Chemical-physical analyses (pharmaceutical analysis)
The principle of the method is to measure the force acting on a rotor (torque) while it rotates at a constant angular velocity (rotational speed) in a liquid. Rotary viscometers are used to measure the viscosity of Newtonian (shear-independent viscosity) or non-Newtonian liquids (shear-dependent viscosity or apparent viscosity).
The distillation range is the temperature range corrected to 101,3 kPa (760 Torr) within which a substance or a certain proportion thereof distils under the conditions described in the pharmacopoeia.
The boiling point is the corrected temperature at which the vapour pressure of a liquid reaches 101.3 kPa.
The melting temperature according to the capillary method is the temperature at which the last solid particle of a compact substance column in the melting point tube passes into the liquid phase.
The drop point is the temperature at which the first drop of the melting substance to be examined falls from a cup under defined conditions.
The freezing point is the maximum temperature occurring during the solidification of a supercooled liquid.
In an amperometric titration, the endpoint is determined by measuring the change in current between 2 electrodes (one measuring electrode and one reference electrode or 2 measuring electrodes) immersed in the solution to be tested and having a constant voltage difference, depending on the quantity of solution added.
In a potentiometric titration, the endpoint is determined by measuring the change in the voltage difference between 2 electrodes (one measuring electrode and one reference electrode or 2 measuring electrodes) immersed in the solution to be tested, depending on the quantity of measured solution added.
Atomic emission is a process that occurs when electromagnetic radiation is emitted by excited atoms or ions. In atomic emission spectrometry, the sample is brought to a sufficiently high temperature so that not only dissociation into atoms occurs, but also a significantly high proportion of collisions, which leads to excitation and ionization of the atoms in the sample. If the atoms and ions are in the excited state, they can fall back to lower energy levels due to thermal and radiant energy transitions, whereby electromagnetic radiation is emitted. An emission spectrum of an element contains significantly more lines than a corresponding absorption spectrum. Atomic emission spectrometry is a method of determining the concentration of an element in a sample by measuring the intensity of a single spectral line of atomic vapor produced from the sample. The measurement is made at the wavelength corresponding to this spectral line.
Atomic absorption is a process that occurs when atoms in the ground state absorb electromagnetic radiation of a specific wavelength and thus enter an excited state. The ground atoms absorb energy at their resonant frequency, thereby attenuating the electromagnetic radiation according to the resonance absorption. Energy absorption is theoretically a direct function of the number of atoms present. The atomization takes place either with a flame or by electrothermal evaporation in a graphite tube furnace.
The IR spectrometer is suitable for recording spectra in the range from 4000 to 650 cm-1. It consists of a suitable radiation source, a monochromator or interferometer and a detector. In addition, the Fourier transform spectrometer uses polychromatic radiation and calculates the spectrum in the frequency domain from the obtained values using the Fourier transform (FT). Usually, spectra are represented as a function of transmission, the ratio of the intensities of the emerging radiation to the incoming radiation, or as a function of absorption.
The absorption of a solution is the decadic logarithm of the reciprocal of the transmission in monochromatic radiation. In the absence of other physico-chemical factors, the absorption of the layer thickness passed through and the concentration of the dissolved substance are proportional (Lambert-Beersches law).
Thin layer chromatography is a separation method in which the stationary phase consists of a suitable material applied uniformly and in a thin layer to a support (plate) of glass, metal or plastic. The solutions to be investigated are applied to the plate before development. Separation is based on adsorption, distribution, ion exchange or combinations of these processes. It is done by migration (development) of the solutions (substances to be studied) with a solvent or a suitable mixture of solvents (superplasticizers) on the thin film (stationary phase).
Gas chromatography (GC) is a chromatographic separation method based on the specific different distribution of substances between 2 immiscible phases. One of these phases is the gaseous mobile phase (carrier gas), which moves through or along the stationary phase in a column. The method can be applied to substances or their derivatives which evaporate at the temperatures applied. GC is based on the principles of adsorption, mass distribution or molecular size exclusion.
Liquid chromatography (LC) is a chromatographic separation method based on differences in the distribution of substances between two immiscible phases in which a liquid mobile phase passes through the stationary phase in a column. The LC is mainly based on the principles of adsorption, mass distribution, ion exchange, molecular size exclusion or stereochemical interactions.
The loss on drying is the mass loss expressed as a percentage (m/m). It is determined by weighing a prescribed quantity of substance into a weighed weighing pan which has previously been dried under the conditions specified for the substance. The substance is dried to constant mass or at the specified temperature for the specified time. The procedure is carried out according to a procedure prescribed for the substance in question by the pharmacopoeia.
Each crystalline phase of a certain substance produces a characteristic X-ray diffraction pattern. The diffractograms can be obtained from randomly oriented crystalline powder particles composed of crystallites or crystalline portions of limited size. Essentially 3 types of information can be obtained from a powder diffractogram: - the diffraction angle (depending on the geometry and dimensions of the unit cell) - the intensities of the diffraction lines (essentially depending on the type of atoms and their arrangement as well as the orientation of the particles in the sample) and - the profile of the diffraction lines (depending on the resolution of the measuring instrument, the crystallite size, the deformation and the thickness of the sample).
Tests that evaluate the diffraction angle and the intensity of the lines are used for qualitative phase analysis (e.g. for identification of crystalline phases) or for quantitative phase analysis of crystalline samples. X-ray powder diffraction (X-Ray Powder Diffraction, XRPD) has the advantage over other analytical methods in that it is generally a non-destructive method (samples are only rubbed to ensure random orientation of powder particles). In addition, this method can be used to perform the tests under in-situ conditions, without exposing the samples to environmental conditions (such as low and high temperatures and low and high humidity).
The current flowing through a conductor is directly proportional to the applied electromotive force and inversely proportional to the resistance of the conductor. The device used measures the resistance of a liquid column between the 2 electrodes of the immersion cell (conductometer measuring cell). The device is operated with alternating current to avoid the effects of electrode polarization. The instrument is equipped with a temperature probe and a temperature compensation arrangement.
Mass spectrometry is based on the direct measurement of the ratio of mass to the number of positive or negative elementary charges of ions (m/z) in the gas phase of the substance to be tested. This ratio is expressed in atomic mass units (1 AME = one twelfth of the mass of 12C) or in daltons (1 Da = mass of a hydrogen atom). The ions generated in the ion source of the instrument are accelerated and then separated by the analyser before reaching the detector. These processes take place in a chamber in which a vacuum between 10-3 and 10-6 Pa is maintained by a pump system. The spectrum obtained shows the relative intensity of the different ion types present as a function of the m/z ratio. The signal corresponding to an ion is represented by several peaks corresponding to the statistical distribution of the different isotopes of that ion. This pattern is called the isotope profile. The information obtained by mass spectrometry is essentially qualitative (determination of the relative molecular mass, information about the structure from the observed fragments) or quantitative (using an internal or external reference substance) with detection limits in the range from picomol to femtomol.
The determination of total organic carbon (TOC) indirectly determines organic substances contained in water for pharmaceutical use. The determination can also be used to monitor the performance of different process steps in drug manufacture and as a sum parameter for cleaning validations.
Inductively coupled plasma mass spectrometry (ICP-MS) is a mass spectrometric method that uses an inductively coupled plasma (ICP) as ionization source. In ICP-MS, the ability of inductively coupled plasma to generate charged ions from the elements contained in a sample and their isotopes is applied. These ions are fed to a mass spectrometer, which separates them according to their mass-to-charge ratio (m/z).
Thioacetamide reagent R is used to carry out the wet chemical methods for the determination of heavy metals as lead. The control solution is prepared with the amount of substance prescribed for the test with the addition of the volume of lead solution prescribed for the preparation of the reference solution. The test may only be evaluated if the control solution is at least as coloured as the reference solution. The determination of heavy metals as lead is no longer included in most current monographs. Instead the heavy metals in pharmaceutical products are determined with ICP-MS according to ICH-Q3D.
The lead is determined by atomic absorption spectrometry (Ph.Eur. 2.2.23, Method II).
A suitable crucible (e.g. made of silicate, platinum, porcelain or quartz glass) is heated for 30 minutes at 600°C, allowed to cool in the desiccator over silica gel or another suitable desiccant and weighed. The prescribed quantity of the substance to be tested is placed in the crucible and both weighed together. Moisten the substance with a small amount of sulphuric acid R (generally 1 ml) and carefully heat at the lowest possible temperature until the substance is completely charred. After cooling, the residue is moistened with a small amount of sulphuric acid R (generally 1 ml), carefully heated until no more white vapours are formed and annealed at 600 °C until the residue is completely ashed. No flames must be produced during the entire ashing process. After cooling in the desiccator over silica gel or another suitable desiccant, the crucible is reweighed and the percentage of residue calculated.
The nickel content is determined by atomic absorption spectrometry (2.2.23, Method II).
A quartz or platinum crucible is heated to red heat for 30 minutes, allowed to cool in the desiccator and weighed. Unless otherwise specified, 1,00 g of substance or powdered drug is evenly distributed in the crucible and dried for 1 h at 100 to 105 °C. The mixture is then left to cool in the desiccator and weighed. The substance is then annealed in a muffle furnace at 600 °C to a constant mass, the crucible being allowed to cool in the desiccator after each annealing.
The determination of the heavy metals is performed by means of inductively coupled plasma-mass spectrometry (ICP-MS) according to Ph.Eur. 2.2.58.
The nickel content is determined by atomic absorption spectrometry (2.2.23, Method I).