Preparation and Physicochemical Stability of Liquid Oral Dosage Forms Free of Potentially Harmful Excipient Designed for Pediatric Patients

Abstract

Dexamethasone, hydrochlorothiazide, spironolactone, and phenytoin are commonly used in neonates, but no age-appropriate formulation containing these active pharmaceutical ingredients (APIs) is commercially available. Thus, pharmaceutical compounding of the liquid oral dosage form is required to enable newborn administration. A problem common to the compounded preparations described in the literature is that they include potentially harmful excipients (PHEs). Therefore, the aim of this study was to evaluate the feasibility of compounding oral liquid dosage forms free of PHE, containing dexamethasone, hydrochlorothiazide, phenytoin, or spironolactone and to assess their physicochemical stability. Due to the poor water solubility of the targeted APIs, oral suspensions were compounded using Syrspend® SF-PH4 Dry, a suspending vehicle free of PHE. Four HPLC coupled to UV spectrometry (HPLC-UV) stability-indicating methods were developed and validated according to international guidelines to assay the strength of the targeted APIs. Whatever storage condition was used (5 ± 3 °C or 22 ± 4 °C), no significant degradation of API occurred in compounded oral suspensions. Overall, the results attest to the physical and chemical stability of the four oral liquid dosage forms over 60 days under regular storage temperatures. Finally, the use of the proposed oral suspensions provides a reliable solution to reduce the exposure of children to potentially harmful excipients.

Accuracy of Dose Administered to Children Using Off-Labelled or Unlicensed Oral Dosage Forms

“…Suspensions were compounded from API raw powder and Syrspend ® SF PH4 Dry as suspending agent. Shelf life of both suspensions were assessed for 60 days [ 25 ]. From each batch, three samples were collected to assess strength and homogeneity using HPLC-UV analysis.…”

<p>Safety and Biopharmaceutical Challenges of Excipients in Off-Label Pediatric Formulations</p>

“…However, liquid dosage forms may require ingredients that are not child-friendly such as preservatives. 30 The addition of preservatives is very crucial for pharmaceutical products in controlling mold, inhibiting yeast growth, and protecting from bacterial propagation. 8 Parabens (Methyl, Ethyl, Propyl, and Butyl)…”

“…This agent provides a reliable solution to reduce the exposure of children, especially newborns, to potentially harmful preservatives, such as parabens. 30 Multiarticulate solid dosage forms could also partly replace the liquids and provide more stable and cheaper alternatives to existing liquid drug products or new developments. Dispersible solid drug dosage forms like orodispersible tablets, mini-tablets and films are also another better opportunity for efficient and safe use in pediatrics.…”

<p>Spotlight on Spironolactone Oral Suspension for the Treatment of Heart Failure: Focus on Patient Selection and Perspectives</p>

“…Prior to the approval of this formulation, patients had to obtain liquid spironolactone as a pharmacy compounded formulation, which commonly had limited shelf-life. Furthermore, an additional problem with these compounded liquid preparations is that they may include potentially harmful excipients 11. Other practices included tablet crushing and mixing it with fluids in order to facilitate swallowing with several drawbacks incurred by such alterations (see discussion below) 12…”