In Situ Co-Amorphization of Olanzapine in the Matrix and on the Coat of Pellets

Abstract

In situ amorphization is a promising approach, considered in the present work, to enhance the solubility and dissolution rate of olanzapine, while minimizing the exposure of the amorphous material to the stress conditions applied during conventional processing. The production of pellets by extrusion/spheronization and the coating of inert beads were investigated as novel methods to promote the co-amorphization of olanzapine, a poorly water-soluble drug, and saccharin. Samples were characterized using differential scanning calorimetry, X-ray powder diffraction, Fourier-transform infrared spectroscopy and scanning electron microscopy, and dissolution and stability testing. The co-amorphous produced were compared with crystalline olanzapine, or physical mixture of olanzapine and saccharin. Results suggested that the addition of water to mixtures containing olanzapine and saccharin during the production of pellets, and the coating of inert beads, induced the in situ co-amorphization of these substances. The coating of inert beads enhanced the solubility and dissolution rate of olanzapine, especially when compared to pellets coated with the crystalline drug, but also with pellets containing the co-amorphous entity in the matrix of beads. Nine months stability tests (23 °C/60% RH) confirmed the preservation of the solid-state properties of the co-amorphous form on/in pellets. Overall, results highlighted the feasibility and benefits of in situ co-amorphization, either when the drug was entrapped in the pellets matrix, or preferentially applied directly on the surface of pellets.

Keywords: (co-)amorphous; dissolution testing; in situ (co-)amorphization; olanzapine; pellets; solubility; stability.

Figure 1

Chemical structure of olanzapine (A) and saccharin (B).

Figure 2

Differential scanning calorimetry thermograms (A) and X-ray powder diffractograms (B) of powdered crystalline saccharin (yellow), crystalline olanzapine (orange), and co-amorphous olanzapine:saccharin (blue). The glass transition of co-amorphous olanzapine:saccharin is highlighted in (A).

Figure 3

Fourier-transform infrared spectra of pure crystalline saccharin (yellow), pure crystalline olanzapine (orange), the physical mixture containing crystalline olanzapine and saccharin (green), and the co-amorphous system produced using both compounds (blue).

Figure 4

Diffractograms of crystalline saccharin (yellow), crystalline olanzapine (orange), and the physical mixtures obtained from the placebo formulation P (blue) and blends containing crystalline olanzapine (green, formulation I) or olanzapine and saccharin (purple, formulation II). Arrows highlight the peaks present in diffractograms, which could be related to either crystalline olanzapine or saccharin.

Figure 5

Diffractograms of samples prepared using crystalline olanzapine and saccharin (as starting material) obtained from the physical mixtures (yellow), extrudates (orange), and pellets (blue). The diffractogram of the physical mixture prepared using the co-amorphous olanzapine was plotted (green) for comparison purposes.

Figure 6

Scores plot from the principal component analysis conducted on the FTIR spectra of samples prepared using the placebo-based formulation (Formulation P, green), formulation I (blue) or formulation II, using the crystalline (orange) or the co-amorphous (yellow) form of olanzapine and saccharin, as starting material. Markers reflect the nature of samples: physical mixtures (circles), extrudates (diamonds), uncoated pellets (triangles), or pellets coated with olanzapine or olanzapine and saccharin (squares).

Figure 7

Dissolution profiles under sink (10 mg/L of OLZ, A,C) and non-sink conditions (100 mg/L of OLZ, B,D), of formulations I (A,B) and II (using the crystalline—solid line—or the co-amorphous form—dashed line—of olanzapine and saccharin, as starting materials) (C,D). Colors reflect the state of samples: physical mixtures (blue), uncoated pellets (yellow), and coated pellets (orange).

Figure 8

Scanning electron microphotographs of placebo-based pellets (A), pellets containing olanzapine (B) or olanzapine and saccharin (C) on the surface and pellets containing olanzapine in the matrix of the bead—formulation I (D) and formulation II, using olanzapine and saccharin in the crystalline (E) or the co-amorphous (F) form, as starting materials.

Figure 9

Diffractograms of samples obtained from pellets containing olanzapine and saccharin on the surface (A) or in the matrix of the beads, using the crystalline (B) or the co-amorphous form (C), as starting materials. Colors reflect the storage time: 0 (black) or 9 months (orange).