(T1030-09-50) Amorphous Solid Dispersions of Spray Dried Celecoxib-SBE7βCD-Polymer Ternary Complexes: Enhancements on Intrinsic Dissolution, Crystallization Prevention, and Stabilizing Effects.

Purpose: Our goal is to use cyclodextrins to enhance the physical stability (prevent crystallization) and dissolution of poorly soluble drugs, at high drug loading in ASDs and operate beyond the limit of congruence of the ASD.

Methods: A phase solubility study was performed to characterize the solubilization capabilities of SBEβCD (Capitsol) on Celecoxib (CXB) at 37 °C in pH 6.5 PBS buffer. Then, a series of spray-dried and physically mixed ternary ASDs constituting different ratios of  CXB: SBEβCD: PVPVA64 were prepared. The stability, crystallinity, and extent of crystallization upon a 10 °C/min heating ramp were studied by DSC. The effect on glass transition temperature by the presence of SBEβCD and PVPVA64 was evaluated by mDSC. DSC was also used to analyze the non-crystallizable CXB portion in the ASD. Next, the intrinsic dissolution behavior of the ASDs were studied using Wood's apparatus stationary disk method. Finally, a tablet was prepared with 60% ASD, 45% Combi-Lac premix, and 2% croscarmellose to study the effect of SBEβCD on tablet disintegration.

Results: The phase solubility study showed a complexation efficiency of 0.0172 for the SBEβCD-CXB complex, a 6-fold improvement over the βCD-CXB complex. The glass transition temperature remained unchanged at 56.5 °C and was unaffected by the addition of SBEβCD to the spray-dried CXB ASDs, while the addition of PVPVA64 to the spray-dried ASD increased the Tg and followed Gordon-Taylor's trend. Spray-dried binary ASDs of CXB: SBEβCD showed 20-30% crystallinity, and the non-crystallizable CXB component increased as the SBEβCD percentage increased as the added SBEβCD was consuming free CXB for complexation. Additionally, all spray-dried ASDs with PVPVA64 showed no crystallinity as measured by DSC and were fully amorphous. The intrinsic dissolution of all SBEβCD-containing ASDs and physical mixtures showed a 20-fold increase compared to non-SBEβCD formulations. Percent crystallinity in solid dispersions was inversely proportional to their corresponding intrinsic dissolution rates.

Conclusion: The presence of SBEβCD can potentially stabilize ASD in its solid state as freely available CXB is consumed to form SBEβCD:CXB complexes. Intrinsic dissolution rates increase > 20-fold for SBEβCD-containing formulations. The impact on intrinsic dissolution rates by the method of preparation of the ASD or percent crystallinity is minimal compared to the impact of SBEβCD.

References: Higuchi T, Connors A. Advances in Analytical Chemistry Instrumentation. Vol. 4. New York NY: Wiley Interscience; 1965. Phase.Solubility Techniques; pp. 117–211

Effects on the glass transition of ternary ASD mixtures of 50% CXB: X% SBE: Y% PVPVA64, measured by mDSC.

Effect on the crystallizable CXB portion as the SBE % increases, measured by DSC.

Intrinsic dissolution enhancements by the presence of SBE in solid dispersions prepared in different ways.