SYNTHESIS AND CHARACTERIZATION OF POTENTIAL IMPURITIES OF ARIPIPRAZOLE

SYNTHESIS AND CHARACTERIZATION OF POTENTIAL IMPURITIES OF ARIPIPRAZOLE

Jitendra Verdia ^*, Pankaj Kumar and Narendra S. Joshi

Research and Development Centre, Amoli Organics Pvt. Ltd., Block No. 422, ECP Canal Road, Village Luna, Padra, Vadodara - 391440, Gujarat, India.

ABSTRACT: Aripiprazole is an anti-psychotic drug used in the treatment of psychosis, including schizophrenia, and during process development for Aripiprazole, we observed two related substances. This paper describes the preparation, identification and proposed structures of the impurities 7-(4-(4-(2-chlorophenyl) piperazine-1-yl) butoxy) - 3, 4 – dihydroquinoline - 2(1H) - one and 7- (4-(4-(3-chlorophenyl)piperazin-1-yl) butoxy)-3,4-dihydroquinoline-2(1H)-one formed during reaction of 7-(4-bromobutoxy)-3, 4-dihydroquinoline-2(1H)-one with 1-(2, 3-dichloro phenyl) Piperazine Hydrochloride to form Aripiprazole.

Aripiprazole, Anti-psychotic drug, Impurities

INTRODUCTION: Aripiprazole knew as 7-(4-(4-(2, 3-Dichlorophenyl)piperazin-1-yl) butoxy)-3, 4-dihydroquinoline-2(1H)-one  is an anti-psychotic drug ^{1, 2} used in the treatment of psychosis including schizophrenia ³. Aripiprazole developed by Otsuka Pharmaceutical Co. Ltd. Schizophrenia is the most common type of psychosis caused by an excessive neurotransmission activity of the dopaminergic nervous system in the CNS. Aripiprazole, a carbostyril derivative, functions as a partial agonist ^4-7 at the dopamine D₂ and serotonin 5 HT_1A receptors and as an antagonist at serotonin 5-HT_2A receptor. It is a novel antipsychotic agent who is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors.

Aripiprazole is known to be effective towards reducing the positive symptoms of schizophrenia with fewer side effects as compared to the psychotic drugs known in the literature. Aripiprazole-induced catalepsy is at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED₅₀ value of 7.8 mol/kg po). Aripiprazole showed lower potential to induce catalepsy than the standard agent and did not show α1-adrenoreceptor antagonist activity. In addition to the dual activities, Aripiprazole reversed the reserpine-induced increase in tyrosine hydroxylase activity in mouse and rat brain. Aripiprazole was also approved for acute manic and mixed episodes associated with bipolar disorder; as an adjunct for major depressive disorder ⁸ and to treat irritability in children with autism ⁹.

The presence of impurities in active pharmaceuticals ingredients (API) can impact the quality and safety of drug products. International Conference on Harmonization (ICH) guidelines recommend identifying and characterizing all impurities present in an API at a level of < 0.15% ¹⁰. This limit is calculated on the bases of daily dosage. However, in Aripiprazole, the limit is further tightening to 0.1%. These impurities are required in pure form to check the analytical performance characteristic such as specificity, linearity, range, accuracy and precision, the limit of detection (LOD), limit of quantification (LOQ), robustness, system suitability testing, and relative retention factor ¹¹.

A number of impurities is possible in final Aripiprazole, some of which are starting material (like 7-hydroxy-3, 4-dihydroquinoline-2(1H)-one and 1 - (2, 3-dichloro phenyl) piperazine hydro-chloride.  Other impurities like Aripiprazole-1-N-oxide, 7-[4-{4-(2,3-dichlorophenyl)-1-piprazinyl} butoxy] - 3, 4-dehydro-2-(1H)-quinolinone are also reported in literature ¹². 1-(2, 3-dichloro phenyl) piperazine hydrochloride is our key starting material for the synthesis of Aripiprazole. In this, there is the possibility of the presence of 1-(2-chloro phenyl) piperazine hydrochloride and 1-(3-chloro phenyl) piperazine hydrochloride as impurities, although their limit is NMT 0.1%.

These also react with 7-(4-bromobutoxy)-3, 4-dihydroquinoline-2(1H)-one  in same fashion as 1-(2, 3-dichloro phenyl) piperazine hydrochloride and form impurities 7-[4-{4-(2-chlorophenyl)- piprazin-1-yl}butoxy]-3, 4-dihydroquinolin-2(1H)-one and 7-[4-{4-(3-chlorophenyl)-piprazin-1-yl}butoxy]-3, 4-dihydroquinolin-2(1H)-one as shown below:

In our current work, we identified these two related substances in Aripiprazole API. Their detection, origin, synthesis, and characterization are described in this article.

EXPERIMENTAL: Solvents and reagents were obtained from commercial sources and used without purifications. The IR spectra (ν max cm^-1) were recorded in solid state KBr dispersion using an FTIR (Shimadzu FTIR Prestige 21 Spectrophotometer operating range 400-4000 cm^-1 with a resolution of 5 cm^-1). The ¹H NMR and ¹³ C NMR spectra recorded on a Bruker AB-400 instrument frequency 400 MHz instrument and Bruker 400 MHz instrument. The mass spectra were recorded on a Thermo Scientific LCQFLEET ion trapped instrument. We have synthesized all these compounds as described in this experimental section.

Preparation of 7- (4-(4-(2-chlorophenyl)-piperazine-1-yl) butoxy)-3, 4-dihydroquinoline-2(1H)-one: A mixture of Acetonitrile (100mL), 7-(4-bromobutoxy)-3, 4-dihydroquinoline-2(1H)-one (10 g), Potassium Carbonate (13.5 g), 1-(2-chloro phenyl) piperazine hydrochloride (9.0 g) and sodium iodide (1 g) heated to 80°C. Reaction mass maintained at this temperature for 3-4 h. After completion of the reaction, mass is cooled to 50-55 °C. Maintain at this temperature for a further 30 min. The reaction mass is filtered to remove insoluble, if any. Clear filtrate, cool to 25-30°C. Product is precipitated and stirs the mass for 30 minute. Filter and dry to get pure 7-(4-(4-(2-chlorophenyl) piperazin-1-yl) butoxy) - 3, 4-dihydroquinoline-2(1H)-one.

Weight: 9.0 g (Yield: 64.8 %); HPLC purity: 99.46%

Off White Solid, Melting Point: 100-107°C; IR (KBr) ν_max (cm^-1) 1678 (-C=O), 1232 1037.7 (-C-O-C), 1182.36 (C-N), 1141.8 (C-Cl), 2951, 2823 (Aliphatic C-H); Mass (%): M+ 414.24 (100); ¹H NMR (MeOD): δ 1.57 (4 H Aliphatic.), 2.43 (2 H Aliphatic.  near to N, 2 H quinolinone), 2.54 (4 H of piperazine), 2.73 (2 H quinolinone), 3.2 (4 H of piperazine), 3.96 (2 H Aliphatic  near to N), 6.34, 7.24 (H Aromatic); ¹³C NMR (MeOD): δ 24.16, 25.43, 68.82, 54.44 (Aliphatic C), 174.01 (amide C), 28.43, 31.96 (quinolinone C), 103.29,160.05 (aromatic C), 48.4,54.4 (piperazine C).

Preparation of 7 - (4-(4-(3-chlorophenyl)-piperazin-1-yl) butoxy) - 3, 4-dihydroquinoline-2(1H)-one: A mixture of Acetonitrile (100 mL), 7-(4-bromobutoxy)-3, 4-dihydroquinoline-2(1H)-one (10 g), Potassium Carbonate (13.5 g), 1-(2-chloro phenyl) piperazine hydrochloride (9.0 g) and Sodium Iodide (1 g) heated to 80°C. Reaction mass maintained at this temperature for 3-4 h. After completion of the reaction, mass is cooled to 50-55 °C. Maintain at this temperature for a further 30 minutes. The reaction mass is filtered to remove insoluble if any.  To the clear filtrate add 150 mL water at room temperature. Product is precipitated and stirs the mass for 30 min. Filter and dry to get 7-(4-(4-(2-chlorophenyl) piperazine-1-yl) butoxy) - 3, 4-dihydroquinoline-2(1H)-one. Product is further recrystallized in ethanol to get the pure compound.

Weight: 8.0 g (Yield: 57.6%); HPLC purity: 98.70%

Off White Solid, Melting Point: 97-99°C. IR (KBr) ν_max (cm^-1) 1678 (-C=O), 1232 1028 (-C-O-C), 1176.58 (C-N), 1151 (C-Cl), 2941, 2819 (Aliphatic C-H); Mass (%): M+ 414.21(100); ¹H NMR (MeOD): δ 1.57 (4 H Aliphatic), 2.42 (2 H Aliphatic  near to N, 2 H quinolinone ), 2.49 (4 H of piperazine), 2.72 (2 H quinolinone), 3.2 (4 H of piperazine), 3.94 (2 H Aliphatic  near to N), 6.34, 7.07 (H Aromatic); ¹³C NMR (MeOD): δ 24.17, 25.43, 69.82, 59.35 (Aliphatic C), 174.07 (amide C), 28.40, 31.97 (quinolinone C), 103.30,160.03 (aromatic C), 48.4,54.1 (piperazine C).

RESULTS AND DISCUSSION: Aripiprazole was synthesized by the known literature synthetic procedure.¹ One key starting material, 7-hydroxy-3, 4-dihydroquinoline-2(1H)-one was reacted with 1,4-dibromobutane in Dimethyl formamide and Potassium Carbonate and quench in water to form 7-(4-bromobutoxy)-3,4-dihydroquinoline-2(1H)-one. 7-(4-bromobutoxy)-3, 4-dihydroquinoline-2(1H)-one is reacted with second key starting material 1-(2, 3-dichloro phenyl) piperazine hydrochloride in the presence of Acetonitrile and Potassium Carbonate to form Aripiprazole Scheme 1.

Stage 1: Preparation of 7-(4-bromobutoxy)-3, 4-dihydroquinoline-2(1H)-one

Stage 2: Preparation of Aripiprazole

SCHEME 1: ROUTE OF SYNTHESIS OF ARIPIPRAZOLE

This second key starting material 1-(2, 3-dichloro phenyl) piperazine hydrochloride may contain 1-(2-chlorophenyl) piperazine hydrochloride and 1-(3-chlorophenyl) piperazine hydrochloride as impurities. 1 - (2-chlorophenyl) piperazine hydrochloride present in second key starting material as an impurity also react with 7- (4-bromobutoxy) - 3, 4-dihydroquinoline-2(1H)-one in presence of Acetonitrile and Potassium Carbonate to form impurity 7 - (4-(4-(2-chlorophenyl) piperazine-1-yl) butoxy) – 3, 4-dihydroquinoline-2(1H)-one  Scheme 2.

SCHEME 2: Synthetic scheme of 7-(4-(4-(2-chlorophenyl) piperazine-1-yl) butoxy)-3, 4-dihydroquinoline-2(1H)-one

The mass spectra of 7-(4-(4-(2-chlorophenyl) piperazine-1-yl) butoxy) -3, 4 - dihydroquinoline-2(1H)-one showed the molecular ion peak at m/z 414.21. The IR spectrum (cm^-1) displayed (-C-O-C) in 1232 and (C-Cl) displayed in 1151. 1-(3-chloro phenyl) piperazine hydrochloride present in second key starting material as an impurity. Also react with 7 - (4-bromobutoxy)-3, 4-dihydroquinoline-2(1H) - one in presence of Acetonitrile and Potassium Carbonate to form impurity 7-(4-(4-(3-chlorophenyl) piperazin-1-yl) butoxy)-3,4-dihydro-quinolin-2(1H)-one Scheme 3.

SCHEME 3: Synthetic scheme of 7-(4-(4-(3-chlorophenyl) piperazine-1-yl) butoxy)-3, 4-dihydroquinoline-2(1H)-one

The mass spectra of 7-(4-(4-(3-chlorophenyl) piperazin-1-yl) butoxy) - 3, 4-dihydroquinolin-2(1H)-one showed the molecular ion peak at m/z 414.24. The IR spectrum (cm^-1) displayed (-C-O-C) at 1176.58 and (C-Cl) displayed at 1151.  Both the impurities 7-(4-(4-(2-chlorophenyl) piperazin-1-yl) butoxy) -3, 4-dihydroquinolin-2(1H)-one and 7-(4-(4-(3-chlorophenyl) piperazin-1-yl) butoxy) -3, 4-dihydroquinolin-2(1H)-one are well controlled below 0.1 % after final purification.

CONCLUSION: To have a thorough understanding of the formation of impurities during the manufacturing of Aripiprazole, it is essential to have detailed information about the impurities, their origin, and synthetic route. Given regulatory importance of the impurities in API, a detailed study on these impurities, which are novel, in Aripiprazole was studied, and these impurities were synthesized and controlled well within a limit ≤ 0.10%. They were characterized using various spectroscopic techniques such as Mass, ¹H NMR, ¹³C NMR, and IR.

ACKNOWLEDGEMENT: The authors are thankful to the management of Amoli Organics Pvt. Ltd. for providing necessary facilities to carry out this research work. The authors are also thankful to the colleagues of the synthetic research and analytical research department for their cooperation.

CONFLICT OF INTEREST: Nil

REFERENCES:

1. Yasuo O and Seiji S: Carbostyril derivatives. US Patent 5006528, 1991.
2. Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR and Mailman RB: Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 1999; 20(6): 612.
3. a) Rowley M, Bristow LJ and Hutson PH: Current and novel approaches to the drug treatment of schizophrenia. J Med Chem 2001; 44: 477.
4. b) Capuno B, Crosby IT and Lloyd EJ: Schizophrenia: Genesis, Receptorology and Current Therapeutics Curr Med Chem 2002; 9: 521.
5. c) Kapur S and Remington G: Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med 2001; 52: 503.
6. d) Kelleher JP, Centorrino F, Albert MJ and Baldessarini RJ: Advances in atypical antipsychotics for the treatment of schizophrenia: new formulations and new agents. CNS Drugs 2002; 16: 249.
7. Jordan S, Koprivica V, Chen R, Tottori K, Kikuchu T and Altar CA: The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. European Journal Pharmacol 2002; 441(3): 137.
8. Oshiro Y, Sato S, Kurahashi N, Tanaka T, Kikuchi T, Tottori K, Uwahodo Y and Nishi T: Novel antipsychotic agents with dopamine autoreceptor agonist properties: synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives. J Med Chem 1998; 41(5): 658.
9. a) Stahl SM: Dopamine System Stabilizers, Aripiprazole, and the Next Generation of Antipsychotics, Part 1: "Goldilocks" Actions at Dopamine Receptors and Dopamine System Stabilizers, Aripiprazole, and The Next Generation of Antipsychotics, Part 2: Illustrating Their Mechanism of Action. J Clin Psychi 2001; 62: 841, 923.
10. b) Tamminga CA and Carlsson A: Partial dopamine agonists and dopaminergic stabilizers, in the treatment of psychosis. Current Drug Targets-CNS and Neurological Disorder 2002; 1: 141.
11. a) Goodnick PJ and Jerry JM: Aripiprazole: profile on efficacy and safety. Expert opin Invest Drugs 2002; 3: 1773.
12. b) Ozdemir V, Fourie J and Ozdoner F: Aripiprazole (Otsuka Pharmaceutical Co). Curr Opin Invest Drugs 2002; 3: 113.
13. c) McGavin JK and Goa KL: Aripiprazole. CNS Drugs, 2002; 16: 779.
14. d) Taylor DM: Aripiprazole: A review of its pharmacology and clinical use. Int J Clin Pract 2003; 57: 49.
15. Hitti: Miranda 20 November 2007.Wikipedia "FDA OKs Abilify for Depression". WebMD. Archived from the original on 5 December 2008. Retrieved 8 December 2008.
16. Keating, Gina (23 November 2009). Wikipedia "FDA OKs Ability for child autism irritability". Reuters. Retrieved 22 September 2010.
17. International Conference on Harmonization (ICH) Q3A(R): Impurities in new drug substances; ICH: Geneva Switzerland 2002.
18. International Conference on Harmonization (ICH) Q2B Validation of Analytical procedure. Methodology; ICH Geneva, Switzerland 1996.
19. Satyanarayan B, Sumalatha Y, Kumar SS, Venkatraman S, Reddy GM and Reddy PP: Synthesis and characterization of N-Oxide and metabolites of the antipsychotic drug, Aripiprazole. Heterocyclic Communications 2005; 11(6): 485-90.
    

    ---

    How to cite this article:

    Verdia J, Kumar P and Joshi NS: Synthesis and characterization of potential impurities of aripiprazole. Int J Pharm Sci & Res 2014; 5(9): 4046-50. doi: 10.13040/IJPSR.0975-8232.5(9).4046-50.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---