A comprehensive industrial perspective on microstructural characterization and relation to bioequivalence of topical dosage forms

Abstract

The effectiveness of topical semi-solid formulations, such as ointments, creams, and gels, relies on their qualitative (Q1) and quantitative (Q2) composition, but most critically, on their internal microphysical and chemical structure (Q3). This review, from an industrial perspective, emphasises the crucial importance of evaluating Q3 in research, development, quality control, and regulatory approval processes. Assessing Q3 involves detailed characterization and comparison of key physicochemical and structural features, such as appearance, rheological properties (e.g., viscosity, yield stress), microstructure (using microscopy, particle size analysis), the drug’s physical state (crystal form and state), in vitro release testing (IVRT), water activity, pH, and drying rate. These parameters create the formulation’s “structural fingerprint, ” bridging manufacturing, product quality, and clinical performance. By examining the scientific rationale, methodologies (including development and validation), and strategies underlying Q3 evaluation within bioequivalence frameworks, the review provides researchers, students, and industry professionals with a comprehensive understanding of these topics. It highlights that, according to the Quality by Design (QbD) approach, thorough knowledge and proper application of Q3 assessments are vital for ensuring consistent performance of locally acting semi-solid drugs, supporting rational generic development, and meeting stricter regulatory standards (e.g., FDA and EMA guidelines). As analytical techniques improve and QbD principles deepen, Q3 assessment will advance semi-solid formulation science from empirical methods to precision-based approaches. Ultimately, this progress will help develop high-quality, accessible medicines that are safe, effective, and cost-efficient for public health. In industrial practice, Q3 evaluation of semi-solid formulations has evolved from a scientific regulatory concept into a core tool that spans research and development, manufacturing, and quality control. By systematically integrating Q1, Q2, and Q3 consistency assessments, this strategy enables precise control of key process parameters during manufacturing, establishes a real-time quality control system based on process analytical technology, and significantly reduces product development and lifecycle management costs. Drawing on industrial applications elucidates the practical value of Q3 evaluation in enhancing process robustness, optimising quality release protocols, and supporting global regulatory submissions, thereby providing a practice-oriented reference for the efficient development and lean manufacturing of semi-solid formulations.

Introduction

Semi-solid preparations are a vital category of topical pharmaceutical forms, with physical states lying between solid and liquid, typically including ointments, creams, gels, pastes, and suppositories. These formulations consist of Active Pharmaceutical Ingredients (APIs) combined with a suitable matrix that serves as a drug carrier. This matrix not only determines the formulation’s physical properties, such as consistency and spreadability, but also significantly influences the drug’s release rate, its ability to penetrate the skin or mucosal barrier, and the product’s chemical and physical stability. Their use has a long history, primarily for delivering drugs directly to specific areas of the body surface or cavities to achieve topical therapeutic effects, such as treating skin inflammation, infections, or joint pain. Some preparations are also designed to enable systemic absorption of the drug through the skin, producing systemic effects, such as nitroglycerin ointment. Because they act directly on the affected area, they often reduce systemic side effects and offer a more targeted dosing option [1, 2].

Semi-solid dosages are crucial in medical practice. They offer the most direct and effective route for topical delivery, allowing high drug concentrations to accumulate at the lesion site for rapid action while reducing exposure and side effects in other organs. This is especially important for drugs like corticosteroids, antibiotics, and local anesthetics. Additionally, these formulations address various clinical needs. For instance, the occlusive nature of ointments suits dry, hyperkeratotic skin lesions, the refreshing texture of creams works well for wet or oozing areas, and gels are more tolerable because of their water-soluble matrix and cooling effect. Moreover, for patients with dysphagia (such as children and the elderly), drugs with significant hepatic first-pass effects, or those needing continuous, sustained-release delivery, transdermal semi-solid dosages provide a safe, convenient, and non-invasive alternative, greatly enhancing medication adherence and quality of life [3, 4].

There is a fundamental difference between semi-solid preparations (e.g., ointments, creams), oral solid preparations (e.g., tablets, capsules), and liquid preparations (e.g., syrups, injections). In terms of administration routes, semi-solid dosage forms are mainly used for topical or transdermal application, whereas oral and injectable forms are designed for systemic therapy. Regarding drug absorption, oral preparations undergo complex processes of gastrointestinal absorption and hepatic metabolism, whereas injections deliver the drug directly into the bloodstream. The absorption of semi-solid dosages depends heavily on the drug’s ability to penetrate the multi-layered skin barrier, which is more complex and variable. More importantly, semi-solid dosage forms are not just simple drug solutions or mixtures but complex multiphase physicochemical systems. For example, a cream is an emulsion system (water-in-oil or oil-in-water). A gel is a polymer network structure, whose effectiveness depends not only on the drug itself but also on the microstructure of the matrix, rheological properties, and the physical state of the drug within the matrix (dissolved or dispersed), all of which influence the performance of the preparation. This differs significantly from tablets or solutions with relatively uniform composition [5, 6].

Semi-solid dosage forms are considered complex due to their multifaceted nature. First, there is the physicochemical complexity of the formulation: materials usually contain a variety of components, such as oil phase, aqueous phase, emulsifier, gel agent, permeation promoter, stabilizer, etc., and the interaction between these components creates a complex thermodynamic system that can be unstable or metastable (such as emulsion, liquid crystal, micelle). This system is susceptible to variations in the production process (e.g., mixing sequence, temperature, and shear rate), which can lead to significant differences in product texture, stability, or efficacy. Secondly, the complexity of quality evaluation arises from the fact that its effectiveness depends not only on drug content but also on the drug’s “release” and “skin permeation,” which are challenging to characterize using traditional content-determination methods. Finally, bioequivalence evaluation is complex: for locally acting semi-solid preparations, demonstrating that they have the same clinical efficacy (i.e., bioequivalence) as reference preparations cannot rely solely on in vivo blood concentration data. Instead, it requires a comprehensive assessment that includes external release, comparison of microstructural physicochemical properties (Q3), and potential human skin pharmacodynamic effects, making it far more complex than the requirements for oral solid preparations [7, 8].

The Q3 evaluation is based on the definition of “formulation quality attributes,” which explicitly requires a comprehensive assessment of the physicochemical and microstructural properties of semi-solid preparations. It extends beyond the traditional comparison of Q1 and Q2 to examine the formulation’s internal structure. Essentially, the Q3 evaluation aims to show that the imitation semi-solid preparation (Test) and the original reference formulation (Reference) not only share the same ingredients and content but also demonstrate a high degree of similarity in their internal physical structure, drug distribution within the matrix, and macroscopic properties. This involves a multi-dimensional comparative analysis centered on the principle that “structure determines performance.” If the microstructures of the two formulations are consistent, their expected in vivo effects—such as drug release and local bioavailability—are more likely to be similar. Therefore, the Q3 evaluation links the formulation process to final clinical efficacy and serves as the primary scientific method for assessing the similarity of semi-solid preparations [9, 10].

The Q3 evaluation is crucial for the research, regulation, and clinical use of semi-solid dosage forms. At the regulatory level, it provides the scientific basis for demonstrating the bioequivalence of generics and reference formulations in locally acting semi-solid preparations. Because traditional pharmacokinetic studies often cannot establish local bioequivalence, regulatory agencies such as the United States Food and Drug Administration (USFDA) and the Europe (EU) European Medicines Agency (EMA) require a comprehensive Q3 feature comparison as key evidence for approving generic drugs, thereby ensuring patients have access to alternatives that match the efficacy and safety of the original medication. For R&D companies, Q3 evaluation functions as a guiding tool for prescription development and process optimization. Through comparative analysis, essential differences between their products and target products can be identified, enabling adjustments to prescriptions and processes that are efficient, reduce the risk of R&D failure, and accelerate product launches. From a broader scientific perspective, Q3 evaluation promotes a deeper understanding of the performance of semi-solid dosage forms, advances analytical techniques, and supports the implementation of QbD, ultimately improving product quality and consistency across the industry [11, 12].

Q3 evaluation covers a series of key physicochemical and structural parameters, including the following: First, rheological properties are measured via viscosity, yield value, thixotropy, and viscoelastic moduli (G’, G’’) to characterize the texture, application, and feel of the preparation. These parameters are directly related to the formulation’s skin spreading behavior and patient compliance. Second, microstructure and morphology are observed using optical microscopy, polarized light microscopy, scanning electron microscopy (SEM), or atomic force microscopy (AFM) to examine the size, shape, and distribution of drug particles, as well as the crystal structure, globule size (for creams), and network structures (for gels) of the matrix. Third, the physical state of the drug in the matrix is determined using techniques such as differential scanning calorimetry (DSC), hot-stage microscopy (HSM), and X-ray powder diffraction (PXRD) to establish whether the drug is in an amorphous state, crystalline state, or solid solution form, which directly influences the drug’s solubility and release rate. Fourth, IVRT utilizes a diffusion cell to measure the rate of drug release from the formulation. It is one of the most relevant in vitro indicators for assessing product performance. Additionally, parameters such as particle size distribution (PSD) (for suspended preparations), pH, water content, and isomerism (polymorphism) are essential for comparison [13, 14].

Q3 evaluation mainly involves the characterization of appearance and texture, phase states, structural organization of matter, polymorphic form of the active ingredient, rheological behavior, water activity and/or drying rate, pH and buffering capacity, oleaginous components, specific gravity, and metamorphosis-related changes. The characterization of a topical product in Q3 involves delineating its physical, chemical, and structural attributes that are distinctive to that product. It provides a reference framework for arranging matter within the drug product. Q3 evaluations are instrumental in identifying the appropriate dosage form of a proposed generic (test) topical product. This characterization describes the essential attributes of a drug product that are potentially critical to its performance. A comparative assessment of Q3 attributes between the test product and the reference standard indicates the potential risk that differences may influence the respective bioavailability (BA) and/or bioequivalence (BE) of the two products. Conversely, demonstrating no significant differences in Q3 attributes between the test product and the reference standard substantially reduces the risk of BE failure modes attributable to such discrepancies [15, 16].

The Q3 evaluation primarily describes the dosage form and helps demonstrate bioequivalence (BE) for a semisolid dosage form, as shown in Fig. 1. Basic Q3 evaluations of a topical product help describe its dosage form, such as an emulsion. When these Q3 characterizations are performed on both the test product and the reference standard (RS), they confirm that the products share the same dosage form. To aid in demonstrating bioequivalence (BE), provide detailed Q3 attributes that precisely describe the product’s nature and the arrangement of matter that could influence the systemic or local availability of the active ingredient(s). A comprehensive Q3 comparison of the test topical product and the Reference Listed Drug (RLD) demonstrates no significant differences in Q3 attributes between the two products [17, 18].

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Shelke, O.S., Bankar, M.M. & Singh, P.K. A comprehensive industrial perspective on microstructural characterization and relation to bioequivalence of topical dosage forms. Discov. Chem. 3, 317 (2026). https://doi.org/10.1007/s44371-026-00768-5