Composition Optimization and Stability Testing of a Parenteral Antifungal Solution based on a Ternary Solvent System

Abstract

Abstract. An intravenous solution is a dosage forms intended for administration into the bloodstream. This route is the most rapid and the most bioavailable method of getting drugs into systemic circulation, and therefore it is also the most liable to cause adverse effects. In order to reduce the possibility of side effects and to ensure adequate clinical dosage of the formulation, the primarily formulated composition should be optimized. It is also important that the composition should retain its therapeutic effectiveness and safety throughout the shelf-life of the product. This paper focuses on the optimization and stability testing of a parenteral solution containing miconazole and ketoconazole solubilized with a ternary solvent system as model drugs. Optimization of the solvent system was performed based on assessing the risk/ benefit ratio of the composition and its properties upon dilution. Stability tests were conducted based on the EMEA (European Medicines Agency) "guideline on stability testing: stability testing of existing active substances and related finished products". Experiments show that both the amount of co-solvent and surface active agent of the solvent system could substantially be reduced, while still maintaining adequate solubilizing power. It is also shown that the choice of various containers affects the stability of the compositions. It was concluded that by assessing the risk/benefit ratio of solubilizing power versus toxicity, the concentration of excipients could be considerably decreased while still showing a powerful solubilizing effect. It was also shown that a pharmaceutically acceptable shelf-life could be assigned to the composition, indicating good long-term stability.

Effect of the excipient concentration on the pharmacokinetics of PM181104, a novel antimicrobial thiazolyl cyclic peptide antibiotic, following intravenous administration to mice

“…Other possible mechanism that can be proposed in this context is the existence of PM181104 as a non-ionized solute having better solubility behavior in non-ionic surfactant. As per our observation the effect of non-ionic surfactant concentration on the particle size of the drug and subsequent solubility is in contrast with the experimental observations made by [11] .…”

“…The advantage of this approach is that the combination of surfactant and polymer may provide better protection against solvent-mediated transformation than the surfactant or polymer alone [9] . However, in order to avoid the possible side effects such as anaphylactic response and vascular irritability which may be caused by surfactants, it is far safe to reduce the types and stoichiometric concentration of the stabilizers used [10,11] . Indeed, there is a set-in guideline by the FDA for choosing an inactive ingredient [36] .…”

Impact of API (Active Pharmaceutical Ingredient) Source Selection on Generic Drug Products

“…Starting materials and the synthetic process can influence the API quality and impurity profile and hence quality of starting material needs to be evaluated. Impurity profile is a key parameter for any API and hence the listed impurities and specified impurities of the API should be considered for evaluation [60][61][62][63][64][65][66][67][68][69][70][71][72].…”

Norelgestromin/ethinyl estradiol intravenous infusion formulation optimization, stability and compatibility testing: A case study to overcome polysorbate 80 interference in chromatographic analysis

“…As such, the primary task of this study was to develop an IV formulation of NE and EE containing therapeutically effective doses of the active ingredients, while exhibiting the least possible toxicity for use in absolute bioavailability studies in humans [8]. This involves solubility testing of NE and EE in compatible vehicles for parenteral administration, stability testing under different storage conditions, compatibility testing in IV infusion sets with and without in-line filters, and the presence of reliable quantification methods for both drugs to validate the results of these tests.…”