Development of a novel physico-chemically and microbiologically stable oral solution of flecainide for pediatrics

Abstract

There is as yet no commercialized preparation for oral administration of flecainide acetate (FA) to children. In such cases, manipulation of commercial tablets is the usual practice in pharmacy services of hospitals and compounding pharmacies, to provide a suitable dosage form for this vulnerable pediatric population group. In this study, we have formulated FA as an oral solution, as an alternative to the suspension elaborated from commercial tablets. Due to this sensitivity of young patients, we have used the pure active pharmaceutical ingredient (API) and the lowest permitted levels of pediatric excipients. Despite being a highly soluble API, only one of the formulations appears as a transparent solution due to complete FA solubilization. The proposed formulation is physico-chemically and microbiologically stable and the mass and dose uniformity is appropriate for 30 days' storage at 25 °C.

Compounded Nonsterile Preparations and FDA-Approved Commercially Available Liquid Products for Children: A North American Update

“…Dosing in children is usually less than 100 mg per dose. A 20 mg/mL formulation using bulk powder and purified water and simple syrup (50:50) resulted in a transparent solution [ 94 ].…”

Critical Aspects in the Preparation of Extemporaneous Flecainide Acetate Oral Solution for Paediatrics

“…With 40% sucrose (F2), in fact, saturation was reached at a lower concentration (about 38 mg/mL). Moreover, the literature reports the sugaring-out of FlAc when trying to prepare a 20 mg/mL solution in simple syrup (i.e., 85% sucrose) [15].…”

“…Moreover, due to children's growth, dosing must be continuously adjusted according to clinical response and the plasma concentration of flecainide (Fl) [13] and, to this purpose, liquid formulations are extemporaneously prepared [14]. The literature reports very few examples of oral solutions [13,[15][16][17][18], mainly at a concentration of 20 mg/mL, obtained by mixing pure FlAc [15] or finely crushed tablets [16][17][18] with a limited number of excipients or, alternatively, with commercially available unmedicated oral liquid vehicles. Generally speaking, the formulation of an oral liquid should take various aspects into consideration, i.e., pH, osmolarity, viscosity, the presence of preservatives, and palatability.…”

“…As an example, consideration should be given to any data regarding the effect of pH on the solubility and stability of the drug. In the case of extemporaneously prepared oral liquids of FlAc, only one is reported to be transparent [15], even though the drug concentration is always far below its solubility limit, suggesting a possible physical incompatibility with the vehicle. Although it is possible to administer the correct dose even from suspensions [17,18], it should be noted that the presence of a precipitate that has not been properly characterised could affect stability and bioavailability in unexpected ways.…”

Stability of extemporaneous sulfadiazine oral suspensions from commercially available tablets for treatment of congenital toxoplasmosis

“…This is most significant for drugs with low solubility, where dissolution is the limiting step for absorption, as for SDZ [34]. Formation of sediments that are difficult to re-disperse implies lower recovery of the drug, thus impairing dose uniformity [35]. Figure 4 shows the pH variation of formulations stored at both temperatures (25°C and 5°C).…”