Development of a Reconstitutable Fulvestrant Microparticle Injection with Release Comparable to the Castor Oil Formulation

Fulvestrant is a selective estrogen receptor degrader used for hormone receptor-positive advanced breast cancer and is marketed as a high-viscosity castor oil-based intramuscular injection containing benzyl alcohol. This study aimed to develop an oil-free, reconstitutable fulvestrant microparticle formulation with sustained drug release comparable to the castor oil formulation. Microparticles were prepared by spray drying, with preliminary poloxamer 188/sodium carboxymethyl cellulose batches followed by optimization using zein, sodium alginate, and mannitol. Final batches F1–F4 contained 25% w/w fulvestrant, 40–60% w/w zein, 5–10% w/w sodium alginate, and 5–30% w/w mannitol, respectively, using ethanol:water (70:30) as the solvent system. F2–F4 produced fine, non-sticky powders with yields of 41.54–46.56%, drug contents of 95.52–98.34%, and reconstitution times of 40–63 s after reconstitution with Water for Injection. Scanning electron microscopy showed spherical microparticles with smooth surfaces and no visible agglomeration, while Fourier-transform infrared spectroscopy indicated no major drug–excipient incompatibility. Reconstituted suspensions showed pH values of 7.15–7.34 and satisfactory syringeability. Quantitative osmolarity was not measured; therefore, isotonicity was assessed microscopically using erythrocyte morphology against 0.9% sodium chloride control, with no swelling, shrinkage, or rupture observed. Sterility was evaluated by direct inoculation using Fluid Thioglycollate Medium and Soybean Casein Digest Medium, with no visible microbial growth after 14 days. No separate validated terminal sterilization process was applied to the spray-dried microparticles. F3, containing 50% w/w zein, was selected based on its balanced formulation performance and sustained release. F3 released 15.1% drug on day 1 and 97.4% by day 15, with a release profile comparable to the castor oil reference (f1 = 5.42; f2 = 69.74). After one month at 40 ± 2 °C/75 ± 5% RH, F3 retained 96.32% drug content and showed a reconstitution time of 73 ± 3 s. The developed microparticles represent a promising oil-free platform for reconstitutable fulvestrant depot injection; however, validated sterile manufacturing, quantitative osmolarity assessment, and in vivo pharmacokinetic and local tolerability studies are required for further development.