Interest of an analytical control by UV spectrophotometry for the control of phenobarbital compounded preparations.

V.Delannoy (1), F. Maillard (1), M. Warembourg (1), I.Soulairol (1-2) 1 Department of Pharmacy, Nîmes University Hospital, Nîmes, France
2 ICGM, University of Montpellier, CNRS, ENSCM, Montpellier, France

Phenobarbital (PHB) is an antiepileptic frequently used in pediatric population for the treatment of epilepsy. To overcome the lack of marketed specialties suitable to this category of patients, hospital pharmacy unit realized compounded of PHB capsule preparations (CP). Currently, in our unit their control is based on the European Pharmacopoeia mass uniformity (UM) test (2.9.5). Nevertheless, the risk assessment of PHB CP is in support of enhancing its control. The objective of this work is to evaluate the interest of a control by UV spectrophotometry (UV spectro) for the control of PHB CP.

Material and method
The developed method was validated according to the ICH Q2 (R1) recommendations. Its linearity was verified for concentrations ranging from 0.007 to 0.06 (r = 0.9996). Accuracy and precision were tested on 2, 20 and 100 mg controls. The coefficients of variation were less than 4% and the bias value for all 3 dosages ranged from -1.08 to -3.33%. The solutions were diluted in 50% methanol (v/v) and then in phosphate buffer solution (pH =6.9). Under these conditions, maximum absorption was observed at a wavelength of 239 nm. The results of the UM test and the UV spectro assay were collected and compared. PHB CP were divided into two categories: those with a PHB content of less than 2 mg (CP ≤ 2 mg) and those with a PHB content between 2 and 25 mg (CP > 2 mg). UV spectroscopy results for CP ≤ 2 mg were compliant if they were within ± 15% as per European Pharmacopoeia, uniformity test of content of single-dose preparations assay B (2.9.6). For CP > 2 mg, they were compliant if they were within ± 10%.

Between December 2018 and June 2020, 37 PHB CP were manufactured including 2 CP ≤ 2 mg and 35 CP > 2 mg. None of the PHB CP were non-compliant (NC) according to the UM test. Results by UV spectro revealed no NC for CP ≤ 2 mg in the ± 15% range. For 28.5% (n=10) of the CP > 2 mg, the UV spectro assay result was outside the ± 10% range and was then NC.

Discussion and conclusion
The NC rates according to UM and UV spectro assay thus demonstrate the value of the determination of PHB content. On the other hand, the level of CP > 2 mg NC observed is consistent with the overall NC level found in our unit for batch preparations controlled according to the uniformity test of content of single-dose preparations (24% NC). UV spectro is an analytical method of choice for the control of CP; the relatively short analysis times allow to include it in their manufacturing and control circuit. Then, these results demonstrate the interest of routine control by UV spectro of PHB CP, but they must be verified on a larger number of CP especially for CP ≤ 2 mg.

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