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Published on: March 28, 2017
Methodology for phase selection of a weak basic drug candidate, utilizing kinetic solubility profiles in bio-relevant
Shuntaro Furukawa1, Chenhua Zhao, Yasuhiro Ohki
1Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan. shuntaro_furukawa@merck.com
Summary
Selecting the optimal active pharmaceutical ingredient (API) phase is crucial for drug development. The disulfate salt of compound A demonstrated superior kinetic solubility and bioavailability compared to free form I.
Area of Science:
- Pharmaceutical Science
- Drug Development
- Physical Chemistry
Background:
- Developing a weak basic active pharmaceutical ingredient (API) requires careful phase selection.
- Limited API quantities necessitate efficient development methodologies.
- Understanding API behavior in bio-relevant media is critical for predicting in vivo performance.
Purpose of the Study:
- To establish a phase selection method for a weak basic API using minimal quantities (<10mg).
- To monitor real-time kinetic solubility of the API in simulated gastric fluid (SGF) and fasted-state intestinal fluid (FaSSIF).
- To compare the development potential of two distinct phases: free form I and a disulfate salt of compound A.
Main Methods:
- Kinetic solubility measurements were performed on free form I and the disulfate salt of compound A.
- Dissolution tests were conducted in SGF and FaSSIF above saturation concentrations.
- Precipitation kinetics were assessed by injecting liquid-state API into FaSSIF.
- Pharmacokinetic profiles were evaluated in dogs following oral administration of both API phases.
Main Results:
- Distinct kinetic solubility profiles were observed for the two API phases under gastrointestinal conditions.
- The disulfate salt exhibited superior kinetic solubility compared to free form I.
- Dog pharmacokinetic studies corroborated the in vitro findings, showing better bioavailability for the disulfate salt.
Conclusions:
- The disulfate salt of compound A is the preferred phase for further drug development due to its enhanced kinetic solubility.
- The developed methodology allows for efficient phase selection with minimal API usage.
- In vitro kinetic solubility directly correlates with in vivo pharmacokinetic performance.
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