The development of amorphous solid dispersions (ASDs) is essential for enhancing the solubility and bioavailability of poorly water-soluble drug candidates, particularly during preclinical stages where material availability is limited. This study investigates two solvent-casting techniques—nitrogen flow evaporation on cover slips and rotary evaporation in scintillation vials—as practical, low-input screening methods to guide polymer selection for spray-dried dispersions (SDDs). The primary objective was to determine whether these film-based approaches could reliably predict both in vitro dissolution behavior and in vivo pharmacokinetic performance.
Three model compounds (A, B, and C) with varying crystallization propensities were selected based on their physicochemical profiles. Drug-polymer films were prepared at 15% drug loading using a 90:10 THF/water solvent system. For nitrogen flow evaporation, 134 µL of solution was applied to 22 mm glass cover slips, followed by drying at 50°C under a nitrogen stream for one hour, then stored overnight under vacuum. For rotary evaporation, 268 µL of solution was placed in 20 mL scintillation vials and dried at 40°C under vacuum. After drying, films were evaluated microscopically for amorphousness before and after dissolution testing.
Dissolution experiments were conducted in FaSSIF media using a Pion Rainbow Micro Dissolution Profiler (37°C, 200 rpm). For nitrogen flow films, samples were mounted on a rotating disc; for rotary evaporation films, stir bars were used to ensure mixing. Samples were collected at 5, 20, 60, and 240 minutes, centrifuged, and analyzed by HPLC or UPLC. The results were compared with those from corresponding SDD powders prepared via miniature spray drying using identical conditions.
For compounds A and B, which remained fully amorphous, the dissolution profiles of the films closely matched those of the SDDs. Both methods identified HPMCAS-HG as the optimal polymer, showing prolonged supersaturation and minimal precipitation. Optical microscopy confirmed no crystalline features post-dissolution, validating the film integrity. Raman spectroscopy further supported these findings, showing no evidence of crystalline drug in the HPMCAS-HG systems.
In contrast, compound C exhibited rapid crystallization during film formation, regardless of polymer type. The film dissolution curves showed consistently low concentrations, failing to reach target levels even after 4 hours. However, SDD powder dissolution revealed significantly higher drug release, especially from HPMCAS-MG and HPMCAS-HG formulations. X-ray diffraction confirmed that the SDDs were amorphous, indicating that the discrepancy stemmed from premature crystallization in the films, not in the final product.METAP2 Antibody Purity & Documentation This demonstrates that film screening is unreliable when crystallization occurs during casting.TIE1 Antibody Purity & Documentation
In vivo studies were conducted in fasted Sprague-Dawley rats (n = 3 per group), administered oral doses of SDD suspensions (40 mg/kg for A and B, 2 mg/kg for D, 75 mg/kg for E). Suspensions were freshly prepared in 0.5% Methocel E4M to minimize stability issues. Plasma samples were collected at multiple time points and analyzed by LC/MS/MS.PMID:34296497 Pharmacokinetic parameters (AUC₀–₂₄, Cmax, Tmax, T½) were calculated using non-compartmental analysis.
For compounds A and B, the polymer ranking derived from the amorphous films accurately predicted in vivo exposure. HPMCAS-HG yielded the highest AUC and Cmax, followed by Eudragit L100 and HPMCAS-MG, while HPMC-E3 showed the lowest exposure. These trends matched the in vitro data exactly. Similarly, for compounds D and E, film screening correctly identified HPMC-HP-55 and PVAP as top performers, with in vivo results confirming superior plasma exposure.
This study confirms that solvent-cast films are a robust tool for early-stage polymer screening—provided they remain fully amorphous. The nitrogen flow method offers advantages in film accessibility and characterization, enabling direct microscopic assessment. When films crystallize prior to dissolution, however, the predictive value collapses, necessitating direct SDD scale-up. Overall, this approach enables efficient, low-material screening that supports informed decisions in preclinical development, reduces unnecessary scale-up efforts, and improves the probability of success in subsequent toxicology and clinical studies.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com