Insight into the Formation of Glimepiride Nanocrystals by Wet Media Milling

Abstract

Nanocrystal formation for the dissolution enhancement of glimepiride was attempted by wet media milling. Different stabilizers were tested and the obtained nanosuspensions were solidified by spray drying in presence of mannitol, and characterized regarding their redispersibility by dynamic light scattering, physicochemical properties by differential scanning calorimetry (DSC), FT-IR spectroscopy, powder X-ray diffraction (PXRD), and scanning electron microcopy (SEM), as well as dissolution rate. Lattice energy frameworks combined with topology analysis were used in order to gain insight into the mechanisms of particle fracture. It was found that nanosuspensions with narrow size distribution can be obtained in presence of poloxamer 188, HPC-SL and Pharmacoat^® 603 stabilizers, with poloxamer giving poor redispersibility due to melting and sticking of nanocrystals during spray drying. DSC and FT-IR studies showed that glimepiride does not undergo polymorphic transformations during processing, and that the milling process induces changes in the hydrogen bonding patterns of glimepiride crystals. Lattice energy framework and topology analysis revealed the existence of a possible slip plane on the (101) surface, which was experimentally verified by PXRD analysis. Dissolution testing proved the superior performance of nanocrystals, and emphasized the important influence of the stabilizer on the dissolution rate of the nanocrystals.

Keywords: crystal morphology; energy vector diagrams; glimepiride; intermolecular interactions; nanocrystals; wet media milling.

Figure 1

Chemical structure of glimepiride.

Figure 2

Glimepiride particle size vs. time profiles recorded during wet media milling with different stabilizers. (a) HPC-SL, HPC-L, Poloxamer 188, Pharmacoat^® 603 and Pharmacoat^® 615; (b) Soluplus^® and PVP K25. Polymers have been grouped according to Z-average diameter scale, for clarity.

Figure 3

FT-IR spectra of: (a) Raw materials, spray dried nanosuspensions (F1–F3) and (b) corresponding physical mixtures (PM1–PM3). GLMP stands for Glimepiride, P603 for Pharmacoat^® 603, and P188 for poloxamer 188.

Figure 4

Differential scanning calorimetry (DSC) thermograms of: raw materials (a) spray dried nanosuspensions (F1–F3) and (b) corresponding physical mixtures (PM1–PM3).

Figure 5

Powder X-ray diffraction (PXRD) patterns of raw materials and spray dried nanosuspensions.

Figure 6

Illustration of the two strongest interacting dimers (11 and 12) in the crystal lattice of glimepiride.

Figure 7

Energy vector diagrams (EVDs) plots viewed along the a—(a), b—(b), and c—(c) crystallographic axis together with an illustration of the (101) slip plane (d).

Figure 8

Crystal morphology of glimepiride calculated according to the attachment energy theory, featuring the orientation of a 3 × 3 supercell relevant to the crystal. The surface chemistry of the (101) Miller plane is illustrated in the insert.

Figure 9

SEM photomicrographs of spray dried glimepiride nanosuspensions: (a,b) F1 (HPC-SL), (c,d) F2 (poloxamer 188), and (e,f) F3 (Pharmacoat^® 603).

Figure 10

Dissolution profiles of glimepiride from the samples of pure drug and spray dried nanosuspensions.