Assessment of analytical techniques for characterization of
               crystalline clopidogrel forms in patent applications

Lira, Luiz Marcelo; Lourenço, Alexandre Lopes; Neves, Guilherme Ferreira; Sousa, Valéria Pereira de; Rodrigues, Carlos Rangel; Cabral, Lúcio Mendes

doi:10.1590/S1984-82502014000200001

home Table of contents navigate_before previous current next navigate_next

home Table of contents

Articles • Braz. J. Pharm. Sci. 50 (2) • Apr-Jun 2014 • https://doi.org/10.1590/S1984-82502014000200001 linkcopy

Assessment of analytical techniques for characterization of crystalline clopidogrel forms in patent applications

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstracts

The aim of this study was to evaluate two important aspects of patent applications of crystalline forms of drugs: (i) the physicochemical characterization of the crystalline forms; and (ii) the procedure for preparing crystals of the blockbuster drug clopidogrel. To this end, searches were conducted using online patent databases. The results showed that: (i) the majority of patent applications for clopidogrel crystalline forms failed to comply with proposed Brazilian Patent Office guidelines. This was primarily due to insufficient number of analytical techniques evaluating the crystalline phase. In addition, some patent applications lacked assessment of chemical/crystallography purity; (ii) use of more than two analytical techniques is important; and (iii) the crystallization procedure for clopidogrel bisulfate form II were irreproducible based on the procedure given in the patent application.

Clopidogrel/crystalline forms/physicochemical characterization; Clopidogrel/crystalline forms/patents; Polymorphism

Descriptors	INPI Database	EPO Patent database	Derwent Innovations Index
Search parameters	Advanced Search 1-title; Search 2-summary	Advanced Field of search “title or summary” field	Advanced Entire text search Chemical section
Key words and Boolean operators	Search syntax: Clopidogrel AND (polymorph* OR crystal* or form* OR thermodynamics* OR solvate* OR hydrate * OR amorph*)	Search syntax: Clopidogrel AND (polymorph* OR crystal* OR form* OR thermodynamics* OR Solvate* OR hydrate* OR amorph*)	Search syntax: Search 1: Clopidogrel Search 2: search 1 AND (Polymorph* OR Crystal* OR form OR Thermodynamics* OR Solvate* OR Hydrate* OR Amorph); Search 2 refined for the Pharmacology and Pharmacy fields*

Database	Number of patents after search	Number of patents after review	Final list after mining
EPO	204	24
DERWENT	426	17	24
INPI	24	2

Patent Application	Priority date	Applicant	Principal Claimed Matter
WO9965915A1 (Bousquet, Castro, Saint-Germain, op cit)	15/06/1998	Sanofi- Synthelabo	Clopidogrel bisulfate form II
WO03051362A2 (Lifshitz-Liron et al, 2003)	18/12/2001	Teva Pharmaceuticals	Clopidogrel bisulfate forms III, IV, V and VI; amorphous clopidogrel bisulfate.
WO03066637A1 (Kótay Nagy et al., 2003)	06/02/2002	Egys Gyogyszervegyeszet Gyar.	Clopidogrel hydrochloride, forms I and II
PL355514A1 (Piechaczek et al., 2004, op cit)	14/08/2002	Instytut Farmaceutyczny.	No data retrieved
WO2004026879A1 (Rao, Kankan, op cit)	19/09/2002	Cipla Ltd.	Amorphous clopidogrel bisulfate; complex with dissolution enhancer
WO2004052966A1 (Narasa et al., 2004)	09/12/2002	Heterodrugs Ltd.	Clopidogrel bisulfate form III
WO2004081015A1 (Parthasaradhi et al., 2004)	10/03/2003	Heterodrugs Ltd.	Amorphous clopidogrel bisulfate
WO2004081016A1 (Lohray et al, 2004)	12/03/2003	Cadila Healthcare Ltd.	Amorphous clopidogrel bisulfate and mixtures with forms I and II
WO2005026174A1 (Arul, et al, 2007)	11/09/2003	Generics Limited	Clopidogrel hydrobromide forms 1, 2 and 3
CZ295386B6 (Hajicek, Pihera, Stepnkova, 2005b)	13/01/2004	Zentiva	Clopidogrel hydrobromide form II
WO2005068471A1 (Hajicek, Pihera, Stepnkova, 2005a)	13/01/2004	Zentiva	Clopidogrel hydrobromide forms I, II and III
WO2005080890A1 (Weber, Levis, Ly, op cit)	24/02/2004	Siegfried Generics Int. Ag.	Clopidogrel hydrobromide forms A, B, C, D, E and F. Clopidogrel napsylate forms A and B
WO2005117866A1 (Kaznakov, Veverkova, Veverka, 2005)	01/06/2004	Ivax Corporation	Clopidogrel hydrochloride amorphous form
WO2006034451A2 (Finkelstein, Arohrime, Tessler, 2006)	21/09/2004	Teva Pharmaceuticals	Clopidogrel hydrobromide Forms I, II, III, IV, V, VI, VII, VIII, IX and X
EP1674468A1 (Jetti, Gersser, 2006)	21/12/2004	Ratiopharm GMBH.	Clopidogrel hydrobromide forms A, B, C, D and E; Clopidogrel hydrobromide monohydrate forms Hy-1 and Hy-2
WO2005103058A1 (Lorimer, Ng, 2005a)	20/04/04	Sanofi Aventis Co.	Clopidogrel hydrobromide forms B, C and D
WO2005103059A1 (Lorimer, Ng, 2005b)	20/04/04	Sanofi Aventis Co.	Several polymorphs and hydrates of clopidogrel 1,5-naphtalenedisulfonate
WO200702096A2 (Gangakhedkar, 2007)	05/09/2005	Ranbaxy Lab. Ltd.	Clopidogrel hydrochloride form III
WO2008034912A2 (Simonic et al., 2008)	22/09/2006	Krka Tovarna Zdravil DD novo.	Several clopidogrel camphor-10-sulfonate forms; Clopidogrel bisulfate form I; Clopidogrel hydrochloride form
EP1903046A1 (Majka et al., 2008)	25/09/2006	Adamed SP ZOO.	Clopidogrel 5- sulfosalicylic acid forms I and II
WO2008046792A1 (Majka, Sawicki, Trizepal, 2008)	17/10/2006	Adamed SP ZOO.	Racemic clopidogrel polymorph
WO2008108742A2 (Veverka et al., 2008)	08/03/2007	Krka Tovarna Zdravil DD novo.	Clopidogrel hydrobromide forms α, β, and γ; Amorphous clopidogrel hydrobromide
KR20090004268A (Ho et al., 2009a)	06/07/2007	SK Chemicals CO Ltd.	No data retrieved
KR20090004269A (Ho et al., 2009b)	06/07/2007	SK Chemicals CO Ltd	No data retrieved

	Clopidogrel bisulfate	PXRD (characteristic peaks, 2θ)	IV (characteristic bands - cm^-1)	DSC (⁰C)
Commercial Samples	Form I	9.26°, 14.39°, 23.15°	2987; 1753; 1222; 1175 and 841	184.0
Commercial Samples	Form II	8.91°, 21.69° and 23.00°	2551; 1753; 1497; 1189 and 1029	178.3
Koradia, Chawla, Bansal, 2004	Form I	9.26°, 14.39°, 23.15°	2987; 1175; 841	181-190, endothermic peak at 186
Koradia, Chawla, Bansal, 2004	Form II	8.91°, 12.44°, 21.69°, 23.00°	1497; 1189; 1029	177-182, endothermic peak at 179
PI9911219 (Bousquet, Castro, Saint-Germain, 2001)	Form I	9.24°, 10.93°, 18.73°, 20.96°, 23.74°, 23.94°, 26.22° (calculated from Bragg’s Law: λ =2dsenθ)	2987, 1753, 1222, 1175, 841	181.2
PI9911219 (Bousquet, Castro, Saint-Germain, 2001)	Form II	12.99°, 13.74°, 15.80°, 17.92°, 22.03°, 24.34°, 25.36° (calculated from Bragg’s Law: λ =2dsenθ)	2551, 1753, 1497, 1189, 1029	176

vertical_align_top show_chart

more_horiz close
- image
- translate
- link
- article
- vertical_align_top
- file_download
- show_chart
- image
- translate
- link
- article

location_on

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br

rss_feed Stay informed of issues for this journal through your RSS reader

[t01TFN01] ^*
- truncation operator.