Probabilistic model of waiting times between large failures in sheared media.

Using a probabilistic approximation of a mean-field mechanistic model of sheared systems, we analytically calculate the statistical properties of large failures under slow shear loading. For general shear F(t), the distribution of waiting times between large system-spanning failures is a generalized exponential distribution, ρ_{T}(t)=λ(F(t))P(F(t))exp[-∫_{0}^{t}dτλ(F(τ))P(F(τ))], where λ(F(t)) is the rate of small event occurrences at stress F(t) and P(F(t)) is the probability that a small event triggers a large failure. We study the behavior of this distribution as a function of fault properties, such as heterogeneity or shear rate. Because the probabilistic model accommodates any stress loading F(t), it is particularly useful for modeling experiments designed to understand how different forms of shear loading or stress perturbations impact the waiting-time statistics of large failures. As examples, we study how periodic perturbations or fluctuations on top of a linear shear stress increase impact the waiting-time distribution.

Elucidating the pathways of degradation of denagliptin.

Stress testing or forced degradation studies of denagliptin (1) tosylate in solution and solid-state, its blends with excipients, and capsules were conducted in order to elucidate degradation pathways, aid formulation development, and generate data to support regulatory filings. In solution, denagliptin was stressed in acid, water, and base using organic cosolvents. In the solid-state, denagliptin was stressed under heat, humidity, and light. Blends of denagliptin with various excipients were stressed under heat and humidity in order to evaluate whether tablet was a viable dosage form. Capsules were stressed under heat, humidity, and light. It was found that denagliptin was stable in the solid-state, but degraded in solution, in blends with all excipients, and in capsules predominantly by cyclization to (3S,7S,8aS) amidine (2), which epimerized to (3S,7S,8aR) amidine (3). (3S,7S,8aR) amidine (3) subsequently hydrolyzed to the corresponding diketopiperazine (4). The purpose of this manuscript is to discuss the results of stress testing studies conducted during the development of denagliptin and the elucidation of its key degradation pathway.

Efficient synthesis of an adenosine A2a agonist: glycosylation of 2-haloadenines and an N2-alkyl-6-chloroguanine.

A convergent synthesis of adenosine A2a agonist 1 in the form of its maleate salt 2 was achieved. The key step in this approach was the highly selective 9beta-glycosylation reaction between 2-haloadenines or an N(2)-alkyl-6-chloroguanine and a D-ribose derivative containing a 2-ethyltetrazolyl moiety. Glycosylations of other purine derivatives were also examined, and the methods developed provide efficient access to a variety of adenosine analogues such as 2-alkylaminoadenosines, an attractive class of compounds with antiinflammatory activity.