Incorporation of micronized poorly soluble drug into orodispersible tablets by aqueous fluid bed granulation of co-processed excipients

Abstract

The layering of active pharmaceutical ingredient (API) suspension on inert carriers through fluid bed granulation has been tackled in several studies. This study investigates the feasibility and impact of aqueous fluid bed granulation of a poorly soluble micronized API suspension directly onto co-processed excipients as active carriers for orally dispersible tablet production. Indomethacin was selected as model API and Parteck ODT® (mannitol based) and StarLac® (lactose-based) were examined as carrier materials. Produced batches were systematically characterized for change in particle size distribution using laser diffraction, flow properties via Hausner ratio determination and morphology using scanning electron microscopy. The solid-state properties were evaluated using differential scanning calorimetry and X-ray powder diffraction (XRPD), and moisture uptake was assessed via dynamic vapour sorption. The initial exposure of the carriers to water induced distinct morphological changes; controlled wetting of Parteck ODT® resulted in particle shrinkage due to surface-confined transient dissolution and subsequent recrystallisation of the mannitol outer layer. On the other hand, wetting the StarLac® caused extensive morphological collapse of it’s spherical structure accompanied with a decrease in all the percentiles of the particle size distribution. Subsequent polymeric processing with hydroxypropyl methyl cellulose solution promoted particle growth and agglomeration for both carriers. Incremental Indomethacin addition further altered the surface, inducing progressive increase in surface roughness, which correlated with diminishing of packing efficiency observed in increase in Hausner ratio, yet all batches remained within passable limits. These findings demonstrate that while aqueous fluid bed layering is a feasible strategy for the solidification of micronized drug suspension onto co-processed excipients, the properties of the product inevitably depend on the inherent properties of the carrier material.

Introduction

The majority of emerging APIs face the challenge of poor intrinsic aqueous solubility which is a rate limiting step for their oral absorption [1], [2], [3]. The dissolution rate is of particular importance for APIs classified as class II under the Biopharmaceutical Classification System as, the bioavailability is dictated by the drug release rate and not by the membrane permeation [4], [5], [6], [7]. Hence, particle size reduction of an API to the lower micron scale forms a key strategy in acceleration of dissolution profile. As the increase of specific surface area, described in Noyes-Whitney’s equation, amplifies the concentration gradient governing the drug dissolution [3], [5], [8], [9]. Despite the fact that, the formation of micronized suspensions support enhancement of bioavailability, these dispersions exhibit agglomeration and sedimentation/caking instabilities leading to the necessity of their conversion into a more stable solid dosage form [10].

Fluidized bed granulation (FBG) is a versatile industrial scalable process for the incorporation of drug suspensions into solid dosage forms [1], [11]. In this process, the API suspension is sprayed directly onto a fluidised bed of carrier particles, where layering and drying occur simultaneously, yielding free-flowing granules utilisable in downstream operations such as tableting or capsule filling. Furthermore, the produced product by FBG has narrow size distribution and is less densified compared to other wet granulation options [12], [13]. Hence, making FBG a valuable approach.

The possibility of API suspension deposition onto solid carriers has been demonstrated by several research groups, each contributing to mechanistic understandings. Basa et al. demonstrated the production feasibility of tablets by incorporation of the Ketoconazole suspension onto lactose carriers, utilizing the fluidized bed process, followed by mixing the product with tableting excipients and consequent tableting [14]. Bose et al. investigated the spray granulation of the API suspension onto mannitol and lactose carriers reaching a drug load of 10 % with comparable dissolution properties to the suspension while the drug load of 20 % presented slower dissolution attributed to increased particle hydrophobicity [2]. Azad et al. demonstrated the effect of carrier particle properties on the subsequent dissolution profile of Itraconazole and Fenofibrate suspensions after fluid bed process application. The authors were able to show that finer carrier particle sizes are associated with faster dissolution rate due to the increase of the specific surface area and the thinner produced shell after coating [8]. Wewers et al. investigated further carrier materials such as, sucrose, mannitol and lactose, and the influence of their properties on the subsequent dissolution rate of the Naproxen suspension and found that sucrose demonstrate superior release followed by mannitol and lactose [15]. The findings showed the correlation between the carrier’s intrinsic dissolution rate together with the amount and type of polymeric excipients to dissolution profile [6]. Thereby, the choice/use of polymeric stabilisers like Hydroxypropyl methyl cellulose (HPMC) is crucial for the stabilization of the suspension during spraying along with the morphological influence on the granules after drying [15].

Multiple studies have demonstrated successful preparation of orodispersible tablets (ODTs) through a sequential approach. Okuda et al. prepared enteric coated particles by first film coating of Tamsulosin with HPMC onto the cellulose spheres and sequentially adding an ethyl cellulose/HPMC layer then finally an enteric coating top layer. The drug coated particles were mixed with the rapid disintegration granules, prepared by coating D-mannitol with suspension containing corn starch and crospovidone (XPVP), before tableting [16]. Similarly Kadota et al. formulated bitter taste-masked ODTs with Memantine using the Wurster fluidized-bed set up in order to prepare taste masked granules that were subsequently blended with XPVP and magnesium stearate before tableting [17]. For a paediatric application, Buck et al. coated Cinnarizine onto mannitol carriers then blended them with extra-granular components such as superdisintegrants e.g. croscarmellose sodium (CCS) and XPVP and viscosity enhancers (xanthan gum and carrageenan) before tableting [18].

Building upon this rationale, this study aims to evaluate whether aqueous fluid-bed layering of a micronized API suspension directly onto co-processed excipients (CPE), as active carriers, can generate API loaded particles that retain their functionality and are suitable for tablet compression to orodispersible tablets. Specifically, we will investigate Parteck ODT® and Starlac®, which combine a water-soluble tablet filler (mannitol or lactose) with integrated super-disintegrants (CCS or maize starch), under the working hypothesis that adequately controlled aqueous fluid bed layering will not irreversibly impair the superdisintegrants integrity. If this hypothesis proves feasible, the produced batches should enable downstream tableting without an additional extra-granular blending step, thereby saving steps in the manufacturing process of orodispersible tablets.

The experimental plan is then set in three phases. The first phase is to spray the CPE with water to observe possible morphological changes. Second phase is to spray the suspension vehicle to observe possible morphological changes and particle growth behaviour. The last phase is to spray the API suspension to observe the particle growth and explore possible API loadings.

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Materials

Micronized Indomethacin, used as model API was obtained from Fagron (Barsbüttel, Germany). Two co-processed excipients were employed as carrier: Parteck ODT® (Merck, Darmstadt, Germany), composed of mannitol as sugar base and CCS as a superdisintegrant and Starlac® (Meggle, Wasserburg, Germany) composed of lactose as a sugar base and maize starch as a superdisinegrant. HPMC Pharmacoat 603® (Shin-Etsu, Tokyo, Japan) was used as a suspension vehicle.

S. Badawi, T. Lillotte, E. Esser, C. Nueboldt, W. Hoheisel, J. Breitkreutz, Incorporation of micronized poorly soluble drug into orodispersible tablets by aqueous fluid bed granulation of co-processed excipients, European Journal of Pharmaceutics and Biopharmaceutics, 2026, 115078, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2026.115078.