本實驗共分成兩部分，第一部份的耐受性試驗包括使用0.1N HCl之酸性試液，0.1N NaOH之鹼性試液，3% H2O2之氧化試液，以及在黑暗中隔水加熱至80℃和使用UV光照試驗。第二部份的實驗為評估控釋處方上的設計對安定性之影響。共有四種處方，分別為添加酸性、鹼性和氧化賦形劑之處方，及以使用不添加任何酸鹼賦形劑之處方做對照，並探討製作錠劑及儲存於60℃，75%RH下及各項製造過程等對fluvastatin可能造成之不純物。本實驗中分析方法乃採用高效能液相層析儀(HPLC)配合紫外光(UV)偵測儀作為主要分析儀器。
During the storage process of drug substances and/or drug products, the chemical structure integrity may vary with time under the influence of different factors such as acid, base, temperature, humidity, oxygen, light, as well as excipients. These factors may result in chemical impurities due to degradation of bulk drugs, causing potential pharmacological problems that cannot be ignored.
The present work will focus on investigating the degradation behavior of fluvastatin in various stress conditions and in its controlled-release formulations. Previous studies showed that statins were easily transformed in water by photo irradiation. Literature results also indicated that statins were sensitive to acid stress.
In the first part of the experiment, fluvastatin solutions were subjected to oxidation (in 3% H2O2), acid (in 0.1N HCl), alkaline (in 0.1N NaOH), photolysis (UV at 254 nm) and heat (on a bath water at 80◦C, in the dark) in stressed conditions. A reverse phase high performance liquid chromatographic (HPLC) method with UV detection was developed to study the stability of fluvastatin. The second part of the experiment was to evaluate the stability profile of fluvastatin in its controlled-release formulations. Four formulations were studied: formulation with acid excipient, formulation with alkaline excipient, and formulation with excipient having oxidization potential. The experiment also evaluated possible impurities during the manufacturing of tablets and its preservation under two weeks of 60◦C, 75%RH conditions. The dissolution stability for the four formulations was also studied.
The result of the first experiment agreed with previous studies that fluvastatin was degraded by photo-irradiation in water when exposed to UV. Under 0.1N HCl, three degradation peaks appeared after the active ingredient. Degradation was also seen under heat stress. Fluvastatin was found to be more stable under alkaline and oxidative stress conditions. From the result of the second experiment, the process of mixing and extracting did not significantly change the amount of the active ingredient and impurities. Through tablet compression, active ingredient changed 1~4%, while the impurities were consistent to the impurities after heat stress. For coated tablet after UV irradiation for 24 hours, the tablets with TiO2 in HPMC-based coating may decrease the degradation caused by photo-irradiation. The dissolution study demonstrated that the dissolution was faster for tablets with alkaline excipient, and the dissolution was slower when acid excipient was added. The dissolution was stable for all formulation after the accelerated stability studies.
In summary, the stability profiles of fluvastatin and its controlled-release formulations were studied. The results suggest that, since fluvastatin can easily degrades under acid or lighting environment, acidic excipients should be avoided; TiO2 in HPMC-based coating should be also added to prevent photodegradation of fluvastatin tablets.