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.

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.

This work aims to provide an effective and feasible solution for direct compaction (DC) production of high loading tablets of directly pulverized herb powders (DPPs). To confirm the generality of the solution, five DDPs with different and representative physical properties were selected to prepare modified composite particles (CPs) by liquid dispersion method with hydrophilic nano-silica (INS). The effects of key process factors were studied by setting (i) different dispersion liquid, i.e., water, 75 % ethanol, and anhydrous ethanol, and (ii) different initial particle sizes of DPPs. All DPPs were modified to meet the SeDeM expert system evaluation criteria which indicate the potential for DC. The tablet made by optimized CPs through continuous DC had less friability and more stable quality compared with the raw powder tablets. It was proved that the dispersion liquid would influence the amount and viscosity of the leaching liquor of the herbs, and, thus, affect the bonding strength of the drug and INS as well as the distribution of INS. However, the initial particle sizes affected little. Furthermore, the relationship between physical properties of powders as well as the moving trend were revealed by principal component analysis, and tablet quality was modelled by using the partial least-squares method.

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.

Pheretima products are widely used, but the stenchy odor is a constraint to their application. In this study, 86 and 673 volatile components (VOCs) were identified in Pheretima and its extracts using headspace gas chromatography-ion mobility spectrometry (HS-GC-IMS) and headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS), respectively. An increase in acid and amine contents after processing was found, which may explain the increased stenchy odor. Through orthogonal partial least squares discriminant analysis (OPLS-DA), 14 differential markers between aqueous and alcoholic extracts were screened, and 3-methylbutanal, pentanal, and trimethylamine were identified as the key differential odor components. Combined with relative odor activity value (ROAV) analysis, 10 key odor components were identified, including: 3-methylbutanal, 1-octen-3-ol, dimethyl trisulfide, (2E,6Z)-nona-2,6-dienal, methyl mercaptan, guaiacol, isobutyraldehyde, 1,8-cineole, 2-pentylfuran, and pentanal. This study provides theoretical support for the optimization of the odor of Pheretima-containing products and promotes their application.

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.

BACKGROUND:The ethanol extract of Pueraria lobatae Radix (EPL), a kind of medicinal herb powder with unacceptable behaviour (poor compactibility and slow dissolution rate), has the potential to be improved by double particle surface design by fluid-bed coating. This involves surface coating with plastic Hydroxypropyl Methylcellulose (HPMC) and surface pore formation induced by NH4HCO3. METHODS:The EPL drug was selected as the model for investigation. The formulation of the Composite Particles (CPs) was optimized using a central composite design. Subsequently, the pivotal tabletrelated attributes were contrasted between the optimized porous HPMC-coated EPL CPs and the pure HPMC-coated EPL CPs. Finally, the stability and applicability of the porous HPMC-coated EPL CPs were studied. RESULTS:The results demonstrated that (i) the optimized use levels of HPMC and NH4HCO3 for the porous CPs were 8.42% and 15.00% (w/w), respectively; (ii) the compactibility and tablet dissolution rate of the porous HPMC-coated EPL CPs were significantly enhanced in comparison to those produced from the pure HPMC-coated CPs; and (iii) the porous HPMC-coated CPs exhibited good stability and universal applicability in direct compaction. CONCLUSION:As a whole, the combination of polymeric coating and porous design proved effective in enhancing the compactibility and dissolution rate of EPL-based CPs while also rendering them suitable for direct compaction. These findings are conducive to the expansion of the application of fluidbed coating technology and the simultaneous improvement of the quality and efficacy of some drug tablets.

Twin-screw wet granulation (TSWG) is an innovative continuous granulation method in the pharmaceutical industry, yet research on its application for natural plant product (NPP) powders is limited. This study aims to investigate the TSWG processes of water extracted (W-E), ethanol extracted (E-E) and direct pulverization (D-P) NPP powders, as well as elucidate the forming mechanisms of different particles during the granulation. Principal component analysis was conducted on the physical properties of NPP and excipients powders, which identified three groups based on maximum liquid absorbency and torque rheological parameters. Granules from Group (1) were relatively dense with large particle size and low friability. In contrast, granules from Groups 2 and 3 were looser with small particle size and high friability. The granule forming mechanism revealed that W-E and E-E NPP powders partially dissolved and, after drying, formed rigid solid bridges that tightly bound the powder together. In contrast, the D-P NPP powders dispersed on the surface of droplets, creating internally porous and interconnected aggregates where the powder particles were held together mainly by intermolecular forces. Overall, this study systematically investigated the properties and TSWG process of NPP powders, and explained the forming mechanism of different NPP powders in TSWG. (c) 2025 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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.

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.

With the rapid development of buccal films (BFs), the demand for film-forming materials and preparation techniques has increased. Cellulose ethers (CEs) exhibit favorable properties, such as effective film formation, mucosal adhesion, and biocompatibility; as such, they are most commonly employed as film-forming materials, essential for BF fabrication. CE-based BFs, classified as orodispersible and buccal mucoadhesive films, can be prepared through solvent casting, inkjet printing, three-dimensional printing, electrospinning, and hot melt extrusion. Hydrophilic CE-based orodispersible films can rapidly dissolve or disintegrate upon contact with saliva to release drugs. High-viscosity or hydrophobic CEs can serve as protective layers for BFs, controlling the unidirectional release of drugs and mitigating the effects of saliva and buccal movements. These mucoadhesive films can firmly adhere to the buccal mucosa for an extended period, prolonging drug release time and enhancing bioavailability. CEs come in various types and grades, exhibiting different rheological and physicomechanical properties, which also provide options for customized design to specific patients. This review provides an overview of CE-based BF technology, analyzes the challenges and development directions of this film, and identifies key areas for scientific research, such as the interactions of bioadhesive materials in buccal mucosal drug delivery. The objectives of this review are to (i) highlight the value of their application in oral drug delivery and (ii) promote the broader adoption of BF-based patient-centric dosing.

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.

Personalized traditional Chinese medicine(TCM) preparations have entered a stage of rapid development. The key to the healthy development of this industry is to establish a sound manufacturing standard and quality control system. This paper analyzed the characteristics of personalized TCM preparations and drew reference from the quality management standards in the production of commissioned decoctions and oral pastes, on the basis of which the production quality management scheme and cautions for the safe production of personalized TCM preparations was put forward with consideration to various problems that may exist and occur in the production of such preparations. It provided references for formulating the production standards and quality management system of personalized TCM preparations. The production standards and quality control system should develop with the times. In the future, modern technologies such as big data and artificial intelligence should be employed to achieve the automated and intelligent production and establish a sound quality traceability system, online control strategy, and safety management mode of personalized TCM preparations, which will ensure the healthy development of this industry under requirement of good manufacturing practice(GMP).

Extracts are important intermediates in the production of traditional Chinese medicines preparations. The drying effect of extracts will directly affect the subsequent production process and the quality of the preparation. To meet the requirements of high drug loading, short time consumption, and simple production process of personalized traditional Chinese medicine preparations, this study explored the application of multi-program microwave vacuum drying process in the extract drying of personalized traditional Chinese medicine preparations. The influencing factors of microwave vacuum drying process were investigated for 5 excipients and 40 prescriptions. Taking the feasibility of drying, drying rate, drying time, and dried extract status as indicators, this study investigated the feeding requirements of microwave vacuum drying. With the dried extract status as the evaluation indicator, the three drying programs(A, B, and C) were compared to obtain the optimal drying condition. The experimental results showed that the optimal feeding conditions for microwave vacuum drying were material layer thickness of 2 cm and C program(a total of 7 drying processes), which solved the problem of easy scorching in microwave drying with process management. Furthermore, the preset moisture content of the dried extract in microwave drying should be 4%-5%, so that the dried extract of traditional Chinese medicine preparation had uniform quality, complete drying, and no scorching. This study lays a foundation for the application of microwave drying in the production of traditional Chinese medicine preparations, promoting the high-quality development of personalized traditional Chinese medicine preparations.

Low-viscosity hydroxypropyl methylcellulose (HPMC) was obtained by electron beam irradiation, and its use as an excipient for improving the properties of spray dried pharmaceutical powders was investigated. The minimum molecular weight of HPMC which could maintain the capacity of encapsulation and powder modification was explored. As the irradiation dose was increased from 10 to 200 kGy, the molecular weight and viscosity of HPMC decreased linearly. However, its main structure and degrees of methoxy and hydroxypropyl substitution were not significantly affected. The irradiated HPMC could encapsulate particles during spray drying and, thus, modify powder properties. Furthermore, the water content of spray-dried powders with irradiated HPMC was lower than that with parent HPMC. After the spray-dried powder with irradiated HPMC was prepared into granules, their dissolution rate was also faster. However, in order to achieve high encapsulation, the molecular weight of HPMC should be ensured to be above 7.5 kDa. The designated low-viscosity HPMC obtained by electron beam irradiation is a suitable powder-modification material for use in spray drying, and it shows promise as a superior excipient in medicine, food, paint industries, among others.