[go: up one dir, main page]

WO2003053985A1 - Sel monosodique d'acide pamidronique et preparation de celui-ci - Google Patents

Sel monosodique d'acide pamidronique et preparation de celui-ci Download PDF

Info

Publication number
WO2003053985A1
WO2003053985A1 PCT/EP2002/012367 EP0212367W WO03053985A1 WO 2003053985 A1 WO2003053985 A1 WO 2003053985A1 EP 0212367 W EP0212367 W EP 0212367W WO 03053985 A1 WO03053985 A1 WO 03053985A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
pamidronate
preparation
pamidronic acid
monosodium
Prior art date
Application number
PCT/EP2002/012367
Other languages
English (en)
Inventor
Simona Grassi
Anna Volante
Original Assignee
Lyogen 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 Lyogen Limited filed Critical Lyogen Limited
Priority to AU2002366719A priority Critical patent/AU2002366719A1/en
Publication of WO2003053985A1 publication Critical patent/WO2003053985A1/fr

Links

Classifications

    • 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)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)

Definitions

  • the present invention relates to a process for the preparation of pamidronic acid monosodium salt, which is suitable for use both as such in pharmaceutical preparations for the oral use, and as an intermediate for the preparation of the lyophilized sodium salt which is used for the preparation of pharmaceutical injectable forms.
  • the two crystalline forms of the monosodium salt, both the anhydrous and the hydrate one, are particularly stable in a wide range of humidity and temperature conditions, and have solubility characteristics by far more advantageous than pamidronic acid when this has to be transformed into the disodium salt for the pharmaceutical injectable preparations.
  • hypercalcemia is widely used for inhibiting hypercalcemia, particularly for the therapy of hypercalcemia due to neoplastic osteolysis and lytic bone metastases.
  • the resulting "amorphous" salt is not at all free from crystallinity and tends to transform into the pentahydrate, at least partly.
  • a first object of the present invention is pamidronic acid monosodium salt, in the anhydrous or hydrate form, and the use thereof as an intermediate for the preparation of the disodium salt or as active ingredient for pharmaceutical compositions.
  • a second object of the invention is a process for the preparation of pamidronic acid amorphous disodium salt, containing a water percentage above 2%, which comprises: a) addition of sodium carbonate, bicarbonate or hydroxide to an alkaline pH of 7.5 + 0.2 to a monosodium pamidronate water suspension; b) sterile filtration of the solution from a); c) lyophilization of the solution frozen at -45°C at a temperature ranging from 0°C to 47°C under pressures below 100 mbars.
  • a further object of the invention is amorphous disodium pamidronate obtainable according to the process described above, characterized by water content above about 2% by weight.
  • pamidronic acid monosodium salt is obtained by suspending pamidronic acid in water, then adding a stoichiometric amount of sodium hydroxide, carbonate or bicarbonate.
  • the hydrate monosodium salt is then crystallized from the resulting solution and can be converted into the anhydrous form by treatment at temperatures ranging from 100 to 200°C for about 10-24 hours.
  • the monosodium salt can be per se useful as active ingredient of pharmaceutical compositions for the treatment of osteoporosis, in that it has adequate solubility in injectable carriers and is particularly suitable in patients requiring reduced intake of sodium ions.
  • a further advantage of the resulting monosodium salt, as already mentioned, is the stability of the crystalline form, which does not undergo conversion into other forms, which conversion would involve technical problems from the formulative and regulatory standpoints.
  • Formulations and dosages are quite similar to those used for the disodium salt.
  • the monosodium salt can advantageously be used as an intermediate, thanks to its solubility characteristics.
  • monosodium pamidronate is treated in water with stoichiometric amounts of sodium carbonate, bicarbonate or hydroxide, preferably carbonate or bicarbonate, to an about 0.5% disodium pamidronate aqueous a solution.
  • the solution is filtered through sterile filter, then frozen at -45°C and finally lyophilized within a temperature range of 0 - 47°C.
  • lyophilization can be carried out using conventional lyophilization carriers, such as lactose, mannitol, and the like.
  • the present invention is illustrated in greater detail in the following examples.
  • a mixture of 54 g of ⁇ -alanine (0.606 mols) and 450 g of phosphorous acid (5.49 mols) is added with 302.4 g of phosphorous oxychloride (1.97 mols).
  • the reaction mixture is heated at 45°C for 17 hours and then at 65- 70°C for 6 hours.
  • the mixture is then cooled to 40°C, added with 630 ml of water and stirred at room temperature overnight. After that, the mixture is refluxed for 6 hours, added with 3 g of charcoal, refluxed for a further 30 minutes and filtered through Celite while hot. pH is adjusted to 4.24 by addition of a 40% NaOH solution.
  • a suspension of 9.45 g of hydrate monosodium pamidronate in 2 1 of water is added with 32.2 ml of IM NaOH to pH 7.5 ⁇ 0.2.
  • the solution is filtered through 0.22 micron filter, frozen at -45 °C and lyophilized ( ⁇ 100 mbars, 0-47°C) to give amorphous disodium pamidronate (DRX as shown in Figure C) with water content > 2%.
  • a suspension of 8.66 g of anhydrous monosodium pamidronate is treated as described in example 4 to obtain amorphous disodium pamidronate with water content > 2%.
  • a suspension of 3.5 g of hydrate monosodium pamidronate in 23 ml of water is added with 12.4 ml of IM sodium hydroxide to pH 7.5 ⁇ 0.2, to obtain a clear solution which is filtered through 0.22 micron filter and lyophilized as described in example 4.
  • Pamidronic acid disodium salt is obtained, in the amorphous form and with water content > 3%.
  • amorphous disodium pamidronate from hydrate monosodium pamidronate
  • a solution of monosodium pamidronate, prepared as in example 7, is filtered through 0.22 micron filter and pumped into a spray-dryer (nozzle temperature 180-200°C) to give amorphous disodium pamidronate with water content >3%.
  • Example 10 Amorphous monosodium pamidronate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne un procédé de préparation de sel monosodique d'acide pamidronique pouvant être utilisé à la fois en tant que tel dans des préparations pharmaceutiques destinées à être administrées par voie orale et comme intermédiaire pour la préparation du sel de sodium lyophilisé qui est utilisé pour la préparation de formes injectables pharmaceutiques. Les deux formes cristallines du sel monosodique, à savoir la forme anhydre et la forme hydratée, sont particulièrement stables dans une grande variété de conditions d'hygrométrie et de température.
PCT/EP2002/012367 2001-12-21 2002-11-06 Sel monosodique d'acide pamidronique et preparation de celui-ci WO2003053985A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002366719A AU2002366719A1 (en) 2001-12-21 2002-11-06 Pamidronic acid monosodium salt and preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI01A002751 2001-12-21
IT2001MI002751A ITMI20012751A1 (it) 2001-12-21 2001-12-21 Sale monosodico dell'acido pamidronico e procedimento per la sua preparazione

Publications (1)

Publication Number Publication Date
WO2003053985A1 true WO2003053985A1 (fr) 2003-07-03

Family

ID=11448738

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/012367 WO2003053985A1 (fr) 2001-12-21 2002-11-06 Sel monosodique d'acide pamidronique et preparation de celui-ci

Country Status (3)

Country Link
AU (1) AU2002366719A1 (fr)
IT (1) ITMI20012751A1 (fr)
WO (1) WO2003053985A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005054260A1 (fr) * 2003-12-04 2005-06-16 Mustafa Nevzat Ilac Sanayii A.S. Procedes de production de pamidronate de disodium pur
CN104072538A (zh) * 2014-07-10 2014-10-01 陕西汉江药业集团股份有限公司 一种双膦酸盐类药物的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0177443A1 (fr) * 1984-08-06 1986-04-09 Ciba-Geigy Ag Modification cristalline de disodium-3-amino-1-hydroxypropane-1,1-diphosphonate
WO2000034293A1 (fr) * 1998-12-10 2000-06-15 Aesgen, Inc. Methode de preparation du pamidronate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0177443A1 (fr) * 1984-08-06 1986-04-09 Ciba-Geigy Ag Modification cristalline de disodium-3-amino-1-hydroxypropane-1,1-diphosphonate
WO2000034293A1 (fr) * 1998-12-10 2000-06-15 Aesgen, Inc. Methode de preparation du pamidronate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KIECZYKOWSKI G R: "Preparation of (4-amino-1-hydroxybutylidene)bisphosphonic acid sodium salt, MK217 (Alendronate Sodium). An improved procedure for the preparation of 1-Hydroxy-1,1-bisphosphonic acids", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 60, no. 25, 1995, pages 8310 - 8312, XP002162672, ISSN: 0022-3263 *
NEVES M ET AL: "Synthesis, characterization and biodistribution of bisphosphonates Sm-153 complexes: correlation with molecular modeling interaction studies", NUCLEAR MEDICINE AND BIOLOGY, ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, US, vol. 29, no. 3, April 2002 (2002-04-01), pages 329 - 338, XP004346639, ISSN: 0969-8051 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005054260A1 (fr) * 2003-12-04 2005-06-16 Mustafa Nevzat Ilac Sanayii A.S. Procedes de production de pamidronate de disodium pur
CN104072538A (zh) * 2014-07-10 2014-10-01 陕西汉江药业集团股份有限公司 一种双膦酸盐类药物的合成方法

Also Published As

Publication number Publication date
AU2002366719A1 (en) 2003-07-09
ITMI20012751A1 (it) 2003-06-21

Similar Documents

Publication Publication Date Title
JP4490100B2 (ja) 薬剤的に許容されるアモルファス形態のアレンドロ酸塩
US5395826A (en) Guanidinealkyl-1,1-bisphosphonic acid derivatives, process for their preparation and their use
IL176487A (en) Ibandronic acid monosodium salt in amorphous form, pharmaceutical compositions containing it and a process for its preparation
NO148583B (no) Kohesive, bare til seg selv og ikke til fremmedlegemer klebende bind for fremstilling av fikseringsbandasjer, og fremgangsmaate til fremstilling av slike bind
JPH058717B2 (fr)
KR20080031475A (ko) 결정형의 졸레드로닉산, 이의 제조방법 및 이를 포함하는약학 조성물
AU2002334200A1 (en) Pharmaceutically acceptable alendronate salts in amorphous form
DK154648B (da) Blandingssalte af glukosaminsulfat og fremgangsmaade til fremstilling deraf
JP2006511489A (ja) ３−ピリジル−１−ヒドロキシエチリデン−１，１−ビスホスホン酸のナトリウム塩の新規な結晶形態
CN101347412B (zh) 三水合氨磷汀结晶冻干制剂及其制备方法
WO2003053985A1 (fr) Sel monosodique d'acide pamidronique et preparation de celui-ci
CA2707344A1 (fr) Sels stables de s-adenosylmethionine et procede de preparation de ceux-ci
EP1723157B2 (fr) Formes amorphes de risedronate monosodique
US6160165A (en) Method for preparation of disodium pamidronate
JP3637019B2 (ja) 新規な結晶性パミドロン酸二ナトリウム水和物及びその製造方法
WO2002098434A1 (fr) Methode de fabrication de gluconolactate de calcium, compositions, processus et utilisations de celui-ci
ES2365919T3 (es) Procedimiento para la preparación de ácidos alquil y arildifosfónicos y las sales de los mismos.
WO2001030788A1 (fr) Nouveaux sels d'acide 4- amino-1-hydroxy-butylidene-1,1-bisphosphonique, leur preparation et utilisation
WO2003064438A1 (fr) Alendronate monosodique amorphe et preparation de celui-ci
AU2150792A (en) Dimethylamino-hydroxy-alkan diphosphonic acids and pharmaceutical compositions containing them
PL87238B1 (fr)
HK1066011B (en) Pharmaceutically acceptable alendronate salts in amorphous form
CN119455093A (zh) 一种多阴离子杂化的非晶骨粉及其制备方法
JP2004514713A (ja) フェニレン−ビス−ベンゾイミダゾール−テトラスルホン酸二ナトリウム塩の製造方法
JPS61254573A (ja) ２−シアナミノ−４，６−ジアルキル−１，３，５−トリアジンの製法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP