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Drug formulations in pharmaceutical science
Drug formulations are a critical aspect of pharmaceutical science, encompassing the various forms in which medications are prepared and administered to achieve optimal therapeutic effects. The design and development of these formulations are guided by a complex interplay of factors, including the physicochemical properties of the active pharmaceutical ingredient (API), the intended route of administration, patient compliance, and the desired release profile. Electron microscopy makes it possible to characterize a variety of attributes in drug formulations to help ensure quality and efficacy.
Drug formulation types
Different types of drug formulations are crafted to meet diverse therapeutic requirements, ranging from immediate relief to sustained therapeutic outcomes. Each type of drug formulation is meticulously developed to address specific medical needs and improve patient outcomes. The drug formulations can be broadly categorized into several types as follows:
The choice of formulation significantly impacts the drug's efficacy, safety, and patient adherence, making it a fundamental consideration in the pharmaceutical development process. To improve performance of the drug and provide it in patient-friendly dosage forms, the drug formulations are optimized and evaluated on several parameters as discussed below.
The need for drug formulation optimization arises from the complex interplay of various factors that influence the performance of a drug, including its physicochemical properties, stability, bioavailability, and patient compliance. Drug formulation optimization is also essential for meeting regulatory requirements and ensuring consistent manufacturing quality. It involves rigorous testing and validation to ensure that each batch of the product meets predefined quality standards, thereby guaranteeing that patients receive a safe and effective medication every time.
For the optimization of drug formulations, several parameters including API concentration, pH, excipients, particle size, process parameters (mixing time, temperature, and pressure during the manufacturing process), and stabilizers are varied (See Table 1). Each of these parameters can significantly impact the final product's efficacy, safety, and stability, and therefore careful analysis of the formulations is necessary. Changes in the final product resulting from drug formulation optimization are measured as critical quality attributes (CQAs).
Critical quality attributes of drug formulations
CQAs encompass essential parameters such as morphology, drug stability, release profile, and patient acceptability, all of which must be meticulously controlled throughout the formulation process. For example, oral formulations like tablets and capsules must meet stringent dissolution and disintegration criteria to ensure proper absorption in the gastrointestinal tract. Inhalation formulations need precise particle size distribution for efficient delivery to the respiratory tract. Transdermal systems must exhibit consistent adhesive properties and controlled drug release rates to provide sustained therapeutic effects. By aligning the choice of drug formulation with these critical quality attributes, pharmaceutical scientists can design medications that not only meet regulatory standards but also deliver optimal therapeutic outcomes for patients. Commonly measured CQAs of drug formulations are:
Table 1. List of critical quality attributes (CQAs) and description of the information obtained from them.
| CQA | Description |
| Purity | The degree to which the drug substance is free from impurities, contaminants, or unwanted components. |
| Particle size distribution, morphology and aggregation | The size range and distribution of particles in the formulation, which can affect dissolution, absorption, and stability. |
| Polymorphism and crystalline/amorphous nature | Whether the API in given drug forms crystals or is amorphous. |
| Surface charge | Often quantified as zeta potential, it influences various properties of the formulation, including stability, bioavailability, and interaction with biological systems. |
| Porosity | It is a measure of void spaces (pores) within a material and can significantly influence the drug's performance, stability, and manufacturability. |
| Entrapment efficiency/potency | The strength or concentration of the active pharmaceutical ingredient (API) in the formulation. |
| Stability | The ability of the drug formulation to maintain its physical, chemical, and therapeutic properties over time under specified storage conditions. |
| Solubility | The speed at which the drug dissolves in the gastrointestinal fluids, which directly impacts its absorption and bioavailability. |
| Content uniformity/uniformity of dosage | Ensuring that each dosage unit (e.g., tablet, capsule) contains the same amount of API within specified limits. |
| Elemental analysis | It is the quantitative and qualitative determination of elemental composition, including the presence of heavy metals, residual catalysts, and other trace elements that could impact the drug's quality and safety. |
| Release profile | The pattern and rate at which the active ingredient is released from the formulation over time. |
| Viscosity | The thickness or resistance to flow of liquid formulations, which can influence the ease of administration and consistency of dosing. |
| pH | The acidity or alkalinity of the formulation, which can affect drug stability, solubility, and absorption. |
| Appearance | The physical characteristics of the formulation, including color, shape, and texture which can affect patient acceptance and compliance. |
Each of these CQAs play a crucial role in ensuring that the drug formulation meets the required standards for safety, efficacy, and quality, ultimately contributing to successful therapeutic outcomes. A variety of techniques including Raman spectroscopy (RS), high-performance liquid chromatography (HPLC), ultraviolet-visible (UV-Vis) spectroscopy, Fourier-transform infrared spectroscopy (FTIR), mercury intrusion porosimetry (MIP), dynamic light scattering (DLS), and electron microscopy (EM) are widely used for drug formulation characterization (See Table 2). While each analytical technique has its unique strengths and applications, EM stands out for its ability to provide high-resolution, three-dimensional images and detailed surface morphology, making it an invaluable tool for assessing the CQAs of drug formulations. Its versatility and capability for elemental analysis further enhance its utility in ensuring the quality and consistency of pharmaceutical products.
Table 2. List of critical quality attributes (CQAs) and the techniques that can provide relevant information. A combination of Raman spectroscopy, Fourier-transform infrared spectroscopy (FTIR) and electron microscopy can be used to analyze and confirm the structure, composition and properties of drug formulations and hence are referred to as correlative workflows here. [Abbreviations: laser diffraction (LD), dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), multiangle light scattering (MALS), atomic force microscopy (AFM), ultraviolet-visible spectroscopy (UV/VIS), high-performance liquid chromatography (HPLC), near-infrared spectroscopy (NIR), Raman spectroscopy (RS), microcrystal electron diffraction (μED), X-ray diffraction (XRD), diffraction scanning calorimetry (DSC), dynamic vapor sorption (DVS), Fourier-transform infrared spectroscopy (FTIR), Zeta potential (ZP), Franz diffusion (FD), reversed-phase HPLC (RP-HPLC), mercury intrusion porosimetry (MIP), phase-contrast computed tomography (PCCT), micro computed tomography (μCT), computed tomography (CT), scanning electron microscopy (SEM), transmission electron microscopy (TEM), focused ion beam SEM (FIB-SEM), electron cryotomography (CryoET)].
Scanning electron microscopy for drug formulation characterization
Scanning electron microscopy (SEM) has emerged as a pivotal tool in the characterization of drug formulations, offering unparalleled resolution and depth of analysis. The primary applications of SEM in this field, as documented in various research articles, encompass several key areas:
Particle size and morphology analysis
Accurate particle size distribution is crucial for drug solubility, bioavailability, and stability. SEM is widely used to assess the size, shape, surface characteristics, aggregation states and surface morphology of drug particles and excipients (Figure 1).
Polymorphism and crystallinity
The polymorphic form of a drug influences its solubility and dissolution rate. EM techniques enable the identification and differentiation of crystalline and amorphous regions in drug formulations. This is vital for ensuring consistency and efficacy in pharmaceutical products (Figure 2).
Porosity analysis
Invasive electron microscopy techniques such as focused ion beam (FIB) milling are useful for preparation of clean cross-sections of the sample. By imaging cross-sections of the drug formulation, SEM allows for the visualization of internal porosity. This can include the size, shape, distribution, and connectivity of pores within the matrix (Figure 2 and 3).
Drug excipient interactions
FIB-SEM can reveal the physical integration and compatibility of different components within complex formulations. The drug and excipient interactions can affect the stability and performance of the final product (Figure 3).
Figure 2: SEM images of IPM-loaded intact (a, c) and FIB-milled (b, d) microcapsules. Particles exhibit spherical morphology with small crystals (red arrows) visible on their surface. Cross sections of the particle prepared by FIB milling show multicore structures. Pores can be differentiated from the matrix due to the differences in the grey value. Image modified from Janich et al., 2019.
Surface chemistry and elemental analysis
Energy-Dispersive X-ray Spectroscopy (EDS) coupled with SEM is employed to analyze the elemental composition of drug formulations. This is essential for detecting impurities, verifying the presence of active pharmaceutical ingredients (APIs), and understanding the distribution of elements within the formulation matrix.
Drug stability studies
EM plays a role in stability studies by monitoring changes in the morphology and structure of drug formulations over time under various storage conditions. This helps in predicting shelf-life and ensuring long-term efficacy and safety
Bioavailability and drug release mechanisms
By examining the microstructure of drug delivery systems, SEM can provide insights into the mechanisms of drug release and absorption. This information is critical for designing formulations with controlled release profiles to improve therapeutic outcomes.
Figure 3: High-resolution visualization of topological features and internal changes in PLGA microspheres during levofloxacin release and particle degradation in the release medium. Initially (day 0), the particles display a spherical morphology with a smooth surface and occasional pores (red arrows). Extended incubation (1-5 days) in the release medium leads to polymer degradation and drug release, resulting in collapsed particles. FIB-milling reveals cross-sections of the particles, highlighting changes in polymer matrix organization over time. The cross-sectional views show the development of cavities within the pores (yellow arrows), with cavity and pore sizes increasing with incubation duration. Figure adapted from Agnoletti et al.,2020.
In conclusion, electron microscopy offers a comprehensive suite of techniques for the detailed characterization of drug formulations. Its ability to provide high-resolution images and elemental analysis makes it an invaluable tool in pharmaceutical research and development. The application of EM in drug formulation characterization facilitates the design of more effective, stable, and safe pharmaceutical products, ultimately enhancing patient care.
Drug formulation and drug characterization references
1. Janich, C., Friedmann, A., Souza e Silva, J. M., et al., Risperidone-Loaded PLGA–Lipid Particles with Improved Release Kinetics: Manufacturing and Detailed Characterization by Electron Microscopy and Nano-CT. Pharmaceutics 2019, 11(12), 665; https://doi.org/10.3390/pharmaceutics11120665.
2. Amoyav, B., and Benny, O., Microfluidic Based Fabrication and Characterization of Highly Porous Polymeric Microspheres. Polymers 2019, 11(3), 419; https://doi.org/10.3390/polym11030419.
3. Agnoletti, M., Rodríguez-Rodríguez, C., Kłodzińska, S. N., et al., Monosized Polymeric Microspheres Designed for Passive Lung Targeting: Biodistribution and Pharmacokinetics after Intravenous Administration. ACS Nano 2020, 14(6), 6693-6706; https://pubs.acs.org/doi/abs/10.1021/acsnano.9b09773.
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