Preparation and in vitro release of dual-drug resinate complexes containing codeine and chlorpheniramine

Abstract

Objective: To develop the dual-drug resinate complexes containing codeine and chlorpheniramine with a novel batch processing, characterize the dual-drug resinate complexes, and study its drug release behavior in vitro. Methods: A procedure of simultaneous dual-drug loading using combination solutions composed of different proportions of codeine phosphate and chlorpheniramine maleate was performed to achieve the specific resinate, and the dual-drug loading content was determined by high-performance liquid chromatography method. The dual-drug resinate complexes were characterized by a scanning electron microscope, and the formation mechanisms were confirmed with X-ray diffraction analyses and differential scanning calorimetric analyses. The release behavior of the two drugs from the dual-drug resinate complexes in vitro was studied in the media simulating in vivo environments (simulated gastric fluid: pH = 1.2 HCl, simulated in vivo ionic strength: 0.15 M NaCl, and simulated intestinal fluid: pH = 6.8 buffer solution containing KH2PO4–NaOH). Results: Scanning electron microscopic analyses proved that the dual-drug resinate complexes had the same appearance and characters as the initiative ion exchange resins (IERs). Via X-ray diffraction and differential scanning calorimetric analyses, it is found that the two drugs in dual-drug resinate complexes were combined with IERs by chemical bond. The drug-resinate complex, like IER, was in amorphous state. More than 90% of codeine phosphate was released in 15 minutes in three different media, whereas little amount of chlorpheniramine maleate was released in all the release time in the medium pH = 1.2 HCl, and the release equilibrium time was about 5 minutes, only 40% was released in the medium 0.15 M NaCl, and the equilibrium time was 40 minutes, and about 90% was released in the medium pH = 6.8 KH2PO4–NaOH. The increased ionic strength generally accelerated the release of the two drugs from the dual-drug resinate complexes. Conclusion: The dual-drug resinate complexes were formed through the reaction between the drugs and the IERs by chemical bond. The release behavior of the drug from the dual-drug resinate complexes in vitro was mainly correlated with the drug molecular structure, the eluting ionic strength, composition, and ionic strength of the release media. The novel dual-drug resinate complexes could be used to deliver two drugs in one therapeutic dose.

• Characterization
• chlorpheniramine maleate
• codeine phosphate
• dual-drug resinate
• ion-exchange resin
• preparation
• release

Acknowledgments

The authors acknowledge the assistance provided by Dr. Liu Hongfei, Mr. Yan Zhigang, and Mr. Huang Kai.

Declaration of interest

The authors acknowledge the financial support of Shenzhen Zhijun Pharmaceutical Co., Ltd. (Guangdong, China). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.