CN110713470B - Flunarizine hydrochloride crystal form B and preparation method thereof - Google Patents
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention relates to a novel crystal form of flunarizine hydrochloride and a preparation method thereof, belonging to the technical field of drug crystallization. The technical scheme of the invention is as follows: a flunarizine hydrochloride crystal form B has the following characteristic peaks in an X-ray powder diffraction pattern at 2 theta +/-0.2 degrees: characteristic absorption peaks exist at 6.35, 6.55, 8.76, 12.76, 13.07, 13.83, 14.17, 14.36, 14.67, 14.93, 15.60, 15.78, 16.64, 17.18, 17.56, 18.19, 18.45, 18.90, 19.05, 19.65 and 19.84. The invention provides a new crystal form of flunarizine hydrochloride with stable performance and a preparation method thereof.
Description
Technical Field
The invention relates to a flunarizine hydrochloride crystal form B and a preparation method thereof, belonging to the technical field of drug crystallization.
Background
Flunarizine Hydrochloride (Flunarizine Hydrochloride) is a diphenyl piperazine derivative developed by Janssen company of belgium for treating diseases such as cerebral blood supply deficiency, vertebral artery ischemia, cerebral thrombosis, tinnitus, cerebral areola, migraine and epilepsy. The medicine is firstly on the market in some countries in Europe in the beginning of the 80 th 20 th century, and is on the market in China in 1989. The flunarizine hydrochloride is white or off-white crystal or crystalline powder; no odor and no taste. The chemical name is as follows: (E) -1- [ bis (4-fluorophenyl) methyl ] -4- (2-propenyl-3-phenyl) -piperazine dihydrochloride, the chemical structural formula of which is shown as the following formula.
Flunarizine hydrochloride is slightly soluble in methanol or ethanol, slightly soluble in chloroform, very slightly soluble in water and hardly soluble in benzene. The existing commercially available flunarizine hydrochloride has strong hygroscopicity, is very easy to adsorb moisture in the air to cause a moisture absorption phenomenon, influences the accurate feeding in the preparation process of the preparation, and often needs special packaging materials to ensure the stability of the quality in the storage process.
The change of the physicochemical properties of the drug can be generally achieved by changing the salt-forming group of the compound or the crystal structure thereof. In order to solve the problem of hygroscopicity of flunarizine hydrochloride, a great deal of research work is carried out by Janssen corporation, wherein patent US2080200474 discloses that the hygroscopicity of flunarizine fumarate and flunarizine benzoate can be satisfied by using fumaric acid and benzoic acid instead of hydrochloric acid group in the flunarizine hydrochloride. Although the moisture-attracting problem is solved by changing a salifying group mode, the medicinal compound is changed, the effectiveness, the toxicity, the stability and the like of the medicinal compound are different from those of flunarizine hydrochloride, the clinical curative effect is difficult to guarantee, even toxicity and clinical tests need to be carried out again, the risk is high, the cost is high, the time consumption is long, and the medicinal compound is not seen to be put on the market as an improved medicament until now.
The study of drug polymorphism is a leading topic in the pharmaceutical field. Different crystal forms of the drug have differences in internal structure, may have different physicochemical properties such as solubility, dissolution rate and the like, and affect the bioavailability of the drug, and may also have different mechanical properties such as flowability, compressibility and the like, and affect the research, development and production of the drug. In addition, the discovery of the new crystal form of the drug can prolong the life cycle of a drug patent and set a technical barrier, and has important significance for the development of solid drugs. Compared with the change of the structure of the medicine, the change of the crystal form of the compound is obviously more practical, safe and economical.
The common crystal form changing methods at present include solution crystallization, melt crystallization, solid-state grinding crystal transformation, solvent-mediated crystal transformation and the like, wherein the solution crystallization is most common in industrial application due to the advantages of easy operation, low equipment requirement and the like. In the process of solution crystallization, the control of the supersaturation degree of the solution is the most important factor of the solution crystallization, and by accurately controlling the supersaturation degree, the dynamics and thermodynamics priority of different crystal forms of a medicament in the crystallization process can be changed, so that the oriented induction of an unstable crystal form, a metastable crystal form and a stable crystal form is realized, and the purpose of preparing a specific crystal form is finally achieved. For the simplest solution crystallization mode, cooling crystallization, the control of the cooling rate is the most important technical means for controlling the supersaturation degree. When the temperature is reduced, the temperature reduction interval is wide, the temperature reduction speed is large and other temperature reduction parameters can be obtained only by a large amount of high-precision experimental design and verification. Therefore, if a new crystal form is to be obtained, not only the existing crystal form needs to be studied in depth, but also the metastable zone information of the drug in different solvents needs to be understood in depth, so that the correct system and cooling parameters of the target crystal form can be selected. On the contrary, if the crystallization system and the temperature reduction parameter are not well controlled, the mixed crystal phenomenon is easily generated and even the crystal is completely transformed into other crystal forms. In addition, the crystal seed is also one of the important factors of the solution crystallization, the crystal seed plays an inducing role in the generation of subsequent crystals, and the crystal form of the crystal seed is well controlled, so that the product with the corresponding crystal form can be obtained more easily in an oriented manner.
At present, the X-ray diffraction pattern of a flunarizine hydrochloride product on the market is shown in the attached figure 1, and the flunarizine hydrochloride product has the following characteristic peaks at 2 theta +/-0.2 degrees: characteristic absorption peaks at 6.63, 7.17, 7.47, 11.55, 12.12, 12.98, 13.26, 14.17, 14.40, 14.64, 14.81, 15.47, 16.24, 16.68, 17.42, 18.04, 19.00, 19.79 etc. have melting points of about 208 ℃ as indicated in the european pharmacopoeia. For convenience of description, we will refer to it as flunarizine hydrochloride form a.
Experiments prove that the crude product obtained in the Chenlianfeng paper of Nanjing university of physical engineering, n-butanol, methanol, ethanol, dichloromethane, dichloroethane and toluene are used as solvents for recrystallization, the crude product is prepared in acetone solution in the synthesis process improvement of flunarizine hydrochloride in the Chenlianfeng paper, and the product obtained by n-butanol recrystallization is in a crystal form A.
For flunarizine hydrochloride, most of the published documents report the synthesis method and optimization of flunarizine hydrochloride, and no research on the polymorphism of flunarizine hydrochloride is involved. If a new flunarizine hydrochloride crystal form which is relatively stable to humidity and convenient to produce and store can be obtained, the crystal form not only has important academic value, but also has great market value and social significance.
Disclosure of Invention
The purpose of the invention is as follows: provides a new crystal form of flunarizine hydrochloride with stable performance and a crystallization preparation method thereof, and provides a bulk drug with stable quality for the quality control of the preparation.
Technical scheme
Upon experimentation, the applicant has invented form B. The technical scheme of the invention is as follows:
a flunarizine hydrochloride crystal form B has the following characteristic peaks in an X-ray powder diffraction pattern at 2 theta +/-0.2 degrees: characteristic absorption peaks exist at 6.35, 6.55, 8.76, 12.76, 13.07, 13.83, 14.17, 14.36, 14.67, 14.93, 15.60, 15.78, 16.64, 17.18, 17.56, 18.19, 18.45, 18.90, 19.05, 19.65 and 19.84.
Preferably, differential scanning calorimetry analysis of the flunarizine hydrochloride crystal form B shows that an endothermic peak exists at 216.23 +/-2 ℃, and no endothermic peak or exothermic peak exists between 40 and 130 ℃.
Preferably, the X-ray powder diffraction pattern of the flunarizine hydrochloride crystal form B has the following typical characteristic absorption peaks at 2 theta +/-0.2 degrees:
thermogravimetric analysis (TGA) of the flunarizine hydrochloride crystal form B shows that the flunarizine hydrochloride crystal form B is a non-solvating crystal form and does not contain crystal water or a crystal solvent.
The invention also provides a preparation method of the flunarizine hydrochloride crystal form B, which comprises the following specific steps:
dissolving flunarizine hydrochloride in an acetonitrile/water mixed solution, wherein the solid-to-liquid ratio of the solution is 0.03-0.1 g/g, and continuously stirring and dissolving for 40-60 minutes at 65-70 ℃; decolorizing and filtering.
The decolorization in the step can be realized by using activated carbon.
Secondly, transferring the filtrate into a crystallizer, keeping the temperature at 50-55 ℃, adding acetonitrile with the solvent amount being 1-3 times of that of the first step into the crystallizer in a flowing manner for 0.5-1 hour until the crystallizer is obviously turbid, and stirring for 1-2 hours at constant temperature; then slowly cooling to 35-45 ℃, stirring at constant temperature for 1-3 hours, then rapidly cooling to 5-10 ℃, and stirring at heat preservation for 0.5-1 hour.
The slow cooling in the step refers to cooling to a target temperature within 2-4 hours.
The rapid cooling in the step refers to cooling to the end point temperature within 30-45 minutes.
And thirdly, filtering, washing a filter cake by using acetonitrile aqueous solution, and finally performing vacuum drying on the product to obtain the new crystal form product of flunarizine hydrochloride with stable moisture.
The drying conditions in the step are that the temperature is 60-70 ℃, the vacuum drying is carried out, the vacuum degree is 0.08-0.1 MPa, and the time is 10-15 hours.
The preparation method of the flunarizine hydrochloride crystal form B is characterized in that the acetonitrile water solution is prepared from acetonitrile 70-80 wt% in a mixed solvent.
Has the advantages that: the invention provides a new flunarizine hydrochloride crystal form with stable performance and a preparation method thereof, and the hygroscopicity of the flunarizine hydrochloride crystal form B prepared by the method is obviously reduced compared with the crystal form A, thereby being very beneficial to the storage of medicaments; meanwhile, the preparation method of the new crystal form is simple, the one-way molar yield of the crystallization process is more than 85%, and the new crystal form is suitable for industrial production.
Drawings
FIG. 1: x-ray powder diffraction patterns of the flunarizine hydrochloride crystal form (the crystal form A) obtained in the comparison example 1 and the comparison example 2 and a commercial flunarizine hydrochloride product.
FIG. 2: differential Scanning Calorimetry (DSC) analysis maps of the flunarizine hydrochloride crystal form (crystal form A) obtained in the comparison example 1 and the comparison example 2 and a commercially available flunarizine hydrochloride product.
FIG. 3: x-ray powder diffraction patterns of the new crystal form (the crystal form B) of flunarizine hydrochloride obtained in the examples 1 to 6.
FIG. 4: differential scanning calorimetry analysis patterns of the new crystal form (crystal form B) of flunarizine hydrochloride obtained in examples 1-6.
FIG. 5: thermogravimetric analysis patterns of the new crystal form (the crystal form B) of flunarizine hydrochloride obtained in the examples 1 to 6.
FIG. 6: microscopic photographs of flunarizine hydrochloride crystal form A (left) and new crystal form B (right).
Detailed Description
Example 1:
putting 10 g flunarizine hydrochloride into 330 g acetonitrile water solution (mass ratio, acetonitrile: water =4:1), and continuously stirring at 65 ℃ for about 40 min until the solution is clear; adding active carbon, stirring for decolorizing for 40 min, and vacuum filtering; transferring the filtrate into a crystallizer at 50 ℃, and preserving heat; adding 330 g of acetonitrile into the crystallizer at a constant speed within 1 h, and continuing stirring at a constant temperature for 2h after the whole solution is obviously turbid; then slowly cooling the system to 35 ℃ within 3 h, and stirring for 4 h at the constant temperature of the cooling end point; then quickly cooling the system to 10 ℃ within 30 min, and stirring for 1 h at the constant temperature of the cooling end point; performing suction filtration, and washing a filter cake by using 70% acetonitrile water solution; collecting filter cake, vacuum drying at 65 deg.C (0.08 MPa) for 12 h, collecting product to obtain white granular crystal flunarizine hydrochloride 8.56 g, yield 85.6%, HPLC purity 99.96%, and detecting by X-ray powder diffraction to obtain crystal form B (shown in figure 3).
Example 2:
putting 10 g flunarizine hydrochloride into 100g acetonitrile water solution (mass ratio, acetonitrile: water =7:3), and continuously stirring for about 1 h at 70 ℃ until the solution is clear; adding active carbon, stirring for decolorizing for 60 min, and vacuum filtering; transferring the filtrate into a crystallizer at the temperature of 55 ℃, and preserving heat; adding 300 g of acetonitrile into the crystallizer at a constant speed within 30 min, and continuing stirring at a constant temperature for 1 h after the whole solution is obviously turbid; then slowly cooling the system to 45 ℃ within 4 h, and stirring for 2h at the constant temperature of the cooling end point; then quickly cooling the system to 5 ℃ within 45 min, and stirring for 3 h at the constant temperature of the cooling end point; performing suction filtration, and washing a filter cake by using an 80% acetonitrile water solution; collecting filter cakes, drying the filter cakes for 15 hours at 60 ℃ in vacuum (0.1 MPa), and collecting the product to obtain white granular crystal flunarizine hydrochloride 9.23 g, wherein the yield is 92.3%, the HPLC purity is 99.97%, and the crystal form B is detected by X-ray powder diffraction.
Example 3:
putting 10 g flunarizine hydrochloride into 180 g acetonitrile water solution (mass ratio, acetonitrile: water =3:1), and continuously stirring at 65 ℃ for about 40 min until the solution is clear; adding active carbon, stirring for decolorizing for 50 min, and vacuum filtering; transferring the filtrate into a crystallizer at 52 ℃, and preserving heat; adding 270 g of acetonitrile into the crystallizer at a constant speed within 45 min, and continuing stirring at a constant temperature for 90min after the whole solution is obviously turbid; then slowly cooling the system to 40 ℃ within 2h, and stirring for 2h at the constant temperature of the cooling end point; then quickly cooling the system to 6 ℃ within 40 min, and stirring at the constant temperature of the cooling end point for 30 min; performing suction filtration, and washing a filter cake by using 75% acetonitrile water solution; collecting filter cakes, drying the filter cakes for 15 hours at 60 ℃ in vacuum (0.08 MPa), and collecting the product to obtain 8.69 g of white granular crystal flunarizine hydrochloride, wherein the yield is 86.9%, the HPLC purity is 99.94%, and the crystal form B is detected by X-ray powder diffraction.
Example 4:
putting 10 g flunarizine hydrochloride into 250 g acetonitrile water solution (mass ratio, acetonitrile: water =4:1), and continuously stirring at 68 ℃ for about 40 min until the solution is clear; adding active carbon, stirring for decolorizing for 45 min, and vacuum filtering; transferring the filtrate into a crystallizer at 50 ℃, and preserving heat; adding 400 g of acetonitrile into the crystallizer at a constant speed within 40 min, and continuing stirring at a constant temperature for 2h after the whole solution is obviously turbid; then slowly cooling the system to 38 ℃ within 3 h, and stirring for 3 h at the constant temperature of the cooling end point; then, quickly cooling the system to 8 ℃ within 40 min, and stirring for 1 h at the constant temperature of the cooling end point; performing suction filtration, and washing a filter cake by using 75% acetonitrile water solution; collecting filter cakes, drying the filter cakes for 10 hours at 70 ℃ under vacuum (0.09 MPa), and collecting the product to obtain white granular crystal flunarizine hydrochloride 8.69 g, wherein the yield is 86.9%, the HPLC purity is 99.95%, and the crystal form B is detected by X-ray powder diffraction.
Example 5:
putting 10 g flunarizine hydrochloride into 150 g acetonitrile water solution (mass ratio, acetonitrile: water =3:1), and continuously stirring at 70 ℃ for about 40 min until the solution is clear; adding active carbon, stirring for decolorizing for 40 min, and vacuum filtering; transferring the filtrate into a crystallizer at 50 ℃, and preserving heat; adding 300 g of acetonitrile into the crystallizer at a constant speed within 45 min, and continuing stirring at a constant temperature for 80 min after the whole solution is obviously turbid; then slowly cooling the system to 40 ℃ within 3 h, and stirring for 2h at the constant temperature of the cooling end point; then quickly cooling the system to 5 ℃ within 50 min, and stirring at the constant temperature of the cooling end point for 40 min; performing suction filtration, and washing a filter cake by using 78% acetonitrile water solution; and collecting a filter cake, drying the filter cake for 12 hours at 65 ℃ in vacuum (0.08 MPa), and collecting a product to obtain 9.07 g of white granular crystal flunarizine hydrochloride, wherein the yield is 90.7%, the HPLC purity is 99.95%, and the crystal form B is detected by X-ray powder diffraction.
Example 6:
putting 10 g flunarizine hydrochloride into 200 g acetonitrile water solution (mass ratio, acetonitrile: water =3:1), and continuously stirring at 65 ℃ for about 40 min until the solution is clear; adding active carbon, stirring for decolorizing for 40 min, and vacuum filtering; transferring the filtrate into a crystallizer at the temperature of 55 ℃, and preserving heat; adding 320 g of acetonitrile into the crystallizer at a constant speed within 40 min, and continuing stirring at a constant temperature for 1 h after the whole solution is obviously turbid; then slowly cooling the system to 35 ℃ within 3 h, and stirring for 2h at the constant temperature of the cooling end point; then quickly cooling the system to 6 ℃ within 30 min, and stirring at the constant temperature of the cooling end point for 30 min; performing suction filtration, and washing a filter cake by using 75% acetonitrile water solution; collecting the filter cake, drying for 10 h at 70 ℃ under vacuum (0.08 MPa), collecting the product to obtain 8.87 g of white granular crystal flunarizine hydrochloride, wherein the yield is 88.7%, the HPLC purity is 99.93%, and the crystal form B is detected by X-ray powder diffraction.
Comparative example 1:
putting 10 g flunarizine hydrochloride into 100g acetonitrile water solution (mass ratio, acetonitrile: water =11:9), and continuously stirring at 60 ℃ for about 40 min until the solution is clear; adding active carbon, stirring for decolorizing for 40 min, and vacuum filtering; transferring the filtrate into a crystallizer at the temperature of 60 ℃, and preserving heat; adding 300 g of acetonitrile into the crystallizer at a constant speed within 10 min, and continuing stirring at a constant temperature for 2h after the whole solution is obviously turbid; then quickly cooling the system to 30 ℃ within 90min, and stirring for 2h at the constant temperature of the cooling end point; then cooling the system to 10 ℃ at a constant speed within 1 h, and stirring for 3 h at the constant temperature of the cooling end point; performing suction filtration, and washing a filter cake by using 75% acetonitrile water solution; the filter cake was collected and dried at 70 ℃ under vacuum (0.08 MPa) for 10 h to give 8.6g of product with HPLC purity of 99.87% and form A detected by X-ray powder diffraction (as shown in figure 1).
Comparative example 2:
putting 10 g flunarizine hydrochloride into 200 g ethanol water solution (mass ratio, ethanol: water =7:3), and continuously stirring at 65 ℃ for about 40 min until the solution is clear; adding active carbon, stirring for decolorizing for 40 min, and vacuum filtering; transferring the filtrate into a crystallizer at the temperature of 40 ℃, and preserving heat; adding 100g of ethanol into the crystallizer at constant speed within 40 min, and continuously stirring for 1 h at constant temperature after the whole solution is obviously turbid; then quickly cooling the system to 20 ℃ within 1 h, and stirring for 1 h at the constant temperature of the cooling end point; then slowly cooling the system to 10 ℃ within 1 h, and stirring for 2h at the constant temperature of the cooling end point; filtering, and washing a filter cake with ethanol; the filter cake was collected and dried at 70 ℃ under vacuum (0.08 MPa) for 10 h to give 8.3 g of product, HPLC purity 99.90%, form A detected by X-ray powder diffraction.
Test example: moisture wicking test:
experiments are designed according to the guiding principle of the medicament hygroscopicity test in the general rule of the 'Chinese pharmacopoeia' 2015 edition:
a dried glass weighing bottle with a plug is taken and placed in a constant temperature dryer at 25 +/-1 ℃ one day before the test, and an ammonium chloride saturated solution (the relative humidity is 80% +/-2%) is placed at the bottom of the dryer. Glass bottle weight m of precision weighing stopper1(ii) a Taking a proper amount of the sample, spreading the sample in the weighing bottle to obtain a sample with a thickness of about 1 mm, and precisely weighing the total weight m2(ii) a Opening the weighing bottle, placing the weighing bottle and the bottle cap in the constant-temperature constant-humidity dryer for 24 h, and precisely weighing the total weight m3。
Percent weight gain = (m)3-m2）/（m2-m1）×100%
Appropriate amounts of the products of examples 1 to 6, comparative examples 1 to 6 and commercially available flunarizine hydrochloride were taken, percentage growth was measured and calculated in the above manner, and the hygroscopicity of the samples was examined and the data are shown in Table 1.
TABLE 1 hygroscopicity test on products of examples 1 to 6 and products of comparative examples 1 to 6
Analysis of the data in table 1 shows that the weight gain percentage of flunarizine hydrochloride crystal form B is between 1.35% and 1.39%, which is obviously better than the weight gain percentage of flunarizine hydrochloride crystal form a (7.17% to 3.02%). According to the definition of Chinese pharmacopoeia on the moisture-attracting weight increment, the flunarizine hydrochloride crystal form B has a slight moisture-attracting property, and the flunarizine hydrochloride has a moisture-attracting property. Obviously, the stability of the flunarizine hydrochloride crystal form B to humidity is better than that of the crystal form A.
Claims (2)
1. A preparation method of a flunarizine hydrochloride crystal form B is provided, wherein the flunarizine hydrochloride crystal form B X-ray powder diffraction pattern has the following characteristic peaks at 2 theta +/-0.2 degrees: 6.35, 6.55, 8.76, 12.76, 13.07, 13.83, 14.17, 14.36, 14.67, 14.93, 15.60, 15.78, 16.64, 17.18, 17.56, 18.19, 18.45, 18.90, 19.05, 19.65, 19.84, characterized in that it comprises the following steps:
dissolving flunarizine hydrochloride in an acetonitrile/water mixed solution, wherein the solid-to-liquid ratio of the solution is 0.03-0.1 g/g, continuously stirring and dissolving at 65-70 ℃ for 40-60 minutes, decoloring and filtering;
secondly, transferring the filtrate into a crystallizer, keeping the temperature at 50-55 ℃, adding acetonitrile with the solvent amount being 1-3 times of that of the first step into the crystallizer in a flowing manner for 0.5-1 hour until the crystallizer is obviously turbid, and stirring for 1-2 hours at constant temperature; then slowly cooling to 35-45 ℃, stirring at constant temperature for 1-3 hours, then rapidly cooling to 5-10 ℃, and stirring at heat preservation for 0.5-1 hour;
and thirdly, filtering, washing a filter cake by using acetonitrile aqueous solution, and finally carrying out vacuum drying on the product to obtain a new crystal form product of flunarizine hydrochloride with stable moisture, wherein the drying condition is that the temperature is 60-70 ℃, the vacuum degree of vacuum drying is 0.08-0.1 MPa, slow cooling refers to cooling to a target temperature within 2-4 hours, and rapid cooling refers to cooling to an end point temperature within 30-45 minutes.
2. The preparation method of the flunarizine hydrochloride crystal form B according to claim 1, characterized in that the acetonitrile water solution in the first step and the third step is 70-80% by mass of acetonitrile in the mixed solvent.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85102263A (en) * | 1985-04-01 | 1986-05-10 | 郑州大学 | Synthetic technique for " new cinnarizine " |
| CN104382878A (en) * | 2014-12-02 | 2015-03-04 | 石家庄市华新药业有限责任公司 | Flunarizine hydrochloride capsules and preparation method thereof |
| CN110467586A (en) * | 2019-08-30 | 2019-11-19 | 威海迪素制药有限公司 | A kind of preparation method of flunarizine hydrochloride crystallization |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20080200474A1 (en) * | 2007-02-15 | 2008-08-21 | Transform Pharmaceuticals, Inc. | Novel flunarizine salt forms and methods of making and using the same |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85102263A (en) * | 1985-04-01 | 1986-05-10 | 郑州大学 | Synthetic technique for " new cinnarizine " |
| CN104382878A (en) * | 2014-12-02 | 2015-03-04 | 石家庄市华新药业有限责任公司 | Flunarizine hydrochloride capsules and preparation method thereof |
| CN110467586A (en) * | 2019-08-30 | 2019-11-19 | 威海迪素制药有限公司 | A kind of preparation method of flunarizine hydrochloride crystallization |
Non-Patent Citations (1)
| Title |
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| 盐酸氟桂利嗪的合成工艺改进;陈连锋;《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》;20160115(第01期);第B016-279页 * |
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