HPLC vs. GC: Key Differences, Applications, and Advantages
June 6, 2025
When it comes to chromatography, high-performance liquid chromatography (HPLC) and gas chromatography (GC) are two of the most widely used techniques in analytical laboratories. Both methods are essential for separating, identifying, and quantifying compounds in various industries, from pharmaceuticals to environmental testing.
While they share the same basic principles of chromatography, HPLC and GC differ in several key areas, including the types of samples they can analyze, the mechanisms they use for separation, and their overall applications.
In this article, we’ll focus on the fundamental differences between HPLC and GC, examine their unique advantages, and help you determine which technique is best suited for your specific analysis needs.
What Is Gas Chromatography Used For?
Gas chromatography is a technique primarily used to separate and analyze organic compounds, especially volatile substances, by passing them through a column with a carrier gas such as helium, hydrogen or nitrogen.
It is a primary analytical method used across various industries, including pharmaceuticals, environmental monitoring, and forensic toxicology, to separate and analyze different constituents of mixtures using a mobile gas phase over a stationary adsorbent. The GC technique includes gas-liquid chromatography (GLC) (the most common) used for for qualitative and quantitative analysis of volatiles and semi volatiles compounds and gas-solid chromatography (GSC) for separating and determining the concentration permanent gases and low-boiling hydrocarbons.
Gas chromatography is often coupled with mass spectrometry (GC-MS) to identify compounds by comparing fragmentation patterns or with a flame ionization detector (GC-FID) to separate and quantify specific chemical constituents.
GC Chromatography is the preferred technique for chemical analysis across multiple industries (environmental, agriculture, petrochemicals, food, forensics and toxicology). Its versatility, reliability, sensitivity, and ability to provide rapid analysis make gas chromatography an invaluable tool in both research and industrial applications.
What is High-Performance Liquid Chromatography Used For?
High-performance liquid chromatography (HPLC) is an analytical technique that uses narrow columns to separate and analyze liquid samples usually at ambient temperatures under high pressure. Detection methods such as ultraviolet absorption and mass spectrometry can help identify and quantify small amounts of solutes in the samples.
HPLC is a versatile and cost-effective analytical technique used for the quantification and separation of components in mixtures. It is widely employed for detecting and quantifying drugs of abuse in various biological matrices, such as urine and blood, due to its high sensitivity and efficiency in separating complex mixtures.
The HPLC technique is especially valuable for evaluating pharmaceuticals API’s and their impurities, analyzing synthetic polymers, monitoring environmental pollution, testing water, and separating analytes from complex matrices such as food or clinical matrices. It offers high precision and can perform quantitative analyses without any solvent peak in the chromatogram. One example, when compared to GC, HPLC is favored for analyzing high concentrations of explosives because it avoids complications linked to the use of elevated temperatures that are required when performing GC analysis.
HPLC has emerged as a powerful analytical method for efficiently monitoring water contaminants due to its sensitivity, specificity, and cost-effectiveness, surpassing traditional GC in many applications.
HPLC vs. GC: Comparison
HPLC and GC are both widely used techniques in analytical chemistry, both having a set of advantages and disadvantages. Both can be ideal according to their unique specifications for specific applications. Here are the factors to be considered when comparing GC vs. HPLC.
Operating Temperature
HPLC is used for analyzing non-volatile substances and works at an ambient temperature of about 20 - 40°C. It can be operated up to 90°C in some modality like Ion-exclusion, while GC works at 150 - 300°C to facilitate volatilization of samples. Such high temperatures can lead to the degradation of sensitive compounds; hence, the need for proper care.
Ultra low temperature high-performance liquid chromatography (HPLC) effectively separates low molecular weight alkanes at -196 °C using a liquefied nitrogen mobile phase. In contrast, GC faces challenges in eluting the same analytes due to strong adsorption under similar conditions.
Nature of Compounds
HPLC is tailored for analyzing non-volatile and thermally unstable biomolecules, making it ideal for more significant compounds like amino acids, proteins, and drugs in liquid samples.
In contrast, GC focuses on volatile organic compounds, such as gases and low-boiling substances, utilizing an inert carrier gas as the mobile phase. While it excels at separating small analytes like steroids and lipids, handling thermally unstable compounds may be challenging due to the high temperatures required for vaporization.
Column Dimensions
In HPLC, column dimensions can vary widely depending on the application. Conventional analytical columns typically range from 5 to 30 cm in length with internal diameters between 2 and 5 mm. However, micro- and nano-scale HPLC columns, with internal diameters as small as 75 µm, are also commonly used in specialized applications such as proteomics, where high sensitivity and low sample volume are critical.
In GC, column dimensions vary significantly depending on the type used. Modern capillary GC columns are typically 15 to 105 meters in length with an internal diameter ranging from 0.1 mm to 0.53 mm. These columns are coated with a stationary phase along the inner wall (in Wall-Coated Open Tubular columns) or contain a thin layer of support material (in Support-Coated Open Tubular columns).
In contrast, older packed GC columns are much shorter, usually 0.5 to 3 meters in length, with internal diameters greater than 2 mm. These are filled with adsorbent particles typically sized 100–250 μm and are now used in only a small fraction of applications, such as gas analysis or legacy systems.
Peak Shape
HPLC produces sharp and symmetrical peaks, indicating good separation efficiency and resolution. Factors like flow rate, column packing, and mobile phase composition can influence the peak shape.
Capillary gas chromatography (GC) typically produces much narrower and sharper peaks than high-performance liquid chromatography (HPLC), due to its higher efficiency—especially for volatile compounds—making it well-suited for precise quantification. However, peak broadening can still occur in GC under certain conditions, such as column overload, temperature fluctuations, or sample–stationary phase interactions.
Detection Principles
HPLC employs various detection techniques like mass spectrometry (MS), ultraviolet absorption, fluorescence, and electrochemical methods. The introduction of MS enhances detection at low concentrations without prior isolation. HPLC detectors respond to specific physicochemical properties—such as light absorbance, refractive index, or fluorescence—as analytes pass through after chromatographic separation.
GC combined with MS or Flame Ionization Detectors (FID) can be used for efficient detection. GC detectors generally respond to physical or chemical changes—such as ionization, conductivity, or electron capture—as volatile analytes exit the column.
Speed
HPLC can take 10-60 mins to analyze a mixture, while GC takes a few minutes to seconds due to the efficient vaporization of volatile gases. The time will vary according to the length of the GC column.
Cost of Operation
HPLC tends to be more expensive than GC due to the need for high-pressure pumps, costly solvents, specialized columns, and a more complex, maintenance-intensive setup.
In contrast, GC requires long and thin columns and can utilize inexpensive inert gases like nitrogen, incurring low operational costs. The maintenance cost is also not so high.
FAQs
What is HPLC, and what is its principle?
High-performance liquid chromatography (HPLC) is an advanced analytical technique used for the separation, identification, and quantification of components in liquid samples. HPLC operates by injecting liquid samples into a column packed with stationary phase particles that can be polymer-based or silica-based.
A liquid mobile phase is then pumped through the column under high pressure, carrying the sample components. As these components interact with the stationary phase, they are separated based on their solubility and affinity and are then detected by the detector, allowing for quantitative and qualitative analysis.
What are the common mobile phases used in HPLC?
Common mobile phases used in HPLC include a variety of solvents that enhance separation based on the nature of the analytes. Typically, polar solvents such as water and methanol are used for separating polar compounds, while non-polar solvents like hexane and acetonitrile are preferred for non-polar analytes.
The choice of the mobile phase is critical, as it influences the retention and resolution of components in the sample, thereby optimizing the separation process for different applications, including pharmaceuticals and environmental analysis.
What is the operating principle of GC?
Gas chromatography (GC) operates on the principle of partitioning volatile compounds between a stationary phase and a mobile phase, where the mobile phase is an inert gas such as helium or nitrogen. As a sample is introduced into the GC system, it vaporizes and is carried by mobile gas through a column packed with a stationary phase, usually a liquid coated on solid particles.
The various components of the sample are separated based on their differing volatilities and interactions with the stationary phase, resulting in distinct retention times that allow for the identification and quantification of individual analytes when they exit the column and are detected by devices like mass spectrometry or flame ionization detectors.
