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.

Polymorphism in the 1/1 Pterostilbene/Picolinic Acid Cocrystal.

The crystal structures of two new polymorphs of the 1/1 pterostilbene/picolinic acid cocrystal have been analyzed by single-crystal X-ray diffraction and studied by means of DFT calculations and a set of computational tools (QTAIM, NCIplot, MEP). The observation of a new R2 2(10) synthon in each of the two polymorphs has been analyzed energetically, characterized using the topology of the electron density, and rationalized using the MEP surfaces. The exceptional bioavailability of the cocrystal is explained on the basis of BFDH morphology calculations, and the study is complemented by a deep analysis of the supramolecular synthons formed by both neutral and zwitterionic forms of picolinic acid, a versatile coformer for crystal engineering.

The Solid State Landscape of the Sildenafil Drug.

Sildenafil, the active ingredient of the drug developed by Pfizer for the treatment of erectile dysfunction was firstly synthesized in 1989 in the United Kingdom and since then it has become one of the most prescribed drugs for sexual performance in the western world with more than 2.7 million prescriptions in the US in 2021. Since its discovery, this drug compound has attracted the interest of formulators and crystallographers, with a high number of crystal forms of sildenafil being found and characterized, including polymorphs, hydrates, solvates, salts and cocrystals, converting it in one of the most promiscuous multicomponent crystal former drugs in the pharmaceutical sciences arena. In this minireview, the polymorph, pseudopolymorph and multicomponent solid forms landscape of sildenafil is presented through a comprehensive compilation of their 42 solid forms reported in literature.

Novel Polymorphic Cocrystals of the Non-Steroidal Anti-Inflammatory Drug Niflumic Acid: Expanding the Pharmaceutical Landscape.

Any time the pharmaceutical industry develops a new drug, potential polymorphic events must be thoroughly described, because in a crystalline pharmaceutical solid, different arrangements of the same active pharmaceutical ingredient can yield to very different physicochemical properties that might be crucial for its efficacy, such as dissolution, solubility, or stability. Polymorphism in cocrystal formulation cannot be neglected, either. In this work, two different cocrystal polymorphs of the non-steroidal anti-inflammatory drug niflumic acid and caffeine are reported. They have been synthesized by mechanochemical methods and thoroughly characterized in solid-state by powder and single crystal X-ray diffraction respectively, as well as other techniques such as thermal analyses, infrared spectroscopy and computational methods. Both theoretical and experimental results are in agreement, confirming a conformational polymorphism. The polymorph NIF-CAF Form I exhibits improved solubility and dissolution rate compared to NIF-CAF Form II, although Form II is significantly more stable than Form I. The conditions needed to obtain these polymorphs and their transition have been carefully characterized, revealing an intricate system.

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.

Potentiometric CheqSol and standardized shake-flask solubility methods are complimentary tools in physicochemical profiling.

The solubility of three drugs (glimepiride, pioglitazone, sibutramine) with different acid/base properties and expected supersaturation behavior was examined in detail using the shake-flask (SF) and potentiometric (CheqSol) methods. Both uncharged (free) species and hydrochloride salts were used as starting materials. On the one hand, the SF method provided information about the thermodynamic solubility at any pH value, including the counterion-dependent solubility of ionic species. Additionally, this method easily allowed the identification of the solid phase in equilibrated solutions by powder X-ray diffraction, and the detection and quantification of aggregation and complexation reactions. On the other hand, CheqSol method permitted the measurement of the equilibrium solubility of neutral species, the observation of changes in solid forms, and the extent and duration of supersaturation (kinetic solubility) for "chaser" compounds. The combined information from both methods gave an accurate picture of the solubility behavior of the studied drugs.

H-Bonded anion-anion complexes in fentanyl citrate polymorphs and solvates.

Herein we report the experimental observation (X-ray characterization) of two different binding modes in H-bonded anion-anion complexes (anion = citrate) in N-(1-(2-phenylethyl)-4-piperidinylium)-N-phenyl-propanamide-citrate (fentanyl citrate). High level DFT calculations indicate that both types of anion-anion complexes (one with two and the other with four H-bonds) are thermodynamically unstable but kinetically stable with respect to the isolated anions with activation barriers as high as 14 kcal mol-1.

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.

The Ca(2+)-EDTA chelation as standard reaction to validate Isothermal Titration Calorimeter measurements (ITC).

A study about the suitability of the chelation reaction of Ca(2+)with ethylenediaminetetraacetic acid (EDTA) as a validation standard for Isothermal Titration Calorimeter measurements has been performed exploring the common experimental variables (buffer, pH, ionic strength and temperature). Results obtained in a variety of experimental conditions have been amended according to the side reactions involved in the main process and to the experimental ionic strength and, finally, validated by contrast with the potentiometric reference values. It is demonstrated that the chelation reaction performed in acetate buffer 0.1M and 25°C shows accurate and precise results and it is robust enough to be adopted as a standard calibration process.

Oxyma: an efficient additive for peptide synthesis to replace the benzotriazole-based HOBt and HOAt with a lower risk of explosion.

Oxyma [ethyl 2-cyano-2-(hydroxyimino)acetate] has been tested as an additive for use in the carbodiimide approach for formation of peptide bonds. Its performance in relation to those of HOBt and HOAt, which have recently been reported to exhibit explosive properties, is reported. Oxyma displayed a remarkable capacity to inhibit racemization, together with impressive coupling efficiency in both automated and manual synthesis, superior to those of HOBt and at least comparable to those of HOAt, and surpassing the latter coupling agent in the more demanding peptide models. Stability assays showed that there was no risk of capping the resin under standard coupling conditions. Finally, calorimetry assays (DSC and ARC) showed decomposition profiles for benzotriazole-based additives that were consistent with their reported explosivities and suggested a lower risk of explosion in the case of Oxyma.

Polymorphism of (S)-triphenylglycol: kinetic dependent transformation of a new multipolymorphic system.

The appearance of six new polymorphic forms of (S)-triphenylglycol and the kinetically dependent transformation observed by DSC by means of quenching from the melt are reported.