Duloxetine hydrochloride

Duloxetine hydrochloride, a novel anti-depressive, is known to be acid labile and, consequently, it has been formulated as an enteric-coated tablet. Interestingly, Jansen et al. [97] subsequently found that the drug was destabilised by degradation products within these enteric polymers. The authors found that succinyl and phthalyl residues from the hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP) formed... 

USAN Duloxetine hydrochloride Trade name Cymbalta ... 

Thomson Micromedex Healthcare Series, DmgPoint Summary for Venlafaxine Hydrochloride, and Duloxetine Hydrochloride. 

Figure 49 Structures of duloxetine hydrochloride and a low level impurity formed upon aging of enteric-coated pellets.

Another example of an amine reacting with a formulation component is found in the case of duloxetine hydrochloride (84). This example, which is also discussed in Chapter 2, is summarized in Figures 49 and 50. In this example, the secondary amine of duloxetine hydrochloride reacted with the enteric coating polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) to form a succinamide degradation product. This reaction occurred under both stress conditions (60°C for 14 days) and during formal stability studies (30°C/60% relative humidity and 40°C/75% relative... 

Figure 50 Proposed pathways for the interaction of duloxetine hydrochloride with HPMCAS to form duloxetine succinamide.

Duloxetine hydrochloride is an example of an aryl ether that is particularly unstable to hydrolysis under acidic conditions (84). The acid instability led to the development of an enteric-coated formulation to protect the compound from the acidic environment of the stomach. The reason for the susceptibility to hydrolysis is the stability of the cationic intermediate (Fig. 70), which is stabilized by delocalization into the aromatic thiophene ring. See Chapter 2 for additional discussion of the chemistry of this compound. 

Figure 70 Hydrolysis of the ether linkage of duloxetine hydrochloride under acidic conditions.

Zhao RK, Cheng G, Tang J et al (2009) Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers a randomized, open-label, single- and multiple-dose study. Clin Ther 31 1022-1036... 

FIGURE 20 Cartoon representation of a cross-sectional view of the duloxetine hydrochloride enteric-coated pellets. 

Cymbalta (Duloxetine hydrochloride). Eli Lilly and Company Ltd UK Summary of product characteristics, November 2006. 

Cymbalta (Duloxetine hydrochloride). EU LiUy and Company. US Prescribing information. May 2007. 

In 2004,17 years after the introduction of Prozac , duloxetine hydrochloride (Cymbalta , Lilly) was approved in the U.S. Duloxetine has a chiral carbon and is the S enantiomer. Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine (SSNRI). It is effective against depression and... 

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