Pharmaceutical novel solid forms of Milrinone with advanced physicochemical properties

Giri, Lopamudra; Rout, Smruti Rekha; Kar, Ananya; Kenguva, Gowtham; Dandela, Rambabu

doi:10.1016/j.molstruc.2022.133746

Cited by 6 publications

(7 citation statements)

References 40 publications

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Section: Table 1 Screening Of Reaction Conditions For T...mentioning

confidence: 99%

“…28 Milrinone, olprinone, and their other analogues containing a fragment of 2-oxo-1,2-dihydropyridine-3-carbonitrile are used as cardiotonic drugs for the treatment of heart failure. [29][30][31] Known methods for obtaining derivatives of 2-oxonicotinonitrile are based on the substitution of the halogen atom in 2-halonicotinonitriles. For this, sodium hydroxide in an alcoholic or aqueous-alcoholic media 32,33 and acidic solutions can be used as reagents.…”

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confidence: 99%

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Simple and Efficient Synthesis of Highly Functional 2-Oxonicotinonitriles from 2-Chloronicotinonitriles

Бардасов

Alekseeva

Sorokin

et al. 2023

Synlett

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A simple strategy for the synthesis of 2-oxo-1,2-dihydropyridine-3-carbonitrile derivatives (2-oxonicotinonitrile, 3-cyanopyridone) in good yields by substituting the halogen atom with an oxime under mild conditions was developed. The proposed approach makes it possible to avoid the problems associated with the hydrolysis of easily modified groups, since the reaction is carried out in the absence of water.

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Section: Table 1 Screening Of Reaction Conditions For T...mentioning

confidence: 99%

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confidence: 99%

Simple and Efficient Synthesis of Highly Functional 2-Oxonicotinonitriles from 2-Chloronicotinonitriles

Бардасов

Alekseeva

Sorokin

et al. 2023

Synlett

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“…The crystal structures of MRN, its hydrate form, and HCl salt have been reported. Binary organic salts of this drug were reported with two aliphatic acid coformers, fumaric acid and adipic acid, and five aromatic carboxylic acid coformers, which are nutraceuticals, namely, 2-hydroxybenzoic acid (2HBA), 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid , syringic acid, and gallic acid. The drug Primacor contains MRN-lactate as the active ingredient and dextrose anhydrous, lactic acid, and sodium hydroxide as excipients.…”

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confidence: 99%

Cocrystals and Salts of Milrinone with Fluoro Coformers: Improving Drug Dissolution and Diffusion and Calculating Normalized Diffusion for Pharmaceutical Cocrystals

Rana,

Garai,

Nangia

2023

Crystal Growth & Design

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Milrinone (MRN) is a second-generation bipyridine phosphodiesterase inhibitor that improves cardiac function and peripheral vasodilation in acute decongested heart failure patients. Due to its poor aqueous solubility and high permeability, it is classified as a biopharmaceutical classification system class II drug. The present study aimed at screening binary cocrystals of MRN with different coformers containing fluoro-substitution. Four cocrystals were obtained with 4-fluorobenzoic acid (4-FBA), 2,5-difluorobenzoic acid (25-DFBA), 3,4,5-trifluorobenzoic acid, and 2,3,4,5tetrafluorobenzoic acid and a salt with 5-fluoro-2-hydroxybenzoic acid (5F-2-HBA). These binary crystalline products were characterized by powder X-ray diffraction, single-crystal X-ray diffraction, IR spectroscopy, differential scanning calorimetry, and thermogravimetry analysis. Their crystal structures were analyzed in terms of hydrogen bonding, supramolecular synthons such as carboxylic acid−pyridine, amide−amide dimer, hydroxyl−pyridine, and weak intermolecular interactions. The polar hydrogen bonding and nonpolar hydrophobic interactions in the crystal structures were partitioned by a Hirshfeld surface analysis. The solubility, dissolution rate, and diffusion/permeability of the MRN cocrystal/salt were studied in a physiological medium of pH 7.0. Fluorinated coformers resulted in faster dissolution and higher diffusion in all cases; specifically, MRN-4-FBA exhibited the highest drug concentration (58 mg/L) and MRN-25-DFBA the highest diffusion (130 mg/L) across dialysis membrane-135 in a pH 7.0 buffer. In addition to bioavailability, which is calculated as solubility × permeability and is a measure of the overall drug concentration in the medium, we propose calculation of drug diffusion normalized for the differences in drug concentration for the different cocrystals/salts in the experimental medium (Diff norm = Diff/Diss), as a corrected parameter to quantitatively measure the change in drug diffusion effects of cocrystals and salts relative to the reference drug concentration.

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“…Many more aspects must be taken into account when switching to a three-component solid. In our prior study, 34 we looked at the generation of binary adducts between 2-HBA and MLN, and hence we presume that the core 2-HBA may function as a possible linker to combine two distinct medications in a dual-drug strategy since 2-HBA forms binary adducts with KTS. In addition, we attempt to investigate any interactions between KTS and MLN, but we end up with a physical mixture (Fig.…”

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“…S6 (ESI †), which reveals that among all the molecular adducts the total contribution of intermolecular interactions involved in KTSÁ2-HBAÁMLN is less than the pure drug KTS. Furthermore, it should be noted that KTSÁ2-HBA (93.2%) and MLN (91.9%) 34 have larger total contact populations than MLNÁ 2-HBA (77.4%), 34 suggesting that this may be one of the factors for the weak dimeric C-HÁÁÁO connection in MLNÁ2-HBA to disintegrate in the tricomponent system while the interactions between MLN and MLN stay intact.…”

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confidence: 99%

Binary to ternary drug–drug molecular adducts of the antihypertensive drug ketanserin (KTS) with advanced physicochemical properties

Rout¹,

Kenguva²,

Giri³

et al. 2023

Chem. Commun.

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Pharmaceutical novel solid forms of Milrinone with advanced physicochemical properties

Cited by 6 publications

References 40 publications

Simple and Efficient Synthesis of Highly Functional 2-Oxonicotinonitriles from 2-Chloronicotinonitriles

Simple and Efficient Synthesis of Highly Functional 2-Oxonicotinonitriles from 2-Chloronicotinonitriles

Cocrystals and Salts of Milrinone with Fluoro Coformers: Improving Drug Dissolution and Diffusion and Calculating Normalized Diffusion for Pharmaceutical Cocrystals

Binary to ternary drug–drug molecular adducts of the antihypertensive drug ketanserin (KTS) with advanced physicochemical properties

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Pharmaceutical novel solid forms of Milrinone with advanced physicochemical properties

Cited by 6 publications

References 40 publications

Simple and Efficient Synthesis of Highly Functional 2-Oxonicotino­nitriles from 2-Chloronicotinonitriles

Simple and Efficient Synthesis of Highly Functional 2-Oxonicotino­nitriles from 2-Chloronicotinonitriles

Cocrystals and Salts of Milrinone with Fluoro Coformers: Improving Drug Dissolution and Diffusion and Calculating Normalized Diffusion for Pharmaceutical Cocrystals

Binary to ternary drug–drug molecular adducts of the antihypertensive drug ketanserin (KTS) with advanced physicochemical properties

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Simple and Efficient Synthesis of Highly Functional 2-Oxonicotinonitriles from 2-Chloronicotinonitriles

Simple and Efficient Synthesis of Highly Functional 2-Oxonicotinonitriles from 2-Chloronicotinonitriles