Classifications

• • 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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• 2012
  • 2012-08-10 WO PCT/CN2012/079973 patent/WO2014023027A1/fr not_active Ceased

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