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WO2013024399A1 - Procédé amélioré de détermination quantitative du prasugrel chlorhydrate - Google Patents

Procédé amélioré de détermination quantitative du prasugrel chlorhydrate Download PDF

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Publication number
WO2013024399A1
WO2013024399A1 PCT/IB2012/054018 IB2012054018W WO2013024399A1 WO 2013024399 A1 WO2013024399 A1 WO 2013024399A1 IB 2012054018 W IB2012054018 W IB 2012054018W WO 2013024399 A1 WO2013024399 A1 WO 2013024399A1
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WO
WIPO (PCT)
Prior art keywords
prasugrel
eluent
hplc
impurities
hplc method
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/IB2012/054018
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English (en)
Inventor
Venkatraman JAYARAMAN
Sundara Kalyana BALAJI
Sanjiv DIXIT
Jagadish KADIA
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.)
Alembic Pharmaceuticals Ltd
Original Assignee
Alembic Pharmaceuticals 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 Alembic Pharmaceuticals Ltd filed Critical Alembic Pharmaceuticals Ltd
Publication of WO2013024399A1 publication Critical patent/WO2013024399A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds

Definitions

  • the present invention relates to an improved reversed-phase liquid chromatographic (RP-LC) method for the quantitative determination of Prasugrel HCl.
  • RP-LC reversed-phase liquid chromatographic
  • the present invention further provides a stability indicating analytical method using the samples generated from forced degradation studies.
  • Prasugrel HCl is chemically known as 2-Acetoxy-5-( ⁇ -cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride
  • Prasugrel is a prodrug, oxidation by intestinal and hepatic cytochrome P-450 enzymes convert prasugrel into its active metabolite.
  • Prasugrel has a rapid and almost complete absorption after oral ingestion of a loading dose. Its active form binds irreversibly to the adenosine diphosphate (ADP) P2Y12 receptor on platelets for their lifespan, thereby inhibiting their activation and decreasing subsequent platelet aggregation.
  • ADP adenosine diphosphate
  • Prasugrel has a greater antiplatelet effect than clopidogrel because it is metabolized more efficiently. Some of the differences in metabolism between clopidogrel and prasugrel may be explained by genetic polymorphisms affecting the cytochrome P-450 system.
  • the product mixture of a reaction rarely is a single compound pure enough to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, be present.
  • the Prasugrel HCl must be analyzed for purity, typically by HPLC or GC analysis, to determine if it is suitable for continued processing or ultimately for use in a pharmaceutical product.
  • CDER The U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER) has promulgated guidelines recommending that drug applicants identify organic impurities of 0.1% or greater in the active ingredient. 'Guideline on Impurities in New Drug Substances,' 61 Fed. Reg. 371 (1996); 'Guidance for Industry ANDAs: Impurities in Drug Substances,' 64 Fed. Reg. 67917 (1999). Unless an impurity has been tested for safety, is in a composition proven to be safe in clinical trials, or is a human metabolite, the CDER further recommends that the drug applicant reduce the amount of the impurity in the active ingredient to below 0.1%.
  • impurities side products, byproducts, and adjunct reagents
  • a peak position in a chromatogram or a spot on a TLC plate
  • the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as the 'retention time' ('Rt').
  • This time period varies daily based upon the condition of the instrumentation and many other factors.
  • practitioners use 'relative retention time' ('RRt') to identify impurities.
  • the present invention provides a reversed-phase liquid chromatographic (RP-LC) method for the quantitative determination of Prasugrel HCl.
  • RP-LC reversed-phase liquid chromatographic
  • the present invention provides an HPLC method for Prasugrel HCl containing less than about 5% area by HPLC, preferably less than about 3% area by HPLC, more preferably less than 1% area by HPLC, of total impurities.
  • the present invention further provides a stability indicating analytical method using the samples generated from forced degradation studies.
  • the present invention provides a simple, accurate and well-defined stability indicating an Ultra performance liquid chromatography (UPLC) method for the determination of Prasugrel HCl in the presence of degradation products.
  • UPLC Ultra performance liquid chromatography
  • the HPLC method described in the present invention has the following advantages when compared with prior art methods for determining the Prasugrel HCl and its related impurities:
  • Fig. 1 illustrates the HPLC chromatograms of spiked ( SC-III, PTSA, Oxo compound, MC-I, MC-II, MC-III and SC-II spiked in Prasugrel HCl) samples.
  • LOD Limit of detection
  • LOQ 'limit of quantization
  • 'gradient elution' refers to the change in the composition of the gradient eluent over a fixed period of time, stepwise or at a constant rate of change, as the percentage of the first eluent is decreased while the percentage of the second eluent is increased.
  • 'gradient eluent' refers to an eluent composed of varying concentrations of first and second eluents.
  • a reversed-phase liquid chromatographic (RP-LC) method for quantifying, by area percent, the amounts of Prasugrel HCl and all impurities, preferably, SC-III,PTSA,Oxo compound, MC-I,MC-II,MC-III and SC-II present in a sample of Prasugrel HCl.
  • RP-LC reversed-phase liquid chromatographic
  • an accurate and well-defined stability indicating an HPLC method for the determination of Prasugrel HCl in the presence of degradation products is provided.
  • the method for determining the amount of impurities in a Prasugrel HCl sample comprises the steps of:
  • the ratio of mobile phase buffer and solvent in step-(d) may be continued at the same ratio for 4 minutes then changed linearly to 30:70 (v/v) within 31 minutes followed by same ratio for 25 minutes. After 2 minutes the initial gradient of 80:20 is for 8 minutes to be conditioned for every analysis.
  • the column temperature may be maintained at about 30°C.
  • Specificity is the ability of the method to measure the analyze response in the presence of its potential impurities and degradation products.
  • the specificity of the LC method for Prasugrel intentional degradation was attempted to stress conditions of acid hydrolysis (using 1.0M HCl), base hydrolysis (using 1M NaOH), and oxidative degradation (using 3.0% H2O2) to evaluate the ability of the proposed method to separate Prasugrel from its degradation products.
  • PDA-UV detector was employed.
  • the limit of detection (LOD) and limit of quantification (LOQ) were estimated by signal to noise ratio method, by injecting a diluted solution with known concentration.
  • the accuracy of the related substances method with the spiked impurities was evaluated at 0.15 % of concentration levels.
  • a chromatographic method to get the separation of all impurities and stress studies degradants from analyte peak. Satisfactory chromatographic separation was achieved using the mobile phase consists of buffer (1 ml triethylamine in 1000ml of HPLC water pH adjusted was 2.5, and solvent acetonitrile.
  • the Prasugrel SC-III, PTSA, Oxo compound, MC-I,MC-II,MC-III and SC-II were well separated with a resolution of greater than 3 and the typical retention times (RT) of SC-III,PTSA, Prasugrel Oxo compound, MC-I,MC-II,MC-III and SC-II were about 2.15, 10.59, 16.35 , 23.82& 24.89 ,26.53,31.23,37.02 and 47.89 minutes , and typically shown in Figure 1.
  • the system suitability results and the developed LC method was found to be specific for Prasugrel and its seven impurities, namely SC-III, PTSA, Oxo compound, MC-I,MC-II,MC-III and SC-II.
  • the percentage recovery of Prasugrel of its impurities in bulk drug samples was done at 0.15 %.
  • the percentage recovery of SC-III, PTSA, Oxo compound, MC-I, MC-II, MC-III and SC-II in bulk drugs samples was ranged from 90.00 to 110.00.
  • the LC system used for method development and forced degradation studies and method validation was Waters-Alliance (manufactured by Waters India Ltd) LC system with a photo diode detector. The out put signal was monitored and processed using Empower software system (designed by Waters India) on IBM computer (Digital Equipment Co).
  • the chromatographic column used was a Waters symmetry C8 250mm ⁇ 4.6 mm column with 5 ⁇ m particles.
  • the mobile phase consists buffer (1 ml of triethylamine in 1000ml of HPLC water pH-2.5 with ortho phosphoric acid), and solvent is acetonitrile.
  • the flow rate of the mobile phase was kept at 1.0 ml/min.Beginning with the gradient ratio of mobile phase buffer and solvent 80:20(v/v), system was continued at the same ratio for 4 minutes. The ratio was changed linearly 30:70(v/v) within 31 minutes and again system was continued at the same ratio for 25 minutes. After 2 minutes the initial gradient of 80:20 is for 8 minutes to be conditioned for every analysis.
  • the column temperature was maintained at 30°C and the wavelength was monitored at a wavelength of 220 nm.
  • the injection volume was 20 ⁇ L for related substances determination. Acetonitrile was used as diluent during the standard and test samples preparation.
  • a working solution of 1000 ⁇ g/ml was prepared for related substances determination analysis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Cette invention concerne un procédé amélioré de chromatographie liquide en phase inverse pour la détermination quantitative du Prasugrel chlorhydrate et un procédé analytique qui indique la stabilité faisant appel aux échantillons générés à partir d'études de dégradation forcée.
PCT/IB2012/054018 2011-08-12 2012-08-07 Procédé amélioré de détermination quantitative du prasugrel chlorhydrate Ceased WO2013024399A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2287/MUM/2011 2011-08-12
IN2287MU2011 2011-08-12

Publications (1)

Publication Number Publication Date
WO2013024399A1 true WO2013024399A1 (fr) 2013-02-21

Family

ID=47714826

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/054018 Ceased WO2013024399A1 (fr) 2011-08-12 2012-08-07 Procédé amélioré de détermination quantitative du prasugrel chlorhydrate

Country Status (1)

Country Link
WO (1) WO2013024399A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101255169A (zh) * 2008-03-26 2008-09-03 山东大学 普拉格雷盐及其制备方法
CN101472929A (zh) * 2006-04-06 2009-07-01 第一三共株式会社 制备高纯度的普拉格雷或其酸加成盐的方法
CN101675058A (zh) * 2007-03-02 2010-03-17 第一三共株式会社 用于制备高纯度普拉格雷盐酸盐的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101472929A (zh) * 2006-04-06 2009-07-01 第一三共株式会社 制备高纯度的普拉格雷或其酸加成盐的方法
CN101675058A (zh) * 2007-03-02 2010-03-17 第一三共株式会社 用于制备高纯度普拉格雷盐酸盐的方法
CN101255169A (zh) * 2008-03-26 2008-09-03 山东大学 普拉格雷盐及其制备方法

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