WO2014023027A1 - Erlotinib hydrochloride polymorph and preparation method therefor - Google Patents

Erlotinib hydrochloride polymorph and preparation method therefor Download PDF

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Publication number
WO2014023027A1
WO2014023027A1 PCT/CN2012/079973 CN2012079973W WO2014023027A1 WO 2014023027 A1 WO2014023027 A1 WO 2014023027A1 CN 2012079973 W CN2012079973 W CN 2012079973W WO 2014023027 A1 WO2014023027 A1 WO 2014023027A1
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Prior art keywords
polymorph
erlotinib hydrochloride
mixture
water
hours
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PCT/CN2012/079973
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French (fr)
Chinese (zh)
Inventor
安晓霞
吕峰
申淑匣
王伟
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上海创诺医药集团有限公司
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Priority to PCT/CN2012/079973 priority Critical patent/WO2014023027A1/en
Publication of WO2014023027A1 publication Critical patent/WO2014023027A1/en

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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
    • A61K31/495—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the invention belongs to the technical field of medicinal chemistry.
  • the present invention relates to polymorphs of erlotinib hydrochloride hemihydrate and a process for the preparation thereof. Background technique
  • Erlotinib N-(3-acetylenephenyl)-[6,7- phenyl-4-amine, and its structural formula is as shown in (1):
  • Erlotinib hydrochloride is commonly used clinically.
  • Erlotinib HCl is a 4-aminophenylquinazoline oral antineoplastic drug developed by OSI Pharmaceuticals Inc. for the treatment of pancreatic cancer and metastatic non-small cell carcinoma.
  • WO0134574 discloses erlotinib hydrochloride Form A and Form B. Among them, the thermal stability of the crystal form A is poor, and the crystal form B is a thermodynamically stable crystal form, but the water solubility is poor.
  • WO2004072049 discloses erlotinib hydrochloride Form E, which is also less stable in thermodynamics.
  • WO2008049645A2 discloses Form I and Form II of erlotinib hydrochloride hemihydrate, and reports the preparation of these two forms.
  • the literature indicates that in the preparation of erlotinib HCl hemihydrate crystal form I and form II, the obtained product is easily mixed with more than 10% of other crystal forms, such as crystal form, crystal form B or crystal form E. . Because it is a mixed crystal with low purity, it is not suitable for pharmaceutical preparations.
  • a polymorph of erlotinib hydrochloride hemihydrate having a purity of 95%.
  • the polymorph has a purity of 99%.
  • the differential scanning calorimetry analysis pattern of the polymorph has a characteristic endothermic peak at 75 to 135 and 140 to 160 ° C, respectively.
  • the differential scanning calorimetry analysis pattern of the polymorph is substantially as shown in FIG.
  • the powder diffraction pattern (XRD pattern) of the polymorph comprises 3 or more 2 ⁇ values selected from the group consisting of: 5.7, 10.6, 11.5, 12.0, 14.5, 15.1. 17.3, 18.6, 20.4, 23.2, 23.5, 25.2, 24.5, 26 ⁇ 3 ⁇ 0 ⁇ 1 ⁇ .
  • the powder diffraction pattern of the polymorph is substantially as shown in FIG.
  • thermogravimetric spectrum of the polymorph has a weight loss of 1.85-2.50% at 102 to 112 °C.
  • thermogravimetric analysis of the polymorph is substantially as shown in FIG.
  • the polymorph is prepared as follows, the method comprising the steps of: (1) providing a mixture comprising erlotinib HCl, the mixture further comprising water or water and an organic solvent Mixed solvent;
  • the step (2) further comprises the steps of: after stirring, controlling the temperature of the obtained mixture to 0 to 5 ° C, stirring for 0.5 to 5 hours (preferably 1 to 2 hours), further Crystallization.
  • the method further comprises the steps of: after stirring, controlling the temperature of the obtained mixture to 0 to 5 ° C, stirring for 0.5 to 5 hours (preferably 1 to 2 hours), and further analyzing crystal.
  • the method further comprises the step of separating the precipitated crystals (such as filtration).
  • the method comprises the steps of: a) providing a mixture containing erlotinib HCl, the mixture further comprising water or a mixed solvent of water and an organic solvent;
  • step b) stirring the mixture of step a) at 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) for 0 to 48 hours (preferably 5 to 10 hours) Crystallization
  • step b) controlling the temperature of the mixture of step b) at 0 to 5 ° C, stirring for 0.5 to 5 hours (preferably 1 to 2 hours), and further crystallization;
  • the step (1) or the step a) is: hydrochloric acid at 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) Erlotinib is mixed with water or a mixed solvent of water and an organic solvent;
  • step (1) in step (1),
  • the volumetric weight (ml/g) ratio of water to erlotinib hydrochloride is 50-600:1 (preferably 200-600:1; more preferably 200-400:1);
  • the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, acetonitrile or a combination thereof; and/or
  • the volume ratio of the organic solvent to water is from 0.1 to 10:1 (preferably from 0.1 to 1: 1).
  • the polymorph prepared by the process has a purity of 95%; preferably 99%.
  • a pharmaceutical composition comprising:
  • the use of the polymorph of erlotinib hydrochloride hemihydrate or the pharmaceutical composition of the third aspect of the first aspect of the invention is provided as an antitumor drug. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Limited to the length, no longer repeated here. DRAWINGS
  • Figure 1 is an XRD pattern of a polymorph of pure erlotinib hydrochloride hemihydrate of the present invention.
  • 2 is an XRD comparison diagram of the hemihydrate crystal form II reported in WO2008049645A2, the hemihydrate crystal form II and the pure form B described in the present invention.
  • Figure 3 is a DSC chart of a polymorph of pure erlotinib hydrochloride hemihydrate of the present invention.
  • 4 is a TGA pattern of a polymorph of pure erlotinib hydrochloride hemihydrate of the present invention. detailed description
  • the present inventors have unexpectedly discovered a method for preparing a polymorph (Eliform II) of erlotinib hydrochloride hemihydrate by a long-term and in-depth study, which completes the preparation of Form II by stirring.
  • the method is easy to control and has short operation time, and is very suitable for industrial use.
  • the crystal form II of erlotinib HCl prepared by the method has high purity, good thermal stability, high humidity stability and pressure stability, and good water solubility, and is very suitable for use in pharmaceutical preparations.
  • the inventors have completed the present invention on this basis. Polymorph of pure erlotinib hydrochloride hemihydrate according to the invention
  • the present invention provides a polymorph of erlotinib hydrochloride hemihydrate, having its crystalline form II.
  • polymorph of pure erlotinib hydrochloride hemihydrate refers to the crystalline form II of erlotinib hydrochloride hemihydrate having a purity of 95%, which means that erlotinib hydrochloride hemihydrate is Form II contains no more than 5% of any other form of erlotinib hydrochloride.
  • said purity is 99%, which means that Form II of erlotinib hydrochloride hemihydrate contains no more than about 1% of any other form of erlotinib hydrochloride.
  • the powder diffraction pattern (XRD pattern) of the Form II includes 3 or more 2 ⁇ values selected from the group consisting of: 5.7, 10.6, 11.5, 12.0, 14.5, 15. 17.3, 18.6, 20.4, 23.2, 23.5, 25.2, 24.5, 26.3 ⁇ 0.1 °.
  • the XRD pattern of the Form II is substantially as shown in Figure 1.
  • the differential scanning calorimetry (DSC pattern) of the Form II is at 75 ⁇
  • the DSC spectrum of the Form II is substantially as shown in Figure 3, and the Onset temperatures are 122.1 ⁇ 1.0 ° C and 149.7 ⁇ 1.0 ° C, respectively.
  • the peak at 122.1 + 1.0 °C is the desorption endothermic peak
  • the peak at 149.7 ⁇ 1.0 °C is the melting endothermic peak.
  • thermogravimetric analysis (TGA pattern) of the Form II has a weight loss of from 1.85 to 2.50% at 102 to 112 °C.
  • TGA spectrum of the Form II is substantially as shown in FIG. 4, wherein the TGA spectrum of the Form II has a weight loss of 3.2 to 2.5% at 102 to 112 ° C, indicating that the erlotinib HCl hemihydrate Form II contains half of the water of crystallization.
  • the invention provides a preparation method of a polymorph of erlotinib hydrochloride hemihydrate with a purity of 95%, preferably comprising the following steps: a) providing a mixture containing erlotinib hydrochloride (a mixture of erlotinib hydrochloride and a solvent), the mixture further comprising water or a mixed solvent of water and an organic solvent;
  • the step a) is: erlotinib hydrochloride with water or water at a temperature of 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C)
  • the mixed solvent of the organic solvent is mixed.
  • the organic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane or acetonitrile;
  • the volume ratio of the organic solvent to water is from 0.1 to 10:1; preferably from 0.1 to 1: l
  • the water is distilled water or deionized water; the volumetric weight (ml/g) ratio of water to erlotinib hydrochloride is 50-600:1, preferably 200-600:1; The good land is 200-400: 1.
  • the erlotinib-containing mixture is composed of erlotinib hydrochloride and water or a mixed solvent of water and an organic solvent.
  • the erlotinib hydrochloride is non-erlotinib hydrochloride Form II, and includes, for example: erlotinib hydrochloride Form B, erlotinib hydrochloride Form A, Ero Hydrochloride Tinier Form E or a combination thereof. b) stirring the mixture of step a) for a period of time (e.g.
  • step b) control the temperature of the solution of step b) at 0 ⁇ 5 ° C, continue to stir for a period of time (such as 0.5 ⁇ 5 hours, preferably 1 ⁇ 2 hours), further crystallization; d) separation and precipitation
  • the crystals thus obtain the polymorph of the pure erlotinib hydrochloride hemihydrate of the present invention.
  • the polymorph has a purity of 95%; preferably, 99%.
  • the separating comprises: filtering, drying, and the like.
  • the invention also provides a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutical compositions of the present invention are useful for treating tumors including, but not limited to, lung cancer, pancreatic cancer, non-small cell carcinoma, and the like.
  • the “active ingredient” as used in the present invention means a polymorph of pure erlotinib hydrochloride hemihydrate according to the present invention. "Safe and effective amount” means that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains from 1 to 2000 mg of the active ingredient per dose, more preferably from 10 to 200 mg of the active ingredient per dose.
  • the “one dose” is a tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gels 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 compatible with the active ingredients of the present invention and between them without significantly reducing the efficacy of the active ingredients.
  • 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 oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moist Wet agents (such as sodium decyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween®
  • moist Wet agents such as sodium decyl sulfate
  • 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.
  • 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, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) moisturizing An agent, for example, glycerin; (d) a disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; f) absorption 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 well 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 composition may also comprise Auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and perfumes.
  • the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these and the like.
  • a suspending agent for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture 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 applied 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 main advantage of the present invention is that - (1)
  • the present invention provides a polymorph of pure erlotinib hydrochloride hemihydrate and a process for the preparation thereof.
  • the preparation method is simple in operation and suitable for industrial production.
  • the polymorph of erlotinib hydrochloride hemihydrate obtained by the method of the invention has the HPLC chemical purity of more than 99.5%, the purity of the crystal form is up to 95%, and has the advantages of good stability and good water solubility. .
  • the present invention also provides the use of a pure polymorph of erlotinib hydrochloride hemihydrate for the preparation of a pharmaceutical composition for treating tumors.
  • the invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are only intended to illustrate the invention and not to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
  • the raw material erlotinib hydrochloride Form A or Form B used in the present invention is prepared according to WO2001034574, and erlotinib hydrochloride Form E is prepared in accordance with WO2004072049.
  • DSC Differential Scanning Calorimetry
  • Thermogravimetric analysis (TGA) instrument SDT Q600 type from TA Company, USA, in the range of 20 ⁇ 450 °C, heating rate 10 °C/min, nitrogen flow rate 50 ml/min.
  • Example 6 Preparation of erlotinib hydrochloride hemihydrate polymorph To 6.00 g of erlotinib hydrochloride (Form B) raw material, 3.6 L of distilled water was added thereto, and the internal temperature was maintained at 5 ° C, and the mixture was stirred under heating for 48 hours. Continue to control the temperature of 0 ⁇ 5 °C and stir for 3 hours. Filtration, solids were collected and dried under reduced pressure at 40 ° C for 10 hours to give pale yellow crystals of 5.55 g.
  • Example 7 Preparation of erlotinib hydrochloride hemihydrate polymorph
  • erlotinib hydrochloride (Form E) was added 1500 ml of a mixed solution of tetrahydrofuran and deionized water (tetrahydrofuran to water volume ratio of 1:5), and the mixture was stirred at an internal temperature of 10 ° C for 15 hours. Slowly cool down to 0 ⁇ 5 °C, keep stirring for 2 hours. After filtration, the solid was collected and dried under reduced pressure at 40 ° C for 10 hr to yield 4.62 g of pale yellow crystals.
  • Example 10 Preparation of erlotinib hydrochloride hemihydrate polymorph
  • erlotinib hydrochloride (Form B) was added 2000 ml of a mixed solution of acetonitrile and deionized water (acetonitrile to water volume ratio of 1:10), and the mixture was stirred at an internal temperature of 20 ° C for 10 hours. Slowly cool down to 0 ⁇ 5 °C, keep warming and continue to stir for 2 hours. Filtration, solids were collected and dried under reduced pressure at 40 ° C for 10 hours to give 4.5 g of pale yellow crystals.
  • Example 11 Preparation of erlotinib hydrochloride hemihydrate polymorph
  • the powder X-ray diffraction pattern is basically shown in Figure 1.
  • the differential thermal scanning spectrum is basically shown in Figure 3.
  • the thermogravimetric analysis is basically shown in Figure 4.
  • the crystal form II of the present invention is more pure than the crystal form II prepared by the method reported in WO2008049645A2.
  • Example 12 Stability Experiment
  • the samples of the above three different treatments were analyzed by XRD, DSC and TGA.
  • the high temperature 60 °C, high humidity 92.5% and ground products showed no change in the crystal form, and the powder X-ray diffraction pattern was basically as follows.
  • the differential thermal scanning spectrum is basically as shown in Fig. 3
  • the thermogravimetric analysis is basically as shown in Fig. 4.
  • Form II of the invention 0.192% Form A 0.194%
  • the crystal form II of erlotinib HCl hemihydrate of the present invention has substantially the same solubility as erlotinib hydrochloride crystal form A and crystal form E, and has good solubility, but the thermodynamics of crystal form A and form E The stability is poor, so it is not suitable for pharmaceutical preparations, and the crystalline form II of erlotinib hydrochloride hemihydrate of the invention has good thermal stability and is suitable for preparation into a pharmaceutical preparation;
  • the known erlotinib hydrochloride Form B is thermodynamically stable, but has poor solubility.
  • the crystal form II of the erlotinib hydrochloride hemihydrate of the present invention is nearly doubled in solubility to the known erlotinib hydrochloride Form B.
  • the erlotinib hydrochloride hemihydrate of the present invention has high purity, good stability and high solubility, and is suitable for use as a pharmaceutical preparation for clinical application.
  • Example 14 Pharmaceutical Composition

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Abstract

Disclosed in the present invention are an Erlotinib hydrochloride polymorph and the preparation method therefor. In particular, disclosed in the present invention are an Erlotinib hydrochloride semihydrate polymorph with a purity ≥95% and the preparation method therefor. The preparation method of the present invention is simple to operate and suitable for industrial production. The polymorph prepared by the preparation method of the invention has the advantages of good stability and high water solubility.

Description

盐酸埃罗替尼多晶型物及其制备方法  Erlotinib hydrochloride polymorph and preparation method thereof
技术领域  Technical field
本发明属于药物化学技术领域。具体地，本发明涉及盐酸埃罗替尼半水合物的 多晶型物及其制备方法。 背景技术  The invention belongs to the technical field of medicinal chemistry. In particular, the present invention relates to polymorphs of erlotinib hydrochloride hemihydrate and a process for the preparation thereof. Background technique
埃罗替尼 (Erlotinib)化学名称为 N-(3-乙炔苯基 )-[6，7- 啉 -4-胺， 其结构式如 (1)所示：  The chemical name of Erlotinib is N-(3-acetylenephenyl)-[6,7- phenyl-4-amine, and its structural formula is as shown in (1):
Figure imgf000003_0001
Figure imgf000003_0001
临床上通常使用盐酸埃罗替尼。 盐酸埃罗替尼是由 OSI制药公司开发的 4-氨 苯基喹唑啉类口服抗肿瘤药， 用于治疗胰腺癌和转移性非小细胞癌。  Erlotinib hydrochloride is commonly used clinically. Erlotinib HCl is a 4-aminophenylquinazoline oral antineoplastic drug developed by OSI Pharmaceuticals Inc. for the treatment of pancreatic cancer and metastatic non-small cell carcinoma.
WO0134574公开了盐酸埃罗替尼晶型 A和晶型 B。其中， 晶型 A热力稳定性 较差， 晶型 B为热力学稳定晶型， 但水溶性较差。  WO0134574 discloses erlotinib hydrochloride Form A and Form B. Among them, the thermal stability of the crystal form A is poor, and the crystal form B is a thermodynamically stable crystal form, but the water solubility is poor.
WO2004072049公开了盐酸埃罗替尼晶型 E， 晶型 E热力学也不太稳定。 WO2004072049 discloses erlotinib hydrochloride Form E, which is also less stable in thermodynamics.
WO2008049645A2公开了盐酸埃罗替尼半水合物的晶型 I和晶型 II，并报道了 这两种晶型的制备方法。该文献指出， 在制备盐酸埃罗替尼半水合物晶型 I和晶型 II的过程中， 得到的产品容易混有 10%以上的其它晶型， 例如晶型 、 晶型 B或 晶型 E。 因为是纯度不高的混晶， 所以不适合用于药物制剂。 另外， WO2008049645A2公开的晶型 II的制备方法中， 需要静置 4天析晶， 析晶后， 晶 体粘在瓶壁上， 因此后续还需要刮晶， 操作极为不便， 不适合工业化生产。 WO2008049645A2 discloses Form I and Form II of erlotinib hydrochloride hemihydrate, and reports the preparation of these two forms. The literature indicates that in the preparation of erlotinib HCl hemihydrate crystal form I and form II, the obtained product is easily mixed with more than 10% of other crystal forms, such as crystal form, crystal form B or crystal form E. . Because it is a mixed crystal with low purity, it is not suitable for pharmaceutical preparations. Further, in the method for preparing the crystal form II disclosed in WO2008049645A2, it is necessary to stand for 4 days to crystallize, and after the crystallizing, the crystal adheres to the bottle wall, so that the subsequent scraping is required, the operation is extremely inconvenient, and it is not suitable for industrial production.
因此， 开发一种热稳定好、水溶性好且适合工业化使用和药物制剂的盐酸埃罗 替尼晶型的制备方法是很有必要的。 发明内容  Therefore, it is necessary to develop a preparation method of erlotinib hydrochloride crystal form which is heat-stable, water-soluble and suitable for industrial use and pharmaceutical preparations. Summary of the invention
本发明的目的是提供一种热稳定好、水溶性好且适合工业化使用和药物制剂的 盐酸埃罗替尼晶型的制备方法， 以克服现有技术存在的上述缺陷。 在本发明第一方面中，提供了一种纯度 95%的盐酸埃罗替尼半水合物的多晶 型物。 SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of a crystal form of erlotinib hydrochloride which is thermally stable, water-soluble and suitable for industrial use and pharmaceutical preparations, in order to overcome the above-mentioned drawbacks of the prior art. In a first aspect of the invention, there is provided a polymorph of erlotinib hydrochloride hemihydrate having a purity of 95%.
在另一优选例中， 所述多晶型物的纯度 99%。  In another preferred embodiment, the polymorph has a purity of 99%.
在另一优选例中， 所述多晶型物的差示扫描量热法分析图谱在 75〜135 、 140〜160°C处分别有特征吸热峰。  In another preferred embodiment, the differential scanning calorimetry analysis pattern of the polymorph has a characteristic endothermic peak at 75 to 135 and 140 to 160 ° C, respectively.
在另一优选例中， 所述多晶型物的差示扫描量热法分析图谱基本如图 2所示。 在另一优选例中， 所述的多晶型物的粉末衍射图谱 (XRD谱图)包括 3个或 3 个以上选自下组的 2Θ值: 5.7、 10.6、 11.5、 12.0、 14.5、 15.1、 17.3、 18.6、 20.4、 23.2, 23.5, 25.2, 24.5, 26·3±0· 1ο。 In another preferred embodiment, the differential scanning calorimetry analysis pattern of the polymorph is substantially as shown in FIG. In another preferred embodiment, the powder diffraction pattern (XRD pattern) of the polymorph comprises 3 or more 2 选自 values selected from the group consisting of: 5.7, 10.6, 11.5, 12.0, 14.5, 15.1. 17.3, 18.6, 20.4, 23.2, 23.5, 25.2, 24.5, 26·3±0· 1 ο .
在另一优选例中， 所述多晶型物的粉末衍射图谱基本如图 1所示。  In another preferred embodiment, the powder diffraction pattern of the polymorph is substantially as shown in FIG.
在另一优选例中， 所述的多晶型物的热重分析谱图在 102〜112°C失重 1.85-2.50%。  In another preferred embodiment, the thermogravimetric spectrum of the polymorph has a weight loss of 1.85-2.50% at 102 to 112 °C.
在另一优选例中， 所述多晶型物的热重分析谱图基本如图 3所示。  In another preferred embodiment, the thermogravimetric analysis of the polymorph is substantially as shown in FIG.
在另一优选例中， 所述多晶型物按如下方法制得， 所述方法包括步骤： (1) 提供一含盐酸埃罗替尼的混合物， 所述混合物还含有水或水与有机溶剂的 混合溶剂；  In another preferred embodiment, the polymorph is prepared as follows, the method comprising the steps of: (1) providing a mixture comprising erlotinib HCl, the mixture further comprising water or water and an organic solvent Mixed solvent;
(2) 在 0〜50°C (较佳地 5-50°C ; 更佳地为 10〜30°C)下， 将步骤 (1)所述的混合 物搅拌 0〜48小时 (优选 5〜10小时)， 进行析晶， 过滤。  (2) stirring the mixture of the step (1) at 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) for 0 to 48 hours (preferably 5 to 10) Hour), crystallization and filtration.
在另一优选例中， 所述步骤 (2)中， 还包括步骤： 在搅拌后， 将所得的混合物 温度控制在 0〜5 °C， 搅拌 0.5〜5小时 (优选 1〜2小时)， 进一步析晶。  In another preferred embodiment, the step (2) further comprises the steps of: after stirring, controlling the temperature of the obtained mixture to 0 to 5 ° C, stirring for 0.5 to 5 hours (preferably 1 to 2 hours), further Crystallization.
在本发明第二方面中，提供了一种如本发明第一方面所述的盐酸埃罗替尼半水 合物的多晶型物的制备方法， 包括步骤：  In a second aspect of the invention, there is provided a process for the preparation of a polymorph of erlotinib hydrochloride hemihydrate according to the first aspect of the invention, comprising the steps of:
(1) 提供一含盐酸埃罗替尼的混合物， 所述混合物还含有水或水与有机溶剂的 混合溶剂；  (1) providing a mixture containing erlotinib hydrochloride, the mixture further comprising water or a mixed solvent of water and an organic solvent;
(2) 在 0〜50°C (较佳地 5-50°C ; 更佳地为 10〜30°C)下， 将步骤 (1)所述的混合 物搅拌 0〜48小时 (优选 5〜10小时)， 进行析晶， 从而得到本发明第一方面所述的 盐酸埃罗替尼半水合物的多晶型物。  (2) stirring the mixture of the step (1) at 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) for 0 to 48 hours (preferably 5 to 10) After crystallization, crystallization is carried out to obtain a polymorph of erlotinib hydrochloride hemihydrate according to the first aspect of the invention.
在另一优选例中， 在步骤 (2)中， 还包括步骤： 在搅拌后， 将所得的混合物温 度控制在 0〜5°C， 搅拌 0.5〜5小时 (优选 1〜2小时)， 进一步析晶。  In another preferred embodiment, in the step (2), the method further comprises the steps of: after stirring, controlling the temperature of the obtained mixture to 0 to 5 ° C, stirring for 0.5 to 5 hours (preferably 1 to 2 hours), and further analyzing crystal.
在另一优选例中，在步骤 (2)中，析晶后还包括步骤：分离析出的晶体 (如过滤)。 在另一优选例中， 包括步骤： a) 提供一含盐酸埃罗替尼的混合物， 所述混合物还含有水或水与有机溶剂的 混合溶剂； In another preferred embodiment, in the step (2), after the crystallization, the method further comprises the step of separating the precipitated crystals (such as filtration). In another preferred embodiment, the method comprises the steps of: a) providing a mixture containing erlotinib HCl, the mixture further comprising water or a mixed solvent of water and an organic solvent;
b) 在 0〜50°C (较佳地 5-50°C ; 更佳地为 10〜30°C)下， 将步骤 a)的混合物搅 拌 0〜48小时 (优选 5〜10小时)， 进行析晶；  b) stirring the mixture of step a) at 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) for 0 to 48 hours (preferably 5 to 10 hours) Crystallization
c) 将步骤 b)的混合物温度控制在 0〜5°C， 搅拌 0.5〜5小时 (优选 1〜2小时)， 进一步析晶；  c) controlling the temperature of the mixture of step b) at 0 to 5 ° C, stirring for 0.5 to 5 hours (preferably 1 to 2 hours), and further crystallization;
d) 分离析出的晶体， 从而得到盐酸埃罗替尼半水合物的多晶型物。  d) Separating the precipitated crystals to obtain a polymorph of erlotinib hydrochloride hemihydrate.
在另一优选例中， 所述的步骤 (1)或步骤 a)为： 在 0〜50°C (较佳地 5-50°C ; 更 佳地为 10〜30°C)下， 将盐酸埃罗替尼与水或水与有机溶剂的混合溶剂混合；  In another preferred embodiment, the step (1) or the step a) is: hydrochloric acid at 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) Erlotinib is mixed with water or a mixed solvent of water and an organic solvent;
在另一优选例中， 在步骤 (1)中，  In another preferred embodiment, in step (1),
水与盐酸埃罗替尼的体积重量 (ml/g)比为 50-600: 1 (优选为 200-600: 1； 更佳 地为 200-400: 1)； 禾口 /或  The volumetric weight (ml/g) ratio of water to erlotinib hydrochloride is 50-600:1 (preferably 200-600:1; more preferably 200-400:1);
所述的有机溶剂选自下组： 甲醇、 乙醇、 正丙醇、 异丙醇、 丙酮、 四氢呋喃、 二氧六环、 乙腈或其组合； 和 /或  The organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, acetonitrile or a combination thereof; and/or
所述的有机溶剂与水的体积比为 0.1-10: 1 (优选为 0.1-1 : 1)。  The volume ratio of the organic solvent to water is from 0.1 to 10:1 (preferably from 0.1 to 1: 1).
在另一优选例中， 所述方法制得的多晶型物的纯度 95%; 较佳地 99%。 在本发明第三方面中， 提供了一种药物组合物， 所述组合物包含：  In another preferred embodiment, the polymorph prepared by the process has a purity of 95%; preferably 99%. In a third aspect of the invention, a pharmaceutical composition is provided, the composition comprising:
(a) 本发明第一方面所述盐酸埃罗替尼半水合物的多晶型物（如 (a) a polymorph of erlotinib hydrochloride hemihydrate according to the first aspect of the invention (e.g.
0.001-99.9wt%, 较佳地 0.01 -99wt%， 更佳地 0.1-90wt%); 以及 0.001 to 99.9% by weight, preferably 0.01 to 99% by weight, more preferably 0.1 to 90% by weight;
(b) 药学上可接受的载体或赋形剂。  (b) a pharmaceutically acceptable carrier or excipient.
在本发明第四方面中，提供了本发明第一方面所述的盐酸埃罗替尼半水合物的 多晶型物或第三方面所述的药物组合物的用途， 用作抗肿瘤药物。 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  In a fourth aspect of the invention, the use of the polymorph of erlotinib hydrochloride hemihydrate or the pharmaceutical composition of the third aspect of the first aspect of the invention is provided as an antitumor drug. It is to be understood that within the scope of the present invention, the various technical features of the present invention and the technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Limited to the length, no longer repeated here. DRAWINGS
图 1是本发明所述的纯的盐酸埃罗替尼半水合物的多晶型物的 XRD图谱。 图 2是 WO2008049645A2报道的半水物晶型 II、 本发明所述的半水物晶型 II 和纯晶型 B的 XRD对比图。 图 3是本发明所述的纯的盐酸埃罗替尼半水合物的多晶型物的 DSC图谱。 图 4是本发明所述的纯的盐酸埃罗替尼半水合物的多晶型物的 TGA图谱。 具体实施方式 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRD pattern of a polymorph of pure erlotinib hydrochloride hemihydrate of the present invention. 2 is an XRD comparison diagram of the hemihydrate crystal form II reported in WO2008049645A2, the hemihydrate crystal form II and the pure form B described in the present invention. Figure 3 is a DSC chart of a polymorph of pure erlotinib hydrochloride hemihydrate of the present invention. 4 is a TGA pattern of a polymorph of pure erlotinib hydrochloride hemihydrate of the present invention. detailed description
本发明人通过长期而深入的研究，意外地发现了一种盐酸埃罗替尼半水合物的 多晶型物 (晶型 II)的制备方法， 所述方法通过搅拌完成了晶型 II的制备， 该方法条 件易控制、操作时间短， 十分适合工业化使用。通过该方法制得的盐酸埃罗替尼半 水合物的晶型 II纯度高， 具有很好的热稳定性、 高湿稳定性和压力稳定性， 且水 溶性好， 十分适合用于药物制剂。 发明人在此基础上完成了本发明。 本发明所述的纯的盐酸埃罗替尼半水合物的多晶型物  The present inventors have unexpectedly discovered a method for preparing a polymorph (Eliform II) of erlotinib hydrochloride hemihydrate by a long-term and in-depth study, which completes the preparation of Form II by stirring. The method is easy to control and has short operation time, and is very suitable for industrial use. The crystal form II of erlotinib HCl prepared by the method has high purity, good thermal stability, high humidity stability and pressure stability, and good water solubility, and is very suitable for use in pharmaceutical preparations. The inventors have completed the present invention on this basis. Polymorph of pure erlotinib hydrochloride hemihydrate according to the invention
本发明提供了一种盐酸埃罗替尼半水合物的多晶型物， 为其晶型 II。  The present invention provides a polymorph of erlotinib hydrochloride hemihydrate, having its crystalline form II.
所述 "纯的盐酸埃罗替尼半水合物的多晶型物"是指纯度 95%的盐酸埃罗替 尼半水合物的晶型 II， 这意味着盐酸埃罗替尼半水合物的晶型 II含不超过 5%的任 何其它形式的盐酸埃罗替尼。 较佳地， 所述的纯度 99%， 这意味着盐酸埃罗替尼 半水合物的晶型 II含不超过约 1%的任何其他形式的盐酸埃罗替尼。  The "polymorph of pure erlotinib hydrochloride hemihydrate" refers to the crystalline form II of erlotinib hydrochloride hemihydrate having a purity of 95%, which means that erlotinib hydrochloride hemihydrate is Form II contains no more than 5% of any other form of erlotinib hydrochloride. Preferably, said purity is 99%, which means that Form II of erlotinib hydrochloride hemihydrate contains no more than about 1% of any other form of erlotinib hydrochloride.
所述晶型 II的粉末衍射图谱 (XRD图谱)包括 3个或 3个以上选自下组的 2Θ值： 5.7、 10.6, 11.5, 12.0, 14.5, 15. 17.3, 18.6, 20.4, 23.2, 23.5, 25.2, 24.5, 26.3±0.1°。 优选地， 所述晶型 II的 XRD图谱基本如图 1所示。  The powder diffraction pattern (XRD pattern) of the Form II includes 3 or more 2 Θ values selected from the group consisting of: 5.7, 10.6, 11.5, 12.0, 14.5, 15. 17.3, 18.6, 20.4, 23.2, 23.5, 25.2, 24.5, 26.3 ± 0.1 °. Preferably, the XRD pattern of the Form II is substantially as shown in Figure 1.
在另一优选例中， 所述晶型 II的差示扫描量热法分析图谱 (DSC图谱)在 75〜 In another preferred embodiment, the differential scanning calorimetry (DSC pattern) of the Form II is at 75~
135°C、 140〜160°C处分别有特征吸热峰。 优选地， 所述晶型 II的 DSC图谱基本 如图 3所示， 图中 Onset温度分别为 122.1 ± 1.0°C、 149.7± 1.0°C。 其中， 122.1 + 1.0°C处的峰为失水吸热峰， 149.7± 1.0°C处的峰为融化吸热峰。 There are characteristic endothermic peaks at 135 ° C and 140 to 160 ° C, respectively. Preferably, the DSC spectrum of the Form II is substantially as shown in Figure 3, and the Onset temperatures are 122.1 ± 1.0 ° C and 149.7 ± 1.0 ° C, respectively. Among them, the peak at 122.1 + 1.0 °C is the desorption endothermic peak, and the peak at 149.7 ± 1.0 °C is the melting endothermic peak.
在另一优选例中， 所述晶型 II的热重分析图谱 (TGA图谱)在 102〜112°C失重 为 1.85-2.50%。 优选地， 所述晶型 II的 TGA图谱基本如图 4所示， 其中所述晶型 II的 TGA图谱在 102〜112°C失重为 2.3〜2.5%， 显示该盐酸埃罗替尼半水合物的 晶型 II含有半个结晶水。 制备方法  In another preferred embodiment, the thermogravimetric analysis (TGA pattern) of the Form II has a weight loss of from 1.85 to 2.50% at 102 to 112 °C. Preferably, the TGA spectrum of the Form II is substantially as shown in FIG. 4, wherein the TGA spectrum of the Form II has a weight loss of 3.2 to 2.5% at 102 to 112 ° C, indicating that the erlotinib HCl hemihydrate Form II contains half of the water of crystallization. Preparation
本发明提供了一种纯度 95%的盐酸埃罗替尼半水合物的多晶型物的制备方 法， 优选包括如下步骤： a) 提供一含盐酸埃罗替尼的混合物 (盐酸埃罗替尼与溶剂形成的混合物)，所述 混合物还含有水或水与有机溶剂的混合溶剂； The invention provides a preparation method of a polymorph of erlotinib hydrochloride hemihydrate with a purity of 95%, preferably comprising the following steps: a) providing a mixture containing erlotinib hydrochloride (a mixture of erlotinib hydrochloride and a solvent), the mixture further comprising water or a mixed solvent of water and an organic solvent;
优选地， 所述步骤 a)为： 在 0〜50°C (较佳地 5-50°C ; 更佳地为 10〜30°C)下， 将盐酸埃罗替尼与水或水与极性有机溶剂的混合溶剂混合。  Preferably, the step a) is: erlotinib hydrochloride with water or water at a temperature of 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) The mixed solvent of the organic solvent is mixed.
所述有机溶剂可以选自下组： 甲醇、 乙醇、正丙醇、异丙醇、 丙酮、 四氢呋喃、 二氧六环或乙腈等；  The organic solvent may be selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane or acetonitrile;
在所述的混合物溶剂中，所述有机溶剂与水的体积比为 0.1-10: 1 ;优选为 0.1-1 : l o  In the mixture solvent, the volume ratio of the organic solvent to water is from 0.1 to 10:1; preferably from 0.1 to 1: l
在另一优选例中，所述的水为蒸馏水或去离子水；水与盐酸埃罗替尼的体积重 量 (ml/g)比为 50-600: 1， 优选为 200-600: 1； 更佳地为 200-400: 1。  In another preferred embodiment, the water is distilled water or deionized water; the volumetric weight (ml/g) ratio of water to erlotinib hydrochloride is 50-600:1, preferably 200-600:1; The good land is 200-400: 1.
在另一优选例中，所述含盐酸埃罗替尼的混合物由盐酸埃罗替尼和水或水与有 机溶剂的混合溶剂组成。  In another preferred embodiment, the erlotinib-containing mixture is composed of erlotinib hydrochloride and water or a mixed solvent of water and an organic solvent.
在另一优选例中， 所述的盐酸埃罗替尼为非盐酸埃罗替尼晶型 II， 例如包括： 盐酸埃罗替尼晶型 B、 盐酸埃罗替尼晶型 A、 盐酸埃罗替尼晶型 E或其组合。 b) 在 0〜50°C (较佳地 5-50°C ; 更佳地为 10〜30°C)下， 将步骤 a)的混合物搅 拌一段时间 (如 0〜48小时， 优选 5〜10小时)， 进行析晶； c) 将步骤 b)的溶液温度控制在 0〜5°C， 继续搅拌一段时间 (如 0.5〜5小时， 优选 1〜2小时)， 进一步析晶； d) 分离析出的晶体， 从而得到本发明所述的纯的盐酸埃罗替尼半水合物的多 晶型物。 所述多晶型物的纯度 95%; 较佳地， 99%。  In another preferred embodiment, the erlotinib hydrochloride is non-erlotinib hydrochloride Form II, and includes, for example: erlotinib hydrochloride Form B, erlotinib hydrochloride Form A, Ero Hydrochloride Tinier Form E or a combination thereof. b) stirring the mixture of step a) for a period of time (e.g. 0 to 48 hours, preferably 5 to 10) at 0 to 50 ° C (preferably 5 to 50 ° C; more preferably 10 to 30 ° C) (hours), crystallization; c) control the temperature of the solution of step b) at 0~5 ° C, continue to stir for a period of time (such as 0.5~5 hours, preferably 1~2 hours), further crystallization; d) separation and precipitation The crystals thus obtain the polymorph of the pure erlotinib hydrochloride hemihydrate of the present invention. The polymorph has a purity of 95%; preferably, 99%.
其中， 所述的分离包括： 过滤， 干燥等步骤。 药物组合物和给药方式  Wherein, the separating comprises: filtering, drying, and the like. Pharmaceutical composition and mode of administration
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 药理上可以接受的赋形剂或载体。本发明的药物组合物可用于***，其中包括 (但并不限于)： 肺癌、 胰腺癌、 非小细胞癌等。  The invention also provides a pharmaceutical composition comprising an active ingredient in a safe and effective amount, together with a pharmaceutically acceptable excipient or carrier. The pharmaceutical compositions of the present invention are useful for treating tumors including, but not limited to, lung cancer, pancreatic cancer, non-small cell carcinoma, and the like.
本发明所述的 "活性成分"是指本发明所述的纯的盐酸埃罗替尼半水合物的多 晶型物。 "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 l-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。 The "active ingredient" as used in the present invention means a polymorph of pure erlotinib hydrochloride hemihydrate according to the present invention. "Safe and effective amount" means that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains from 1 to 2000 mg of the active ingredient per dose, more preferably from 10 to 200 mg of the active ingredient per dose. Preferably, the "one dose" is a tablet.
"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活性成分以及它们之间相互惨和，而不明显 降低活性成分的药效。 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 (如吐温 ®)、 润湿剂 (如十二垸基硫 酸钠)、 着色剂、 调味剂、 稳定剂、 抗氧化剂、 防腐剂、 无热原水等。  "Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gels 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 compatible with the active ingredients of the present invention and between them without significantly reducing the efficacy of the active ingredients. Examples of 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), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween®), moist Wet agents (such as sodium decyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
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。  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.
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。  Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
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、 聚乙烯基吡咯垸酮、 蔗糖和***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、 十二垸基硫酸钠， 或其混合物。 胶囊剂、 片 剂和丸剂中， 剂型也可包含缓冲剂。  In these solid dosage forms, 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, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) moisturizing An agent, for example, glycerin; (d) a disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; f) absorption accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc , calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.
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。  The solid dosage forms can also be prepared with coatings and shell materials, such as casings and other materials well 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.
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。 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active ingredient, 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. In addition to these inert diluents, the composition may also comprise Auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and perfumes.
除了活性成分外， 悬浮液可包含悬浮剂， 例如， 乙氧基化异十八垸醇、 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。  In addition to the active ingredient, the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these and the like.
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。  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.
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。  The compounds of the invention may be administered alone or in combination with other therapeutic agents, such as chemotherapeutic agents.
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 l〜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) 本发明提供了一种纯的盐酸埃罗替尼半水合物的多晶型物及其制备方法。 所述制备方法操作简单，适合工业化生产。通过本发明的方法得到的盐酸埃罗 替尼半水合物的多晶型物，其 HPLC化学纯度可达 99.5%以上，晶型纯度可达 95%， 且具有稳定性好、 水溶性好等优点。  When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is applied 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. Of course, 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 main advantage of the present invention is that - (1) The present invention provides a polymorph of pure erlotinib hydrochloride hemihydrate and a process for the preparation thereof. The preparation method is simple in operation and suitable for industrial production. The polymorph of erlotinib hydrochloride hemihydrate obtained by the method of the invention has the HPLC chemical purity of more than 99.5%, the purity of the crystal form is up to 95%, and has the advantages of good stability and good water solubility. .
(2) 本发明还提供了一种纯的盐酸埃罗替尼半水合物的多晶型物的应用， 用于 制备***的药物组合物。 下面结合具体实施， 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， 否则百分比和份数按 重量计算。  (2) The present invention also provides the use of a pure polymorph of erlotinib hydrochloride hemihydrate for the preparation of a pharmaceutical composition for treating tumors. The invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are only intended to illustrate the invention and not to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.
本发明所用原料盐酸埃罗替尼晶型 A或晶型 B 按 WO2001034574制备，盐酸 埃罗替尼晶型 E按照 WO2004072049制备。  The raw material erlotinib hydrochloride Form A or Form B used in the present invention is prepared according to WO2001034574, and erlotinib hydrochloride Form E is prepared in accordance with WO2004072049.
X-射线粉末衍射仪器： Dedye〜Scherrer INEL CPS〜120 X-射线粉末衍射仪； 福 I寸源： α!=1.54060θΑ, α2=1.54439 A; Generator kv : 40kv; Generator mA: 30mA; 起始的 2Θ: 2.000。， 扫描范围: 2.0000〜50.000。。 差示扫描量热法 (DSC)仪器： 美国 TA公司的 Q2000型， 20〜450°C范围内， 加热速率 10°C/min， 氮气流速 50ml/min。 X-ray powder diffraction instrument: Dedye~Scherrer INEL CPS~120 X-ray powder diffractometer; Fu I inch source: α!=1.54060θΑ, α 2 =1.54439 A; Generator kv : 40kv ; Generator mA: 30mA; 2Θ: 2.000. , Scan range: 2.0000~50.000. . Differential Scanning Calorimetry (DSC) instrument: Model Q2000 from TA, USA, in the range of 20 to 450 ° C, heating rate 10 ° C / min, nitrogen flow rate 50 ml / min.
热重分析 (TGA)仪器： 美国 TA公司的 SDT Q600型， 20〜450°C范围内， 加热 速率 10°C/min， 氮气流速 50ml/min。  Thermogravimetric analysis (TGA) instrument: SDT Q600 type from TA Company, USA, in the range of 20~450 °C, heating rate 10 °C/min, nitrogen flow rate 50 ml/min.
实施例 1 盐酸埃罗替尼半水合物多晶型物的制备  Example 1 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼 (晶型 B)原料中， 加入 1000ml蒸馏水， 保持温度 30°C 搅拌 10小时。缓慢降温至 0〜5°C，保温继续搅拌 1小时。过滤，收集固体并于 40 °C 减压干燥 10小时， 得到 4.74g淡黄色晶体， HPLC化学纯度为 99.75 %。  To 5.00 g of erlotinib hydrochloride (Form B), 1000 ml of distilled water was added, and the mixture was stirred at a temperature of 30 ° C for 10 hours. Slowly cool down to 0~5 °C, keep stirring for 1 hour. Filtration, solids were collected and dried under reduced pressure at 40 °C for 10 hr to yield 4.74 g of pale yellow crystals.
实施例 2 盐酸埃罗替尼半水合物多晶型物的制备  Example 2 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼 (晶型 A)原料中，加入 2000ml去离子水，保持温度 20 °C 搅拌 8小时。缓慢降温至 0〜5°C，保温继续搅拌 1小时。过滤，收集固体并于 40°C 减压干燥 10小时， 得到 4.63g淡黄色晶体， HPLC化学纯度为 99.76%。  To 5.00 g of erlotinib hydrochloride (Form A), 2000 ml of deionized water was added, and the mixture was stirred at a temperature of 20 ° C for 8 hours. Slowly cool down to 0~5 °C, keep stirring for 1 hour. After filtration, the solid was collected and dried under reduced pressure at 40 ° C for 10 hr to yield 4.63 g of pale yellow crystals.
实施例 3 盐酸埃罗替尼半水合物多晶型物的制备  Example 3 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼 (晶型 E)原料中， 加入 1500ml蒸馏水， 保持温度 10°C 搅拌 10小时。 缓慢降温至 0〜5°C， 保温继续搅拌 2小时。 过滤， 40°C减压干燥 10 小时， 得到 4.69g淡黄色晶体， HPLC化学纯度为 99.72%。  To 5.00 g of erlotinib hydrochloride (Form E), 1500 ml of distilled water was added thereto, and the mixture was stirred at a temperature of 10 ° C for 10 hours. Slowly cool down to 0~5 °C, keep stirring for 2 hours. Filtration and drying under reduced pressure at 40 ° C for 10 hours gave 4.69 g of pale-yellow crystals, and the HPLC chemical purity was 99.72%.
实施例 4 盐酸埃罗替尼半水合物多晶型物的制备  Example 4 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼 (晶型 E)原料中， 加入 250ml蒸馏水， 保持温度 40°C搅 拌 24小时。 缓慢降温至 0〜5°C， 保温继续搅拌 2小时。 过滤， 收集固体并于 40°C 减压干燥 10小时， 得到 4.78g淡黄色晶体， HPLC化学纯度为 99.57%。  To 5.00 g of erlotinib hydrochloride (Form E), 250 ml of distilled water was added, and the mixture was stirred at a temperature of 40 ° C for 24 hours. Slowly cool down to 0~5 °C, keep stirring for 2 hours. Filtration, solids were collected and dried under reduced pressure at 40 ° C for 10 hours to give 4.78 g of pale yellow crystals.
实施例 5 盐酸埃罗替尼半水合物多晶型物的制备  Example 5 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼 (晶型 A)原料中， 加入 500ml去离子水， 保持温度 50°C 搅拌 5小时。缓慢降温至 0〜5°C，保温继续搅拌 5小时。过滤，收集固体并于 40°C 减压干燥 10小时， 得到 4.74g淡黄色晶体， HPLC化学纯度为 99.65%。  To 5.00 g of erlotinib hydrochloride (Form A), 500 ml of deionized water was added, and the mixture was stirred at a temperature of 50 ° C for 5 hours. Slowly cool down to 0~5 °C, keep stirring for 5 hours. After filtration, the solid was collected and dried under reduced pressure at 40 ° C for 10 hr to yield 4.74 g of pale yellow crystals.
实施例 6 盐酸埃罗替尼半水合物多晶型物的制备 向 6.00g盐酸埃罗替尼 (晶型 B)原料中， 加入 3.6L蒸馏水， 保持内温为 5°C， 保温搅拌 48小时。 继续控温 0〜5°C， 搅拌 3小时。 过滤， 收集固体并于 40°C减压 干燥 10小时， 得到淡黄色晶体 5.55g， HPLC化学纯度为 99.89%。 实施例 7 盐酸埃罗替尼半水合物多晶型物的制备 Example 6 Preparation of erlotinib hydrochloride hemihydrate polymorph To 6.00 g of erlotinib hydrochloride (Form B) raw material, 3.6 L of distilled water was added thereto, and the internal temperature was maintained at 5 ° C, and the mixture was stirred under heating for 48 hours. Continue to control the temperature of 0~5 °C and stir for 3 hours. Filtration, solids were collected and dried under reduced pressure at 40 ° C for 10 hours to give pale yellow crystals of 5.55 g. Example 7 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼 (晶型 A)原料中， 加入 500ml异丙醇和去离子水的混合 溶液 (异丙醇和水体积比为 1 : 3),保持内温 30°C搅拌 10小时。缓慢降温至 0〜5°C， 保温继续搅拌 1小时。 过滤， 收集固体并于 40°C减压干燥 10小时， 得到 4.51g淡 黄色晶体， HPLC化学纯度为 99.67%。 实施例 8 盐酸埃罗替尼半水合物多晶型物的制备  To a raw material of 5.00 g of erlotinib hydrochloride (Form A), 500 ml of a mixed solution of isopropyl alcohol and deionized water (isopropyl alcohol and water volume ratio of 1:3) was added, and the mixture was stirred at an internal temperature of 30 ° C for 10 hours. Slowly cool to 0~5 °C, keep stirring for 1 hour. After filtration, the solid was collected and dried under reduced pressure at 40 ° C for 10 hours to give 4.51 g of pale yellow crystals. Example 8 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.0g盐酸埃罗替尼 (晶型 B)原料中加入 1000ml丙酮和蒸馏水的混合溶液 (丙 酮和水体积比为 1 : 1)， 保持内温 20°C搅拌 24小时。 缓慢降温至 0〜5°C， 保温继 续搅拌 2小时。 过滤， 收集固体并于 40°C减压干燥 10小时， 得到 4.58g淡黄色晶 体， HPLC化学纯度为 99.58%。 实施例 9 盐酸埃罗替尼半水合物多晶型物的制备  To 5.0 g of erlotinib hydrochloride (Form B) was added 1000 ml of a mixed solution of acetone and distilled water (volume ratio of acetone to water of 1:1), and the mixture was stirred at an internal temperature of 20 ° C for 24 hours. Slowly cool to 0~5 °C, keep stirring for 2 hours. After filtration, the solid was collected and dried under reduced pressure at 40 ° C for 10 hr to yield 4.58 g of pale yellow crystals. Example 9 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼 (晶型 E)原料中加入 1500ml四氢呋喃和去离子水的混合 溶液 (四氢呋喃和水体积比为 1 : 5)，保持内温 10°C搅拌 15小时。缓慢降温至 0〜5°C， 保温继续搅拌 2小时。 过滤， 收集固体并于 40°C减压干燥 10小时， 得到 4.62g淡 黄色晶体， HPLC化学纯度为 99.55%。 实施例 10 盐酸埃罗替尼半水合物多晶型物的制备  To 5.00 g of erlotinib hydrochloride (Form E) was added 1500 ml of a mixed solution of tetrahydrofuran and deionized water (tetrahydrofuran to water volume ratio of 1:5), and the mixture was stirred at an internal temperature of 10 ° C for 15 hours. Slowly cool down to 0~5 °C, keep stirring for 2 hours. After filtration, the solid was collected and dried under reduced pressure at 40 ° C for 10 hr to yield 4.62 g of pale yellow crystals. Example 10 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.0g盐酸埃罗替尼 (晶型 B)原料中加入 2000ml乙腈和去离子水的混合溶液 (乙腈和水体积比为 1 : 10)，保持内温 20°C搅拌 10小时。 缓慢降温至 0〜5°C， 保温 继续搅拌 2小时。过滤， 收集固体并于 40°C减压干燥 10小时， 得到 4.5g淡黄色晶 体， HPLC化学纯度为 99.69%。 实施例 11 盐酸埃罗替尼半水合物多晶型物的制备  To 5.0 g of erlotinib hydrochloride (Form B) was added 2000 ml of a mixed solution of acetonitrile and deionized water (acetonitrile to water volume ratio of 1:10), and the mixture was stirred at an internal temperature of 20 ° C for 10 hours. Slowly cool down to 0~5 °C, keep warming and continue to stir for 2 hours. Filtration, solids were collected and dried under reduced pressure at 40 ° C for 10 hours to give 4.5 g of pale yellow crystals. Example 11 Preparation of erlotinib hydrochloride hemihydrate polymorph
向 5.00g盐酸埃罗替尼原料 (CAS:183319-69-9， 购自百灵威科技有限公司）中， 加入 1000ml蒸馏水， 保持温度 30°C搅拌 10小时。 缓慢降温至 0〜5°C， 保温继续 搅拌 1小时。 过滤， 收集固体并于 40°C减压干燥 10小时， 得到 5g淡黄色晶体， HPLC化学纯度为 99.50 %。 对于实施例 1-11制备的淡黄色晶体， 经 X-射线粉末衍射及差示扫描量热法、 热重分析法分析证实， 所得晶体均为本发明所述的盐酸埃罗替尼半水合物的晶型To 5.00 g of erlotinib HCl raw material (CAS: 183319-69-9, purchased from Belling Technology Co., Ltd.), 1000 ml of distilled water was added, and the mixture was stirred at a temperature of 30 ° C for 10 hours. Slowly cool down to 0~5 °C, keep warming Stir for 1 hour. Filtration, solids were collected and dried under reduced pressure at 40 ° C for 10 hours to give 5 g of pale yellow crystals. The pale yellow crystals prepared in Examples 1-11 were confirmed by X-ray powder diffraction and differential scanning calorimetry and thermogravimetric analysis. The obtained crystals were all erlotinib hydrochloride hemihydrate according to the present invention. Crystal form
II。 其粉末 X射线衍射图基本如图 1所示， 差热扫描谱图基本如图 3所示， 热重分 析基本如图 4所示。 II. The powder X-ray diffraction pattern is basically shown in Figure 1. The differential thermal scanning spectrum is basically shown in Figure 3. The thermogravimetric analysis is basically shown in Figure 4.
由图 2可知， 较 WO2008049645A2所报道的方法制备的晶型 II， 本发明的晶 型 II更纯。 实施例 12 稳定性实验  As can be seen from Fig. 2, the crystal form II of the present invention is more pure than the crystal form II prepared by the method reported in WO2008049645A2. Example 12 Stability Experiment
取上述实施例 1制得的盐酸埃罗替尼半水合物的晶型 II三份， 将其分别进行 如下处理：  The crystal form II of erlotinib HCl hemihydrate prepared in the above Example 1 was taken in triplicate, and the treatment was carried out as follows:
在 60°C减压放置 3天；  Placed under reduced pressure at 60 ° C for 3 days;
在相对湿度为 92.5%、 25°C放置 3天；  Placed at a relative humidity of 92.5% and 25 ° C for 3 days;
在研钵中强力研磨 30分钟。  Grind for 30 minutes in a mortar.
取上述三种不同处理后的样品，进行 XRD、DSC和 TGA分析发现经高温 60 °C、 高湿 92.5%和研磨后的产品， 其晶型均未发生变化， 其粉末 X射线衍射图基本如 图 1所示， 差热扫描谱图基本如图 3所示， 热重分析基本如图 4所示。  The samples of the above three different treatments were analyzed by XRD, DSC and TGA. The high temperature 60 °C, high humidity 92.5% and ground products showed no change in the crystal form, and the powder X-ray diffraction pattern was basically as follows. As shown in Fig. 1, the differential thermal scanning spectrum is basically as shown in Fig. 3, and the thermogravimetric analysis is basically as shown in Fig. 4.
实验结果表明： 本发明所述方法制得的盐酸埃罗替尼半水合物的晶型 II具有 良好的热稳定性、 高湿稳定性和压力稳定性。 实施例 13 溶解性实验  The experimental results show that the crystalline form II of erlotinib hydrochloride hemihydrate prepared by the method of the present invention has good thermal stability, high humidity stability and pressure stability. Example 13 Solubility test
取过量的已知盐酸埃罗替尼晶型 A、 晶型 B和晶型 E以及本发明制得的盐酸 埃罗替尼半水合物的晶型 II样品， 分别加入 0.5ml水中，然后通过超声操作数分钟 (约 3分钟)， 将其分散和溶解。 在室温静置 30分钟后， 通过离心操作分离上清液; 通过 HPLC测定上清液中的样品浓度 (定义为表观溶解度)， 测定结果见表 1所示。  Excess a sample of crystal form II of known erlotinib hydrochloride Form A, Form B and Form E and erlotinib hydrochloride hemihydrate prepared according to the present invention were respectively added to 0.5 ml of water and then passed through ultrasound. Operate for a few minutes (about 3 minutes), disperse and dissolve. After standing at room temperature for 30 minutes, the supernatant was separated by centrifugation; the concentration of the sample in the supernatant (defined as apparent solubility) was determined by HPLC, and the results are shown in Table 1.
表 1 溶解性实验结果  Table 1 Solubility test results
样品 表观溶解度  Sample apparent solubility
本发明的晶型 II 0.192% 晶型 A 0.194% Form II of the invention 0.192% Form A 0.194%
晶型 B 0.098%  Form B 0.098%
晶型 E 0.191%  Form E 0.191%
由上结果可知，  As can be seen from the above results,
1. 本发明的盐酸埃罗替尼半水合物的晶型 II与盐酸埃罗替尼晶型 A和晶型 E 的溶解度基本一致， 具有良好的溶解性， 但是晶型 A和晶型 E热力学稳定性差， 故不适合药物制剂， 而本发明的盐酸埃罗替尼半水合物的晶型 II热稳定性好， 适 合制成药物制剂；  1. The crystal form II of erlotinib HCl hemihydrate of the present invention has substantially the same solubility as erlotinib hydrochloride crystal form A and crystal form E, and has good solubility, but the thermodynamics of crystal form A and form E The stability is poor, so it is not suitable for pharmaceutical preparations, and the crystalline form II of erlotinib hydrochloride hemihydrate of the invention has good thermal stability and is suitable for preparation into a pharmaceutical preparation;
2. 已知的盐酸埃罗替尼晶型 B热力学稳定， 但是溶解度较差。 本发明的盐酸 埃罗替尼半水合物的晶型 II比已知的盐酸埃罗替尼晶型 B溶解度提高了近 1倍。 综上所述， 本发明的盐酸埃罗替尼半水合物的晶型 II纯度高， 且稳定性好、 溶解度高， 适合制成药物制剂用于临床应用。 实施例 14 药物组合物  2. The known erlotinib hydrochloride Form B is thermodynamically stable, but has poor solubility. The crystal form II of the erlotinib hydrochloride hemihydrate of the present invention is nearly doubled in solubility to the known erlotinib hydrochloride Form B. In summary, the erlotinib hydrochloride hemihydrate of the present invention has high purity, good stability and high solubility, and is suitable for use as a pharmaceutical preparation for clinical application. Example 14 Pharmaceutical Composition
实施例 1制得的盐酸埃罗替尼半水合物的晶型 II 20g  Form 1 of erlotinib hydrochloride hemihydrate prepared in Example 1 II 20g
淀粉 140g  Starch 140g
微晶纤维素 60g  Microcrystalline cellulose 60g
按常规方法， 将上述物质混合均匀后， 装入普通明胶胶囊， 得到 1000颗胶囊。 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。  The above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules. All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the present invention.

Claims

权 利 要 求 书 claims
1、 一种纯度 95%的盐酸埃罗替尼半水合物的多晶型物。 1. A polymorphic form of erlotinib hydrochloride hemihydrate with a purity of 95%.
2、 如权利要求 1所述的多晶型物， 其特征在于， 所述多晶型物的差示扫描量 热法分析图谱在 75〜135°C、 140〜160°C处分别有特征吸热峰。 2. The polymorph according to claim 1, wherein the differential scanning calorimetry analysis spectrum of the polymorph has characteristic absorption at 75~135°C and 140~160°C respectively. Hot peak.
3、 如权利要求 1所述的多晶型物， 其特征在于， 所述的多晶型物的粉末衍射 图谱 (XRD谱图)包括 3个或 3个以上选自下组的 2Θ值： 5.7、 10.6、 11.5、 12.0、 14.5、 15. K 17.3, 18.6, 20.4, 23.2, 23.5, 25.2, 24.5, 26·3±0· 1ο。 3. The polymorph of claim 1, wherein the powder diffraction pattern (XRD pattern) of the polymorph includes 3 or more 2Θ values selected from the following group: 5.7 , 10.6, 11.5, 12.0, 14.5, 15. K 17.3, 18.6, 20.4, 23.2, 23.5, 25.2, 24.5, 26·3±0·1 ο .
4、 如权利要求 1所述的多晶型物， 其特征在于， 所述的多晶型物的热重分析 谱图在 102〜112°C失重 1.85-2.50%。 4. The polymorph according to claim 1, wherein the thermogravimetric analysis spectrum of the polymorph shows a weight loss of 1.85-2.50% at 102~112°C.
5、 如权利要求 1所述的多晶型物， 其特征在于， 所述多晶型物按如下方法制 得， 所述方法包括步骤： 5. The polymorph of claim 1, wherein the polymorph is prepared as follows, and the method includes the steps:
(1) 提供一含盐酸埃罗替尼的混合物， 所述混合物还含有水或水与有机溶剂的 混合溶剂； (1) Provide a mixture containing erlotinib hydrochloride, the mixture also contains water or a mixed solvent of water and an organic solvent;
(2) 在 0〜50°C下， 将步骤 (1)所述的混合物搅拌 0〜48小时， 进行析晶， 过滤。 (2) Stir the mixture described in step (1) at 0 to 50°C for 0 to 48 hours, crystallize, and filter.
6、如权利要求 1〜5任一项所述的盐酸埃罗替尼半水合物的多晶型物的制备方 法， 其特征在于， 包括步骤： 6. The method for preparing the polymorph of erlotinib hydrochloride hemihydrate according to any one of claims 1 to 5, characterized in that it includes the steps:
(1) 提供一含盐酸埃罗替尼的混合物， 所述混合物还含有水或水与有机溶剂的 混合溶剂； (1) Provide a mixture containing erlotinib hydrochloride, the mixture also contains water or a mixed solvent of water and an organic solvent;
(2) 在 0〜50°C下， 将步骤 (1)所述的混合物搅拌 0〜48小时， 进行析晶， 从而 得到权利要求 1〜5任一项所述的盐酸埃罗替尼半水合物的多晶型物。 (2) Stir the mixture described in step (1) for 0 to 48 hours at 0 to 50°C, and crystallize to obtain the erlotinib hydrochloride hemihydrate described in any one of claims 1 to 5 Polymorphs of substances.
7、 如权利要求 6所述的制备方法， 其特征在于， 在步骤 (2)中， 还包括步骤： 在搅拌后， 将所得的混合物温度控制在 0〜5°C， 搅拌 0.5〜5小时， 进一步析晶。 7. The preparation method according to claim 6, characterized in that in step (2), it also includes the steps of: after stirring, controlling the temperature of the resulting mixture at 0~5°C, stirring for 0.5~5 hours, further crystallization.
8、 如权利要求 6所述的制备方法， 其特征在于， 包括步骤： 8. The preparation method according to claim 6, characterized in that it includes the steps of:
a) 提供一含盐酸埃罗替尼的混合物， 所述混合物还含有水或水与有机溶剂的 混合溶剂； a) Provide a mixture containing erlotinib hydrochloride, the mixture also contains water or a mixed solvent of water and organic solvent;
b) 在 0〜50°C下， 将步骤 a)的混合物搅拌 0〜48小时， 进行析晶； b) Stir the mixture of step a) at 0 to 50°C for 0 to 48 hours to crystallize;
c) 将步骤 b)的混合物温度控制在 0〜5°C， 搅拌 0.5〜5小时， 进一步析晶； d) 分离析出的晶体， 从而得到盐酸埃罗替尼半水合物的多晶型物。 c) Control the temperature of the mixture in step b) at 0 to 5°C, stir for 0.5 to 5 hours, and further crystallize; d) Separate the precipitated crystals to obtain the polymorph of erlotinib hydrochloride hemihydrate.
9、 如权利要求 6所述的制备方法， 其特征在于， 在步骤 (1)中， 9. The preparation method according to claim 6, characterized in that, in step (1),
水与盐酸埃罗替尼的体积重量 (ml/g)比为 50-600: 1； 和 /或 所述的有机溶剂选自下组： 甲醇、 乙醇、 正丙醇、 异丙醇、 丙酮、 四氢呋喃、 二氧六环、 乙腈或其组合； 和 /或 The volume to weight (ml/g) ratio of water to erlotinib hydrochloride is 50-600: 1; and/or The organic solvent is selected from the following group: methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, dioxane, acetonitrile or a combination thereof; and/or
所述的有机溶剂与水的体积比为 0.1-10: 1。 The volume ratio of the organic solvent to water is 0.1-10:1.
10、 一种药物组合物， 其特征在于， 所述组合物包含： 10. A pharmaceutical composition, characterized in that the composition contains:
(a) 权利要求 1〜5任一项所述盐酸埃罗替尼半水合物的多晶型物； 以及 (a) The polymorph of erlotinib hydrochloride hemihydrate according to any one of claims 1 to 5; and
(b) 药学上可接受的载体或赋形剂。 (b) Pharmaceutically acceptable carrier or excipient.
11、 如权利要求 1 所述的盐酸埃罗替尼半水合物的多晶型物或如权利要求 10 所述的药物组合物的用途， 其特征在于， 用作抗肿瘤药物。 11. Use of the polymorph of erlotinib hydrochloride hemihydrate as claimed in claim 1 or the pharmaceutical composition as claimed in claim 10, characterized in that it is used as an anti-tumor drug.
PCT/CN2012/079973 2012-08-10 2012-08-10 Erlotinib hydrochloride polymorph and preparation method therefor WO2014023027A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2610337C1 (en) * 2015-12-10 2017-02-09 Индивидуальный предприниматель Михайлов Олег Ростиславович CRYSTALLINE β-MODIFICATION OF N-(3-ETHYLPHENYL)-6,7-BIS(2 METHOXYETHOXY)QUINAZOLINE-4-AMINE HYDROCHLORIDE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON

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WO2008049645A2 (en) * 2006-10-27 2008-05-02 Synthon B.V. Hydrates of erlotinib hydrochloride
CN101547910A (en) * 2006-07-28 2009-09-30 合成纤维有限公司 Crystalline erlotinib
WO2012028861A1 (en) * 2010-07-23 2012-03-08 Generics [Uk] Limited Pure erlotinib

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CN101547910A (en) * 2006-07-28 2009-09-30 合成纤维有限公司 Crystalline erlotinib
WO2008049645A2 (en) * 2006-10-27 2008-05-02 Synthon B.V. Hydrates of erlotinib hydrochloride
WO2012028861A1 (en) * 2010-07-23 2012-03-08 Generics [Uk] Limited Pure erlotinib

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2610337C1 (en) * 2015-12-10 2017-02-09 Индивидуальный предприниматель Михайлов Олег Ростиславович CRYSTALLINE β-MODIFICATION OF N-(3-ETHYLPHENYL)-6,7-BIS(2 METHOXYETHOXY)QUINAZOLINE-4-AMINE HYDROCHLORIDE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON

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