Temperature prodrug

Similarly, chemical hydrolysis of a number of a-amino acyl prodrugs of metronidazole (8.100, R=H see Sect. 8.5.4) was compared to the serum-catalyzed reaction [135][136]. The amino acids used for esterification included alanine, glycine, isoleucine, leucine, lysine, phenylalanine, and valine. Under physiological conditions of pH and temperature, ty2 values for hydrolysis in human serum ranged from 4.5 min for the Phe ester to 96 h for the lie ester. A good linear relationship was established between the log of the rate constant of enzymatic hydrolysis and the log of the rate constant of HO-cata-... 

The reversibility of lactone hydrolysis in HMG-CoA reductase inhibitors has been demonstrated at gastric pH and temperature (pH 2.0, 37°) [186], For the prodrug lovastatin (8.148), reversible lactone hydrolysis to its active hydroxy acid (8.149) occurred with a f1/2 value of ca. 1 h and an equilibrium constant close to one. Similar results were obtained for some closely related compounds. In contrast, this reversible hydrolysis was much slower under the nearly neutral pH conditions of the intestine. 

Four/V-[(acyloxy)methyl] derivatives of 5-FU (8.152, R = AcOCH2, Et-COOCH2, PrCOOCH2, and (7-Bu)COOCH2) were very stable in buffer at pH 7.4 and 37° (t1/2 70, 90, 140, and 700 h, respectively) [219], In 80% human plasma under the same conditions of pH and temperature, the f1/2 values were 14, 9.6, 2.3, and 40 h, respectively, i.e., a marked substrate-dependent acceleration. In rat liver homogenates, the tm values for decomposition were in the order of a few minutes or less. Clearly enzymatic hydrolysis is possible for such compounds and may even be quite significant. Additional data on A-[(acyloxy)methyl] prodrugs have confirmed their potential for topical delivery of 5-FU [220],... 

Under physiological conditions of temperature and pH, tm values for lactonization of tens to hundreds of hours were seen. Thus, prodrugs of this type are useful only when the nature of the substituents allows lactonization to be sufficiently fast. 

Ideally, a water-soluble prodrug product should have a shelf life of 2 years or more at room temperature, in which case the half-lifevitro should be at least 13 years. If the only purpose of prodrug formation is to improve the aqueous solubility of the parent compound, then bioconversion in vivo should be extremely rapid. If it is assumed that more than 90% of the prodrug is converted to the parent drug within 30 min of the injection, tlrevivo half-life should be 10 min or less. 

Oleic acid is the common name for (Z)-9-octadece-noic acid and is a nearly colorless liquid at room temperature with a melting point of 5-7°C. Oleic acid is practically insoluble in water but has been used as a solvent for oral delivery of hydrophobic drugs in soft gelatin capsules. Oleic acid is used to solubilize ritonavir in Norvir and Kaletra soft gelatin capsules (see section Microemulsion Oral Formulations ). Testosterone undecanoate is an ester prodrug of testosterone intended for oral administration in hormone replacement therapy, and is solubilized in oleic acid in 40 mg Restandol 40 mg soft gelatin capsules. 

As already mentioned, isoxazoles such as I FT are prodrugs and are not sufficiently persistent in plants to inhibit the HP PD enzyme. It is the first metabolite of isoxaflutole, the so-called DKN (diketonitrile) 3-cyclopropyl-2-[2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl]-3-oxopropanenitrile (25) that is the herbicidally active entity. In soil, and also in plants, I FT undergoes rapid conversion into DKN [25]. In aqueous solutions there is an influence of temperature and pH on the chemical hydrolysis of IFT to DKN. The hydrolysis increases with increasing pH and temperature for 295 K and pH 9.3 the rate of degradation was 100-fold faster than at pH 3.8. (Scheme 4.4.7) [26]. The DT50 in water is 11 days at pH 5, 20 h at pH 7 and 3 h at pH 9 [22]. 

Another prodrug synthesis using a microfluidic reaction system is that of the antibiotic ciprofloxacin [10], A microreaction system developed by CPC systems (CYTOS) was used as a reaction apparatus. This system is the size of a videotape with a holdup of 1.8 ml. The high surface-to-volume ratio for the mixing section as well as for the temperature-controlled reaction channels allows heat transfer coefficients of up to 2,000 Wm K . The synthesis has demonstrated the potential for faster development, particularly in the preparation of relevant quantities for development studies, such as clinical trials, using the microreaction systems. 

Starting from biotin-A/-hydroxysuccinate 75, the biotin—lipid conjugates 76a—c were prepared by reaction with aminoalcohols at room temperature in DMF. Then, the phosphonate prodrugs 77a—c were obtained after reaction with (S)-HPMPC 55 in the presence of N,N-diisopropyle-thylamine (DIEA) and benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) in DMF at 45 °C. 

---