WO2003050127A1 - Methode de preparation de pamidronate disodique anhydre - Google Patents

Methode de preparation de pamidronate disodique anhydre Download PDF

Info

Publication number
WO2003050127A1
WO2003050127A1 PCT/EP2002/014136 EP0214136W WO03050127A1 WO 2003050127 A1 WO2003050127 A1 WO 2003050127A1 EP 0214136 W EP0214136 W EP 0214136W WO 03050127 A1 WO03050127 A1 WO 03050127A1
Authority
WO
WIPO (PCT)
Prior art keywords
process according
disodium pamidronate
comprised
suspension
solution
Prior art date
Application number
PCT/EP2002/014136
Other languages
English (en)
Inventor
Piergiorgio Anzaghi
Original Assignee
Istituto Biochimico Pavese Pharma S.P.A.
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 Istituto Biochimico Pavese Pharma S.P.A. filed Critical Istituto Biochimico Pavese Pharma S.P.A.
Priority to AU2002361063A priority Critical patent/AU2002361063A1/en
Publication of WO2003050127A1 publication Critical patent/WO2003050127A1/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 disodium pamidronate in amorphous and substantially anhydrous form.
  • Disodium pamidronate is an amino-substituted biphosphonate of formula:
  • Disodium pamidronate has therefore a potent inhibitory effect on bone reabsorption and is used in the treatment of Paget's disease and of the hypercalcaemia associated with bone reabsorption due to osteoporosis, hyperparathyroidism, multiple myeloma and bone metastasis (Martindale 32 nd Edition, 1999).
  • a crystalline and pentahydrate form of disodium pamidronate is present on the market as a medicine in reconstitutible lyophilised form (Aredia®, Novartis Pharmaceuticals Corp.) for administration by endovenous infusion.
  • patents US 4639338 and US 471880 in the name of Ciba Geigy, describe the preparation of a crystalline pentahydrate form of disodium pamidronate by crystallisation from an aqueous solution or by treatment of a solid form of the salt with a quantity of water necessary to obtain a crystal from crystallisation water .
  • Such a form is proposed for oral, rectal or endovenous use.
  • the International patent application W00142134 in the name of Hanlim Pharm Co Ltd, describes a process for the preparation of crystalline disodium pamidronate as a mixture of trihydrate and tetrahydrate forms.
  • Figure 1 shows an X ray diffractogram of disodium pamidronate obtained by the process of the invention, in the operative conditions described in Example 1.
  • Figures 2-7 show the SEM images of the morphological analysis of disodium pamidronate obtained by: - lyophilisation . with freezing at -35°C according to the parameters claimed in patent WO0034293 (Fig. 2 secondary electrons image, magnification 300x, Fig.3 secondary electrons image, magnification ⁇ 500x)
  • the present invention refers to a process for the preparation of disodium pamidronate in amorphous and substantially anhydrous form characterised in that it comprises the nebulisation of an aqueous solution of disodium pamidronate having a pH comprised between 6 and 7.
  • said process comprises the following steps: a) preparing an aqueous suspension of pamidronic acid; b) adding a sodium base to the suspension of step a) until reaching a pH comprised between 6 and 7, thereby obtaining a clear solution; c) filtering the solution coming from step (b); d) nebulising the solution coming from step (b).
  • the step a) suspension contains between 1 and 10 % w/v of pamidronic acid.
  • the above mentioned suspension contains also mannitol, preferably in concentrations comprised between 1 and 6% w/v.
  • sodium base is intended a base having a sodium ion as counterion.
  • said base is sodium hydroxide or sodium carbonate.
  • said pH is comprised between 6.5 and 6.9.
  • step b) and step c) the solution is diluted with water until obtaining a concentration of sodium pamidronate comprised between 10 mg/ml and 100 mg/ml.
  • step (c) the filtration is preferably performed using filters having a porosity of less than 0.45 ⁇ m
  • step (d) the nebulisation is performed in a nitrogen flow.
  • Said flow has preferably an inlet temperature comprised between 110° and 160°C and an outlet temperature comprised between 90° and 105°C.
  • the process of the invention can be carried out in a sterile environment.
  • the disodium pamidronate is suspended in sterile water, for example water for injectable preparation, filtered through filters having porosity of 0.2 ⁇ m and nebulised using a sterile nitrogen flow.
  • a sterile product can also be obtained by operating in non-sterile environments and sterilising the powder obtained from step d) with ⁇ or ⁇ rays.
  • the process of the invention is rapid and low-cost and facilitates the attainment of disodium pamidronate in amorphous and substantially anhydrous form with yields greater than 90%.
  • the product obtained with the above mentioned process is stable, also without the use of supports, and has a high solubilisation speed. Thanks to these characteristics it is therefore suitable to be used in the field of pharmaceuticals, in particular for injectable preparations.
  • the sterile powder obtained as described above can be repackaged into calcium free, not releasing silicon, previously depyrogenated glass vials, and sterilised in quantities of 15, 30 , 60 or 90 mg per vial. At the time of use the powder is dissolved in an appropriate quantity of water for injectable preparation.
  • anhydrous pamidronic acid In a sterile environment, 4 g of pharmaceutical grade anhydrous pamidronic acid are suspended in approx. 50 ml of water for injectable preparation under good agitation. To the suspension a solution of 1 N NaOH is then slowly added whilst constantly monitoring the pH until a clear solution having a pH of 6.8 is obtained. The solution is then adjusted to 100 ml with water (final concentration: 47.4 mg/ml), filtered through a filter having a porosity of 0.2 ⁇ m and nebulised with a nitrogen current with an inlet temperature of 160°C and an outlet temperature of 105°C. A white powder of disodium pamidronate is obtained with a yield of 95% by weight comprising that recovered from the filters, which is repackaged in sterile vials in doses of 30 mg.
  • Example 1 The powder obtained in Example 1 has been characterised as follows. a) The disodium pamidronate titre of the product obtained has been measured by
  • Example 4 The vials are immediately stoppered and ring-sealed in a nitrogen atmosphere, still working in a sterile environment.
  • the product obtained, analysed as described in Example 2, is completely amorphous and readily soluble and has a water content of 0.9% and a titre of 99.1%.
  • Example 4
  • Example 5 In a sterile environment, with good agitation 63 g of mannitol are dissolved in 300 ml of water for injectable preparation. In the solution are suspended 4 g of pamidronic acid. 1 N NaOH is added with constant control of the pH until a pH of 6.82 is reached.
  • the volume is adjusted to 350 ml with water for injectable preparation (final concentration of 13.5 mg/ml of disodium pamidronate), filtered with a filter of porosity 0.2 ⁇ m and nebulised with a nitrogen inlet temperature of 140°C and outlet temperature of 96°C.
  • a white powder is obtained with a yield greater than 97% including the recovered material.
  • This is repackaged into 140 sterile vials of 430 mg each, which are immediately stoppered and ring-sealed in a nitrogen atmosphere in the same sterile environment.
  • the product, analysed as described in Example 2 has a titre of 97.7%, is completely amorphous, contains 1.68% of water and is readily soluble.

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)
  • Orthopedics, Nursing, And Contraception (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une méthode de préparation de pamidronate disodique sous une forme amorphe et sensiblement anhydre, qui consiste en la nébulisation d'une solution aqueuse de pamidronate disodique dont le pH est compris entre 6 et 7.
PCT/EP2002/014136 2001-12-13 2002-12-12 Methode de preparation de pamidronate disodique anhydre WO2003050127A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002361063A AU2002361063A1 (en) 2001-12-13 2002-12-12 Preparation method for anhydrous disodium pamidronate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI20012634 ITMI20012634A1 (it) 2001-12-13 2001-12-13 Metodo di preparazione del panidronato disodico anidro
ITMI01A002634 2001-12-13

Publications (1)

Publication Number Publication Date
WO2003050127A1 true WO2003050127A1 (fr) 2003-06-19

Family

ID=11448693

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/014136 WO2003050127A1 (fr) 2001-12-13 2002-12-12 Methode de preparation de pamidronate disodique anhydre

Country Status (3)

Country Link
AU (1) AU2002361063A1 (fr)
IT (1) ITMI20012634A1 (fr)
WO (1) WO2003050127A1 (fr)

Cited By (1)

* 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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034293A1 (fr) * 1998-12-10 2000-06-15 Aesgen, Inc. Methode de preparation du pamidronate
WO2001042134A1 (fr) * 1999-12-10 2001-06-14 Hanlim Pharm. Co., Ltd. Nouvel hydrate de pamidronate disodique cristallin et methode de preparation
EP1236733A1 (fr) * 2001-02-23 2002-09-04 Bioindustria Laboratorio Italiano Medicinali S.p.a. Procédé de préparation de pamidronate disodique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034293A1 (fr) * 1998-12-10 2000-06-15 Aesgen, Inc. Methode de preparation du pamidronate
WO2001042134A1 (fr) * 1999-12-10 2001-06-14 Hanlim Pharm. Co., Ltd. Nouvel hydrate de pamidronate disodique cristallin et methode de preparation
EP1236733A1 (fr) * 2001-02-23 2002-09-04 Bioindustria Laboratorio Italiano Medicinali S.p.a. Procédé de préparation de pamidronate disodique

Cited By (1)

* 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

Also Published As

Publication number Publication date
ITMI20012634A1 (it) 2003-06-13
AU2002361063A1 (en) 2003-06-23

Similar Documents

Publication Publication Date Title
ES2271375T3 (es) Sales farmaceuticamente aceptables de alendronato en forma amorfa.
EP1930011B1 (fr) Forme cristalline de ibandronate de sodium
US8951540B2 (en) Biomimetic hydroxyapatite synthesis
EP0216459B1 (fr) Monohydrates de guanine substitués en position 9
AU2002334200A1 (en) Pharmaceutically acceptable alendronate salts in amorphous form
JP2004513970A (ja) 凍結乾燥したパントプラゾール製剤及びパントプラゾール注射剤
PT94188B (pt) Processo para a purificacao de acidos aminometilenofosfonicos
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
WO1997002827A1 (fr) Utilisation therapeutique de l'acide 1-amino-3-(n,n-dimethylamino)-propylidene-1,1-bisphosphonique et des sels dudit acide
JPH08500830A (ja) ジホスホン酸およびその塩を含有する医薬品
CN101663314B (zh) D-异谷氨酰基-d-色氨酸的一钠盐的晶态形式
WO2003050127A1 (fr) Methode de preparation de pamidronate disodique anhydre
Dorozhkin et al. Precipitation of carbonateapatite from a revised simulated body fluid in the presence of glucose
US6160165A (en) Method for preparation of disodium pamidronate
IL39005A (en) Salts of iodomethanesulphonic acid with pentahydroxyhexylamine and n-alkyl derivatives thereof
PL196046B1 (pl) Postać krystaliczna monohydratu cytrynianu (2S,3S)-N-(2-metoksy-5-t-butylofenylo)metylo-2-difenylometylo-1-azabicyklo[2.2.2]oktano-3-aminy, środek farmaceutyczny, zastosowanie tej postaci krystalicznej i sposób wytwarzania tej postaci krystalicznej
IE66515B1 (en) Stable solutions of rebeccamycin analog and preparation thereof
EP0006223A1 (fr) Sels cristallins de sodium et de potassium de l'indométhacine et leurs trihydrates, leur procédé de préparation et compositions pharmaceutiques les contenant
EP0891979B1 (fr) Une forme cristalline du monohydrate du sel monosodique de l'acide N,N-diméthyl-3-amino-1-hydroxypropane-1,1-diphosphonique
JP2002220395A (ja) ホスホノセフェム化合物
RU2042686C1 (ru) Кристаллический этопозид 4`-фосфат диэтанолсольват и способ его получения
EP3149014B1 (fr) Procédé pour fabriquer du dtpmp cristallin
JPH10511383A (ja) 高純度のｎ−（４−〔ｎ，ｎ−ビス（２−ヨードエチル）アミノ〕フェノキシカルボニル）−ｌ−グルタミン酸
JPH11335377A (ja) クエン酸水素マグネシウム水和物およびその製法

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 SC SD SE SG 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 SI 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