Behavior of Decomposition of Rifampicin in the Presence of Isoniazid in the pH Range 1–3

Abstract

The extent of decomposition of rifampicin in the presence of isoniazid was determined in the pH range 1-3 at 37 degrees C in 50 min, the mean stomach residence time. With increase in pH, the degradation initially increased from pH 1 to 2 and then decreased, resulting in a bell-shaped pH-decomposition profile. This showed that rifampicin degraded in the presence of isoniazid to a higher extent at pH 2, the maximum pH in the fasting condition, under which antituberculosis fixed-dose combination (FDC) products are administered. At this pH and in 50 min, rifampicin decomposed by approximately 34%, while the fall of isoniazid was 10%. The extent of decomposition for the two drugs was also determined in marketed formulations, and the values ranged between 13-35% and 4-11%, respectively. The extents of decomposition at stomach residence times of 15 min and 3 h were 11.94% and 62.57%, respectively, for rifampicin and 4.78% and 11.12%, respectively, for isoniazid. The results show that quite an extensive loss of rifampicin and isoniazid can occur as a result of interaction between them in fasting pH conditions. This emphasizes that antituberculosis FDC formulations, which contain both drugs, should be designed in a manner that the interaction of the two drugs is prevented when the formulations are administered on an empty stomach.

Substandard rifampicin based anti-tuberculosis drugs common in Ugandan drug market

“…The more the number of drugs incorporated in a fixed dose combination, the higher is the likelihood of compromised quality, a finding similar to what other researchers reported from the global drug market (Bhutani, 2004;. Previous studies have attributed the frequent occurrence of substandard rifampicin content in four-drug and three-drug FDCs to the presence of ethambutol in the formulations, which creates an environment that causes rifampicin to be degraded in the presence of isoniazid (Singh, 2001;Sankar, 2003). However, bad formulations due to poor manufacturing practice are more likely to be the reason for the poor quality products found in this study.…”

Study of the interaction between rifapentine and isoniazid under acid conditions

“…Both the drugs showed bell-shaped pH- dependent decomposition, with maximum degradation occurring at pH 2, the loss of Rp and H being ∼30 and ∼9%, respectively. The profiles as well as the extent of decomposition were similar to that observed for the combination of R (∼33%) and H (∼10%) [9].…”

Mechanistic explanation to the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and isoniazid in anti-TB FDCs

“…In this pH range, rifampicin degrades in a facile manner in the presence of isoniazid to HYD [13]. This reaction has been ascribed to be responsible for the reduction of in vivo bioavailability of rifampicin from FDC products [6,8].…”