Irbesartan

Structural formula
	; ;
	Structural formulas of the two tautomeric forms: polymorph A (top) and polymorph B (bottom)
General
Non-proprietary name	Irbesartan
other names	2-butyl-3 - ({4- [2-1 H -1,2,3,4-tetrazol-5-yl) phenyl] phenyl} methyl) -1,3-diazaspiro [4.4] non-1-en -4-on ( IUPAC )
Molecular formula	C 25 H 28 N 6 O
External identifiers / databases
EC number	604-078-2
ECHA InfoCard	100.119.966
PubChem	3749
DrugBank	DB01029
Wikidata	Q947266
Drug information
ATC code	C09 CA04
Drug class	Antihypertensive drug
Mechanism of action	AT 1 antagonist
properties
Molar mass	428.54 g · mol -1
Melting point	181 ° C ( polymorph A) ; 186 ° C (polymorph B) ;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Irbesartan is a drug from the AT ₁ antagonist group that is used in the treatment of high blood pressure and mild to moderate heart failure when ACE inhibitor therapy is unsuitable.

Application areas (indications)

Irbesartan is used to treat the following diseases:

Essential hypertension
Kidney disease in patients with hypertension and type 2 diabetes mellitus as part of antihypertensive treatment.

Presentation and extraction

The multi-stage synthesis of irbesartan starts from cyclopentanone , the 1-amino-1-cyclopentanecarbonitrile being obtained in the first step by reaction with sodium cyanide and ammonia . A spiro intermediate compound is formed via amide formation with pentanoic acid chloride and subsequent basic cyclization . Then in the presence of sodium hydride and dimethylformamide with 4 '- (bromomethyl) -biphenyl-2-carbonitrile the biphenyl substructure is inserted into the molecule . In the last synthesis step, the target compound is obtained by means of sodium azide by forming the tetrazole function from the cyano group .

properties

The compound occurs in two polymorphic crystal forms. Polymorph A melts at 181 ° C with a heat of fusion of 91 J g ⁻¹ , polymorph B at 186 ° C with 116 J g ⁻¹ . Both forms are monotropic to one another. The polymorph B is the thermodynamically stable crystal form. The two polymorphic crystal forms differ with regard to the tautomerism of the tetrazole structure. Polymorph A corresponds to the 4 H tetrazole structure, polymorph B to the 2 H tetrazole structure. Polymorph A crystallizes in a hexagonal crystal system , while polymorph B in a triclinic crystal system .

Carcinogenic contaminants

Due to contamination with the potentially carcinogenic N -nitrosodiethylamine (NDEA) at the active ingredient manufacturer Aurobindo Pharma Limited from Hyderabad, there have been several recalls of drugs containing Irbesartan since October 2018.

Individual evidence

↑ ^a ^b ^c ^d ^e N. Boutonnet-Fagegaltier, J. Menegotto, A. Lamure, H. Duplaa, A. Caron, C. Lacabanne, M. Bauer: Molecular Mobility Study of Amorphous And Crystalline Phases of a Pharmaceutical Product by Thermally Stimulated Current Spectrometry. In: J Pharm Sci . Volume 91, 2002, pp. 1548-1560, doi: 10.1002 / jps.10146 .
↑ ^a ^b data sheet Irbesartan, European Pharmacopoeia (EP) Reference Standard from Sigma-Aldrich , accessed on November 1, 2016 ( PDF ).
↑ RED LIST 2013. 53rd edition. Verlag Rote Liste Service, Frankfurt am Main, ISBN 978-3-939192-70-1 , p. 662.
^ Axel Kleemann , Jürgen Engel, Bernd Kutscher, Dieter Reichert: Pharmaceutical Substances. 4th edition. 2 volumes. Thieme-Verlag, Stuttgart 2000, ISBN 1-58890-031-2 ; online since 2003 with biannual additions and updates.
↑ M. Bauer, RK Harris, RC Rao, DC Apperley, CA Rodger: NMR study of desmotropy in irbesartan, a tetrazole-containing pharmaceutical compound. In: J. Chem. Soc. Perkin Trans. 1998, pp. 475-481.
↑ Z. Böcskei, K. Simon, RC Rao, A. Caron, CA Rodger, M. Bauer: Irbesartan crystal form B. In: Acta Cryst. C 54, 1998, pp. 808-810.
↑ NDEA: Second Irbesartan recall, first irbesartan CEP withdrawn . In: Deutsche Apotheker Zeitung . October 11, 2018.

[Menegotto-1] N. Boutonnet-Fagegaltier, J. Menegotto, A. Lamure, H. Duplaa, A. Caron, C. Lacabanne, M. Bauer: Molecular Mobility Study of Amorphous And Crystalline Phases of a Pharmaceutical Product by Thermally Stimulated Current Spectrometry. In: J Pharm Sci . Volume 91, 2002, pp. 1548-1560, doi: 10.1002 / jps.10146 .

[Sigma-2] ta sheet Irbesartan, European Pharmacopoeia (EP) Reference Standard from Sigma-Aldrich , accessed on November 1, 2016 ( PDF ).

[ROTE_LISTE-3] RED LIST 2013. 53rd edition. Verlag Rote Liste Service, Frankfurt am Main, ISBN 978-3-939192-70-1 , p. 662.

[Kleemann-4] Axel Kleemann , Jürgen Engel, Bernd Kutscher, Dieter Reichert: Pharmaceutical Substances. 4th edition. 2 volumes. Thieme-Verlag, Stuttgart 2000, ISBN 1-58890-031-2 ; online since 2003 with biannual additions and updates.

[Bauer-5] M. Bauer, RK Harris, RC Rao, DC Apperley, CA Rodger: NMR study of desmotropy in irbesartan, a tetrazole-containing pharmaceutical compound. In: J. Chem. Soc. Perkin Trans. 1998, pp. 475-481.

[Böcskei-6] Z. Böcskei, K. Simon, RC Rao, A. Caron, CA Rodger, M. Bauer: Irbesartan crystal form B. In: Acta Cryst. C 54, 1998, pp. 808-810.

[DAZ-20181011-7] NDEA: Second Irbesartan recall, first irbesartan CEP withdrawn . In: Deutsche Apotheker Zeitung . October 11, 2018.