Abstract
Flutamide (FLT) is an anticancer agent used in the treatment of prostatic carcinoma. FLT amorphous solid dispersions (SDs) and solid lipid nanoparticles (SLNs) were prepared to overcome limited solubility. Investigation of drug-polymer and drug-lipid miscibility was carried out to enhance drug performance by assessing solubility and particle size. Miscibility was then correlated to performance to determine successful preparation of FLT SDs and SLNs.|Four polymers used to prepare SDs included polyvinylpyrrolidone K90 (PVP), hydroxypropyl methylcellulose (HPMC), eudragit (EPO), and polyethylene glycol 8000 (PEG). Miscibility of drug and polymer at 90:10, 70:30, and 50:50 w/w (drug:polymer) was assessed through modulated differential scanning calorimetry (MDSC). FLT SDs were characterized by powder X-ray diffraction (PXRD). Molecular interactions were determined using infrared and Raman spectroscopy and molecular modeling using Jaguar. Polymer precipitation inhibition efficiency and dissolution studies were conducted at 0.1 mg/mL and 0.05 mg/mL (70:30 w/w).|Glyceryl monoleate (GMO), Precirol® (glyceryl distearate, PRE), glyceryl monostearate (GMS) and COM® (glyceryl dibehenate, COM) were prepared with Gelucire (GEL) 44/14 or 50/13 as surfactant at 5:2 w/w (lipid:surfactant) and 2:1 w/w (FLT:lipids/surfactants). Miscibility of lipid and surfactant mixtures with and without FLT were investigated using MDSC. SLNs with and without drug-loading were prepared by ultrasonication and characterized for particle size. Drug-loaded SLNs were lyophilized and characterized in a similar manner.|Miscibility between FLT-PVP and FLT-PEG was observed in MDSC results. PXRD indicated the formation of FLT-PVP amorphous SDs, while FLT-PEG formed a crystalline eutectic mixture. Molecular modeling studies confirmed potential interactions formed between FLT-PVP and FLT-PEG. PVP and PEG were shown to be the most efficient FLT precipitation inhibitors and displayed enhanced dissolution profiles.|Miscibility between GMO and GMS with GEL 50/13 was observed in MDSC results in the presence or absence of FLT. The particle size of SLNs prepared from GMO and GMS was found to be <100 nm compared to >200 nm obtained from PRE and COM. Similar trends regarding particle size were seen upon lyophilization. Miscibility of FLT with polymers and lipids demonstrated enhanced performance suggesting FLT SDs and SLNs would result in increased solubility and bioavailability.