Bis(ammonium) Zoledronate Dihydrate

Neutralization of 2-(1-imidazole)-1-hydroxyl-1,1′-ethylidenediphosphonic acid (zoledronic acid) by an excess of ammonia yielded bis(ammonium) zoledronate dihydrate, { , 2(H4N+), 2(H2O)}. The product is readily soluble in water and forms monocrystals for which the X-ray structural analysis was carried out. The zoledronic anion is of double negative charge due to deprotonation of three P–OH groups and protonation of the nitrogen in the imidazole ring. The structure is stabilized by extensive network of N–H？O and O–H？O hydrogen bonds expanding through the crystal in plane (002). The imidazole ring is involved in - stacking interactions with its symmetry equivalents related by inversion centers at (1？0？0) and (1？1/2？0), with distances between centroids (Cg–Cg) of 3.819 (2) and 3.881 (2) ？, respectively. 1. Introduction Bisphosphonates have been subject of intensive research mainly due to their application in medicine as bone resorption inhibitors [1]. 2-(1-imidazole)-1-hydroxyl-1,1′-ethylidenediphosphonic acid, known as zoledronic acid, is regarded as the third generation of drugs for osteoporosis. Due to its structure, imidazolyl –CH2–C(OH){O=P(OH)2}2, the acid may be deprotonated at all four P–OH groups and protonated at the imidazolic N atom. The kind of the ion formed should influence not only coordination mode and intermolecular interactions but also the water solubility of the product, which may alter bioavailability. Salts of zoledronic acid in the solid state usually contain monovalent anion resulting from deprotonation of two OH groups and protonation of the imidazole nitrogen. Examples include salts of sodium Na+ C5H9N2O7 4H2O [3] and a series of compounds of general formula (C5H9N2O7 )2M(H2O)2 M=Mg [4], Zn [5], Mn [6], Cu [7], Co, and Ni [8]. In some cases (for Cu, Co, Mn, and Ni), polynuclear complexes or coordination polymers are formed, with potentially interesting magnetic properties (e.g., [9]). Doubly negative anion was encountered in the catena((μ3-zoledronato)aqua calcium) [10]. Triply negative anion was found in a tris(dicyclohexylammonium) zoledronate ethanol solvate monohydrate [11]. It is one of the few structures reported with nonprotonated imidazole ring. The other two are the cobalt derivative with coordination of the ring nitrogen to a metal atom Co N [9] and the mentioned above calcium salt [10]. Structure of another organic ammonium salt of the acid was recently reported (albeit with mononegative anion)—cytosinium zoledronate trihydrate [12]. In this paper, we carried out neutralization of zoledronic acid with excess of ammonia