US20080090784A1 - Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it - Google Patents

Crystalline form of the zoledronic acid, a process to obtain it and the pharmaceutical composition comprising it Download PDF

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US20080090784A1
US20080090784A1 US11/837,277 US83727707A US2008090784A1 US 20080090784 A1 US20080090784 A1 US 20080090784A1 US 83727707 A US83727707 A US 83727707A US 2008090784 A1 US2008090784 A1 US 2008090784A1
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zoledronic acid
procedure
trihydrate
water
crystalline
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Rafael Labriola
Dora Tombari
Adriana Vecchioli
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Gador SA
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Gador SA
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Assigned to GADOR S.A. reassignment GADOR S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LABRIOLA, RAFAEL ALBERTO, TOMBARI, DORA GRACIELA, VECCHIOLI, ADRIANA
Publication of US20080090784A1 publication Critical patent/US20080090784A1/en
Priority to US12/700,082 priority Critical patent/US8952172B2/en
Priority to US12/700,067 priority patent/US8338619B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]

Definitions

  • This invention refers to a new crystalline form of zoledronic acid, characterized by its diffractogram of X-rays as well as by its spatial atomic distribution in the crystalline network and its thermal analysis curves.
  • this crystalline form which comprises the synthesis of the corresponding acid and the pharmaceutical composition comprised by this crystalline form.
  • Zoledronic acid (I) is a bisphosphonic acid, which acts as an inhibitor of bone osteoclastic resorption. This compound, chemically called 1-hydroxy-2-(1-imidazoyl) ethydilene bisphosphonic acid, is sold in the USA under the trade name of Zometa® (zoledronic acid for injectables).
  • Zoledronic acid belongs to the family of the bisphosphonates well known for its features useful when treating diseases caused by dysfunctions in the metabolism of calcium and phosphorous [see for example K. R. Williams—J. C'hem. Ed. 81, 1406 (2004)].
  • This invention refers to a new polymorphic form of zoledronic: acid which exists in the form of a trihydrate, and to its method of obtaining it.
  • the invention is based on the discovery that trihydrate formation is ruled by crystallization temperature, such that trihydrate is obtained when dissolved zoledronic acid is crystallized at a temperature between 5 and 35° C., preferably between 15 and 25° C.
  • FIG. I shows the X-rays powder diffractogram of this new crystalline form.
  • FIG. II corresponds to the curves obtained through the TGA analysis (Thermogravimetric Analysis) and DSC (Differential Scanning Calorimetry) of this new crystalline form.
  • FIG. III corresponds to the infrared spectrum of this new crystalline form.
  • FIG. IV corresponds to the spatial disposition of the atoms in the unit cell of this new crystalline form.
  • FIGS. V a and V b show representative thermogravimetric analysis curves obtained during thermogravimetric analysis.
  • FIG. VI illustrates the concept of activation energy Ea showed in a graph of reaction profile.
  • FIGS. VII and VII are TGA kinetics analysis plots, plotting heating rate versus F[p(x)] for different fractions of conversion (a) for the analyzed data files.
  • the X-ray diffraction analysis and the thermal analysis were carried out at the Atomic Energy National Commission—Condensed Matter Group.
  • the equipment used is a Philips model X'Pert with a PW3710 unit to obtain the diffractograms of the samples.
  • a K-Alpha wavelength of 1.54060 ⁇ was used.
  • the water losses were determined through the TGA (Thermogravimetric Analysis) with a Shimadzu DTG-50 equipment with a 40 mi/mm dry air flow.
  • the melting points result from the curves obtained through DSC (Differential Scanning Calorimetry) in a Shimadzu DSC-60 equipment at 10° C./min with a 30 ml/min nitrogen flow.
  • the infrared spectra were carried out in a Shimadzu FTIR-8 100 equipment, using a solid substance in the form of pills with KBr.
  • the new crystalline form corresponds to a trihydrate, its study by means of X rays of a single crystal shows that the distribution of its atoms in the crystalline network corresponds to the special group P-1, characterized by the following cell parameters ( ⁇ ): a: 6.874; b: 9.450; c: 10.825; ⁇ (alpha): 65.140; ⁇ (beta): 76.83 0; ⁇ (gamma): 81.390.
  • FIG. I shows the X-rays powder diffractogram (XRPD) of this new crystalline form.
  • FIG. II corresponds to the curves obtained through the TGA analysis (Thermogravimetric Analysis) and DSC (Differential Scanning Calorimetry) of this new crystalline form.
  • FIG. III corresponds to the infrared spectrum of this new crystalline form.
  • FIG. IV corresponds to the spatial disposition of the atoms in the unit cell of this new crystalline form.
  • the trihydrate crystalline form described in this document by means of the exposure in an environment with 75 to 96% relative humidity at 30-40° C. during 24 hours, does not absorb water and maintains its X-rays powder diffractogram and its thermal profile (TGA and DSC) unchanged.
  • This new crystalline form of this invention is characterized for presenting in its X ray powder diffractogram peaks in angles of 2 ⁇ of 9.2; 10.4; 10.8; 14.7; 16.4; 17.1; 18.4; 21.5; 21.8; 22.8; 25.0; 25.4; 27.8° ⁇ 0.2°.
  • the XRDP is the best analytical tool, it should not be used alone in the identification and characterization of the solid phases. Some drugs have the same. diffractogram (lines) under different solid phases. For the characterization of solid phases, it is always suggested the use of at least three or four analytical tools, i.e.: IR, TG, DSC together with the XRDP.
  • the product is also characterized because its thermal analysis (TGA and DSC) show an endotherm between 68-128° C. associated to a loss of mass of around 16-17%, which corresponds to a trihydrate and a melting endotherm followed by decomposition at around 211-215° C.
  • TGA and DSC thermal analysis
  • Zoledronic acid was prepared by a method not described for this substance and advantageous because of the yield and the quality of the obtained crude product.
  • the same consists of reacting 1- imidazol-1-yl acetic acid with phosphorous trichloride and water, in the presence of methanesulphonic acid.
  • the suspension is heated at 60-65° C. over 10-15 hours, preferably between 9-12 hours, whereupon it turns into a viscous solution.
  • the crude zoledronic acid may be obtained by means of drying at 50-80° C. with a yield exceeding 80% and a quality apt for the obtention of the crystalline trihydrate form.
  • an aqueous hot solution of zoledronic acid which concentration varies between 1.5 and 10% (w/v), preferably between 2 and 4% (w/v), is crystallized at a temperature between 5 and 35° C., preferably between 15 and 25° C.
  • the hot solution is poured over a small amount of water, kept at the wanted crystallization temperature.
  • the crystallization temperature is adjusted regulating the volume of the hot solution added and the flow of the refrigerating liquid.
  • This substance presents the following physicochemical characteristics.
  • polymorph according to the FDA in its Guidance for Industry—ANDAs: Pharmaceutical Solid Polymorphism—July 2007: Polymorphic forms in the context of this guidance refer to crystalline and amorphous forms as well as solvate and hydrate forms, which are described below:
  • Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice
  • Amorphous forms consists of disordered arrangements of molecules that do not posses a distinguishable crystal lattice
  • Solvates are crystals forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
  • Other drugs may have different solid phases (polymorph) of a trihydrated phase, but to date this is not the case for the zoledronic acid.
  • the following phases have been identified and characterized: one solid phase for monohydrate, one solid phase for trihydrate and one or two anhydrous (with this last phase we still have some doubts).
  • the different trihydrate solid phases that may exist, as well as the different solid phases of a monohydrate and/or all possible phases of the anhydride form are collectively referred to as a polymorph.
  • Phosphorous trichloride (856 ml) is slowly added with stirring to a suspension of 1-imidazol-1-yl acetic acid (200 g) in methanesulfonic acid 98-99% (240 ml)
  • the temperature is increased until reaching 55° C., reflux is observed.
  • the resulting solution is partially neutralized at a temperature of 30-40° C. with a sodium hydroxide aqueous solution 50% (w/v) until obtaining a pH of 0.25 ⁇ 0.03.
  • the solid is washed by resuspension once in water (500 ml) and twice in methanol (500 ml each time).
  • the precipitate is dried in an oven at 50-60° C., thus obtaining the crude zoledronic acid with a potentiometric titre equal to or exceeding 98%.
  • the yield is 83%.
  • the suspension is heated at reflux, thus obtaining a solution.
  • This hot solution is slowly added and stirring to a refrigerated container, containing water (50 ml).
  • the internal temperature is adjusted by means of the flow of refrigerant fluid and the volume of aggregate of the hot concentrated solution, in order to keep it between 15 and 25° C.
  • the diffractogram is the one shown in FIG. I.
  • the crude wet zoledronic acid (equivalent to 190.3 g dry product), obtained according to Example I, is suspended in water (3050 ml).
  • the suspension is heated at reflux, with agitation.
  • Water is added up to a total volume of 3750 ml, by which a total dissolution is obtained.
  • the heating and the agitation is then interrupted, allowing it to slowly cool down to ambient temperature.
  • the ambient temperature is cooled down to 2-5° C., maintained at that temperature during 11 ⁇ 2 hours, filtered and the solid is washed with ice water.
  • FIG. 1 A shows its diffractogram of powder X-rays
  • FIG. IV A the arrangement of the atoms in the unit cell of the crystalline network for this form.
  • Polymorphs as hydrates of an active pharmaceutical ingredient, may differ in key properties such as solubility, dissolution rate, stability, and particle habit. Hydrates represent different chemical entities as defined primarily by the stoichiometry of water to the active and in certain cases by different crystal structures. Depending upon the nature of the hydrate, the water content may or may not change over time with ambient humidity, temperature, or other processing and storage conditions. Accordingly, it is important to know, during the development of pharmaceuticals, if the water molecules are tightly coordinated and packed inside the crystal lattice. Depending on that, several problems could be generated. Many drugs are receiving regulatory approval for only a single crystal form or “polymorph”.
  • thermogravimetric analysis is used as an analytical methodology to quantify the thermal stability parameters of solid chemicals.
  • the data generated from these measurements is analyzed to obtain Arrhenius kinetic parameters such us activation energy (Ea) and preexponential factor.
  • the activation energies of two different hydrates—zoledronic acid monohydrate and trihydrate— is obtained to analyze the dehydration reaction of these two forms to anhydrous form so that the their relative solid-state thermal stability can be ranked based on their activation energy values.
  • TGA Thermogravimetric analysis
  • TGA Kinetics Analysis method covers determination of the kinetic parameters, Arrhenius activation energy preexponential factor by thermogravimetry, based on the assumption that the decomposition to obeys first-order kinetics.
  • This program utilizes data gathered by running a sample at various heating rates.
  • the program allows analysis of results from TGA data files to calculate the heating rate at each conversion percentage, and then generate plots and tables of kinetic analysis results.
  • the program operates in accordance with the ASTM Standard E1641 (Standard Test Method for Decomposition Kinetics by Thermogravimetry).
  • thermogravimetric analysis have been used to obtain kinetic information, with the constant heating rate method developed by Flynn & Wall being preferred because it requires less experimental time.
  • the constant heating rate, or conventional TGA, approach is based on the Flynn & Wall method which requires three or more determinations at different linear heating rates, usually between 0.5 and 50° C./minute.
  • Zoledronic acid monohydrate BFI 10929 and trihydrate BFI 10781 was obtained from GADOR S. A. API Division, R&D lab. The samples were characterized by loss on drying and X-ray diffraction.
  • X-ray Diffraction X-ray powder diffraction was executed using a Philips equipment X′ Pert model with the unit PW3710. Scans were performed over the range of 5°-40° 2 ⁇ , at a 0.02° step size for 2 s per step.
  • Thermogravimetry analysis curves were generated using a TGA Q-500 V6.4 TAInstruments®. The analysis was performed with TGA Kinetics Analysis TA Instruments®; program Specialty Library V2. 1 Build 2.1.0.1.
  • the heating rate versus F[p(x)] was graphed for different fraction of conversion (a) for the analyzed data files. Data points fit closely to the straight line, so the experimental data fits the mathematical model on which the determination is based.
  • activation energy Ea represents the amount of energy necessary to begin a chemical reaction and so convert the reagents to products.
  • the activation energy parameter represents the amount of energy necessary for hydrate forms of Zoledronic acid to start the loss of water molecules.
  • Zoledronic acid monohydrate had an Activation energy 152.0 kJ/ mole at 50.0 percent of conversion level.
  • Zoledronic acid trihydrate had an Activation energy 179.9.0 kJ/mole at 50.0 percent of conversion level.
  • TGA thermogravimetric analysis
  • the product solution was composed of the following: Ingredient Function Weight/vial Zoledronic acid, Active 4.794 mg trihydrate ingredient (Eq 4 mg zoledronic acid) Sodium Chloride Tonicity agent 43.000 mg Sodium Hydroxide pH adjuster 1.100 mg (or up to pH 6.0-6.5) Water for injection Vehicle Qs To 5 ml
  • Zoledronic acid was dissolved with water at room temperature. The rate of dissolution was further increased by the addition of sodium hydroxide which lead to the formation of a sodium salt (disodium salt in greater percentage) of zoledronic acid.
  • Sodium chloride was selected as a tonicity agent and sodium hydroxide as a pH-adjusting agent.
  • the compatibility of the bulk solution with the filters and tubing material was studied.
  • the compatibility of the concentrate for solution for infusion with packaging materials (vials +stoppers) and with infusion media (5% glucose solution and 0.9% sodium chloride solution in plastic and glass devices) was be demonstrated by verifying the compliance with drug product specifications during stability studies.
  • As part of the container/closure integrity test a microbiological challenge test with the primary packaging materials (upright and inverted position) was performed.
  • step 6 The solution from step 6 was added to the bulk solution in a quantity sufficient to reach a target pH of 6.2 (range: 6.0-6.5), under constant mechanical stirring.
  • the solution was sterile-filtered. Chemical quality control and bacterial endotoxins were determined in a sample.
  • Sterile bulk solution was aseptically filled into sterilized (plastic) or depyrogenized (glass) vials. Fill volume (or its equivalent weight) was checked.
  • the crystalline trihydrate form of the zoledronic acid demonstrated good relative kinetic-thermal stability (providing a direct benefit for the active agent in bulk formulations, achieving a longer storage period in the warehouse, and a lesser chance for the solid active to undergo any changes during storage in the warehouse) and also API characteristics that improved stability and handling during formulation. Many other crystal hydrates, in contrast, tend to lose water and release it into the environment during the formulation process, increasing the possibility of drug degradation. These technical improvements do not affect the drug's bioavailability, since same is administered via injection.

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ARP050103131A AR054673A1 (es) 2005-07-28 2005-07-28 Una forma cristalina del acido zoledronico, un proceso para su obtencion y la composicion farmaceutica que la comprende
PCT/EP2006/004473 WO2007016982A1 (fr) 2005-07-28 2006-05-12 Forme cristalline de l'acide zoledronique, son procede d'obtention et composition pharmaceutique la renfermant

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US20110014265A1 (en) * 2005-02-22 2011-01-20 John Dennis Bobyn Implant Improving Local Bone Formation
US20110028435A1 (en) * 2009-07-31 2011-02-03 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability
CN110551152A (zh) * 2018-05-31 2019-12-10 四川科伦药物研究院有限公司 唑来膦酸一水合物及无水物晶型制备方法

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WO2007032808A1 (fr) * 2005-09-12 2007-03-22 Dr. Reddy's Laboratories Ltd. Trihydrate cristallin de l'acide zolédronique
WO2007125521A2 (fr) * 2006-05-02 2007-11-08 Ranbaxy Laboratories Limited Formes polymorphiques de l'acide zolédronique et leurs procédés de synthèse
EP1925621A1 (fr) * 2006-11-27 2008-05-28 Novartis AG Formes cristallines de l'acide zolédronique
EA201270328A1 (ru) * 2009-08-28 2012-09-28 Синтон Б. В. Способ получения 1-гидроксиалкилиден-1,1-дифосфоновых кислот
US8882740B2 (en) 2009-12-23 2014-11-11 Stryker Trauma Gmbh Method of delivering a biphosphonate and/or strontium ranelate below the surface of a bone
HU230718B1 (hu) 2011-02-08 2017-11-28 Richter Gedeon Nyrt. Új eljárás dronsavak gyógyszeripari előállítására
CN102690288B (zh) * 2012-06-07 2015-06-17 吉林大学 一种双膦酸类化合物的制备方法

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Cited By (14)

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US8309536B2 (en) 2005-02-22 2012-11-13 John Dennis Bobyn Implant improving local bone formation
US20110014265A1 (en) * 2005-02-22 2011-01-20 John Dennis Bobyn Implant Improving Local Bone Formation
US8071574B2 (en) 2005-02-22 2011-12-06 John Dennis Bobyn Implant improving local bone formation
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US8933057B2 (en) 2009-07-31 2015-01-13 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US20110028435A1 (en) * 2009-07-31 2011-02-03 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9334296B2 (en) 2009-07-31 2016-05-10 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US10323052B2 (en) 2009-07-31 2019-06-18 Grunenthal Gmbh Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
US10519176B2 (en) 2010-11-24 2019-12-31 Thar Pharma, Llc Crystalline forms
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability
CN110551152A (zh) * 2018-05-31 2019-12-10 四川科伦药物研究院有限公司 唑来膦酸一水合物及无水物晶型制备方法

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US8338619B2 (en) 2012-12-25
AR054673A1 (es) 2007-07-11
AU2006278951B2 (en) 2012-01-12
NZ565356A (en) 2010-01-29
EP1924587A1 (fr) 2008-05-28
WO2007016982A1 (fr) 2007-02-15
CA2615418C (fr) 2011-04-26
CA2615418A1 (fr) 2007-02-15
AU2006278951A1 (en) 2007-02-15
US8952172B2 (en) 2015-02-10
ZA200800729B (en) 2009-08-26
KR20080031475A (ko) 2008-04-08
BRPI0613924A2 (pt) 2012-03-20
US20100197931A1 (en) 2010-08-05
KR20140023949A (ko) 2014-02-27

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