Carboxylic Acid Counterions in FDA-Approved Pharmaceutical Salts

Bharate, Sonali S.

doi:10.1007/s11095-021-03080-2

Cited by 29 publications

(14 citation statements)

References 71 publications

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“…Unlike Equation ( 1), the G b -E HB approach can be applied to intramolecular H-bonds [82,83], which play a structure-directed role in pharmaceutical multicomponent organic crystals [84,85]. It should be noted that empirical approaches use different geometric parameters to estimate the energies of inter-and intramolecular H-bonds in organic crystals, compare [42] with [86].…”

Section: Fast Quantum Approach For Evaluating the Energy Of Intermole...mentioning

confidence: 99%

Fast Quantum Approach for Evaluating the Energy of Non-Covalent Interactions in Molecular Crystals: The Case Study of Intermolecular H-Bonds in Crystalline Peroxosolvates

et al. 2022

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Energy/enthalpy of intermolecular hydrogen bonds (H-bonds) in crystals have been calculated in many papers. Most of the theoretical works used non-periodic models. Their applicability for describing intermolecular H-bonds in solids is not obvious since the crystal environment can strongly change H-bond geometry and energy in comparison with non-periodic models. Periodic DFT computations provide a reasonable description of a number of relevant properties of molecular crystals. However, these methods are quite cumbersome and time-consuming compared to non-periodic calculations. Here, we present a fast quantum approach for estimating the energy/enthalpy of intermolecular H-bonds in crystals. It has been tested on a family of crystalline peroxosolvates in which the H∙∙∙O bond set fills evenly (i.e., without significant gaps) the range of H∙∙∙O distances from ~1.5 to ~2.1 Å typical for strong, moderate, and weak H-bonds. Four of these two-component crystals (peroxosolvates of macrocyclic ethers and creatine) were obtained and structurally characterized for the first time. A critical comparison of the approaches for estimating the energy of intermolecular H-bonds in organic crystals is carried out, and various sources of errors are clarified.

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Section: Fast Quantum Approach For Evaluating the Energy Of Intermole...mentioning

confidence: 99%

Fast Quantum Approach for Evaluating the Energy of Non-Covalent Interactions in Molecular Crystals: The Case Study of Intermolecular H-Bonds in Crystalline Peroxosolvates

et al. 2022

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“…Similarly, in the period of 2007-2016, the maleate anion was used in 4.3% of drugs that contained basic active pharmaceutical ingredients [47]. Some recent or well-known examples of marketed drugs that contain a maleate anion [48] are afatinib dimaleate (contains two basic sites with pKa values of 8.2 and 5.0) [49], neratinib monomaleate (contains two basic sites with pKa values of 7.65 and 4.66) [50], sunitinib monomaleate (contains one basic site with a pKa of 8.95) [51] and enalapril monomalate (contains one basic site with a pKa of 5.5) [52]. These data suggest that the maleate anion is used in active pharmaceutical ingredients that contain basic moieties with a pKa of 5 or higher, which facilitates salt-species formation.…”

Section: Discussionmentioning

confidence: 99%

Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue

et al. 2022

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Glasdegib is a recently approved drug for the treatment of acute myeloid leukemia. It is formulated and marketed in monomaleate salt form. In our investigation, we were able to prepare a glasdegib dimaleate form, which could, in theory, exist in double-salt form or as a mixture of salt and co-crystal species. Therefore, the obtained crystals of glasdegib dimaleate were characterized via 15N ssNMR and single-crystal X-ray diffraction, which revealed that the obtained glasdegib dimaleate exists in double-salt form. This is a surprising finding based on the pKa values for glasdegib and maleic acid. Furthermore, we fully characterized the new dimaleate form using thermal analyses (DSC and TGA) and spectroscopy (IR and Raman). Finally, the physicochemical properties, such as solubility and chemical stability, of both forms were determined and compared.

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“…In the pharmaceutical industry, salt formation with a suitable counterion is considered to be one of the most preferred solutions to address the issue of low solubility of active pharmaceutical ingredients (APIs) [ 1 , 2 ], with hydrochlorides being a common option to consider [ 3 , 4 ]. Organic counterions, in particular fumaric and maleic acids [ 5 ], have gained increased attention in terms of their use in modern pharmaceutical formulations [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…2-aminopyridine (2AmPyr) and 2-aminonicotinic acid (2AmNic) were chosen as model APIs, and maleic acid (Mle) as the coformer ( Scheme 1 ). In pharmaceutical multicomponent organic crystals, maleic acid usually exists as a monoanion, while API molecules exist as cations (or protonated zwitterions) [ 5 , 9 , 10 ]. The main type of non-covalent interactions that stabilize the systems under consideration are intermolecular hydrogen bonds (H-bonds) [ 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…The existing force fields have limited applicability for the systems under consideration, since intramolecular H-bonds are realized in them. Unlike biomolecules, such H-bonds often occur in pharmaceutical cocrystals [ 5 , 32 , 33 ]. Thus, MD simulation of associations of [API + coformer] systems involves the parametrization of classical force fields for the correct description of intramolecular H-bonds of various types and strengths.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics Simulation of Association Processes in Aqueous Solutions of Maleate Salts of Drug-like Compounds: The Role of Counterion

Vener

Makhrov

Voronin

et al. 2022

IJMS

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The study of the formation of microstructures during the interaction of a protonated drug-like compound (API) with a maleic acid monoanion sheds light on the assembly processes in an aqueous solution at the molecular level. Molecular dynamics (MD) simulations coupled with density functional theory (DFT) calculations made it possible to find initial hydrogen bonding motifs during the assembly process, leading to the formation of heterodimers and trimers. The process of trimer formation [protonated API—maleic acid monoanion—protonated API] proceeds through the formation of three intermolecular H-bonds by the CO2− group of the maleic acid monoanion in both systems. The total enthalpy/energy of these H-bonds is more than 70 kJ/mol. Thus, the maleic acid monoanion plays a key role in the processes of association in aqueous solution, and the interaction of the maleic acid monoanion with API is more preferable than the interaction of API molecules with each other. DFT computations in the discrete continuum approximation reveal the spectral features of heterodimers and trimers, and the ATR-IR spectra confirmed these findings. MD simulations followed by DFT calculations made it possible to describe the initial stages of the formation of pharmaceutical cocrystals in an aqueous solution.

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Carboxylic Acid Counterions in FDA-Approved Pharmaceutical Salts

Cited by 29 publications

References 71 publications

Fast Quantum Approach for Evaluating the Energy of Non-Covalent Interactions in Molecular Crystals: The Case Study of Intermolecular H-Bonds in Crystalline Peroxosolvates

Fast Quantum Approach for Evaluating the Energy of Non-Covalent Interactions in Molecular Crystals: The Case Study of Intermolecular H-Bonds in Crystalline Peroxosolvates

Glasdegib Dimaleate: Synthesis, Characterization and Comparison of Its Properties with Monomaleate Analogue

Molecular Dynamics Simulation of Association Processes in Aqueous Solutions of Maleate Salts of Drug-like Compounds: The Role of Counterion

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