Optimization of the preparation and control of melatonin capsules

Background and objectives
In the absence of existing pharmaceutical specialties in immediate release, the pharmacotechnics department of CHUGA prepares 2 and 5 mg melatonin capsules. These hospital preparations were introduced in 2017 at the request of neurologists wishing to induce sleep and thus facilitate the performance of nap electroencephalograms in children (1). Based on published data, their use was extended to the realization of magnetic resonance imaging (2) and the recording of auditory evoked potentials (3) leading to a strong increase in demand (+1000% in 3 years). At the same time, we have noticed a 23% rejection rate of batches in one year, requiring an optimization of the realization and control of these preparations.
The objective of this work is to identify the origin of these nonconformities, to optimize the preparation and control of these capsules in order to reduce the rejection rate.

Material and methods
1) Retrospective analysis of batch records to identify the origin of nonconformities.
2) Optimization of the preparation method, control and composition (diluents tested: caspulac lactose, microcrystalline cellulose, silica monohydrate and flow agents: talc and magnesium stearate) without interfering with the assay method (UV-2600 model, Shimadzu)

Results
Batch rejections are only for the 2 mg capsule batches and correspond to underdosing, justifying optimization of the preparation method, control, or even composition.
Silica, cellulose and magnesium stearate require filtration and interfere with the dosing method. Batches conforming to EP specifications (mass and content uniformity (4-5)) were obtained either by adding 0.5% talc causing a matrix effect, or by reducing the number of steps during preparation and control.

Discussion and conclusion
We have chosen to optimize only the preparation and control steps without modifying the excipient composition. This work also allowed us to review our capsule preparation practices, to homogenize and standardize them. The estimated time saving is 10 minutes during the preparation and 30 minutes on the control of each batch. This optimization was a first mandatory step before the switch to a 300 unit capsule, allowing us to improve our efficiency.

Références biblio
(1) Sander J. et al. Eur J Pediatr. 2012;171(4):675-9.
(2) Pasini A. et al. Eur J Pediatr 2018 ; 177(9):1359-1362
(3) Casteil L. et al. AFORL 2017 ; 134 (6) : 357-359
(4) Monographie 2.9.6. Uniformité de teneur Pharmacopée européenne, 10^ème ed
(5) Monographie 2.9.5. Uniformité de masse Pharmacopée européenne, 10^ème ed

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