Newer Process Development of Trimetazidine Dihydrochloride

 

Dr. Nandini R. Pai and Swapnali Suhas Patil*

Department of Chemistry, D.G. Ruparel College, Mahim, Mumbai 400016, Maharashtra, INDIA

*Corresponding Author E-mail: nandini_pai@hotmail.com / swapnali22@gmail.com

 

For the given chemicals to react, the species involved in any reaction must undergo a rearrangement of chemical bonds. The slowest step in the bond rearrangement produces what is termed a transition state - a chemical species that is neither a reactant nor a product, but is an intermediate between the two. Energy is required to form the transition state. This energy is called the Energy of Activation or Ea. Reactants with energy lower than Ea cannot pass through the transition state to react and become products.

 

A catalyst works by providing a different route, with lower Ea, for the reaction. In any given time interval, the presence of a catalyst allows a greater proportion of the reactant species to acquire sufficient energy to pass through the transition state and become products.

 

 

INTRODUCTION:

Trimetazidine Dihydrochloride is a cellular acting anti-ischemic agent. It has three main properties by which it acts as a cytoprotective agent. It inhibits the anaerobic glycolysis and fatty acid metabolism, thus allowing only aerobic glycolysis. This action helps to restore the energy balance in the cell. It inhibits acidosis and free radical accumulation in the cell. All these actions help the cell to restore the normal ionic and metabolic balance.

 

Trimetazidine dihydrochloride is manufactured in two stages. In the 1^st stage 2, 3, 4-trimethoxy benzaldehyde reacts with piperazine to give trimetazidine base. Reaction time taken for this conversion is 14 -16 h. So current process is developed using a catalyst to accelerate the rate of this reaction and improve quality of trimetazidine dihydrochloride.[6][7]

 

MATERIAL AND METHOD:

Purity of the compound was monitored on silica gel 60 F₂₅₄ purchased from Merck and solvent from Aldrich chemical Co Ltd. Anhydrous silica gel 60 was used as solid support after dehydration in oven at 100°C for 5 min. Mobile phase used was benzene: ethyl acetate  (7:3) as an eluent. TLC spots were detected in UV chamber. Structural interpretation was done by performing Mass spectra, IR and HPLC which were compared with reference standard.

 

Synthesis of Trimetazidine Base

10 g of 2, 3, 4 -trimethoxy benzaldehyde  was dissolved in 25 mL  of formic acid and 1g of tetra butyl ammonium bromide or para toluene sulphonic acid  was added to it at room temperature.  22g of piperazine was added to above reaction mass under stirring at room temperature which rises to 85°C (exothermic reaction). After addition, reaction mass was heated to 110 to 115°C and maintained for 4-5 h. Reaction was monitored till completion on TLC.  Reaction mass was then quenched with 70 g of ice. pH was adjusted to 9.2 to 9.5 with 50% caustic solution, dimmer impurity precipitates. Dimmer was filtered, clear filtrate was   extracted with methylene dichloride three times (30 mL: 30 mL:15mL) respectively.  Organic layer was washed with water till neutral pH. Methylene dichloride was concentrated under vacuum and degassed with 10 mL of isopropyl alcohol. 30 mL of isopropyl alcohol was added and heated to 70°C for complete dissolution. 2g of activated charcoal was added and maintained for 15min, hot reaction mass was filtered. Clear filtrate was then chilled to give 11.5 g of trimetazidine base. [5]

 

General method of conversion of Trimetazidine Base to Trimetazidine Dihydrochloride

Trimetazidine base was dissolved in isopropyl alcohol. Analytical grade Hydrochloric acid was added to it (cooling is required as reaction is exothermic). Reaction mass was refluxed for 8 h and cooled to 30°C and then chilled to 5°C and the temperature is maintained between 5-10°C for 1h. The reaction mass was filtered to obtain trimetazidine dihydrochloride, But trimetazidine dihydrochloride synthesized by above method failed in single and total impurity. The consent impurities are starting material impurity and process impurity. Hence purification and re-purification is required which tend to loss of material resulting in low yield. [4] [3] 

 

Conventional method of preparing Trimetazidine Dihydrochloride salt. 

15.0 g of Trimetazidine base was dissolved in 150 mL of isopropyl alcohol and 2.4 mL of water was added under stirring.  18 g of analytical grade Hydrochloric acid was added to it (Cooling is required as reaction is exothermic) and refluxed for 8 h. Reaction mass is then cooled to 30°C and chilled to 5°C which was maintained for 1h at 5-10°C and was filtered to obtain trimetazidine dihydrochloride 14.0 g. This trimetazidine dihydrochloride showed single impurity less than 0.1% and total impurity less than 0.2 % which matches to European pharmacopoeia.[1][2] 10.5 % of moisture content should be present in reaction mass that include moisture present in isopropyl alcohol and hydrochloric acid, to get trimetazidine dihydrochloride material of the above grade. Purity of the compound was matched with standard trimetazidine dihydrochloride   and found to be 99.98% on H.P.L.C.[2].

 

Reaction of Trimetazidine Dihydrochloride

 

Stage II:

 

Synthesized  trimetazidine dihydrochloride  was white crystalline freely soluble in water sparingly soluble in alcohol  matched with standard trimetazidine dihydrochloride   by HPLC, IR  and by Mass Spectra.[1][2]

 

Mass Spectra of Trimetazidine Dihydrochloride

 

IR Spectra

 

 

Fig 1:Blank

 

Fig 2: Working Standard  Trimetazidine Dihydrochloride

 

Fig 3: Sample  of Trimetazidine Dihydrochloride General method

 

Fig 4 : Sample of Trimetazidine Dihydrochloride by conventional method

 

CONCLUSION:

By using tetra butyl ammonium bromide or para toluene sulphonic acid as catalyst for synthesis of trimetazidine base reduced reaction time thus increase in productivity. By adjusting moisture content in hydrochloride salt formation, utility cost is decreased and  unwanted impurity is reduced to give the desirable purity.

 

ACKNOWLEDGEMENTS:

I am thankful to Ultratech India Ltd. and D. G. Ruparel College for providing all the necessary analytical details of the compound, required support and co-operation for executing this project. I am also thankful to Mr. Deepak U. Shanbhag for help and cooperation.

 

REFERENCES:

1.        International Conference on Harmonisation tripartite guideline (ICH), Impurities In New Drug Substances Q3A (R2), Current Step 4 version dated 25 October 2006.

2.        BP, British Pharmacopoeia (2009).

3.        Hand book of pharmaceutical catalysis by JonhsonMatthey

4.        Name reaction by Li Jie Jack

5.        http://www.organic-chemistry.org

6.        www.rxlist

7.        http://www.wipo.int/pctdb/en/

 

 

Accepted on 01.08.2013         © RJPT All right reserved