Soluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm. In contrast to caudal epididymal mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. In addition to preventing the capacitation-induced stimulation of sAC and protein kinase A activities, tyrosine phosphorylation, alkalinization, beat frequency, and acrosome reaction in dormant mouse sperm, sAC inhibitors interrupt each of these capacitation-induced changes in ejaculated human sperm. Furthermore, we show for the first time that sAC is required during acrosomal exocytosis in mouse and human sperm. These data define sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.
BF3 complexes of typical benzylic, allylic and saturated N-methyl tertiary amines were a-lithiated, with lithium tetramethylpiperidide (LTMP) or sec-butyllithium, and were treated with electrophiles.This Communication describes the concept of facilitating a-deprotonation of heteroatom compounds by complexation with a Lewis acid, and shows its utility for regioselective formation of C-C bonds in some tertiary amines (Scheme 1). $ Tertiary amines offer a real test of this idea since nitrogen, unlike phosphorus and sulphur, does not provide sufficient t Part of this work was presented at the 17th IUPAC International
Our objective is to mechanistically understand the implications of processing-induced lattice disorder on the stability of pharmaceutical cocrystals. Caffeine−oxalic acid (CAFOXA) and dicalcium phosphate anhydrate (DCPA) were the model cocrystal (drug) and excipient, respectively. Cocrystal−excipient mixtures were milled for short times (≤2 min) and stored at room temperature (RT)/75% RH. Milling-induced lattice disorder was quantified using powder X-ray diffractometry and gravimetric water sorption. Milling for even 10 s resulted in measurable disorder and an attendant tendency of the solid to sorb water. This was followed by cocrystal−excipient interaction leading to dissociation. The proposed mechanism of cocrystal dissociation entails the following sequence: sorption of water by disordered regions, dissolution of CAFOXA and DCPA in the sorbed water, followed by proton transfer from the coformer (oxalic acid) to DCPA, and the formation of hydrates of caffeine and calcium oxalate. As such, CAFOXA is a robust cocrystal, stable even under elevated humidity conditions (RT/98% RH). However, in a drug product environment, routine pharmaceutical processing steps such as milling and compaction have the potential to induce sufficient disorder to render it unstable.
Levothyroxine
sodium pentahydrate (LSP; C15H10I4NNaO4·5H2O) gradually loses
one molecule of water of crystallization as the water vapor pressure
is decreased from 90% to 15% RH (40 °C), a behavior characteristic
of nonstoichiometric hydrates. LSP loses four molecules of water of
crystallization to form levothyroxine sodium monohydrate (LSM; C15H10I4NNaO4·H2O) under realistic storage conditions (40 °C/0% RH for 3 h).
The crystal structure of LSP was determined following which the specimen
was partially dehydrated in situ to form LSM. The
crystal structure of LSM provided insight into its potential for high
reactivity. Thus, its presence in a drug product is undesirable. In
LSP–oxalic acid mixtures stored in a hermetic container at
40 °C, there was moisture transfer from drug to excipient. Synchrotron
X-ray diffractometry revealed dehydration of LSP resulting in LSM,
while anhydrous oxalic acid transformed to its dihydrate. In formulations
of LSP, chemical degradation of levothyroxine sodium may be preceded
by its partial dehydration.
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