Total organic carbon (TOC) is the amount of carbon bound in an organic compound and is often used as a non-specific indicator of water quality or cleanliness of pharmaceutical manufacturing equipment.
A typical analysis for TOC measures both the total carbon present as well as the inorganic carbon (IC). Subtracting the inorganic carbon from the total carbon yields TOC. Another common variant of TOC analysis involves removing the IC portion first and then measuring the leftover carbon. This method involves purging an acidified sample with carbon-free air or nitrogen prior to measurement, and so is more accurately called non-purgeable organic carbon (NPOC).
Introduction of organic matter into water systems occurs not only from living organisms and from decaying matter in source water, but also from purification and distribution system materials. A relationship may exist between endotoxins, microbial growth, and the development of biofilms on pipeline walls and biofilm growth within pharmaceutical distribution systems. A correlation is believed to exist between TOC concentrations and the levels of endotoxins and microbes. Sustaining low TOC levels helps to control levels of endotoxins and microbes and thereby the development of biofilm growth. The United States Pharmacopoeia (USP), European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP) recognize TOC as a required test for purified water and water for injection (WFI). For this reason, TOC has found acceptance as a process control attribute in the biotechnology industry to monitor the performance of unit operations comprising purification and distribution systems. As many of these biotechnology operations include the preparation of medicines, the Food, Drug Administration (FDA) enacts numerous regulations to protect the health of the public and ensure the product quality is maintained. To make sure there is no cross contamination between product runs of different drugs, various cleaning procedures are performed. TOC concentration levels are used to track the success of these cleaning validation procedures especially clean-in-place (CIP).
To understand the analysis process better, some key basic terminologies should be understood and their relationships to one another (Figure 1).
Total Carbon (TC) – all the carbon in the sample, including both inorganic and organic carbon
Total Organic Carbon (TOC) – material derived from decaying vegetation, bacterial growth, and metabolic activities of living organisms or chemicals.
Non-Purgeable Organic Carbon (NPOC) – commonly referred to as TOC; organic carbon remaining in an acidified sample after purging the sample with gas.
Purgeable (volatile) Organic Carbon (POC) – organic carbon that has been removed from a neutral , or acidified sample by purging with an inert gas. These are the same compounds referred to as Volatile Organic Compounds (VOC) and usually determined by Purge and Trap Gas Chromatography.
Dissolved Organic Carbon (DOC) – organic carbon remaining in a sample after filtering the sample, typically using a 0.45 micrometer filter.
Suspended Organic Carbon – also called particulate organic carbon (PtOC); the carbon in particulate form that is too large to pass through a filter.
Since all TOC analyzers only actually measure total carbon, TOC analysis always requires some accounting for the inorganic carbon that is always present. One analysis technique involves a two-stage process commonly referred to as TC-IC. It measures the amount of inorganic carbon (IC) evolved from an acidified aliquot of a sample and also the amount of total carbon (TC) present in the sample. TOC is calculated by subtraction of the IC value from the TC the sample. Another variant employs acidification of the sample to evolve carbon dioxide and measuring it as inorganic carbon (IC), then oxidizing and measuring the remaining non-purgeable organic carbon (NPOC). This is called TIC-NPOC analysis. A more common method directly measures TOC in the sample by again acidifying the sample it to a pH value of two or less to release the IC gas but in this case to the air not for measurement. The remaining non-purgeable CO2 gas (NPOC)contained in the liquid aliquot is then oxidized releasing the gases. These gases are then sent to the detector for measurement.
Whether the analysis of TOC is by TC-IC or NPOC methods, it may be broken into three main stages:
The first stage is acidification of the sample for the removal of the IC and POC gases. The release of these gases to the detector for measurement or to the air is dependent upon which type of analysis is of interest, the former for TC-IC and the latter for TOC (NPOC).
Prepared samples are combusted at 1,350o C in an oxygen rich atmosphere. All carbon present converts to carbon dioxide, flows through scrubber tubes to remove interferences such as chlorine gas, and water vapor, and the carbon dioxide is measured either by absorption into a strong base then weighed, or using an Infrared Detector. Most modern analyzers use non-dispersive infrared (NDIR) for detection of the carbon dioxide.
Oxidation of the sample is complete after injection into the furnace, turning oxidizable material in the sample into gaseous form. A carbon-free carrier gas transports the CO2, through a moisture trap and halide scrubbers to remove water vapor and halides from the gas stream before it reaches the detector. These substances can interfere with the detection of the CO2 gas. The HTCO method may be useful in those applications where difficult to oxidize compounds, or high molecular weight organics, are present as it provides almost complete oxidation of organics including solids and particulates small enough to be injected into the furnace. The major drawback of HTCO analysis is its unstable baseline resulting from the gradual accumulation of non-volatile residues within the combustion tube. These residues continuously change “TOC” background levels requiring continuous background correction. Because aqueous samples are injected directly into a very hot , usually quartz, furnace only small aliquots (less than 2 milliliters and usually less than 400 micro-liters) of sample can be handled making the methods less sensitive than chemical oxidation methods capable of digesting as much as 10 times more sample. Also, the salt content of the samples do not combust, and so therefore, gradually build a residue inside the combustion tube eventually clogging the catalyst resulting in poor peak shapes, and degraded accuracy or precision.
In this oxidation scheme, ultra-violet light alone oxidizes the carbon within the sample to produce CO2. The UV oxidation method offers the most reliable, low maintenance method of analyzing TOC in ultra-pure waters.
The UV/chemical oxidation method offers a relatively low maintenance, high sensitivity method for a wide range of applications. However, there are oxidation limitations of this method. Limitations include the inaccuracies associated with the addition of any foreign substance into the analyte and samples with high amounts of particulates. By performing "System Blanks", which is to analyze then subtract the amount of carbon contributed by the chemical additive, helps lower inaccuracies but analyses in levels below 200 ppb TOC are still difficult.
Also known as heated persulfate, the method utilizes the same free radical formation as UV persulfate oxidation except uses heat to magnify the oxidizing power of persulfate. Chemical oxidation of carbon with a strong oxidizer, such as persulfate, is highly efficient, and unlike UV, is not susceptible to lower recoveries caused by turbidity in samples. The analysis of system blanks, necessary in all chemical procedures, is especially necessary with heated persulfate TOC methods because the method is so sensitive that reagents cannot be prepared with carbon contents low enough to not be detected. Persulfate methods are used in the analysis of wastewater, drinking water, and pharmaceutical waters. When used in conjunction with sensitive NDIR detectors heated persulfate TOC instruments readily measure TOC at single digit parts per billion(ppb) up to hundreds of parts per million(ppm) depending on sample volumes.
Accurate detection and quantification are the most vital components of the TOC analysis process. Conductivity and non-dispersive infrared (NDIR) are the two common detection methods used in modern TOC analyzers.
The non-dispersive infrared analysis (NDIR) method offers the only practical interference-free method for detecting CO2 in TOC analysis. The principal advantage of using NDIR is that it directly and specifically measures the CO2 generated by oxidation of the organic carbon in the oxidation reactor, rather than relying on a measurement of a secondary, corrected effect, such as used in conductivity measurements.
A traditional NDIR detector relies upon flow-through-cell technology, the oxidation product flows into and out of the detector continuously. A region of adsorption of infrared light specific to CO2, usually around 4.26 µm (2350 cm-1), is measured over time as the gas flows through the detector. The infrared absorption spectra of CO2 and other gases is shown in Figure 3. A second reference measurement that is non-specific to CO2 is also taken and the differential result correlates to the CO2 concentration in the detector at that moment. As the gas continues to flow into and out of the detector cell the sum of the measurements results in a peak that is integrated and correlated to the total CO2 concentration in the sample aliquot.
Recent Advances in NDIR Technology
A new advance of NDIR technology is Static Pressurized Concentration (SPC).
The exit valve of the NDIR is closed to allow the detector to become pressurized. Once the gases in the detector have reached equilibrium, the concentration of the CO2 is analyzed. This pressurization of the sample gas stream in the NDIR, a patent-pending technique, allows for increased sensitivity and precision by measuring the entirety of the oxidation products of the sample in one reading, compared to flow-through cell technology. The output signal is proportional to the concentration of CO2 in the carrier gas, from the oxidation of the sample aliquot. UV/ Persulfate oxidation combined with NDIR detection provides good oxidation of organics, low instrument maintenance, good precision at ppb levels, relatively fast sample analysis time and easily accommodates multiple applications, including purified water (PW), water for injection (WFI), CIP, drinking water and ultra-pure water analyses.
A total organic carbon analyzer determines the amount of carbon in a water sample. By acidifying the sample and flushing with nitrogen or helium the sample removes inorganic carbon, leaving only organic carbon sources for measurement. There are two types of analyzers. One uses combustion and the other chemical oxidation. This is used as a water purity test, as the presence of bacteria introduces organic carbon.
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3- ↔ 2H+ + CO32-
This is then sent to a detector for measurement. The other half of the sample is injected into a combustion chamber which is raised to between 600–700°C, some even up to 1200°C. Here, all the carbon reacts with oxygen, forming carbon dioxide. It's then flushed into a cooling chamber, and finally into the detector. Usually, the detector used is a non-dispersive infrared spectrophotometer. By finding the total inorganic carbon and subtracting it from the total carbon content, the amount of organic carbon is determined.
TOC detection is an important measurement because of the effects it may have on the environment, human health, and manufacturing processes. TOC is a highly sensitive, non-specific measurement of all organics present in a sample. It, therefore, can be used to regulate the organic chemical discharge to the environment in a manufacturing plant. In addition, low TOC can confirm the absence of potentially harmful organic chemicals in water used to manufacture pharmaceutical products. TOC is also of interest in the field of potable water purification due to disinfection of byproducts. Inorganic carbon poses little to no threat.
N1: K2Cr2O7 normality
V1: K2Cr2O7 volume (mL)
V2: FeSO4 volume (mL)
Organic carbon percentage:
A: meq K2Cr2O7 = (mL K2Cr2O7 x N K2Cr2O7)
B: meq FeSO4•7H2O = (mL FeSO4•7H2O x N FeSO4•7H2O)
C: grams of sample
0.3: Conversion factor to carbon weight, We have milliequivalents as result of the difference between A and B, and they need to be converted to carbon milliequivalents in order to get the units we need, for that it is necessary to do the next operation:
Eq.3 The 0.3 conversion factor has units of carbon grams and involves the constant to convert a fraction to percent units; hence equation 2 does not have the factor 100. Walkey-Black constant for sediments. 75% is the mean recuperation of carbon in solids and sediments by using this method, that's why the final result has to be multiplied by 1.33 in order to get the real value, this constant is not used when determining carbon in KHP standard because almost all its carbon content is recovered.
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