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Crystal structures, dissolution and pharmacokinetic study on a novel phosphodiesterase-4 inhibitor chlorbipram cocrystals.
- Source :
-
International journal of pharmaceutics [Int J Pharm] 2020 Feb 25; Vol. 576, pp. 118984. Date of Electronic Publication: 2019 Dec 21. - Publication Year :
- 2020
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Abstract
- Cocrystallization of chlorbipram (ChBP), a novel phosphodiesterase-4 (PDE) inhibitor with water insoluble property developed in our lab, was performed to improve the physicochemical properties and bioavailability in the present study. Three new cocrystals with fumaric aicd (FA), gentisic acid (GA) and salicylic acid (SA) as coformers were synthesized and fully characterized by using the combination of multi-techniques. The cocrystals are phase stable even under high humidity conditions. In vitro study indicates that the solubility of ChBP-GA and ChBP-SA cocrystals increase to 3724.4 ± 58.7, 2897.4 ± 81.9 μg/mL in comparison with ChBP (2561.3 ± 150.4 μg/mL), the intrinsic dissolution rates (IDRs) of ChBP-GA and ChBP-SA cocrystals (721.3 ± 8.0, 614.4 ± 13.2 μg/min/cm <superscript>2</superscript> ) are both higher than ChBP (537.9 ± 12.0 μg/min/cm <superscript>2</superscript> ). The blood concentration peak values of ChBP-GA and ChBP-SA cocrystals (165.8 ± 50.9, 105.3 ± 35.6 ng/mL) are both higher than ChBP (51.3 ± 15.1 ng/mL) in in vivo evaluation. It presents the same order in in vitro/vivo study: ChBP-GA > ChBP-SA > ChBP > ChBP-FA. ChBP-FA cocrystal presents a longer elimination half life (t <subscript>1/2</subscript> = 10.0 ± 2.6 h), which makes it a potential candidate for prolonged controlled release formulation. ChBP-GA and ChBP-SA cocrystals both present enhanced solubility and bioavailability in comparison with ChBP, making them a better candidate for the solid dosage formulation development.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Biological Availability
Crystallization methods
Delayed-Action Preparations chemistry
Delayed-Action Preparations pharmacokinetics
Fumarates chemistry
Fumarates pharmacokinetics
Gentisates chemistry
Gentisates pharmacokinetics
Half-Life
Male
Rats
Rats, Sprague-Dawley
Salicylic Acid chemistry
Salicylic Acid pharmacokinetics
Solubility
Phosphodiesterase 4 Inhibitors chemistry
Phosphodiesterase 4 Inhibitors pharmacokinetics
Pyridazines chemistry
Pyridazines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-3476
- Volume :
- 576
- Database :
- MEDLINE
- Journal :
- International journal of pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 31870960
- Full Text :
- https://doi.org/10.1016/j.ijpharm.2019.118984