Solubility-pH profiles of a free base and its salt: sibutramine as a case study

In the present study the solubility-pH profiles of sibutramine free base and its hydrochloride salt were determined in the pH range between 2.0 and 9.5 by means of the recommended shake-flask method, and the solids collected were dried and studied by X-ray diffraction in order to elucidate their free base or salt structure. Above pHmax (or Gibbs pKa) the solid collected was always identified as free base, whatever the sibutramine species (free base or hydrochloride salt) initially solved. However, in the pH range below pHmax different solids were isolated depending on the buffers employed

DFT–Assisted Structure Determination from Powder X-ray Diffraction Data of a New Zonisamide/ϵ-Caprolactam Cocrystal

The crystal structure of a new zonisamide cocrystal, an anticonvulsant drug used to treat the symptoms of epilepsy and Parkinson’s disease, with ϵ-caprolactam is reported herein. The structure has been solved by direct space methodologies from powder X-ray diffraction data. The refinement of the structure was conducted by the Rietveld method assisted by the dispersion-corrected density-functional theory (D-DFT) calculations and periodic boundary conditions. Further analysis of the structure reveals several H-bonded synthons and self–assembled dimers that have been further analyzed by DFT calculations and other computational tools such as molecular electrostatic potential (MEP) surfaces and the quantum theory of “atom-in-molecules” (QTAIM)

Assembling the Puzzle of Apixaban Solid Forms

An in-depth analysis of the solid forms of the anticoagulant drug Apixaban (APX) has been conducted to sort out the confusion in the scientific and patent literature regarding the solid forms landscape. The nomenclature employed and the accompanying characterization data are often unclear and incomplete, leading to a situation in which apparently the same form has been reported by different authors or claimed by different inventors. A comprehensive solid forms screen and a full and careful comparison with the literature data has been performed to draw a reliable picture of the solid forms landscape of APX

Sildenafil–Resorcinol Cocrystal: XRPD Structure and DFT Calculations

Herein, the X-ray powder diffraction (XRPD) crystal structure of a new Sildenafil cocrystal is reported, where resorcinol has been used as the coformer. The crystal structure has been solved by means of direct space methods used in combination with density functional theory (DFT) calculations. In the structure, the Sildenafil and resorcinol molecules form cooperative hydrogen bond (HB) and π-stacking interactions that have been analyzed using DFT calculations, the molecular electrostatic potential (MEP) surface, and noncovalent interaction plot (NCI plot). The formation of O–H⋯N H-bonds between resorcinol and Sildenafil increases the dipole moment and enhances the antiparallel π-stacking interaction

Synthesis and Characterization of a New Norfloxacin/Resorcinol Cocrystal with Enhanced Solubility and Dissolution Profile

A new cocrystal of Norfloxacin, a poorly soluble fluoroquinolone antibiotic, has been synthetized by a solvent-mediated transformation experiment in toluene, using resorcinol as a coformer. The new cocrystal exists in both anhydrous and monohydrate forms with the same (1:1) Norfloxacin/resorcinol stoichiometry. The solubility of Norfloxacin and the hydrated cocrystal were determined by the shake-flask method. While Norfloxacin has a solubility of 0.32 ± 0.02 mg/mL, the cocrystal has a solubility of 2.64 ± 0.39 mg/mL, approximately 10-fold higher. The dissolution rate was tested at four biorelevant pH levels of the gastrointestinal tract: 2.0, 4.0, 5.5, and 7.4. In a first set of comparative tests, the dissolution rate of Norfloxacin and the cocrystal was determined separately at each pH value. Both solid forms showed the highest dissolution rate at pH 2.0, where Norfloxacin is totally protonated. Then, the dissolution rate decreases as pH increases. In a second set of experiments, the dissolution of the cocrystal was evaluated by a unique dissolution test, in which the pH dynamically changed from 2.0 to 7.4, stepping 30 min at each of the four biorelevant pH values. Results were quite different in this case, since dissolution at pH 2 affects the behavior of Norfloxacin at the rest of the pH values

Polymorphism of Sildenafil: A New Metastable Desolvate

A new anhydrous polymorph of the free base of sildenafil and two solvates (acetonitrile and propanenitrile) have been discovered and fully characterized. The new polymorph can be considered a desolvate of the acetonitrile solvate and is related to the most stable form I by morphotropism. The new polymorph can only be obtained by desolvation of the acetonitrile solvate. Thus, this study is a new example of the importance of this multicomponent family of solid forms in the discovery of new polymorphs of active pharmaceutical ingredients

Static discrete disorder in the crystal structure of iododiflunisal: on the importance of hydrogen bond, halogen bond and π-stacking interactions

This manuscript reports a combined computational/crystallographic analysis of iododiflunisal (IDIF), a difluorophenyl derivative of salicylic acid (2′,4′-difluoro-4-hydroxy-5-iodo-[1,1′]-biphenyl-3-carboxylic acid). This drug is used to target transthyretin related amyloidosis. In the solid state it shows static discrete disorder and forms the typical R22(8) centrosymmetric dimer that is common in carboxylic acids (via double OH⋯O H-bonds). Parallel face-to-face stacking interactions are also observed in its crystal packing where these R22(8) centrosymmetric dimers are propagated forming infinite 1D columns. Moreover, the presence of iodine, which exhibits a region of large and positive electrostatic potential (σ-hole) along the C-Ha bond and a belt of negative electrostatic potential (σ-lumps) facilitates the formation of halogen bonds (HaBs) and halogen⋯halogen contacts that are also relevant in the solid state. The crystalline disorder was analyzed by means of Hirshfeld surfaces, and hydrogen, halogen and π-π bonding assemblies were analyzed using density functional theory (DFT) calculations, molecular electrostatic potential (MEP) surfaces, the quantum theory of “atom-in-molecules” (QTAIM) and the noncovalent interaction plot (NCIplot).We thank the MICIU/AEI of Spain (project PID2020-115637GB-I00 FEDER funds). Part of the work was supported by a grant from the Fundació Marató de TV3 (neurodegenerative diseases call, project reference: 20140330-31-32-33-34, https://www.ccma.cat/tv3/marato/en/projectes-financats/2013/212/).Peer reviewe

An experimental and computational investigation of the elusive anhydrous form of Oxyma-B

We report the crystal structure of the anhydrous form of Oxyma-B, a relevant racemization suppressor for peptide synthesis, solved by direct space methodologies with X-Ray Powder Diffraction data. The structure had remained elusive since only monohydrate crystals are readily obtained from slow crystal growth experiments. An extensive combined experimental and computational study has allowed us to obtain deeper insight into the solid-state landscape of Oxyma-B and its tendency for hydration. The singular network of H-bonds and energetically relevant O⋯π interactions formed by the two symmetrically independent molecules of anhydrous Oxyma-B has been analysed by using the quantum theory of “atoms-in-molecules” (QTAIM) and the noncovalent interaction plot (NCIplot).We thank the MICIU/AEI of Spain (projects PID2020-115637GB-I00, TED2021-130946B-100, FEDER funds) for funding and also the CTI (UIB) for computational facilities. We thank Yoav Luxembourg (Luxembourg Bio Technologies, Ness Ziona, Israel) for encouraging this kind of research.Peer reviewe

Virtual Cocrystal Screening of Adefovir Dipivoxyl: Identification of New Solid Forms with Improved Dissolution and Permeation Profiles.

The application of a computational screening methodology based on the calculation of intermolecular interaction energies has guided the discovery of new multicomponent solid forms of the oral antiviral Adefovir Dipivoxyl. Three new cocrystals with resorcinol, orcinol and hydroquinone have been synthesized and thoroughly characterized. They show improved dissolution profiles with respect to the single solid form, particularly the cocrystals of orcinol and resorcinol, which have 3.2- and 2-fold faster dissolution rates at stomach conditions (pH 1.5). Moreover, dynamic dissolution experiments that simultaneously mimic both the pH variation along the gastrointestinal tract and the partition into biological membranes show that, in addition to the faster initial dissolution, Adefovir Dipivoxyl also penetrates faster into the organic membranes in the form of resorcinol and orcinol cocrystals