(T1030-02-12) Consistent Dry-Coating Process for Preparing Functional Particles with Novel Coating Using Two-Step Melt Granulation

Purpose: Fine-particle coatings are commonly used to impart functionality (e.g., bitter taste masking, enteric and sustained release coatings) to drug-containing particles (DCPs). The fine-particle coating process can be broadly classified as either a ‘wet’ or ‘dry’ process. Although wet coating is generally employed in order to add functionality to DCPs, dry-coating has the advantages of high manufacturing efficiency and applicability to drugs that are unstable in solvents. However, no consistent dry process has been reported for preparing functional DCPs, from particle preparation to coating, using general-purpose equipment. We have previously reported a two-step melt granulation method (MALCORE^®) for the preparation of DCPs [1-4]. In the 1st step of MALCORE^®, melting-component adsorbed particles (MAs) are prepared by adsorption of low-melting-point material into a porous carrier. In the 2nd step, DCPs can be prepared by layering drug and polymer onto MAs. MALCORE^® is a useful method that can efficiently prepare spherical DCPs for stable fine-particles coating process by heating and mixing without any solvents. However, no studies have been reported on functionalization of DCPs using a dry-coating process. The aim of this study is to develop a novel dry-coating method for applying functional polymers to DCPs prepared via MALCORE^🄬

Methods: The manufacturing equipment used in this study was a general-purpose high-shear granulator. A schematic diagram of the manufacturing process from preparing DCPs to dry-coating is shown in Fig. 1. First, DCPs were prepared by MALCORE^® using duloxetine hydrochloride (DLX) as the model drug. In a separate step, triethyl citrate adsorbed particles (TEC-APs) were prepared by adsorbing TEC, an oily plasticizer, into fine porous silica. The TEC-APs were layered onto the DCPs by heating and mixing. In the next heating and mixing step, hydroxypropylmethylcellulose acetate succinate (HPMCAS), an enteric polymer, was coated on the particle. The dry-coating processes of TEC-APs and HPMCAS were performed with the same high-shear granulator used in the preparation process of DCPs. Finally, a curing process was carried out at 80°C for 240 minutes using a bench-top incubator. The particle shape and drug dissolution properties of the resulting dry-coated particles were evaluated by varying the amounts of TEC-APs and HPMCAS.

Results: The mean particle size (d₅₀) of the DCPs was 767 µm, confirming their spherical shape with a drug layer (Fig. 2 (A, B)). The dissolution profiles of the DCPs showed immediate release in both pH 1.2 and 6.8 medium (Fig. 3 (A)). On the other hand, the steady decrease in the dissolution rate over time in pH 1.2 medium was observed because of the instability of DLX in the acidic condition. The d₅₀ of the dry-coated particles was approximately 950 µm as a result of the additional TEC-APs and HPMCAS layers on top of the DCPs. The dry-coated particles were also spherical in shape, and the internal structure showed the multiple symmetrical layers as shown in the scanning electron microscope (SEM) and X-ray images (Fig. 2 (C, D)). When the amount of TEC-APs was verified, it showed that the DLX dissolution in pH 1.2 medium was suppressed with increasing amounts of TEC-APs in the formulation (Fig. 3 (B)). This is due to the increased amount of plasticizers which enhanced the curing efficiency of HPMCAS, resulting in the formation of a continuous film. An investigation into the amount of HPMCAS showed marginal dissolution pH 1.2 medium at amounts of 160 g or more (Figure 3(C)). In addition, approximately 100% DLX dissolution was observed at 6 hours in pH 6.8 medium (Figure 3(D)). This is due to HPMCAS having high solubility at pH 6.8. These results indicate that HPMCAS-derived functionality can be imparted to DCPs by optimizing the amount of TEC-APs and HPMCAS in the formulation using a dry-coating process.

Conclusion: We have succeeded in preparing particles with HPMCAS-derived functionality without any solvents via two-step melt granulation using this novel dry-coating process. The findings in this study will be useful supporting the implementation of a consistent dry-coating method for the efficient preparation of functional particles.

References: [1] Yoshihara N., Kimata R., Terukina T., Kanazawa T., and Kondo H. Adv. Powder. Technol., 33, 103409 (2022).
[2] Kimata R., Yoshihara N., Terukina T., Kanazawa T., and Kondo H. AAPS PharmSciTech., 24, 28 (2023).
[3] Yoshihara N., Kimata R., Terukina T., and Kondo H. J. Pharm. Innov., 18, 2158–2169 (2023).
[4] Kimata R., Yoshihara N., Tomita Y., Terukina T., and Kondo, H. AAPS PharmSciTech, 25, 81 (2024).


A schematic diagram of the manufacturing process from preparing DCPs to dry-coating.


Scanning electron microscope and X-ray CT images of (A) the appearance of DCPs, (B) the internal structure of DCPs, (C) the appearance of dry-coated particle, and (D) the internal structure of dry-coated particle.


Drug dissolution profiles. (A) DCPs in pH 1.2 and 6.8 media, (B) the effect of the amount of TEC-APs on the dry-coated particles in pH 1.2 medium, (C) and (D) the effects of the amount of HPMCAS on the dry-coated particles in pH 1.2 and pH 6.8 media.