Acid–base crystalline complexes and the pKa rule

Cruz‐Cabeza, Aurora J.

doi:10.1039/c2ce26055g

Cited by 547 publications

(505 citation statements)

References 19 publications

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“…These acids were chosen in an attempt to evaluate the extent of proton transfer to the 5-FC molecules, based on the pK a rule, 26,27,39 contributing to the study of the salt/cocrystal continuum and providing information related to the capability of predicting and controlling the synthesis of compounds containing the fluoropyrimidine group.…”

Section: Discussionmentioning

confidence: 99%

Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK_a Rule

Silva

Pepino

Melo

et al. 2014

Crystal Growth & Design

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5-Fluorocytosine (5-FC) was investigated for the controlled synthesis of cocrystals by applying the pK a rule. Five cocrystals were designed and developed with adipic, succinic, terephtalic, benzoic, and malic acids, all exhibiting negative ΔpK a values ranging from close to zero up to roughly −1. The synthesized cocrystals were analyzed by single crystal X-ray diffraction, and the observed supramolecular synthons were compared to the reported structures containing 5-FC. In the first four cocrystals, the intermolecular interactions between adjacent 5-FC molecules form two different homodimers showing R 2 2 (8) motifs and assembled via complementary N−H···O and N−H···N hydrogen bonds, respectively. However, in the cocrystal with malic acid (ΔpK a = −0.1), an intermediate supramolecular synthon pattern between salts and cocrystals is observed. In this crystal packing, the homodimer of 5-FC molecules held by the N−H···O interactions is preserved, but a new heterodimer is formed between 5-FC and the acid molecule, such as the ones observed for 5-FC salts. These differences were analyzed using UNI Force Field Calculations to establish the intermolecular potentials of the synthons. As an application, we synthesized a cocrystal of 5-FC with 5-fluorouracil. This can be considered the first step toward the application of 5-FC for the design of new tailor-made drugs.

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Section: Discussionmentioning

confidence: 99%

Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK_a Rule

Silva

Pepino

Melo

et al. 2014

Crystal Growth & Design

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“…We are confident that this training data is a useful set for predicting co-crystal formation due to the low number of salts found in the CSD, and the low success of salt formation from dry grinding, although the likelihood of co-crystal over salt formation can be assessed by comparing co-former and API pK a values. 33 Machine learning algorithms and performance metrics from version 17.0 of the scikit-learn package were used. 34 Support vector machines (SVMs) were used as the machine Fig.…”

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confidence: 99%

Will they co-crystallize?

et al. 2017

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“…It is widely accepted in the literature that whether an API and a guest molecule form a salt or cocrystal can be predicted in terms of the ∆pKa rule (ΔpKa = pKa (base) − pKa (acid) ) [28][29][30]. When the ΔpKa is greater than 4, the components tend to form a salt.…”

Section: Crystal Structuresmentioning

confidence: 99%

Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

et al. 2015

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Salts of the antiviral drug arbidol (umifenovir) (Arb) with maleate (Mlc) and fumarate (Fum) anions have been obtained, and their crystal structures have been described. The crystal structure of arbidol maleate has been redetermined by single crystal X-ray diffraction at 180K. A new arbidol cocrystal in zwitterion form with succinic acid (Suc) has also been found and characterized. The arbidol zwitterion was not previously seen in any of the drug crystal forms, and the [Arb + Suc] cocrystal seems to be the first found instance. Analysis of the conformational preferences of the arbidol molecule in the crystal structures has shown that it adopts two types of conformations, namely "open" and "closed" ones. Thermal stability of the arbidol salts and cocrystal have been analyzed by means of differential scanning calorimetry, thermogravimetric, and mass-spectrometry analysis. The dissolution study of the arbidol salts and cocrystal performed in aqueous buffer solutions with pH 1.2 and 6.8 has shown that both the salts and the cocrystal dissolve incongruently to form an arbidol hydrochloride monohydrate at pH 1.2 and an OPEN ACCESSCrystals 2015, 5 651 arbidol base at pH 6.8, respectively. The cocrystal reaches the highest solubility level in both pH 1.2 and pH 6.8 solutions.

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Acid–base crystalline complexes and the pKa rule

Cited by 547 publications

References 19 publications

Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK_a Rule

Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK_a Rule

Will they co-crystallize?

Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

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Acid–base crystalline complexes and the pKa rule

Cited by 547 publications

References 19 publications

Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pKa Rule

Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pKa Rule

Will they co-crystallize?

Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

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Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK_a Rule

Controlled Synthesis of New 5-Fluorocytosine Cocrystals Based on the pK_a Rule