Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate

John, Christopher T.; Xu, Wei; Lupton, Lisa K.; Harmon, Paul A.

doi:10.1007/s11095-013-1002-y

Cited by 48 publications

(94 citation statements)

References 30 publications

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“…Furthermore, properties of the byproducts produced because of drug–excipient interaction can also affect the performance of API. John et al observed a unique disproportionation behavior of an HCl salt in the presence of magnesium stearate because of in situ formation of magnesium chloride, and where its deliquescent nature was responsible for the enhanced disproportionation of the HCl salt. Thus, it is important to investigate the influence of excipients on the performance of oral solid dosage forms as early as possible during development to identify and avoid performance‐related issues attributed to the excipients.…”

Section: Introductionmentioning

confidence: 99%

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Miniaturized Approach for Excipient Selection During the Development of Oral Solid Dosage Form

Raijada

Müllertz

Cornett

et al. 2014

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 99%

“…A well‐designed excipient screening study during early development can help selecting suitable excipients that improve the functionality of the API . Also, it can help in the elimination of excipients having deleterious effect on the performance of API and/or find the solutions to mitigate the issues attributed to the excipient …”

Section: Introductionmentioning

confidence: 99%

Miniaturized Approach for Excipient Selection During the Development of Oral Solid Dosage Form

Raijada

Müllertz

Cornett

et al. 2014

Journal of Pharmaceutical Sciences

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“…Eight different USP buffers were used: hydrochloric acid buffers pH 1.2 and 2.0 and phosphate buffers pH 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0. 36 The pH-solubility curve was plotted to determine the pH max of the IIIM-290·HCl salt.…”

Section: Methodsmentioning

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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“…In many instances, the high energy formulation strategies that are typically utilised to enhance the exposure of poorly soluble APIs, such as size reduction via wet‐bead milling, amorphous stabilised dosage form using lyophilisation, spray‐drying or hot melt granulation, are better served using the free acid/base version of the drug, which is less prone to disproportionation [113]. In addition to the impact of the secondary process, the formulation itself can influence the degree of disproportionation [114,115]. Merritt et al .…”

Section: Alignment Of Solid‐state Strategies With Formulation Strategiesmentioning

confidence: 99%

“…[113] In addition to the impact of the secondary process, the formulation itself can influence the degree of disproportionation. [114,115] Merritt et al developed a modelling approach (using QbD approaches) to understand disproportionation and select the optimum combination of excipients. [116] A recent review outlined the formulation strategies used to optimise clinical exposure of a novel API and the impact on the solid-state strategy.…”

Section: Alignment Of Solid-state Strategies With Formulation Strategiesmentioning

confidence: 99%

The solid-state continuum: a perspective on the interrelationships between different solid-state forms in drug substance and drug product

Elder

Patterson

Holm

2015

Journal of Pharmacy and Pharmacology

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Objective The objective of the review is to provide an overview of the nomenclature used in the solid-state continuum and relate these to the development of drug substances and drug products. Key findings The importance of a rational approach to solid-state form selection, including integrated decision making (ensuring equal weight is given to the needs of the drug substance and the drug product), is vital for the effective development of a drug candidate. For example, how do secondary processing considerations influence the selection of drug substance solid-state form and resulting formulation, and how can drug substance solid-state form be used to optimise secondary processing? Further, the potential use of 'crystal' engineering to optimise stability, purity and optical resolutions, and the linked regulatory requirements, will be discussed. Summary The nomenclature used in the solid-state continuum, which contains a large number of different crystalline and non-crystalline forms, for example, amorphous systems, was reviewed. Further, the significant role of the drug substance within the solid oral dose form from a physicochemical perspective was covered.

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Formulating Weakly Basic HCl Salts: Relative Ability of Common Excipients to Induce Disproportionation and the Unique Deleterious Effects of Magnesium Stearate

Cited by 48 publications

References 30 publications

Miniaturized Approach for Excipient Selection During the Development of Oral Solid Dosage Form

Miniaturized Approach for Excipient Selection During the Development of Oral Solid Dosage Form

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

The solid-state continuum: a perspective on the interrelationships between different solid-state forms in drug substance and drug product

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