(W1030-03-17) Amorphous Stabilization of BCS II Drugs Using Mesoporous Silica

Purpose: This research aimed to study the amorphous stabilization of BCS Class II drugs using mesoporous silica as a carrier to produce amorphous solid dispersions. A solvent immersion technique was used to load the drug into the mesoporous silica particles, followed by solvent removal through spray drying. Ibuprofen, fenofibrate, and budesonide were selected as model drugs to evaluate the impact of molecular weight and log p on the solid state of drug-loaded mesoporous silica particles.

Methods: The model drugs were loaded into three grades of mesoporous, SYLYSIA SY730, SYLYSIA SY430, and SYLYSIA SY350, with pore diameters of 2.5nm, 17nm, and 21nm, respectively, at 1:3, 1:2, and 3:1, carrier to drug ratios. Also, the potential influence of drug loading concentration was evaluated at three different concentrations. Solid-state characterization of the drug-loaded MS particles was performed using differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). Enthalpy data collected from the DSC thermograms were analyzed using response surface regression analysis and Classification and Regression Tree analysis methods to investigate critical parameters for minimizing the crystallization of drug loaded MS particles.

Results: DSC thermograms of SY430 and SY350 samples exhibited melting point depressions which may indicate constriction of crystallization inside the pores, whereas SY730 samples with melting points matching the pure API may be a result of surface crystallization. PXRD diffractogram showed all crystalline samples matched the diffraction patterns of their respective pure API, which confirms that the melting point depressions observed for SY430 and SY350 samples were not caused by transitions of polymorphic states. All samples prepared with a 3:1 ratio exhibited amorphous halo profiles in the PXRD diffractograms, which was corroborated by having the lowest enthalpy values as observed in the DSC thermograms. Contour and surface plots, from response surface regression analysis, and the predictive decision tree, from CART regression analysis, suggest that carrier-to-drug ratios, followed by the molecular weight of the model drug, have the most significant impact on the crystallinity of a drug-loaded into MS particles.

Conclusion: Ibuprofen, fenofibrate, and budesonide were loaded onto three grades of mesoporous silica in the amorphous state using a solvent immersion technique and spray drying with varying degrees of success. Based on the results of response surface regression analysis and CART regression models, the primary factor influencing the extent of crystallization of all three BCS II drugs was found to be the ratio of mesoporous silica to drug, with the crystalline content decreasing with increasing ratios. As predicted by the CART regression decision tree, the most optimal condition for minimizing the crystalline content of all three BCS II drugs was to prepare drug-loaded samples at an MS:API ratio > 2.5. All drug-loaded samples with SY430 and SY350 exhibited melting point depressions with no change in the crystalline structure, which suggests the occurrence of constricted internal crystallization inside the pores of the mesoporous silica as described by the Gibbs-Thomson equation. Interestingly, all drug-loaded samples with SY730, except for FEN and BUD samples with MS:API ratio of 3, demonstrated external crystallization based on exhibiting identical melting points as the pure APIs. The pore size of SY730 may be insufficient to accommodate proper loading of the drug molecules resulting in surface crystallization. Additionally, both response surface regression analysis and CART regression models identified MW as the second most influential factor for crystal formation, followed by pore diameter.


Solid state characterization of Budesonide-loaded mesoporous silica particles


Solid state characterization of Fenofibrate-loaded mesoporous silica particles


Solid state characterization of Ibuprofen-loaded mesoporous silica particles