An Approach to Early-Phase Salt Selection:  Application to NBI-75043

Gross, Timothy D.; Schaab, Kevin M.; Ouellette, Michael A.; Zook, Scott; Reddy, Jayachandra P.; Shurtleff, Arthur; Sacaan, Aida; Alebic-Kolbah, Tanja; Bozigian, Haig

doi:10.1021/op060221a

Cited by 25 publications

(13 citation statements)

References 12 publications

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“…Salt formation can be employed to augment their melting points and convert and maintain the solid state. For example, Bozigian et al reported that compound NBI-75043, which is an investigational compound for the treatment of insomnia, was a crystalline, free base with a low melting point (64 °C) [ 10 ]. One of the important pharmaceutical requirements for this compound was to develop a salt that possessed a higher melting point.…”

Section: Drug Chemistry Considerationsmentioning

confidence: 99%

“…Since the low melting point was one of the concerns for this drug, initial approaches to characterize salt forms included differential scanning calorimetry (DSC), which is an important tool for determining the melting point as well as crystallinity, solvates, and presence or absence of the polymorphs. They were able to successfully find the salt form of NBI-75043 by focusing on the chemistry of the drug [ 10 ].…”

Section: Drug Chemistry Considerationsmentioning

confidence: 99%

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Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations

et al. 2018

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The physicochemical and biological properties of active pharmaceutical ingredients (APIs) are greatly affected by their salt forms. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. However, the incorrect salt form can have the opposite effect, and can be quite detrimental for overall drug development. This review summarizes several criteria for choosing the appropriate salt forms, along with the effects of salt forms on the pharmaceutical properties of APIs. In addition to a comprehensive review of the selection criteria, this review also gives a brief historic perspective of the salt selection processes.

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Section: Drug Chemistry Considerationsmentioning

confidence: 99%

Section: Drug Chemistry Considerationsmentioning

confidence: 99%

Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations

et al. 2018

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“…Gross et al 25 performed a salt formation evaluation of the next generation H-1 antagonist, NBI-75043.…”

Section: The Need For Stronger Counter-ionsmentioning

confidence: 99%

“…Gross et al 25 looked at alternative salt forms of NBI-75043, as the initially selected tartrate salt had low melting point (948C), it was hygroscopic and had a propensity to form solvates and hydrates. Subsequently, they selected the besylate salt as it crystallized in high purity and yield from multiple solvent systems, gave the highest melting point (165-1688C) and existed as a single polymorphic form.…”

Section: Salt Formation and Form (Polymorph) Considerationsmentioning

confidence: 99%

The Utility of Sulfonate Salts in Drug Development

Elder

Delaney²,

Teasdale

et al. 2010

Journal of Pharmaceutical Sciences

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“…7 The salt screening and solid form selection in early drug discovery has a major impact on both preclinical and clinical developments of the lead candidate. 8 In a typical organic chemistry laboratory, the preparation of salt of any organic compound requires atleast 50 mg quantity of the compound. Thus, optimization of a suitable counterion using such a strategy in a chemistry lab would require a larger amount of compound, may be up to 1–2 g. However, gram-sized quantities are only available when the molecule enters in the developmental stages.…”

Section: Introductionmentioning

confidence: 99%

Selection of a Water-Soluble Salt Form of a Preclinical Candidate, IIIM-290: Multiwell-Plate Salt Screening and Characterization

et al. 2018

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IIIM-290, a semisynthetic derivative of natural product rohitukine, is an orally bioavailable Cdk inhibitor, efficacious in the xenograft models of colon, pancreatic, and leukemia cancer. Its low aqueous solubility (∼8.6 μg/mL) could be one of the reasons for achieving optimal in vivo efficacy relatively at a higher dose. Being a nitrogenous compound, salt formation was envisaged as one of the ideal approaches to enhance its solubility and dissolution profile. Thus, herein, a solubility-guided miniaturized 96-well plate salt screening protocol was devised for identification of the suitable salt form of this preclinical candidate. The solubility-guided strategy has resulted in the identification of hydrochloride as the most favorable counterion, resulting in 45-fold improvement in aqueous solubility. The HCl salt was then scaled up at a gram size and characterized using 1H and 13C NMR, scanning electron microscopy, powder X-ray diffraction, Fourier-transform infrared, and differential scanning calorimetry studies. The HCl salt displayed enhancement in the in vitro dissolution profile as well as improved plasma exposure in the pharmacokinetic study. The oral administration of the IIIM-290·HCl salt in BALB/c mice resulted in >1.5-fold improvement in areas under the curve, Cmax, and half-life. The prepared salt also did not alter its cyclin-dependent kinase (Cdk)-2 and Cdk-9 inhibition activity. This biopharmaceutically improved lead has a potential to investigate further in preclinical studies. The solubility-guided salt screening strategy implemented herein could be utilized for other preclinical leads.

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An Approach to Early-Phase Salt Selection: Application to NBI-75043

Abstract: A strategy for the salt selection of NBI-75043 is presented and summarized in a decision-tree format. This is followed by the first scale-up of the process, confirmation of a new polymorph, and description of a method for its conversion to the initial form.

Cited by 25 publications

References 12 publications

Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations

Salts of Therapeutic Agents: Chemical, Physicochemical, and Biological Considerations

The Utility of Sulfonate Salts in Drug Development

Selection of a Water-Soluble Salt Form of a Preclinical Candidate, IIIM-290: Multiwell-Plate Salt Screening and Characterization

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