WO2016078543A1 - 一种盐酸洛氟普啶多晶型物及其制备方法 - Google Patents

一种盐酸洛氟普啶多晶型物及其制备方法 Download PDF

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WO2016078543A1
WO2016078543A1 PCT/CN2015/094463 CN2015094463W WO2016078543A1 WO 2016078543 A1 WO2016078543 A1 WO 2016078543A1 CN 2015094463 W CN2015094463 W CN 2015094463W WO 2016078543 A1 WO2016078543 A1 WO 2016078543A1
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polymorph
hydrochloride
loflupredil
powder
detected
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PCT/CN2015/094463
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English (en)
French (fr)
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刘文峥
王国成
侯庆伟
孟洪光
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江苏天士力帝益药业有限公司
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Priority to US15/520,290 priority Critical patent/US10005757B2/en
Priority to CA2966859A priority patent/CA2966859A1/en
Priority to RU2017117180A priority patent/RU2017117180A/ru
Priority to KR1020177013753A priority patent/KR20170084107A/ko
Priority to JP2017524002A priority patent/JP2017534635A/ja
Publication of WO2016078543A1 publication Critical patent/WO2016078543A1/zh
Priority to ZA2017/02351A priority patent/ZA201702351B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • the invention belongs to the field of pharmacy, relates to a crystalline form of a pharmaceutical compound and a preparation method thereof, and particularly to a polymorphic substance of a reversible proton pump inhibitor drug loflupredil hydrochloride and a preparation method thereof.
  • Revaprazan Hydrochloride is a new generation of reversible proton pump inhibitors and the only commercially available potassium competitive acid pump inhibitor in the world. Due to the rapid onset of action, the peak plasma concentration can be reached in about 1 hour, so it is used for rapid relief of symptoms caused by gastric acid, and it also has important clinical significance in meeting the treatment needs and controlling gastrointestinal bleeding in patients.
  • the pharmacodynamics are linear with the oral dose, which means that the optimal dose of gastric acid can be adjusted by adjusting the dose to meet the individualized treatment of different patients for the treatment of peptic ulcers and other related to excessive gastric acid secretion. disease.
  • Loflupromone hydrochloride was launched in 2007. Although many literatures have reported its synthesis process, no reports on the purification methods and crystal forms of lofluprene hydrochloride have been reported so far. Literature (WO9742186; WO9818784; Chinese Journal of Pharmaceutical Industry 2008, 39(5), 321-324; Synthetic Chemistry 2008, 16(4), 490-492; Chinese Journal of New Drugs 2013, 22(14), 1694-1696) reports hydrochloric acid The melting point of lolfipidine is 255-256 ° C, while the melting point of Lofluzine hydrochloride is 205-208 ° C in WO9605177 and MERCK index. We studied the purification method and crystal form, and found that different ratios of ethanol solution were used. Recrystallization of lofluprene hydrochloride yields a product having a different crystalline form with a melting point between 210 and 226 °C.
  • the present invention provides a polymorph of loflupredne hydrochloride, specifically including five crystal forms.
  • the invention also provides a preparation method of the above five crystal forms.
  • a polymorph of loflupredne hydrochloride according to the present invention which has a melting point of 210 to 226 °C.
  • a form of loflupredyl hydrochloride polymorph I said polymorph I having a melting point of 221-226 °C.
  • the powder X-ray diffraction pattern of the polymorph I has a characteristic diffraction peak at 2 ⁇ in degrees 10.240.2, 21.920.2, 17.540.2, 26.700.2, 20.720.2.
  • the powder X-ray diffraction peak of the polymorph I is shown in Table 21.
  • thermogravimetry-differential thermal analysis pattern TG-DTA of the polymorph I showed an endothermic peak at 223 °C.
  • the infrared spectrum of the polymorph I is shown at 3429.20, 3263.33, 2297.82, 2934.24, 1643.24, 1633.59, 1583.45, 1504.37, 1434.94, 1413.72, 1340.43, 1303.79, 1218.93, 1155.28, 1147.78, 1064.63, 1039.56, 972.06, 862.12. 833.19, 773.40, 757.97, and 514.96 cm -1 have characteristic absorption peaks.
  • the invention relates to a loFopidine hydrochloride polymorph II, wherein the polymorph II has a melting point of 218-222 °C.
  • the polymorph II has a characteristic diffraction peak at 2 ⁇ in degrees 10.260.2, 24.480.2, 7.620.2, 2.194.002, 26.760.22, 28.000.2.
  • polymorph II which has a powder X-ray diffraction peak, as shown in Table 22.
  • thermogravimetry-differential thermal analysis pattern TG-DTA showed an endothermic peak at 220 ° C and an exothermic peak at 137 ° C.
  • the polymorph II the infrared spectrum shows at 3431.13, 3056.96, 2297.82, 2931.60, 1643.24, 1633.59, 1584.45, 1504.37, 1434.94, 1415.65, 1340.43, 1305.72, 1213.14, 1155.28, 1114.78, 1064.63, 1041.49, 972.06, 862.12 833.19, 773.40, 757.97, and 514.96 cm -1 have characteristic absorption peaks.
  • the present invention relates to a loFopidine hydrochloride polymorph III, said melting point of 216-220 ° C.
  • the polymorph III has a characteristic diffraction peak at 2 ⁇ in degrees 7.740.2, 24.420.2, 13.800.2, 7.380.2, 25.620.2.
  • polymorph III which has a powder X-ray diffraction peak, as shown in Table 23.
  • thermogravimetry-differential thermal analysis pattern TG-DTA showed an endothermic peak at 218 ° C and an exothermic peak at 140 ° C.
  • the polymorph III the infrared spectrum shows, at 3421.48, 3265.26, 3034.46, 2297.82, 2931.60, 1643.24, 1633.59, 1584.45, 1504.37, 1434.94, 1413.72, 1340.43, 1303.79, 1128.93, 1155.28, 1114.78, 1064.63, 1039.56, 972.06, 862.12, 833.19, 773.40, 757.97, and 514.96 cm -1 have characteristic absorption peaks.
  • a loflupredil hydrochloride polymorph IV of the invention having a melting point of 215-219 °C.
  • the polymorph IV has a characteristic diffraction peak at 2 ⁇ in degrees 7.70.02, 10.340.2, 24.520.2, 20.040.2, 13.780.2.
  • polymorph IV which has a powder X-ray diffraction peak, as shown in Table 24.
  • thermogravimetry-differential thermal analysis pattern TG-DTA showed an endothermic peak at 217 °C and an exothermic peak at 130 °C.
  • the polymorph IV the infrared spectrum shows, at 3347.56, 3407.98, 3629.12, 3060.82, 2981.74, 2293.53, 2896.88, 1643.24, 1633.59, 1585.38, 1504.37, 1430.11, 1415.35, 1340.43, 1305.72, 1211.21, 1157.21, 1112.85, 1062.70, 1043.42, 966.27, 833.19, 771.47, 757.97, and 518.82 cm -1 have characteristic absorption peaks.
  • a loflupredyl hydrochloride polymorph V of the invention said melting point 210-218 ° C.
  • the polymorph V has characteristic diffraction peaks at 2 ⁇ of 7.680.2, 24.520.2, 13.740.2, 8.060.2, 19.540.2 expressed in degrees.
  • polymorph V the powder X-ray diffraction peaks of which are shown in Table 25.
  • thermogravimetry-differential thermal analysis pattern TG-DTA showed an endothermic peak at 216 ° C and an exothermic peak at 143 ° C.
  • the polymorph V the infrared spectrum shows, at 3347.63, 3141.84, 3267.19, 300.8.82, 2981.74, 2931.60, 2896.88, 1643.24, 1633.59, 1585.38, 1504.37, 1430.11, 1415.35, 1338.51, 1305.72, 1211.21, 1157.21, 1112.85, 1062.70, 1043.42, 966.27, 833.19, 771.47, 757.97, and 518.82 cm -1 have characteristic absorption peaks.
  • a formulation comprising a polymorph of lifluramine hydrochloride of the present invention consists of any of the lofluprimyl hydrochloride polymorphs I-V and a pharmaceutically acceptable adjuvant.
  • the loflupredil hydrochloride polymorph of the present invention may comprise from 0.1 to 99.9% by weight of the formulation, with the balance being a pharmaceutically acceptable carrier.
  • the preparation of the present invention is in the form of a unit dose of a pharmaceutical preparation, and the unit dosage form means a unit of the preparation, such as each tablet of the tablet, each capsule of the capsule, each bottle of the oral solution, granules per bag, and the like.
  • the pharmaceutical preparation form of the present invention may be any pharmaceutically acceptable dosage form including: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, oral liquids. Oral, granules, granules, pills, powders, ointments, dans, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches.
  • the preparation of the present invention is preferably an oral dosage form such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, an agent, a paste or the like.
  • the orally administered preparation of the present invention may contain usual excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a wetting agent, if necessary.
  • the tablets are coated.
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, Tween 80, polyoxyethylene 35 castor oil, sucrose fatty acid esters.
  • Solid oral compositions can be prepared by conventional methods such as mixing, filling, tableting, and the like. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts of filler.
  • the oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use.
  • Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats.
  • Emulsifiers such as lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), such as almond oil, fractionated coconut oil, oily esters of esters such as glycerol, propylene glycol or ethanol;
  • the agent for example, p-hydroxybenzyl or propylparaben or sorbic acid, and if desired, may contain conventional flavoring or coloring agents.
  • the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle.
  • This compound can be suspended or dissolved depending on the carrier and concentration.
  • the solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing. Excipients such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier.
  • the composition can be frozen after filling the vial and the water removed under vacuum.
  • the invention may optionally be added to a suitable pharmaceutically acceptable carrier when prepared as a medicament, the pharmaceutically acceptable carrier being selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, hydrochloric acid.
  • the dosage can be taken one to three times a day, 1-20 doses each time, such as: 1-20 bags or tablets or tablets.
  • the invention provides a method for preparing a polymorph of liflurazine hydrochloride according to the invention, which comprises the following steps:
  • a stirring and heating dissolution method is employed to completely dissolve the lofluprene hydrochloride.
  • the heating dissolution can also be carried out under the protection of argon or nitrogen. Nitrogen is preferred.
  • the cooling in the above step (2) may be carried out by using an ice salt bath or an ice water bath, preferably an ice salt bath.
  • the aqueous alcohol described in the above step (1) includes, but is not limited to, ethanol, methanol, preferably ethanol.
  • the aqueous alcohol concentration is 45-98%.
  • the loflupremazine hydrochloride is placed in a reaction flask, and a solution of 88-98% (preferably 90%) of ethanol is added in an amount of 3-20 times (preferably 5-10 times, weight ratio, w/w), and heated by stirring. Soluble to all, slightly cold, add activated carbon to decolorize for 5-15 minutes, filter while hot, cool to 0-15 ° C, stir and crystallize, filter, then wash with 88-98% (preferably 90%) aqueous ethanol solution, filter, dry, That is, much crystal form I.
  • the aqueous alcohol is 85% ethanol, and the resulting polymorph is polymorph II.
  • the loflupredil hydrochloride is placed in a reaction flask, and a 3-20 times (preferably 5-10 times, weight ratio, w/w) 85% aqueous ethanol solution is added, and the mixture is heated until completely dissolved, slightly cold. Adding activated carbon to decolorize for 5-15 minutes, filtering while hot, cooling to 0-15 ° C, stirring and crystallization, filtering, washing, drying, ie, much crystal form II.
  • the aqueous alcohol is 75% ethanol and the resulting polymorph is polymorph III.
  • the loflupremazine hydrochloride is placed in a reaction flask, and a 3-20-fold (preferably 5-10 times weight ratio, w/w) 75% ethanol aqueous solution is added, and the mixture is heated until completely dissolved, slightly cold. Adding activated carbon to decolorize for 5-15 minutes, filtering while hot, cooling to 0-15 ° C, stirring and crystallization, filtering, washing and drying, ie, much crystal form III.
  • the step of the aqueous alcohol is 70% ethanol and the resulting polymorph is polymorph IV.
  • the loflupredil hydrochloride is placed in a reaction flask, and a 3-20 times amount (5-10 times weight ratio, w/w) of a 70% aqueous solution of ethanol is added, and the mixture is heated until completely dissolved, slightly cooled, and added.
  • the activated carbon is decolorized by reflux for 5-15 minutes, filtered while hot, cooled to 0-15 ° C, stirred and crystallized, filtered, washed, dried, ie, much crystalline form IV.
  • the aqueous alcohol is 50% ethanol
  • the resulting polymorph is a polymorph V.
  • the loflupredil hydrochloride is placed in a reaction flask, and a 3-20 times amount (5-10 times by weight, w/w) of a 50% aqueous solution of ethanol is added, and the mixture is heated until completely dissolved, slightly cooled, and added.
  • the activated carbon was decolorized by reflux for 5-15 minutes, filtered while hot, and cooled to 0-15 ° C to stir and crystallize. Filtration, washing, drying, ie, much crystal form V.
  • the loFopidine hydrochloride polymorph I was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 1.
  • the polymorph I hydrochloride was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 2.
  • the loflupredil hydrochloride polymorph I was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 3.
  • the loflupredil hydrochloride polymorph I was sealed with a polyethylene film bag and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 6 months, respectively at the first, second, third, and sixth Samples were taken at the end of the month and the results are shown in Table 4.
  • the loflupredyl hydrochloride polymorph II was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled at 5 and 10 days. The results are shown in Table 5.
  • the loflupredil hydrochloride polymorph II was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 6.
  • the loflupredil hydrochloride polymorph II was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 7.
  • the loflupredil hydrochloride polymorph II was sealed with a polyethylene film bag, placed at a temperature of 40 ⁇ 2 ° C, and the relative humidity was 75 ⁇ 5%, placed for 6 months, respectively, at 1, 2, 3, 6 Samples were taken at the end of the month and the results are shown in Table 8.
  • the loFopidine hydrochloride polymorph III was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 9.
  • the polymorph III of loflupredil hydrochloride was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 10.
  • the loflupredil hydrochloride polymorph III was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 11.
  • the loflupredil hydrochloride polymorph III was sealed with a polyethylene film bag and placed at a temperature of 40 ⁇ 2 ° C, and the relative humidity was 75 ⁇ 5% for 6 months, respectively, at 1, 2, 3, and 6. Samples were taken at the end of the month and the results are shown in Table 12.
  • the loflupredyl hydrochloride polymorph IV was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 13.
  • the polymorphic form IV of loflupredil hydrochloride was placed in a 60 ° C incubator and sampled at 5 and 10 days. The results are shown in Table 14.
  • the loflupredil hydrochloride polymorph IV was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 15.
  • the loFopidine hydrochloride polymorph IV is sealed with a polyethylene film bag and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 6 months, respectively, at 1, 2, 3, and 6 Samples were taken at the end of the month and the results are shown in Table 16.
  • Lolfiridine hydrochloride polymorph V (Test Example 5)
  • the loflupredyl hydrochloride polymorph V was irradiated under the condition of light intensity of 4500 ⁇ 500 Lx, and sampled and detected at 5 and 10 days. The results are shown in Table 17.
  • the loflupremazine hydrochloride Form 4 was placed in a 25 ° C incubator (relative humidity of 75 ⁇ 5%) and sampled at 5 and 10 days. The results are shown in Table 19.
  • the loflupredil hydrochloride polymorph V is sealed with a polyethylene film bag and placed at a temperature of 40 ⁇ 2° C. and a relative humidity of 75 ⁇ 5% for 6 months, respectively, at 1, 2, 3, and 6 Samples were taken at the end of the month and the results are shown in Table 20.
  • the five crystal forms of lofluprene hydrochloride prepared by the method of the invention have high purity of 99.9% or more; the yield is high, about 90%.
  • the five crystal forms were stable by illumination, high temperature, high humidity and accelerated test, and the purity did not change significantly.
  • Figure 4 Form II powder X-ray diffraction pattern
  • Figure 10 Form IV powder X-ray diffraction pattern
  • the powder X-ray diffraction pattern of loflupredil hydrochloride polymorph I expressed as 2 ⁇ at 10.240.2, 21.920.2, 17.540.2, 26.700.2, 20.720.2 have characteristic diffraction peaks. Its powder X-ray diffraction data is shown in Table 21, and its powder X-ray diffraction pattern is shown in Fig. 1.
  • Powder X-ray diffraction pattern of loflupredil hydrochloride polymorph II characteristic diffraction of 2 ⁇ at 10.260.2, 24.480.2, 7.620.2, 21.940.2, 26.760.2, 28.000.2 peak.
  • the specific powder X-ray diffraction data is shown in Table 22, and the powder X-ray diffraction pattern is shown in Fig. 4.
  • Thermogravimetry-differential thermal analysis showed that Form II had an endothermic peak at 220 ° C and an exothermic peak at 137 ° C, as shown in Figure 5.
  • Infrared spectrum of Form II shows, at 3431.13, 3056.96, 2297.82, 2931.60, 1643.24, 1633.59, 1584.45, 1504.37, 1434.94, 1415.65, 1340.43, 1305.72, 1213.14, 1155.28, 1114.78, 1064.63, 1041.49, 972.06, 862.12, 833.19, 773.40, 757.97, and 514.96 cm -1 have characteristic absorption peaks. Its infrared spectrum is shown in Figure 6.
  • the powder X-ray diffraction pattern of loflupremazine hydrochloride polymorph III has a characteristic diffraction peak at 2 ⁇ of 7.740.2, 24.420.2, 13.800.2, 7.380.2, 25.620.2.
  • the specific powder X-ray diffraction data is shown in Table 23, and its powder X-ray diffraction pattern is shown in Fig. 7.
  • Thermogravimetry-differential thermal analysis showed that Form III had an endothermic peak at 218 °C and an exothermic peak at 140 °C, see Figure 8.
  • the infrared spectrum of Form III shows that it is 3421.48, 3265.26, 3034.46, 2297.82, 2931.60, 1643.24, 1633.59, 1584.45, 1504.37, 1434.94, 1413.72, 1340.43, 1303.79, 1218.93, 1155.28, 1114.78, 1064.63, 1039.56, 972.06, 862.12, 833.19, 773.40, 757.97, and 514.96 cm -1 have characteristic absorption peaks. Its infrared spectrum is shown in Figure 9.
  • the powder X-ray diffraction pattern of loflupredyl hydrochloride polymorph IV has a characteristic diffraction peak of 2 ⁇ at 7.700.2, 10.340.2, 24.520.2, 20.040.2, 13.780.2.
  • the specific powder X-ray diffraction data is shown in Table 24, and its powder X-ray diffraction pattern is shown in Fig. 10.
  • Its powder X-ray diffraction pattern has a characteristic diffraction peak at 2 ⁇ of 7.680.2, 24.520.2, 13.740.2, 8.060.2, 19.540.2 expressed in degrees.
  • the specific powder X-ray diffraction data is shown in Table 25, and its powder X-ray diffraction pattern is shown in Fig. 13.
  • Thermogravimetry-differential thermal analysis showed that Form V had an endothermic peak at 216 °C and an exothermic peak at 143 °C, see Figure 14.
  • the infrared spectrum of the crystal form V shows that it is at 3347.63, 3141.84, 3267.19, 3068.82, 2981.74, 2931.60, 2896.88, 1643.24, 1633.59, 1585.38, 1504.37, 1430.11, 1415.35, 1338.51, 1305.72, 1211.21, 1157.21, 1112.85, 1062.70, 1043.42. 966.27, 833.19, 771.47, 757.97, and 518.82 cm -1 have characteristic absorption peaks.
  • the infrared spectrum is shown in Figure 15.
  • Example 1-5 Take the product of Example 1-5, 0.5 g of any polymorph, and 10.5 g of polyethylene glycol-6000, mix uniformly, heat and melt, transfer the material to the drip of dripping pills, and drop the liquid to a liquid of 6-8 ° C. In paraffin, degreasing, made 400 pills.
  • Example 1-5 The product of Example 1-5 was 0.5 g of any polymorph, 4.5 g of glucose, 0.9 g of sodium thiosulfate and 1 ml of distilled water. The above components were uniformly mixed, freeze-dried, and 500 parts were obtained.
  • Example 1-5 Take the product of Example 1-5, any polymorph 0.5g, mannitol 5.5g, calcium edetate 0.9g and distilled water 2ml, the above components are mixed, freeze-dried, and 300 parts are obtained. .
  • Example 1-5 The product of Example 1-5 was obtained by adding 0.5 g of any polymorph, 50 g of starch, and 50 g of sucrose. After the above components were mixed, granulation was carried out, and tablets were obtained by tableting.
  • Example 1-5 The product of Example 1-5 was obtained by adding 0.5 g of any polymorph, 50 g of starch, and 50 g of sucrose. After the above components were mixed, granulation was carried out, and capsules were obtained by capsule filling.

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Abstract

本发明提供了盐酸洛氟普啶晶型及其制备方法。该方法包括将盐酸洛氟普啶溶于乙醇中或溶于不同比例的乙醇水溶液中进行重结晶的步骤。

Description

一种盐酸洛氟普啶多晶型物及其制备方法 技术领域
本发明属于药学领域，涉及药物化合物晶型及其制备方法，特别涉及一种可逆质子泵抑制剂药物盐酸洛氟普啶多晶型物及其制备方法。
背景技术
盐酸洛氟普啶(Revaprazan Hydrochloride)是新一代可逆质子泵抑制剂，也是全球唯一上市的钾竞争性酸泵抑制剂。由于起效迅速，一般在1h左右即能达到血药浓度峰值，因此用于胃酸引起症状的迅速缓解，而且在满足治疗需求和控制患者胃肠道出血方面，也具有重要的临床意义，该药药效与口服剂量呈线性关系，这意味着可通过调节药物剂量以提供最佳的胃酸控制水平，从而满足不同患者的个体化治疗，用于治疗消化性溃疡以及其它与胃酸分泌过多有关的疾病。
盐酸洛氟普啶于2007年上市，虽然有多篇文献报道其合成工艺，但至今未见有关盐酸洛氟普啶精制方法和晶型的报道。文献(WO9742186；WO9818784；中国医药工业杂志2008，39(5)，321-324；合成化学2008，16(4)，490-492；中国新药杂志2013,22(14)，1694-1696)报道盐酸洛氟普啶的熔点均为255-256℃，而WO9605177和MERCK索引报道盐酸洛氟普啶熔点为205-208℃，我们对其精制方法和晶型进行研究，结果发现用不同比例的乙醇水溶液对盐酸洛氟普啶进行重结晶，获得的产品呈现不同的晶型，熔点在210-226℃之间。
发明内容
为了解决上述技术问题，本发明提供了一种盐酸洛氟普啶多晶型物，具体包括5种晶型物。
本发明还提供了上述5种晶型物的制备方法。
本发明的一种盐酸洛氟普啶多晶型物，其特征在于，熔点在210-226℃。
一种盐酸洛氟普啶多晶型物I，所述的多晶型I熔点221-226℃。
所述多晶型物I的粉末X-射线衍射图，以度表示的2θ在10.240.2、21.920.2、17.540.2、26.700.2、20.720.2有特征衍射峰。
进一步优选多晶型物I的粉末X-射线衍射峰见表21。
所述多晶型物I的热重-差热分析图谱TG-DTA显示，在223℃有吸热峰。
所述多晶型物I红外光谱图显示，在3429.20、3263.33、2979.82、2914.24、1643.24、1633.59、1583.45、1504.37、1434.94、1413.72、1340.43、1303.79、1218.93、1155.28、1114.78、1064.63、1039.56、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。
本发明一种盐酸洛氟普啶多晶型物II，所述多晶型II熔点218-222℃。
所述多晶型物II，其粉末X-射线衍射图，以度表示的2θ在10.260.2、24.480.2、7.620.2、21.940.2、26.760.2、28.000.2有特征衍射峰。
进一步优选多晶型物II，其粉末X-射线衍射峰，见表22。
所述多晶型物II，热重-差热分析图谱TG-DTA显示，在220℃有吸热峰，在137℃有放热峰。
所述多晶型物II，红外光谱图显示在3431.13、3056.96、2979.82、2931.60、1643.24、1633.59、1583.45、1504.37、1434.94、1415.65、1340.43、1305.72、1213.14、1155.28、1114.78、1064.63、1041.49、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。
本发明一种盐酸洛氟普啶多晶型物III，所述的熔点216-220℃。
所述多晶型物III，其粉末X-射线衍射图，以度表示的2θ在7.740.2、24.420.2、13.800.2、7.380.2、25.620.2有特征衍射峰。
进一步优选多晶型物III，其粉末X-射线衍射峰，见表23。
所述多晶型物III，热重-差热分析图谱TG-DTA显示，在218℃有吸热峰，在140℃有放热峰。
所述多晶型物III，红外光谱图显示，在3421.48、3265.26、3043.46、2979.82、2931.60、1643.24、 1633.59、1583.45、1504.37、1434.94、1413.72、1340.43、1303.79、1218.93、1155.28、1114.78、1064.63、1039.56、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。
本发明的一种盐酸洛氟普啶多晶型物IV，所述熔点215-219℃。
所述多晶型物IV，其粉末X-射线衍射图，以度表示的2θ在7.700.2、10.340.2、24.520.2、20.040.2、13.780.2有特征衍射峰。
进一步优选多晶型物IV，其粉末X-射线衍射峰，见表24。
所述多晶型物IV，热重-差热分析图谱TG-DTA显示，在217℃有吸热峰，在130℃有放热峰。
所述多晶型物IV，红外光谱图显示，在3473.56、3407.98、3269.12、3060.82、2981.74、2933.53、2896.88、1643.24、1633.59、1585.38、1504.37、1433.01、1415.65、1340.43、1305.72、1211.21、1157.21、1112.85、1062.70、1043.42、966.27、833.19、771.47、757.97、518.82cm-1有特征吸收峰。
本发明的一种盐酸洛氟普啶多晶型物V，所述熔点210-218℃。
所述多晶型物V，其粉末X-射线衍射图，以度表示的2θ在7.680.2、24.520.2、13.740.2、8.060.2、19.540.2有特征衍射峰。
进一步优选多晶型物V，其粉末X-射线衍射峰见表25。
所述多晶型物V，热重-差热分析图谱TG-DTA显示在216℃有吸热峰，在143℃有放热峰。
所述多晶型物V，红外光谱图显示，在3471.63、3411.84、3267.19、3060.82、2981.74、2931.60、2896.88、1643.24、1633.59、1585.38、1504.37、1433.01、1415.65、1338.51、1305.72、1211.21、1157.21、1112.85、1062.70、1043.42、966.27、833.19、771.47、757.97、518.82cm-1有特征吸收峰。
本发明的一种含有盐酸洛氟普啶多晶型物的制剂，是由所述盐酸洛氟普啶多晶型物I-V任意一个与药剂上可接受的辅料组成。
本发明的盐酸洛氟普啶多晶型物，其在制剂中所占重量百分比可以是0.1-99.9％，其余为药物可接受的载体。
本发明的制剂，是单位剂量的药物制剂形式，所述单位剂量形式是指制剂的单位，如片剂的每片，胶囊的每粒胶囊，口服液的每瓶，颗粒剂每袋等。
本发明的药物制剂形式可以是任何可药用的剂型，这些剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂。本发明的制剂，优选的是口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。
本发明的口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠、聚氧乙烯氢化蓖麻油、吐温80、聚氧乙烯35蓖麻油、蔗糖脂肪酸酯。
可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了 提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
本发明在制备成药剂时可选择性的加入适合的药物可接受的载体，所述药物可接受的载体选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
在使用时根据病人的情况确定用法用量，可每日服一到三次，每次1-20剂，如：1-20袋或粒或片。
本发明的一种盐酸洛氟普啶多晶型物制备方法，其特征在于包括如下步骤：
(1)将盐酸洛氟普啶用含水醇溶解；
(2)加入活性炭回流脱色，过滤得滤液；
(3)滤液降温搅拌析晶，过滤、洗涤，得固体，干燥，即得多晶型物。
上述步骤(1)中采用搅拌加热溶解方式，使盐酸洛氟普啶完全溶解。所述加热溶解也可以在氩气或氮气保护下进行。优选为氮气。
上述步骤(2)中所述降温可用冰盐浴，也可用冰水浴，优选冰盐浴。
上述步骤(1)中所述的含水醇，包括但不限于乙醇、甲醇，优选乙醇。所述含水醇浓度为45-98％。
进一步优选用含水醇为88-98％乙醇，得到的多晶型物是多晶型物I。
具体为将盐酸洛氟普啶置于反应瓶中，加入3-20倍量(优选5-10倍量，重量比，w/w)的88-98％(优选90％)乙醇水溶液，搅拌加热至全部溶解，稍冷，加入活性炭回流脱色5-15分钟，趁热过滤，降温到0-15℃搅拌析晶，过滤，再88-98％(优选90％)乙醇水溶液洗涤，过滤，干燥，即得多晶型物I。
进一步优选用含水醇为85％乙醇，得到的多晶型物是多晶型物II。
具体为：将盐酸洛氟普啶置于反应瓶中，加入3-20倍量(优选5-10倍量，重量比，w/w)的85％乙醇水溶液，搅拌加热至全部溶解，稍冷，加入活性炭回流脱色5-15分钟，趁热过滤，降温到0-15℃搅拌析晶，过滤，洗涤，干燥，即得多晶型物II。
进一步优选含水醇为75％乙醇，得到的多晶型物是多晶型物III。
具体为：将盐酸洛氟普啶置于反应瓶中，加入3-20倍量(优选5-10倍量重量比，w/w)的75％乙醇水溶液，搅拌加热至全部溶解，稍冷，加入活性炭回流脱色5-15分钟，趁热过滤，降温到0-15℃搅拌析晶，过滤，洗涤，干燥，即得多晶型物III。
进一步优选所述步骤含水醇为70％乙醇，得到的多晶型物是多晶型物IV。
具体为：将盐酸洛氟普啶置于反应瓶中，加入3-20倍量(5-10倍量重量比，w/w)的70％乙醇水溶液，搅拌加热至全部溶解，稍冷，加入活性炭回流脱色5-15分钟，趁热过滤，降温到0-15℃搅拌析晶，过滤，洗涤，干燥，即得多晶型物IV。
进一步优选含水醇为50％乙醇，得到的多晶型物是多晶型物V。
具体为：将盐酸洛氟普啶置于反应瓶中，加入3-20倍量(5-10倍量重量比，w/w)的50％乙醇水溶液，搅拌加热至全部溶解，稍冷，加入活性炭回流脱色5-15分钟，趁热过滤，降温到0-15℃搅拌析晶。过滤，洗涤，干燥，即得多晶型物V。
有益效果
为了更好的说明本发明的盐酸洛氟普啶多晶型物的有益效果，下面通过稳定性试验加以说明。
试验例：稳定性
1、盐酸洛氟普啶晶型I的稳定性
盐酸洛氟普啶多晶型物I(实施例1)
1.1 光照射试验
取盐酸洛氟普啶多晶型物I置于光强度4500±500Lx的条件下照射，于5、10天取样检测，结果见表1。
表1盐酸洛氟普啶多晶型物I强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.27 99.96 未检出
5天 白色粉末 0.28 99.92 未检出
10天 白色粉末 0.30 99.94 未检出
1.2 高温试验
取盐酸洛氟普啶多晶型物I置60℃恒温箱中，于5、10天取样检测，结果见表2。
表2盐酸洛氟普啶多晶型物I高温试验结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.21 99.96 未检出
5天 白色粉末 0.23 99.95 未检出
10天 白色粉末 0.24 99.98 未检出
1.3 高湿试验
将盐酸洛氟普啶多晶型物I置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表3。
表3盐酸洛氟普啶多晶型物I高湿试验结果
时间(天) 外观色泽 吸湿增重(％) 纯度(％) 有关物质
0天 白色粉末 0 99.96 未检出
5天 白色粉末 0.42 99.93 未检出
10天 白色粉末 0.63 99.95 未检出
1.4 加速试验
盐酸洛氟普啶多晶型物I用聚乙烯薄膜袋密封，置于温度40±2℃，相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月月末取样检测，结果见表4。
表4盐酸洛氟普啶多晶型物I加速试验结果
试验时间 外观色泽 纯度(％) 有关物质
0月 白色粉末 99.96 未检出
1月 白色粉末 99.97 未检出
2月 白色粉末 99.92 未检出
3月 白色粉末 99.96 未检出
6月 白色粉末 99.95 未检出
结果表明：盐酸洛氟普啶多晶型物I在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、纯度和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
2、盐酸洛氟普啶多晶型物II的稳定性
盐酸洛氟普啶多晶型物II(实施例2)
2.1 光照射试验
取盐酸洛氟普啶多晶型物II置于光强度4500±500Lx的条件下照射，于5、10天取样检。结果见表5。
表5盐酸洛氟普啶多晶型物II强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.25 99.94 未检出
5天 白色粉末 0.26 99.97 未检出
10天 白色粉末 0.28 99.94 未检出
2.2 高温试验
取盐酸洛氟普啶多晶型物II置60℃恒温箱中，于5、10天取样检测，结果见表6。
表6盐酸洛氟普啶多晶型物II高温试验结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.23 99.94 未检出
5天 白色粉末 0.27 99.97 未检出
10天 白色粉末 0.29 99.95 未检出
2.3 高湿试验
将盐酸洛氟普啶多晶型物II置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表7。
表7盐酸洛氟普啶多晶型物II高湿度试验结果
时间(天) 外观色泽 吸湿增重(％) 纯度(％) 有关物质
0天 白色粉末 0 99.94 未检出
5天 白色粉末 0.42 99.93 未检出
10天 白色粉末 0.64 99.95 未检出
2.4 加速试验
盐酸洛氟普啶多晶型物II用聚乙烯薄膜袋密封，置于温度40±2℃，相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月月末取样检测，结果见表8。
表8盐酸洛氟普啶多晶型物II加速试验结果
试验时间 外观色泽 纯度(％) 有关物质
0月 白色粉末 99.94 未检出
1月 白色粉末 99.93 未检出
2月 白色粉末 99.95 未检出
3月 白色粉末 99.96 未检出
6月 白色粉末 99.95 未检出
结果表明：盐酸洛氟普啶多晶型物II在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、纯度和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
3、盐酸洛氟普啶多晶型物III的稳定性
盐酸洛氟普啶多晶型物III(实施例3)
3.1 光照射试验
盐酸洛氟普啶多晶型物III置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表9。
表9盐酸洛氟普啶多晶型物III强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.28 99.95 未检出
5天 白色粉末 0.25 99.92 未检出
10天 白色粉末 0.29 99.95 未检出
3.2 高温试验
取盐酸洛氟普啶多晶型物III置60℃恒温箱中，于5、10天取样检测，结果见表10。
表10盐酸洛氟普啶多晶型物III高温试验稳定性结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.22 99.95 未检出
5天 白色粉末 0.26 99.94 未检出
10天 白色粉末 0.26 99.92 未检出
3.3 高湿试验
将盐酸洛氟普啶多晶型物III置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表11。
表11盐酸洛氟普啶多晶型物III高湿度试验稳定性结果
时间(天) 外观色泽 吸湿增重(％) 纯度(％) 有关物质
0天 白色粉末 0 99.95 未检出
5天 白色粉末 0.47 99.92 未检出
10天 白色粉末 0.59 99.94 未检出
3.4 加速试验
盐酸洛氟普啶多晶型物III用聚乙烯薄膜袋密封，置于温度40±2℃，相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月月末取样检测，结果见表12。
表12盐酸洛氟普啶晶型III加速试验结果
试验时间 外观色泽 纯度(％) 有关物质
0月 白色粉末 99.95 未检出
1月 白色粉末 99.92 未检出
2月 白色粉末 99.91 未检出
3月 白色粉末 99.93 未检出
6月 白色粉末 99.95 未检出
结果表明：盐酸洛氟普啶多晶型物III在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、纯度和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
4、盐酸洛氟普啶多晶型物IV的稳定性
盐酸洛氟普啶多晶型物IV(试验例4)
4.1 光照射试验
取盐酸洛氟普啶多晶型物IV置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表13。
表13盐酸洛氟普啶多晶型物IV强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.27 99.93 未检出
5天 白色粉末 0.29 99.95 未检出
10天 白色粉末 0.31 99.92 未检出
4.2 高温试验
取盐酸洛氟普啶多晶型物IV置60℃恒温箱中，于5、10天取样检测，结果见表14。
表14盐酸洛氟普啶多晶型物IV高温试验稳定性结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.25 99.93 未检出
5天 白色粉末 0.27 99.91 未检出
10天 白色粉末 0.27 99.92 未检出
4.3 高湿试验
将盐酸洛氟普啶多晶型物IV置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表15。
表15盐酸洛氟普啶多晶型物IV高湿度试验稳定性结果
时间(天) 外观色泽 吸湿增重(％) 纯度(％) 有关物质
0天 白色粉末 0 99.93 未检出
5天 白色粉末 0.44 99.96 未检出
10天 白色粉末 0.62 99.93 未检出
4.4 加速试验
盐酸洛氟普啶多晶型物IV用聚乙烯薄膜袋密封，置于温度40±2℃，相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月月末取样检测，结果见表16。
表16盐酸洛氟普啶多晶型物IV加速试验结果
试验时间 外观色泽 纯度(％) 有关物质
0月 白色粉末 99.93 未检出
1月 白色粉末 99.91 未检出
2月 白色粉末 99.90 未检出
3月 白色粉末 99.95 未检出
6月 白色粉末 99.94 未检出
结果表明：盐酸洛氟普啶多晶型物IV在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、纯度和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
5、盐酸洛氟普啶多晶型物V的稳定性
盐酸洛氟普啶多晶型物V(试验例5)
5.1 光照射试验
取盐酸洛氟普啶多晶型物V置于光强度4500±500Lx的条件下照射，于5、10天取样检测。结果见表17。
表17盐酸洛氟普啶多晶型物V强光照射试验结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.24 99.94 未检出
5天 白色粉末 0.27 99.95 未检出
10天 白色粉末 0.30 99.95 未检出
5.2 高温试验
取盐酸洛氟普啶晶型4置60℃恒温箱中，于5、10天取样检测，结果见表23。
表18盐酸洛氟普啶多晶型物V高温试验稳定性结果
时间(天) 外观色泽 干燥失重(％) 纯度(％) 有关物质
0天 白色粉末 0.29 99.94 未检出
5天 白色粉末 0.30 99.95 未检出
10天 白色粉末 0.32 99.92 未检出
5.3 高湿试验
将盐酸洛氟普啶晶型4置于25℃恒温箱(相对湿度为75±5％)中，于5、10天取样检测。结果见表19。
表19盐酸洛氟普啶多晶型物V高湿度试验稳定性结果
时间(天) 外观色泽 吸湿增重(％) 纯度(％) 有关物质
0天 白色粉末 0 99.94 未检出
5天 白色粉末 0.42 99.94 未检出
10天 白色粉末 0.66 99.96 未检出
5.4 加速试验
盐酸洛氟普啶多晶型物V用聚乙烯薄膜袋密封，置于温度40±2℃，相对湿度在75±5％条件下，放置6个月，分别于第1、2、3、6个月月末取样检测，结果见表20。
表20盐酸洛氟普啶多晶型物V加速试验结果
试验时间 外观色泽 纯度(％) 有关物质
0月 白色粉末 99.94 未检出
1月 白色粉末 99.98 未检出
2月 白色粉末 99.95 未检出
3月 白色粉末 99.97 未检出
6月 白色粉末 99.94 未检出
结果表明：盐酸洛氟普啶多晶型物V在强光照射、高温、高湿和加速试验条件稳定，外观色泽、干燥失重、纯度和有关物质没有明显变化，在高湿条件下稍有吸湿增重。
用本发明方法制得的盐酸洛氟普啶5种晶型，产品纯度高，都在99.9％以上；收率高，都在90％左右。此外，5种晶型经过光照、高温、高湿和加速试验均稳定，纯度没有发生明显变化。
附图说明
图1晶型I的粉末X-射线衍射图
图2晶型I的TG-DTA图
图3晶型I的红外光谱图
图4晶型II粉末X-射线衍射图
图5晶型II的TG-DTA图
图6晶型II红外光谱图
图7晶型III粉末X-射线衍射图
图8晶型III的TG-DTA图
图9晶型III红外光谱图
图10晶型IV粉末X-射线衍射图
图11晶型IV的TG-DTA图
图12晶型IV红外光谱图
图13晶型V粉末X-射线衍射图
图14晶型V的TG-DTA图
图15晶型V红外光谱图
具体实施方式
以下通过实施例对本发明作进一步的说明，但不是对本发明的进一步限定。
产品实施例
实施例1盐酸洛氟普啶多晶型物I
盐酸洛氟普啶多晶型物I其粉末X-射线衍射图，以度表示的2θ在10.240.2、21.920.2、17.540.2、 26.700.2、20.720.2有特征衍射峰。其粉末X-射线衍射数据如表21，其粉末X-射线衍射图见图1。
表21盐酸洛氟普啶晶型物I粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.300 12.0996 15
2 10.240 8.6314 100
3 12.160 7.2725 28
4 13.240 6.6816 17
5 14.660 6.0374 5
6 16.300 5.4335 29
7 16.840 5.2605 19
8 17.540 5.0521 42
9 18.240 4.8597 4
10 19.580 4.5301 25
11 20.720 4.2833 32
12 21.920 4.0515 45
13 22.200 4.0010 25
14 22.480 3.9518 10
15 23.220 3.8275 17
16 24.240 3.6687 14
17 25.440 3.4983 24
18 25.920 3.4346 13
19 26.700 3.3360 33
20 27.980 3.1862 31
21 29.440 3.0315 17
22 31.160 2.8679 7
23 31.920 2.8014 7
24 33.040 2.7089 5
25 34.600 2.5903 6
26 36.300 2.4728 6
27 37.620 2.3890 7
28 39.680 2.2696 6
热重-差热分析图谱(TG-DTA)显示，晶型物I在223℃有吸热峰，见图2。晶型物I红外光谱图显示，在3429.20、3263.33、2979.82、2914.24、1643.24、1633.59、1583.45、1504.37、1434.94、1413.72、1340.43、1303.79、1218.93、1155.28、1114.78、1064.63、1039.56、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。其红外光谱图见图3。
实施例2盐酸洛氟普啶多晶型物II
盐酸洛氟普啶多晶型物II的粉末X-射线衍射图，以度表示的2θ在10.260.2、24.480.2、7.620.2、21.940.2、26.760.2、28.000.2有特征衍射峰。具体的粉末X-射线衍射数据如表22，其粉末X-射线衍射图见图4。
表22盐酸洛氟普啶晶型物II粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.300 12.0996 25
2 7.620 11.5922 55
3 8.020 11.0149 32
4 10.260 8.6146 100
5 12.200 7.2487 29
6 13.280 6.6616 20
7 13.740 6.4396 42
8 15.620 5.6685 15
9 16.040 5.5210 20
10 16.320 5.4269 32
11 16.880 5.2481 21
12 17.560 5.0464 42
13 18.240 4.8597 14
14 18.480 4.7972 14
15 18.840 4.7063 15
16 19.580 4.5301 35
17 19.960 4.4447 30
18 20.760 4.2752 44
19 21.940 4.0478 49
20 22.220 3.9974 30
21 22.520 3.9449 15
22 23.320 3.8113 37
23 24.480 3.6333 58
24 25.440 3.4983 36
25 26.020 3.4216 24
26 26.760 3.3287 46
27 27.260 3.2687 20
28 28.000 3.1840 46
29 29.060 3.0702 14
30 29.560 3.0194 24
31 30.020 2.9742 22
32 30.800 2.9006 16
33 31.200 2.8644 13
34 31.540 2.8342 12
35 31.900 2.8031 13
36 33.240 2.6931 12
热重-差热分析图谱(TG-DTA)显示，晶型物II在220℃有吸热峰，在137℃有放热峰，见图5。晶型物II红外光谱图显示，在3431.13、3056.96、2979.82、2931.60、1643.24、1633.59、1583.45、1504.37、1434.94、1415.65、1340.43、1305.72、1213.14、1155.28、1114.78、1064.63、1041.49、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。其红外光谱图见图6。
实施例3盐酸洛氟普啶多晶型物III
盐酸洛氟普啶多晶型物III其粉末X-射线衍射图，以度表示的2θ在7.740.2、24.420.2、13.800.2、7.380.2、25.620.2有特征衍射峰。其具体的粉末X-射线衍射数据如表23，其粉末X-射线衍射图见图7。
表23盐酸洛氟普啶晶型物III粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.380 11.9687 77
2 7.740 11.4128 100
3 8.120 10.8795 68
4 10.360 8.5317 55
5 11.400 7.7556 35
6 11.820 7.4809 32
7 12.300 7.1900 24
8 13.800 6.4117 79
9 14.680 6.0293 28
10 15.660 5.6541 38
11 16.060 5.5142 59
12 16.940 5.2296 38
13 17.540 5.0521 33
14 18.340 4.8335 38
15 18.880 4.6964 40
16 19.540 4.5392 45
17 20.060 4.4227 60
18 20.520 4.3246 52
19 21.000 4.2268 53
20 22.040 4.0297 44
21 22.840 3.8903 41
22 23.440 3.7921 53
23 24.420 3.6421 98
24 25.620 3.4741 70
25 26.120 3.4088 52
26 26.740 3.3311 57
27 27.580 3.2315 49
28 27.940 3.1907 47
29 29.160 3.0599 31
30 30.120 2.9646 38
31 30.860 2.8951 32
32 31.540 2.8342 27
热重-差热分析图谱(TG-DTA)显示，晶型物III在218℃有吸热峰，在140℃有放热峰，见图8。晶型物III红外光谱图显示，在3421.48、3265.26、3043.46、2979.82、2931.60、1643.24、1633.59、1583.45、1504.37、1434.94、1413.72、1340.43、1303.79、1218.93、1155.28、1114.78、1064.63、1039.56、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。其红外光谱图见图9.
实施例4盐酸洛氟普啶多晶型物IV
盐酸洛氟普啶多晶型物IV其粉末X-射线衍射图，以度表示的2θ在7.700.2、10.340.2、24.520.2、20.040.2、13.780.2有特征衍射峰。其具体的粉末X-射线衍射数据如表24，其粉末X-射线衍射图见图10。
表24盐酸洛氟普啶晶型物IV粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.700 11.4720 100
2 8.100 10.9063 37
3 10.340 8.5481 76
4 13.100 6.7527 6
5 13.780 6.4210 42
6 14.340 6.1714 5
7 15.360 5.7638 11
8 15.700 5.6398 11
9 16.120 5.4938 16
10 16.480 5.3746 7
11 17.520 5.0578 9
12 18.280 4.8492 9
13 18.560 4.7767 9
14 18.880 4.6964 11
15 19.560 4.5347 13
16 20.040 4.4271 45
17 20.460 4.3372 10
18 21.020 4.2229 21
19 21.940 4.0478 7
20 22.280 3.9868 7
21 22.700 3.9140 6
22 23.440 3.7921 27
23 24.060 3.6957 13
24 24.520 3.6274 56
25 25.460 3.4956 13
26 26.240 3.3934 16
27 26.860 3.3165 13
28 27.340 3.2594 18
29 27.980 3.1862 15
30 28.760 3.1016 8
31 29.180 3.0579 9
32 30.080 2.9684 16
33 30.860 2.8951 14
34 31.620 2.8273 8
35 32.120 2.7844 7
36 33.260 2.6915 11
37 33.680 2.6589 8
38 34.320 2.6108 6
39 35.160 2.5503 5
40 37.340 2.4062 8
41 43.200 2.0924 6
42 44.940 2.0154 6
热重-差热分析图谱(TG-DTA)显示，晶型物IV在217℃有吸热峰，在130℃有放热峰，见图11。晶型 物IV红外光谱图显示，在3473.56、3407.98、3269.12、3060.82、2981.74、2933.53、2896.88、1643.24、1633.59、1585.38、1504.37、1433.01、1415.65、1340.43、1305.72、1211.21、1157.21、1112.85、1062.70、1043.42、966.27、833.19、771.47、757.97、518.82cm-1有特征吸收峰。其红外光谱图见图12.
实施例5盐酸洛氟普啶多晶型物V
其粉末X-射线衍射图，以度表示的2θ在7.680.2、24.520.2、13.740.2、8.060.2、19.540.2有特征衍射峰。其具体的粉末X-射线衍射数据如表25，其粉末X-射线衍射图见图13。
表25盐酸洛氟普啶晶型物V粉末X-射线衍射图特征峰参数
序号 2θ d值 相对强度I/I0
1 7.680 11.5018 100
2 8.060 10.9604 62
3 10.280 8.5979 6
4 13.060 6.7733 9
5 13.740 6.4396 66
6 14.280 6.1972 9
7 14.500 6.1037 9
8 15.340 5.7713 13
9 15.660 5.6541 21
10 16.100 5.5005 25
11 18.300 4.8439 15
12 18.540 4.7818 17
13 18.860 4.7014 19
14 19.540 4.5392 18
15 20.040 4.4271 41
16 20.440 4.3414 14
17 21.020 4.2229 30
18 22.200 4.0010 6
19 22.700 3.9140 8
20 23.420 3.7953 35
21 24.060 3.6957 18
22 24.520 3.6274 96
23 25.200 3.5311 19
24 25.440 3.4983 18
25 26.220 3.3960 26
26 26.860 3.3165 18
27 27.340 3.2594 23
28 27.940 3.1907 21
29 28.780 3.0995 12
30 29.160 3.0599 12
31 30.080 2.9684 18
32 30.800 2.9006 18
33 31.600 2.8290 12
34 32.140 2.7827 8
35 33.200 2.6962 11
36 33.660 2.6604 12
37 34.260 2.6152 7
38 35.140 2.5517 6
39 37.280 2.4100 11
40 38.140 2.3576 7
41 43.160 2.0943 8
42 44.980 2.0137 8
热重-差热分析图谱(TG-DTA)显示，晶型物V在216℃有吸热峰，在143℃有放热峰，见图14。晶型物V红外光谱图显示，在3471.63、3411.84、3267.19、3060.82、2981.74、2931.60、2896.88、1643.24、1633.59、1585.38、1504.37、1433.01、1415.65、1338.51、1305.72、1211.21、1157.21、1112.85、1062.70、1043.42、966.27、833.19、771.47、757.97、518.82cm-1有特征吸收峰。其红外光谱图见图15。
制备方法实施例
实施例1盐酸洛氟普啶晶型I的制备
将盐酸洛氟普啶粗品10g置于反应瓶中，加入87％乙醇水溶液30g，氮气保护下，搅拌加热至全部溶解，稍冷，加入活性炭0.1g，回流脱色15分钟，趁热过滤，降温到15℃搅拌析晶。过滤，用87％乙醇水溶液洗涤，干燥，得产品8.9g。
实施例2盐酸洛氟普啶晶型I的制备
将盐酸洛氟普啶粗品50g置于反应瓶中，加入90％乙醇水溶液250g，氮气保护下，搅拌加热至全部溶解，稍冷，加入活性炭0.5g，回流脱色10分钟，趁热过滤，降温到0℃搅拌析晶。过滤，用90％乙醇水溶液洗涤，干燥，得产品47.3g。
实施例3盐酸洛氟普啶晶型I的制备
将盐酸洛氟普啶粗品20g置于反应瓶中，加入95％乙醇水溶液200g，氮气保护下，搅拌加热至全部溶解，稍冷，加入活性炭0.2g，回流脱色5分钟，趁热过滤，降温到5℃搅拌析晶。过滤，用95％乙醇水溶液洗涤，干燥，得产品18.9g。
实施例4盐酸洛氟普啶晶型I的制备
将盐酸洛氟普啶粗品10g置于反应瓶中，加入98％乙醇水溶液150g，搅拌加热至全部溶解，稍冷，加入活性炭0.1g，回流脱色15分钟，趁热过滤，降温到10℃搅拌析晶。过滤，用98％乙醇水溶液洗涤，干燥，得产品9.3g。
实施例5盐酸洛氟普啶晶型I的制备
将盐酸洛氟普啶粗品5g置于反应瓶中，加入无水乙醇水溶液100g，搅拌加热至全部溶解，稍冷，加入活性炭0.1g，回流脱色15分钟，趁热过滤，降温到15℃搅拌析晶。过滤，用无水乙醇水溶液洗涤，干燥，得产品4.6g。
实施例6盐酸洛氟普啶晶型II的制备
将盐酸洛氟普啶粗品20g置于反应瓶中，加入85％乙醇水溶液200g，氮气保护下，搅拌加热至全部溶解，稍冷，加入活性炭0.2g，回流脱色5分钟，趁热过滤，降温到15℃搅拌析晶。过滤，用85％乙醇水溶液洗涤，干燥，得产品18.1g。
实施例7盐酸洛氟普啶晶型III的制备
将盐酸洛氟普啶粗品30g置于反应瓶中，加入75％乙醇水溶液150g，氮气保护下，搅拌加热至全部溶解，稍冷，加入活性炭0.3g，回流脱色15分钟，趁热过滤，降温到15℃搅拌析晶。过滤，用75％乙醇水溶液洗涤，干燥，得产品27.6。
实施例8盐酸洛氟普啶晶型IV的制备
将盐酸洛氟普啶粗品30g置于反应瓶中，加入70％乙醇水溶液300g，搅拌加热至全部溶解，稍冷，加入活性炭0.3g，回流脱色5分钟，趁热过滤，降温到15℃搅拌析晶。过滤，用70％乙醇水溶液洗涤，干燥，得产品27.1g。
实施例9盐酸洛氟普啶晶型V的制备
将盐酸洛氟普啶粗品30g置于反应瓶中，加入50％乙醇水溶液180g，氮气保护下，搅拌加热至全部溶解，稍冷，加入活性炭0.3g，回流脱色5分钟，趁热过滤，降温到5℃搅拌析晶。过滤，用50％乙醇水溶液洗涤，干燥，得产品27.0g。
制剂实施例
实施例1
取产品实施例1-5任意一种多晶型物0.5g与10.5g聚乙二醇-6000混合均匀，加热熔融，化料后移至滴丸滴灌中，药液滴至6-8℃液体石蜡中，除油，制得滴丸400粒。
实施例2
取产品实施例1-5任意一种多晶型物0.5g、葡萄糖4.5g、硫代硫酸钠0.9g和蒸馏水1ml，上述组分混合均匀后，冷冻干燥，分装500支，即得。
实施例3
取产品实施例1-5任意一种多晶型物0.5g、甘露醇5.5g、依地酸钙钠0.9g和蒸馏水2ml，上述组分混匀后，冷冻干燥，分装300支，即得。
实施例4
取产品实施例1-5任意一种多晶型物0.5g、淀粉50g、蔗糖50g，上述组分混匀后，制粒，压片即得片剂。
实施例5
取产品实施例1-5任意一种多晶型物0.5g、淀粉50g、蔗糖50g，上述组分混匀后，制粒，装胶囊即得胶囊剂。

Claims (13)

  1. 一种盐酸洛氟普啶多晶型物，其特征在于，熔点在210-226℃。
  2. 如权利要求1所述的盐酸洛氟普啶多晶型物，其特征在于，
    所述的熔点为221-226℃是盐酸洛氟普啶多晶型物I；
    或所述熔点为218-222℃是盐酸洛氟普啶多晶型物II；
    或所述熔点为216-220℃是盐酸洛氟普啶多晶型物III；
    或所述熔点为215-219℃是盐酸洛氟普啶多晶型物IV；
    或所述熔点为210-218℃是盐酸洛氟普啶多晶型物V。
  3. 如权利要求2所述的多晶型物，其特征在于，所述的盐酸洛氟普啶多晶型物I其粉末X-射线衍射图，以度表示的2θ在10.240.2、21.920.2、17.540.2、26.700.2、20.720.2有特征衍射峰。
  4. 如权利要求3所述的多晶型物，其特征在于，所述的盐酸洛氟普啶多晶型物I其粉末X-射线衍射图，以度表示的2θ的特征衍射峰：
    序号 2θ d值 相对强度I/I0 1 7.300 12.0996 15 2 10.240 8.6314 100 3 12.160 7.2725 28 4 13.240 6.6816 17 5 14.660 6.0374 5 6 16.300 5.4335 29 7 16.840 5.2605 19 8 17.540 5.0521 42 9 18.240 4.8597 4 10 19.580 4.5301 25 11 20.720 4.2833 32 12 21.920 4.0515 45 13 22.200 4.0010 25 14 22.480 3.9518 10 15 23.220 3.8275 17 16 24.240 3.6687 14 17 25.440 3.4983 24 18 25.920 3.4346 13 19 26.700 3.3360 33 20 27.980 3.1862 31 21 29.440 3.0315 17 22 31.160 2.8679 7 23 31.920 2.8014 7 24 33.040 2.7089 5 25 34.600 2.5903 6 26 36.300 2.4728 6 27 37.620 2.3890 7 28 39.680 2.2696 6
  5. 如权利要求2所述多晶型物，其特征在于，所述盐酸洛氟普啶多晶型物I的热重-差热分析图谱TG-DTA显示，在223℃有吸热峰。
  6. 如权利要求2所述多晶型物，其特征在于，所述盐酸洛氟普啶多晶型物I的红外光谱图显示，在 3429.20、3263.33、2979.82、2914.24、1643.24、1633.59、1583.45、1504.37、1434.94、1413.72、1340.43、1303.79、1218.93、1155.28、1114.78、1064.63、1039.56、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。
  7. 如权利要求2所述多晶型，其特征在于：所述的盐酸洛氟普啶多晶型物II其粉末X-射线衍射图，以度表示的2θ在10.260.2、24.480.2、7.620.2、21.940.2、26.760.2、28.000.2有特征衍射峰；和/或
    所述盐酸洛氟普啶多晶型物II的热重-差热分析图谱TG-DTA显示，在220℃有吸热峰，在137℃有放热峰；和/或
    所述盐酸洛氟普啶多晶型物的红外光谱图显示在3431.13、3056.96、2979.82、2931.60、1643.24、1633.59、1583.45、1504.37、1434.94、1415.65、1340.43、1305.72、1213.14、1155.28、1114.78、1064.63、1041.49、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。
  8. 如权利要求2所述多晶型物，其特征在于，所述的盐酸洛氟普啶多晶型物III其粉末X-射线衍射图，以度表示的2θ在7.740.2、24.420.2、13.800.2、7.380.2、25.620.2有特征衍射峰；和/或
    所述的盐酸洛氟普啶多晶型物III的热重-差热分析图谱TG-DTA显示，在218℃有吸热峰，在140℃有放热峰；和/或
    所述的盐酸洛氟普啶多晶型物III的红外光谱图显示，在3421.48、3265.26、3043.46、2979.82、2931.60、1643.24、1633.59、1583.45、1504.37、1434.94、1413.72、1340.43、1303.79、1218.93、1155.28、1114.78、1064.63、1039.56、972.06、862.12、833.19、773.40、757.97、514.96cm-1有特征吸收峰。
  9. 如权利要求2所述多晶型物IV，其特征在于，所述的盐酸洛氟普啶多晶型物IV其粉末X-射线衍射图，以度表示的2θ在7.700.2、10.340.2、24.520.2、20.040.2、13.780.2有特征衍射峰；和/或
    所述的盐酸洛氟普啶多晶型物IV的热重-差热分析图谱TG-DTA显示，在217℃有吸热峰，在130℃有放热峰；和/或
    所述的盐酸洛氟普啶多晶型物IV的红外光谱图显示，在3473.56、3407.98、3269.12、3060.82、2981.74、2933.53、2896.88、1643.24、1633.59、1585.38、1504.37、1433.01、1415.65、1340.43、1305.72、1211.21、1157.21、1112.85、1062.70、1043.42、966.27、833.19、771.47、757.97、518.82cm-1有特征吸收峰。
  10. 如权利要求2所述多晶型物V，其特征在于，所述的盐酸洛氟普啶多晶型物V其粉末X-射线衍射图，以度表示的2θ在7.680.2、24.520.2、13.740.2、8.060.2、19.540.2有特征衍射峰；和/或
    所述的盐酸洛氟普啶多晶型物V的热重-差热分析图谱TG-DTA显示在216℃有吸热峰，在143℃有放热峰；和/或
    所述的盐酸洛氟普啶多晶型物V的红外光谱图显示，在3471.63、3411.84、3267.19、3060.82、2981.74、2931.60、2896.88、1643.24、1633.59、1585.38、1504.37、1433.01、1415.65、1338.51、1305.72、1211.21、1157.21、1112.85、1062.70、1043.42、966.27、833.19、771.47、757.97、518.82cm-1有特征吸收峰。
  11. 一种含有盐酸洛氟普啶多晶型物的制剂，其特征在，权利要求1-9任意一项所述盐酸洛氟普啶多晶型物与药剂上可接受的辅料组成。
  12. 如权利要求1所述的一种盐酸洛氟普啶多晶型物制备方法，其特征在于包括如下步骤：
    (1)将盐酸洛氟普啶用含水醇溶解；
    (2)加入活性炭回流脱色，过滤得滤液；
    (3)滤液降温搅拌析晶，过滤、洗涤，得固体，干燥，即得多晶型物。
  13. 如权利要求11所述的一种盐酸洛氟普啶多晶型物的制备方法，其特征在于，所述步骤含水醇为87-98％乙醇，得到的多晶型物是盐酸洛氟普啶多晶型物I；
    或所述步骤含水醇为85％乙醇，得到的多晶型物是盐酸洛氟普啶多晶型物II；
    或所述步骤含水醇为75％乙醇，得到的多晶型物是盐酸洛氟普啶多晶型物III；
    或所述步骤含水醇为70％乙醇，得到的多晶型物是盐酸洛氟普啶多晶型物IV；
    或所述步骤含水醇为50％乙醇，得到的多晶型物是盐酸洛氟普啶多晶型物V。
PCT/CN2015/094463 2014-11-19 2015-11-12 一种盐酸洛氟普啶多晶型物及其制备方法 WO2016078543A1 (zh)

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