Table of Contents
What is High-purity?
Purity can be defined as the state or quality of being pure, i.e., the state of not being mixed with anything else (free from adulteration) and being homogenous or uniform in composition. There is no one definition of what levels of purity correlate to “high purity” which is universally acknowledged by everyone.
There are many aspects of purity. Depending on the application (end use), one or more of the below parameters can play a vital role in determining the purity of a chemical compound. Purity can be in terms of the following-
- Organic impurities present in an organic molecule
- Solvate/hydrate form
- The crystalline structure
- Inorganic and elemental impurities (heavy metal impurities) present
- Volatile substances present in the chemical compound
- Residual solvents used in the manufacturing process being remained in the compound
- Particle size distribution (PSD)
- Morphology/shape of the particles
Where high-purity chemicals are used ?
The major industries/fields where high-purity chemicals are generally used include Aerospace, Electronics, Pharmaceuticals, Specialty materials, Biopharmaceutical, Research and development, Food and cosmetic industries, Diagnostics, Analytical Laboratories, Clinical Laboratories etc.
Types of Impurities
According to the ICH (International Council for Harmonization), impurities can be categorized as follows-
Organic impurities are frequently drug-related or process-related impurities found in chemical products and are more likely to be introduced into the substance during the manufacturing, purification, or storage processes. They could be identifiable or unidentifiable, volatile or inert. Examples include –
- Impurities in Starting Materials
- Impurities in By-products
- Impurities in Intermediates
- Degradation Products formed during synthesis or storage
- Reagents, Ligands & Catalysts remained in the final product
Furthermore, organic impurities can be categorized according to their toxicity potential, as follows-
Mutagenic/Genotoxic Impurities: Impurities that have a potential to cause mutation (a change in the DNA of a cell) or direct DNA damage comes under this category.
Carcinogenic Impurities: Impurities that are capable of causing cancer are referred to as Carcinogenic impurities or Carcinogens. A few well-known carcinogens are asbestos, nickel, cadmium, radon, vinyl chloride, benzidene, and benzene.
Nitrosamine Impurities: Nitrosamines, also referred to more accurately as N-nitrosoamines, are any molecules that have the nitroso functional group present in them. These compounds are of significant concern since nitrosamine impurities are likely carcinogenic to humans.
Inorganic impurities are typically detected and quantified using pharmacopeial or other appropriate standards and are derived from excipients and manufacturing processes. The most prevalent types of inorganic impurities are-
- Heavy Metals or other Residual Metals
- Inorganic Salts
- Reagents, Ligands & Catalysts
- Filter Aids, Charcoal & Other materials
These impurities are residuals of solvents involved in the production process. Even in extremely minute quantities, the presence of these unintended substances can have a negative impact on the effectiveness and safety of the finished product. The existence of residual solvents has the potential to alter the characteristics of the substance, including its color, crystalline nature, and dissolution characteristics.
Analytical techniques used to detect impurities
Thin Layer Chromatography (TLC)
Thin layer chromatography (TLC) is an affinity-based method used to separate compounds in a mixture. It is a separation technique based on differential partitioning of compounds between a solid surface, coated with a thin layer of an adsorbent material (silica gel, aluminium oxide (alumina), or cellulose) known as stationary phase, and a solvent or solvent mixture, known as the mobile phase.
Principle – TLC is based on the principle of separation through adsorption. The separation is dependent on the relative affinity of chemicals to both phases. Compounds in the mobile phase travel across the surface of the stationary phase. Compounds with a greater affinity for the stationary phase move more slowly than other compounds. Hence, the mixture gets separated. At the conclusion of the separation procedure, the separate components of the mixture emerge on the plates as spots at their respective levels, which are then identified and characterized using suitable techniques. Thus, it helps to detect the foreign constituent (impurity) present in the sample.
High Performance Thin Layer Chromatography (HPTLC)
HPTLC is an improved, automated and sophisticated version of the TLC to boost the achieved resolution and enable more precise quantitative measurements.
High Performance Liquid Chromatography (HPLC)
High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify the various components of a mixture. It is a process of separating components in a liquid mixture.
Principle – Pumps move a pressurized liquid solvent containing the sample mixture through a column of solid adsorbent material. Each component of the sample interacts with the adsorbent material in a slightly different way. This causes the different components to flow at different rates, which separates them as they flow out of the column. It is a dependable way to obtain and ensure product purity.
Mass Spectrometry (MS)
Mass spectrometry is an analytical technique that can be utilized for the purpose of determining the mass-to-charge ratio (m/z) of one or more molecules present in a sample. The findings are given in the form of a mass spectrum, which is a graph that shows intensity as a function of the mass-to-charge ratio. These spectra are utilized to determine the elemental or isotopic signature of a sample, the masses of particles and molecules, and to reveal the chemical identity or structure of molecules and other chemical compounds.
Principle – The mass spectrometry principle is the creation of many ions from the sample. In addition, these ions are sorted according to their mass-to-charge ratio, also denoted as m/z, and the relative abundance of each ion is recorded.
Gas Chromatography (GC)
Gas chromatography is a method that can be used to separate, identify, and quantify components of a mixture of organic compounds. This is accomplished through the selective partitioning of components between the stationary phase and mobile phase within a column, which is then followed by the sequential elution of the components that have been successfully separated. Testing the purity of a certain substance is one of the most common applications of GC.
Principle – The column of a gas chromatograph is a thin tube through which the vaporized sample is conveyed by a continuous flow of an inert or nonreactive gas. Components of the sample flow through the column at varying rates, based on their chemical and physical properties and their interactions with the stationary phase, which is the column lining or filling. Typically, the column is contained in a temperature-controlled oven. Once the chemicals exit the end of the column, they are electronically detected and identified.
Gas Chromatography–Mass Spectrometry (GC-MS)
The analytical technique known as GC-MS, combines the characteristics of gas chromatography with mass spectrometry in order to determine the presence of various compounds inside a test sample. The gas chromatography–mass spectrometry (GC–MS) technique has come to be known as the “gold standard” for forensic substance identification. This is due to the fact that it can be utilized to carry out a test that is 100 percent specific and definitively identifies the presence of a particular substance.
Nuclear Magnetic Resonance (NMR) Spectroscopy
The study of molecules through the recording of the interaction of radiofrequency (Rf) electromagnetic radiations with the nuclei of molecules that have been placed in a strong magnetic field is known as nuclear magnetic resonance (NMR) spectroscopy. The sample is placed in a magnetic field, and the NMR signal is generated by exciting the nuclei sample with radio waves into nuclear magnetic resonance, which is then detected by sensitive radio receivers. The intramolecular magnetic field surrounding an atom in a molecule alters the resonance frequency, thereby revealing the electronic structure and individual functional groups of the molecule. NMR spectroscopy is the definitive method for identifying monomolecular organic compounds in modern organic chemistry practice, as the fields are unique or highly characteristic of each chemical.
Principle – The NMR principle typically consists of the following three successive steps:
- The alignment (polarization) of the magnetic nuclear spins in an applied, constant magnetic field B0.
- The perturbation of this alignment of the nuclear spins by a weak oscillating magnetic field, usually referred to as a radio-frequency (RF) pulse.
- Detection and analysis of the electromagnetic waves emitted by the nuclei of the sample as a result of this perturbation.
Quantitative Nuclear Magnetic Resonance (qNMR) Spectroscopy
qNMR is a versatile method for measuring the concentration or purity of organic substances. The method is based on a direct comparison between the NMR signal intensities of the target compound and reference signals. Any internal reference compound with a known structure and purity can be used to derive the reference signal. In the event of an impurity analysis, the signals of the principal chemical can frequently serve as a reference for the investigation.
Infrared (IR) Spectroscopy
Infrared spectroscopy is the measurement of the absorption, emission, or reflection of infrared radiation by matter (sample). It is used to examine and identify solid, liquid, or gaseous chemical compounds or functional groups. It can be used to characterize new materials, as well as to identify and validate known and unknown samples.
Principle – The concept that molecules have a tendency to absorb specific frequencies of light that are typical of the corresponding structure of the molecules, is the basis of the IR spectroscopy theory. The energies are determined by the contours of the molecular surfaces, the related vibronic coupling, and the masses of the atoms that they correspond to.
Inductively coupled plasma mass spectrometry (ICP-MS)
Inductively coupled plasma mass spectrometry (ICP-MS) is a form of mass spectrometry in which the sample is ionized using an inductively coupled plasma. The material is atomized, and atomic and small polyatomic ions are subsequently measured. It is known and utilized for its capacity to detect metals and numerous non-metals at very low concentrations in liquid samples. It can detect various isotopes of the same element, making it a flexible instrument for isotopic tagging. It is a method of analysis that is used for quality control of high-purity materials as well as for the analysis of trace levels of hazardous metals present in any compound.
X-Ray Diffraction (XRD) Analysis
The X-ray diffraction analysis, often known as XRD, is a method that is utilized in the field of materials science to ascertain the crystallographic structure of a substance. The X-ray powder diffraction technique works by subjecting a sample to incident X-rays, after which the intensities and scattering angles of the X-rays that emerge from the sample are measured. The identification of materials based on their diffraction patterns is one of the most important applications of XRD analysis. In addition, it provides information on how the actual structure deviates from the ideal structure due to internal stresses and defects.
Popular Purification Methods
The most commonly used purification methods by a chemical synthesis company are as follows-
Recrystallization, commonly referred to as fractional crystallization, is a method for purifying an impure substance in a solvent. The solubilities of substances rise as temperatures increase. This characteristic of solids is utilized to remove contaminants from precious solids. When a compound and impurities mixture is dissolved in an appropriate solvent, either the desired compound or the impurities can be extracted from the solution, leaving the other behind.
The process of recrystallization basically involves dissolving the mixture of “compound A” and “impurity B” in the smallest amount of hot solvent to fully dissolve the mixture, thus making a saturated solution. After that, the solution is allowed to cool down. The solubility of the compounds in the solution decreases as the solution cools, and the crystallization of the solute takes place. Impurities are excluded from the crystal lattice as the crystal grows, completing the purification process. The crystals are then collected, cleansed, and dried off.
Solvent Extraction (Liquid-Liquid Extraction)
Solvent extraction, also known as liquid-liquid extraction (LLE) and partitioning, is a technique for separating chemicals according to their relative solubilities in two immiscible liquids. Immiscible liquids are those that cannot be combined and separate into distinct layers when shaken. Typically, these liquids consist of water (polar) and an organic solvent (non-polar). A net transfer of one or more species takes place from one liquid into another liquid phase, typically from an aqueous phase into an organic phase.
When extracting solvent is stirred with a solution containing solute then solute from the original solvent gets transferred into the extracting solvent. When stirring is stopped, extracting solvent form a separate layer containing the solute of interest.
On a small scale, solvent extraction is frequently performed by synthetic lab chemists using a separatory funnel, Craig equipment, or membrane-based approaches. However, on an industrial scale, the two liquid phases are typically brought into contact by machines such as centrifugal contactors, Thin Layer Extraction, spray columns, pulsed columns, and mixer-settlers.
It is a Purification process of crude material using partially soluble solvent at preferred temperature in which the impurity is removed due to partial solubility. In the slurry wash purification, the product is partially soluble with impurities and due to saturation the product is precipitated and impurities remain in soluble form in the mother liquor.
Anti-solvent crystallization, also known as precipitation, is a technique widely used in the pharmaceutical and fine chemical industries to recover a product from solution in a solvent with high solubility. This method is used for impurity removal. The desired product is dissolved in soluble solvent and then precipitated out by using product insoluble solvent (antisolvent).
Chromatographic techniques such as column chromatography can also be used for purification of the compounds. It is a preparatory method that is utilized in the purification of chemicals depending on the hydrophobicity or polarity of those substances. During this chromatography method, the molecule mixture is separated according to its differentials partitioning between a stationary phase and a mobile phase.
Purification by preparative HPLC
Similar to its analytical counterpart, preparative high performance liquid chromatography (HPLC) allows rapid and sensitive separations of mixtures utilizing high pressures and flow rates. It is an effective method for separating components from even the most complicated combinations.
The process of acid–base extraction, falls under the category of liquid–liquid extractions and involves the separation of a chemical substance from other acidic or basic substances. Typically, it is carried out during the work-up phase following a chemical synthesis to purify crude molecules. A separating funnel is commonly used to perform an acid-base extraction. Acid-base extraction employs the difference in a compound’s solubility in its acid or basic form to facilitate separation.
The desired component is often converted into its charged acid or basic form. This causes the compound to become soluble in aqueous solution, allowing it to be extracted from the non-aqueous (organic) layer. It is a simpler alternative to processes such as chromatography, which are more involved and complicated.
Purification by Protection-Deprotection Method
The product is protected by groups like acetic acid ester, benzoic acid ester etc. depending on the functional group present in it. This process is followed by the purification of the protected compound. As the impurity is not protected by any functional group, it easily gets separated/removed during the purification process. The compound is then deprotected (attached functional group is removed) again, providing us with the pure product. Examples include Methylene Blue, Fluorescein Sodium, etc.
Purification by using Filter-aid & Charcoal
Purification can be achieved by using “activated charcoal”. It works through the phenomenon of adsorption and physically adheres to impurities.
Our expertise in synthesizing high-purity chemicals
Macsen Labs has gained expertise in Organic & Inorganic chemical synthesis from lab to plant scale, through the years of experience in developing our own products and can offer contract and custom synthesis manufacturing services. We can synthesize and supplu organic and inorganic compounds in quantities ranging from milligrammes to tonnes by employing a wide variety of chemical techniques, reaction settings, procedures, isolation and purification methods.
Our in-house high-tech sophisticated analytical instrumentation facility having instruments like LC-MS/MS, GC-MS/MS, ICP-OES, FTIR, HPLC etc. enables us to perform difficult chemical reactions & synthesize high purity compounds with very less turnaround time.
Our scientists are experienced in chemical conversions like heterocyclic chemistry, metal mediated synthesis, reductive amination, reductions, oxidations, cyanation, chlorination, nitration, Friedel-Crafts reactions, C, O, N-alkylations, chiral resolutions and many more.
We can also outsource highly specialized analytical techniques such as NMR, QNMR, QTOF, ICP-MS, CHNS, TGA, SEM, TEM, XRD, XRF, EDAX.
For synthesizing high-purity chemicals for various industries and applications (Aerospace, Electronics, Pharmaceuticals, Biopharmaceutical, Research and development, Food and cosmetic industries, Diagnostics, Analytical and Clinical Laboratories), we undertake custom synthesis projects, catering to your specific requirements.
We can support your research & product development requirements for organic and inorganic compounds from milligrams to tons involving different kinds of chemistries, by offering our Custom Chemical Synthesis Services.
Resource on Custom Synthesis