Sandrien Janssens

Review: physical chemistry of solid dispersions.

Objectives With poorly soluble drug candidates emerging in the drug discovery pipeline, the importance of the solid dispersion formulation approach is increasing. This strategy includes complete removal of drug crystallinity, and molecular dispersion of the poorly soluble compound in a hydrophilic polymeric carrier. The potential of this technique to increase oral absorption and hence bioavailability is enormous. Nevertheless, some issues have to be considered regarding thermodynamic instability, as well in supersaturated solutions that are formed upon dissolution as in the solid state.

Influence of Preparation Methods on Solid State Supersaturation of Amorphous Solid Dispersions: A Case Study with Itraconazole and Eudragit E100

PurposeThe present study aims to determine the drug / polymer miscibility level as a function of the preparation method for an amorphous solid dispersion model system containing itraconazole and eudragit E100. This value was compared to the theoretical crystalline drug solubility in the amorphous polymer and the miscibility of the amorphous drug in the amorphous polymer.MethodsThe amorphous solid dispersions were prepared via spray drying and film casting in order to evaluate the influence of the solvent drying rate. The experimental miscibility level was estimated using XRPD, MDSC, FT-IR, HPLC and TGA. The solubility and miscibility were estimated using the Flory-Huggins mixing theory and experimental drug in monomer solubility data.ResultsThe experimental miscibility level was found to be 27.5% w/w for spray-dried and 15% for film-casted solid dispersions. FT-IR measurements confirmed the absence of saturable interactions like hydrogen bonds, and analysis of the mixed glass transition temperatures suggested low adhesion forces in the amorphous mixture. The solubility analysis rendered a positive FH interaction parameter, a crystalline solubility of approximately 0.012% w/w and an amorphous drug-polymer miscibility of approximately 7.07% w/w.ConclusionThe solid dispersions are significantly supersaturated with respect to both crystalline solubility and amorphous miscibility demonstrating the influence of manufacturing methodology.

Spray drying from complex solvent systems broadens the applicability of Kollicoat IR as a carrier in the formulation of solid dispersions

The presented study aims to explore the feasibility of preparing solid dispersions of the poorly soluble drug, itraconazole, with Kollicoat IR via spray drying, in order to broaden the application window of the polymer. In order to circumvent the need for a common solvent, Kollicoat IR was dissolved in a 50/50 (v/v) water/ethanol mixture and itraconazole was dissolved in a 50/50 (v/v) dichloromethane/ethanol mixture. In a first approach these two solutions were simultaneously spray dried via a spray nozzle with two inlets. In a second approach the two solutions were mixed prior to spray drying and the metastable solution was spray dried via a spray nozzle with a single inlet. This approach was also varied by adding HCl to the water phase of the Kollicoat IR solution. The resulting solid dispersions were characterized with MDSC, XRPD and their dissolution was followed in SGF. The results of the three data sets show that as the mixing between itraconazole and Kollicoat IR improves, the dissolution improves as well. Using the first approach, no mixing was observed between polymer and drug. The second approach on the other hand led to a reasonable degree of mixing as the solid dispersions were XRPD amorphous and no glassy mesofase of itraconazole was observed.

Physical stability of ternary solid dispersions of itraconazole in polyethyleneglycol 6000/hydroxypropylmethylcellulose 2910 E5 blends

In order to understand the influence of temperature and moisture, polymer blends of polyethyleneglycol 6000 (PEG 6000) and hydroxypropylmethylcellulose 2910 E5 (HPMC 2910 E5) and solid dispersions of itraconazole in these polymer blends were spray dried, further dried for 2 weeks and stored at three different conditions: 25 degrees C, 0% relative humidity (RH); 25 degrees C, 52% RH; 60 degrees C, 0% RH. MTDSC analysis of the polymer blends revealed that at 25 degrees C, 52% RH, PEG 6000 recrystallized to a high extent. At 60 degrees C, 0% RH the two polymers were miscible, probably due to the removal of bound water. In the ternary dispersions the polymers behaved similarly. The crystallinity degree of itraconazole in samples stored at 25 degrees C, 52% RH and at 60 degrees C, 0% RH was increased compared to the samples stored at 25 degrees C, 0% RH, probably due to the plasticizing effect of moisture at 25 degrees C, 52% RH and to an increased mobility at 60 degrees C, 0% RH. XPS analysis revealed a redistribution of itraconazole at the surface as itraconazole recrystallized from the blend. Dissolution tests revealed that a decrease in the itraconazole release was directly related to its crystallinity degree, no correlation was found with the crystallinity degree of PEG 6000.

Characterization of ternary solid dispersions of Itraconazole in polyethylene glycol 6000/polyvidone-vinylacetate 64 blends.

The good compatibility between Itraconazole and polyvidone-vinylacetate 64 (PVPVA 64) was pointed out previously. However, the dissolution properties of these systems left room for improvement. Therefore polyethylene glycol 6000 (PEG 6000), known for its solubilizing and wetting properties, was added to the PVPVA 64 matrix. Physicochemical analysis showed that up to 10% of PEG 6000 could be mixed with PVPVA 64. Addition of 10%, 20% or 40% of Itraconazole rendered amorphous solid dispersions consisting of a ternary mixed phase and a PVPVA 64 rich amorphous phase. If the PEG 6000 fraction was elevated up to 25% of the carrier, the PEG 6000 crystallinity degree was around 73+/-0.6%. Up to 20% of Itraconazole could be molecularly dispersed in the 25/75 w/w polymer blend. An Itraconazole melting peak could be detected for the sample containing 40% of drug. Dissolution experiments showed that no benefit was obtained by adding PEG 6000 to the PVPVA 64 matrix for samples containing up to 20% of Itraconazole. The dissolution of the ternary dispersions with 40% of Itraconazole on the other hand showed improvement compared to binary Itraconazole/PVPVA 64 dispersions.

Influence of polyethylene glycol chain length on compatibility and release characteristics of ternary solid dispersions of Itraconazole in polyethylene glycol/hydroxypropylmethylcellulose 2910 E5 blends

The present study aims to elucidate the influence of the polyethylene glycol chain length on the miscibility of PEG/HPMC 2910 E5 polymer blends, the influence of polymer compatibility on the degree of molecular dispersion of itraconazole, and in vitro dissolution. PEG 2000, 6000, 10,000 and 20,000 were included in the study. Solid dispersions were prepared by spray drying and characterized with MDSC, XRPD and in vitro dissolution testing. The polymer miscibility increased with decreasing chain length due to a decrease in the Gibbs free energy of mixing. Recrystallization of itraconazole occurred as soon as a critical temperature of ca. 75 degrees C was reached for the glass transition that represents the ternary amorphous phase. Due to the lower miscibility degree between the longer PEG types and HPMC 2910 E5, the ternary amorphous phase was further separated, leading to a more rapid decrease of the ternary amorphous phase glass transition as a function of PEG and itraconazole weight percentage and hence, itraconazole recrystallization. In terms of release, an advantage of the shorter chain length PEG types (2000, 6000) over the longer chain length PEG types (10,000, 20,000) was observed for the polymer blends with 5% of PEG with respect to the binary itraconazole/HPMC 2910 E5 solid dispersion. Among the formulations with a 15/85 (w/w) PEG/HPMC 2910 E5 ratio on the other hand, there was no difference in the release profile.

Evaluation of the formulation of solid dispersions by co-spray drying itraconazole with Inutec SP1, a polymeric surfactant, in combination with PVPVA 64

In order to improve the in vitro performance and stability of co-spray-dried itraconazole/Inutec SP1 systems, the influence of adding PVPVA 64, a polymer that is compatible with itraconazole, was evaluated. Dissolution tests were carried out on several itraconazole/PVPVA 64/Inutec SP1 compositions and spray-dried itraconazole/PVPVA 64 powders were used as references. The physicochemical properties of the samples were assessed with modulated temperature differential scanning calorimetry (MDSC), X-ray powder diffraction (XRD) and environmental scanning electron microscopy (ESEM). Physicochemical analysis revealed that there is no interaction between itraconazole and Inutec SP1 and that sufficient amount of PVPVA 64 is required to keep the drug molecularly dispersed. The improvement of the ternary solid dispersions over the binary solid dispersions was composition dependent. On one hand the increased drug/PVPVA 64 ratio in the ternary systems slowed dissolution down, on the other hand this was compensated by the solubilizing power of Inutec SP1.