Telescoped approach to aryl hydroxymethylation in the synthesis of a key pharmaceutical intermediate.

An efficient synthetic approach leading to introduction of the hydroxymethyl group to an aryl moiety via combination of the Bouveault formylation and hydride reduction has been optimized using a rational, mechanistic-based approach. This approach enabled telescoping of the two steps into a single efficient process, readily amenable to scaleup.

Optimization of LY545694 tosylate controlled release tablets through pharmacoscintigraphy.

PURPOSE: To optimize a controlled release (CR) matrix formulation with two goals: (1) effectively deliver a prodrug to a preferred absorption region of the upper GI tract, and (2) afford a PK profile similar to a "reference" CR formulation. METHODS: A pharmacoscintigraphic clinical study was conducted using a flexible formulation design space. A six-arm, three-prototype study was employed to cover the formulation design space and assess performance against the reference formulation. Pharmacokinetic and scintigraphic data from the first three dosing arms were used to select prototypes to be dosed in subsequent arms. RESULTS: Of three prototypes tested, the third prototype had an optimal release rate. The in vivo erosion rate was observed via scintigraphy to reach 90% in 3 h. The AUC ratio relative to the reference for the prodrug was 1.25, while the C(max) ratio was 1.07. The ratios for the active moiety were 1.31 (AUC) and 1.01 (C(max)). CONCLUSIONS: A single pharmacoscintigraphic study efficiently investigated a wide formulation design space and precisely optimized the release rate with few formulation iterations. The selected formulation provided the desired exposure at a 30% lower dose. The approach is beneficial when drug absorption is limited to a region of the GI tract.

Strategies for the investigation and control of process-related impurities in drug substances.

The understanding, identification, quantification and control of impurities in drug substances are essential as new molecular entities are evaluated in clinical development. As chemical processes used to produce drug substances mature from the early phases of development through registration, a concomitant maturing of process-related impurity understanding and control is required. This paper outlines strategies available to pharmaceutical scientists to aid in that understanding. Methodology aspects for impurity investigations are discussed along with an emphasis on understanding the origin and fate of impurities to guide decisions on process controls and specifications. Orthogonal analytical approaches for impurity investigations to provide a complete understanding of a drug substance impurity profile and to aid chemical process development are described. Special considerations necessary for stereochemical impurity investigations are also discussed. Considerations for control of toxic impurities include sensitive and selective analytical methodology and determination of the process capability for removing the impurity. A case study is given where routine analytical testing for a toxic impurity was not required because a high impurity rejection efficiency of the synthetic process was demonstrated. Quality assessment of starting materials from multiple sources and the impact of starting material impurities on the impurity profile of the drug substance are discussed with illustrative examples. Knowledge gained from these investigations provides a sound basis for setting specifications for impurities in key starting materials.