Role of Salt Selection in Drug Discovery and Development

Acharya, Pratap Chandra; Marwein, Sarapynbiang; Mishra, B.; Ghosh, Rajat; Vora, Amisha; Tekade, Rakesh K.

doi:10.1016/b978-0-12-814423-7.00013-7

Cited by 6 publications

(4 citation statements)

References 103 publications

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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 drug compounds, 6,7 with hydrochlorides being a common option to consider. 8,9 However, organic counterions have gained increased attention in terms of their use in modern pharmaceutical formulations, 8 since they are less likely to disproportionate in aqueous solutions due to the smaller pK a difference 10,11 and may also have better solubility in gastric media in comparison to hydrochloride salts that tend to suffer from the common ion effect. In a 2007 article, Paulekuhn et al noted a declining trend in chloride ion selection for pharmaceutical salt preparation and a clear tendency toward a broader diversity of organic counterions applied in solid formulations of basic drugs.…”

Section: Introductionmentioning

confidence: 99%

Pharmaceutical Salts of Fenbendazole with Organic Counterions: Structural Analysis and Solubility Performance

Surov

Vasilev

Vener

et al. 2021

Crystal Growth & Design

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In this work, three new pharmaceutical salts of fenbendazole (FNB), a benzimidazole-based anthelmintic drug, with sulfonic acids have been obtained and thoroughly investigated by different analytical techniques, including thermal methods, infrared/Raman spectroscopy, and theoretical methods (periodic DFT computations and Bader analyses of the crystalline electronic density). Single-crystal and high-resolution synchrotron powder X-ray diffraction data for the first time made it possible to determine the crystal structures of mesylate and tosylate salts of the drug, which were further validated by dispersion-corrected density functional theory calculations. All the solid forms were stabilized by a robust R2 2(8) supramolecular motif formed by relatively strong N–H···O hydrogen bonds. In the monohydrate of FNB tosylate, a considerable gain in the stabilization energy was due to the intermolecular interactions generated by the water molecules. A careful examination of the solubility–pH profile of the FNB salts revealed that, despite being thermodynamically unstable within the physiologically relevant pH range, the new solid forms demonstrated superior dissolution performance in terms of both the apparent solubility and the release rate in comparison to the parent drug. Since FNB has also been reported to possess anticancer activity, improving the drug’s poor physicochemical properties through salt formation with the selected sulfonic acids is expected to promote further investigations toward repurposing of this potent compound.

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Section: Introductionmentioning

confidence: 99%

Pharmaceutical Salts of Fenbendazole with Organic Counterions: Structural Analysis and Solubility Performance

Surov

Vasilev

Vener

et al. 2021

Crystal Growth & Design

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“…Amino acids that have overall positive or negative charges are all of hydrophilic nature, with an exception of hydrophobic arginine [162]. Amino acid-based salt formation of a drug requires the selection of appositely charged amino acids to balance the total charge on the resultant salt [167]. These appositely charged counterions interact with acidic or basic ionised drugs in their solutions via strong electrostatic forces of attraction to form stable and neutral salts [154].…”

Section: Amino Acids As Solubility Enhancing Agentsmentioning

confidence: 99%

Multimodal Role of Amino Acids in Microbial Control and Drug Development

et al. 2020

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Amino acids are ubiquitous vital biomolecules found in all kinds of living organisms including those in the microbial world. They are utilised as nutrients and control many biological functions in microorganisms such as cell division, cell wall formation, cell growth and metabolism, intermicrobial communication (quorum sensing), and microbial-host interactions. Amino acids in the form of enzymes also play a key role in enabling microbes to resist antimicrobial drugs. Antimicrobial resistance (AMR) and microbial biofilms are posing a great threat to the world’s human and animal population and are of prime concern to scientists and medical professionals. Although amino acids play an important role in the development of microbial resistance, they also offer a solution to the very same problem i.e., amino acids have been used to develop antimicrobial peptides as they are highly effective and less prone to microbial resistance. Other important applications of amino acids include their role as anti-biofilm agents, drug excipients, drug solubility enhancers, and drug adjuvants. This review aims to explore the emerging paradigm of amino acids as potential therapeutic moieties.

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“…Nearly half of all drug molecules are delivered in the form of salt ( Acharya et al, 2018 ). Traditionally, improving solubility is one of the basic reasons for adopting salt forms, but numerous studies have shown that a unique salt form may have an impact far beyond solubility.…”

Section: Introductionmentioning

confidence: 99%

Development of o-aminobenzamide salt derivatives for improving water solubility and anti-undifferentiated gastric cancer

et al. 2023

Front. Pharmacol.

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Background: Gastric cancer is one of the cancers with wide incidence, difficult treatment and high mortality in the world, especially in Asia and Africa. In our previous work, a novel o-aminobenzamide analogue F8 was identified as an early preclinical candidate for treatment of undifferentiated gastric cancer (IC50 of 0.26 μM for HGC-27). However, the poor water solubility of compound F8 prevents its further progress in preclinical studies.Aim: To improve the water solubility and drug-likeness of F8 via salt formation.Method: Different acids and F8 were reacted to obtain different salt forms. Physicochemical property screening, pharmacokinetic property research, and antitumor biological activity evaluation in vitro and in vivo were used to obtain the optimal salt form with the best druggability.Results: our continuous efforts have finally confirmed F8·2HCl as the optimal salt form with maintained in vitro antitumor activity, improved water solubility and pharmacokinetic properties. Importantly, the F8·2HCl displayed superior in vivo antitumor efficacy (TGI of 70.1% in 75 mg/kg) in HGC-27 xenograft model. The further immunohistochemical analysis revealed that F8·2HCl exerts an antitumor effect through the regulation of cell cycle-related protein (CDK2 and p21), apoptosis-related protein Cleaved Caspase-3, proliferation marker Ki67, and cell adhesion molecule E-cadherin. In addition, F8·2HCl showed acceptable safety in the in vivo acute toxicity assay.Conclusion: Salting is an effective means to improve the drug-like properties of compound F8, and F8·2HCl can serve as a promising therapeutic agent against undifferentiated gastric cancer.

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Role of Salt Selection in Drug Discovery and Development

Cited by 6 publications

References 103 publications

Pharmaceutical Salts of Fenbendazole with Organic Counterions: Structural Analysis and Solubility Performance

Pharmaceutical Salts of Fenbendazole with Organic Counterions: Structural Analysis and Solubility Performance

Multimodal Role of Amino Acids in Microbial Control and Drug Development

Development of o-aminobenzamide salt derivatives for improving water solubility and anti-undifferentiated gastric cancer

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