WO2014167578A2 - Novel polymorph of isobutyric acid 2-((r)-3-diisopropyl amino-1-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride and process for preparation thereof - Google Patents

Novel polymorph of isobutyric acid 2-((r)-3-diisopropyl amino-1-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride and process for preparation thereof Download PDF

Info

Publication number
WO2014167578A2
WO2014167578A2 PCT/IN2014/000191 IN2014000191W WO2014167578A2 WO 2014167578 A2 WO2014167578 A2 WO 2014167578A2 IN 2014000191 W IN2014000191 W IN 2014000191W WO 2014167578 A2 WO2014167578 A2 WO 2014167578A2
Authority
WO
WIPO (PCT)
Prior art keywords
phenylpropyl
hydroxymethyl
phenyl ester
isobutyric acid
diisopropylamino
Prior art date
Application number
PCT/IN2014/000191
Other languages
French (fr)
Other versions
WO2014167578A3 (en
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Peri Seetha Rama Sarma
Original Assignee
Msn Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Msn Laboratories Limited filed Critical Msn Laboratories Limited
Publication of WO2014167578A2 publication Critical patent/WO2014167578A2/en
Publication of WO2014167578A3 publication Critical patent/WO2014167578A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton

Definitions

  • the present invention provides a novel polymorph of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride represented by the following structural formula- la and process for its preparation.
  • Isobutyric acid 2-((R)-3-diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester commonly known as Fesoterodine is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.
  • U.S. Patent No. 6,713,464 Bl discloses a variety of 3,3-diphenylpropylamine derivatives, processes for their preparation, pharmaceutical compositions comprising their derivatives and methods of use thereof. These compounds are anti-muscarinic agents with superior pharmacokinetic properties compared to existing drugs such as oxybutynin and tolterodine which are useful in the treatment of urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions.
  • isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.
  • the said '650' patent discloses the hydrochloride salt of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester in hydrate form and process for its preparation.
  • the said process involves the treatment of isobutyric acid 2-((R)- 3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester with isobutyryl chloride in dichloromethane results in amorphous solid foam of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride salt which on further crystallization from a mixture of acetone/water/diethyl ether by treatment with ultrasound provides crystalline isobutyric acid 2-((R)-3-diisopropylamino- 1 -phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in hydrate form having melting point 97.1°C and 97.0% of purity by HPLC.
  • the said patent did not provide the solid state characteristics of the obtained solid.
  • the product is initially obtained as an amorphous solid, which is further crystallized from the above said solvent mixture by treatment with ultrasound. Ultrasound technique is not advisable on industrial scale. Further the disclosed process is a lengthy process and involves the usage of number of solvents. Further in this process, isobutyryl chloride is used as HC1 source, which is not simple when compared to the conventional HC1 sources such as dry HC1 or other commercial HC1 sources like isopropyl alcohol-HCl, ethyl acetate-HCl etc.
  • Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound.
  • the difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum.
  • One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) which have been used to distinguish polymorphic forms.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the present inventors surprisingly found the novel anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, which is having advantageous properties when compared to the prior known hydrate form and amorphous form.
  • the first aspect of the present invention is to provide anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, herein after designated as crystalline form-M.
  • the second aspect of the present invention is to provide a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride.
  • the third aspect of the present invention is to provide another process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l -phenyl propyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
  • the fourth aspect of the present invention is to provide a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
  • Figure-1 Illustrates the PXRD pattern of crystalline form-M of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la.
  • Figure-2 Illustrates the DSC thermogram of crystalline form-M of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la.
  • the present invention involves the usage of simple and commercially available HC1 sources for the preparation of HC1 salt instead of isobutyryl chloride.
  • the present invention provides anhydrous Fesoterodine HC1, which is highly stable.
  • the present invention provides anhydrous Fesoterodine HC1 in highly pure form.
  • the anhydrous Fesoterodine HC1 of the present invention is non-hygroscopic in nature which is highly advantageous for formulators.
  • Anhydrous Fesoterodine HC1 of the present invention is more suitable for pharmaceutical compositions.
  • hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, toluene, xylene and the like
  • ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like
  • esteer solvents such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like
  • polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methyl pyrrolidone and the like
  • nitrile solvents such as
  • suitable base refers to "alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert.butoxide, lithium tertbutoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; alkali metal salts of acetic acid such as sodium acetate, potassium acetate and the like;
  • the first aspect of the present invention provides anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, which is herein after designated as crystalline form-M.
  • the said crystalline form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at 9.3, 10.6, 11.7, 16.7, 16.9, 17.5, 18.7, 19.9, 23.2, 24.6, 24.9, 25.6, 25.8, 28.0, 28.7, 30.4 and 32.1 ⁇ 0.2 degrees of 2-theta.
  • the crystalline form-M of the present invention is further characterized by its X-Ray powder diffraction pattern having additional peaks at 12.3, 14.2, 14.8, 18.1, 21.7, 26.9, 28.3 and 29.6 ⁇ 0.2 degrees of 2-theta.
  • the crystalline form-M is further characterized by its PXRD pattern as illustrated in figure- 1 and its differential scanning calorimetric (DSC) thermogram having an endotherm at 147.03°C as illustrated in figure-2.
  • DSC differential scanning calorimetric
  • the crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la is further characterized by its IR absorption spectrum having absorption bands at 3327, 2975, 2938, 2610, 1751, 1601, 1497, 1226, 1174, 866 and 701 cm “1 .
  • X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
  • intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
  • persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
  • the skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure.
  • a measurement error of a diffraction angle in an X-ray powder diffraction pattern is typically ⁇ 0.2° of 2-theta.
  • melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting the DSC data. As a skilled person will realize, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point. Therefore, the melting points disclosed herein may vary by ⁇ 5°C from the values quoted herein.
  • the anhydrous crystalline form-M of isobutyric acid 2-((R)-3-diisopropylarriino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride obtained in the present invention is highly stable and non-hygroscopic in nature.
  • the non-hygroscopic nature of the compound is determined by the method described in European pharmacopeia.
  • the non-hygroscopic nature of crystalline form-M obtained by the process of the present invention is confirmed by the fact that there is no substantial change in the water content even after the compound is placed in a desiccator containing aqueous ammonium chloride solution for a period of 24 hours at 80 ⁇ 2% relative humidity (RH).
  • the water content of crystalline form-M produced according to the present invention is increased by 0.02% in 24 hours, which confirms the non-hygroscopic nature of the compound.
  • the said characteristic nature is always an advantageous property for formulations.
  • the crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride salt of the present invention can be utilized in the preparation of pharmaceutical compositions useful for the treatment of overactive bladder syndrome.
  • the second aspect of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- la, which comprises of: a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester acetyl mandelate salt with a suitable base in a suitable solvent or mixture of solvents,
  • the suitable solvent used in step-a) is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents or mixtures thereof;
  • the suitable base used is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates; and the reaction in step-a) is carried out at a temperature of 0°C to reflux temperature of the solvent used, preferably at 0-5°C;
  • the suitable solvent used in step-d) and step-g) is selected from ester solvents, ketone solvents, ether solvents, alcohol solvents, nitrile solvents or mixtures thereof;
  • the suitable HCl source is selected from dry HC1 gas, methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethereal HCl, ethyl acetate-HCl, acetyl chloride, tri(Ci- C 6 alkyl)silyl chloride, NH 4 CI and the like, wherein acetyl chloride and tri(Ci-C6 alkyl)silyl chloride are used preferably in combination with alcohol solvents.
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
  • the other embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
  • the third aspect of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
  • the suitable solvent used in step-a) and step-d) is selected from ester solvents, ketone solvents, ether solvents, alcohol solvents, nitrile solvents or mixtures thereof;
  • step-b) the suitable temperature ranges from -10°C to 20°C, preferably 0-5°C;
  • step-c) the suitable HC1 source is same as defined for step-f) of the second aspect of the present invention.
  • a preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
  • the other embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- 1 a, comprising of:
  • the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester acetyl mandelate salt and isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester used in the present invention can be prepared by using any of the prior known methods or they can be prepared by the processes disclosed in our earlier PCT application WO2012098560 A2.
  • the fourth aspect of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylan ino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- 1 a, comprising of; a) Dissolving isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in a suitable solvent or mixture of solvents at a suitable temperature,
  • the suitable solvent is selected from ketone solvents, alcohol solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, nitrile solvents or mixtures thereof; and the suitable temperature ranges between 40°C to reflux temperature of the solvent used; and
  • step-b) the suitable temperature ranges from -15°C to 30°C.
  • a preferred embodiment of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride, comprising of;
  • the other preferred embodiment of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride, comprising of;
  • step-a) of the fourth aspect can be synthesized by the processes disclosed in the second and third aspects of the present invention. The formation of the following impurities has been observed in the synthesis of
  • the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride compound of formula- la obtained by the process of the present invention is highly pure compound, which is having purity of greater than 98%, preferably greater than 99%, more preferably greater than 99.5%, most preferably greater than 99.9% by HPLC.
  • Apparatus A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Column: Inert sustain CI 8, 250x4.6 mm, 5um or equivalent; Flow rate: 1.2 mL/min; Wavelength: 220 nm; Column temperature: 45°C; Auto sampler temperature: 5°C; Injection volume: 20 Run time: 55 min; Elution: gradient; Buffer: 3 mL of H 3 P0 4 (85%) and 1.0 gm of 1 -octane sulfonic acid sodium salt anhydrous in 1000 mL of milli Q water and adjust its pH to 7.2 with dil.KOH and filtered the solution through 0.22 ⁇ Nylon membrane paper and sonicate to degas it; Mobile phase-A: Buffer: acetonitrile (60:40 v/v); Mobile phase-B: Acetonitrile: water (90: 10, v/v); Diluent: Mobile phase-A.
  • Apparatus A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Column: Chiral pack 3-IC 250x4.6 mm, 3 ⁇ or equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: 25°C; Auto sampler temperature: 5°C; Injection volume: 20 ⁇ ; Run time: 30 min; Elution: Isocratic; Diluent: n-hexane; Mobile phase: n-hexane: isopropyl alcohol: diethylamine (95:05:0.1) v/v.
  • the PXRD analysis of the crystalline compound of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.
  • DSC Differential scanning calorimetric
  • Fesoterodine HC1 having an average particle size in the range of 5 to 200 ⁇ , preferably 10 to 100 ⁇ , more preferably 20 to 75 ⁇ .
  • the present invention provides Fesoterodine HC1 having particle size distribution of D(0.9) less than 200 ⁇ .
  • the present invention provides Fesoterodine HC1 having particle size distribution of D(0.9) less than 100 ⁇ , preferably less than 50 ⁇ .
  • Fesoterodine HC1 obtained by the process of the present invention can further be micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product. The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
  • Example-1 Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la)
  • Ethyl acetate 600 ml was added to the obtained compound at 25-30°C and cooled the reaction mixture to 0-5°C. Dry HCl gas was passed into the reaction mixture at 0-5°C until the pH of the reaction mixture reached to 2.0 and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
  • Example-2 Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la)
  • Example-3 Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyi)phenyl ester hydrochloride (Formula-la)
  • Example-4 Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymetfayl)phenyl ester hydrochloride (Formula-la) Ethyl acetate (1000 ml) was added to isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester (100 gm) at 25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C.
  • Acetone 250 ml was added to isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (50 gm) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the pure title compound.
  • D(0.1) is 5.74 ⁇ ; D(0.5) is 24.16 ⁇ ; D(0.9) is 54.67 ⁇ , D(4,3) is 27.67 ⁇ .
  • Example-6 Purification of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)- 4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la)
  • Diol impurity 0.02%
  • Propionate impurity 0.02%
  • Toluoyl hydroxy impurity 0.01%
  • Double bond impurity Not detected
  • Benzyloxy impurity Not detected
  • S-isomer impurity Not detected.
  • D(0.1) is 10.1 ⁇ ; D(0.5) is 48.98 ⁇ ; D(0.9) is 98.43 ⁇ , D(4,3) is 52.67 ⁇ .
  • D(0.1) is 3.05 ⁇
  • D(0.5) is 8.68 ⁇
  • D(0.9) is 27.21 ⁇
  • D(4,3) is 12.74 ⁇ .

Abstract

The present invention relates to a novel polymorph of isobutyric acid 2-((R)-3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride represented by the following structural formula-1a and process for its preparation.

Description

Novel polymorph of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hvdroxymethyl)phenyl ester hydrochloride and process for preparation thereof Related Application:
This application claims the benefit of priority of our Indian patent application number 1364/CHE/2013 filed on 27th March 2013 which is incorporated herein by reference.
Field of the invention:
The present invention provides a novel polymorph of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride represented by the following structural formula- la and process for its preparation.
Figure imgf000002_0001
Formula- la
Background of the invention:
Isobutyric acid 2-((R)-3-diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester, commonly known as Fesoterodine is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.
U.S. Patent No. 6,713,464 Bl discloses a variety of 3,3-diphenylpropylamine derivatives, processes for their preparation, pharmaceutical compositions comprising their derivatives and methods of use thereof. These compounds are anti-muscarinic agents with superior pharmacokinetic properties compared to existing drugs such as oxybutynin and tolterodine which are useful in the treatment of urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions. Among them, isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester is a new, potent and competitive muscarinic antagonist and useful in the potential treatment of urinary incontinence.
Pharmaceutically acceptable salts of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester and processes for their preparation is specifically disclosed in US 6,858,650 Bl (herein after referred as '650' patent).
The said '650' patent discloses the hydrochloride salt of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester in hydrate form and process for its preparation. The said process involves the treatment of isobutyric acid 2-((R)- 3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester with isobutyryl chloride in dichloromethane results in amorphous solid foam of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride salt which on further crystallization from a mixture of acetone/water/diethyl ether by treatment with ultrasound provides crystalline isobutyric acid 2-((R)-3-diisopropylamino- 1 -phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in hydrate form having melting point 97.1°C and 97.0% of purity by HPLC. The said patent did not provide the solid state characteristics of the obtained solid. In the said process the product is initially obtained as an amorphous solid, which is further crystallized from the above said solvent mixture by treatment with ultrasound. Ultrasound technique is not advisable on industrial scale. Further the disclosed process is a lengthy process and involves the usage of number of solvents. Further in this process, isobutyryl chloride is used as HC1 source, which is not simple when compared to the conventional HC1 sources such as dry HC1 or other commercial HC1 sources like isopropyl alcohol-HCl, ethyl acetate-HCl etc.
Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid. Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) which have been used to distinguish polymorphic forms.
The discovery of new polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.
The present inventors surprisingly found the novel anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, which is having advantageous properties when compared to the prior known hydrate form and amorphous form.
Brief description of the invention:
The first aspect of the present invention is to provide anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, herein after designated as crystalline form-M.
The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride.
The third aspect of the present invention is to provide another process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l -phenyl propyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
The fourth aspect of the present invention is to provide a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride. Brief description of the drawings:
Figure-1: Illustrates the PXRD pattern of crystalline form-M of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la.
Figure-2: Illustrates the DSC thermogram of crystalline form-M of isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la.
Advantages of the present invention:
• The present invention involves the usage of simple and commercially available HC1 sources for the preparation of HC1 salt instead of isobutyryl chloride.
• Direct formation of crystalline Fesoterodine HC1 without involving the formation of amorphous compound.
• The present invention provides anhydrous Fesoterodine HC1, which is highly stable.
• The present invention provides anhydrous Fesoterodine HC1 in highly pure form.
• The anhydrous Fesoterodine HC1 of the present invention is non-hygroscopic in nature which is highly advantageous for formulators.
• The present invention involves lesser number of steps.
• Avoids the usage of ultrasound technique (not suggestible on industrial scale) for crystallization.
• Anhydrous Fesoterodine HC1 of the present invention is more suitable for pharmaceutical compositions.
Detailed description of the invention:
As used herein the present invention the term "suitable solvent" refers to
"hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet ether, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methyl pyrrolidone and the like; "nitrile solvents" such as acetonitnle, propionitnle, isobutyronitrile and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; acetic acid or mixtures thereof.
As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert.butoxide, lithium tertbutoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; alkali metal salts of acetic acid such as sodium acetate, potassium acetate and the like; "organic bases" like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO) and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.
The first aspect of the present invention provides anhydrous crystalline form of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, which is herein after designated as crystalline form-M. The said crystalline form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at 9.3, 10.6, 11.7, 16.7, 16.9, 17.5, 18.7, 19.9, 23.2, 24.6, 24.9, 25.6, 25.8, 28.0, 28.7, 30.4 and 32.1 ± 0.2 degrees of 2-theta. The crystalline form-M of the present invention is further characterized by its X-Ray powder diffraction pattern having additional peaks at 12.3, 14.2, 14.8, 18.1, 21.7, 26.9, 28.3 and 29.6 ± 0.2 degrees of 2-theta.
The crystalline form-M is further characterized by its PXRD pattern as illustrated in figure- 1 and its differential scanning calorimetric (DSC) thermogram having an endotherm at 147.03°C as illustrated in figure-2.
The crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la is further characterized by its IR absorption spectrum having absorption bands at 3327, 2975, 2938, 2610, 1751, 1601, 1497, 1226, 1174, 866 and 701 cm"1.
It is known in the art that X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure.
Generally, a measurement error of a diffraction angle in an X-ray powder diffraction pattern is typically ± 0.2° of 2-theta.
A person skilled in the art will also appreciate that slight variations in the melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting the DSC data. As a skilled person will realize, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point. Therefore, the melting points disclosed herein may vary by ± 5°C from the values quoted herein.
The anhydrous crystalline form-M of isobutyric acid 2-((R)-3-diisopropylarriino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride obtained in the present invention is highly stable and non-hygroscopic in nature. The non-hygroscopic nature of the compound is determined by the method described in European pharmacopeia.
The non-hygroscopic nature of crystalline form-M obtained by the process of the present invention is confirmed by the fact that there is no substantial change in the water content even after the compound is placed in a desiccator containing aqueous ammonium chloride solution for a period of 24 hours at 80±2% relative humidity (RH). The water content of crystalline form-M produced according to the present invention is increased by 0.02% in 24 hours, which confirms the non-hygroscopic nature of the compound. The said characteristic nature is always an advantageous property for formulations.
The crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride salt of the present invention can be utilized in the preparation of pharmaceutical compositions useful for the treatment of overactive bladder syndrome.
The second aspect of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- la, which comprises of: a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester acetyl mandelate salt with a suitable base in a suitable solvent or mixture of solvents,
b) separating the organic and aqueous layers,
c) distilling off the solvent completely from the organic layer,
d) adding a suitable solvent to the obtained compound,
e) cooling the reaction mixture, f) treating the reaction mixture with a suitable HC1 source,
g) filtering the precipitated solid and washing with a suitable solvent to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester hydrochloride.
The suitable solvent used in step-a) is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents or mixtures thereof; the suitable base used is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates; and the reaction in step-a) is carried out at a temperature of 0°C to reflux temperature of the solvent used, preferably at 0-5°C;
The suitable solvent used in step-d) and step-g) is selected from ester solvents, ketone solvents, ether solvents, alcohol solvents, nitrile solvents or mixtures thereof;
In step-f) the suitable HCl source is selected from dry HC1 gas, methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethereal HCl, ethyl acetate-HCl, acetyl chloride, tri(Ci- C6 alkyl)silyl chloride, NH4CI and the like, wherein acetyl chloride and tri(Ci-C6 alkyl)silyl chloride are used preferably in combination with alcohol solvents.
A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester acetyl mandelate salt with aqueous sodium carbonate solution in a mixture of dichloromethane and water,
b) separating the organic and aqueous layers,
c) distilling off the solvent completely from organic layer,
d) adding ethyl acetate to the obtained compound,
e) cooling the reaction mixture to 0-5°C,
f) passing the dry HCl gas into the reaction mixture,
g) filtering the precipitated solid and washing with ethyl acetate to get Crystalline form-M of compound of formula- la. The other embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydro ymethyl) phenyl ester acetyl mandelate salt with aqueous sodium carbonate solution in a mixture of dichloromethane and water,
b) separating the aqueous and organic layers,
c) distilling off the solvent completely from organic layer,
d) adding ethyl acetate to the obtained compound,
e) cooling the reaction mixture to 0-5°C,
f) treating the reaction mixture with ethyl acetate-HCl,
g) filtering the precipitated solid and washing with ethyl acetate to get crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
The third aspect of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester in a suitable solvent,
b) cooling the reaction mixture to a suitable temperature,
c) treating the reaction mixture with a suitable HC1 source,
d) filtering the precipitated solid and washing with a suitable solvent to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester hydrochloride.
Wherein, the suitable solvent used in step-a) and step-d) is selected from ester solvents, ketone solvents, ether solvents, alcohol solvents, nitrile solvents or mixtures thereof;
In step-b) the suitable temperature ranges from -10°C to 20°C, preferably 0-5°C;
In step-c) the suitable HC1 source is same as defined for step-f) of the second aspect of the present invention. A preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester in ethyl acetate,
b) cooling the reaction mixture to 0-5°C,
c) passing the dry HC1 gas into the reaction mixture,
d) filtering the precipitated solid and washing with ethyl acetate to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-
(hydroxymethyl)phenyl ester hydrochloride.
The other embodiment of the present invention provides a process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride compound of formula- 1 a, comprising of:
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester in ethyl acetate,
b) cooling the reaction mixture to 0-5°C,
c) treating the reaction mixture with ethyl acetate-HCl,
d) filtering the precipitated solid and washing with ethyl acetate to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride.
The isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester acetyl mandelate salt and isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester used in the present invention can be prepared by using any of the prior known methods or they can be prepared by the processes disclosed in our earlier PCT application WO2012098560 A2. The fourth aspect of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylan ino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- 1 a, comprising of; a) Dissolving isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in a suitable solvent or mixture of solvents at a suitable temperature,
b) cooling the reaction mixture to a suitable temperature,
c) filtering the precipitated solid to get pure isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
Wherein, in step-a) the suitable solvent is selected from ketone solvents, alcohol solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, nitrile solvents or mixtures thereof; and the suitable temperature ranges between 40°C to reflux temperature of the solvent used; and
in step-b) the suitable temperature ranges from -15°C to 30°C.
A preferred embodiment of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride, comprising of;
a) Dissolving isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in acetone by heating,
b) cooling the reaction mixture,
c) filtering the precipitated solid to get pure isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
The other preferred embodiment of the present invention provides a process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride, comprising of;
a) Dissolving isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in isopropyl alcohol by heating,
b) cooling the reaction mixture,
c) filtering the precipitated solid to get pure isobutyric acid 2-((R)-3-diisopropylarnino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride. The isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride utilized in step-a) of the fourth aspect can be synthesized by the processes disclosed in the second and third aspects of the present invention. The formation of the following impurities has been observed in the synthesis of
Fesoterodine hydrochloride as per the process disclosed in the present invention.
Figure imgf000013_0001
Double bond impurity Benzyloxy impurity S-isomer impurity
All the above said impurities are controlled well within the limits in the final compound as set by ICH. The isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl) phenyl ester hydrochloride compound of formula- la obtained by the process of the present invention is highly pure compound, which is having purity of greater than 98%, preferably greater than 99%, more preferably greater than 99.5%, most preferably greater than 99.9% by HPLC.
The purity of Fesoterodine hydrochloride compound of formula- la of the present invention was analyzed by HPLC under the following conditions:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Column: Inert sustain CI 8, 250x4.6 mm, 5um or equivalent; Flow rate: 1.2 mL/min; Wavelength: 220 nm; Column temperature: 45°C; Auto sampler temperature: 5°C; Injection volume: 20
Figure imgf000014_0001
Run time: 55 min; Elution: gradient; Buffer: 3 mL of H3P04 (85%) and 1.0 gm of 1 -octane sulfonic acid sodium salt anhydrous in 1000 mL of milli Q water and adjust its pH to 7.2 with dil.KOH and filtered the solution through 0.22μπι Nylon membrane paper and sonicate to degas it; Mobile phase-A: Buffer: acetonitrile (60:40 v/v); Mobile phase-B: Acetonitrile: water (90: 10, v/v); Diluent: Mobile phase-A.
The chiral purity of Fesoterodine HC1 of the present invention was analyzed by HPLC under the following conditions:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV detector and integrator; Column: Chiral pack 3-IC 250x4.6 mm, 3 μπι or equivalent; Flow rate: 1.0 mL/min; Wavelength: 225 nm; Column temperature: 25°C; Auto sampler temperature: 5°C; Injection volume: 20 μί; Run time: 30 min; Elution: Isocratic; Diluent: n-hexane; Mobile phase: n-hexane: isopropyl alcohol: diethylamine (95:05:0.1) v/v.
The PXRD analysis of the crystalline compound of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A° and at a continuous scan speed of 0.03°/min.
Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C/min.
In one aspect, there is provided Fesoterodine HC1 having an average particle size in the range of 5 to 200 μπι, preferably 10 to 100 μιη, more preferably 20 to 75 μιη.
In another aspect, the present invention provides Fesoterodine HC1 having particle size distribution of D(0.9) less than 200 μπι.
In another aspect, the present invention provides Fesoterodine HC1 having particle size distribution of D(0.9) less than 100 μπι, preferably less than 50 μηι. Fesoterodine HC1 obtained by the process of the present invention can further be micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product. The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la)
Dichloromethane (500 ml) and water (100 ml) were added to isobutyric acid 2-((R)-3- diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester acetyl mandelate (100 gm) at 25-30°C and cooled the reaction mixture to 0-5°C. Basified the reaction mixture using 10% sodium carbonate solution (70 gm of sodium carbonate in 700 ml of water). Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate (600 ml) was added to the obtained compound at 25-30°C and cooled the reaction mixture to 0-5°C. Dry HCl gas was passed into the reaction mixture at 0-5°C until the pH of the reaction mixture reached to 2.0 and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
The PXRD of the obtained compound is shown in figure- 1.
Yield: 68.0 gm; Purity by HPLC: 99.46%; Water content: 0.07% w/w.
Example-2: Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la)
Ethyl acetate (1000 ml) was added to isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester (100 gm) at 25-30°C and cooled the reaction mixture to 0-5°C. Dry HCl gas was passed into the reaction mixture at 0-5°C until the pH of the reaction mixture reached to 2.0 and stirred the reaction mixture for 2 hrs at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound.
The PXRD of the obtained compound is shown in figure- 1.
Yield: 92.0 gm; Purity by HPLC: 99.48%; Water content: 0.09% w/w.
Example-3: Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymethyi)phenyl ester hydrochloride (Formula-la)
Dichloromethane (1200 ml) and water (1000 ml) were added to isobutyric acid 2- ((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester acetyl mandelate (200 gm) at 25-30°C and cooled the reaction mixture to 0-5°C. Basified the reaction mixture using aqueous sodium carbonate solution (52.4 gm of sodium carbonate in 200 ml of water) at 0-5°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with aqueous sodium carbonate solution followed by water. Distilled off the solvent completely from the organic layer and co-distilled with ethyl acetate. Ethyl acetate (1000 ml) was added to the obtained compound at 25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C. Adjusted the pH of the reaction mixture to 3.0 using ethyl acetate- HC1 (181 ml) at 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried the material to get the title compound. The PXRD of the obtained compound is shown in figure- 1.
Yield: 135.0 gm.
Example-4: Preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)-4-(hydroxymetfayl)phenyl ester hydrochloride (Formula-la) Ethyl acetate (1000 ml) was added to isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester (100 gm) at 25-30°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C. Adjusted the pH of the reaction mixture to 3.0 using ethyl acetate-HCl (130 ml) at 0-5°C and stirred for 45 min at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried the material to get the title compound. The PXRD of the obtained compound is shown in figure-1.
Yield: 92.3 gm. Example-5: Purification of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)- 4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la)
Acetone (250 ml) was added to isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride (50 gm) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the pure title compound.
The PXRD of the obtained compound is shown in figure- 1.
Yield: 42.0 gm;
Particle size distribution: D(0.1) is 5.74 μιη; D(0.5) is 24.16 μιη; D(0.9) is 54.67 μηι, D(4,3) is 27.67 μιη.
Example-6: Purification of isobutyric acid 2-((R)-3-diisopropyl amino-l-phenylpropyl)- 4-(hydroxymethyl)phenyl ester hydrochloride (Formula-la)
A mixture of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-
(hydroxymethyl)phenyl ester hydrochloride (100 gm) and isopropyl alcohol (400 ml) was heated to 50-55°C and stirred for 30 min at the same temperature. Filtered the reaction mixture and washed with isopropyl alcohol. Slowly cooled the reaction mixture to 0-5°C and stirred for 1 hr at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried the material to get the pure title compound. The PXRD of obtained compound is shown in fig- 1.
Yield: 75.0 gm; MR: 139-143°C; Water content: 0.09% w/w; Purity by HPLC: 99.95%; Chiral purity by HPLC: 100%.
Diol impurity: 0.02%, Propionate impurity: 0.02%, Toluoyl hydroxy impurity: 0.01%, Double bond impurity: Not detected; Benzyloxy impurity: Not detected, S-isomer impurity: Not detected.
Particle size distribution:
Before micronization: D(0.1) is 10.1 μπι; D(0.5) is 48.98 μηι; D(0.9) is 98.43 μπι, D(4,3) is 52.67 μιη.
After micronization: D(0.1) is 3.05 μπι; D(0.5) is 8.68 μιη; D(0.9) is 27.21 μπι, D(4,3) is 12.74 μπι.

Claims

We Claim:
1. Anhydrous crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride.
Crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride, characterized by its powder X-Ray diffraction pattern having peaks at 9.3, 10.6, 11.7, 16.7, 16.9, 17.5, 18.7, 19.9, 23.2, 24.6, 24.9, 25.6, 25.8, 28.0, 28.7, 30.4 and 32.1 ± 0.2 degrees of 2-theta.
Crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride according to claim 2, characterized by its powder X-Ray diffraction pattern substantially as illustrated in figure- 1,
Crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxy methyl)phenyl ester hydrochloride characterized by its differential scanning calorimetric (DSC) thermogram having an endotherm at 147.03 °C substantially in accordance with figure-2.
Crystalline isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride according to any of the preceding claims, which is non-hygroscopic in nature.
A process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3- diisopropyl amino- l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of;
a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl) phenyl ester acetyl mandelate with a suitable base in a suitable solvent or mixture of solvents,
b) separating the organic and aqueous layers,
c) distilling off the solvent completely from the organic layer,
d) adding a suitable solvent to the obtained compound,
e) cooling the reaction mixture,
f) treating the reaction mixture with a suitable HC1 source, g) filtering the precipitated solid and washing with a suitable solvent to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride.
7. The process according to claim 6, wherein
in step-a) the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ether solvents, ester solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures; the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates;
in step-d) and step-g) the suitable solvent is selected from ester solvents, ketone solvents, ether solvents, alcohol solvents, nitrile solvents or their mixtures;
in step-f) the suitable HCl source is selected from dry HCl gas, methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethereal HCl, ethyl acetate-HCl, acetyl chloride and tri(Ci-C6 alkyl)silyl chloride, wherein acetyl chloride and tri Ci-Ce alkyl)silyl chloride are used in combination with alcohol solvents.
8. A process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3- diisopropyl amino- l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of;
a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester acetyl mandelate with aqueous sodium carbonate solution in a mixture of dichloromethane and water,
b) separating the organic and aqueous layers,
c) distilling off the solvent completely from the organic layer,
d) adding ethyl acetate to the obtained compound,
e) cooling the reaction mixture,
f) passing dry HCl gas into the reaction mixture,
g) filtering the precipitated solid and washing with ethyl acetate to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylarnino-l-phenylpropyl)-4-(hydroxy methyl)phenyl ester hydrochloride.
9. A process for preparation of crystalline form-M of isobutyric acid 2-((R)-3-diisopropyl amino- l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of; a) Treating the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester acetyl mandelate with aqueous sodium carbonate solution in a mixture of dichloromethane and water,
b) separating the organic and aqueous layers,
c) distilling off the solvent completely from the organic layer,
d) adding ethyl acetate to the obtained compound,
e) cooling the reaction mixture,
f) treating the reaction mixture with ethyl acetate-HCl,
g) filtering the precipitated solid and washing with ethyl acetate to provide crystalline form-M of isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride. 10. Process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3- diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of:
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester in a suitable solvent,
b) cooling the reaction mixture to a suitable temperature,
c) treating the reaction mixture with a suitable HC1 source,
d) filtering the precipitated solid and washing with a suitable solvent to provide compound of formula- 1 a. 11. A process according to claim 10, wherein;
the suitable solvent used in step-a) and step-d) is selected from ester solvents, ketone solvents, ether solvents, alcohol solvents, nitrile solvents or their mixtures;
in step-b) the suitable temperature ranges from -10°C to 20°C, preferably 0-5°C;
in step-c) the suitable HC1 source is selected from dry HC1 gas, methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, ethereal HC1, ethyl acetate-HCl, acetyl chloride and tri(Ci-C6 alkyl)silyl chloride, wherein acetyl chloride and tri Q-Ce alkyl)silyl chloride are used in combination with alcohol solvents.
12. A process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3- diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of;
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester in ethyl acetate,
b) cooling the reaction mixture to 0-5°C,
c) passing dry HC1 gas into the reaction mixture,
d) filtering the precipitated solid to provide crystalline form-M of isobutyric acid 2-((R)- 3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la.
13. A process for the preparation of crystalline form-M of isobutyric acid 2-((R)-3- diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of;
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester in ethyl acetate,
b) cooling the reaction mixture to 0-5°C,
c) treating the reaction mixture with ethyl acetate-HCl,
d) filtering the precipitated solid to provide crystalline form-M of compound of formula- la.
14. A process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride compound of formula- la, comprising of;
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in a suitable solvent selected from ketone solvents, alcohol solvents, ether solvents, polar solvents, ester solvents, hydrocarbon solvents, nitrile solvents or their mixtures by heating to a suitable temperature, b) cooling the reaction mixture to a suitable temperature,
c) filtering the precipitated solid to provide pure compound of formula- 1 a.
15. A process according to claim 14, wherein;
in step-a) the suitable temperature ranges between 40°C to reflux temperature of the solvent used; and
in step-b) the suitable temperature ranges between -15°C to 30°C.
16. A process for the purification of isobutyric acid 2-((R)-3 -diisopropylamino- 1- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of;
a) Dissolving the isobutyric acid 2-((R)-3 -diisopropylamino- l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in acetone by heating,
b) cooling the reaction mixture,
c) filtering the precipitated solid to provide pure isobutyric acid 2-((R)-3- diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
17. A process for the purification of isobutyric acid 2-((R)-3-diisopropylamino-l- phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride, comprising of;
a) Dissolving the isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4- (hydroxymethyl)phenyl ester hydrochloride in isopropyl alcohol by heating, b) cooling the reaction mixture,
c) filtering the precipitated solid to provide pure isobutyric acid 2-((R)-3- diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride.
18. A pharmaceutical composition comprising non-hygroscopic anhydrous crystalline isobutyric acid 2-((R)-3 -diisopropylamino- 1 -phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride and at least one pharmaceutically acceptable excipient.
19. Isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride having purity of greater than 98%, preferably greater than 99%, more preferably greater than 99.5%, most preferably greater than 99.9% by HPLC. 20. Isobutyric acid 2-((R)-3-diisopropylamino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride having an average particle size in the range of 5 to 200 μιη.
21. Isobutyric acid 2-((R)-3-diisopropylarriino-l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride having particle size distribution of D(0.9) less than 200 μηι.
22. Isobutyric acid 2-((R)-3 -diisopropylamino- l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride according to claim 21, having D(0.9) less than 100 μηι.
23. Isobutyric acid 2-((R)-3 -diisopropylamino- l-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride according to claim 21, having D(0.9) less than 50 μηι.
PCT/IN2014/000191 2013-03-27 2014-03-26 Novel polymorph of isobutyric acid 2-((r)-3-diisopropyl amino-1-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride and process for preparation thereof WO2014167578A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1364/CHE/2013 2013-03-27
IN1364CH2013 2013-03-27

Publications (2)

Publication Number Publication Date
WO2014167578A2 true WO2014167578A2 (en) 2014-10-16
WO2014167578A3 WO2014167578A3 (en) 2014-12-24

Family

ID=51690087

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2014/000191 WO2014167578A2 (en) 2013-03-27 2014-03-26 Novel polymorph of isobutyric acid 2-((r)-3-diisopropyl amino-1-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride and process for preparation thereof

Country Status (1)

Country Link
WO (1) WO2014167578A2 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009122303A2 (en) * 2008-04-04 2009-10-08 Actavis Group Ptc Ehf Novel mandelate salt of fesoterodine
WO2011029005A1 (en) * 2009-09-03 2011-03-10 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Crystalline forms of fesoterodine fumarate and fesoterodine base
WO2012025941A2 (en) * 2010-08-25 2012-03-01 Cadila Healthcare Limited Processes for the preparation of fesoterodine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009122303A2 (en) * 2008-04-04 2009-10-08 Actavis Group Ptc Ehf Novel mandelate salt of fesoterodine
WO2011029005A1 (en) * 2009-09-03 2011-03-10 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Crystalline forms of fesoterodine fumarate and fesoterodine base
WO2012025941A2 (en) * 2010-08-25 2012-03-01 Cadila Healthcare Limited Processes for the preparation of fesoterodine

Also Published As

Publication number Publication date
WO2014167578A3 (en) 2014-12-24

Similar Documents

Publication Publication Date Title
US11168057B2 (en) Polymorphs and co-crystals of roxadustat
US8946477B2 (en) Solid forms of an N-(phenylmethyl) propanamide derivative and processes of preparation
WO2012093402A1 (en) Processes for the preparation of n-[2-(7-methoxy-1-naphthyl)ethyl]acetamide
US20090298947A1 (en) Polymorphic and amorphous forms of lacosamide and amorphous compositions
WO2017221189A1 (en) An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof
WO2014108919A2 (en) NOVEL INTERMEDIATE AND POLYMORPHS OF 1-(4-METHOXYPHENYL)-7-OXO-6-[4-(2-OXOPIPERIDIN-1-YL)PHENYL]-4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[3,4-c] PYRIDINE-3-CARBOXAMIDE AND PROCESS THEREOF
WO2012025944A2 (en) Sitagliptin, salts and polymorphs thereof
EP2539321A1 (en) Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof
EP3262039A2 (en) Process for the preparation of amorphous (1s)-1,5-anhvdro-1-[3-[[5-(4 fluorophennyl)-2-thienyl]methvl]-4-methylphenyl]-d-glucitol and its polymorphs thereof
JP6225998B2 (en) Method for producing indoline compound
CA2890961A1 (en) Novel polymorphs of azilsartan medoxomil
JP2006528203A (en) Levalbuterol hydrochloride polymorph A
EP2598147A1 (en) N-methylformamide solvate of dasatinib
US20220363680A1 (en) Processes for the synthesis of valbenazine
WO2016139677A1 (en) Improved process for the preparation of 2-({6-[(3r)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihvdropvrimidin-1(2h)-yl}methyl)benzonitrile and pharmaceutically acceptable salts thereof
WO2014167578A2 (en) Novel polymorph of isobutyric acid 2-((r)-3-diisopropyl amino-1-phenylpropyl)-4-(hydroxymethyl)phenyl ester hydrochloride and process for preparation thereof
US8304544B2 (en) Palonosetron free base and process for its preparation
WO2006087996A1 (en) Process for production of carbapenem derivative and crystalline intermediate therefor
EP3604284B1 (en) Crystalline eltrombopag monoethanolamine salt form d
US20100274050A1 (en) Solid milnacipran and process for the preparation of the same
JP5569397B2 (en) Method for producing 2-hydroxymethylmorpholine salt
US20220324838A1 (en) An Improved Process Of Preparation Of Ivosidenib
WO2021117057A1 (en) Polymorph of n-ethyl-1-(3-(trifluoromethyl)phenyl)propan-2-amine hydrochloride and process for preparation thereof
WO2022215083A1 (en) Solid state forms of (s)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl) carbamate or salts and process for its preparation thereof
WO2013114379A1 (en) Novel polymorphs of n-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester and processes thereof

Legal Events

Date Code Title Description
122 Ep: pct application non-entry in european phase

Ref document number: 14782203

Country of ref document: EP

Kind code of ref document: A2