Solid-state characterization and solubility enhancement strategies for Olaparib in formulation development

Abstract

During the formulation development of anticancer drug Olaparib (OLA), we observed that two batches (Batch 1 and Batch 2) obtained from the same supplier exhibited different solubility and dissolution behavior despite their identical chemical purity (99.9 %).

A comprehensive solid-state characterization was conducted. The Differential Scanning Calorimetry analysis showed distinct thermal behavior, with endothermic peaks at 202 and 215 °C, attributed to two polymorphic forms, as confirmed by Fourier Transform Infrared Spectroscopy and Thermogravimetric Analysis. Powder X-ray Diffraction analysis revealed that Batch 1 contained a mixture of OLA Form A (major) and Form L (minor, ∼15 % w/w), and exhibited lower crystallinity compared to Batch 2. Batch 2 consisted exclusively of pure OLA Form L, whose crystal structure was reported here for the first time. Morphology analysis indicated that Batch 1 presented particles with heterogeneous dimensions (2–60 μm), while Batch 2 showed a homogeneous size distribution (∼5 μm), resulting in differences in density and specific surface area. These differences in solid-state properties further contributed to observed variations in equilibrium solubility and intrinsic dissolution rate (IDR), with Batch 1 exhibiting a higher solubility and IDR (0.1239 mg/mL; 26.74 mg/cm²·min⁻¹) than Batch 2 (0.0609 mg/mL; 13.13 mg/cm²·min⁻¹) at 37 °C.

The addition of Soluplus® and hydroxypropyl-β-cyclodextrin significantly enhanced OLA solubility in concentration-dependent manner, up to 1.2-fold and 12-fold for Batch 1 and 2.5-fold and 26-fold for Batch 2, respectively, after 72 h of incubation. These findings demonstrate that, despite initial differences in polymorphic composition and particle morphology, appropriate solubilizing agents can mitigate batch-to-batch variability and optimize OLA solubility.