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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.
Introduction to drug formulation types
Drug formulations are designed to meet diverse therapeutic needs, from immediate relief to sustained outcomes. The choice of formulation impacts the drug's efficacy, safety, and patient adherence, making it a crucial aspect of pharmaceutical development.
The drug formulations can be broadly categorized into several types. Click the + on each panel to see more information.
Sustained release drugs
- Tablets: Compressed powder forms of the drug that can be coated or uncoated. They may include immediate-release, extended-release, or enteric-coated versions to control the drug release rate.
- Capsules: Gelatin or hydroxypropyl methylcellulose (HPMC) shells filled with the drug in powder, granule, or liquid form. Capsules can be hard or soft, depending on their content and intended release characteristics.
- Lozenges and troches: Solid dosage forms that dissolve slowly in the mouth to provide localized or systemic effects.
Parenteral formulations
Parenteral formulations are sterile preparations intended for administration by injection, allowing for rapid and controlled drug delivery. They are further classified into:
- Intravenous (IV) injections: Direct administration of the drug into the bloodstream for immediate effect.
- Intramuscular (IM) injections: Injection into muscle tissue, providing a slower absorption rate compared to IV.
- Subcutaneous (SC) injections: Injection into the subcutaneous tissue, offering a slower and more sustained release of the drug.
- Intrathecal and epidural injections: Administration into the spinal canal or epidural space for targeted effects on the central nervous system.
Oral liquid formulations
These are pharmaceutical preparations designed for administration by mouth in a liquid form. It includes solutions, suspensions, and emulsions, each tailored to optimize the delivery and absorption of active ingredients. Oral liquids can provide more precise dosing and faster onset of action compared to solid dosage forms.
Cutaneous drug formulations
Pharmaceutical preparations designed for application on the skin to deliver therapeutic agents either locally or systemically. These formulations are tailored to treat a variety of skin conditions, provide symptomatic relief, or deliver drugs through the skin barrier into the systemic circulation.
- Creams: Semi-solid emulsions of oil and water that are easy to spread and absorb into the skin.
- Ointments: Greasy, semi-solid preparations that provide a protective barrier and are used for their occlusive properties.
- Gels: Transparent or translucent formulations that are typically water-based and provide a cooling effect upon application.
- Lotions: Low-viscosity, liquid formulations that are easy to spread over large areas of the skin.
- Patches: Adhesive preparations that deliver drugs through the skin into the systemic circulation over an extended period.
- Foams: Light, airy preparations that are easy to apply and spread, often used for their aesthetic appeal and convenience.
Inhalation formulations
Inhalation formulations are designed for delivery to the respiratory system, providing rapid onset of action for respiratory conditions.
- Metered-dose inhalers (MDIs): Pressurized canisters that deliver a specific dose of the drug as an aerosol.
- Dry powder inhalers (DPIs): Devices that deliver the drug in a dry powder form, activated by the patient's inhalation.
- Nebulizers: Devices that convert liquid formulations into a fine mist for inhalation, often used in hospital settings.
Transdermal patches
Adhesive patches that are designed for systemic delivery of the drug through the skin, providing a controlled release into the bloodstream over an extended period
Critical quality attributes of drug formulations
To ensure optimal performance and patient-friendly dosage forms, drug formulations are carefully optimized and evaluated on various parameters such as API concentration, pH, excipients, and particle size. They can influence the drug’s efficacy, safety, and stability, including its physicochemical properties and bioavailability. Drug formulation optimization is essential for meeting regulatory requirements and ensuring consistent manufacturing quality. Changes in the final product resulting from drug formulation optimization are measured as critical quality attributes (CQAs).
CQAs include key parameters such as morphology, drug stability, release profile, and more, which must be carefully controlled during formulation. For example, oral formulations like tablets and capsules must meet strict dissolution and disintegration criteria for proper absorption in the gastrointestinal tract. Inhalation formulations require precise particle size distribution for effective delivery to the respiratory tract. Transdermal systems need consistent adhesive properties and controlled drug release rates for sustained therapeutic effects. By aligning drug formulations with these CQAs, pharmaceutical scientists can create medications that meet regulatory standards and provide optimal therapeutic outcomes for patients.
Commonly measured CQAs of drug formulations
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. |
Drug formulation characterization techniques
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 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.
Advanced SEM and FIB-SEM characterization techniques
Scanning electron microscopy (SEM) and focused ion beam scanning electron microscopy (FIB-SEM) have emerged as pivotal tools for characterizing drug formulations, offering greater resolution and depth of analysis than other techniques. These techniques provide micro-to-nano-scale information on drug formulations, including particle size and morphology analysis, porosity analysis, drug excipient interactions, and much more.
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).
Figure 1: Electron micrographs showing the morphology of porous (PLA, PLGA 75:25, PLGA 50:50) hollow (PCL 14 kDa) and non-porous (PCL 80 kDa) microspheres obtained using different polymers and molecular weights. Image adopted from Amoyav and Benny, 2019.
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.
Electron microscopes for drug formulation characterization
Advanced imaging techniques such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), focused ion beam scanning electron microscopy (FIB-SEM), and cryo-electron tomography (cryo-ET) offer detailed insights into the structural and morphological properties of drug delivery vehicles at the nanoscale, enabling precise analysis and optimization of formulations. With electron microscopy, researchers can achieve a deeper understanding of the efficacy, safety, and stability of various formulations.
Thermo Scientific SEMs, FIB-SEMs, and TEMs offer innovative features and technology designed to extend accessibility, reduce the need for user intervention, and help you easily organize, view, and share data.
Resources
Header image adapted from Amoyav B and Benny O. Polymers 11:3 (2019). doi: 10.3390/polym11030419
For Research Use Only. Not for use in diagnostic procedures.