Preformulation investigation of some clopidogrel addition salts.
Physico-chemical properties of active substances such as solubility, dissolution rate, chemical stability, pharmaceutical processibility, etc. can be improved by salt formation of active substances. Characterization of physical properties of such salts is important for selection of an optimal salt having required biopharmaceutical properties, stability and manufacturability. The present study deals with the preformulation study of selected clopidogrel acid addition salts, i.e. hydrogen sulfate, hydrochloride (HCl), hydrobromide (HBr), besylate and (-)-camphor-10-sulfonate salt (CSA) and two commercially available polymorphic forms of hydrogen sulphate salt, i.e. form 1 (HS F1) and form 2 (HS F2). Clopidogrel salts were characterized by means of thermal analysis (TG, DSC), X-ray powder diffraction (XRPD), infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic vapor sorption (DVS), true density, scanning electron microscopy (SEM) and solubility. Distinct differences in tested parameters were found among acid addition salts and crystalline forms of clopidogrel. Higher melting point of both hydrogen sulphate salt was attributed to presence of hydrogen bonds among HS anions, connecting them into a chain. All salts included in the present study were anhydrous, except HBr which was in the form of monohydrate. The two tested polymorphic forms of clopidogrel HS salt are enantiotropically related to each other and showed the highest hygroscopicity among the tested salts. This is important for development of solid dosage form containing both polymorphic forms and for selection of primary packaging. Solubility studies in different aqueous media showed comparable solubility for clopidogrel hydrogen sulfate (polymorphic forms 1 and 2), hydrochloride (form 1) and hydrobromide hydrate (form 1) whereas clopidogrel camphorsulfonate (CSA) and besylate salt showed slightly lower solubility.
Vinko
V
Zupančič
Matej
M
Smrkolj
Promož
P
Benkič
Igor
I
Simonič
Miha
M
Plevnik
Gregor
G
Ritlop
Albin
A
Kristl
Franc
F
Vrečer