WO2017128837A1 - 达卡他韦新晶型及其制备方法 - Google Patents

达卡他韦新晶型及其制备方法 Download PDF

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WO2017128837A1
WO2017128837A1 PCT/CN2016/107526 CN2016107526W WO2017128837A1 WO 2017128837 A1 WO2017128837 A1 WO 2017128837A1 CN 2016107526 W CN2016107526 W CN 2016107526W WO 2017128837 A1 WO2017128837 A1 WO 2017128837A1
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crystalline form
crystal form
dihydrobromide
bis
toluenesulfonate
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PCT/CN2016/107526
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English (en)
French (fr)
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李巍
任毅
王琼
朱燕燕
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上海众强药业有限公司
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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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular, the present invention relates to novel crystalline forms of dacavitavir, as well as methods and uses for the preparation of novel crystalline forms.
  • Daclatasvir is a hepatitis C treatment developed by BMS and has the structure shown in Formula I.
  • Daclatasvir was approved for marketing in Europe in August 2014 and was approved by the FDA in July 2015. Daclatasvir belongs to the HCV NS5A protease inhibitor and is indicated for adults infected with HCV genotypes 1, 2, 3 and 4. The cure rate of oral daktavitavir plus sofosbuvir in clinical trials is as high as 100%, including patients with advanced liver disease, genotype 3, and patients with previous protease inhibitor treatment failure.
  • a crystalline form of dacavavir selected from the group consisting of a crystalline form of d-p-toluenesulfonate of Daccavir, a crystal form of dacotavir dihydrobromide, and Dhaka Hewei bisphosphonate crystal form.
  • the crystalline form is a bis-p-toluenesulfonate crystalline form of dacavitavir, and the X-ray powder diffraction pattern of the bis-p-toluenesulfonate crystalline form comprises three or more selected 2 ⁇ values from the next group:
  • the X-ray powder diffraction pattern of the bis-p-toluenesulfonate crystal form includes three Or more than 3 2 ⁇ values selected from the following Table 1:
  • the X-ray powder diffraction pattern of the bis-p-toluenesulfonate crystal form is substantially characterized as in Figure 1.
  • the bis-p-toluenesulfonate crystal form has a melting onset temperature of 119 ° C ⁇ 3 ° C.
  • the DSC pattern of the bis-p-toluenesulfonate crystal form is characterized in Figure 2.
  • the TGA pattern of the bis-p-toluenesulfonate crystal form is characterized in Figure 3.
  • the crystalline form is a crystalline form of dacotavir dihydrobromide
  • the X-ray powder diffraction pattern of the dihydrobromide crystal form comprises 3 or more 2 ⁇ selected from the group consisting of value:
  • the X-ray powder diffraction pattern of the dihydrobromide salt crystal form comprises 3 or more 2 ⁇ values selected from the following Table 2:
  • the X-ray powder diffraction pattern of the dihydrobromide crystal form is substantially characterized as in Figure 4.
  • the dihydrobromide crystal form has a melting onset temperature of 255 ° C ⁇ 3 ° C.
  • the DSC pattern of the dihydrobromide crystal form is characterized in Figure 5.
  • the TGA profile of the dihydrobromide crystal form is characterized in Figure 6.
  • the crystalline form is a crystal form of dacotavir bisphosphonate
  • the X-ray powder diffraction pattern of the bisphosphonate crystal form comprises 3 or more 2 ⁇ selected from the group consisting of 2 value:
  • the X-ray powder diffraction pattern of the bisphosphonate crystal form comprises 3 or more 2 ⁇ values selected from the following Table 3:
  • the X-ray powder diffraction pattern of the bisphosphonate crystal form is substantially characterized as in Figure 7.
  • the bisphosphonate crystal form has a melting onset temperature of 171 ° C ⁇ 3 ° C.
  • the DSC pattern of the bisphosphonate crystal form is characterized in Figure 8.
  • the TGA pattern of the bisphosphonate crystal form is characterized in Figure 9.
  • a method of preparing the crystalline form of the dadocitavir bis-p-toluenesulfonate comprising the steps of:
  • the molar ratio of the p-toluenesulfonic acid to the free base of dacavitavir is from 0.1 to 5.0, preferably from 1.0 to 3.5, more preferably from 1.5 to 2.5, Crystallization, thereby obtaining the crystalline form of the bis-p-toluenesulfonate.
  • the solvent in the step (i) is selected from the group consisting of water, methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, acetone, methyl t-butyl. Ketone, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof.
  • the crystallization temperature in the step (ii) ranges from -40 to 70 ° C, preferably from -20 to 50 ° C.
  • the crystallization time in the step (ii) ranges from 1 min to 90 h, preferably from 5 min to 72 h.
  • a method of preparing the crystalline form of the dacavitavir dihydrobromide comprising the steps of:
  • the solvent in the step (i) is selected from the group consisting of water, methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, acetone, methyl t-butyl. Ketone, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof.
  • the crystallization temperature in the step (ii) ranges from -40 to 70 ° C, preferably from -20 to 50 ° C.
  • the crystallization time in the step (ii) ranges from 1 min to 90 h, preferably from 5 min to 72 h.
  • a method of preparing the crystalline form of the dacotavir bisphosphonate comprising the steps of:
  • the molar ratio of the phosphoric acid to the free base of dacavitavir is from 0.1 to 5.0, preferably from 1.0 to 3.5, more preferably from 1.5 to 2.5, and crystallization, thereby obtaining the Bisphosphonate crystals.
  • the solvent in the step (i) is selected from the group consisting of water, methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, acetone, methyl t-butyl. Ketone, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof.
  • the crystallization temperature in the step (ii) ranges from -40 to 70 ° C, preferably from -20 to 50 ° C.
  • the crystallization time in the step (ii) ranges from 1 min to 90 h, preferably from 5 min to 72 h.
  • HCV hepatitis C
  • a pharmaceutical composition comprising (a) a crystalline form according to the first aspect of the invention, and (b) a pharmaceutically acceptable carrier.
  • Figure 1 shows the X-ray powder diffraction pattern (XRPD) of daclivitavir di-p-toluenesulfonate.
  • Figure 2 shows the DSC analysis spectrum of daclitaxel bis-p-toluenesulfonate.
  • Figure 3 shows the TGA analysis spectrum of daclitaxel bis-p-toluenesulfonate.
  • Figure 4 shows the X-ray powder diffraction pattern (XRPD) of dacotavir dihydrobromide.
  • Figure 5 shows the DSC analysis spectrum of daclitaxel dihydrobromide.
  • Figure 6 shows the TGA analysis spectrum of daclitaxel dihydrobromide.
  • Figure 7 shows the X-ray powder diffraction pattern (XRPD) of dacabavir bisphosphonate.
  • Figure 8 shows the DSC analysis spectrum of daclitaxel bisphosphonate.
  • Figure 9 shows the TGA analysis spectrum of daclitaxel bisphosphonate.
  • daclatasvir can form salts with p-toluenesulfonic acid, hydrobromic acid and phosphoric acid, and these salts have good crystallinity, exhibiting good purification effects and physical and chemical properties. Properties, and the volatility of these acids is much lower than that of hydrochloric acid, which reduces corrosion on production equipment and improves health. Product safety. On this basis, the inventors completed the present invention.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • the present invention provides a crystalline form of dacavitavir selected from the group consisting of a crystal form of biscavitavir, a form of dadocitavir dihydrobromide, and a drug of dacavitavir diphosphate. Salt crystal form.
  • the crystalline form is a bis-p-toluenesulfonate crystalline form of dacavitavir, and the X-ray powder diffraction pattern of the bis-p-toluenesulfonate crystalline form comprises three or more selected 2 ⁇ values from the next group:
  • the X-ray powder diffraction pattern of the bis-p-toluenesulfonate crystal form comprises 3 or more 2 ⁇ values selected from Table 1 below:
  • the X-ray powder diffraction pattern of the bis-p-toluenesulfonate crystal form is substantially as shown in the figure. 1 characterized.
  • the bis-p-toluenesulfonate crystal form has a melting onset temperature of 119 ° C ⁇ 3 ° C.
  • the DSC pattern of the bis-p-toluenesulfonate crystal form is characterized in Figure 2.
  • the TGA pattern of the bis-p-toluenesulfonate crystal form is characterized in Figure 3.
  • the crystalline form is a crystalline form of dacotavir dihydrobromide
  • the X-ray powder diffraction pattern of the dihydrobromide crystal form comprises 3 or more 2 ⁇ selected from the group consisting of value:
  • the X-ray powder diffraction pattern of the dihydrobromide salt crystal form comprises 3 or more 2 ⁇ values selected from the following Table 2:
  • the X-ray powder diffraction pattern of the dihydrobromide crystal form is substantially characterized as in Figure 4.
  • the dihydrobromide crystal form has a melting onset temperature of 255 ° C ⁇ 3 ° C.
  • the DSC pattern of the dihydrobromide crystal form is characterized in Figure 5.
  • the TGA profile of the dihydrobromide crystal form is characterized in Figure 6.
  • the crystalline form is a crystal form of dacotavir bisphosphonate
  • the X-ray powder diffraction pattern of the bisphosphonate crystal form comprises 3 or more 2 ⁇ selected from the group consisting of 2 Value:
  • the X-ray powder diffraction pattern of the bisphosphonate crystal form comprises 3 or more 2 ⁇ values selected from the following Table 3:
  • the X-ray powder diffraction pattern of the bisphosphonate crystal form is substantially characterized as in Figure 7.
  • the bisphosphonate crystal form has a melting onset temperature of 171 ° C ⁇ 3 ° C.
  • the DSC pattern of the bisphosphonate crystal form is characterized in Figure 8.
  • the TGA pattern of the bisphosphonate crystal form is characterized in Figure 9.
  • the invention provides a preparation method of daclitaxel di-p-toluate, the method comprising the steps of:
  • the molar ratio of the p-toluenesulfonic acid to the free base of dacavitavir is from 0.1 to 5.0, preferably from 1.0 to 3.5, more preferably from 1.5 to 2.5, Crystallization, thereby obtaining the crystalline form of the bis-p-toluenesulfonate.
  • the solvent in the step (i) is selected from the group consisting of water, methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, acetone, methyl t-butyl. Ketone, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof.
  • the crystallization temperature in the step (ii) ranges from -40 to 70 ° C, preferably from -20 to 50 ° C.
  • the crystallization time in the step (ii) ranges from 1 min to 90 h, preferably from 5 min to 72 h.
  • the solvent in the step (i) is selected from the group consisting of water, methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, acetone, methyl t-butyl. Ketone, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof.
  • the crystallization temperature in the step (ii) ranges from -40 to 70 ° C, preferably from -20 to 50 ° C.
  • the crystallization time in the step (ii) ranges from 1 min to 90 h, preferably from 5 min to 72 h.
  • the present invention provides a method for preparing a crystal form of daclivitavir diphosphate, the method comprising the steps of:
  • the molar ratio of the phosphoric acid to the free base of dacavitavir is from 0.1 to 5.0, preferably from 1.0 to 3.5, more preferably from 1.5 to 2.5, and crystallization, thereby obtaining the Bisphosphonate crystals.
  • the solvent in the step (i) is selected from the group consisting of water, methanol, ethanol, isopropanol, ethyl acetate, ethyl formate, isopropyl acetate, acetone, methyl t-butyl. Ketone, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof.
  • the crystallization temperature in the step (ii) ranges from -40 to 70 ° C, preferably from -20 to 50 ° C.
  • the crystallization time in the step (ii) ranges from 1 min to 90 h, preferably from 5 min to 72 h.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable carrier.
  • the “active ingredient” as used in the present invention refers to the form of dadocitavir bis-p-toluenesulfonate, dacarevir dihydrobromide and/or bisphosphate crystal form according to the present invention.
  • the "active ingredient" and pharmaceutical composition of the present invention are useful for the preparation of a medicament for the prevention and/or treatment of hepatitis C (HCV), or for the preparation of a medicament for inhibiting hepatitis C (HCV).
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • the administration form of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration forms include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example,
  • the solid dosage forms can also be prepared with coatings and shell materials, such as casings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other therapeutic agents, such as chemotherapeutic agents.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the dadocitavir bis-p-toluenesulfonate, the dihydrobromide salt and the bisphosphonate of the present invention have good crystallinity and impurity removal effect, and are advantageous for preparing a high-quality drug of dacataxa.
  • dadocitavir bis-p-toluenesulfonate, dihydrobromide and bisphosphonate of the invention have good thermodynamics and illumination stability, and are favorable for stable quality control and industrial application;
  • dadocitavir bis-p-toluenesulfonate, the dihydrobromide salt and the bisphosphonate of the present invention are simple in preparation and stable in process.
  • X-ray powder diffraction instrument PANalytical Empyean X-ray powder diffractometer, Cu target, Ka wavelength, tube voltage 40 KV, tube current 40 mA. Scanning range: 3-40°2-Theta; stepping: 0.02°; scanning speed: 1 step/second.
  • Example 1 Differential Scanning Calorimetry (DSC) Apparatus: DSC: TA Q2000 Differential Scanning Calorimeter; Temperature Range: 30-280 ° C; Heating Rate: 10 ° C/min.
  • DSC Differential Scanning Calorimetry
  • Example 2 Differential Scanning Calorimetry (DSC) Apparatus: DSC: TA Q2000 Differential Scanning Calorimeter; Temperature Range: 30-300 ° C; Heating Rate: 10 ° C/min.
  • DSC Differential Scanning Calorimetry
  • Example 3 Differential Scanning Calorimetry (DSC) Apparatus: DSC: TA Q2000 Differential Scanning Calorimeter; Temperature Range: 30-300 ° C; Heating Rate: 10 ° C/min.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis (TGA) instrument NETZSCH TG 209F3 thermogravimetric analyzer; temperature range: 30-400 ° C; heating rate: 10 ° C / min.
  • HPLC Agilent 1260 high performance liquid chromatography, Xbridge C18 column, 3.5 ⁇ m, 4.6 x 150 mm.
  • Ion chromatography Dionex ICS 2100, mobile phase: 30 mM NaOH, detector: ECD, column temperature: 35 ° C, flow rate: 1.0 ml/min, suppressor: ASRS 4 mm, Dionex IonPac AS18 (250 x 4 mm) separation column.
  • Dakavira free base powder (74 mg) was added to a 1.5 ml centrifuge tube, 1 mL of acetone was added and sonicated until dissolved. P-toluenesulfonic acid monohydrate (38 mg) was added, and a precipitate formed immediately. After stirring at room temperature overnight, it was confirmed to be a crystal by a polarizing microscope.
  • the centrifuge tube was placed in a centrifuge (Eppendorf minispin) and centrifuged at 12,000 rpm for 5 minutes, the supernatant was removed, and the separated solid was dried at room temperature for 1 hour.
  • the dried solids were tested for p-toluenesulfonate content by HPLC and characterized by solid morphology by XRPD, DSC and TGA.
  • HPLC analysis showed that the HPLC purity of daclivitavir increased from 98.6% to 99.5% after crystallization from the free base to bis-p-toluenesulfonate, with significant impurity removal.
  • Dakavira free base powder (74 mg) was added to a 1.5 ml centrifuge tube, 200 ⁇ L of ethyl acetate was added, and sonicated until dissolved. 100 ⁇ L of a 2 M aqueous solution of hydrobromic acid was added thereto, and a precipitate was formed immediately, and the mixture was stirred at room temperature overnight, and crystals were confirmed by a polarizing microscope.
  • the centrifuge tube was placed in a centrifuge (Eppendorf minispin) and centrifuged at 12,000 rpm for 5 minutes, the supernatant was removed, and the separated solid was dried at room temperature for 1 hour.
  • the dried solids were tested for bromide ion content by ion chromatography through XRPD, DSC and TGA was characterized by solid morphology.
  • the results of ion chromatography showed that the bromide ion content of the dabacitide hydrobromide salt was 19.4% by weight. It is in good agreement with the theoretical content of bromide ion of dacarbavir dihydrobromide (17.8wt%).
  • the dabavitavir hydrobromide salt should be the dihydrobromide salt of dacavitavir.
  • HPLC analysis showed that the HPLC purity of daclivitavir increased from 98.5% to 99.6% after crystallization from the free base to the dihydrobromide salt, with significant impurity removal.
  • Dakavira free base powder (74 mg) was added to a 1.5 ml centrifuge tube and 200 ⁇ L of methanol was added. Ultrasound to dissolve. 100 ⁇ L of a 2 M solution of phosphoric acid in methanol was added thereto, and a precipitate was formed immediately, and the mixture was stirred at room temperature overnight, and crystals were confirmed by a polarizing microscope.
  • the tube was placed in a centrifuge (Eppendorf minispin) and centrifuged at 12,000 rpm for 5 minutes, and the supernatant was removed.
  • a centrifuge Eppendorf minispin
  • the solid obtained by centrifugation was tested for phosphate ion content by ion chromatography, and the solid form was characterized by XRPD, DSC and TGA.
  • thermogravimetric curve of daclitaxel bisphosphonate had a significant 5% weight loss step between 30-120 ° C. Compared with DSC data, this weight loss should be caused by residual solvent evaporation. The weight loss after 200 ° C is caused by sample decomposition.
  • HPLC analysis showed that the HPLC purity of daclivitavir increased from 98.5% to 99.6% after crystallization from the free base to bisphosphonate, with significant impurity removal.
  • Accelerated stability The accelerated stability of daclitaxel dihydrochloride, bis-p-toluenesulfonate, dihydrobromide and bisphosphonate was investigated. Samples of different salt types were placed in a watch glass and spread into a thin layer having a thickness of not more than 1 mm, and placed in a stability test chamber at 40 ° C / RH 75% for 4 weeks.
  • dacabavir free base powder (74 mg) was added to a series of 1.5 ml centrifuge tubes and 100 ⁇ L of ethanol was added, respectively. Ultrasound to dissolve. Two equivalents of the acid solution were added dropwise.
  • the bisphosphonate, p-toluenesulfonate and hydrobromide salt of the present invention have good crystallinity and stability compared to other salt forms.

Abstract

本发明提供了达卡他韦新晶型及其制备方法，具体地，本发明披露了结晶性的达卡他韦的双对甲苯磺酸盐、双磷酸盐和双氢溴酸盐，所述的新晶型具备较好的理化性质，有利于达卡他韦的质量控制和制剂应用。

Description

达卡他韦新晶型及其制备方法 技术领域
本发明涉及药物化学领域，具体地，本发明涉及达卡他韦的新晶型，以及新晶型的制备方法和用途。
背景技术
达卡他韦(Daclatasvir，DCV)是BMS开发的丙肝治疗药物，结构如式I所示。
Figure PCTCN2016107526-appb-000001
达卡他韦于2014年8月在欧洲批准上市，2015年7月被FDA批准在美国上市。Daclatasvir属于HCV NS5A蛋白酶抑制剂，它适用于HCV基因型1、2、3和4感染的成年人。口服达卡他韦联合索菲布韦在临床试验中的治愈率高达100％，包括晚期肝病、基因型3的患者和既往蛋白酶抑制剂治疗失败的患者。
由于分子结构的特点，达卡他韦游离碱本身结晶性差，需要通过成盐的方式得到结晶性的原料药。目前，就本发明人所知范围，仅有BMS公司的一篇专利WO2009020828申请保护了达卡他韦双盐酸盐。达卡他韦双盐酸盐展现了较好的结晶纯化效果和理化性质，但是由于盐酸的高挥发性和对不锈钢设备的高腐蚀性，对其生产设备的要求和安全性要求较高。
综上所述，本领域迫切需要开发新的达卡他韦盐型，以满足达卡他韦原料药的纯化需求并具备适宜的理化性质，并降低原料药生产的设备要求并提高安全性。
发明内容
本发明的目的在于提供一种达卡他韦的新晶型，以及新晶型的制备方法和用途。
本发明第一方面，提供一种达卡他韦的晶型，所述晶型选自达卡他韦的双对甲苯磺酸盐晶型、达卡他韦双氢溴酸盐晶型、和达卡他韦双磷酸盐晶型。
在另一优选例中，所述晶型为达卡他韦的双对甲苯磺酸盐晶型，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：
5.20±0.2°、6.40±0.2°、13.80±0.2°、14.60±0.2°、19.40±0.2°、21.30±0.2°。
在另一优选例中，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱包括3个 或3个以上选自下表1所示的2θ值：
2θ(°) 2θ(°)
5.2 16.7
6.4 17.1
8.5 17.8
9.0 18.5
9.4 18.9
10.0 19.4
10.4 19.9
10.7 21.3
11.3 22.6
13.3 23.0
13.8 24.1
14.6 26.1
15.5 27.2。
在另一优选例中，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱基本如图1所表征。
在另一优选例中，所述双对甲苯磺酸盐晶型的熔融起始温度为119℃±3℃。
在另一优选例中，所述双对甲苯磺酸盐晶型的DSC图谱如图2所表征。
在另一优选例中，所述双对甲苯磺酸盐晶型的TGA图谱如图3所表征。
在另一优选例中，所述晶型为达卡他韦双氢溴酸盐晶型，所述双氢溴酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：
5.80±0.2°、10.30±0.2°、13.00±0.2°、13.40±0.2°、22.40±0.2°、20.50±0.2°。
在另一优选例中，所述双氢溴酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下表2所示的2θ值：
2θ(°) 2θ(°)
5.8 22.4
10.3 23.0
12.2 23.5
13.0 23.9
13.4 24.2
15.4 24.6
16.5 25.0
17.0 25.8
17.4 26.1
18.5 26.3
19.1 26.9
19.9 27.5
20.1 27.8
20.5 29.0
20.8 30.3
21.3 31.1
22.2 33.3。
在另一优选例中，所述双氢溴酸盐晶型的X射线粉末衍射图谱基本如图4所表征。
在另一优选例中，所述双氢溴酸盐晶型的熔融起始温度为255℃±3℃。
在另一优选例中，所述双氢溴酸盐晶型的DSC图谱如图5所表征。
在另一优选例中，所述双氢溴酸盐晶型的TGA图谱如图6所表征。
在另一优选例中，所述晶型为一种达卡他韦双磷酸盐晶型，所述双磷酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：
4.40±0.2°、6.50±0.2°、6.10±0.2°、7.50±0.2°、11.30±0.2°、13.40±0.2°。
在另一优选例中，所述双磷酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下表3所示的2θ值：
2θ(°) 2θ(°)
4.4 11.8
4.6 13.6
5.1 14.3
6.1 16.5
6.5 17.4
7.0 18.6
7.5 20.0
8.0 20.2
8.5 21.0
8.7 22.2
11.3 22.8。
在另一优选例中，所述双磷酸盐晶型的X射线粉末衍射图谱基本如图7所表征。
在另一优选例中，所述双磷酸盐晶型的熔融起始温度为171℃±3℃。
在另一优选例中，所述双磷酸盐晶型的DSC图谱如图8所表征。
在另一优选例中，所述双磷酸盐晶型的TGA图谱如图9所表征。
本发明第二方面，提供一种制备所述达卡他韦双对甲苯磺酸盐晶型的方法，所述方法包括如下步骤：
(i)将达卡他韦的游离碱溶解于溶剂中，制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
(ii)将对甲苯磺酸加入上述溶液，所述对甲苯磺酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双对甲苯磺酸盐晶型。
在另一优选例中，所述步骤(i)中溶剂选自下组：水、甲醇、乙醇、异丙醇、乙酸乙酯、甲酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基酮、四氢呋喃、甲基四氢呋喃、或其组合。
在另一优选例中，所述步骤(ii)中析晶温度范围为-40至70℃，较佳地-20至50℃。
在另一优选例中，所述步骤(ii)中析晶时间范围为1min-90h，较佳地为5min-72h。
本发明第三方面，提供一种制备所述达卡他韦双氢溴酸盐晶型的方法，所述方法包括如下步骤：
(i)将达卡他韦的游离碱溶解于溶剂中制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
(ii)将氢溴酸加入上述溶液，所述氢溴酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双氢溴酸盐晶体。
在另一优选例中，所述步骤(i)中溶剂选自下组：水、甲醇、乙醇、异丙醇、乙酸乙酯、甲酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基酮、四氢呋喃、甲基四氢呋喃、或其组合。
在另一优选例中，所述步骤(ii)中析晶温度范围为-40至70℃，较佳地-20至50℃。
在另一优选例中，所述步骤(ii)中析晶时间范围为1min-90h，较佳地为5min-72h。
本发明第四方面，提供一种制备所述达卡他韦双磷酸盐晶型的方法，所述方法包括如下步骤：
(i)将达卡他韦的游离碱溶解于溶剂中制得溶液，重量体积比为约1-800mg /ml，较佳地为5-500mg/ml；
(ii)将磷酸加入上述溶液，所述磷酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双磷酸盐晶体。
在另一优选例中，所述步骤(i)中溶剂选自下组：水、甲醇、乙醇、异丙醇、乙酸乙酯、甲酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基酮、四氢呋喃、甲基四氢呋喃、或其组合。
在另一优选例中，所述步骤(ii)中析晶温度范围为-40至70℃，较佳地-20至50℃。
在另一优选例中，所述步骤(ii)中析晶时间范围为1min-90h，较佳地为5min-72h。
本发明第五方面，提供一种本发明第一方面所述的晶型的用途，用于制备预防和/或治疗丙型肝炎(HCV)的药物。
本发明第六方面，提供一种医药组合物，所述的组合物包含(a)本发明第一方面所述的晶型，以及(b)药学上可接受的载体。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了达卡他韦双对甲苯磺酸盐X-射线粉末衍射谱图(XRPD)。
图2显示了达卡他韦双对甲苯磺酸盐的DSC分析谱图。
图3显示了达卡他韦双对甲苯磺酸盐的TGA分析谱图。
图4显示了达卡他韦双氢溴酸盐X-射线粉末衍射谱图(XRPD)。
图5显示了达卡他韦双氢溴酸盐的DSC分析谱图。
图6显示了达卡他韦双氢溴酸盐的TGA分析谱图。
图7显示了达卡他韦双磷酸盐X-射线粉末衍射谱图(XRPD)。
图8显示了达卡他韦双磷酸盐的DSC分析谱图。
图9显示了达卡他韦双磷酸盐的TGA分析谱图。
具体实施方式
本发明人经过长期而深入的研究，发现达卡他韦(Daclatasvir)可以与对甲苯磺酸、氢溴酸和磷酸成盐，这些盐的结晶性好，展现了较好的纯化效果和的理化性质，同时这些酸的挥发性远低于盐酸，从而降低了对生产设备的腐蚀并提高了生 产的安全性。在此基础上，发明人完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
多晶型物
本发明提供一种达卡他韦的晶型，所述晶型选自达卡他韦的双对甲苯磺酸盐晶型、达卡他韦双氢溴酸盐晶型、和达卡他韦双磷酸盐晶型。
在另一优选例中，所述晶型为达卡他韦的双对甲苯磺酸盐晶型，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：
5.20±0.2°、6.40±0.2°、13.80±0.2°、14.60±0.2°、19.40±0.2°、21.30±0.2°。
在另一优选例中，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下表1所示的2θ值：
2θ(°) 2θ(°)
5.2 16.7
6.4 17.1
8.5 17.8
9.0 18.5
9.4 18.9
10.0 19.4
10.4 19.9
10.7 21.3
11.3 22.6
13.3 23.0
13.8 24.1
14.6 26.1
15.5 27.2。
在另一优选例中，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱基本如图 1所表征。
在另一优选例中，所述双对甲苯磺酸盐晶型的熔融起始温度为119℃±3℃。
在另一优选例中，所述双对甲苯磺酸盐晶型的DSC图谱如图2所表征。
在另一优选例中，所述双对甲苯磺酸盐晶型的TGA图谱如图3所表征。
在另一优选例中，所述晶型为达卡他韦双氢溴酸盐晶型，所述双氢溴酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：
5.80±0.2°、10.30±0.2°、13.00±0.2°、13.40±0.2°、22.40±0.2°、20.50±0.2°。
在另一优选例中，所述双氢溴酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下表2所示的2θ值：
2θ(°) 2θ(°)
5.8 22.4
10.3 23.0
12.2 23.5
13.0 23.9
13.4 24.2
15.4 24.6
16.5 25.0
17.0 25.8
17.4 26.1
18.5 26.3
19.1 26.9
19.9 27.5
20.1 27.8
20.5 29.0
20.8 30.3
21.3 31.1
22.2 33.3。
在另一优选例中，所述双氢溴酸盐晶型的X射线粉末衍射图谱基本如图4所表征。
在另一优选例中，所述双氢溴酸盐晶型的熔融起始温度为255℃±3℃。
在另一优选例中，所述双氢溴酸盐晶型的DSC图谱如图5所表征。
在另一优选例中，所述双氢溴酸盐晶型的TGA图谱如图6所表征。
在另一优选例中，所述晶型为一种达卡他韦双磷酸盐晶型，所述双磷酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：
4.40±0.2°、6.50±0.2°、6.10±0.2°、7.50±0.2°、11.30±0.2°、13.40±0.2°。
在另一优选例中，所述双磷酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下表3所示的2θ值：
2θ(°) 2θ(°)
4.4 11.8
4.6 13.6
5.1 14.3
6.1 16.5
6.5 17.4
7.0 18.6
7.5 20.0
8.0 20.2
8.5 21.0
8.7 22.2
11.3 22.8。
在另一优选例中，所述双磷酸盐晶型的X射线粉末衍射图谱基本如图7所表征。
在另一优选例中，所述双磷酸盐晶型的熔融起始温度为171℃±3℃。
在另一优选例中，所述双磷酸盐晶型的DSC图谱如图8所表征。
在另一优选例中，所述双磷酸盐晶型的TGA图谱如图9所表征。
制备方法
达卡他韦双对甲苯磺酸盐的制备
本发明提供了达卡他韦双对甲苯酸盐的制备方法，所述方法包括步骤：
(i)将达卡他韦的游离碱溶解于溶剂中，制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
(ii)将对甲苯磺酸加入上述溶液，所述对甲苯磺酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双对甲苯磺酸盐晶型。
在另一优选例中，所述步骤(i)中溶剂选自下组：水、甲醇、乙醇、异丙醇、乙酸乙酯、甲酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基酮、四氢呋喃、甲基四氢呋喃、或其组合。
在另一优选例中，所述步骤(ii)中析晶温度范围为-40至70℃，较佳地-20至50℃。
在另一优选例中，所述步骤(ii)中析晶时间范围为1min-90h，较佳地为5min-72h。
达卡他韦双氢溴酸盐的制备
(i)将达卡他韦的游离碱溶解于溶剂中制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
(ii)将氢溴酸加入上述溶液，所述氢溴酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双氢溴酸盐晶体。
在另一优选例中，所述步骤(i)中溶剂选自下组：水、甲醇、乙醇、异丙醇、乙酸乙酯、甲酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基酮、四氢呋喃、甲基四氢呋喃、或其组合。
在另一优选例中，所述步骤(ii)中析晶温度范围为-40至70℃，较佳地-20至50℃。
在另一优选例中，所述步骤(ii)中析晶时间范围为1min-90h，较佳地为5min-72h。
达卡他韦双磷酸盐晶型的制备
本发明提供了达卡他韦双磷酸酸盐晶型的制备方法，所述方法包括步骤：
(i)将达卡他韦的游离碱溶解于溶剂中制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
(ii)将磷酸加入上述溶液，所述磷酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双磷酸盐晶体。
在另一优选例中，所述步骤(i)中溶剂选自下组：水、甲醇、乙醇、异丙醇、乙酸乙酯、甲酸乙酯、乙酸异丙酯、丙酮、甲基叔丁基酮、四氢呋喃、甲基四氢呋喃、或其组合。
在另一优选例中，所述步骤(ii)中析晶温度范围为-40至70℃，较佳地-20至50℃。
在另一优选例中，所述步骤(ii)中析晶时间范围为1min-90h，较佳地为5min-72h。
药物组合物
本发明还提供了一种药物组合物，它包含安全有效量范围内的活性成分，以及药学上可接受的载体。
本发明所述的“活性成分”是指本发明所述的达卡他韦双对甲苯磺酸盐、达卡他韦双氢溴酸盐和/或双磷酸盐晶型。
本发明所述的“活性成分”和药物组合物用于制备预防和/或治疗丙型肝炎(HCV)的药物、或用于制备抑制丙型肝炎(HCV)的药物。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2016107526-appb-000002
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制。本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他治疗药物(如化疗药)联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点在于：
(1)本发明的达卡他韦双对甲苯磺酸盐、双氢溴酸盐和双磷酸盐具有较好的结晶性和杂质去除效果，有利于制备高质量的达卡他韦原料药。
(2)本发明的达卡他韦双对甲苯磺酸盐、双氢溴酸盐和双磷酸盐具有较好的热力学和光照稳定性，有利于稳定的质量控制和工业应用；
(3)本发明的达卡他韦双对甲苯磺酸盐、双氢溴酸盐和双磷酸盐制备简单，工艺稳定。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
通用方法
XRD图谱测定方法
X-射线粉末衍射仪器：XRPD：PANalytical Empyean X-射线粉末衍射仪，Cu靶，Ka波长，管电压40KV，管电流40mA。扫描范围：3-40°2-Theta；步进：0.02°；扫描速度：1步/秒。
DSC图谱测定方法
实施例1：差示扫描量热法(DSC)仪器：DSC：TA Q2000差示扫描量热仪；温度范围：30-280℃；加热速率：10℃/分钟。
实施例2：差示扫描量热法(DSC)仪器：DSC：TA Q2000差示扫描量热仪；温度范围：30-300℃；加热速率：10℃/分钟。
实施例3：差示扫描量热法(DSC)仪器：DSC：TA Q2000差示扫描量热仪；温度范围：30-300℃；加热速率：10℃/分钟。
TGA图谱测定方法
热重分析(TGA)仪器：NETZSCH TG 209F3热重分析仪；温度范围：30-400℃；加热速率：10℃/分钟。
高效液相色谱
HPLC：Agilent 1260高效液相色谱仪，Xbridge C18色谱柱，3.5μm，4.6×150mm。
离子色谱
离子色谱：Dionex ICS2100，流动相：30mM NaOH，检测器：ECD，柱温：35℃，流速：1.0ml/min，抑制器：ASRS 4mm，Dionex IonPac AS18(250×4mm)分离柱。
实施例1达卡他韦双对甲苯磺酸盐的制备
将达卡他韦游离碱粉末(74mg)加入1.5ml离心管中，加入1mL丙酮，超声至溶解。加入对甲苯磺酸一水合物(38mg)，马上有沉淀形成。在室温下搅拌过夜，经偏光显微镜确认为晶体。
将离心管置于离心机(Eppendorf minispin)在12000转离心5分钟，移去上清液，将分离到的固体于室温下干燥1小时。
将干燥后的固体通过HPLC对对甲苯磺酸根含量进行测试，通过XRPD、DSC和TGA进行固体形态的表征。
HPLC分析结果表明，达卡他韦对甲苯磺酸盐中对甲苯磺酸根含量为30.7wt％。与达卡他韦双对甲苯磺酸盐的对甲苯磺酸根理论含量(32.5wt％)较为吻合。结合成盐过程中对甲苯磺酸与达卡他韦的摩尔比(2:1)，达卡他韦对甲苯磺酸盐应该为双对甲苯磺酸盐。
结果：达卡他韦双对甲苯磺酸盐的XRPD图谱基本如图1所示，主要衍射峰以及相对强度如表1所示。
表1.达卡他韦双对甲苯磺酸盐的衍射峰及相对强度
Pos.[°2Th.] Rel.Int.[％]
5.2 35.3
6.4 67.6
8.5 14.7
9.0 19.1
9.4 14.9
10.0 23.5
10.4 36.8
10.7 32.4
11.3 17.6
13.3 52.9
13.8 61.2
14.6 70.6
15.5 19.1
16.7 17.6
17.1 20.6
17.8 22.1
18.5 51.5
18.9 31.8
19.4 48.5
19.9 23.5
21.3 100
22.6 29.4
23.0 26.5
24.1 32.4
26.1 17.6
27.2 26.5
达卡他韦双对甲苯磺酸盐的DSC分析结果如图2所示。结果表明在30-280℃之间，达卡他韦双对甲苯磺酸盐的热流曲线有一个起始温度为119℃的吸热峰。
达卡他韦双对甲苯磺酸盐的TGA分析结果如图3所示。结果表明在80-130℃之间有0.72％的失重，是由溶剂挥发造成。220℃以后的失重是由于样品分解造成。
HPLC分析表明从游离碱结晶为双对甲苯磺酸盐后，达卡他韦的HPLC纯度从98.6％提高到了99.5％，有明显的杂质去除效果。
实施例2达卡他韦双氢溴酸盐的制备
将达卡他韦游离碱粉末(74mg)加入1.5ml离心管，加入200μL乙酸乙酯，超声至溶解。加入100μL 2M的氢溴酸乙醇溶液，马上有沉淀形成，在室温下搅拌过夜，经偏光显微镜确认为晶体。
将离心管置于离心机(Eppendorf minispin)在12000转离心5分钟，移去上清液，将分离到的固体于室温下干燥1小时。
将干燥后的固体通过离子色谱对溴离子含量进行测试，通过XRPD、DSC和 TGA进行固体形态的表征。
离子色谱分析结果表明，达卡他韦氢溴酸盐中溴离子含量为19.4wt％。与达卡他韦双氢溴酸盐溴离子理论含量(17.8wt％)较为吻合。结合成盐过程中氢溴酸与达卡他韦的摩尔比(2:1)，达卡他韦氢溴酸盐应该为达卡他韦的双氢溴酸盐。
结果：达卡他韦双氢溴酸盐的XRPD图谱基本如图4所示，主要衍射峰以及相对强度如表2所示。
表2.达卡他韦双氢溴酸盐的的衍射峰及相对强度
Pos.[°2Th.] Rel.Int.[％]
5.8 45.0
10.3 100.0
12.2 37.5
13.0 83.6
13.4 47.5
15.4 30.0
16.5 22.5
17.0 22.5
17.4 17.5
18.5 19.0
19.1 25.0
19.9 22.0
20.1 27.5
20.5 50.0
20.8 25.8
21.3 39.0
22.2 47.5
22.4 73.8
23.0 48.8
23.5 20.0
23.9 35.0
24.2 30.0
24.6 27.5
25.0 19.5
25.8 17.5
26.1 21.3
26.3 12.5
26.9 23.8
27.5 26.3
27.8 40.0
29.0 22.5
30.3 22.5
31.1 21.3
33.3 15.0
达卡他韦双氢溴酸盐的DSC分析结果如图5所示。结果表明在30-300℃之间，达卡他韦双氢溴酸盐的热流曲线有一个起始温度为255℃的吸热峰。
达卡他韦双氢溴酸盐的TGA分析结果如图6所示。结果表明在30-250℃之间，晶型A的热重曲线有一个轻微的0.85％的失重，应该是溶剂挥发造成。
HPLC分析表明从游离碱结晶为双氢溴酸盐后，达卡他韦的HPLC纯度从98.5％提高到了99.6％，有明显的杂质去除效果。
实施例3达卡他韦双磷酸盐的制备
将达卡他韦游离碱粉末(74mg)加入1.5ml离心管，加入200μL甲醇。超声至溶解。加入100μL 2M的磷酸甲醇溶液，马上有沉淀形成，在室温下搅拌过夜，经偏光显微镜确认为晶体。
将离心管置于离心机(Eppendorf minispin)在12000转离心5分钟，移去上清液。
将离心得到的固体通过离子色谱对磷酸根离子含量进行测试，通过XRPD、DSC和TGA进行固体形态的表征。
离子色谱分析结果表明，达卡他韦磷酸盐中磷酸根含量为21.5wt％。与达卡他韦双磷酸盐的磷酸根离子理论含量(20.9wt％)较为吻合。结合成盐过程中磷酸与达卡他韦的摩尔比(2:1)，达卡他韦磷酸盐应该为达卡他韦的双磷酸盐。
结果：达卡他韦双磷酸盐的XRPD图谱基本如图7所示，主要衍射峰以及相对强度如表3所示。
表3.达卡他韦双磷酸盐的的衍射峰及相对强度
Pos.[°2Th.] Rel.Int.[％]
4.4 62.5
4.6 18.8
5.1 20.0
6.1 100.0
6.5 45.8
7.0 12.5
7.5 95.8
8.0 21.7
8.5 12.3
8.7 12.5
11.3 33.3
11.8 41.7
13.6 43.8
14.3 24.8
16.5 18.8
17.4 20.8
18.6 16.7
20.0 22.9
20.2 29.2
21.0 20.8
22.2 16.7
22.8 20.8
达卡他韦双磷酸盐的DSC分析结果如图8所示。结果表明在30-300℃之间，达卡他韦双磷酸盐的热流曲线有一个起始温度为171℃的吸热峰，50-120℃之间的宽幅吸热峰应该为残留溶剂挥发造成。
达卡他韦双磷酸盐的TGA分析结果如图9所示。结果表明在30-120℃之间，达卡他韦双磷酸盐的热重曲线有一个明显的5％的失重台阶，经与DSC数据对比，此失重应该为残留溶剂挥发造成。200℃之后的失重为样品分解造成。
HPLC分析表明从游离碱结晶为双磷酸盐后，达卡他韦的HPLC纯度从98.5％提高到了99.6％，有明显的杂质去除效果。
实施例4
稳定性评估
(1)加速稳定性：对达卡他韦双盐酸盐、双对甲苯磺酸盐、双氢溴酸盐和双磷酸盐的加速稳定性进行了考察。将不同盐型的样品置于表面皿中，摊成厚度不超过1mm的薄层，放置于40℃/RH75％的稳定性试验箱中，持续4周。
(2)光照稳定性：对达卡他韦双盐酸盐、双对甲苯磺酸盐、双氢溴酸盐和双磷酸盐的光照稳定性进行了考察。将不同盐型的样品置于表面皿中，摊成厚度不超过1mm的薄层，放置于光照强度为4400lux的LS-3000光照试验箱中，持续12天光照。总照度为1.2M lux·hours。
(3)应用HPLC对稳定性样品纯度进行检查并与初始纯度进行对比。结果表 明，与达卡他韦双盐酸盐相比，达卡他韦双对甲苯磺酸盐的光稳定性更优，达卡他韦双氢溴酸盐和达卡他韦双磷酸盐的光稳定性也展现了足够的光稳定性。与达卡他韦双盐酸盐相比，达卡他韦双对甲苯磺酸盐、达卡他韦双氢溴酸盐和达卡他韦双磷酸盐所有的盐都展现相当的热稳定性。
表4.光照稳定性结果
Figure PCTCN2016107526-appb-000003
实施例5达卡他韦盐的筛选
配制不同酸(见表5)的乙醇或乙腈溶液。
将达卡他韦游离碱粉末(74mg)加入一系列1.5ml离心管中，分别加入100μL乙醇。超声至溶解。滴加2当量的酸溶液。
如果有沉淀生成，通过偏光显微镜确认沉淀是否为晶体。
如果形成澄清溶液，则敞口置于室温缓慢挥发溶剂。
表5.达卡他韦盐的筛选
酸 现象 结果
硫酸 油状物析出 无定型
磷酸 固体沉淀析出 达卡他韦双磷酸盐
醋酸 油状物析出 无定型
草酸 固体沉淀析出 无定型
甲磺酸 澄清溶液，溶剂挥发后油状物析出 无定型
对甲苯磺酸 固体沉淀析出 达卡他韦双对甲苯磺酸盐
富马酸 澄清溶液，溶剂挥发后油状物析出 无定型
己二酸 澄清溶液，溶剂挥发后油状物析出 无定型
L-苹果酸 澄清溶液，溶剂挥发后油状物析出 无定型
琥珀酸 澄清溶液，溶剂挥发后油状物析出 无定型
戊二酸 澄清溶液，溶剂挥发后油状物析出 无定型
苯甲酸 澄清溶液，溶剂挥发后油状物析出 无定型
酒石酸 澄清溶液，溶剂挥发后油状物析出 无定型
氢溴酸 固体沉淀析出 达卡他韦双氢溴酸盐
柠檬酸 澄清溶液，溶剂挥发后油状物析出 无定型
马来酸 澄清溶液，溶剂挥发后油状物析出 无定型
由上表可以看出，本发明的双磷酸盐、对甲苯磺酸盐以及氢溴酸盐相比其他盐型，具有良好的结晶性和稳定性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种达卡他韦的晶型，其特征在于，所述晶型选自达卡他韦的双对甲苯磺酸盐晶型、达卡他韦双氢溴酸盐晶型、和达卡他韦双磷酸盐晶型。
  2. 如权利要求1所述的晶型，其特征在于，所述晶型为达卡他韦的双对甲苯磺酸盐晶型，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：5.20±0.2°、6.40±0.2°、13.80±0.2°、14.60±0.2°、19.40±0.2°、21.30±0.2°。
  3. 如权利要求2所述的晶型，其特征在于，所述双对甲苯磺酸盐晶型的X射线粉末衍射图谱基本如图1所表征。
  4. 如权利要求1所述的晶型，其特征在于，所述晶型为达卡他韦双氢溴酸盐晶型，所述双氢溴酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：5.80±0.2°、10.30±0.2°、13.00±0.2°、13.40±0.2°、22.40±0.2°、20.50±0.2°。
  5. 如权利要求4所述的晶型，其特征在于，所述双氢溴酸盐晶型的X射线粉末衍射图谱基本如图4所表征。
  6. 如权利要求1所述的晶型，其特征在于，所述晶型为达卡他韦双磷酸盐晶型，所述双磷酸盐晶型的X射线粉末衍射图谱包括3个或3个以上选自下组的2θ值：4.40±0.2°、6.50±0.2°、6.10±0.2°、7.50±0.2°、11.30±0.2°、13.40±0.2°。
  7. 如权利要求6所述的晶型，其特征在于，所述双磷酸盐晶型的X射线粉末衍射图谱基本如图7所表征。
  8. 一种制备如权利要求1所述的达卡他韦双对甲苯磺酸盐晶型的方法，其特征在于，所述方法包括如下步骤：
    (i)将达卡他韦的游离碱溶解于溶剂中，制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
    (ii)将对甲苯磺酸加入上述溶液，所述对甲苯磺酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双对甲苯磺酸盐晶型。
  9. 一种制备如权利要求4所述的达卡他韦双氢溴酸盐晶型的方法，其特征在于，所述方法包括如下步骤：
    (i)将达卡他韦的游离碱溶解于溶剂中制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
    (ii)将氢溴酸加入上述溶液，所述氢溴酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双氢溴酸盐晶体。
  10. 一种制备如权利要求6所述的达卡他韦双磷酸盐晶型的方法，其特征在于，所述方法包括如下步骤：
    (i)将达卡他韦的游离碱溶解于溶剂中制得溶液，重量体积比为约1-800mg/ml，较佳地为5-500mg/ml；
    (ii)将磷酸加入上述溶液，所述磷酸与达卡他韦的游离碱摩尔比为0.1-5.0，较佳地为1.0-3.5，更佳地为1.5-2.5，析晶，从而得到所述的双磷酸盐晶体。
  11. 一种如权利要求18所述的晶型的用途，用于制备预防和/或治疗丙型肝炎(HCV)的药物。
  12. 一种医药组合物，所述的组合物包含(a)权利要求1至权利要求8所述的晶型，以及(b)药学上可接受的载体。
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CN101778840A (zh) * 2007-08-08 2010-07-14 百时美施贵宝公司 ((1s)-1-(((2s)-2-(5-(4’-(2-((2s)-1-((2s)-2-((甲氧羰基)氨基)-3-甲基丁酰基)-2-吡咯烷基)-1h-咪唑-5-基)-4-联苯基)-1h-咪唑-2-基)-1-吡咯烷基)羰基)-2-甲基丙基)氨基甲酸甲酯二盐酸盐的晶型
WO2015109445A1 (zh) * 2014-01-21 2015-07-30 杭州普晒医药科技有限公司 一种化合物的盐及晶型或无定型物、其制备方法、含有它们的药物组合物和用途
CN105566303A (zh) * 2016-01-25 2016-05-11 上海众强药业有限公司 达卡他韦新晶型及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101778840A (zh) * 2007-08-08 2010-07-14 百时美施贵宝公司 ((1s)-1-(((2s)-2-(5-(4’-(2-((2s)-1-((2s)-2-((甲氧羰基)氨基)-3-甲基丁酰基)-2-吡咯烷基)-1h-咪唑-5-基)-4-联苯基)-1h-咪唑-2-基)-1-吡咯烷基)羰基)-2-甲基丙基)氨基甲酸甲酯二盐酸盐的晶型
WO2015109445A1 (zh) * 2014-01-21 2015-07-30 杭州普晒医药科技有限公司 一种化合物的盐及晶型或无定型物、其制备方法、含有它们的药物组合物和用途
CN105566303A (zh) * 2016-01-25 2016-05-11 上海众强药业有限公司 达卡他韦新晶型及其制备方法

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