K.Veldre Drug Discovery in Preclinical Research
Department of Chemistry
University of Latvia
University of Latvia
Riga
LV 1586, Latvia
Abstract:
Ipidacrine hydrochloride hydrate C12H16N2*HCl*H2O is active pharmaceutical ingredient of Neiromidin. It is white or almost white fine powder with good solubility in water and several organic solvents (solubility in water 0.14 g/mL at 20oC temperature) [1].
It is reversible cholinesterase inhibitor which also induces a direct excitation of nerve fibers and synaptic transmission in neurotransmission end because of the blockade potassium channels [2,3]. Detailed investigation of ipidacrine hydrochloride crystalline forms is published 1997 in Japan [1,4]. In the literature it was determined that ipidacrine hydrochloride crystallizes in two monohydrate forms: A and B, where B is metastable. Our investigations showed that besides these two monohydrates A and B which are related monotropically and where monohydrate A is thermodynamically stable, exist several anhydrous and hydrated forms which may have potential use in pharmacy.On heating at 120oC temperature, monohydrate B transforms to nonstoichiometric hydrate C, which can be reconverted to monohydrate B (by exposing it to relative humidity 55% in 22oC) or converted to other nonstoichiometric hydrate: form D. Water content as determined from KF titration and TG analysis varies from 4.8 to 6.5% for C form and from 2.5 to 3.8 % for D form. Complete dehydration of monohydrate B leads to formation of anhydrous form E. Exposure of anhydrous form E to ambient conditions leads to formation of monohydrate B. By heating monohydrate A at temperatures from 100 to 150oC hemihydrate F forms and then at temperatures above 160oC it transforms to anhydrous form G. Extended heating of ipidacrine anhydrous form at temperatures 160oC and higher leads to decomposition of ipidacrine. At temperatures higher than 270oC it rapidly loses hydrogen chloride.
Hemihydrate F and anhydrous form G easily transforms to metastable monohydrate B if exposed to ambient conditions. Powder X-ray diffraction, DTA/TG analysis and Karl Fisher titration were used for investigations.
References
1. H. Sugimoto, Y. Yamanishi, Donepezil Hydrochloride (E2020) and Other Acetylcholinesterase Inhibitors. Current Medical Chemistry, No. 7, 2000, p. 303-339
2. 3. J. Kojima, K. Onodera, Ipidacrine (NIK-247): A Review of Multiple Mechanisms as an Antidementia Agent. CNS Drug
3. V.Klusa, J. Rumaks, Neuromidin attenuates neuropathic pain in the streptozocin-induced diabetes model in rats. Proceeding of the Latvian Academy of sciences, Section B, Vol. 62. No. 3., 2008, p. 85 - 90 Reviews, Vol. 4, No. 3, 1998, p. 247 - 259
4. H. Omori, Process for the preparation of ipidacrine or ipidacrine hydrochloride hydrate, United States Patent, No. US 6,433173 B1, Aug. 13, 2002
