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WO2014203177A1 - Amorphous (r) -3- [1- (2, 6-dichloro-3-fluorophenyl) methoxy] -5- [1- (piperidin-4- yl) -1h-pyrazol-4-yl] pyridin-2-amine - Google Patents

Amorphous (r) -3- [1- (2, 6-dichloro-3-fluorophenyl) methoxy] -5- [1- (piperidin-4- yl) -1h-pyrazol-4-yl] pyridin-2-amine Download PDF

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WO2014203177A1
WO2014203177A1 PCT/IB2014/062361 IB2014062361W WO2014203177A1 WO 2014203177 A1 WO2014203177 A1 WO 2014203177A1 IB 2014062361 W IB2014062361 W IB 2014062361W WO 2014203177 A1 WO2014203177 A1 WO 2014203177A1
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dichloro
piperidin
pyrazol
amine
ethoxy
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French (fr)
Inventor
Lavkumar UPALLA
Rampalli SRIRAM
Chantibabu PATNEEDI
Chandrasekhar DANGUDUBIYYAM
Akshaykant CHATURVEDI
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Shilpa Medicare Ltd
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Shilpa Medicare Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a process for preparation of amorphous (R)-3-[l -(2,6- Dichloro-3-fluorophenyl) ]pyridin-2-amine (I).
  • the present invention also relates to the process for the preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4- yl]pyridin-2-amine premix.
  • the invention further relates to pharmaceutical compositions comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin- 2-amine or its premix, having anti-cancer activity.
  • Crizotinib is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive. It was approved by USFDA in August of 2011 and is marketed under the trade name XALKORITM. Crizotinib is also undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children. Crizotinib is chemically mentioned in the USFDA label as (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l -amine (I).
  • Crizotinib structure contains one chiral center. It is a non-hygroscopic, white to pale yellow powder which is insoluble in water, though being highly soluble in acidic pH. Crizotinib is defined in class IV (low solubility and low permeability) under the Biopharmaceutics Classification System (BCS).
  • BCS Biopharmaceutics Classification System
  • Cui, et al. in US 7,230,098 B2 provided the first generic disclosure of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine (also known as Crizotinib). Further Cui, et al. in US 7,858,643 B2 provided the specific disclosure of Crizotinib and its pharmaceutically acceptable salts. This patent also describes the process for preparation of Crizotinib.
  • Example 19 of U.S. patent application Ser. No. 11/212,331 i.e. US 7,858,643 B2 describes the preparation of Crizotinib (Compound I) which was found to be amorphous. However actually this disclosure appears to relate with compound other than Crizotinib. It is also disclosed in this patent that new polymorphic forms of Crizotinib base were required so as to have improved crystallinity, dissolution properties, and/or decreased hygroscopicity, while maintaining chemical and enantiomeric stability properties.
  • Example 19 of US 7,858,643 B2 example 19 compound is 3-[(R)-l-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(l-piperidin-4- yl- lH-pyrazol-4-yl)-pyridin-2-ylamine acetate, which is not Crizotinib.
  • Even the analytical data provided for this compound of Example 19 shows- a. LCMS mass value of 434 [M+], which is indicative of absence of Crizotinib; and b. l H NMR results with three extra protons at ⁇ 5—1.80 ppm because of presence of acetate salt, indicating absence of Crizotinib which is a free base compound.
  • Amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present invention is non-hygroscopic, chemically and enantiomerically stable and has good dissolution properties.
  • the present invention provides an amorphous (R)-3-[l-(2,6-Dichloro- 3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine.
  • the present invention also relates to a process for preparation of amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine (I)
  • the present invention also relates to a composition
  • a composition comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4- yl]pyridin-2-amine, of which at least 95% by total weight of (R)-3-[l-(2,6-Dichloro-3-fluoro phenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in the composition, is the amorphous form.
  • composition is substantially free of any other known forms of (R)-3- [ 1 -(2,6 -Dichloro-3 -fluorophenyl)ethoxy] -5 - [ 1 -(piperidin-4-yl)- 1 H-pyrazol-4-yl]pyridin-2- amine.
  • the present application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine or its premix of the present application and at least one or more pharmaceutically acceptable excipients.
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • XRPD X-ray powder diffraction
  • Fig. 2 is an example of FT-IR spectrum of (R)-3-[l -(2,6-Dichloro-3-fiuorophenyl)ethoxy]- 5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 3 is an example of l H NMR spectrum of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 4 is an example of mass spectrum of (R)-3-[l -(2,6-Dichloro-3-fiuorophenyl)ethoxy]- 5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 5 is an example of TGA thermogram of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) emoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
  • Fig. 6 is an example of X-ray powder diffraction ("XRPD") pattern of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine premix amorphous form as obtained according to example 3.
  • XRPD X-ray powder diffraction
  • embodiments of the present invention relate to the amorphous (R)- 3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -IH- pyrazol-4-yl] pyridine -2-amine and process for preparation thereof.
  • Step a) comprises providing a solution of (R)-3-[l -(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent;
  • Crizotinib base Crizotinib base (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine (or Crizotinib base) is provided as a solution in an organic solvent wherein organic solvent may be selected from a water miscible organic solvent comprising of C 1 -C 4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, NMP or a mixture thereof.
  • C 1 -C 4 alcohol may further be selected from methanol, ethanol, wo-propanol, «-butanol or tert- butanol.
  • the reaction solution is prepared at an ambient temperature of 25-30 °C.
  • amount of organic solvent used to prepare the reaction solution may range from 2 to 25 times w/v (g/mL) as compared to the weight of Crizotinib used as the starting material.
  • Step b) comprises heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;
  • Reaction mixture prepared in step a) is heated to a temperature ranging between 40 °C and the boiling point of the organic solvent used, along with continuous stirring to provide a clear solution.
  • temperature employed for the current step was 50-55 °C.
  • the reaction mixture is maintained at the same raised temperature for a time duration of 20 mins to 1 hr.
  • Step c) comprises cooling the reaction mixture to a temperature of 30°C or below;
  • reaction mixture obtained in step b) is slowly cooled to a temperature of 30°C or below. In one of the specific embodiment reaction mixture temperature is lowered to 25 °C.
  • Step d) comprises adding a co-solvent to the reaction mixture
  • co-solvent is added at the same temperature.
  • Co-solvent may be selected from water, C 1 -C 4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, hexane, NMP or a mixture thereof, with the proviso that organic solvent used in step a) and the co-solvent used in this step are not the same.
  • Amount of co-solvet used may range from 15 to 50 times (v/w: mL/g) w.r.t. the amount of Crizotinib used as starting material.
  • Addition of the co-solvent to the reaction mixture shall be performed slowly over a time duration ranging from 10 mins to 1 hour. In one of the preferred embodiments the addition of 3.0 mL co-solvent water to the reaction mixture was done drop- wise over a time duration of 10 mins. With the addition of co-solvent turbidity starts to appear in the reaction mixture.
  • Step e) comprises isolating the amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5- [ 1 -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine.
  • the solvents are recovered up to 40 to 85% of the original reaction mass.
  • Recovery of the solvent may be performed under reduced pressure conditions by techniques known to the person skilled in the art. In one of the preferred embodiment recovery of the solvent may be performed by distillation under vacuum at a raised temperature of 35-55 °C.
  • reaction mass obtained is then cooled to a temperature below 20 °C. In one of the preferred embodiment cooling of the reaction mass is performed till 10-15 °C. The cooled reaction mass is subjected to stirring for time duration of
  • the reaction mass may optionally be filtered by employing any of the conventional process for filtration.
  • filtration was performed by using micron filter paper.
  • the solid mass obtained is given washing with a suitable solvent like chilled DM water etc. and then subjected to drying till a constant weight is acheived. Drying may be performed at a raised temperature of 45-75 °C, depending upon the choice of solvents initially used in the process.
  • Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed for time ranging from 2 to 20 hrs depending upon the physical attributes of the end product obtained i.e. amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-
  • Process of isolating amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine may further comprise processes but not limited to conventional processes including scrapping and if required filtering from slurry which may be carried out at room temperature for the suitable durations to retain the amorphous form characteristics.
  • the process related impurities that appear in the impurity profile of the (R)-3-[l-(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH ⁇ yrazol-4-yl]pyridin-2-amine may be substantially removed by the process of the present invention resulting in the formation of amorphous material of high purity.
  • the merit of the process according to the present invention resides in that - product isolated after drying is directly obtained as amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH ⁇ yrazol-4-yl]pyridin-2-amine. Said material is found devoid of any crystal lattice and is adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.
  • Amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH ⁇ yrazol-4-yl]pyridin-2-amine obtained according to the process of the present invention results in the final API purity by HPLC of more than 99 % w/w.
  • Amorphous (R)-3-[l -(2, 6-Dichloro-3-fiuorophenyl) ethoxy]-5-[l-(piperidin-4-yl)-lH- pyrazol-4-yl] pyridin-2-amine obtained by the process of the present invention has XRPD pattern similar to Fig- 1 (indicating a solid form that lacks the long-range order-a characteristic of crystals, and having no pattern or structure), FTIR spectrum similar to Fig-2, l H NMR spectrum similar to Fig-3, Mass spectrum similar to Fig-4 and TGA thermograph similar to Fig-5.
  • end product obtained by following the complete process of the present invention is substantially amorphous which has at least more than 90% amorphous nature.
  • Amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present invention is found to be non-hygroscopic, chemically and enantiomerically stable and posseses good dissolution properties.
  • amorphous Crizotinib of this invention may be a solvated or a non-solvated form. In a preferred embodiment, it has been observed by the inventors of the present application that the amorphous Crizotinib obtained by the present process is non-solvated and remains so on storage with loss on drying as measured by TGA up to not more than 2%.
  • amorphous (R)-3-[l-(2,6-Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine described herein may be characterized by X-ray powder diffraction pattern (XRPD).
  • the invention also relates to a composition containing amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, of which at least 95 % by total weight of (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine in the composition, is the amorphous form.
  • the composition may be substantially free of any other known forms of (R)-3-[l- (2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine.
  • the amorphous (R)-3-[l-(2,6-Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
  • premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, while retaining the amorphous nature of the premix.
  • Amorphous premix may be prepared by conventional process of dissolving in the organic solvent along with requisite amount of pharmaceutically acceptable excipients required in premix composition.
  • compositions include but are not limited to polymers like HPMC, MCC or PVP.
  • the solvent is removed by conventional processes like use of rotavapor or spray drying - to achieve the amorphous premix solid dispersion.
  • the present invention also includes a process for the preparation amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine (I)
  • the amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine remains well dispersed in the solid form, of which at least 95% by total weight of (R)-3-[l-(2,6-Dichloro-3-fiuoro phenyl)ethoxy]-5-[l- (piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine is the amorphous form.
  • amorphous solid dispersion comprising of polyvinylpyrrolidone and (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4- yl) -1H- pyrazol-4-yl] pyridine -2- amine (in weight ratio of 50:50) was found to be completely amorphous in nature with no crystalline peaks observed during their conventional stability studies-while packed and shelved under suitable conditions.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine according to the present application include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-ge latinized starch and the like; dis integrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate,
  • compositions / dosage forms of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine and its premix according to the present application may also comprise to include the pharmaceutically acceptable carriers used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Example-01 Process for preparation of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine
  • the solvent mixture from the reaction was recovered upto about 75% v/v of the total volume by distillation under vacuum at a temperature of 35 °C,.
  • the reaction mass was cooled to 25-30 °C and then further cooled to 15°C, where it was stirred for 2 h.
  • the isolated product was filtered and washed with 0.6 mL chilled DM water.
  • Example-02 Process for preparation of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine
  • Example-03 Process for preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine (Using Povidone)
  • Example-04 Process for preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine (Using Povidone and microcrystalline cellulose)

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Abstract

The present invention relates to a process for preparation of amorphous (R)-3-[1-(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine (I) or its premix. (I) The present invention also relates to the amorphous (R)-3-[1-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin-2-amine (I) having mass spectrum peak at about [M+] = 450.1, at least three IR peaks selected from 3470 cm -1, 3388 cm -1, 1117 cm -1, 1252 cm -1, or 740 cm -1 ± 2.0 cm -1 and less than 2% w/w of volatiles measured up to 170 °C by TGA. The invention further relates to pharmaceutical compositions comprising amorphous (R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]pyridin- 2-amine or its premix, having anti-cancer activity.

Description

AMORPHOUS (R) -3- [1 - (2, 6-DICHLORO-3-FLUOROPHENYL) METHOXY] -5- [1 - (PIPERIDIN-4- YL) -1 H-PYRAZOL-4-YL] PYRIDIN-2-AMINE
FIELD OF THE INVENTION
The present invention relates to a process for preparation of amorphous (R)-3-[l -(2,6- Dichloro-3-fluorophenyl) ]pyridin-2-amine (I).
Figure imgf000002_0001
The present invention also relates to the amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH^yrazol-4-yl]pyridin-2-amine (I) having mass spectrum peak at about [M+] = 450.1 , at least three IR peaks selected from 3470 cm"1, 3388 cm"1, 1 117 cm"1, 1252 cm"1, or 740 cm"1 ± 2.0 cm l and less than 2% w/w of volatiles measured up to 170 °C by TGA.
The present invention also relates to the process for the preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4- yl]pyridin-2-amine premix.
The invention further relates to pharmaceutical compositions comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin- 2-amine or its premix, having anti-cancer activity.
INTRODUCTION
Crizotinib is a kinase inhibitor indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive. It was approved by USFDA in August of 2011 and is marketed under the trade name XALKORI™. Crizotinib is also undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children. Crizotinib is chemically mentioned in the USFDA label as (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l -amine (I).
Figure imgf000003_0001
Crizotinib structure contains one chiral center. It is a non-hygroscopic, white to pale yellow powder which is insoluble in water, though being highly soluble in acidic pH. Crizotinib is defined in class IV (low solubility and low permeability) under the Biopharmaceutics Classification System (BCS).
Cui, et al. in US 7,230,098 B2 provided the first generic disclosure of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine (also known as Crizotinib). Further Cui, et al. in US 7,858,643 B2 provided the specific disclosure of Crizotinib and its pharmaceutically acceptable salts. This patent also describes the process for preparation of Crizotinib.
Then, Cui, et al. in US 8,217,057 B2 disclosed a crystalline form of the free base of (R)- 3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(l -piperidin-4-yl-lH-pyrazol-4-yl)-pyridin-2- ylamine, designated as Form 1. US 8,217,057 B2 mentions that the crystalline form of the free base of (R)-3-[l-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(l -piperidin-4-yl- lH-pyrazol-4-yl)- pyridin-2-ylamine is an anhydrous or a hydrate form.
Also, US 8,217,057 B2 mentions that Example 19 of U.S. patent application Ser. No. 11/212,331 i.e. US 7,858,643 B2 describes the preparation of Crizotinib (Compound I) which was found to be amorphous. However actually this disclosure appears to relate with compound other than Crizotinib. It is also disclosed in this patent that new polymorphic forms of Crizotinib base were required so as to have improved crystallinity, dissolution properties, and/or decreased hygroscopicity, while maintaining chemical and enantiomeric stability properties.
Careful observation of the disclosure of US 8,217,057 B2 and US 7,858,643 B2, shows that the Compound I of US 8,217,057 B2 is Crizotinib i.e (R)-3-[l-(2,6-dichloro-3-fluoro- phenyl)-ethoxy]-5-(l ^iperidin-4-yl-lH-pyrazol-4-yl)-pyridin-2-ylamine which is the active ingredient of the drug XALKORI™,
Figure imgf000004_0001
Compound I of US 8,217,057 B2 but the compound shown in Example 19 of US 7,858,643 B2 is not Crizotinib. Infact, the
Figure imgf000004_0002
Compound of Example 19 of US 7,858,643 B2 example 19 compound is 3-[(R)-l-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(l-piperidin-4- yl- lH-pyrazol-4-yl)-pyridin-2-ylamine acetate, which is not Crizotinib. Even the analytical data provided for this compound of Example 19 shows- a. LCMS mass value of 434 [M+], which is indicative of absence of Crizotinib; and b. lH NMR results with three extra protons at <5—1.80 ppm because of presence of acetate salt, indicating absence of Crizotinib which is a free base compound.
Hence, it is apparent that only authentic polymorphism details known till now, for (R)- 3-[l-(2,6-dichloro-3-fluoro^henyl)-ethoxy]-5-(l ^iperidin-4-yl-lH-pyrazol-4-yl)-pyridin-2- ylamine are about its existence in the form of crystalline compound only. Also, inventors of the present application observed during their attempt to achieve the amorphous form of Crizotinib, that no amorphous material could be isolated by the said process of US 7,858,643 B2. In the endeavor to achieve pure amorphous form, extensive work with large number of possible solvent systems and permutations resulted in certain specific aspects only to achieve the amorphous material in stable form. As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles, stable amorphous form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability.
Exploring new or stable forms which are amenable to scale up for pharmaceutically active / useful compounds such as (R)-3-[l -(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine may thus provide an opportunity to improve the drug performance characteristics of such products.
Hence, inventors of the present application report- a stable and usable form of (R)-3-[l- (2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine and processes for its preparation, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions. The present invention provides an amorphous form of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4- yl]pyridin-2-amine and process for preparation thereof. Amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present invention is non-hygroscopic, chemically and enantiomerically stable and has good dissolution properties.
SUMMARY OF INVENTION
Particular aspects of the present specification relate to the amorphous (R)-3-[l -(2,6- Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine and process for preparation thereof.
In one aspect according to the present invention, it provides a process for preparation of amorphous (R)-3-[l -(2, 6-Dichloro-3-fiuorophenyl) ethoxy]-5-[l-(piperidin-4-yl)- lH-pyrazol- 4-yl] pyridin-2-amine (I) having, XRPD pattern similar to Fig-1 , FTIR spectrum similar to Fig- 2, lH NMR spectrum similar to Fig-3, Mass spectrum similar to Fig-4 and TGA thermograph similar to Fig- 5,
Figure imgf000006_0001
comprising the steps of:
a) Providing a solution of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin- 4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent;
b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;
c) Cooling the reaction mixture to a temperature of 30°C or below;
d) Adding a co-solvent to the reaction mixture;
e) Isolating amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4- yl)-lH-pyrazol-4-yl]pyridin-2-amine.
In another aspect, the present invention provides an amorphous (R)-3-[l-(2,6-Dichloro- 3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine. Amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl)ethoxy]-5-[l -(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin- 2-amine of the present invention is characterized by any of the folio wing- a. Mass spectrum peak at about [M+] = 450.1 ;
b. FT-IR spectrum with at least three IR peaks selected from 3470 cm"1, 3388 cm"1, 1117 cm"1, 1252 cm"1, or 740 cm"1 ± 2.0 cm l ;
c. less than 2% w/w of volatiles measured up to 170 °C by TGA.
In another aspect, the present invention also relates to a process for preparation of amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine (I)
Figure imgf000006_0002
comprising the steps of: a) providing a solution of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin- 4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent;
b) heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;
c) adding excipient to the reaction mixture; and
d) isolating amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4- yl)-l H-pyrazol-4-yl]pyridin-2-amine premix.
In another aspect, the present invention also relates to a composition comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4- yl]pyridin-2-amine, of which at least 95% by total weight of (R)-3-[l-(2,6-Dichloro-3-fluoro phenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in the composition, is the amorphous form. Such composition is substantially free of any other known forms of (R)-3- [ 1 -(2,6 -Dichloro-3 -fluorophenyl)ethoxy] -5 - [ 1 -(piperidin-4-yl)- 1 H-pyrazol-4-yl]pyridin-2- amine.
In another aspect, the present application also relates to a pharmaceutical composition comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine or its premix of the present application and at least one or more pharmaceutically acceptable excipients.
Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
Fig. 2 is an example of FT-IR spectrum of (R)-3-[l -(2,6-Dichloro-3-fiuorophenyl)ethoxy]- 5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
Fig. 3 is an example of lH NMR spectrum of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
Fig. 4 is an example of mass spectrum of (R)-3-[l -(2,6-Dichloro-3-fiuorophenyl)ethoxy]- 5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine amorphous form. Fig. 5 is an example of TGA thermogram of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) emoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine amorphous form.
Fig. 6 is an example of X-ray powder diffraction ("XRPD") pattern of (R)-3-[l -(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine premix amorphous form as obtained according to example 3.
ABBREVIATIONS
Figure imgf000008_0001
DETAILED DESCRIPTION OF THE INVENTION
As set forth herein, embodiments of the present invention relate to the amorphous (R)- 3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -IH- pyrazol-4-yl] pyridine -2-amine and process for preparation thereof.
In one of the embodiment of the present application, it provides a process for preparation of amorphous (R)-3-[l -(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4- yl) - IH- pyrazol-4-yl] pyridine -2- amine, comprising the steps of- a) Providing a solution of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin- 4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent;
b) Heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used; c) Cooling the reaction mixture to a temperature of 30°C or below;
d) Adding a co-solvent to the reaction mixture;
e) Isolating amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4- yl)-lH-pyrazol-4-yl]pyridin-2-amine.
The individual steps of the process according to the present invention for preparing amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine are detailed separately herein below.
Step a) comprises providing a solution of (R)-3-[l -(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent;
(R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine or Crizotinib, from any source i.e. its crystalline form or any of its less stable form or impure form obtained by any of the processes known in the prior art may be utilized as the starting material for preparation of amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine, by the process of the present invention.
A synthetic process for the preparation of (R)-3-[l-(2, 6-Dichloro-3-fluorophenyl) ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine or Crizotinib base utilized in
Figure imgf000009_0001
Stage-ll Stage-Ill Amorphous form of
Crizotinib base Crizotinib base (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine (or Crizotinib base) is provided as a solution in an organic solvent wherein organic solvent may be selected from a water miscible organic solvent comprising of C1-C4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, NMP or a mixture thereof. C1-C4 alcohol may further be selected from methanol, ethanol, wo-propanol, «-butanol or tert- butanol.
The reaction solution is prepared at an ambient temperature of 25-30 °C. Depending upon the solubility, amount of organic solvent used to prepare the reaction solution may range from 2 to 25 times w/v (g/mL) as compared to the weight of Crizotinib used as the starting material.
Step b) comprises heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;
Reaction mixture prepared in step a) is heated to a temperature ranging between 40 °C and the boiling point of the organic solvent used, along with continuous stirring to provide a clear solution. In one particular embodiment of the present application, wherein methanol was used as a solvent, temperature employed for the current step was 50-55 °C. After the clear solution is obtained, the reaction mixture is maintained at the same raised temperature for a time duration of 20 mins to 1 hr.
Step c) comprises cooling the reaction mixture to a temperature of 30°C or below;
The clear reaction mixture obtained in step b) is slowly cooled to a temperature of 30°C or below. In one of the specific embodiment reaction mixture temperature is lowered to 25 °C.
Step d) comprises adding a co-solvent to the reaction mixture;
To the cooled reaction mixture obtained in step c) co-solvent is added at the same temperature. Co-solvent may be selected from water, C1-C4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, hexane, NMP or a mixture thereof, with the proviso that organic solvent used in step a) and the co-solvent used in this step are not the same. Amount of co-solvet used may range from 15 to 50 times (v/w: mL/g) w.r.t. the amount of Crizotinib used as starting material. Addition of the co-solvent to the reaction mixture shall be performed slowly over a time duration ranging from 10 mins to 1 hour. In one of the preferred embodiments the addition of 3.0 mL co-solvent water to the reaction mixture was done drop- wise over a time duration of 10 mins. With the addition of co-solvent turbidity starts to appear in the reaction mixture.
Step e) comprises isolating the amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5- [ 1 -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine.
From the reaction mixture obtained in step d) the solvents are recovered up to 40 to 85% of the original reaction mass. Recovery of the solvent may be performed under reduced pressure conditions by techniques known to the person skilled in the art. In one of the preferred embodiment recovery of the solvent may be performed by distillation under vacuum at a raised temperature of 35-55 °C.
After recovery of the solvents, the reaction mass obtained is then cooled to a temperature below 20 °C. In one of the preferred embodiment cooling of the reaction mass is performed till 10-15 °C. The cooled reaction mass is subjected to stirring for time duration of
1- 4 hrs depending upon the progress of the crystallization, while maintaining the reduced temperature conditions.
The reaction mass may optionally be filtered by employing any of the conventional process for filtration. In one particular embodiment of the current application, filtration was performed by using micron filter paper. The solid mass obtained is given washing with a suitable solvent like chilled DM water etc. and then subjected to drying till a constant weight is acheived. Drying may be performed at a raised temperature of 45-75 °C, depending upon the choice of solvents initially used in the process.
Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed for time ranging from 2 to 20 hrs depending upon the physical attributes of the end product obtained i.e. amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-
2- amine. Process of isolating amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine may further comprise processes but not limited to conventional processes including scrapping and if required filtering from slurry which may be carried out at room temperature for the suitable durations to retain the amorphous form characteristics.
The process related impurities that appear in the impurity profile of the (R)-3-[l-(2,6- Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH^yrazol-4-yl]pyridin-2-amine may be substantially removed by the process of the present invention resulting in the formation of amorphous material of high purity.
The merit of the process according to the present invention resides in that - product isolated after drying is directly obtained as amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH^yrazol-4-yl]pyridin-2-amine. Said material is found devoid of any crystal lattice and is adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics. Amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH^yrazol-4-yl]pyridin-2-amine obtained according to the process of the present invention results in the final API purity by HPLC of more than 99 % w/w.
Amorphous (R)-3-[l -(2, 6-Dichloro-3-fiuorophenyl) ethoxy]-5-[l-(piperidin-4-yl)-lH- pyrazol-4-yl] pyridin-2-amine obtained by the process of the present invention has XRPD pattern similar to Fig- 1 (indicating a solid form that lacks the long-range order-a characteristic of crystals, and having no pattern or structure), FTIR spectrum similar to Fig-2, lH NMR spectrum similar to Fig-3, Mass spectrum similar to Fig-4 and TGA thermograph similar to Fig-5.
In another embodiment of the present application, it provides amorphous (R)-3-[l -(2,6- Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine or Crizotinib (I):
Figure imgf000013_0001
The amorphous (R)-3-[l-(2,6-Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine produced by the inventors of the present application is characterized by any of the folio wing-
1. XRPD pattern similar to as shown in FIG. 1 ;
2. Mass spectrum peak at about [M+] = 450.1 ;
3. FT-IR spectrum with at least three IR peaks selected from 3470 cm"1, 3388 cm"1, 1117 cm"1, 1252 cm"1, or 740 cm"1 ± 2.0 cm" 1 ;
4. less than 2% w/w of volatiles measured up to 170 °C by TGA.
In one of the embodiment of the present application end product obtained by following the complete process of the present invention, is substantially amorphous which has at least more than 90% amorphous nature.
Amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present invention is found to be non-hygroscopic, chemically and enantiomerically stable and posseses good dissolution properties. According to another embodiment of the present specification amorphous Crizotinib of this invention, may be a solvated or a non-solvated form. In a preferred embodiment, it has been observed by the inventors of the present application that the amorphous Crizotinib obtained by the present process is non-solvated and remains so on storage with loss on drying as measured by TGA up to not more than 2%.
The amorphous (R)-3-[l-(2,6-Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine described herein may be characterized by X-ray powder diffraction pattern (XRPD). The samples of amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. Illustrative examples of analytical data for the amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine obtained in the examples are set forth in the Figs. 1-5.
In a further embodiment according to this specification, the invention also relates to a composition containing amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, of which at least 95 % by total weight of (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine in the composition, is the amorphous form. In yet another embodiment of the invention, the composition may be substantially free of any other known forms of (R)-3-[l- (2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine.
The amorphous (R)-3-[l-(2,6-Dichloro-3 -fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, while retaining the amorphous nature of the premix. Amorphous premix may be prepared by conventional process of dissolving in the organic solvent along with requisite amount of pharmaceutically acceptable excipients required in premix composition. Pharmaceutically acceptable excipients of the said premix composition include but are not limited to polymers like HPMC, MCC or PVP. The solvent is removed by conventional processes like use of rotavapor or spray drying - to achieve the amorphous premix solid dispersion. In another embodiment the present invention also includes a process for the preparation amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine (I)
Figure imgf000015_0001
comprising the steps of providing a solution of (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl)ethoxy]- 5-[l-(piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent selected from a water miscible organic solvent comprising of THF, C1-C4 alcohol MTBE, DMF, DMSO, DMAc, NMP or a mixture thereof; heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used; Adding excipient to the reaction mixture; wherein excipients of the said premix composition are selected from HPMC, MCC or PVP, carboxymethyl cellulose (CMC) and mixtures thereof and; isolating amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)-lH-pyrazol-4- yl]pyridin-2-amine.
The amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine remains well dispersed in the solid form, of which at least 95% by total weight of (R)-3-[l-(2,6-Dichloro-3-fiuoro phenyl)ethoxy]-5-[l- (piperidin-4-yl)-lH-pyrazol-4-yl]pyridin-2-amine is the amorphous form.
In a particular embodiment, amorphous solid dispersion comprising of polyvinylpyrrolidone and (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4- yl) -1H- pyrazol-4-yl] pyridine -2- amine (in weight ratio of 50:50) was found to be completely amorphous in nature with no crystalline peaks observed during their conventional stability studies-while packed and shelved under suitable conditions.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fiuorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine according to the present application include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-ge latinized starch and the like; dis integrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the formulations / dosage forms of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine and its premix according to the present application may also comprise to include the pharmaceutically acceptable carriers used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
EXAMPLES
Example-01 : Process for preparation of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine
Methanol (0.45 ml) was charged in a 25 ml round bottom single neck flask at 25-30°C and 0.15 g Crizotinib base (also known as (R)-3-[l -(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine) was added to the reaction mixture. Temperature of the reaction mixture was then raised to -55 °C and stirring was performed till the solution became clear. After obtaining the clear solution reaction mixture was cooled to 30°C and 3.0 mL DM water was added to it drop wise over a period of 10 mins. The solvent mixture from the reaction was recovered upto about 75% v/v of the total volume by distillation under vacuum at a temperature of 35 °C,. The reaction mass was cooled to 25-30 °C and then further cooled to 15°C, where it was stirred for 2 h. The isolated product was filtered and washed with 0.6 mL chilled DM water. The product obtained was dried at ~55°C for 12 h till constant weight was achieved to obtain 0.05 g of amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l - (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, having XRPD pattern similar to Fig- 1 , FTIR spectrum similar to Fig-2 and TGA thermogram similar to Fig- 5.
*H NMR (400 MHz, DMSO-d6) S 7.91-7.98 (s, 1H), 7.75 (s, 1H), 7.55-7.59 (m, 1H), 7.52 (s, 1H), 7.42-7.46 (m, 1H), 6.89-6.90 (m, 1H), 6.06-6.1 1 (q, 1H), 5.64 (s, 2H), 4.11 -4.16 (m, 1H), 2.95-3.09 (m, 2H), 2.55-2.67 (m, 2H), 1.82-2.12 (m, 3H), 1.79 (d, 3H), 1.69-1.76 (m, 1H) LCMS (m/z): 450.1 [M+]
Example-02: Process for preparation of amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine
THF (3.0 ml) was charged in a 25 ml round bottom single neck flask at 25-30°C and 0.15 g Crizotinib base was added to the reaction mixture. Temperature of the reaction mixture was then raised to ~50°C and stirring was performed till the solution becomes clear. After obtaining the clear solution reaction mixture was cooled to 25°C and 6.0 mL DM water was added drop wise over a period of 15 mins. The solvent mixture from the reaction was recovered upto 80% v/v (with respect to the total volume) by distillation under vacuum at a temperature of 40°C, . Then the reaction mass was initially cooled to 25 °C and then to 10 °C, where it was stirred for 2.5 h. The isolated product was filtered and washed with 0.3 mL chilled DM water. The product obtained was dried at -50 °C for 14 h till constant weight was achieved to obtain 0.065 g of amorphous (R)-3-[l -(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, having XRPD pattern similar to Fig-1 , FTIR spectrum similar to Fig-2 and TGA thermogram similar to Fig-6. Example-03: Process for preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine (Using Povidone)
Methanol (6 ml) was charged in a 25 ml round bottom single neck flask at 25-30°C and 0.5 g Crizotinib base was added to the reaction mixture. Temperature of the reaction mixture was then raised to -55 °C and stirring was performed till the solution became clear. After obtaining the clear solution reaction mixture, Povidone (0.5gm) was added to it at 50-55°C. The solvent mixture was stirred for 15 min at at 50-55°C. Distilled off Methanol under vacuum to get the solid. The solid obtained was dried at -50 °C till constant weight was achieved to obtain 0.8 g of amorphous premix of (R)-3-[l -(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine, having XRPD pattern similar to Fig-6.
Example-04: Process for preparation of amorphous premix of (R)-3-[l-(2,6-Dichloro-3- fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) -1H- pyrazol-4-yl] pyridine -2- amine (Using Povidone and microcrystalline cellulose)
Methanol (6 ml) was charged in a 25 ml round bottom single neck flask at 25-30°C and 0.5 g Crizotinib base was added to the reaction mixture. Temperature of the reaction mixture was then raised to -55 °C and stirring was performed till the solution became clear. After obtaining the clear solution reaction mixture, Povidone (0.5gm) was added to it at 50-55°C. The solvent mixture was stirred for 15 min at at 50-55°C. After obtaining the clear solution reaction mixture, Micro crystalline cellulose (0.5gm) was added to it at 50-55 °C. The solvent mixture was stirred for 15 min at at 50-55 °C. Distilled off Methanol under vacuum to get the solid. The solid obtained was dried at -50 °C till constant weight was achieved to obtain 1.1 g of amorphous premix of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl) ethoxy] -5-[l- (piperidin-4-yl) - 1H- pyrazol-4-yl] pyridine -2- amine.
While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims

Claims:
1) A process for preparation of amorphous (R)-3-[l -(2, 6-Dichloro-3-fluorophenyl) ethoxy]-5- [l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine (I)
Figure imgf000019_0001
comprising the steps of:
a) providing a solution of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l - (piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine in an organic solvent;
b) heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;
c) cooling the reaction mixture to a temperature of 30°C or below;
d) adding a co-solvent to the reaction mixture; and
e) isolating amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l -(piperidin- 4-yl)-lH-pyrazol-4-yl]pyridin-2-amine.
2) A process for preparation of amorphous (R)-3-[l -(2, 6-Dichloro-3-fluorophenyl) ethoxy]-5- [l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine, according to claim- 1 , wherein organic solvent is selected from a water miscible organic solvent comprising of C1-C4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, NMP or a mixture thereof.
3) A process for preparation of amorphous (R)-3-[l -(2, 6-Dichloro-3-fluorophenyl) ethoxy]-5- [l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine, according to claim-2, wherein C1-C4 alcohol is selected from methanol, ethanol, «σ-propanol, «-butanol or teri-butanol.
4) A process for preparation of amorphous (R)-3-[l -(2, 6-Dichloro-3-fluorophenyl) ethoxy]-5- [l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine, according to claim-1 , wherein co- solvent is selected from water, C1-C4 alcohol, THF, acetone, MTBE, DMF, DMSO, DMAc, hexane, NMP or a mixture thereof, with the proviso that organic solvent used in step a) and the co-solvent used in step d) are not the same.
A process for preparation of amorphous (R)-3-[l -(2, 6-Dichloro-3-fluorophenyl) ethoxy]-5- [l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine, according to claim- 1 , wherein step e) further comprises the steps of- a) Recovering the solvents from the reaction mixture upto 40 to 85% v/v of the total reaction mass;
b) Cooling the obtained reaction mass to a temperature below 20 °C;
c) Optionally filtering the cooled reaction mass;
d) Washing the solid with a solvent;
e) Drying the product, to obtain amorphous (R)-3-[l-(2,6-Dichloro-3- fluorophenyl)ethoxy]-5-[l-(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine.
Amorphous (R)-3-[ 1 -(2,6-Dichloro-3-fluorophenyl)ethoxy] -5 -[1 -(piperidin-4-yl)- 1H- pyrazol-4-yl]pyridin-2-amine (I) having up to less than 2% w/w of volatiles measured up to 170 °C by TGA and characterized by IR spectrum having at least three IR peaks selected from 3470 cm"1, 3388 cm"1, 11 17 cm"1, 1252 cm"1, or 740 cm"1 ± 2.0 cm"1 and presence of mass spectrum peak at about [M+] = 450.1.
A process for preparation of amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine (I)
Figure imgf000020_0001
comprising the steps of:
a) providing a solution of (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin- 4-yl)-l H-pyrazol-4-yl]pyridin-2-amine in an organic solvent; b) heating the reaction mixture to a temperature ranging between 40 °C and the boiling point of the organic solvent used;
c) adding excipient to the reaction mixture;
d) isolating amorphous (R)-3-[l-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[l-(piperidin-4- yl)-l H-pyrazol-4-yl]pyridin-2-amine premix.
8) A process for preparation of amorphous (R)-3-[l -(2, 6-Dichloro-3-fluorophenyl) ethoxy]-5- [l-(piperidin-4-yl)-lH-pyrazol-4-yl] pyridin-2-amine premix, according to claim-8, wherein organic solvent is/are selected from a water miscible organic solvent comprising of THF, Ci-C4 alcohol, MTBE, DMF, DMSO, DMAc, NMP or a mixture thereof.
9) A process for preparation of amorphous premix of (R)-3-[l-(2, 6-Dichloro-3 -fluorophenyl) ethoxy]-5-[l-(piperidin-4-yl)- lH-pyrazol-4-yl] pyridin-2-amine, according to claim-8, wherein excipients of the said premix composition are selected from HPMC, MCC or PVP.
10) A pharmaceutical composition comprising amorphous (R)-3-[l-(2,6-Dichloro-3-fluoro phenyl)ethoxy]-5-[l -(piperidin-4-yl)- lH-pyrazol-4-yl]pyridin-2-amine or its premix according to any of the preceding claims, and at least one or more pharmaceutically acceptable excipients.
PCT/IB2014/062361 2013-06-18 2014-06-18 Amorphous (r) -3- [1- (2, 6-dichloro-3-fluorophenyl) methoxy] -5- [1- (piperidin-4- yl) -1h-pyrazol-4-yl] pyridin-2-amine Ceased WO2014203177A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104730028A (en) * 2015-03-12 2015-06-24 浙江华峰氨纶股份有限公司 Near-infrared spectral detection method for residual content of solvent in polyurethane elastic fiber filaments
CN105294657A (en) * 2015-10-30 2016-02-03 西华大学 Preparation method of crizotinib

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WO2006021884A2 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
WO2006021881A2 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
EP2620140A1 (en) * 2012-01-26 2013-07-31 ratiopharm GmbH Crizotinib containing compositions
WO2013181251A1 (en) * 2012-05-29 2013-12-05 Ratiopharm Gmbh Crizotinib hydrochloride salt in crystalline

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WO2006021884A2 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
WO2006021881A2 (en) * 2004-08-26 2006-03-02 Pfizer Inc. Pyrazole-substituted aminoheteroaryl compounds as protein kinase inhibitors
EP2620140A1 (en) * 2012-01-26 2013-07-31 ratiopharm GmbH Crizotinib containing compositions
WO2013181251A1 (en) * 2012-05-29 2013-12-05 Ratiopharm Gmbh Crizotinib hydrochloride salt in crystalline

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104730028A (en) * 2015-03-12 2015-06-24 浙江华峰氨纶股份有限公司 Near-infrared spectral detection method for residual content of solvent in polyurethane elastic fiber filaments
CN105294657A (en) * 2015-10-30 2016-02-03 西华大学 Preparation method of crizotinib

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