(98g) Reduction of Punch-Sticking Propensity of Celecoxib By Spherical Crystallization Via Polymer Assisted Quasi-Emulsion Solvent Diffusion

Punch sticking is a common problem in tablet manufacturing that leads to poor tablet quality, such as tablet weight variation. This work was aimed at overcoming punch sticking problems using spherical crystallization achieved through quasi-emulsion solvent diffusion (QESD). The hypothesis is that a suitable polymer containing both hydrophilic and hydrophobic moieties facilitates the formation of emulsions because of its simultaneous interactions with water and celecoxib (CEL). Such a polymer is expected to remain largely at the water-drug interface, which results in CEL spherulites coated with polymer. Both the size enlargement and surface coating reduce punch sticking propensity by reducing direct contact between CEL and punch during compaction.

Methods

Celecoxib, a COX-2 selective nonsteroidal anti-inflammatory drug for treating pain and inflammation associated with osteoarthritis or rheumatoid arthritis, was selected as a model drug because it exhibits high punch sticking propensity. HPMC was used as an emulsion stabilizer. To prepare CEL spherical crystals, a CEL solution in ethyl acetate was added dropwise into HPMC aqueous solutions at different concentrations (0.1 %, 0.3 %, 0.5 %, w/w) while mixed by an overhead stirrer at 600 rpm. The growth process of CEL spherulites was monitored by observing samples under an optical microscope at 0.5, 1, 3, 6, 10, and 15 min. The appropriate concentration of HPMC sufficient to eliminate punch sticking was determined based on the cleanness of punch surface after compressing CEL spherulites at 50 MPa. The phase purity of the CEL spherulite powders was verified by DSC and PXRD. The particle size and shape were analyzed by laser diffraction and microscopy, respectively. Sticking kinetics of direct compression formulations, consisting of 20% of CEL 79.5% Avicel PH102 and 0.5% magnesium stearate, were assessed using a punch with a removable tip on a compaction simulator. The amount of material transferred to punch was determined gravimetrically every 10 compressions up to 50 compactions. Powder flow properties were characterized using a ring shear tester and powder tabletability was determined on a Zwick universal material testing machine. HPMC content was measured via size-exclusion chromatography (SEC). Surface coating of HPMC on CEL spherulites was studied by scanning electronic microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). A solution 1D ¹H NMR was carried out to understand the mechanism of the QESD process.

Results

Spherical CEL was successfully prepared through a QESD process. No detectable punch sticking was observed when the HPMC concentration was 0.5 % (w/w), which was selected for further study. The CEL crystals were spherulites when HPMC was used but irregular in shape without using HPMC. Upon adding the CEL ethyl acetate solution into the HPMC aqueous solution, emulsions form with size of drug rich droplets gradually grew and eventually solidified. The PXRD, DSC and TGA of the spherical CEL matched well with the CEL as-received, suggesting the phase purity and negligible residual solvents. The amount of HPMC in the CEL QESD powder was determined 1.1 ± 0.1 % (w/w). Both tabletability and flowability of the CEL spherical crystals were much better than the as-received CEL. The spherical CEL crystals exhibited significantly lower punch sticking propensity compared to that of as-received CEL. SEM images showed that the spherulites were covered by materials with irregular morphology distinct from that of the CEL crystals. The significantly reduced signals of fluorine and nitrogen atoms on the top surface of a compressed tablet than that of a CEL tablet suggested that the spherulites were coated by HPMC. Addition of HPMC into a 3 mg/mL CEL DMSO solution shifted the peaks within 7.50 ~ 7.60 ppm, 7.16 ~ 7.24 ppm and 2.28 ~ 2.36 ppm, to the upfield, corresponding to the H atoms on aromatic ring and methyl group of a CEL molecule.

Conclusion

This was the first work that reported polymer assisted QESD process to reduce the punch sticking propensity, attributed to the polymer on the surface of CEL particles, higher bonding strength and enlarged particle size of CEL QESD. Polymer coating was confirmed through: (1) surface observation by SEM, where the rough and irregular surface of QESD instead of sharp and smooth surface of as-received was observed, and (2) elemental composition analysis by XPS, where the peak intensity of feature elements F and N of CEL significant reduced in QESD compared to as-received. Mechanism investigation on polymer coating on SA surface through solution NMR suggested that the strong interactions between the hydrophobic groups on CEL and HPMC played a crucial role on the surface coverage of SA by HPMC but not HPC and PVP, whose intermolecular interactions with CEL were much weaker due to the lack of hydrophobic functional groups. Collectively, QESD is a powerful API crystal engineering approach to enable the successful development of direct compression tablets of sticky drugs.