Stability of Clozapine Stored in Oral Suspension Vehicles at Room Temperature: DISCUSSION part 2
Because only small changes in clozapine concentration could be detected under the storage conditions studied, assurance of the specificity of the analytical method is very important. In addition, the separation and detection of intact drug in the presence of degradation compounds must be assured before the method can be considered suitable for indicating stability. The specificity of the analytical method was demonstrated during the accelerated degradation studies (Figure 1). In these studies, the clozapine concentrations declined as the concentration of apparent degradation products increased.
Demonstrating a trend toward a substantial decline in concentration was considered more important than demonstrating a statistical difference in concentration between any 2 days. In fact, random fluctuations in concentration around the initial concentration are not of practical importance and should be considered “noise” or experimental error. Linear regression indicated that the concentration on day 63 was within 3% of the initial concentration and that concentrations on day 63 would not be expected to fall below 93.97% of the initial clozapine concentration, with 95% confidence.
Given that the degradation rate or change in clozapine concentration over the 63-day study period did not differ among the suspending agents, the choice of an ideal suspending agent defaults to palatability and ease of preparation. Since both the suspending vehicle of the Hospital for Sick Children and Guy’s pediatric mixture involve the time-consuming process of creating a methylcellulose solution, formulations using these vehicles cannot be considered ideal. Simple syrup is not as viscous as Ora-Sweet and Ora-Plus formulations and generally does not suspend particles as well. Furthermore, suspensions using simple syrup as the vehicle might be more prone to caking after standing for a prolonged period of time, although this problem was not observed in the current study. The Ora-Sweet and Ora-Plus vehicles do not present problems of preparation, suspension, or caking.
In conclusion, 20 mg/mL suspensions of clozapine prepared in Ora-Sweet, Ora-Plus, a 1:1 mixture of Ora-Sweet and Ora-Plus, the suspending vehicle of the Hospital of Sick Children, simple syrup, and Guy’s pediatric mixture were stable insofar as they retained at least 93.97% of the initial clozapine concentration when stored in amber plastic containers at 23°C for 63 days. Because no difference in stability was observed with different suspending vehicles, the choice of suspending vehicle can be based on other variables such as cost, physical compatibility, availability, and patient preference. The authors consider the clozapine formulations prepared with commercially available Ora-Sweet or Ora-Plus products preferable to formulations prepared with the other vehicles and recommend these formulations because of their stability and ease of preparation.
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