Specialty pharmaceutical excipients manufacturing by co-processing and their advanced characterization techniques

Abstract

Manufacturing co-processed pharmaceutical excipients is a great innovation in drug delivery, with improved compressibility, flowability, disintegration, and reduced moisture sensitivity. Co-processing combines different excipients to obtain synergistic effects without chemical modifications. Manufacturing techniques, such as spray drying, hot melt extrusion, co-crystallization, wet granulation, dry granulation, co-precipitation, co-milling, gelatinization, and freeze-thawing, improve excipient performance. Advanced materials require advanced characterization tools to ensure the product quality, stability, and functionality of co-processed excipients. A range of advanced analytical techniques is employed to comprehensively characterize excipients and their suitability for formulation development. Particle size, shape, and surface morphology can be evaluated using dynamic light scattering (DLS), laser diffraction (LD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM). Molecular interactions are typically investigated through Fourier-transform infrared spectroscopy (FT-IR). Thermal properties, including phase transitions and stability, can be assessed by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), while crystallinity is determined using X-ray powder diffraction (XRPD). Additionally, moisture-related characteristics are examined through dynamic vapour sorption (DVS) and Karl Fischer titration, ensuring that the excipient’s physicochemical attributes align with the requirements of the intended formulation. Despite the advantages of fast manufacturing and efficient formulation, co-processed excipients are burdened by regulatory challenges associated with non-standardized monographs. This review underlines the tremendous transformative potential of co-processed excipients in pharmaceutical manufacturing while underlining the critical need for harmonized regulatory frameworks to include them in international pharmacopeial standards.

Introduction

Co-processing is a revolutionary idea that modifies excipient functionality by adding fresh characteristics while maintaining the advantages. The International Pharmaceutical Excipients Council (IPEC) defines excipients as “substances other than the active pharmaceutical ingredients (API) which have been appropriately evaluated for safety and are intentionally included in a drug delivery system” [1]. The co-processed excipients, according to the IPEC definition, are “a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing and without significant chemical change.” Co-processing refers to the physical blending of two or more pharmaceutical excipients without inducing chemical alterations that modify their properties [2]. Because every formulation contains more than one excipient, combining the existing excipient’s novelty offers a fascinating chance for enhancing excipient activity. Co-processed excipients are primarily used to address different formulation factors such as compressibility, disintegration potential, and flow ability [3]. Characteristics at the molecular level include polymorphism, pseudo-polymorphism, the amorphous state, and the spatial distribution of molecules in a crystal lattice. The particle level encompasses characteristics such as particle morphology, size, surface area, and porosity.

Finally, the bulk level refers to the collective behaviour of the particles, which includes attributes like flow ability, compressibility, and dilution potential, all being critical to the functional performance of excipients these three levels are related to each other, therefore, changes in one level affect the others [4]. Co-processed excipients are multi-functional drug auxiliaries engineered to improve formulation performance through flow enhancement, compressibility, and stability. In direct compression tablets, co-processed excipients like microcrystalline cellulose-lactose (MCC-lactose) support smooth powder flow and excellent compactability. Wet granulation-based formulations are augmented by excipients such as starch-polyvinylpyrrolidone (starch-PVP), which promote granule cohesion and mechanical strength. Orally disintegrating tablets (ODTs) employ co-processed mannitol-crosslinked polyvinylpyrrolidone for fast disintegration and enhanced organoleptic qualities.

Sustained-release dosage forms utilize co-processed hydroxypropyl methylcellulose-lactose (HPMC-lactose) to control drug release kinetics. Effervescent products use co-processed citric acid-sodium bicarbonate for controlled effervescence and solubilization. In capsules, MCC-silicon dioxide enhances consistent powder flow and minimizes moisture sensitivity. Dry powder inhalers (DPIs) use co-processed lactose-mannitol to modulate aerodynamic particle dispersion. Suspension systems utilize microcrystalline cellulose-carboxymethylcellulose (MCC-CMC) to improve thixotropic stability and inhibit sedimentation. These co-processed excipients improve drug manufacturability, stability, and bioavailability. The choice of excipients depends on several important factors, such as physical and chemical stability, biological inertness, high flexibility, thermal stability, availability, pharmaceutical acceptability, and cost-effectiveness [5]. The infographic illustrates (Fig. 1) the market growth and most significant characteristics of pharmaceutical co-processed excipients, with a projected compound annual growth rate (CAGR) of 6.20% from 2023-2032, with market size increasing from USD 5.0 billion to 8.5 billion. It adopts major manufacturing techniques like spray drying, hot melt extrusion, solvent evaporation, granulation, and co-crystallization. Organizations like BASF SE, JRS Pharma, Meggle, SPI Pharma, and Roquette are major industry players. Applications are pharmaceutical formulations and nutraceuticals with a market presence in North America, Europe, Asia Pacific, and the rest of the world. The futuristic theme highlights the growth of the industry and the rising demand for advanced drug formulation techniques [6].

This review underlines the progress and significance of co-processed excipients in the pharmaceutical sector, like improving functional properties, such as moisture resistance, stability, bioavailability, aerodynamic performance, and thixotropic properties in pharmaceutical formulations, without changing their chemical properties. Here, we covered various conventional or advanced manufacturing techniques that are used for the manufacturing of co-processed excipients. The techniques include spray drying, hot-melt extrusion, wet granulation, roller compaction or dry granulation, solvent evaporation, co-precipitation, co-crystallization, gelatinization, co-milling, and freeze-thawing. These advanced materials require specific advance techniques for their suitable characterization to meet the regulatory requirements. Various advanced analytical techniques like Dynamic light scattering (DLS), Dynamic vapour sorption (DVS), Laser diffraction (LD), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), Atomic Force Microscopy (AFM), Karl Fischer titration, Ultraviolet-visible (UV-Vis) Spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, Mass spectroscopy (MS), Nuclear magnetic resonance (NMR), X-ray powder diffraction (XRPD), Differential scanning calorimetry (DSC), Thermogravimetric analysis (TGA), Brunauer-Emmett-Teller (BET) analysis, Dynamic mechanical analyzer (DMA), texture analysis, tensile strength, and high performance liquid chromatography (HPLC) are used for the characterization of co-processed excipients. Although co-processed excipients bring many benefits, including easier manufacture and better bioavailability of drugs, their application is still limited by regulatory barriers. There is no standard monograph for these products; hence, getting approval is cumbersome. Overcoming these regulatory hurdles, the implementation of Process Analytical Technology (PAT) in co-processed excipients to ensure the real-time monitoring, consistency, and quality control during manufacturing is a big challenge in this segment. Innovation in excipient technology will make co-processed excipients part and parcel of global pharmacopeial standards, opening wider doors for their application in pharmaceutical development.

Excipients with superior properties can be created by the co-processing technique as a new grade of premixed old ingredients or innovative combinations of old materials. A complicated and expensive regulatory approval process must be completed by any novel combinations being created as excipients to avoid toxicity and ensure safety. Over the past few decades, the development of novel excipients with enhanced physical and chemical properties has emerged as the most effective approach to advancing excipient functionality. Since all formulations contain more than one excipient, combining new excipients with old ones is an innovative possibility for enhancing excipient functionality. Many excipient combinations are available to achieve the necessary performance attributes. However, developing such a combination is difficult because one excipient may interfere with another excipient’s ability to operate.

Recent pharmaceutical formulations highlight the value of improving the flowability, compressibility, stability, and drug release properties in addition to manufacturing. Conventional excipients would frequently have a disadvantage when direct compression-based approaches are employed because of their poor compressibility and flowability. However, the use of co-processed excipients in tablets promotes compaction, diminishes segregation, and enhances the ability to formulate high doses. Having more than one functionality as fillers and binders, they substitute two or more excipients to yield a relatively more simplified formulation development. Oral disintegrating tablets (ODTs) ensure rapid disintegration, pleasant mouthfeel, and patient acceptance, while in sustained- and modified-release formulations, their main role is to enhance matrix formation and function to control the drug release rate. Thus, each formulation type requires specific materials to achieve the delivery goals. These excipients can even help to skip specific unit operation like granulation, thus shortening processing time and averting moisture-related stability problems for hygroscopic APIs. Moreover, co-processing can enhance mechanical strength and mouthfeel in chewable and effervescent tablets while improving solubility and bioavailability in lipid-based and liquid-filled capsules. In injectables, use of co-processed excipients can improve drug solubility, isotonicity, suspension stability, and prevent precipitation. Co-processed excipients for topical and transdermal products help to improve spreadability, drug permeation, texture enhancement, and emulsion stabilization. Ophthalmic products apply them for modifying viscosity, controlled release of drugs, and preservative-free systems to possess better ocular retention. In pulmonary drug delivery devices, e.g., dry powder inhalers (DPIs), they control flow properties, aerosolization, and moisture stability for effective lung deposition can be achieved by co-processed excipients. In liquid or parenteral pharmaceutical products, the co-processed excipients can even help in taste masking, suspension uniformity, and crystallization prevention, increasing patient compliance. In suppositories, co-processed excipients offer better melting characteristics, drug distribution in a uniform manner, and stability of polymorphic transition. Further, in emerging drug delivery systems like nanocarriers and liposomes, co-processed excipients impart better bioavailability, targeted delivery, and formulation stability. In biopharmaceuticals, their role is more significant, as they stabilize proteins, peptides, and nucleic acids by inhibiting aggregation/degradation and maintaining biological activity. They can also improve solubility, help in sustained release, and delivery of sensitive biologics, with ensuring efficacy and safety of the drug product. Their multifunctionality simplifies formulation challenges, removes excipient variability, and improves overall product performance in broad pharmaceutical and biopharmaceutical applications.

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Himanshu Vishwakarma, Shubham Ghatole, Sunil Kumar Sah, Santanu Kaity, Specialty pharmaceutical excipients manufacturing by co-processing and their advanced characterization techniques, Progress in Engineering Science, 2025, 100176, ISSN 2950-4252, https://doi.org/10.1016/j.pes.2025.100176.

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