Discovery of a Stable Molecular Complex of an API With HCI : A Long Journey to a Conventional Salt (original) (raw)
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Discovery of a stable molecular complex of an API with HCl: A long journey to a conventional salt
Journal of Pharmaceutical Sciences, 2008
We report formation and characterization of the first pharmaceutically acceptable and stable molecular complex of a mono-HCl salt of Compound 1 with HCl. The novelty of this discovery is due to the fact that there is only one major basic site in the molecule. Thus this complex is reminiscent of other noncovalent crystalline forms including solvates, hydrates, cocrystals and others. To the best of our knowledge, the observed bis-HCl salt appears to be the first example of an active pharmaceutical ingredient in a form of a stable HCl complex. The paucity of stable complexes of APIs with HCl is likely due to the fact that HCl is a gas at ambient conditions and can easily evaporate compromising physical (and chemical) stability of a drug. The bis-HCl salt was chemically/physically stable at low humidity and the molecular HCl stays in the lattice until heated above 1408C under nitrogen flow. Structure solution from powder diffraction using the Monte Carlo simulated annealing method as well as variable temperature ATR-FTIR suggest the possibility of weak hydrogen bonding between the molecular HCl and the nitrogen atom of the amide group. Two years later after the search for a suitable pharmaceutical salt began, the elusive conventional mono-HCl salt was obtained serendipitously concluding the lengthy quest for a regular salt. This work emphasizes the necessity to be open-minded during the salt selection process. It also highlights the difficult, lengthy and often serendipitous path of finding the most appropriate form of an API for pharmaceutical development. ß
European Journal of Medicinal Chemistry, 2014
Salification of new drug substances in order to improve physico-chemical or solid-state properties (e.g. dissolution rate or solubility, appropriate workup process, storage for further industrial and marketing development) is a well-accepted procedure. Amino acids, like aspartic acid, lysine or arginine take a great part in this process and are implicated in several different formulations of therapeutic agent families, including antibiotics (amoxicillin from beta lactam class or cephalexin from cephalosporin class), NSAIDs (ketoprofen, ibuprofen and naproxen from profen family, acetylsalicylic acid) or antiarrhythmic agents (e.g. ajmaline). Even if more than a half of known pharmaceutical molecules possess a salifiable moiety, what can be done for new potential drug entity that cannot be improved by transformation into a salt? In this context, after a brief review of pharmaceutical salts on the market and the implication of amino acids in these formulations, we focus on the advantage of using amino acids even when the target compound is not salifiable by exploiting their zwitterionic potentialities for cocrystal edification. We summarize here a series of new examples coming from literature to support the advantages of broadening the application of amino acids in formulation for new drug substances improvement research for nonsalifiable molecules.
Acta Crystallographica Section E Crystallographic Communications, 2022
The reaction of β-(thiomorpholin-1-yl)propioamidoxime with tosyl chloride in CHCl3 in the presence of DIPEA when heated at 343 K for 8 h afforded the title hydrated salt, C7H14N3S+·Cl−·H2O, in 84% yield. This course of the tosylation reaction differs from the result of tosylation obtained for this substrate at room temperature, when only 2-amino-8-thia-1,5-diazaspiro[4.5]dec-1-ene-5-ammonium tosylate was isolated in 56% yield. The structure of the reaction product was established by physicochemical methods, spectroscopy, and X-ray diffraction. The single-crystal data demonstrated that the previously reported crystal structure of this compound [Kayukova et al. (2021). Chem. J. Kaz, 74, 21–31] had been refined in a wrong space group. In the extended structure, the chloride anions, water molecules and amine groups of the cations form two-periodic hydrogen-bonded networks with the fes topology.
Inorganic Chemistry, 2006
The metal ion-complexing properties of 1,10-phenanthroline-2,9-dicarboxylic acid (PDA) are reported. The protonation constants (pK 1) 4.75, pK 2) 2.53) and formation constants (log K 1) for PDA with Mg(II) (3.53), Ca(II) (7.3), Sr(II) (5.61), Ba(II) (5.43), La(III) (13.5), Gd(III) (16.1), Zn(II) (11.0), Cd(II) (12.8), Pb(II) (11.4), and Cu(II) (12.8) were determined by UV−vis spectroscopy in 0.1 M NaClO 4 at 25°C. The log K 1 values for most of these metal ions were high enough that they were not displaced from their PDA complexes even at pH 2. The log K 1 values were determined using the UV spectra to monitor the competition with EDTA (or DTPA; EDTA) ethylendiamine tetraacetic acid, DTPA) diethylenetriamine pentaacetic acid) as a function of pH according to the equilibrium: M(EDTA) + PDA + nH +) M(PDA) + EDTAH n. The log K 1 values indicate that the rigid extended aromatic backbone of PDA leads to high levels of ligand preorganization and selectivity toward large metal ions (e.g., Ca(II), Cd(II), Gd(III)) with an ionic radius of about 1.0 Å and greatly enhanced thermodynamic stability as compared to similar ligands without the reinforcing aromatic backbone. The structure of [Ca(PDA)(H 2 O) 2 ]‚2H 2 O (1) is reported: orthorhombic, Fdd2, a) 44.007(9) Å, b) 18.945(4) Å, c) 7.2446(14) Å, V) 6040(2) Å 3 , Z) 16, R) 0.0882. The Ca(II) ion has a coordination number of eight, lying in the plane of the tetradentate PDA, with Ca−N bonds averaging 2.55 Å and Ca−O bonds to the two acetate groups of PDA averaging 2.45 Å. These are very close to the normal Ca−L bonds of this type, supporting the idea that a metal ion the size of Ca(II) (ionic radius ≈ 1.0 Å) will fit into PDA in a low-strain manner. The remaining four coordination sites on Ca(II) in 1 come from two coordinated water molecules and a chelating carboxylate bridging from an adjacent [Ca(PDA)(H 2 O) 2 ]‚2H 2 O complex. Potential applications of PDA as a ligand in biomedical applications such as Gd(III) contrast agents in MRI are discussed.
2014
A 0-dimensional (0D) hybrid compound, (C 6 H 22 N 4 ) 2 H 9 O 4 CdCl 6 CdCl 5 Cl 2 has been prepared by a facile conventional evaporation method. The crystal packing of discrete constituents of [Cd(1)Cl 6 ] octahedra, [Cd(2)Cl 5 ] trigonal bipyramids, Cl – ions, protonated tris(2-aminoethyl)amine molecules ([(C 2 H 7 N) 3 NH] 4+ ) and H 9 O 4 + ions, is stabilized by diverse hydrogen bonds of N-H···Cl, C-H···Cl and C-H···O. Uncommonly, an isolated chlorine ion (i.e. Cl(4)) is fixed at a special position at 12 c (3.) by hydrogen bonds from four surrounding hydrogen atoms at a trigonal pyramidal configuration whereas other chlorine atoms Cl(1), Cl(2) and Cl(3) are stabilized by hydrogen bonds from 2, 2 and 3 hydrogen atoms at bifurcated, linear and trigonal configurations, respectively. The ordered arrangement of [Cl(4) [Cl(4)···H 4 ] trigonal pyramidal configuration upward or downward is responsible for the long c -axis of the title compound. Additionally, a H 9 O 4 + ion is entangle...