Tablet Compression and Performance of Artocarpus altilis as a Starch-Rich Natural-Source Excipient with Different APIs

Abstract

Background/Objectives: Excipients play a key role in the manufacturability and performance of solid oral dosage forms, particularly for drug candidates with diverse solubility, permeability, and mechanical properties. Understanding excipient behavior during tablet compression is essential for robust formulation design. Starch-rich natural-source material have emerged as promising candidates due to their availability and favorable deformation behavior. However, there is limited understanding of their tablet compression performance and interactions with active pharmaceutical ingredients (APIs). This study aimed to evaluate the tablet compression behavior and functional performance of a starch-rich natural-source excipient prepared from whole Artocarpus altilis fruit material when formulated with APIs representing all four classes of the Biopharmaceutics Classification System.

Methods: Tablets were prepared using a hydraulic press at compression pressures ranging between 296 and 591 MPa. Model APIs included acetaminophen, clarithromycin, vitamin C, and berberine hydrochloride. Tablet compression behavior was characterized using tabletability, compressibility, and compactability profiles, while tablet performance was evaluated through friability, disintegration, and dissolution testing.

Results: Densification behavior was controlled primarily by the Artocarpus altilis excipient, whereas tensile strength development and compactability were strongly influenced by API properties. Formulations containing clarithromycin and berberine HCl exhibited enhanced tabletability and compactability, achieving higher tensile strengths at comparable solid fractions. Acetaminophen and vitamin C formulations showed limited strength gains despite similar densification. Formulations containing clarithromycin and berberine HCl maintained low friability, while enabling rapid disintegration and dissolution in acetaminophen and vitamin C formulations.

Conclusions: Tabletability and compactability trends varied among formulations, likely reflecting differences in API physical properties and formulation-dependent interparticle interactions, whereas compressibility primarily reflected excipient-controlled densification. Distinct trends were observed across BCS classes, with low-solubility APIs producing stronger tablets and highly soluble APIs showing lower mechanical strength and faster disintegration. Overall, Artocarpus altilis functions as a mechanically robust yet performance-adaptive excipient suitable for tablet formulations across diverse biopharmaceutical contexts.

Introduction

In solid oral dosage forms, therapeutic performance depends on the combined behavior of the active pharmaceutical ingredient (API) and the excipients under both processing and physiological conditions. Excipients play a critical role beyond serving as inert fillers, as they directly influence formulation properties such as powder flow, compaction behavior, mechanical integrity, disintegration, dissolution, and drug availability [1,2,3]. This role makes the selection and design of modern excipients critical to the development of robust solid oral formulations, particularly as modern drug candidates increasingly present challenges related to solubility, permeability, and mechanical behavior [4,5,6,7].

Many commercially available excipients exhibit limited functional flexibility and often require extensive chemical modification or co-processing to meet formulation requirements [8,9,10]. These approaches can increase manufacturing complexity and restrict the formulation design space. In response, regulatory agencies such as the U.S. Food and Drug Administration (FDA) have emphasized the need for novel excipients capable of expanding functionality while maintaining manufacturing feasibility and regulatory compliance [11]. Additionally, the development of such excipients requires a fundamental understanding of their behavior during critical unit operations, particularly tablet compression, where material properties and process conditions interact to determine final product performance.

Given the need to enhance excipient functionality while maintaining manufacturability, starch-based materials have been extensively studied as pharmaceutical excipients due to their availability, biocompatibility, and favorable deformation behavior during compaction [12,13]. Previous studies have evaluated starches derived from various botanical sources, primarily focusing on their use as binders or disintegrants, and often relying on extraction or modification processes to tailor their performance [14,15,16,17,18,19,20].

Recent studies have analyzed the use of whole food-derived ingredients rather than isolated components for tablet formation [21,22,23,24]. Among these materials, Artocarpus altilis has emerged as a promising natural-source, starch-rich excipient with potential pharmaceutical applications [25,26]. Previous work has demonstrated the feasibility of using chemically unmodified breadfruit granules as excipients, showing acceptable tablet formation and performance [27]. However, limited studies have examined the use of whole food matrices as excipients and their interactions with APIs of differing physicochemical characteristics, as well as how these interactions influence compression behavior and final tablet performance.

This study focuses on evaluating the tablet compression behavior and performance attributes of Artocarpus altilis as a natural-source, high-starch excipient formulated with different APIs. These APIs were selected using the Biopharmaceutics Classification System (BCS), which provides a framework to categorize APIs based on solubility and permeability [28], including acetaminophen (BCS Class I), clarithromycin (BCS Class II), vitamin C (BCS Class III), and berberine HCl (BCS Class IV). Tablet compression behavior (i.e., tabletability, compressibility, and compactability profiles) was examined following the United States Pharmacopeia (USP) protocol USP <1062>, together with critical quality attributes (i.e., friability, disintegration, and dissolution behavior) to understand the relationship between API-excipient interactions and tablet performance. By understanding these formulation behaviors, this work aims to provide mechanistic insight into API-excipient interactions by systematically evaluating the compression behavior of a starch-rich natural-source excipient derived from whole Artocarpus altilis across APIs representing all four BCS classes. These findings may also support the development of sustainable and environmentally conscious formulation strategies based on non-toxic, natural-source excipients for modern solid oral dosage forms.

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Materials

For the natural-source, starch-rich excipient, whole Artocarpus altilis (white cultivar) was used. The raw material was harvested in Puerto Rico and sourced primarily from the southwest region of the island. The processing workflow followed the procedure previously reported by Torrens-Sotomayor et al. [27], with minor adjustments specific to the present study. No starch extraction or additional chemical or physical modification was performed. The material was used as a whole-food-derived powder to evaluate its performance as a natural-source excipient.

The material was dried in a HerathermTM oven (Thermo Fisher Scientific, Waltham, MA, USA) at 55 °C until a target moisture content of approximately 10 wt.% was reached. The measured moisture content of the processed powder was 10.97 ± 0.33%, determined according to AOAC Method 925.10 for moisture determination [29]. The dried material was milled using a FitzMill Comminutor Model L1A (The Fitzpatrick Company, Elmhurst, IL, USA) at 3000 rpm and a 685.8 µm round-hole perforated screen.

The physicochemical properties of the resulting powder were characterized to evaluate its suitability as a pharmaceutical excipient. Particle size distribution was determined using laser diffraction (Insitec RT Sizer, Malvern Panalytical Ltd., Malvern, UK).The total starch content of the material was determined using the Total Starch Assay Protocol (K-TSTA-50A/K-TSTA-100A; Megazyme, Bray, Ireland) following AOAC Method 996.11 and AACC Method 76-13.01.The solubility of the powder was determined using the water solubility index following a method based on Anderson et al., as described in previous studies [30]. The aqueous solubility of the powder was evaluated using the water solubility index (WSI) following a method based on Anderson et al., as described in previous studies [30]. Measurements were conducted at 21 °C and 37 °C to assess the temperature dependence of solubility.

Torrens-Sotomayor, L.F.; Velázquez-Figueroa, C. Tablet Compression and Performance of Artocarpus altilis as a Starch-Rich Natural-Source Excipient with Different APIs. Pharmaceutics 2026, 18, 819. https://doi.org/10.3390/pharmaceutics18070819

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