Self-Association of Rafoxanide in Aqueous Media and Its Application in Preparing Amorphous Solid Dispersions

Abstract

Our primary objective is to characterize the self-association of rafoxanide in alkaline media. The second objective is to illustrate the feasibility of using rafoxanide micellar solution as the feed solution to prepare amorphous solid dispersion via spray drying. Rafoxanide is a poorly water-soluble drug. It is a weak acid, and its poor aqueous solubility is due to its hydrophobicity. The surface-active property of rafoxanide has not been previously reported. It was discovered that the addition of a small percentage of organic solvents is required to elevate the solubility of rafoxanide above the critical micelle concentration to allow for the formation of micelles. Our fluorescence decay study confirms the self-association of rafoxanide in a cosolvent consisting of 70%, v/v, NaOH solution and 30%, v/v, acetone. The position of each functional group in the micellar structures using the H NMR technique was identified. The critical micelle concentration of rafoxanide in the cosolvent is determined to be 302 μg/mL using a surface tension method. The solubility of rafoxanide in 0.1 N NaOH solution is less than 11 μg/mL. Interestingly, the apparent solubility increased to 38,400 μg/mL in the presence of 30% acetone as the result of micelle formation. This unique solubility characteristic makes it feasible to prepare rafoxanide amorphous solid dispersions by spray drying a predominantly aqueous (70% 0.1 N NaOH solution and 30% acetone) based feed solution. Povidone and copovidone were both used as polymeric carriers. Based on solid-state characterization, including differential scanning calorimetry, X-ray powder diffraction, and hot-stage polarized light microscopy, our results indicate that rafoxanide solid dispersions prepared using this novel process are amorphous. Approximately 750-fold increase in the concentration of rafoxanide in aqueous media at pH 6.8 was achieved with the amorphous solid dispersions.

Understanding Molecular Interactions in Rafoxanide–Povidone Amorphous Solid Dispersions from Ultrafast Magic Angle Spinning NMR

“…Through the association with PVP, RAF in a 0.1 N NaOH solution can have a 7000-fold increase in solubility, even upon the removal of organic solvent. We previously investigated the association mechanism of RAF–PVP in two types of cosolvents and demonstrated that preparing spray-dried ASDs of RAF and PVP in an aqueous and organic solvent is an efficient method to enhance the kinetic solubility of RAF. , In this study, we leverage our understanding of RAF–PVP interactions in ASDs by ssNMR spectroscopy and compare the effects of different cosolvents on the interactions in the solid state. Routine 1D 13 C and 15 N MAS spectra were first utilized to investigate the formation of hydrogen bonding between RAF and PVP in ASDs prepared via the spray-drying process using aqueous or organic solvents.…”

“…RAF−ASD (aq) was successfully developed in our previous study, which showed faster in vitro release and greater in vivo absorption rates than traditional RAF−ASD (org) and the physical mixture. 13,55 The RAF− ASDs (aq) were also found to be in a single amorphous phase after one year of storage (data not shown), indicating that PVP is an effective crystallization inhibitor for RAF. In this study, we explore the solvent effect on the formation of RAF−PVP complexes in ASDs spray-dried using aqueous and organic solvents.…”

“…Very interestingly, these intermolecular drug–polymer interactions remain in the solution state and enhance the supersaturation during the dissolution process. , Specifically, strong hydrophobic interactions among RAF molecules are formed in an aqueous solvent (the 70% NaOH (0.1 N) in water and 30% acetone mixture) as confirmed solution NMR, which facilitate the formation of the so-called RAF–PVP complex. The phenolic hydroxyl group (OH) of crystalline RAF stays neutral and becomes ionized in the 70% NaOH (0.1 N) in the water–30% acetone mixture, leaving the amide group (N–H) of RAF as the only possible hydrogen bond donor, as shown in Figure (RAF structure in the middle). , RAF and PVP form the CO···HN hydrogen bond in the addition to the hydrophobic interaction in an aqueous medium. Due to the largely different solvent polarity, the hydrophobic RAF–RAF interactions are not preferred in co-organic solvents (80% acetone and 20% ethanol mixtures).…”

“…The phenolic hydroxyl group (OH) of crystalline RAF stays neutral and becomes ionized in the 70% NaOH (0.1 N) in the water−30% acetone mixture, leaving the amide group (N−H) of RAF as the only possible hydrogen bond donor, as shown in Figure 10 (RAF structure in the middle). 55,77 RAF and PVP form the CO•••HN hydrogen bond in the addition to the hydrophobic interaction in an aqueous medium. Due to the largely different solvent polarity, the hydrophobic RAF−RAF interactions are not preferred in co-organic solvents (80% acetone and 20% ethanol mixtures).…”

“…For example, RAF interacts with PVP in an aqueous solution of NaOH and acetone, but not in organic cosolvents of acetone and ethanol . We have also thoroughly investigated the feasibility of improving in vitro dissolution and in vivo absorption of RAF by using the ASD technique. , We spray-dried two RAF ASDs obtained from feed solutions based on two different media. The first ASD is a complexation-based spray-drying using a NaOH solution with acetone, referred to as RAF–ASD (aq).…”