IriSys was requested to develop a novel tablet formulation of a poorly water soluble, high dose, steroidal analgesic. The formulation was intended to reduce inter-subject bioavailability variability. Pharmacokinetic studies indicated approximately a 10-fold variability in C_max after administration when previously formulated as a blend with commonly used excipients and filled into capsules.

Selected preformulation studies were conducted. Forced degradation indicated the drug was not degraded by peroxide and only slightly by acid. In basic solution, the drug was very susceptible to degradation. A pH stability study showed significant degradation at pH 8. Maximum solubility in aqueous solution at lower pH values was about 15 µg/mL. Log P was determined to be 2.96. An excipient compatibility study was performed demonstrating the drug was inherently stable and highly compatible with the selected excipients. Tablet direct compression was evaluated in a composition of drug, and lactose and microcrystalline cellulose (MCC).

Dibasic calcium phosphate, dihydrate (DCP), MCC, crospovidone and magnesium stearate (MS) preparations were also studied. Subsequent experiments showed that the addition of DCP and MCC would provide a blend having the blend characteristics to meet all specifications including manufacturability. Formulations were prepared with and without bioavailability enhancing ingredients. Target fill weight and hardness met specifications. Content uniformity of 10 tablets was 98.5% with a relative standard deviation of 3.1%. Dissolution using the basket configuration at 100 RPM provided complete dissolution in 30 minutes. 

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