Investigation of the physicochemical stability of chlordiazepoxide in poly (d,l-lactide-co-glycolide) microspheres

Date of Completion

January 2001


Chemistry, Pharmaceutical|Health Sciences, Pharmacy




Biodegradable polymers have long been used for the controlled delivery of therapeutic agents. However recent developments of biodegradable synthetic polymers such as polylactic acid (PLA) and poly (d,l-lactide-co-glycolide) (PLGA) have resulted in formulations that release drugs from days to several months. Commercially available products that contain PLGA include Lupron Depot ® and Zoladex®. ^ One of the problems associated with PLGA as a drug delivery system is that it degrades to form lactic and glycolic acids and these acids may degrade therapeutically active agents included within the dosage form. There is literature that indicates a decrease in pH. However controversy exists over the pH range associated with the polymer degradation. The objective of this research is to investigate the physicochernical stability of chlordiazepoxide, a model basic drug, in PLGA microspheres. The physical and chemical state of a drug may be altered during incorporation of the drug into microspheres. Chlordiazepoxide was chosen because of its instability in acid conditions and low solubility at physiological pH. Studies were conducted to investigate the physical and chemical stability of chlordiazepoxide during manufacture and also to determine the chemical stability of chlordiazepoxide within microspheres in pH 2.0 and pH 7.4 PBS buffer. ^ Chlordiazepoxide was shown to exist both in the amorphous and crystalline states within the microspheres. The amorphous state readily converts into the crystalline phase on heating past the thermal glass transition temperature. The drug exhibits weak intermolecular hydrogen bonding with the polymer in organic solutions used in the microsphere manufacture. Water-soluble crystals of chlordiazepoxide HCI were successfully entrapped with no change in thermodynamic or chemical stability. Chlordiazepoxide, in PLGA microspheres, was found to be unstable in both pH 2.0 and 7.4 media. The intrinsic solubility of the drug increased in pH 7.4 media possibly as a result of complex formation. A method was developed to improve the thermodynamic and chemical stability of chlordiazepoxide by complexing with a model macromolecule, heparin. This complex was successfully incorporated into the PLGA microspheres. ^