The widespread adoption of direct compression has increased the performance requirements for pharmaceutical excipients. While single excipients often fail to meet these multifaceted demands, co-processed excipients integrate multiple components through specialized processes to create superior multifunctional systems, thereby emerging as a pivotal solution for advancing DC formulations. This review systematically summarizes recent advances in CPEs, outlining their applications in modulating drug release, improving compressibility, and enhancing compatibility with moisture-sensitive drugs. It further elucidates the structure-performance relationships of various manufacturing techniques and analyzes the decisive role of key material attributes in dictating product performance. This review aims to offer valuable theoretical guidance for the future development and application of high-performance CPEs.

Roll compaction/dry granulation and tableting (RCDG-T) process frequently impacts the quality and efficiency of tablets due to the loss of tabletability (LoT). The process parameters have a major impact on this issue, which arises from the multi-scale interaction between the raw material powder, the ribbon, and the particle properties. The cross-scale transmission of material properties and the dynamic coupling of process parameters are difficult to uncover through traditional research, and the fundamental mechanism of LoT remains unclear. It is necessary to build a methodical technique that integrates multi-scale material evolution with process parameters in order to investigate the compaction mechanism of this process. The structural reorganization of granular systems under processing circumstances, starting with micro-scale bonding, moving through mesoscale force chains and pore network evolution, and finally dictating macroscopic features, is the fundamental process of tablet manufacturing. Therefore, it is crucial to establish systematic characterization methods that encompass micro-, meso-, and macro-scales to gain a deeper understanding of this process and optimize tablet quality. This review aims to establish a multi-scale research framework for the RCDG-T process, with an emphasis on the interactions between material attributes and process parameters at each scale. This work will elucidate cross-scale causal relationships from process conditions to macroscopic properties, review characterization and monitoring techniques for key material properties and process parameters, and explore the role of computational simulation in mechanism analysis and performance prediction, along with the feasibility of constructing predictive digital twins. Integrating these multi-scale insights will establish a scientific foundation for developing mechanism-based process digital twins.

Abstract Plant polyphenols have emerged as a highly versatile “molecular glue” for driving the formation of multifunctional hydrogels. This comprehensive review systematically explores the entire development pipeline of plant polyphenol-based hydrogels, spanning from their fundamental assembly mechanisms and biological functions to advanced manufacturing processes and biomedical applications. First, the diverse interactions dictated by specific polyphenol structures are elucidated to demonstrate how they govern macroscopic network architectures and endow the resulting materials with intrinsic bioactivity. Building on these fundamental mechanisms, one framework is introduced that maps structural features to optimized macroscopic manufacturing strategies. Furthermore, this review highlights the broad utility of these materials in advanced clinical scenarios. Finally, major clinical translation barriers such as oxidation tendencies, sterilization, and industrial standardization are critically evaluated. By bridging molecular fundamentals with macroscopic engineering and clinical challenges, this review provides practical design guidance to accelerate the future development and clinical translation of plant polyphenol-based biomaterials.

The global supply of mannitol offers diverse grades, typically categorized by manufacturers into “spray-dried” or “granulated” types for direct compression (DC). However, relying solely on these nominal process labels can be misleading for formulation development. This study established a quantitative, functionality-based classification system by systematically evaluating thirteen commercial mannitol grades through multivariate statistical analysis. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) revealed that the manufacturing process label does not strictly dictate functional performance. Notably, three specific granulated grades were found to functionally cluster with spray-dried materials (Cluster 1) due to their shared porous micromorphology and high specific surface area, exhibiting superior tabletability (ka) and compressibility (kG). In contrast, Cluster 2, characterized by dense crystalline structures, demonstrated distinct mechanical behaviors dominated by high elasticity (kFES) and fragmentation tendency (f). Partial least squares (PLS) regression further elucidated the critical mechanisms governing tablet quality, identifying yield pressure (Py) and tabletability (ka) as the primary positive determinants for tensile strength, while excessive fragmentation and elastic recovery negatively impacted mechanical integrity. A trade-off was also observed where enhanced compressibility facilitated rapid disintegration, whereas excessive interparticle bonding could delay it. In summary, this property-driven classification framework provides a more rational strategy for excipient selection than commercial labels, enabling the identification of optimal materials for robust DC formulations based on intrinsic functional attributes.

A comprehensive evaluation was conducted on 27 directly pulverized natural medicinal plant and mineral products (DP-NPs) by analyzing their fundamental and functional characteristics. Multiple analytical methods were employed to establish different classification systems or models, as well as to investigate the influence of powder properties upon critical tablet attributes. The results indicated that: (i) The fundamental properties of DP-NPs showed considerable variation (particularly in the mineral powders), e.g., wettability (contact angle, 64.7(o) to 121.7(o)) and flowability (angle of repose, 42.2(o) to 63.0(o)); (ii) a classification system for wet-granulation suitability was established with medium and high Liquid/Solid ratio powders (e.g., leaf powders) demonstrated suitability for granulation; (iii) powders were grouped into three categories based on tableting performance: Group 2 (the best: Lycii Fructus/FR3, TS = 3.56 MPa under 240 MPa) > Group 1 (e.g., Gypsum Fibrosum) > Group 3 (the worst: Lablab Semen Album, TS = 0.01 MPa under 240 MPa) using multiple analysis; (iv) powders were categorized into three classes according to their tablet disintegration kinetics: disintegrating (e.g., root powders), expansive (e.g., leaf powders), and dissolved (FR3) ones; and (v) Elastic Net Regression modeling revealed a positive correlation between tensile strength and disintegration time of tablets for the majority of DP-NPs, identifying key variables (e.g., yield pressure) influencing the two critical quality attributes. In summary, this study provides a systematic framework for understanding and predicting the behavior of DP-NPs in tablet production, establishing a scientific foundation for rational formulation design under the Quality by Design (QbD) paradigm.

Palatability is a critical determinant of acceptability and adherence for oral drug products, especially in pediatric and geriatric populations, yet its evaluation remains fragmented across dosage forms and often disconnected from formulation-development decisions. In this review, we propose Palatability-by-Design (PbD) as a unified framework that treats palatability not as a loosely defined sensory outcome, but as a development variable with identifiable failure modes, measurable sensory critical quality attributes (CQAs), and controllable formulation/process levers. We first define a two-dimensional framework comprising swallowability (oral physical comfort) and palatability (sensory appreciation), and then outline major sensory failure modes that are relevant to oral drug development. Next, we compare subjective and objective evaluation methods using a fit-for-purpose logic, emphasizing decision relevance, surrogate calibration, and the need to anchor instrumental readouts to perception-relevant endpoints. We further integrate these elements into a PbD workflow that links sensory CQAs to risk assessment, formulation/process variables, acceptance criteria, and verification. Finally, we summarize failure-mode-guided optimization strategies, including taste masking and dosage-form modification, and discuss future needs for data standardization, translational calibration, and patient-centred implementation. By aligning sensory science with pharmaceutical quality and control logic, PbD provides a more practical basis for rational, patient-focused oral product development.

By investigating three single herbal groups and seven validation groups, where Puerariae Lobatae Radix (PLR) extract was respectively combined with four directly pulverized natural plant powders (DP-NPPs) and three excipients, this study examined the effects of composition and process (wet co-processing and physical mixing) on powder tabletability, revealing a positive deviation (i.e., the measured tabletability exceeds the theoretical additive one) for co-processed powders (CPs) with high extract ratios. For example, the tensile strength of tablets of 80% PLR extract-20% DP Turpiniae Folium CP tableted under 100 MPa is 5.1 times of the theoretical value. To elucidate the underlying mechanism, the role of bonding area (BA), bonding strength (BS), and their interplay were explored. DP-NPPs exhibited poorer compressibility (BA) compared to extracts, whereas their σ0 (apparent BS) was unexpected significantly higher than that of extracts (e.g., σ0 of DP-PLR is 37.8 times that of PLR extract). The mechanism underlying the positive deviation can be categorized as the positive BS one (e.g., PLR-CP containing 67% extract) and the BA-BS synergistic one (e.g., Sophorae Flavescentis Radix CP containing 80% extract). Moreover, this study reveals that the threshold of extract ratio for CPs to exhibit positive deviation is governed by the BS and tabletability difference between DP-NPP and extract: the greater the BS difference and the smaller the tabletability difference, the lower the threshold. Overall, this study provides some theoretical evidence for the combined use of DP-NPPs with extracts in herbal tablets, and is conducive to the formulation and process design of herbal tablets.

Particle size is a critical powder attribute affecting tablet disintegration, yet its underlying mechanism remains insufficiently elucidated. This study systematically investigates the role of particle size in regulating the disintegration behavior and mechanism of Natural Plant Product (NPP) tablets. NPP powders with different particle size distributions were prepared and characterized, which were subsequently compressed into tablets. Disintegration kinetics were quantitatively evaluated using stress relaxation method, while the dynamic disintegration process was visually captured through optical microscopy. K-means clustering analysis was employed to objectively classify disintegration modes based on the kinetic profiles. The results indicate that particle size governs swelling behavior during disintegration by affecting tensile strength and pore structure. Notably, larger particles were found to induce more pronounced swelling, which in turn facilitated faster and more complete disintegration. Furthermore, variations in particle size could alter the predominant disintegration mechanism. This work provides a particle-level perspective on the disintegration dynamics of NPP tablets, offering mechanistic insights that bridge raw material properties and dosage form performance.

Orally disintegrating tablets (ODTs) have been a popular dosage form in recent years known for easy administration and fast action. In the case of the global shortage of pediatric-specific medicines and the limited market scale, which are prevalent issues that require urgent attention and resolution, ODTs have great potential to improve medication compliance and expand patient coverage for pediatric population. Through analysing information on manufacturing technologies, excipients, and quality control difficulties of pediatric ODTs from the unique aspects of pediatric patients in this review, the implementation of quality controls, trends of future development and application with possible challenges of pediatric ODTs are prospected. Under the core principle of Quality by Design (QbD) and the development trend of personalized drug delivery, the quality control of pediatric ODTs would continuously optimize in a cycle involving four perspectives: research and development, manufacture, market, and clinical practice. The future application of pediatric ODTs would mainly focus on acute diseases, mental disorders, oral health care, and respiratory diseases in children. It is hoped that through the multi-faceted analysis and future outlook of pediatric ODTs in this review, a reference can be provided for the development of pediatric ODTs.

Poor medication adherence is a pervasive issue in oral administration. Oral medicated jellies/gels are semisolid formulations that leverage the advantages of both solid and liquid formulations and have a promising potential. They help to increase patient comfort, simplify the medication process, and improve the medication experience, thereby improving medication adherence and alleviating many common barriers to adherence. This review analyzes the advantages of oral jellies from the perspective of improving adherence and summarizes the current state of research on this dosage form at five levels: improved bioavailability, drug release, swallowability, palatability, and appearance appeal. Finally, we discuss future research directions for this formulation.

In recent years, mannitol has been widely used in the pharmaceutical industry as a substitute for lactose. Mannitol is widely available and can be produced by a variety of methods. Due to its water solubility, low hygroscopicity and chemical inertness, it is commonly added to various formulations, especially tablet formulations. A better understanding of the Critical Material Attributes (CMAs) of raw materials can help guide tablet quality improvement and mannitol development based on quality by design. In addition, co-processing of mannitol can introduce more desirable properties to the resulting particles. In this review, we focused specifically on the recent advances and development of mannitol on direct compression (DC) tableting, including the functions in tablet formulations, potential CMAs, and mannitol-based co-processed excipients, therefore providing a reference for further studies.

The effect of binder types on the granule properties and tablet quality for high shear wet granulation and tableting (HSWG-T) was studied. Furthermore, attribute correlation was established by multivariate models based on a systematical study of the binder's properties, wetting mass's physical properties, granules' properties, and tablet quality. The results show that: (i) povidone K30 exhibited the largest wetting mass's adhesiveness, while hydroxypropyl methylcellulose E15 had smallest wetting mass's cohesiveness and resilience; (ii) copovidone S630 had greatest wetting mass's hardness and smallest adhesiveness, smallest granules' particle size, and the best compressibility, but it had poor compactibility; (iii) The granules prepared with povidone K90 had the worst compressibility at high liquid-solid (L/S), but tablets had the highest compactibility at low L/S; (iv) Multivariate models indicated that the tablet tensile strength and friability correlated with the binder's glass transition temperature, surface tension, viscosity, wetting mass's resilience, the granules' angle of repose and true density, and parameters tau 0, b, alpha, and kG. Nevertheless, the tablet disintegration time correlated with wetting mass cohesiveness, granules' bulk density, tapped density, and median particle size, and parameters y0 and a. Overall, this study systematically revealed that the binder types have a critical impact on the HSWG-T process.

In the context of Industry 4.0, and Pharma 4.0, the application of machine learning (ML) is gaining growing recognition in the field of drug formulation, where the application of these technologies has the potential to significantly improve the agility, efficiency, flexibility, and quality of production in the pharmaceutical industry. Establishing control strategies that meet product performance requirements and have robust processes allows for precise quality control, enabling pharmaceutical scientists to enhance the safety and effectiveness of drug formulations. Compared to traditional prescription development, big data-based ML formulation development focuses on integrating and mining data and extracting data features to better guide the formulation design. This review starts from the perspective of big data-based ML drug formulation development processes, summarizes recent advancements in utilizing ML tools to address significant challenges, and highlights successful cases in formulation research and development. It provides a comprehensive summary and synthesis of quality control measures and process evaluation methodologies employed in ML-driven drug formulation development and manufacturing, effectively implementing the entire life-cycle of drug formulations. This review is devoted to an in-depth discussion on the Intelligence of drug formulation production and development, which is of great significance in guiding the application of efficient and safe drug formulation.

This study aims to optimize the prediction model of personalized water pills that has been established by our research group. Dioscoreae Rhizoma, Leonuri Herba, Codonopsis Radix, Armeniacae Semen Amarum, and calcined Oyster were selected as model medicines of powdery, fibrous, sugary, oily, and brittle materials, respectively. The model prescriptions were obtained by uniform mixing design. With hydroxypropyl methylcellulose E5(HPMC-E5) aqueous solution as the adhesive, personalized water pills were prepared by extrusion and spheronizaition. The evaluation indexes in the pill preparation process and the multi-model statistical analysis were employed to optimize and evaluate the prediction model of personalized water pills. The prediction equation of the adhesive concentration was obtained as follows: Y_1=-4.172+3.63X_A+15.057X_B+1.838X_C-0.997X_D(adhesive concentration of 10% when Y_1<0, and 20% when Y_1>0). The overall accuracy of the prediction model for adhesive concentration was 96.0%. The prediction equation of adhesive dosage was Y_2=6.051+94.944X_A~(1.5)+161.977X_B+70.078X_C~2+12.016X_D~(0.3)+27.493X_E~(0.3)-2.168X_F~(-1)(R~2=0.954, P<0.001). Furthermore, the semantic prediction model for material classification of traditional Chinese medicines was used to classify the materials contained in the prescription, and thus the prediction model of personalized water pills was evaluated. The results showed that the prescriptions for model evaluation can be prepared with one-time molding, and the forming quality was better than that established by the research group earlier. This study has achieved the optimization of the prediction model of personalized water pills.

The complex physical properties of natural plant products (NPPs) greatly influence the disintegration of NPP tablets, and the evaluation of their disintegration properties is generally overlooked. To solve this problem, the study aimed to reveal the disintegration behavior of NPP tablets by the stress relaxation method of texture analyzer and investigate the key attributes affecting the disintegration of NPPs. 24 types of NPPs were systematically evaluated and divided into 3 kinds of groups: expansive NPPs, dissolved NPPs, and disintegrating NPPs. The disintegration characteristics of each group were significantly different. 9 kinds of characteristic parameters of disintegration kinetics of NPP tablets were used to analyze in detail. The results of Pearson’s correlation coefficient showed that there was a strong correlation between the fundamental properties of powders and the disintegration kinetics of tablets. The results of principal component analysis (PCA) confirmed the validity of the classification method. Additionally, the medicament portions and texture characteristics of NPPs are the key factors influencing tablet disintegration. The disintegration of NPPs may also be affected by the dissolution. Thus, the disintegration behavior of NPP tablets was investigated and the factors influencing disintegration were revealed.

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Lactose is one of the most commonly used tablet diluents and fillers. However, the moisture sorption of lactose powder could exert detrimental effects on the excipient itself, as well as on the tablet quality. The effects of storage relative humidity (RH) conditions for different grades of lactose powders and tablets on compression behavior and tablet qualities were investigated. Four types of lactose were selected in this study: sieved lactose (Pharmatose 110M), granulated lactose (SuperTab 30GR), anhydrous lactose (SuperTab 21AN), and spray-dried lactose (SuperTab 14SD). These powders and tablets were stored at three RH levels (33, 58, 75%) for a certain period of time before determining their properties. For the moisture-sorbed powder, there was little change in the basic physical properties of lactose powder. Based on the dynamic vapor sorption (DVS) results, the lactose grades determined their hygroscopic properties. The reduction in mechanical strength of lactose powder during storage became less pronounced except for 14SD. But a reduction was observed in the tensile strength (TS) of the 14SD powder from 2.1 to 0.9 MPa after storage at 75% RH for 30 days. The fragmentation of lactose increased with increasing storage humidity. By using multivariate statistical analysis, the similarity and variation of powder properties between 14SD and other types of lactose were visualized. For the moisture-sorbed tablet, the TS became higher and the friability became lower. The TS of lactose tablets exhibited an increase of up to 59.8%. Whether water uptake occurred before or after compression adversely affected tablet disintegration. In conclusion, adverse phenomena during production and storage can be effectively minimized by a better understanding of the effects of moisture sorption on lactose powder and tablets.

Biomaterials capable of achieving effective sealing and hemostasis at moist wounds are in high demand in the clinical management of acute hemorrhage. Bletilla striata polysaccharide (BSP), a natural polysaccharide renowned for its hemostatic properties, holds promising applications in biomedical fields. In this study, a dualdynamic-bonds crosslinked hydrogel was synthesized via a facile one-pot method utilizing poly(vinyl alcohol) (PVA)-borax as a matrix system, followed by the incorporation of BSP and tannic acid (TA). Chemical borate ester bonds formed around borax, coupled with multiple physical hydrogen bonds between BSP and other components, enhanced the mechanical properties and rapid self-healing capabilities. The catechol moieties in TA endowed the hydrogel with excellent adhesive strength of 30.2 kPa on the surface of wet tissues and facilitated easy removal without residue. Benefiting from the synergistic effect of TA and the preservation of the intrinsic properties of BSP, the hydrogel exhibited outstanding biocompatibility, antibacterial, and antioxidant properties. Moreover, it effectively halted acute bleeding within 31.3 s, resulting in blood loss of 15.6 % of that of the untreated group. As a superior hemostatic adhesive, the hydrogel in this study is poised to offer a novel solution for addressing future acute hemorrhage, wound healing, and other biomedical applications.

Porosity variations have an impact on the disintegration behavior of tablets whereas the influence on the disintegration characteristics of natural plant product (NPP) tablets has not been extensively studied. Revealing the pore structure of NPP tablets provides a new and important clue to elucidate the phenomenal behavior and underlying mechanisms of tablet disintegration. In this study, the effect of porosity variation on disintegration of NPP tablets was evaluated for the first time. The disintegration performance of NPP tablets was evaluated using tablet attributes, disintegration kinetics, and the wicking process. Mercury intrusion porosimetry (MIP) and X-ray computed microtomography (XlCT) were used to characterize the microstructure of the tablets. Curcuma Longa Linn. extractions were compacted into tablets with different solid fractions. Tablet qualities changed significantly with increasing porosity. An increase in the wicking rate with porosity changed by visualizing the wicking process. The disintegration kinetics of tablets showed a sensitive variation after an increase in porosity. The pore structure of tablets including parameters such as pore size distribution, tortuosity, and connectivity were identified as direct drivers of wicking and disintegration. The current study provides new insights into the disintegration mechanism of dissolved NPP tablets by exploring the evolution of the pore microstructure. (c) 2024 Published by Elsevier B.V. on behalf of The Society of Powder Technology Japan. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Lactose is one of the most widespread excipients used in the pharmaceutical industry. Because of its water solubility and acceptable flowability, lactose is generally added into tablet formulation to improve wettability and undesirable flowability. Based on Quality by Design, a better understanding of the critical material attributes (CMAs) of raw materials is beneficial in guiding the improvement of tablet quality and the development of lactose. Additionally, the modifications and co-processing of lactose can introduce more-desirable characteristics to the resulting particles. This review focuses on the functionality, CMAs, applications, modifications and co-processing of lactose in tablets.