(W1030-11-71) Development of Tablets with Biologics: Effect of Freeze-Dried and Spray-Dried Powders on the Compaction Behavior

Purpose: Last decades have witnessed a significant expansion of biological drug market. Oral delivery of biological drugs (in the form of tablets) would be preferable due to the easy administration and high patient compliance¹. Nevertheless, a successful development of tablets with biologics is usually challenged if the peptides/proteins or excipients are poorly tabletable^2,3. Recently, it has been reported that the compaction behavior of the powders can be adjusted by tailoring the properties of the particles and an improved tabletability was found with small and non-hollow paritlces³. Therefore, it is of crucial importance to link the particle design into the compaction behavior of powders. Freeze drying (FD) and spray drying (SD) are commonly used drying methods to prepare powders of biologics. Based on different drying principles, particles with different properties, i.e. morphology, size, surface composition will be obtained⁴. We hypothesize that biological dry powders prepared from FD and SD probably have different compaction behaviors. The aim of this study was to investigate compaction behaviors of biological dry powders prepared from FD and SD for the rational design of tablets with biologics, using trypsin as a model protein drug.

Methods: The raw material of FD trypsin powders was purchased from Sigma-Aldrich and used as received. It was a mixture of trypsin and lactose and the content of trypsin was around 15% (w/w). The FD powders were first reconstituted in Milli-Q water and transformed into SD powders using a B-290 Mini-spray dryer. Then, the FD and SD powders were characterized in terms of true density, morphology, residual moisture content (RMC), solid form using helium pycnometry, scanning electron microscope (SEM), thermogravimetric analysis (TGA) and X-ray powder diffraction (XRPD), respectively. Subsequently, Huxley Bertram 10 (HB 10), a compaction simulator was employed to prepare tablets within the compaction pressure range of 25 to 400 MPa (3 tablets at each pressure). Magnesium stearate in ethanol (5%, w/v) was used as external lubricant to rinse the die before every compaction. The crushing force of tablets was determined by a hardness tester and the tensile strength was calculated using the following equation:
Tensile strength = 2P/πDt
where P is the crushing force, D is the diameter of the tablet, and t is the thickness of the tablet. The solid fraction was calculated as the ratio of tablet density and material true density.

Results: As shown in Fig. 1, FD presented large and flat flakes-like particles while small, wrinkled and irregular particles were obtained by SD. Both FD and SD powders were in amorphous form (Fig. 2) and the RMCs were 3.9 ± 0.0 and 5.8 ± 0.5 (w/w), respectively. Intact tablets were obtained at all compaction pressures using the FD powders, while for the SD powders, tablets capping and lamination were observed when compaction pressure was higher than 50 MPa. Compressibility, compactability and tabletability were evaluated by investigating compression pressure as a function of solid fraction, solid fraction as a function of tensile strength, and compression pressure as a function of tensile strength, respectively (Fig. 3). According to Fig. 3A, higher solid fractions (0.76 ± 0.01 at 25 MPa and 0.79 ± 0.01 at 50 MPa) were obtained for the FD powders as compared to the SD powders (0.57 ± 0.02 at 25 MPa and 0.66 ± 0.01 at 50 MPa), indicating the FD powders have a better compressibility. However, according to Fig 3B, the tensile strength of the SD powders was 1.1 ± 0.3 MPa at solid fraction of 0.57, while the tensile strength of the FD powders was only 0.3 ± 0.0 MPa at a higher solid fraction of 0.76. In addition, as shown in Fig 3C, at 50 MPa, the tensile strength of the SD powders was 2.6 ± 0.4 MPa, while at the same compaction pressure, the tensile strength of the FD powders was only 0.6 ± 0.0 MPa. It suggests a better compactability and tabletability of the SD powders compared to those of the FD powders.

Conclusion: FD and SD produced particles with significant different morphologies. The compressibility of FD powders was better than that of SD powders, however, the SD powders showed enhanced compactability and tabletability. It indicates that SD could be a promising technology to improve the compaction performance of powders comprising poorly-tabletable peptides/proteins or excipients. However, the compressibility should be ameliorated and the capping/lamination tendency should be avoided by either dry granulation, the optimization of the process parameters or the addition of excipients during the SD process.

References: 1. Anselmo, A. C; Gokarn, Y; Mitragotri, S., Nat. Rev. Drug Discov. 2019, 18, 19-40
2. Fan, W.; Wang, A.; Wu, Y., et al, J. Pharm. Sci. 2019, 108, 2128-2135
3. Pedersen, M.; Megarry A.; Naelapää, K., et al, Int. J. Pharm. 2023, 631, 122526
4. Cun, D.; Zhang, C.; Bera, H., et al, Adv. Drug Deliv. Rev. 2021, 174, 140-167

Acknowledgements: We acknowledge the China Scholarship Council (CSC) for the scholarship to C.Z. (202009210026).

Fig. 1. SEM images of FD (left) and SD trypsin/lactose powders (right)

Fig. 2. XRPD patterns of FD and SD trypsin/lactose powders

Fig. 3. Compressibility (A), compactability (B) and tabletability (C) of FD and SD trypsin/lactose powders (data of SD trypsin/lactose powders compacted at compaction pressures higher than 50 MPa were not included due to the tablets capping/lamination).