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WO2013048996A1 - Procédé de purification de précurseur d'agent d'imagerie peptidique - Google Patents

Procédé de purification de précurseur d'agent d'imagerie peptidique Download PDF

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Publication number
WO2013048996A1
WO2013048996A1 PCT/US2012/057010 US2012057010W WO2013048996A1 WO 2013048996 A1 WO2013048996 A1 WO 2013048996A1 US 2012057010 W US2012057010 W US 2012057010W WO 2013048996 A1 WO2013048996 A1 WO 2013048996A1
Authority
WO
WIPO (PCT)
Prior art keywords
column
peptide
imaging agent
based imaging
stationary phase
Prior art date
Application number
PCT/US2012/057010
Other languages
English (en)
Inventor
Willy SKJOLD
Dimitrios Mantzilas
Original Assignee
Ge Healthcare Limited
Medi-Physics, Inc.
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 Ge Healthcare Limited, Medi-Physics, Inc. filed Critical Ge Healthcare Limited
Publication of WO2013048996A1 publication Critical patent/WO2013048996A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/32—Bonded phase chromatography
    • B01D15/325—Reversed phase
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
    • B01D15/20—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to the conditioning of the sorbent material
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C07K1/20—Partition-, reverse-phase or hydrophobic interaction chromatography

Definitions

  • the present invention relates to a method for purifying a peptide-based imaging agent precursor useful in the synthesis of a positron emission tomography (PET) imaging agent, namely, [ 18 F]fluciclatide.
  • PET positron emission tomography
  • [ 18 F]-Fluciclatide is a diagnostic PET agent for the imaging, among other things, malignant diseases, heart diseases, endometriosis, inflammation-related diseases,
  • [ F]-Fluciclatide is also useful in anti- angiogenic imaging and therapy follow-up against, e.g. , high-grade glioma, renal cell carcinoma, melanoma, invasive breast tumors, distant metastases, head, and neck tumors.
  • the end synthesis of the agent can be performed at PET centers using automated synthesis platforms including the TRACERlab FX F-N platform or the FASTlab platform, both from GE Healthcare Ltd, Amersham, U.K.
  • the peptide-based imaging agent precursor of [ 18 F]-fluciclatide, AH111695 is typically purified, after synthesis, using high-performance liquid chromatography
  • the invention relates to a method for purifying a peptide-based imaging agent precursor comprising directing a composition comprising said peptide- based imaging agent precursor though a spring-loaded chromatrography column having an inner diameter and comprising a stationary phase modified to contain a hydrocarbon chain having a length longer than C-4.
  • the stationary phase is modified to contain a hydrocarbon chain having a length longer than C-8.
  • the stationary phase is modified to contain a C-18 hydrocarbon chain.
  • the column has an inner diameter of 2d, and when compared with a column of the same length but having an inner diameter of d, although the flow rate is increased by a factor of four, the amount of peptide-based imaging agent precursor loaded, in grams, onto the column increases by at least a factor of seven. In certain other embodiments, the amount of peptide-based imaging agent precursor loaded, in grams, onto the column increases by at least a factor of nine.
  • the invention in another aspect, relates to a spring-loaded column having an inner diameter and comprises a stationary phase modified to contain a hydrocarbon chain having a length longer than C-4, wherein said column comprises a peptide-based imaging agent precursor loaded thereon.
  • the stationary phase is modified to contain a hydrocarbon chain having a length longer than C-8.
  • the stationary phase is modified to contain a C-18 hydrocarbon chain.
  • the column has an inner diameter of 2d, and when compared with a column of the same length but having an inner diameter of d, although the flow rate is increased by a factor of 4, the amount of peptide-based imaging agent precursor loaded, in grams, onto the column increases by at least a factor of 7. In certain other embodiments, the amount of peptide-based imaging agent precursor loaded, in grams, onto the column increases by at least a factor of 9.
  • Another aspect of the present invention provides of a method of improving a column performance/efficiency for purifying a peptide-based imaging agent precursor by directing a composition including the peptide-based imaging agent precursor though a spring-loaded chromatography column having an inner diameter and comprising a stationary phase modified to contain a hydrocarbon chain having a length longer than C-4; where the improvement comprises: a) increasing the inner diameter by a factor of 2, and b) increasing the amount of peptide-based imaging agent precursor loaded, in grams, onto said column by at least a factor of 7 or up to at least a factor of nine. Additionally, the flow rate in such an improved column may be increased by a factor of four.
  • FIGS. 1A-1C depict a cross-section of a portion of a spring-loaded column.
  • FIG. 2 depicts an HPLC trace of crude AH111695 , monitored at 215 nm (UV- detection), prior to purification according to the methods described herein.
  • FIG. 3 depicts an HPLC trace for the purification run, monitored at 214 nm (UV-detection).
  • FIG 4 depicts an HPLC trace for the AH111695, monitored at 215 nm (UV- detection), purified according to the methods described hrein. DETAILED DESCRIPTION OF THE INVENTION
  • the crude [ F]FBA is typically purified on a SPE (solid phase extraction) cartridge to remove excess 4-trimethyl ammonium benzaldehyde, reaction by-products, Kryptofix 222, and other impurities.
  • SPE solid phase extraction
  • the peptide-based imaging agent precursor to [ 18 F]-fluciclatide, AH111695 is manufactured via a multi-step synthesis culminating in preparative HPLC purification.
  • the HPLC purification is carried out by chromatographing the peptide-based imaging agent precursor though a spring-loaded column comprising a C- 18 stationary phase.
  • the term "spring-loaded column” refers to columns that contain a dynamic axial compression system that avoids the formation of a void at the column inlet by continually forcing a piston against the stationary phase at the column inlet. See FIGS. 1A-1C.
  • the column 100 includes an elongate tubular body 102 parts of it filled with stationary phase 106.
  • Column 100 also includes a piston 104 which includes circular, disc-shaped piston elements 108 and 110 spanning across cavity 106 with a dynamic axial compression system 112 between the two piston elements.
  • column 100 is, in some embodiments, about 5 to about 25 cm in length (e.g. , about 5 to about 25 cm; about 10 to about 25 cm; about 5 to about 15 cm in length; about 10 to about 15 cm in length; about 5 to about 10 cm in length; or about 8 to about 15 cm in length) and the cavity 106 about 5 to about 15 cm in diameter (e.g. , about 5 to about 10 cm in diameter; or about 10 to about 15 cm in diameter), although the size and shape of column 100 may be selected as will be suitable for its intended purpose.
  • the spring-loaded column should have the capacity for purifying a peptide-based imaging agent precursor, such as AH111695 in a scale of 1 g to 7 g or more. In other embodiments, the spring-loaded column should have the capacity for purifying a peptide-based imaging agent precursor in a scale of 10 g or more. In some embodiments, the length of the column 100 is 25 cm and the diameter is 10.1 cm. [0016] As used herein, the term “diameter" refers to inner diameter.
  • a void 114 forms upon application of, e.g. , axial pressure from the solvent being pushed through the column 100 (see FIG. IB), the dynamic axial compression system 112 automatically expands or elongates, thereby eliminating the void 114 (see FIG. 1C).
  • Exemplary spring-loaded columns useful in the embodiments of the present invention include MODcol ® Dynamic Axial Compression Spring ® Columns available from Grace Davison Discovery Sciences, Lokeren, Belgium.
  • the spring-loaded column contains a stationary phase (e.g. , silica gel or a polymer polystyrene divinylbenzene resin with reverse-phase chromatography properties) that has been modified.
  • the stationary phase is modified to contain a hydrocarbon chain having a length longer than C-4, C-8 or longer than C-18.
  • the stationary phase is modified to contain a C-18 hydrocarbon chain.
  • Exemplary, non-limiting stationary phases include Luna C-18 stationary phases available from Phenomenex, Torrance, CA.
  • the column is a MODcol ® Dynamix Axial Compression Spring ® Column having a 10.1 cm diameter and a 25 cm length; and the stationary phase is a Luna C-18 stationary phase.
  • the spring-loaded column of the embodiments of the present invention is in fluid connection with a preparative, high-performance liquid chromatography (HPLC) apparatus.
  • HPLC high-performance liquid chromatography
  • the HPLC unit contains one or more pumps that force a liquid phase through the column, under pressure.
  • the liquid phase in some embodiments contains water and a proportion of an organic solvent. In some embodiments, the liquid phase is 100% water, but may contain up to 30 % of an organic solvent, e.g.
  • the liquid phase is 100% water, but may contain up to 50 % of an organic solvent, e.g. , from about 2% to about 50%; about 10% to about 50%; about 10% to about 15%; or about 15% to about 50%.
  • the mobile phase flows through the spring-loaded column and the mobile phase is adjusted such that there is a solvent gradient flowing through the column that can be changed in an automated fashion, to vary as a function of time.
  • the mobile phase can be changed, over time, such that the amount of organic solvent can be ramped up from 5% up to 30%; e.g. , from about 13% to about 26% over a certain period of time (e.g. , over 30 minutes).
  • the percentage of water can be proportionately decreased over time.
  • Exemplary organic solvents include acetonitrile, hydoxylic solvents or mixtures thereof.
  • Exemplary hydroxylic solvents include, without limitation, methanol, ethanol, propanol (e.g., n-butanol and iso-propanol), and butanol (e.g., n-butanol, iso- butanol, sec-butanol, and t-butanol), or mixtures thereof.
  • the water and/or the organic solvent can contain trifluoroacetic acid (e.g. , 0.1 % TEA). Other acids may be used in addition to or instead of trifluoroacetic acid.
  • the Scale up Factor is even lower than the theoretical value (observed with other large scale column technologies).
  • the scale up factor in the instant applications have increased by at least a factor of 7.
  • the scale up factor increases by at least a factor of 9.
  • the flow rate is increased by a factor of 4
  • the amount of peptide-based imaging agent precursor loaded, in grams, onto the column increases by at least a factor of 7, when compared with a column of the same length but with an inner diameter of d.
  • the amount of peptide-based imaging agent precursor loaded, in grams, onto the column increases by at least a factor of 9.
  • the present invention provdes a method of improving a column performance/efficiency for purifying a peptide-based imaging agent precursor by directing a composition including the peptide-based imaging agent precursor though a spring-loaded chromatography column having an inner diameter and comprising a stationary phase modified to contain a hydrocarbon chain having a length longer than C-4; where the improvement comprises: a) increasing the inner diameter by a factor of 2, and b) increasing the amount of peptide-based imaging agent precursor loaded, in grams, onto said column by at least a factor of seven or up to at least a factor of nine. Additionally, the flow rate in such an improved column may be increased by a factor of four.
  • the fluid collected from the HPLC containing the purified peptide-based imaging agent precursor can be passed through an Solid Phase Extraction (SPE) cartridge or column, thereby trapping the precursor in the SPE cartridge or column; and washing said SPE cartridge or column with a solvent (e.g. , acetonitrile, hydoxilic solvents or mixtures thereof) thereby releasing the precursor from the SPE cartridge or column.
  • SPE Solid Phase Extraction
  • a solvent e.g. , acetonitrile, hydoxilic solvents or mixtures thereof
  • Suitable stationary phases for use in an SPE cartridge or column can be any stationary phase known in the art, including a C-30 stationary phase.
  • the stationary phase can be a polymer based medium for high pH applications.
  • the purified peptide-based imaging agent precursor will be contained in the mobile phase that flows through the spring-loaded column.
  • the mobile phase can be removed via evaporation using a roto-evaporator, by distillation, by spray-drying, by freeze-drying or a combination of these techniques.
  • the residue that remains after the removal of the solvent is isolated peptide-based imaging agent precursor.
  • the purity of the imaging agent precursor can be evaluated by methods known in the art, including, 1H NMR, UV-Vis, LC-MS and/or IR.
  • the isolated peptide-based imaging agent precursor may require further processing to remove, e.g. , trifluoroacetic acid (TFA) that may be left over from prep- HPLC purification according to the embodiments of the present invention.
  • TFA trifluoroacetic acid
  • Removal of contaminants like TFA can be effected by adding water to the residue and removing the water by freeze-drying.
  • the TFA may be effectively removed by adding water containing 5-15% acetonitrile, then removing the water-acetonitrile in vacuo.
  • AH111695 was synthesized according to a procedure similar to the one described in WO2006/030291 , which is incorporated by reference as if fully set forth herein. Briefly, 38 g (0.02 mol)the compound of the formula (AH111570):
  • a 7.5 g portion of AH111695 was dissolved in 240 mL CH 3 CN/H 2 0 + 0.1 % TEA (10/90) .
  • the sample was loaded onto the column by a dedicated product injection pump via the injection port of the HPLC.
  • a fixed gradient (water+ 0.1% TFA; acetonitrile + 0.1 % TFA) was run for 28 minutes at a flow rate of 280 mL/min. During that time, the percent acetonitrile was increased from 13% to 26%.
  • the total run time was 48 minutes, including wash-out and re-equilibration periods.
  • the retention time of the AH111695 was 20 minutes.
  • the AH111695 was isolated in about 1.3 L of solvent (i.e. , mobile phase) at a concentration of approximately 4-6 mg/mL.
  • FIG. 2 depicts an HPLC trace of crude AH111695 , monitored at 215 nm (UV- detection), prior to purification according to the methods described herein.
  • the crude product purity was 92.5 area%.
  • FIG. 3 depicts an HPLC trace for the purification run, monitored at 214 nm (UV-detection).
  • FIG. 4 depicts an HPLC trace for the AH111695, monitored at 215 nm (UV-detection) sandwich purified according to the methods described hrein.
  • the product purity was 99.8 area%.

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  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un procédé de purification d'un précurseur d'agent d'imagerie peptidique, ledit procédé comportant la chromatographie d'une composition comportant ledit précurseur d'agent d'imagerie peptidique à travers une colonne à ressort ayant un diamètre interne et comportant une phase stationnaire C-18.
PCT/US2012/057010 2011-09-30 2012-09-25 Procédé de purification de précurseur d'agent d'imagerie peptidique WO2013048996A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161541647P 2011-09-30 2011-09-30
US61/541,647 2011-09-30
US201261583717P 2012-01-06 2012-01-06
US61/583,717 2012-01-06

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WO2013048996A1 true WO2013048996A1 (fr) 2013-04-04

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015046278A1 (fr) 2013-09-24 2015-04-02 富士フイルム株式会社 Nouveau composé contenant de l'azote ou son sel, ou son complexe métallique
KR20170117577A (ko) 2015-03-25 2017-10-23 후지필름 가부시키가이샤 신규인 함질소 화합물 또는 그 염의 제조 방법 및 이들의 제조 중간체
US11841350B2 (en) 2021-03-16 2023-12-12 Bio-Rad Laboratories, Inc. Dynamic axial compression for preparative columns using external compression

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5951873A (en) * 1997-12-23 1999-09-14 Modcol Corporation Chromatographic device with piston locking mechanism and method of packing same
US20050070466A1 (en) * 2001-07-10 2005-03-31 Alan Cuthbertson Peptide-based compounds
WO2006030291A2 (fr) 2004-09-14 2006-03-23 Ge Healthcare As Composes pour diagnostics
WO2011044422A2 (fr) * 2009-10-08 2011-04-14 Ge Healthcare Limited Procédé de purification par extraction en phase solide
WO2011098808A1 (fr) * 2010-02-09 2011-08-18 Biotica Technology Limited Composés à base de sangliféhrine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5951873A (en) * 1997-12-23 1999-09-14 Modcol Corporation Chromatographic device with piston locking mechanism and method of packing same
US20050070466A1 (en) * 2001-07-10 2005-03-31 Alan Cuthbertson Peptide-based compounds
WO2006030291A2 (fr) 2004-09-14 2006-03-23 Ge Healthcare As Composes pour diagnostics
WO2011044422A2 (fr) * 2009-10-08 2011-04-14 Ge Healthcare Limited Procédé de purification par extraction en phase solide
WO2011098808A1 (fr) * 2010-02-09 2011-08-18 Biotica Technology Limited Composés à base de sangliféhrine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Grace Prep and Process Purification, Prepacked Columns", 19 December 2007 (2007-12-19), XP055044648, Retrieved from the Internet <URL:http://www.discoverysciences.com/uploadedFiles/Preparative_and_Process/PrepProcessPurif_ProdInfo_PrepackedCols_p148to151_p156to161.pdf> [retrieved on 20121119] *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015046278A1 (fr) 2013-09-24 2015-04-02 富士フイルム株式会社 Nouveau composé contenant de l'azote ou son sel, ou son complexe métallique
EP3929196A1 (fr) 2013-09-24 2021-12-29 FUJIFILM Corporation Nouveau composé contenant de l'azote ou son sel ou son complexe métallique
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
EP4249471A2 (fr) 2013-09-24 2023-09-27 FUJIFILM Corporation Composition pharmaceutique d'un composé contenant de l'azote ou son sel ou son complexe métallique
KR20170117577A (ko) 2015-03-25 2017-10-23 후지필름 가부시키가이샤 신규인 함질소 화합물 또는 그 염의 제조 방법 및 이들의 제조 중간체
EP3872079A1 (fr) 2015-03-25 2021-09-01 FUJIFILM Corporation Procédé de production d'un nouveau composé contenant de l'azote ou d'un sel de ce composé, et produit intermédiaire de production correspondant
EP4059936A1 (fr) 2015-03-25 2022-09-21 FUJIFILM Corporation Procédé de fabrication d'un nouveau composé contenant de l'azote ou son sel et intermédiaire de fabrication d'un nouveau composé contenant de l'azote ou son sel
US11841350B2 (en) 2021-03-16 2023-12-12 Bio-Rad Laboratories, Inc. Dynamic axial compression for preparative columns using external compression

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