LC–MS Stability Assessment of Ethanol-Free Buprenorphine Oral Syringes for Neonatal Therapy

A widely used formulation of uprenorphine (BUP), which is considered advantageous in the management of neonatal opioid withdrawal syndrome (NOWS) contains 30% ethanol. A study conducted at Thomas Jefferson University, (Philadelphia, Pennsylvania) aimed to investigate the stability of BUP in compounded ethanol-free oral syringes using pH and liquid chromatography-mass spectrometry (LC-MS) analysis after compounding and at 7, 30, and 60 days of storage. A paper based on their efforts was published in The Journal of Pediatric Pharmacology and Therapeutics.¹

What is Buprenorphine?

BUP is a natural semi-synthetic partial µ-opioid receptor agonist used sublingually in the treatment of NOWS.² The most used formulation for NOWS is 75 mcg/mL BUP in 30% ethanol compounded from BUP injection 0.3 mg/mL administered by the sublingual route.³ While BUP offers excellent efficacy, there is hesitation for use by clinicians due to the presence of ethanol, inspiring the Thomas Jefferson University team to assess the stability via physiochemical testing of a 75 mcg/mL ethanol-free formulation of BUP compounded in oral syringes, stored at room temperature and refrigerated conditions for 60 days.¹

What is Neonatal Opioid Withdrawal Syndrome?

There has been an increasing number of infants since 2000 with a history of in utero exposure to opioids. The sudden cessation of placentally transmitted opioids can cause a constellation of clinical signs of withdrawal that may occur in neonates after in utero exposure to opioids and other substances, referred to as NOWS.⁴ Symptoms of this syndrome include irritability, fussiness, and difficulty consoling; more severe symptoms include the impairment of maternal bonding and weight gain. First-line therapies are non-pharmacological, such as swaddling, a low-stimuli environment, and mother–to–child bonding. When these do not control symptoms, an opioid is administered to the infant.¹

How Was This Study Conducted?

A 75-mcg/mL BUP solution was prepared for this study by diluting the commercial injectable solution with water for irrigation, transferred into amber oral syringes, and stored at either room temperature (n = 3) and refrigerated (n = 3) conditions. Microbial testing of the compounded oral syringes was performed to determine microbial growth for 24 and 48 hours at 37°C.¹

The researchers found that the concentration of BUP at all time points was between 90% and 110% of the baseline on day 0. Concentration increased slightly in the oral syringes after day 30, likely due to moisture loss, as there were no degradation peaks observed in chromatograms. There was no microbial growth or visual change observed for the compounded ethanol-free BUP oral syringes. The pH of the oral syringes was consistent through 60 days for both room-temperature and refrigerated samples.¹

“Buprenorphine in an ethanol-free formulation,” wrote the authors of the paper,¹ “is stable and can be easily compounded in pediatric pharmacies. This formulation is appealing for the treatment of NOWS.”

Although the formulation has worked well in real clinical use, the researchers are of the opinion that more testing in patients is still needed to confirm how it behaves in the body. Furthermore, the team only tested storage at room temperature and in the refrigerator; the researchers suggest that future studies explore more extreme conditions to confirm durability. While no breakdown products or microbes were found, the team believes that more sensitive testing methods could provide additional reassurance. Finally, the researchers pointed out that their study also focused on one specific concentration, offering a starting point for developing more formulations in the future.¹

References

1. Soni, V.; Shah, S. A.; Kraft, W. K. et al. Stability Study of Compounded Ethanol-Free Buprenorphine Oral Syringes for the Treatment of Neonatal Opioid Withdrawal Syndrome. J Pediatr Pharmacol Ther. 2026, 31 (2), 233-237. DOI: 10.5863/JPPT-25-00058
2. Devlin, L. A.; Young, L. W.; Kraft, W. K. et al. Neonatal Opioid Withdrawal Syndrome: A Review of the Science and a Look Toward the Use of Buprenorphine for Affected Infants. J Perinatol. 2022, 42 (3), 300-306. DOI: 10.1038/s41372-021-01206-3
3. Kraft, W. K.; Adeniyi-Jones, S. C.; Chervoneva, I, et al. Buprenorphine for the Treatment of Neonatal Abstinence Syndrome. N Engl J Med. 2017, 376(24), 2341–2348. DOI:10.1056/NEJMoa1614835
4. Jilani, S. M.; Jones, H. E.; Grossman, M. et al. Standardizing the Clinical Definition of Opioid Withdrawal in the Neonate. J Pediatr. 2022, 243, 33-39, e1. DOI: 10.1016/j.jpeds.2021.12.021