal form D, which comprises the following steps: crystallizing duloxetine hydrochloride in a solution of an organic solvent to obtain a duloxetine hydrochloride crystal form D, wherein the organic solvent is a mixed solvent of a chloroalkane solvent and water, or C1-C3A mixed solvent of an alcohol solvent and t-butanol.
In the preparation method of the duloxetine hydrochloride crystal form D, the step of crystallizing duloxetine hydrochloride in an organic solvent comprises the following steps: dissolving the duloxetine hydrochloride in the chloroalkane solvent, filtering to obtain chloroalkane solution of the duloxetine hydrochloride, adding water into the chloroalkane solution, and crystallizing; or dissolving said duloxetine hydrochloride in said C1-C3Filtering the solution in an alcohol solvent to obtain C of duloxetine hydrochloride1-C3Adding tert-butyl alcohol into the alcoholic solution, and crystallizing; wherein, the chloralkane solution of the duloxetine hydrochloride or C of the duloxetine hydrochloride1-C3The alcoholic solution is preferably in a saturated state.
In the preparation method of the duloxetine hydrochloride crystal form D, the duloxetine hydrochloride can be in a crystal form and/or an amorphous form except the duloxetine hydrochloride crystal form D, and preferably is in an amorphous form, a duloxetine hydrochloride crystal form A, a duloxetine hydrochloride crystal form B, a duloxetine hydrochloride crystal form II or a combination thereof.
In the preparation method of the duloxetine hydrochloride crystal form D, the chloroalkane solvent is preferably chloroform and/or dichloromethane, and more preferably chloroform.
In the preparation method of the duloxetine hydrochloride crystal form D, the step C1-C3The alcoholic solvent is preferably methanol and/or ethanol, more preferably methanol.
In the preparation method of the duloxetine hydrochloride crystal form D, when the organic solvent is a mixed solvent of a chlorinated alkane solvent and water, the volume ratio of the chlorinated alkane solvent to the water is preferably 1: 4-4: 1, and more preferably 1: 1.
In the preparation method of the duloxetine hydrochloride crystal form D, when the organic solvent is a mixed solvent of a chloroalkane solvent and water, the chloroalkane solvent can be used in an amount which is conventional in the field. The volume-mass ratio of the chloroalkane solvent to the duloxetine hydrochloride is preferably 3:1 mL/g-5: 1mL/g, for example 10:3 mL/g.
In the preparation method of the duloxetine hydrochloride crystal form D, when the organic solvent is C1-C3When the mixed solvent of alcohol solvent and tert-butyl alcohol is used, the solvent C1-C3The volume ratio of the alcohol solvent to the tertiary butanol is preferably 1:2 to 1:10, and more preferably 1: 8.
In the preparation method of the duloxetine hydrochloride crystal form D, when the organic solvent is C1-C3When the mixed solvent of alcohol solvent and tert-butyl alcohol is used, the solvent C1-C3The amount of alcoholic solvent may be that conventionally used in such procedures in the art. Said C is1-C3The volume-to-mass ratio of the alcoholic solvent to the duloxetine hydrochloride is preferably 1.5:1mL/g to 2:1mL/g, for example 1.6:1 mL/g.
In the preparation method of the duloxetine hydrochloride form D, the crystallization mode can adopt a crystallization mode conventional in the field, such as solvent volatilization, and the solvent volatilization can be carried out under vacuum conditions.
In the preparation method of the duloxetine hydrochloride crystal form D, the crystallization temperature can be a crystallization temperature which is conventional in the art, such as 10-40 ℃, 10-30 ℃, 25-40 ℃.
In the preparation method of the duloxetine hydrochloride crystal form D, the crystallization time is not particularly limited as long as crystals can be precipitated, for example, 24 hours to 7 days.
The invention also provides a pharmaceutical composition, which comprises the duloxetine hydrochloride crystal form D and a pharmaceutically acceptable carrier.
The invention also provides an application of the duloxetine hydrochloride crystal form D or the pharmaceutical composition in preparation of a medicament for treating depression.
In the present invention, the X-ray powder diffraction patterns are all measured using the Ka line of the Cu target.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the novel duloxetine hydrochloride crystal form with low hygroscopicity is prepared by a simple and feasible preparation method, is beneficial to product storage and subsequent preparation operation, and has stable and reliable quality.
Terms and definitions
In the present invention, the term "pharmaceutical composition" refers to a formulation of duloxetine hydrochloride form D of the present invention with carriers, excipients and/or vehicles generally accepted in the art for the delivery of biologically active compounds to organisms (e.g. humans). The purpose of the pharmaceutical composition is to facilitate the administration of duloxetine hydrochloride form D of the present invention to an organism.
In the present invention, the term "pharmaceutically acceptable carrier" refers to carriers and diluents which do not significantly irritate the organism and do not impair the biological activity and performance of the active compound, and includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, preservative, dye/colorant, taste-modifying enhancer, surfactant, wetting agent, dispersing agent, disintegrating agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifier which can be used in humans or livestock animals. Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, and the like.
Administration of a compound of the invention in pure form or in a suitable pharmaceutical composition may be carried out by any acceptable mode of administration providing agents of similar use. The pharmaceutical compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, diluent or excipient, and can be formulated into solid, semi-solid, liquid or gaseous formulations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.
Drawings
FIG. 1 is an X-ray powder diffraction (XRPD) pattern of duloxetine hydrochloride form D obtained in example 1;
FIG. 2 is a Differential Scanning Calorimetry (DSC) curve of form D of duloxetine hydrochloride prepared in example 1;
figure 3 is a thermogravimetric analysis (TGA) plot of duloxetine hydrochloride form D prepared in example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The reagents and methods employed in the examples of the invention are conventional in the art. It will be clear to those skilled in the art that, unless otherwise specified, temperatures are expressed in degrees Celsius (C.) and operating temperatures are carried out at ambient temperature, which is between 10℃ and 30℃, preferably between 20℃ and 25℃.
The detection method comprises the following steps:
1. x-ray powder diffraction (XRPD)
A Rigaku Ultima IV powder diffractometer was used, which was irradiated with Cu-Ka (40kV, 40mA) at room temperature using a D/tex Ultra detector. The scan range is from 3 ° to 45 ° in the 2 θ interval, and the scan speed is 20 °/min.
The differences in measurements associated with such X-ray powder diffraction analysis results arise from a number of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak position), and (e) properties of the substance (e.g., preferred orientation errors). Calibration errors and sample height errors often result in a shift of all peaks in the same direction. When a flat holder is used, small differences in sample height will result in large shifts in XRPD peak positions. Systematic studies show that sample height differences of 1mm can result in peak shifts of 2 θ up to 1 °. These shifts can be identified from the X-ray diffraction patterns and can be eliminated by compensating for them (using the system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.
2. Differential Scanning Calorimetry (DSC)
Using a TA Q2000 differential scanning calorimeter, N2The gas flow rate is 50mL/min, and the temperature rise rate is 10 ℃/min.
3. Thermogravimetric analysis (TGA)
Using a TA Q500 thermogravimetric analyzer, N2The gas flow rate is 50mL/min, and the temperature rise rate is 10 ℃/min.
Example 1: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 1:1, shaking uniformly, and drying in a vacuum drying oven (vacuum degree-0.1 MPa) at 25 ℃ for 7 days to obtain a white solid target product. The XRPD detection shows that the product is duloxetine hydrochloride crystal form D, and the peak width and the peak height relative intensity in an X-ray powder diffraction pattern expressed by a 2 theta angle are as follows:
the XRPD pattern is shown in FIG. 1.
The DSC spectrum is shown in figure 2, which has an endothermic peak at 167.03 + -2 deg.C.
The TGA profile is shown in figure 3, where the corresponding weight loss before 120 ℃ is 0.008842%, indicating that the crystalline form has little solvent residue.
Example 2: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 1:1, shaking uniformly, and drying in a vacuum drying oven (vacuum degree of-0.1 MPa) at 40 ℃ for 24h to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 3: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 1:1, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 4: preparation of duloxetine hydrochloride crystal form D
Taking 2.5g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 4mL of methanol, stirring, filtering to obtain a methanol saturated solution of duloxetine hydrochloride, mixing the clear methanol saturated solution with tert-butyl alcohol according to the volume ratio of 1:8, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 5: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form B prepared by the method disclosed in the patent US2006/0270859, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 1:1, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 6: preparation of duloxetine hydrochloride crystal form D
Taking 3g of amorphous duloxetine hydrochloride prepared by the method described in patent US2006/0270859, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 1:1, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 7: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form II prepared by the method in patent CN101595099B, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 1:1, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 8: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 10mL of dichloromethane, stirring, filtering to obtain a dichloromethane saturated solution of duloxetine hydrochloride, mixing the clear dichloromethane saturated solution with purified water according to the volume ratio of 1:1, shaking uniformly, and drying in a vacuum drying oven (vacuum degree of-0.1 MPa) at 40 ℃ for 24h to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 9: preparation of duloxetine hydrochloride crystal form D
Taking 2.5g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 4mL of ethanol, stirring, filtering to obtain an ethanol saturated solution of duloxetine hydrochloride, mixing the clear ethanol saturated solution with tert-butyl alcohol according to the volume ratio of 1:8, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 10: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 4:1, shaking uniformly, and drying in a vacuum drying oven (vacuum degree of-0.1 MPa) at 40 ℃ for 24 hours to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 11: preparation of duloxetine hydrochloride crystal form D
Taking 3g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886, adding 10mL of chloroform, stirring, filtering to obtain a chloroform saturated solution of duloxetine hydrochloride, mixing the clear chloroform saturated solution with purified water according to the volume ratio of 1:4, shaking uniformly, and drying in a vacuum drying oven (vacuum degree of-0.1 MPa) at 40 ℃ for 24h to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 12: preparation of duloxetine hydrochloride crystal form D
Taking 2.5g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886A, adding 4mL of methanol, stirring, filtering to obtain a methanol saturated solution of duloxetine hydrochloride, mixing the clear methanol saturated solution with tert-butyl alcohol according to the volume ratio of 1:2, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Example 13: preparation of duloxetine hydrochloride crystal form D
Taking 2.5g of duloxetine hydrochloride crystal form A prepared by the method described in patent US5362886A, adding 4mL of methanol, stirring, filtering to obtain a methanol saturated solution of duloxetine hydrochloride, mixing the clear methanol saturated solution with tert-butyl alcohol according to the volume ratio of 1:10, shaking uniformly, and volatilizing at room temperature to obtain a white solid target product. The XRPD detection result shows that the product is duloxetine hydrochloride crystal form D, and the identification data of the product is basically the same as that of example 1.
Effect example 1: comparison of hygroscopicity of different crystal forms of duloxetine hydrochloride
A hygroscopicity experiment of duloxetine hydrochloride crystal form D is carried out according to guiding principles of medicine hygroscopicity experiments in four parts of Chinese pharmacopoeia 2015 edition, and is compared with a commercially available reagent crystal form A, and the specific operation is as follows:
1. weighing a dry glass weighing bottle with a plug, placing the glass weighing bottle in a proper temperature of 25 +/-1 ℃ and relative humidity of 80 +/-2% one day before the preliminary experiment, and precisely weighing the glass weighing bottle (m)1)。
2. Spreading appropriate amount of duloxetine hydrochloride crystal form D and crystal form A in the weighing bottle to obtain sample with thickness of about 1mm, and precisely weighing2)。
3. The weighing bottle is opened and is placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.
4. The weighing bottle cap is covered well, and the weight (m) is precisely weighed3)。
Percent weight gain (m)3-m1)/(m2-m1)×100％
The results are shown in table 2:
table 2: moisture absorption test results of duloxetine hydrochloride crystal form A and crystal form D
The duloxetine hydrochloride crystal form D provided by the invention is superior to the crystal form A in hygroscopicity, and is beneficial to links such as drug production, storage, subsequent preparation processing and the like.
Claims (10)
1. A duloxetine hydrochloride crystal form D has characteristic diffraction peaks at 9.8 +/-0.2 degrees, 10.9 +/-0.2 degrees, 13.6 +/-0.2 degrees, 16.4 +/-0.2 degrees, 18.4 +/-0.2 degrees, 22.0 +/-0.2 degrees, 24.9 +/-0.2 degrees and 27.6 +/-0.2 degrees in an X-ray powder diffraction pattern expressed by a 2 theta angle.
2. Form D of duloxetine hydrochloride of claim 1, having characteristic diffraction peaks, expressed in terms of 2 θ angle, at 5.4 ± 0.2 °, 9.8 ± 0.2 °, 10.9 ± 0.2 °, 13.6 ± 0.2 °, 14.7 ± 0.2 °, 16.4 ± 0.2 °, 17.3 ± 0.2 °,17.9 ± 0.2 °, 18.4 ± 0.2 °, 19.8 ± 0.2 °, 20.1 ± 0.2 °, 22.0 ± 0.2 °, 22.6 ± 0.2 °, 23.4 ± 0.2 °, 24.0 ± 0.2 °, 24.9 ± 0.2 ° and 27.6 ± 0.2 °.
3. Form D of duloxetine hydrochloride according to claim 1, wherein the form D has an X-ray powder diffraction pattern with 2 Θ angles having the 2 Θ values and peak relative intensities as shown in the following table:
and/or the differential scanning calorimetry analysis curve of the crystal form D has an endothermic peak at 167.03 +/-5 ℃.
4. Form D of duloxetine hydrochloride according to claim 1, wherein the form D exhibits an X-ray powder diffraction pattern expressed in terms of 2 θ angles as shown in figure 1;
and/or the differential scanning calorimetry analysis curve of the form D is shown in figure 2;
and/or the thermogravimetric analysis curve of form D is shown in figure 3.
5. A process for preparing form D of duloxetine hydrochloride according to any of claims 1 to 4, wherein the solution of duloxetine hydrochloride in an organic solvent is subjected to crystallization to obtain form D of duloxetine hydrochloride, wherein the organic solvent is (i) a mixed solvent of a chlorinated alkane solvent and water, or (ii) C1-C3A mixed solvent of an alcohol solvent and t-butanol.
6. The process of claim 5, wherein the duloxetine hydrochloride is in a crystalline form other than duloxetine hydrochloride form D and/or is amorphous;
and/or the chloroalkane solvent is chloroform and/or dichloromethane;
and/or, said C1-C3The alcohol solvent is methanol and/or ethanol;
and/or when the organic solvent is a mixed solvent of a chlorinated alkane solvent and water, the volume ratio of the chlorinated alkane solvent to the water is 1: 4-4: 1;
and/or when the organic solvent is a mixed solvent of chloroalkane solvent and water, the volume-mass ratio of the chloroalkane solvent to the duloxetine hydrochloride is 3:1 mL/g-5: 1 mL/g;
and/or, when the organic solvent is C1-C3When the mixed solvent of alcohol solvent and tert-butyl alcohol is used, the solvent C1-C3The volume ratio of the alcohol solvent to the tertiary butanol is 1: 2-1: 10;
and/or, when the organic solvent is C1-C3When the mixed solvent of alcohol solvent and tert-butyl alcohol is used, the solvent C1-C3The volume-mass ratio of the alcohol solvent to the duloxetine hydrochloride is 1.5:1 mL/g-2: 1 mL/g;
and/or the crystallization mode is solvent volatilization;
and/or the crystallization temperature is 10-40 ℃;
and/or the crystallization time is 24 hours to 7 days.
7. The process of claim 6, wherein the duloxetine hydrochloride is amorphous duloxetine hydrochloride, form A duloxetine hydrochloride, form B duloxetine hydrochloride, form II duloxetine hydrochloride, or a combination thereof;
and/or the chloroalkane solvent is chloroform;
and/or, said C1-C3The alcohol solvent is methanol;
and/or when the organic solvent is a mixed solvent of a chloroalkane solvent and water, the volume ratio of the chloroalkane solvent to the water is 1: 1;
and/or when the organic solvent is a mixed solvent of a chloroalkane solvent and water, the volume-to-mass ratio of the chloroalkane solvent to the duloxetine hydrochloride is 10:3 mL/g;
and/or, when the organic solvent is C1-C3When the mixed solvent of alcohol solvent and tert-butyl alcohol is used, the solvent C1-C3The volume ratio of the alcohol solvent to the tertiary butanol is 1: 8;
and/or, when the organic solvent is C1-C3When the mixed solvent of alcohol solvent and tert-butyl alcohol is used, the solvent C1-C3The volume-mass ratio of the alcohol solvent to the duloxetine hydrochloride is 1.6:1 mL/g;
and/or, the solvent evaporation is carried out under vacuum conditions;
and/or the crystallization temperature is 10-30 ℃ or 25-40 ℃.
8. The method of claim 5, wherein the step of crystallizing duloxetine hydrochloride in an organic solvent comprises:
dissolving the duloxetine hydrochloride in the chloroalkane solvent, filtering to obtain chloroalkane solution of the duloxetine hydrochloride, adding water into the chloroalkane solution, and crystallizing; or
Dissolving said duloxetine hydrochloride in said C1-C3Filtering the solution in an alcohol solvent to obtain C of duloxetine hydrochloride1-C3Adding tert-butyl alcohol into the alcoholic solution, and crystallizing;
wherein, the chloralkane solution of the duloxetine hydrochloride or C of the duloxetine hydrochloride1-C3The alcoholic solution is preferably in a saturated state.
9. A pharmaceutical composition comprising duloxetine hydrochloride form D of any of claims 1 to 4, and a pharmaceutically acceptable carrier.
10. Use of duloxetine hydrochloride form D according to any of claims 1 to 4 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the treatment of depression.
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| CN101631783A (en) * | 2006-06-23 | 2010-01-20 | 箭锋国际有限公司 | Crystalline duloxetine hydrochloride |
| CN103626735A (en) * | 2012-08-28 | 2014-03-12 | 石药集团中奇制药技术（石家庄）有限公司 | Duloxetine hydrochloride crystal form and preparation method thereof |
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