CN111093654A - Bendamustine hydrochloride crystal and preparation method thereof - Google Patents
Bendamustine hydrochloride crystal and preparation method thereof Download PDFInfo
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- CN111093654A CN111093654A CN201880059253.2A CN201880059253A CN111093654A CN 111093654 A CN111093654 A CN 111093654A CN 201880059253 A CN201880059253 A CN 201880059253A CN 111093654 A CN111093654 A CN 111093654A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention relates to a bendamustine hydrochloride crystal and a preparation method thereof. The crystal of the invention has excellent fluidity and can be better used for production and clinical treatment.
Description
The present application claims priority from chinese patent application CN201711084907.0 filed on 2017, 11/07/2017. The present application refers to the above-mentioned chinese patent application in its entirety.
The invention relates to a bendamustine hydrochloride crystal and a preparation method thereof, and application of the bendamustine hydrochloride crystal in preparation of medicines for treating diseases such as cancers.
Bendamustine hydrochloride (bendamustine hydrochloride) is an alkylating antineoplastic drug, developed and marketed by Cephalon corporation in the United states under the trade name of Cephalon
The preparation formulation comprises a freeze-dried powder preparation and a concentrated solution preparation, and is clinically used for single treatment or combined treatment of breast cancer, chronic lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin disease and plasmacytoma. Clinical application shows that the medicine has definite curative effect on breast cancer by single treatment or combined medication, can obviously reduce recurrence rate and death rate, and has small adverse reaction and good safety.
Bendamustine hydrochloride has multiple crystalline forms. CN101980698A discloses 1, 2, 3 and 4 crystalline forms of bendamustine hydrochloride. Wherein forms 1, 3 and 4 are anhydrous and form 2 is a monohydrate. CN102351799A discloses crystalline form I of bendamustine hydrochloride. Through research on the bendamustine hydrochloride crystal forms reported in the patent, the crystal forms are mostly strip-shaped or powdery crystals, the problems of poor fluidity and low stability are generally existed, and the preparation difficulty of preparation products is increased due to the defects.
Disclosure of Invention
The invention aims to provide a novel crystal form of bendamustine hydrochloride, which has good fluidity and can be better applied to the preparation and clinical use of medicaments.
In one aspect, the invention provides bendamustine hydrochloride crystals having an angle of repose θ of no greater than 45 °, for example, the angle of repose may be no greater than 44 °, 43 °, 42 °, 41 °, 40 °, 39 °, 38 °, 37 °, 36 °, 35 °, 34 °, 33 °, 32 °, 31 °, 30 °, 29 °, 28 °, 27 °, 26 °, or 25 °.
In certain embodiments, the shape factor of the crystals is from 0.4 to 1, preferably from 0.6 to 1.
In certain embodiments, the crystals are spherical or ellipsoidal.
In certain embodiments, the bendamustine hydrochloride is an anhydrate.
In certain embodiments, the bendamustine hydrochloride is a hydrate, such as a monohydrate.
In certain embodiments, the bendamustine hydrochloride crystals are characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2-theta angles using Cu-K α radiation having characteristic peaks at 2-theta angles of 10.010, 10.503, 11.273, 12.372, 13.543, 14.983, 19.990, 20.102, 20.655, and 22.831.
In a preferred embodiment, Cu-K α radiation is used to obtain an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ, which has characteristic peaks at 2 θ angles of 10.010, 10.503, 11.273, 12.372, 13.543, 14.983, 19.990, 20.102, 20.655, 22.831, 24.911, 26.116, 27.311, 28.632, 30.214, 30.556, 31.472, 34.540 and 40.825.
In a preferred embodiment, Cu-K α radiation is used and the resulting X-ray powder diffraction pattern is shown in FIG. 1.
In certain embodiments, the bendamustine hydrochloride may be bendamustine hydrochloride form 1, 2, 3, 4, I, etc., preferably form 2.
In certain embodiments, the bendamustine hydrochloride content (in weight percent) of the bendamustine hydrochloride crystals may be greater than 90%, or greater than 92%, or greater than 93%, or greater than 94%, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
In certain preferred embodiments, the present invention provides crystalline bendamustine hydrochloride having an angle of repose θ of no greater than 45 °, preferably no greater than 35 °, more preferably no greater than 30 °, and a shape factor of from 0.4 to 1, preferably from 0.6 to 1, in crystalline form 2, wherein the amount (in weight percent) of bendamustine hydrochloride is greater than 95%, preferably greater than 97%.
In another aspect, the present invention provides a method for preparing bendamustine hydrochloride crystals, the method comprising: and mixing the bendamustine hydrochloride with the solvent under the stirring condition to precipitate bendamustine hydrochloride crystals.
Wherein the solvent may be C1-C6One or more of alkyl alcohols (e.g., methanol, ethanol, isopropanol, etc.), water, and isopropyl acetate.
In certain embodiments, bendamustine hydrochloride is first dissolved in a solvent, which may be C1-C6One or more of alkyl alcohol and water, and mixing with solvent B, wherein the solvent B can be isopropyl acetate, and precipitating bendamustine hydrochloride crystals.
In certain embodiments, bendamustine hydrochloride is first dissolved in a solvent, which may be C1-C6One or more of alkyl alcohol and water, adding solvent B, which can be isopropyl acetate, into the system, and precipitating bendamustine hydrochloride crystals.
The concentration of the added bendamustine hydrochloride may be 1-500mg/ml, preferably 50-150 mg/ml.
The stirring speed can be 100r/min-1000 r/min.
The reaction temperature of the process may be from 0 ℃ to 60 ℃, preferably from 0 ℃ to 40 ℃.
The present invention further relates to a pharmaceutical composition comprising the bendamustine hydrochloride crystals of the present invention, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present invention further relates to a pharmaceutical composition prepared by mixing the crystalline bendamustine hydrochloride of the present invention with one or more pharmaceutically acceptable carriers, diluents, or excipients.
The present invention further relates to a process for the preparation of a pharmaceutical composition comprising the bendamustine hydrochloride crystals of the present invention, which comprises mixing the bendamustine hydrochloride crystals of the present invention with one or more pharmaceutically acceptable carriers, diluents or excipients.
The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the crystal or pharmaceutical preparation of the present invention can be formulated as tablets, capsules, pills, crystals, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays.
The invention further relates to a pharmaceutical drug of bendamustine hydrochloride, which comprises the bendamustine hydrochloride crystal. The bendamustine hydrochloride crystals may be present in an amount greater than 50%, preferably greater than 70%, more preferably greater than 80%, and most preferably greater than 90%, based on the total weight of the drug substance.
In another aspect, the invention provides a powder-liquid multi-chamber infusion bag product comprising at least one powder chamber and at least one liquid chamber, wherein the powder chamber contains bendamustine hydrochloride crystals according to the invention and the liquid chamber contains one or more pharmaceutically acceptable carriers, diluents or excipients.
The powder chamber and the liquid chamber can be separated by a plurality of weak welding separating strips.
The invention further relates to the use of the bendamustine hydrochloride crystals, pharmaceutical compositions or drug substance of the invention in the manufacture of a medicament for the treatment of cancer, such as chronic lymphocytic leukemia, hodgkin's disease, non-hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma or breast cancer.
The crystal obtained by the invention is subjected to structure determination and crystal form research through X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The starting material used in the crystal preparation process of the present invention may be bendamustine hydrochloride in any form, including but not limited to: amorphous, any crystal form, any hydrate or solvate, and the like.
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,
the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
The 2 theta or 2 theta angle refers to a diffraction angle, theta is a Bragg angle and has the unit of DEG or degree, and the error range of 2 theta is +/-0.3 or +/-0.2 or +/-0.1.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice intoJuxtaposed parallelepiped units, called interplanar spacings. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
The "angle of repose" described in the present invention refers to the maximum angle measured in a static state when the gravity force exerted on the particles and the frictional force between the particles are balanced when the particles slide on the free inclined surface of the powder accumulation layer in the gravity field. The angle of repose of the particles is measured by a funnel method, the particulate materials flow out of a funnel and fall on a plane to form a cone, and the angle of repose is taken as the angle of repose. The calculation formula is as follows:
where h and r are the height and radius of the cone, respectively.
The shape factor (Form factor) of the invention is a parameter reflecting the shape of the particle, namely reflecting the degree and irregularity of the difference between the cross-sectional shape of the particle and the circle, and the calculation formula is as follows:
where Area represents the cross-sectional Area of the particle and Perimeter represents the Perimeter of the cross-sectional Area of the particle. The shape factor is 1.0 when the particles are circular, and the value is less than 1.0 when the particle shape deviates from circular. The more irregular the shape of the particle, the smaller the shape factor value, i.e. the further the particle deviates from a circular shape.
Advantageous effects of the invention
The bendamustine hydrochloride crystal prepared by the invention has the advantages of good fluidity, good solubility, quick redissolution, high crystal form purity, good crystal form stability under the conditions of illumination, high temperature and high humidity, stability in the processes of preparation, storage and drying, excellent biocompatibility, stable production process, repeatability and controllability, and suitability for industrial production, and can meet the medicinal requirements of production, transportation and storage. When the bendamustine hydrochloride crystal is used for a powder-liquid double-chamber bag preparation, the bendamustine hydrochloride crystal can be quickly dissolved in a liquid diluent, the defects of time consumption, easy medicine pollution and the like in the preparation process of an injection are avoided, and the bendamustine hydrochloride crystal can be better applied to clinic.
Fig. 1 is an XRPD pattern of the crystalline form of bendamustine hydrochloride obtained in example 1;
fig. 2 is a DSC profile of the crystalline form of bendamustine hydrochloride obtained in example 1;
fig. 3 is a TGA profile of the crystalline form of bendamustine hydrochloride obtained in example 1;
fig. 4 is a photomicrograph of bendamustine hydrochloride crystals obtained in example 1;
fig. 5 is a micrograph of bendamustine hydrochloride 2 crystalline form prepared according to the CN101980698A method.
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the test:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettler Toledo DSC 3+STARe System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 40-300 deg.C
2. X-ray Diffraction Spectroscopy (XRPD)
The instrument model is as follows: BRUKER D8 Discover A25X-ray powder diffractometer
Monochromatic Cu-K α radiation (λ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 2-40 °
Voltage: 40KV, current: 40mA
3. Thermogravimetric Analyzer (Thermal Gravimetric Analyzer)
The instrument model is as follows: mettler Toledo TGA
The heating rate is as follows: 10 ℃/min
Nitrogen purging speed: 60mL/min
4. Optical Microscope (Optical Microscope)
The instrument model is as follows: nikon high-flux microscopic imaging platform Ti-E
Example 1
Adding 20mg of bendamustine hydrochloride into 200 mul of mixed solvent of methanol and water for dissolving, wherein the volume ratio of the methanol to the water is 1:1, dropwise adding 3ml of isopropyl acetate into the solution under stirring, and keeping the temperature at room temperature to precipitate bendamustine hydrochloride crystals. The X-ray diffraction pattern of the crystal sample is shown in figure 1, the DSC pattern is shown in figure 2, the TGA pattern is shown in figure 3, and the micrograph is shown in figure 4. The bendamustine hydrochloride crystal form 2 is determined and confirmed, and the characteristic peak positions are shown in the following table:
TABLE 1 bendamustine hydrochloride crystal form characteristic peaks
Example 2
Adding 2.5mg of bendamustine hydrochloride into 100 mul of mixed solvent of ethanol and water for dissolving, wherein the volume ratio of the ethanol to the water is 1:1, dropwise adding 3ml of isopropyl acetate into the solution under stirring, and keeping the temperature at room temperature to precipitate bendamustine hydrochloride crystals. The XRPD detection of the crystal confirms that the product is 2 crystal forms.
Example 3
Crystals of bendamustine hydrochloride were obtained by flash evaporation in acetic acid according to the procedure of CN101980698A, and the micrograph thereof is shown in fig. 5.
Example 4
The repose angle test device is constructed according to the regulations of the national standard GB11986-89 on the measurement of repose angles of surfactant powder and particles (the repose angles of the powder and the particles can be measured according to the regulations). Three parallel tests show that the angle of repose of the bendamustine hydrochloride crystals obtained in example 1 is as follows: 29.84 °, 27.05 ° and 25.55 °; the angle of repose of the bendamustine hydrochloride crystals obtained in example 3 were: 48.21 °, 49.22 °, and 49.64 °.
Claims (18)
- Bendamustine hydrochloride crystals having an angle of repose theta of not more than 45 deg.
- Bendamustine hydrochloride crystals according to claim 1, characterized in that the shape factor of the crystals is 0.4-1, preferably 0.6-1.
- The bendamustine hydrochloride crystal according to claim 1, wherein the crystal is spherical or ellipsoidal.
- The bendamustine hydrochloride crystal according to claim 1, characterized in that an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ angle is obtained using Cu-K α irradiation, which has characteristic peaks at 2 θ angles of 10.010, 10.503, 11.273, 12.372, 13.543, 14.983, 19.990, 20.102, 20.655 and 22.831.
- The bendamustine hydrochloride crystal according to claim 1, characterized in that an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ angle is obtained using Cu-K α irradiation, and has characteristic peaks at 2 θ angles of 10.010, 10.503, 11.273, 12.372, 13.543, 14.983, 19.990, 20.102, 20.655, 22.831, 24.911, 26.116, 27.311, 28.632, 30.214, 30.556, 31.472, 34.540, and 40.825.
- The crystalline bendamustine hydrochloride according to claim 1, wherein an X-ray powder diffraction pattern obtained using Cu-K α radiation is shown in fig. 1.
- The bendamustine hydrochloride crystals according to claim 1, wherein the bendamustine hydrochloride content (in weight%) of the bendamustine hydrochloride crystals is greater than 90%, preferably greater than 95%, more preferably greater than 97%, and most preferably greater than 99%.
- The bendamustine hydrochloride crystal has an angle of repose theta not greater than 45 degrees, preferably not greater than 35 degrees, more preferably not greater than 30 degrees, and a shape factor of 0.4-1, preferably 0.6-1, wherein the bendamustine hydrochloride crystal is irradiated by Cu-K α to obtain an X-ray powder diffraction pattern as shown in figure 1, and the content (in weight percentage) of bendamustine hydrochloride is greater than 95%, preferably greater than 97%.
- A process for preparing bendamustine hydrochloride crystals as claimed in any one of claims 1 to 8, comprising: mixing bendamustine hydrochloride with a solvent under stirring, wherein the solvent is selected from C1-C6One or more of alkyl alcohol, water and isopropyl acetate, preferably one or more of methanol, ethanol, water and isopropyl acetate.
- The process according to claim 9, wherein the bendamustine hydrochloride is present in a concentration of 1 to 500mg/ml, preferably 50 to 150 mg/ml.
- The method of claim 9, wherein the reaction temperature of the method is 0 ℃ to 60 ℃.
- A pharmaceutical composition comprising bendamustine hydrochloride crystals according to any one of claims 1-8, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
- A pharmaceutical composition prepared by mixing the crystalline bendamustine hydrochloride of any one of claims 1-8 with one or more pharmaceutically acceptable carriers, diluents, or excipients.
- A drug substance of bendamustine hydrochloride comprising bendamustine hydrochloride crystals according to any one of claims 1-8 in an amount greater than 50%, preferably greater than 70%, more preferably greater than 80%, most preferably greater than 90%, based on the total weight of the drug substance.
- A process for the preparation of a pharmaceutical composition comprising bendamustine hydrochloride which comprises mixing bendamustine hydrochloride crystals as claimed in any one of claims 1 to 8 with one or more pharmaceutically acceptable carriers, diluents or excipients.
- Use of the crystalline bendamustine hydrochloride according to any one of claims 1-8, the pharmaceutical composition according to any one of claims 12 and 13, or the drug substance of bendamustine hydrochloride according to claim 14 for the manufacture of a medicament for the treatment of cancer, preferably chronic lymphocytic leukemia, hodgkin's disease, non-hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma or breast cancer.
- A powder-liquid multi-chamber infusion bag product comprising at least one powder chamber containing bendamustine hydrochloride crystals according to any one of claims 1-8 and at least one liquid chamber containing one or more pharmaceutically acceptable carriers, diluents or excipients.
- A powder-liquid multi-chamber infusion bag product according to claim 17, wherein the powder chamber and the liquid chamber are separated by a number of weak weld spacer bars.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711084907 | 2017-11-07 | ||
| CN2017110849070 | 2017-11-07 | ||
| PCT/CN2018/114148 WO2019091373A1 (en) | 2017-11-07 | 2018-11-06 | Crystal of bendamustine hydrochloride and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN111093654A true CN111093654A (en) | 2020-05-01 |
| CN111093654B CN111093654B (en) | 2023-03-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201880059253.2A Active CN111093654B (en) | 2017-11-07 | 2018-11-06 | Bendamustine hydrochloride crystal and preparation method thereof |
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| CN (1) | CN111093654B (en) |
| TW (1) | TWI690514B (en) |
| WO (1) | WO2019091373A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101980698A (en) * | 2008-03-26 | 2011-02-23 | 赛福伦公司 | Novel solid forms of bendamustine hydrochloride |
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2018
- 2018-11-06 CN CN201880059253.2A patent/CN111093654B/en active Active
- 2018-11-06 WO PCT/CN2018/114148 patent/WO2019091373A1/en active Application Filing
- 2018-11-06 TW TW107139295A patent/TWI690514B/en not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101980698A (en) * | 2008-03-26 | 2011-02-23 | 赛福伦公司 | Novel solid forms of bendamustine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| 殷昕: "伏立诺他和盐酸苯达莫司汀的合成与结构修饰.", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 陈磊 等: "盐酸苯达莫司汀的合成工艺改进", 《中国药师》 * |
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| Publication number | Publication date |
|---|---|
| TW201922716A (en) | 2019-06-16 |
| CN111093654B (en) | 2023-03-10 |
| WO2019091373A1 (en) | 2019-05-16 |
| TWI690514B (en) | 2020-04-11 |
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