An investigation into the utility of a multi-compartmental, dynamic, system of the upper gastrointestinal tract to support formulation development and establish bioequivalence of poorly soluble drugs.

In recent years mechanical systems have been developed that more closely mimic the full dynamic, physical and biochemical complexity of the GI Tract. The development of these complex systems raises the possibility that they could be used to support formulation development of poorly soluble compounds and importantly may be able to replace clinical BE studies in certain circumstances. The ability of the TNO Simulated Gastro-Intestinal Tract Model 1 (TIM-1) Dynamic Artificial Gastrointestinal System in the 'lipid membrane' configuration to support the development of Biopharmaceutics Classification System Class 2 compounds was investigated by assessing the performance of various AZD8055 drug forms and formulations in the TIM-1 system under standard fasting and achlorhydric physiological conditions. The performance data were compared with exposure data from the phase 1 clinical study. Analysis of the AZD8055 plasma concentrations after tablet administration supported the conclusions drawn from the TIM-1 experiments and confirmed that these complex systems can effectively support the product development of poorly soluble drugs. Particularly, the TIM-1 system was able to show that AZD8055 exposure would increase in an approximately dose proportional manner and not be limited by the solubility or dissolution. Additionally, the investigations also showed that the exposure produced by a solution and a tablet would be the same. Specific instances when the TIM-1 system may not be predictive of clinical product performance have also been identified.

CE hydrogen deuterium exchange-MS in peptide analysis.

CE and hydrogen-deuterium (H/D) exchange MS are useful tools in the analysis and characterisation of peptides. This study reports the facile coupling of these tools in the H/D exchange CE-MS analysis of model and pharmaceutically important peptides, using a sheath flow interface. The peptides varied in mass from 556 (leucine enkephalin) to 1620 Da (bombesin), and in charge state from 0.33 (leucine enkephalin) to 3.0 (substance P). The application of a BGE composed of ammonium formate buffer (25 mM, pD 3.5 in D(2)O (>98% D atom)), a sheath liquid composed of formic acid (0.25% v/v in D(2)O) and ACN (30:70 v/v), and dissolving the samples in a mixture of ACN/D(2)O (50:50 v/v) facilitates complete H/D exchange. Because of complete H/D exchange the ESI mass spectra produced are easy to interpret and comparable to those obtained from LC-MS analysis. The CE-H/D-MS approach has the advantage of requiring lower volumes of deuterated solvents. The b- and y-series fragments produced by using in-source decomposition correspond to those predicted. With the peptides studied, the complete exchange H/D exchange observed with both the molecular and fragment ions helps to confirm both amino acid composition and sequence.