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

Abstract

The availability of liquid oral preparations compounded by pharmacists is essential to meet paediatric needs which remain unanswered by the pharmaceutical industry. Unfortunately, compendial monographs are often not available and, in many cases, pre-formulation studies (e.g., compatibility with other excipients and solubility evaluations) are not performed in-depth, leading, in some rare cases, to the inadvertent administration of a toxic dose. In this study, the preparation of an oral liquid formulation for paediatric use, containing flecainide acetate at different strengths, was considered, taking into account the possible effects of conventionally used excipients. First, the optimal vehicle was selected based on a solubility study, evidencing some unexpected formations of precipitates. As a matter of fact, the buffers commonly used for oral solutions significantly reduced flecainide solubility, and the concomitant presence of citrate buffer and methylparaben even caused the formation of non-resuspendable crystals. Then, chemical, physical, and microbiological stability were assessed. Solutions at strengths of 10 and 20 mg/mL flecainide acetate were stable up to 8 weeks when compounded by using a 40% sucrose solution as a vehicle. Microbiological data showed that the use of methylparaben was not necessary over this time period.

Stability of Oral Liquid Dosage Forms in Pediatric Cardiology: A Prerequisite for Patient’s Safety—A Narrative Review

“…• captopril generates captopril disulfide as a major degradation product; however, these processes are pH dependent [56], and some excipients can even enhance the degradation process [57]; • hydrochlorothiazide (rapid degradation to aminochlorobenzenedisulphonamide) [58]; • difficulty to achieve an adequate dosage and also to maintain stability at the same time [59]; • crystal formation [60]; • poor solubility [13,31,61];…”

“…The organoleptic properties, such as appearance, odour, and colour, are strong indicators of the stability of the drug product and these are susceptible to change due to several factors: photosensitivity, microbial growth, and chemical interactions between the components [9]. Appearance testing is important also in suspensions, as it can indicate sediment formation [60]. Another reliable indicator of the stability of the oral liquid dosage forms is the pH level; changes in this parameter can severely affect the drug product solubility in the initial phase and the solution/suspension stability in the later phase.…”

“…Forced degradation studies were conducted in order to establish the stability-indicating method for most of the studies, which were developed or adapted from existing methods from the literature [60,80,92,93]. From forced degradation studies, several potential degradation products can be obtained which can or cannot be indicative of the actual degradation pathways of the drug product [19,94].…”

“…Regarding the storage conditions, room temperature (RT) storage seems to be the condition of choice. Refrigeration is often preferable with the scope of maximizing the chemical stability; however, precipitation of the active substance or the increase of viscosity can occur, limiting the shelf-life or even causing instability [60,112].…”