Stability of Clozapine Stored in Oral Suspension Vehicles at Room Temperature: DISCUSSION
During the study period, the concentration of clozapine observed in all study samples remained within 5% of the initial concentration. Multiple linear regression detected a significant (p = 0.0379) trend for a change in concentration over the study period, but the change averaged only 2.56%. There were no significant differences in the rate of clozapine degradation among the suspension vehicles, and the lowest percentage of initial concentration remaining, estimated with 95% confidence on day 63, was 93.97%. Furthermore, degradation products observed during the accelerated degradation of clozapine were not observed during the stability study. Assuming no degradation and assuming that all concentration determinations represented estimates of an unchanging concentration, the inter-day reproducibility of sample concentrations was less than 1.7% (CV expressed as a percentage), which is similar to the error observed during the assay validation of quality control samples and standards (1.4%).
In considering extemporaneous formulation of a clozapine oral liquid, the authors set the following criteria for an acceptable formulation: palatable to patients; easily compounded, preferably using a commercially available suspending agent; stable for at least 60 days; and of sufficient concentration to avoid the need to administer large volumes. The suspending agents tested were Ora-Sweet, Ora-Plus, a 1:1 mixture of Ora-Sweet and Ora-Plus, the suspending vehicle used by the Hospital for Sick Children, simple syrup, and Guy’s pediatric mixture. Ora-Sweet and Ora-Plus are commercially available suspending vehicles. Ora-Sweet is a mixture of sucrose, glycerin, and sorbitol, and Ora-Plus contains carboxymethyl cellulose, microcrystalline cellulose xanthan gum, and carrageen. The Hospital for Sick Children’s suspending vehicle is a methylcellulose and simple syrup mixture that is not commercially available and must be manufactured. Similarly, Guy’s pediatric mixture must be extemporaneously manufactured. Simple syrup is essentially a saturated solution of sucrose in water that is widely available from numerous distributors.
To properly evaluate the stability of a clozapine suspension, a suitable analytical method was required. Although a few publications have described analytical methods for measuring clozapine and its metabolites in biological samples, the authors were aware of only one method for analyzing clozapine and its degradation products in pharmaceutical products. However, even with the information from that publication, a stability- indicating analytical method for clozapine had to be developed and validated before the stability study could be initiated. This analytical method was required to ensure that clozapine could be accurately and reproducibly measured in the presence of clozapine degradation products in different suspending agents.