Types of impurities

Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified and volatile or non-volatile, and include  

Inorganic impurities can result from the manufacturing process. They are normally known and identified, and include  

Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are generally of known toxicity, the selection of appropriate controls is easily accomplished (ICH Q3C (R3) Impurities Guideline on Residual Solvents). 

In general, according to ICH guidelines on impurities in new drug products, identification of impurities below the 0.1% level is not considered to be necessary unless the potential impurities are expected to be unusually potent or toxic. (In all cases, impurities should be qualified.) If data are not available to qualify the proposed specification level of an impurity, studies to obtain such data maybe needed. 

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Chemical tests for particular types of impurities, e.g. for peroxides in aliphatic ethers (with acidified KI), or for water in solvents (quantitatively by the Karl Fischer method, see Fieser and Fieser, Reagents for Organic Synthesis J. Wiley Sons, NY, Vol 1 pp. 353, 528, 1967, Library of Congress Catalog Card No 66-27894). 

The corrosivity of a natural water depends on the concentration and type of impurity dissolved in it and especially on its oxygen content. Waters of similar oxygen content have generally similar corrosivities, e.g. well-aerated quiescent sea-water corrodes cast iron at ratesof 0 05-0-1 mm/y while most well-aerated quiescent fresh waters corrode iron at O Ol-O-1 mm/y. 

This illustrates the fact that impurity segregation and purification processes are dependent upon the type of impurity involved and its individual segregation coeffleient. As we illustrated above in 6.8.1., the problem is that the impurity is initially rejected from the solid, but its concentration builds up in front of the growing OTStal. The segregation coefficient, k,, then operates on that increased concentration and the product, ki Co. increases. 

Schirmer has succinctly summarized the strengths and limitations of phase solubility analysis [40]. The principal advantages are that (1) a reference standard known purity is not required, (2) the number and types of impurities in the sample need not be known, (3) all required solubility information is obtained from the analysis, (4) the technique can be applied to the analysis of any solute that can be dissolved in some solvent, (5) the deduced results are both precise and... 

Keeping in view the various methods of manufacture of a pharmaceutical substance vis-a-vis its standards of purity, types of impurity and changing pattern of stability, a broad-based highest attainable standard is always fixed. A few typical examples are stated below ... 

The flat band potential Ea, (the Fermi level cp at the flat band) depends on the impurity concentration but the band edge potentials Ec and E (the band edge levels and ev) are characteristic of individual semiconductor electrodes, irrespective of the type of impurity (n-type or p-type). The relationship between the flat band potential and the band edge potentials is given in Eqn. 5- 1 ... 

Starting materials can be defined as the raw materials that form the basis of a chemical reaction as a part of the synthesis of an intermediate in the production of a drug substance. Catalysts typically include any material added to a mixture to accelerate, control, or otherwise modify a chemical reaction. Intermediates are those products of a synthesis scheme that will undergo further reaction. By-products are the side-products of a chemical reaction, and may include conjugates, dimers, enantiomers, unintended salts or free-bases, over-substitution, others. These types of impurities are usually considered to be process impurities and are not expected to increase in concentration over time. 

In addition to the discussion of the types of impurities that are typically found in a pharmaceutical ingredient and product, the ICH Q3A guideline also describes how these impurities should be expressed. Impurities may be described as specified or unspecified. 

The generic representation in Figure 1 illustrates the various types of impurities that may arise during the production of a dosage form. It is not all inclusive, as each dosage form has unique sources of impurities, but it includes most of the important ones. The sources of impurities increase with the increase in the number of components and the number of steps in the process. Each drug substance and excipient has its own impurity profile and the potential for interactions and reactions. 

As mentioned, metalloids will, under certain circumstances, conduct electricity. Therefore, they are often called semiconductors. Elements listed as semiconductors or metalloids are crystalline in structure. As very small amounts of impurities are added to their crystal structure, their capabihty of conducting electricity or acting as insulators increases or decreases. These impurities affect the capacity of electrons to carry electric currents. The flow of electricity is restricted according to the degree and type of impurities. This is why the semi is included in their name. 

Two types of impurities should be distinguished namely, acceptor and donor impurities which play the part of traps (i.e., localization centers) for the free electrons and the free holes, respectively. It should be especially stressed that foreign particles dissolved in the crystal may act as acceptors or donors depending not only on their nature, but also on whether they enter the lattice (interstitially or substitutionally). For example, the interstitial Li atoms in the NiO lattice are donors, but the same Li atoms when replacing the Ni atoms act as acceptors. In the case of a substitutional solution, the foreign atoms of a given type may be either acceptors or donors depending on the lattice in which they are dissolved. For example, Ga atoms are donors in the ZnO lattice and acceptors in the Ge lattice. Thus, if the adsorbed particles are, say, acceptors, the same particles when dissolved in the volume of the crystal may act as donors, and vice versa. 

There is some doubt about the exact value reported unit cell parameters vary rather widely. This presumably reflects varying amounts and types of impurity, often added to stabilise the p-form... 

In some systems an impurity may partition itself in such a way that it is swept to the top of the ingot, and of course both types of impurity may occur in the same material. In such cases only the middle part of the ingot has the required purity. (The author thanks Prof. J. N. Sherwood for some personal advice on this point.)... 

The second type of impurity, substitution of a lattice atom with an impurity atom, allows us to enter the world of alloys and intermetallics. Let us diverge slightly for a moment to discuss how control of substitutional impurities can lead to some useful materials, and then we will conclude our description of point defects. An alloy, by definition, is a metallic solid or liquid formed from an intimate combination of two or more elements. By intimate combination, we mean either a liquid or solid solution. In the instance where the solid is crystalline, some of the impurity atoms, usually defined as the minority constituent, occupy sites in the lattice that would normally be occupied by the majority constituent. Alloys need not be crystalline, however. If a liquid alloy is quenched rapidly enough, an amorphous metal can result. The solid material is still an alloy, since the elements are in intimate combination, but there is no crystalline order and hence no substitutional impurities. To aid in our description of substitutional impurities, we will limit the current description to crystalline alloys, but keep in mind that amorphous alloys exist as well. 

Chemical tests for particular types of impurities, e.g. for peroxides in aliphatic ethers (with acidified KI), or... 

Table 13.1 describes the most frequent types of impurities and contaminants, indicating the most suitable detection methods as a guide. 

The impurity profile (synthesis related impurities) was actually better for dilevalol than for the parent compound, labetalol, reflecting the benefits of further purification during the DBTA resolution step. Thus, although dilevalol hydrochloride contained traces of DBTA itself, no tertiary amine impurities or brominated dilevalol could be detected—both types of impurity are present at very low levels in labetalol. 

In general, recyclability is crucial for the design of sustainable chemical processes [83]. The aspect that should be elaborated here is the possibility of regeneration and reuse of the ionic liquid, depending on the type of impurity and the sensitivity of the specific application towards contamination. 

Simple distillation cannot separate aromatics from noD -aromatic, because the relative volatilities are very low, and many azeotropes are formed. Azeotropic distillation is based on the formation of an azeotrope betu een the non-aromatic hydrocarbons and a low boiling polar solveat It is select among the hrst terms of the series of alcohols, ketones, aldehydes and nitriles, and is employed pure or mixed with water. If the solvent forms a hetero-azeotrope, its recovery is accordbgly facilitated. The )aeld is not limited in principle. The impurity content of the feedstock and the composition of the azeotrope determine the amount of solvent required. Cuts rich in aromatics can be treated in this way fairly economically. However, any variation in the type of impurity to be removed, and consequently in the composition of the azeotrope, may lead to less perfect purification. Furthermore, this method can be applied only to a narrow cut which contains... 

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