Stability of Oxytocin Preparations in Malawi and Rwanda: Stabilizing Effect of Chlorobutanol

Abstract

Oxytocin is used for the prevention and treatment of postpartum hemorrhage, the leading cause of maternal mortality in low-and middle-income countries. Because of the high instability of oxytocin, most products are labeled for storage at 2-8°C. Some other products are on the market which are labeled for non-refrigerated storage, but independent evaluations of their stability hardly exist. In the present study, seven brands (nine batches) of oxytocin were purchased from wholesalers and medical stores in Malawi and Rwanda and investigated by accelerated stability testing according to the ICH/WHO guidelines. Two oxytocin brands approved by a stringent regulatory authority (SRA) or by the WHO Prequalification of Medicines program and purchased in Europe were used as comparison. All investigated brands which were either produced in countries with SRAs, or were WHO-prequalified products, were labeled for storage at 2-8°C, and all of them passed stability testing with very good results. Even exposure to 25°C or 30°C for several months hardly affected their oxytocin content. However, two other investigated brands were labeled for non-refrigerated storage, and both of them had been produced in countries without SRAs. These two preparations showed not higher but lower stability than the brands labeled for storage at 2-8°C, and, for both of them, noncompliance with pharmacopoeial specifications was found after accelerated stability testing. At 40°C, and in forced degradation studies at 80°C, chlorobutanol showed a remarkable stabilizing effect on oxytocin, which may deserve further investigation. The results of the present study support the policy "Buy Quality Oxytocin, Keep It Cool."

Quality assessment of oxytocin injection and misoprostol tablets in Côte d’Ivoire and Senegal

“…This study represents the first assessment of oxytocin and misoprostol quality in West Africa, showing results consistent with similar surveys conducted in Anglophone African countries [13,[18][19][20][21][22].…”

“…These findings align with other studies conducted LMICs assessing the quality of oxytocin and misoprostol, revealing instances of unregistered or unlicensed medicines. [13,[18][19][20]23] Typically, unregistered medicines are commonly discovered in private and informal sectors during such surveys. However, this study identified unregistered medicines in level-2 and level-3 of public health facilities in all regions evaluated, except in Abidjan in Côte d'Ivoire.…”

Quality of oxytocin and misoprostol in health facilities of Rwanda

“…The package inserts of the preparations by Sterop (Belgium), Grindeks (Latvia) and Rotexmedica GmbH Arzneimittelwerk (Germany) stated the excipients, i.e. sodium chloride, different buffering agents, water for injection, and in case of the Sterop preparation also chlorobutanol, a preservative and stabilizing agent [ 40 ]. In contrast, no excipients were stated for the product by Jiangxi Xierkangtai.…”

“…Obviously, the use of oxytocin products which do not have to be stored in a refrigerator appears to be an attractive option, especially in LMICs. However, recent studies have shown that oxytocin products labeled for non-refrigerated storage may not have any better stability than products labeled for refrigerated storage, and on the contrary may even be less stable [ 40 , 44 ]. Therefore, international stakeholders including WHO have issued the recommendation “Buy quality oxytocin, keep it cool” and recommended that all oxytocin products should be stored at 2–8°C [ 16 , 48 ], irrespective of the manufacturer’s storage recommendation.…”

In Vivo Evaluation of the Oral Toxicity of the Chlorobutanol

“…Furthermore, CB is known to undergo hydrolysis at elevated temperatures, forming hydrochloric acid and other acidic reaction products [9]. This is likely to explain the change in pH of preparations that contain CB, which has been observed at 40 • C. As expected, this effect was even more pronounced at 80 • C, with both preparations showing a pH of 2.0 in 5 days [10].…”