Absorption and Physicochemical Properties of the NCE

Selbo, Jon G.; Chiang, Po‐Chang

doi:10.1002/9780470915110.ch3

Cited by 3 publications

(12 citation statements)

References 79 publications

(83 reference statements)

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“…In order to avoid ex vivo salt conversion, a non-aqueous vehicle was used for formulation preparation (25,26). Phenytoin free acid, phenytoin Na salt, and phenytoin piperazine salt were suspended in Miglyol 810.…”

Section: Formulation Preparationmentioning

confidence: 99%

“…The described results suggest that aside from the sodium and piperazine salts, all other phenytoin salts experienced conversion back to the free acid form during solubility testing. Furthermore, this suggests that the true solubility of the ethylenediamine, ethanolamine, and piperidine salts could be higher than the measured values since it is unlikely that the samples of these salts were at conditions where solubility is determined by the K sp for the entire duration of the solubility test (25,26). Since we wanted to test salts with the largest range of solubility, the sodium and piperazine salts were selected for further evaluation.…”

Section: Evaluation Of Water Solubility Of Phenytoin Saltsmentioning

confidence: 99%

“…Medicinal chemists often identify drug candidates with ionizable groups that are amenable to salt formation (24,25). For ionizable compounds, the intrinsic solubility is defined by the unionized form.…”

Section: Introductionmentioning

confidence: 99%

“…In the process of salt formation, the above relationship only holds true before the pH of maximum solubility (pH max ) is reached. At the pH max , the compound forms a salt and the solubility product of the salt (K sp ) determines the solubility (24)(25)(26). This is typically referred to for an acid as the region of pH> pH max (the pH where the solution is saturated with respect to both the free and salt forms).…”

Section: Introductionmentioning

confidence: 99%

“…Differences in oral exposure due to salt solubility may be less obvious at lower doses compared to higher doses since complete dissolution in the gastric is more likely. Therefore, for a given compound, the salt solubility required for optimal in vivo performance is dependent on various factors such as dose, solubility (supersaturation), and permeability, rather than a single solubility measurement (24)(25)(26). Thus, a better understanding of optimal salt solubility and dose relationship are advantageous early in the salt selection process.…”

Section: Introductionmentioning

confidence: 99%

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Incorporation of Physiologically Based Pharmacokinetic Modeling in the Evaluation of Solubility Requirements for the Salt Selection Process: A Case Study Using Phenytoin

Chiang¹,

Wong²

2013

AAPS J

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Abstract. In the pharmaceutical industry, salt is commonly used to improve the oral bioavailability of poorly soluble compounds. Currently, there is a limited understanding on the solubility requirement for salts that will translate to improvement in oral exposure. Despite the obvious need, there is very little research reported in this area mainly due to the complexity of such a system. To our knowledge, no report has been published to guide this important process and salt solubility requirement still remains unanswered. Physiologically based pharmacokinetic (PBPK) modeling offers a means to dynamically integrate the complex interplay of the processes determining oral absorption. A sensitivity analysis was performed using a PBPK model describing phenytoin to determine a solubility requirement for phenytoin salts needed to achieve optimal oral bioavailability for a given dose. Based on the analysis, it is predicted that phenytoin salts with solubility greater than 0.3 mg/mL would show no further increases in oral bioavailability. A salt screen was performed using a variety of phenytoin salts. The piperazine and sodium salts showed the lowest and highest aqueous solubility and were tested in vivo. Consistent with our analysis, we observed no significant differences in oral bioavailability for these two salts despite an approximate 60 fold difference in solubility. Our study illustrates that higher solubility salts sometimes provide no additional improvements in oral bioavailability and PBPK modeling can be utilized as an important tool to provide guidance to the salt selection and define a salt solubility requirement.

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Section: Formulation Preparationmentioning

confidence: 99%

Section: Evaluation Of Water Solubility Of Phenytoin Saltsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Incorporation of Physiologically Based Pharmacokinetic Modeling in the Evaluation of Solubility Requirements for the Salt Selection Process: A Case Study Using Phenytoin

Chiang¹,

Wong²

2013

AAPS J

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Synthesis, physicochemical properties of allopurinol derivatives and their biological activity against Trypanosoma cruzi

Raviolo

Solana

Novoa

et al. 2013

European Journal of Medicinal Chemistry

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Synthesis and pharmaceutical properties of N-acyloxymethyl prodrugs of Allop with potential anti-trypanosomal activity

Gualdesi

Ortiz

Raviolo

2015

Drug Development and Industrial Pharmacy

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We report herein the synthesis, and the physicochemical and pharmacokinetic properties of N-acyloxymethyl prodrugs of allopurinol (Allop) (2a-f). Allop is a compound with activity against Trypanosoma cruzi, a causative agent of Chagas disease. Its pathology leads to a huge number of infections and deaths per year, because in addition to many sufferers only having limited access to health services only an inefficient chemotherapy is available. Relevant pharmaceutical properties (pKa, stability, solubility, lipophilicity, in vitro permeability, binding protein, xanthine oxidase binding) were also determined. The results obtained showed that derivatives behave as prodrugs of Allop, since they exhibit improved physicochemical and pharmacokinetic properties relative to their precursor. This behavior turns these compounds into active reservoirs of Allop, and reduces its unfavorable characteristics, so 2a-f compounds are excellent candidates for the treatment of Chagas disease. This work is therefore an important contribution leading to the suppression of Chagas disease.

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Absorption and Physicochemical Properties of the NCE

Cited by 3 publications

References 79 publications

Incorporation of Physiologically Based Pharmacokinetic Modeling in the Evaluation of Solubility Requirements for the Salt Selection Process: A Case Study Using Phenytoin

Incorporation of Physiologically Based Pharmacokinetic Modeling in the Evaluation of Solubility Requirements for the Salt Selection Process: A Case Study Using Phenytoin

Synthesis, physicochemical properties of allopurinol derivatives and their biological activity against Trypanosoma cruzi

Synthesis and pharmaceutical properties of N-acyloxymethyl prodrugs of Allop with potential anti-trypanosomal activity

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