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WO2009053994A1 - Procédé pour préparer un chlorhydrate de quinapril amorphe pur - Google Patents

Procédé pour préparer un chlorhydrate de quinapril amorphe pur Download PDF

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Publication number
WO2009053994A1
WO2009053994A1 PCT/IN2007/000574 IN2007000574W WO2009053994A1 WO 2009053994 A1 WO2009053994 A1 WO 2009053994A1 IN 2007000574 W IN2007000574 W IN 2007000574W WO 2009053994 A1 WO2009053994 A1 WO 2009053994A1
Authority
WO
WIPO (PCT)
Prior art keywords
quinapril hydrochloride
solvent
quinapril
hydrochloride
pure amorphous
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/IN2007/000574
Other languages
English (en)
Inventor
Om Dutt Tyagi
Indukuri Venkata Sunil Kumar
Jammula Vera Venkata Krishna Kishore
Patneedi Chanti Babu
Yerva Eswara Reddy
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.)
Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories Ltd
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 Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2009053994A1 publication Critical patent/WO2009053994A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • This invention in general, relates to an improved process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts.
  • Quinapril hydrochloride hydrochloride is an ethyl ester of a nonsulfhydryl Angiotension-Converting Enzyme (ACE) inhibitor.
  • Quinapril hydrochloride is chemically described as (3S- (2(R*)),3R*)) -2- (2- ((l-(ethoxycarbonyl)- 3 - phenylpropyl) amino) -1-oxopropyl) -l,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride.
  • hydrochloride salt is active as Angiotensin Converting Enzyme (ACE) inhibitors and is commercially important anti-hypertensive agent.
  • ACE Angiotensin Converting Enzyme
  • Angiotensin I is converted by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II.
  • ACE angiotensin converting enzyme
  • the latter is an active pressor substance which has been implicated as the causative agent in various forms of hypertension in various mammalian species, e.g., rats and dogs.
  • the ACE inhibitors intervene in the rennin > angiotensin I > angiotensin II sequence by inhibiting angiotensin I converting enzyme and reducing or eliminating the formation of the pressor substance angiotensin II, and therefore are useful in reducing or relieving hypertension.
  • a composition containing one or a combination of amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts hypertension in the species of mammal suffering therefrom is alleviated.
  • Quinapril hydrochloride was first disclosed in US 4,344,949 which describes a process for preparation of quinapril hydrochloride comprising deprotection of benzyl or t-butyl ester of quinapril by catalytic hydrogenolysis in the presence of the catalyst, 20% Pd/C at low pressure followed by isolation of quinapril hydrochloride by adding ether.
  • the benzyl or t-butyl ester of quinapril is unprotected by treatment with trifluoroacetic acid followed by treatment with dry hydrogen chloride in dry ether and quinapril hydrochloride thus obtained by lyophilization of an aqueous solution.
  • the reaction scheme is illustrated herein below:
  • Quinapril obtained by this process is invariably contaminated with diketopiperazine derivative formed either during removal of the carboxylic acid protective group i.e. deprotection by catalytic hydrogenolysis or treatment with trifluoroacetic acid or during isolation of quinapril, as quinapril degrades easily due to intramolecular cyclization to yield a diketopiperazine both in aqueous or organic solution as well as in the solid state.
  • Quinapril hydrochloride is generally available in two forms namely crystalline and amorphous.
  • acetonitrile is a class 2 solvent, defined by ICH as a Non-mutagenic carcinogen in animals or possible cause of other irreversible toxicity such as neurotoxicity, teratogenesis and therefore proportion has to be limited, hi the case of acetonitrile, the ICH recommends a limit not above 250 ppm (0.025 %). This limit is difficult to achieve at the industrial scale due to the less stability of the product.
  • the abovementioned patent also discloses that the crystalline material thus obtained contains equimolar amounts of acetonitrile/acetone as part of the crystal lattice.
  • the patent further reveals that the solvent(s) present in the crystal structure can be removed under vacuum at a temperature of about 50°C.
  • the crystallinity of the substance is lost due to desolvation during drying, and an amorphous material is obtained which is claimed to be free of impurities, specially the diketopiperazine.
  • Solvents like methyl acetate and ethyl formate have low flash point (i.e. methyl formate- 16° C and ethyl formate -20° C) because of which they are unsafe and have to be carefully handled. Therefore, the process is not commercially viable.
  • WO 2004/054980 provides a process for the preparation of a pure crystalline quinapril hydrochloride associated with the solvate of nitroalkane. On de-solvation of the nitroalkane solvate, amorphous quinapril hydrochloride is obtained. Desolvation is cumbersome to carry out as it involves drying at 40°C/0.5 mm Hg for 60 hrs. US 6.858,735 describes a process for the preparation of quinapril hydrochloride in amorphous and crystalline forms.
  • the tert.butyl ester of quinapril hydrochloride is deprotected by treatment with aqueous or anhydrous hydrogen chloride in the presence of aprotic or protic solvents to yield quinapril hydrochloride in solution, which is converted into acetone solvate and subsequently re-crystallized with acetonitrile.
  • the solvate is dried to obtain amorphous quinapril hydrochloride.
  • the process is complicated and time consuming as two solvates are involved in order to get pure compound.
  • WO 2007/054966 unveils the process for the preparation of quinapril hydrochloride. This process offers reduced quantity of diketopiperazine impurity and prevention of degradation of the product.
  • the solution of benzyl ester of quinapril hydrochloride is prepared with an alkyl nitrile and is subjected to catalytic hydrogenolysis, after pH adjustment of the solution to 0.8 to 1 by adding 3 to 17% solution of hydrogen chloride in dry ether or dry alkyl nitrile.
  • the solvent is distilled out to 50-70% of its volume to obtain crystalline quinapril hydrochloride, which is washed with n-pentane and dried.
  • J.Pharm.Sci. VoI 89, 128-143 (2000) describes physical characteristics and chemical degradation of amorphous quinapril hydrochloride.
  • This paper investigates the relationship between the solid-state chemical instability and physical characteristics quinapril in amorphous state.
  • This paper describes the preparation of amorphous quinapril hydrochloride samples were prepared by rapid evaporation from dichloromethane solution and by grinding and subsequent heating of the crystalline form.
  • a process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts wherein the obtained amorphous quinapril hydrochloride is devoid of diketopiperazine and other related impurities and are characterized by using PXRD.
  • a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts having absolutely no crystallinity in its wet condition.
  • a simple and commercially viable process for preparing a pure amorphous quinapril hydrochloride and its other pharmaceutically acceptable salts comprising of dissolving or suspending crystalline or solvate form of quinapril hydrochloride in a suitable solvent, adding a second solvent, which is immiscible with the solvent, followed by gradual cooling and isolating the pure amorphous quinapril hydrochloride.
  • a method of packing quinapril hydrochloride comprising of placing quinapril hydrochloride in a sealed container under an inert atmosphere, placing the sealed container, a desiccant, and an oxygen adsorbent in a second sealed container, placing the second sealed container in a triple laminated bag and sealing and enclosing the triple laminated bag in a closed high density polyethylene container.
  • Figure 1 is the X-ray powder diffraction pattern of wet cake of quinapril hydrochloride.
  • Figure 2 is the X-ray powder diffraction pattern of dry product of quinapril hydrochloride.
  • Figure 3 is the X-ray powder diffraction pattern of commercially available quinapril hydrochloride.
  • Figure 4 is the X-ray powder diffraction pattern of pure amorphous quinapril hydrochloride.
  • the present invention provides a process for essentially pure amorphous quinapril hydrochloride.
  • amorphous materials are prepared by precipitation, spray drying, freeze drying (lyophilisation), melt precipitation, vapor condensation, crash cooling, from supercritical fluids e.g using Solution Enhanced Dispersion by Supercritical fluids (SEDS), Rapid Expansion of Supercritical Solution (RESS) processes etc. from among the methods mentioned above, precipitation using an anti-solvent is advantageous industrially.
  • SEDS Solution Enhanced Dispersion by Supercritical fluids
  • RSS Rapid Expansion of Supercritical Solution
  • this invention details the preparation of amorphous quinapril, wherein any form of quinapril hydrochloride is dissolved in a suitable solvent such as alcohol and subsequently adding the anti-solvent selected form aliphatic hydrocarbons such as pentane, hexanes, heptane, etc.
  • amorphous form of a drug may exhibit different dissolution characteristics and in some case different bioavailability patterns compared to crystalline forms.
  • amorphous and crystalline forms of a drug may have different handling properties, dissolution rates, solubility, and stability, access to a choice between the amorphous or crystalline forms of a drug is desirable for different applications.
  • different physical forms may have different particle size, hardness and glass transition temperatures. Amorphous materials do not exhibit the three-dimensional long-range orders found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random.
  • Amorphous solids do not give a definitive X-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a melting point and tend to liquefy at some point beyond the glass transition temperature. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide enhanced bioavailability characteristics such as a higher rate and extent of absorption of the compound from the gastrointestinal tract. Also, amorphous forms of a drug may offer significant advantages over crystalline forms of the same drug in solid dosage form manufacture process such as compressibility, economically or environmentally suitable solvents or process, or higher purity or yield of the desired product.
  • any form' includes solvated and desolvated forms, crystalline forms and other non-crystalline forms.
  • solvated crystalline quinapril hydrochloride is dissolved in C 1 -C 4 alcohol. After dissolution, the alcohol was reduced to 1/3 of its volume and aliphatic hydrocarbon solvent is added and stirred for 10-30 minutes.
  • Ci-C 4 alcoholic solvents employed for dissolution of quinapril hydrochloride are selected form methanol, ethanol, isopropanol and n-butanol.
  • the aliphatic hydrocarbons employed as anti-solvent are selected form n-pentane, hexanes etc.
  • the preferred solvent is methanol and anti-solvent is n-pentane.
  • the crystalline quinapril used in the process of the present invention is prepared by prior-art methods.
  • the advantage realized in the present process of the invention is that there is absolutely no crystallinity observed even in the wet product. As the wet product is also amorphous then in drying there is obtained a pure amorphous compound and no sharp peaks are observed in PXRD.
  • the inventors have observed that commercially available amorphous quinapril hydrochloride contains some amount of crystallinity, whereas the present process of the invention yields essentially pure amorphous quinapril hydrochloride.
  • the commercially available amorphous quinapril hydrochloride when analysed contains detectable amounts of both crystalline and amorphous having both characteristic sharp peaks and the diffuse halo(s) on XRPD.
  • the present invention provides pure amorphous quinapril hydrochloride characterized by PXRD containing one or more broad diffuse halo, and lack of discernible acute peaks which are characteristics of crystalline compounds.
  • the essentially pure amorphous quinapril hydrochloride is prepared by converting the crystalline quinapril hydrochloride which is depicted in Fig 1. This crystalline material after drying gives amorphous quinapril hydrochloride contaminated with some crystalline peaks which is depicted in Fig 2.
  • the polymorphs form of the present invention is characterized by their X-ray powder diffraction pattern.
  • the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ⁇ / ⁇ configuration and X'Celerator detector.
  • the Cu- anode X-ray tube was operated at 4OkV and 3OmA. The experiments were conducted over the 2 ⁇ range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
  • the packaging conditions have been modified for the quinapril hydrochloride to provide consistent purity, resistant to moisture and formation of diketopiperazine impurity.
  • the susceptibility of quinapril hydrochloride to moisture leads to deviating drug regulatory requirements.
  • a packaging and storage method for stabilizing hygroscopic quinapril hydrochloride comprises of placing quinapril hydrochloride in a sealed container under an inert atmosphere, placing the sealed container, a desiccant, and an oxygen adsorbent in a second sealed container, placing the second sealed container in a triple laminated bag and sealing and enclosing the triple laminated bag in a closed high density polyethylene container.
  • the inert atmosphere disclosed in the method can be provided to the compound, which is kept in a polythene bag, or has been stored in a more rigid container.
  • the bag or container, which is used to provide the inert atmosphere to quinapril hydrochloride, is sealed airtight after providing the inert atmosphere.
  • the container employed to provide the inert atmosphere to quinapril hydrochloride is transparent and exposes the product to light, then it can be covered using a non-transparent material.
  • Suitable moisture adsorbents is used in the present invention include, but are not limited to molecular sieve zeolites, high silica zeolites, having a high silica/alumina ratio of 25 or more, such as ZSM-5 (made by Mobil Oil Co., silica/alumina ratio of 400), silicalite, USY (Ultra Stable Y type zeolite, by PQ Corp., silica/alumina ratio of 78), mordenite and the like, a low silica system zeolite such as Ca-X type zeolite, Na-X type zeolite, silica super fine granulated particle (for example, particles having an average particle size of 1.5 mm which has been obtained by granulating the si
  • Suitable oxygen adsorbents include, but are not limited to CuO (activated by reduction with hydrogen) on an inorganic oxide, sachet of Ageless Z
  • Ageless Z sachets contain fine iron powder covered with sea salt and a natural zeolite impregnated with a NaCl solution.
  • One sachet of Ageless Z 200 adsorbs 2000 ml of oxygen (the oxygen from 10 L of air) and other similar oxygen absorbents can be used.
  • the package containing the compound and the oxygen and moisture adsorbents are kept in a triple laminated bag, having layers of polyethylene terephthalate film, aluminum foil, and linear low-density polyethylene film.
  • the triple laminated bag provides protection to the contents from oxygen, moisture, light, and other contaminants.
  • an additional desiccant moisture adsorbent
  • moisture adsorbent is put into the triple laminated bag as an additional precaution to adsorb any moisture.
  • the triple laminated bag is heat sealed to prevent the entry of any contaminants.
  • the heat sealing can be done using a vacuum nitrogen sealer (VNS) for effective sealing and thereafter storing the triple laminated bag in a High-density polyethylene (HDPE) container.
  • VNS vacuum nitrogen sealer
  • HDPE High-density polyethylene
  • the packaging and storage process disclosed herein provides substantially pure quinapril hydrochloride, which is stable during storage and does not undergo agglomeration, and also results in minimizing diketopiperazine impurity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé pour préparer et conditionner un chlorhydrate de quinapril amorphe pur et d'autres sels pharmaceutiquement acceptables du quinapril. Le procédé consiste à dissoudre ou à mettre en suspension une forme cristalline ou solvatée du chlorhydrate de quinapril dans un solvant convenable ; à ajouter un second solvant ; puis à refroidir progressivement et à isoler le chlorhydrate de quinapril amorphe pur.
PCT/IN2007/000574 2007-10-26 2007-12-10 Procédé pour préparer un chlorhydrate de quinapril amorphe pur Ceased WO2009053994A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2432CH2007 2007-10-26
IN2432/CHE/2007 2007-10-26

Publications (1)

Publication Number Publication Date
WO2009053994A1 true WO2009053994A1 (fr) 2009-04-30

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Application Number Title Priority Date Filing Date
PCT/IN2007/000574 Ceased WO2009053994A1 (fr) 2007-10-26 2007-12-10 Procédé pour préparer un chlorhydrate de quinapril amorphe pur

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0992495A1 (fr) * 1997-05-29 2000-04-12 Esteve Quimica, S.A. Procede pour l'obtention de chlorhydrate de quinapryl et solvates utiles pour l'isolement et la purification de chlorhydrate de quinapryl
WO2003075842A2 (fr) * 2002-03-08 2003-09-18 Teva Pharmeceuticals Usa, Inc. Formulations stables d'inhibiteurs de l'enzyme de conversion de l'angiotensine (ace)
US20040192613A1 (en) * 2003-03-31 2004-09-30 Jennings Sandra Marie Preparation of quinapril hydrochloride

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0992495A1 (fr) * 1997-05-29 2000-04-12 Esteve Quimica, S.A. Procede pour l'obtention de chlorhydrate de quinapryl et solvates utiles pour l'isolement et la purification de chlorhydrate de quinapryl
WO2003075842A2 (fr) * 2002-03-08 2003-09-18 Teva Pharmeceuticals Usa, Inc. Formulations stables d'inhibiteurs de l'enzyme de conversion de l'angiotensine (ace)
US20040192613A1 (en) * 2003-03-31 2004-09-30 Jennings Sandra Marie Preparation of quinapril hydrochloride

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 200560, Derwent World Patents Index; Class B03, AN 2005-585366, XP002514007 *
YUSHEN GUO ET AL: "Physical Characteristics and Chemical Degradation of Amorphous Quinapril Hydrochloride", JOURNAL OF PHARMACEUTICAL SCIENCE, AMERICAN PHARMACEUTICAL ASSOCIATION. WASHINGTON.; US, vol. 89, no. 1, 1 January 2000 (2000-01-01), pages 128 - 143, XP002504224, ISSN: 0022-3549 *

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