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WO2022250620A1 - Procédé amélioré s'appliquant au chlorhydrate de bensérazide extrêmement pur et nouveau polymorphe anhydre de celui-ci - Google Patents

Procédé amélioré s'appliquant au chlorhydrate de bensérazide extrêmement pur et nouveau polymorphe anhydre de celui-ci Download PDF

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Publication number
WO2022250620A1
WO2022250620A1 PCT/TR2021/050491 TR2021050491W WO2022250620A1 WO 2022250620 A1 WO2022250620 A1 WO 2022250620A1 TR 2021050491 W TR2021050491 W TR 2021050491W WO 2022250620 A1 WO2022250620 A1 WO 2022250620A1
Authority
WO
WIPO (PCT)
Prior art keywords
benserazide hydrochloride
benserazide
hydrochloride
crystalline
hydrochloride form
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/TR2021/050491
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English (en)
Inventor
Philipp Daniel Haas
Hartwig Andreas Steckel
Esen Bellur Atici
Halil Yilmaz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Deva Holding AS
Original Assignee
Deva Holding AS
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 Deva Holding AS filed Critical Deva Holding AS
Priority to PCT/TR2021/050491 priority Critical patent/WO2022250620A1/fr
Publication of WO2022250620A1 publication Critical patent/WO2022250620A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C243/34—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a carbon skeleton further substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to an improved method for synthesis of 2-amino-3-hydroxy-N-(2,3,4- trihydroxybenzyl)propanehydrazide hydrochloride (Benserazide HC1) and preparation of its novel stable crystalline polymorph “Form H”.
  • Benserazide is used for treatment of Parkinson’s disease in combination with Levodopa, which is marketed as its hydrochloride salt under the brand names Madopar in the UK and Prolopa in Canada. Benserazide is chemically designated aass 2-amino-3-hydroxy-N'-(2,3,4- trihydroxybenzyl)propanehydrazide and structurally represented as below;
  • Benserazide and its salt form is first mentioned in the patent application WO 2006116764, which does not mention any details about the character of the solid form of the product.
  • the commercial tablet formulation of benserazide hydrochloride contains crystalline Form I.
  • WO 2015197909 discloses an X-ray diffraction pattern of crystalline Form I as depicted in Fig. 1.
  • Different solid states of an active pharmaceutical ingredient may provide additional opportunities for an improved drug substance and product properties.
  • Different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density and dissolution rates.
  • the present invention provides an improved and economically preferable process for manufacturing of benserazide hydrochloride with high-purity and high yield. Besides, the present invention relates to a novel stable form of benserazide hydrochloride.
  • Active pharmaceutical ingredients are individual components that are used as a part of finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.
  • 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 crystalline forms having distinct crystal structures and physical properties. Difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.
  • the solid state form of an active pharmaceutical ingredient may affect its stability as in finished product.
  • Stability of active pharmaceutical ingredients is the key factor in stability evaluation of finished pharmaceutical products (FPPs). On this ground, stability testing of API in FPP must be conducted.
  • the relative humidity and/or temperature of the environment may cause increase in impurity amount of API.
  • stable polymorph which does not change on storage and does not require any special conditions for storage, is always preferred.
  • Performance characteristics of a pharmaceutical product can be improved by means of discovery of new polymorphic forms.
  • the first aspect of the present invention relates to an improved method wherein the process comprises of reacting 2,3,4-trihydroxybenzaldehyde with a amino-3-hydroxypropanehydrazide hydrochloride in presence of solvent to obtain 2-amino-3-hydroxy-N'-(2,3,4- trihydroxybenzylidene)propanehydrazide hydrochloride.
  • the second aspect of the present invention relates to a process for preparing benserazide hydrochloride wherein the compound of 2-amino-3-hydroxy-N'-(2,3,4- trihydroxybenzylidene)propanehydrazide hydrochloride hydrogenated in presence of catalyst and solvent to obtain benserazide hydrochloride.
  • This improved method is described in Scheme 2.
  • the suitable solvent employed in step (i) and step (ii) is selected from the group of alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, butanol or organic solvents such as DMF, NMP,
  • step (i) the solvent DMF is used in step (i) and DMF-methanol mixture is used in step (ii).
  • the catalyst employed in the step (ii) is selected from Pd/C or Pt/C.
  • the third aspect of the present invention relates to a novel polymorphic anhydrous form of benserazide hydrochloride, herein after designated as Form H.
  • Form H is characterized by an
  • the fourth aspect of the present invention relates to a process for preparation of crystalline Form
  • H of benserazide hydrochloride comprises; a) providing a mixture by addition of methanol, water and benserazide hydrochloride DMF- solvate form synthesized according to the process described in Scheme 2, b) then stirring the mixture at a suitable temperature for a suitable timec) addition a suitable solvent into the mixture in step (b) d) filtering the crystals; and e) washing the crystals with a suitable solvent, and f) finally drying the crystals in vacuo.
  • suitable solvent in step (c) and (e) is selected from, 2-propanol, 1 -propanol, 1 -butanol, 2-butanol, tert-butyl alcohol, 1 -pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2 -pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, toluene, xylene, chloroform, dichloromethane, carbontetrachloride, ethylene dichloride, chlorobenzene, acetonitrile, diethyl ether, diisopropyl ether, tert-butyl methyl ether, di
  • the suitable temperature used in step (b) is selected from room temperature to reflux temperature of the solvent used.
  • the suitable time used in stirring the mixture in step (b) is between 1 - 16 hours.
  • the degree of purity of the active ingredient and the resulting possible changes of the efficacy, further important properties for the pharmaceutical processing can be affected in an adverse manner, e.g. the capability to be pressed to form tablets by an impairment of the pourability or flowability of the crystalline form.
  • the process of the present invention affords crystalline Form H of benserazide hydrochloride in high purity and high yield.
  • the crystalline Form H of benserazide hydrochloride is obtained having purity greater than 99% by area percentage in HPLC.
  • Stability plays an important role in the drug development process. Stability of a pharmaceutical product may be defined as the capability of that particular formulation, in a specific container or closure system, to remain within its chemical, physical, microbiological, therapeutic and toxicological specifications to assure its attributed quality, e.g., identity, purity, strength etc. until drug expiry.
  • Stability of a pharmaceutical product is strongly influenced by changes in solid-state form of the API.
  • the changes in solid state form of the API may be resulted from the conditions of product manufacturing process. Examples of processing that may cause polymorphic changes including grinding, milling, heating, and applying compression. Manufacturing conditions that include a solvent (e.g., wet granulation, polymorphs in solution, and polymorphs in suspension) may facilitate changes in the solid-state form of API.
  • solvent e.g., wet granulation, polymorphs in solution, and polymorphs in suspension
  • These variations comprising polymorphic transformations, hydrate/solvate formations and dehydration/desolvation reactions in the solid- state form of API, may cause stability problems in FFPs.
  • crystalline stability of API has a critical role on satisfying the essentialities of qualified pharmaceutical product and stable polymorphs of API should be used in pharmaceutical formulations.
  • the crystalline stability referred to here is the stability of a polymorphic form of API with respect to polymorph transformations, hydration or dehydration, salt disproportionation, crystallization, or amorphization through time under the conditions 25 °C, 60% RH for 6 months after preparation.
  • Crystalline form H shows crystalline stability under 25 °C, 60% relative humidity for 6 months.
  • X-ray diffractogram of crystalline Form H kept under the conditions at 25 °C, 60% relative humidity for 6 months is given in Fig. 7 clearly shows that 2-theta values of characteristic peaks did not change when exposed to accelerated stability conditions.
  • the chemical stability of crystalline Form H of benserazide hydrochloride is also important and its stability in finished product at room-temperature storage can be predicted from shorter-term storage under accelerated conditions of high temperature and humidity.
  • samples of obtained crystalline Form H and Form I of benserazide hydrochloride are stored for 6 months in stability chambers under following conditions of 25 °C
  • Table 1 shows the stability results of benserazide hydrochloride Form H prepared according to the present invention in comparison to benserazide hydrochloride Form I.
  • Form H and Form I were kept at 25 °C and 60% relative humidity conditions for 6 months, Initial total impurity amounts were 0.2% for Form H and 0.8% for Form I.
  • the total impurity amounts at the end of 6 months were 0.24% for Form H and 0.87% for Form I.
  • the total impurity amounts showed that
  • Form H is slightly more stable than Form I.
  • a pharmaceutical composition comprising a therapeutically effective amount of benserazide hydrochloride Form H and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein benserazide hydrochloride
  • Fig. 1 shows the X-Ray Powder Diffraction (XRPD) pattern of benserazide hydrochloride Form I
  • Fig. 2 shows the X-Ray Powder Diffraction (XRPD) pattern of benserazide hydrochloride DMF solvate
  • Fig. 3 shows the X-Ray Powder Diffraction (XRPD) pattern of benserazide hydrochloride designated as Form H obtained in example 2
  • Fig. 4 shows the differential scanning calorimetry (DSC) thermogram of benserazide hydrochloride designated as Form H
  • Fig. 5 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of benserazide hydrochloride Form H
  • Fig. 6 shows the Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectra of benserazide hydrochloride Form H (after storage for 6 months at 25 °C and 60% relative humidity conditions)
  • Fig. 7 shows the X-Ray Powder Diffraction (XRPD) pattern of benserazide hydrochloride designated as Form H (after storage for 6 months at 25 °C and 60% relative humidity conditions)
  • XRPD samples were analyzed on a Shimadzu 6100 X-Ray Diffractometer. The measurement conditions were as following:
  • Benserazide hydrochloride DMF-solvate (5.0 g as DMF-free) was suspended in methanol (10 mL) and stirred for 1 h at room temperature. Afterwards, 2-propanol (20 mL) was added and the suspension was stirred overnight at room temperature, and then stirred at 0 °C for 4 h. The product was filtered, washed with 2-propanol and dried in vacuo at 60 °C (4.12 g, 82%, Form I; HPLC purity: 99.79%).
  • Benserazide hydrochloride DMF-solvate (5.0 g as DMF-free) was suspended in methanol (15 mL) and stirred for 30 min at room temperature. Afterwards, water (3 mL) was added and stirred until dissolution at room temperature. 2-Propanol (20 mL) was added and stirred overnight at room temperature, and then stirred at 0 °C for 4 h. The product was filtered, washed with 2- propanol and dried in vacuo at 60 °C (3.93 g, 79%, Form I, HPLC purity: 99.73%).
  • Benserazide hydrochloride DMF-solvate (5.0 g as DMF-free) was dissolved in methanol (20 mL) and stirred for 1 h at room temperature. Afterwards, 2-propanol (30 mL) was added and stirred overnight at room temperature, then stirred at 0 °C for 4 h. The product was filtered, washed with 2-propanol and dried in vacuo at 60 °C (4.11 g, 82%, Form I, HPLC purity: 99.88%).
  • Benserazide hydrochloride Form H (obtained in example 2; 5.0 g) was dissolved in methanol (20 mL) and stirred for 1 h at room temperature. Afterwards, 2-propanol (30 mL) was added and stirred overnight at room temperature, then stirred at 0 °C for 4 h. The product was filtered, washed with 2-propanol and dried in vacuo at 60 °C (4.67 g, 93%, Form I, HPLC purity: 99.96%).
  • Example 7 Preparation of benserazide hydrochloride Form H
  • Benserazide hydrochloride Form I (5.0 g) was dissolved in water and methanol mixture (20 mL, v:v; 50:50) and stirred for 18 h at room temperature. Afterwards, 2 -propanol (20 mL) was added and stirred at 0 °C for 4 h. The product was filtered, washed with 15 mL 2 -propanol and dried in vacuo at 60 °C (4.85 g, 97%, Form H, HPLC purity: 99.92%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau polymorphe cristallin de chlorhydrate de bensérazide. Plus spécifiquement, l'invention concerne une nouvelle forme H de chlorhydrate de bensérazide, un procédé de préparation de la nouvelle forme de chlorhydrate de bensérazide et des formulations pharmaceutiques comprenant la nouvelle forme de chlorhydrate de bensérazide.
PCT/TR2021/050491 2021-05-26 2021-05-26 Procédé amélioré s'appliquant au chlorhydrate de bensérazide extrêmement pur et nouveau polymorphe anhydre de celui-ci Ceased WO2022250620A1 (fr)

Priority Applications (1)

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PCT/TR2021/050491 WO2022250620A1 (fr) 2021-05-26 2021-05-26 Procédé amélioré s'appliquant au chlorhydrate de bensérazide extrêmement pur et nouveau polymorphe anhydre de celui-ci

Applications Claiming Priority (1)

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PCT/TR2021/050491 WO2022250620A1 (fr) 2021-05-26 2021-05-26 Procédé amélioré s'appliquant au chlorhydrate de bensérazide extrêmement pur et nouveau polymorphe anhydre de celui-ci

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT202300020187A1 (it) * 2023-09-29 2025-03-29 Dipharma Francis Srl Preparazione di una forma cristallina di un farmaco utilizzato nel trattamento del parkinson

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3178476A (en) * 1961-06-16 1965-04-13 Hoffmann La Roche Di-or tri-hydroxybenzyl hydrazides
WO2015197909A1 (fr) * 2014-06-27 2015-12-30 Fermion Oy Procédé pour la préparation d'un polymorphe cristallin de chlorhydrate de 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (bensérazide)
CN110511159A (zh) * 2019-09-20 2019-11-29 上海倍殊生物科技有限公司 一种盐酸苄丝肼的合成方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3178476A (en) * 1961-06-16 1965-04-13 Hoffmann La Roche Di-or tri-hydroxybenzyl hydrazides
WO2015197909A1 (fr) * 2014-06-27 2015-12-30 Fermion Oy Procédé pour la préparation d'un polymorphe cristallin de chlorhydrate de 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (bensérazide)
CN110511159A (zh) * 2019-09-20 2019-11-29 上海倍殊生物科技有限公司 一种盐酸苄丝肼的合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DI STEFANO, A. ET AL.: "Synthesis and preliminary evaluation of L-dopa/benserazide conjugates as dual acting codrugs", LETTERS IN DRUG DESIGN & DISCOVERY, vol. 3, no. 10, 2006, pages 747 - 752, XP008100266 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT202300020187A1 (it) * 2023-09-29 2025-03-29 Dipharma Francis Srl Preparazione di una forma cristallina di un farmaco utilizzato nel trattamento del parkinson
EP4545513A1 (fr) * 2023-09-29 2025-04-30 Dipharma Francis S.r.l. Préparation d'une forme cristalline d'un médicament anti-parkinson

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