Rolf Brickl

Is bicarbonate buffer suitable as a dissolution medium

The objectives of this study were to compare two methods for the preparation of bicarbonate buffer, and to compare media prepared with bicarbonate buffer with commonly used biorelevant and pharmacopoeial media in terms of their suitability for dissolution testing. The various media were compared with regard to ease of preparation, robustness and reproducibility of composition. The dissolution of three formulations of a typical Biopharmaceutical Classification System Class II drug (BIXX) was compared in bicarbonate buffer, standard phosphate buffer, a biorelevant buffer (fasted‐state simulating intestinal fluid, FaSSIF) and a modified FaSSIF prepared with bicarbonate buffer. The bicarbonate buffer used for dissolution testing was produced by supplying carbon dioxide to a saline solution (0.9% NaCl, to which 12 or 42 mmol NaOH had been added). The bicarbonate buffer had to be prepared in‐situ, which proved to be time‐consuming, and the pH stability of the bicarbonate buffer could only be maintained under constant CO2 supply. To minimize the mechanical stress caused by inflow and evaporation of gas, the carbon dioxide was supplied above the medium during the dissolution test. Despite taking these measures, use of bicarbonate buffer led to less reproducible dissolution results than the phosphate buffers commonly used to prepare compendial media and FaSSIF, with coefficient of variance values 1.5‐ to 5‐times higher in bicarbonate buffer. It was concluded that although a bicarbonate buffer system would be physiologically relevant for the fasted state in the small intestine, its suitability for dissolution testing is restricted by lack of practicability and poor reproducibility of results.

Instant FaSSIF and FeSSIF—Biorelevance Meets Practicality

The objective of this study was to prepare an “instant” form of FaSSIF and FeSSIF that could be implemented easily and reproducibly in the laboratory setting. Concentrated solutions containing bile salts and lecithin were freeze-dried and further processed into bulk packs, blisters, or tablets, or sealed in powder form under nitrogen in vials. Physical properties as well as solubility and dissolution data for two poorly soluble compounds, danazol and a Boehringer-Ingelheim development compound (BIXX), were compared with data for freshly prepared FaSSIF and FeSSIF and a commercially available “instant” product. After the freeze-dried FaSSIF and FeSSIF media were reconstituted with appropriate buffers, their properties were close to those of freshly prepared media and a commercially available product for reconstitution, SIF Powder. Additionally, the solubility and dissolution profiles of danazol and BIXX in media prepared by all three methods were similar. Reconstitution of freeze-dried “instant” FaSSIF and FeSSIF appears to be an accurate, reproducible, and efficient way of preparing biorelevant dissolution media.

Pharmacokinetics of Single-Dose Telmisartan 120 mg Given during and between Hemodialysis in Subjects with Severe Renal Insufficiency: Comparison with Healthy Volunteers

The pharmacokinetics of oral telmisartan 120 mg evaluated in subjects with severe renal insufficiency between dialyses and during hemodialysis were compared with those observed in healthy male subjects. Between dialyses and during dialysis, the plasma concentration‐time curves of subjects with renal insufficiency were lower than those of healthy subjects. The mean plasma protein binding of telmisartan was 99.5% in healthy subjects, compared with mean values of 99.1% between dialyses and 98.8% during dialysis. Only very small amounts of telmisartan were removed by dialysis. Single doses of telmisartan 120 mg were well tolerated in subjects with severe renal insufficiency when administered either between dialyses or during dialysis, and no clinically relevant changes in vital signs were detected. In conclusion, the maximum plasma concentrations of telmisartan and areas under the plasma concentration‐time curves in subjects with severe renal insufficiency were markedly reduced compared with healthy subjects. The fraction of telmisartan not bound to plasma proteins was increased approximately twofold. Changes in the pharmacokinetic profile in subjects with renal insufficiency did not affect the safety profile of telmisartan, which was well tolerated in these subjects.