Crystalline forms and aqueous solubilities of an IBSdrug, tegaserod

A co-crystallization of three drug molecules, niacin (3-pyridine-carboxylic acid = NIA), allopurinol (pyrazolo(3,4-d)pyrimidin-4-one = ALP), and amiloride (3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine = AMI), with the same coformer, 2,4-pyridinedicarboxylic acid (PDA), resulted in three new crystalline products, (NIA)(PDA) (1), (ALP)2(PDA)·1.5H2O (2), and (AMI)2(PDA)2(H2O)2 (3). The formation of new phases was confirmed by IR spectra and X-ray single-crystal and powder diffraction analysis. The proton transfer resulted in the zwitterionic co-crystal 1. In co-crystal 2, neutral ALP molecules existed in the oxo-tautomeric form. Compound 3 crystallizes as the salt with the guanidinium cationic part as in the started amiloride hydrochloride hydrate, and the PDA coformer as the zwitterionic pyridinium dicarboxylate anion. Thus, the diversity of the PDA coformer ionization states included the neutral, zwitterion, and zwitterion anionic forms. All compounds were layered structures where the heterocyclic molecules were linked in the H-bonded corrugated layers stabilized by the diverse conventional and charge-assisted hydrogen bonds with π–π stacking interactions between the layers supported by the mediated water molecules in 2 and 3.

Section: Introductionmentioning

confidence: 99%

Adducts of N-Heterocyclic Drugs, Niacin, Allopurinol, and Amiloride, with 2,4-Pyridinedicarboxylic Acid Coformer

Bejagam

Fonarı

Аверкиев

et al. 2017

“…Polymorphism 1 still represents one of the major challenges in current day crystallization processes of active pharmaceutical ingredients. [2][3][4][5][6][7][8][9][10][11][12][13] The deliberate and reproducible synthesis of metastable polymorphs from solution remains difficult and is still far from trivial. The differences in physical and chemical properties as well as the legal and economic implications 14 are additional important driving forces for research on polymorphism.…”

Section: Introductionmentioning

confidence: 99%

Wöhler and Liebig Revisited: 176 Years of Polymorphism in Benzamide - and the Story Still Continues!

Thun

Seyfarth

Butterhof

et al. 2009

In 1832, Friedrich Wo ¨hler and Justus von Liebig described the existence of polymorphism in molecular crystals for the first time in the case of benzamide. 175 years later, the crystal structure of this historical polymorph could be finally solved. Surprising similarities regarding the packing motifs between all three known forms can be found. According to Ostwald's rule, high supersaturations are needed to crystallize the most unstable Form II from solution. Herein we present a way in which all three known forms for benzamide can be concomitantly crystallized out of solution. With this trimorphic mixture at hand, a more detailed stability test could be performed and further characterization applying solid-state NMR-, Raman, and IR-spectroscopy was possible. † Dedicated to Prof. Reinhard Nesper on the occasion of his 60th birthday.

“…These demonstrate that the pH of the saturated solution is a major factor in salt solubility, a feature of considerable importance in both salt isolation and in determining bioavailability of pharmaceutical products. While solubility data are not always accompanied by measurement of an associated pH, 9 Jones et al 10 have recently shown how the simultaneous determination of the pH and solubility can be used to calculate the thermodynamic solubility product (K sp ). This method, which needs only one solubility value at a known pH together with the pK of each component, is employed in this paper.…”

mentioning

confidence: 99%

On the Solubility of Saccharinate Salts and Cocrystals

Cooke

Davey

2008

A simple relationship allows pH versus solubility plots for molecular salts to be calculated from known pKʼs together with one measurement of solubility and the pH of the corresponding supersaturated solution. Using this methodology the solubility of a series of salts may be properly compared and judged against that of a cocrystal. One advantage of this method is that the equations also allow the calculation of an important thermodynamic parameterthe solubility product.