Development of an experimental drug and implementation of its preparation on automatic capsule fillers

Introduction et Objective
To evaluate the effectiveness of prophylactic antiepileptic treatment during the acute phase of intracerebral hemorrhages, the automated production of levetiracetam capsules (250 mg) was requested. The main objective of this study was to assess the feasibility of filling levetiracetam capsules without excipients using an automatic capsule-filling machine.

Materials and Methods
According to the Biopharmaceutics Classification System, levetiracetam is a Class I active ingredient (high permeability, high solubility), which theoretically does not require excipients to improve its intestinal permeability and aqueous solubility. Immediate-release capsules (size 2) were chosen to administer a 250 mg dose of levetiracetam. To evaluate the feasibility of automatic capsule filling using an automatic capsule-filling machine, a particle size distribution analysis of levetiracetam was performed by sieving (test 2.9.38 of the European Pharmacopoeia) from a powdered sample of levetiracetam sieved for 5 minutes. This analysis was complemented by optical microscope observation (magnification x 100) of the different powdered fractions of levetiracetam retained on each sieve. Following this particle size analysis, the levetiracetam powder capsules were filled using an automatic capsule-filling machine at a rate of 3000 capsules per hour. The mass uniformity of the capsules (Ph.Eur. 2.9.5) was verified on a sample of 20 randomly selected capsules during production.

Results
The particle size distribution of levetiracetam determined by sieving (total material loss < 5%) and by microscopic observation ranged between 50 µm-56 µm (52%) and 224 µm-280 µm (44%). The mass uniformity of the capsules after filling met the specifications of the European Pharmacopoeia (error ≤ 10%).

Discussions and Conclusions
The optimal particle size for capsule filling depends on several factors, such as the type of active ingredient, the excipients used, and the type of capsule-filling machine. In this study, a particle size of levetiracetam between 50 µm and 200 µm was chosen to ensure optimal flow and uniform filling of the capsules using an automatic capsule-filling machine. The simplicity of automated production ensures a homogeneous distribution of the active ingredient in each capsule, guaranteeing precise dosing and optimal therapeutic efficacy. A stability study is underway to determine whether the addition of an excipient to improve levetiracetam’s stability is necessary.

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