Formulation and stability study of low-dose midazolam capsules for clinical trial

In patients suffering from chronic liver disease, hepatic metabolism of drugs is perturbed and the metabolic capacity is difficult to assess. Midazolam, an imidazobenzodiazepine, could be used as phenotypical probe to predict metabolic capacity of cytochrome P450 3A in order to adjust dosages of drugs substrate of this cytochrome. In this context, a prospective clinical trial is going to be conducted in our institution. Subjects recruited will receive 1 mg of midazolam dose. Midazolam oral solid form is not available in our country, therefore a hospital preparation of midazolam capsules suitable for the clinical trial was developed. The objectives of the present work were (i) to develop a low-dose solid form of midazolam, (ii) to develop a stability-indicating method and for preparation quality control and (iii) to assess the physicochemical stability of the formulation in order to set a shelf life.

Three batches of 1 mg capsules were prepared using midazolam hydrochloride and microcrystalline cellulose as a diluent. The capsules were stored at ambient temperature (23°C ± 2°C), and protected from light. To measure the evolution of the capsules content, a stability-indicating high-performance liquid chromatography (HPLC) method was developed with ultraviolet (UV) detection at 254 nm. Data were confirmed using a liquid chromatography tandem-mass spectrometry (LC-MS/MS) analytical method.

The HPLC method was validated in terms of linearity, accuracy, precision and specificity and displayed stability indicating capacity. Forced degradation studies showed that no degradation products were co-eluted with the midazolam peak. After 90 days, midazolam hydrochloride content remained higher than 95% of the initial concentration in capsules.

The preliminary results show that 1 mg midazolam capsules are stable for 90 days at room temperature and under dark conditions and can be used for clinical trial purpose. The stability study is still underway to extend the shelf life to one year.