RESIDUAL SOLVENTS IN PRODUCTS

There are generally two types of analyses that are requested with reference to solvents. The first is the identification of residual solvents in products, and the second is the identification of impurities in common industrial solvents. Certain GC conditions have been found to separate most of the common solvents. Always examine the mass spectra at the front and back of the GC peaks to determine if they are homogeneous. Also remember that isomers may not be detected by this approach if they are not separated. 

Two solvent processes for preparation of Ca(OCl)2 have been described. In one, a CCl solution of /-C H OCl is allowed to react with a thin lime slurry and the aqueous phase, a solution of Ca(OCl)2, is evaporated to a product with a purity of >95% (217). In the other, a solution of HOCl in methyl ethyl ketone reacts with either CaO or Ca(OH)2 (133). FoUowing filtration, the residual solvent in the product is removed under vacuum. 

GL18 Impurities Residual Solvents Impurities residual solvents in new veterinary medicinal products, active substances and excipients... 

Gas chromatography is commonly used to analyse mixtures for quantification. A wide variety of special detectors with adequate linear response ranges are available for quantification of various classes of compounds (cf. Table 4.14). Quantification by direct injection may be used to determine additives, residual monomers and solvents in product formulations, coated films, and solid materials [109]. On the other hand, reliable quantification by means of solid-injection PTV-GC, HS-GC and PyGC techniques is not always trivial. 

In theory, all impurities should be eliminated. In practice, it is generally not economically feasible to totally eliminate all impurities. However, the levels of all impurities should be controlled to provide a consistent product. In most cases, only low levels of impurities should be allowed, but in rare cases, even quite high levels of impurities are tolerated. In some cases, for example, biotechnology derived products such as macrocyclic antibiotics, or extracts of a botanical source such as some dietary supplements, the drug substance or active component contains multiple compounds, all of which have biological activity. However, only organic impurities, which include residual solvents in the drug substance, are addressed in this chapter. 

Impurities, in contrast to degradation products, might or might not have any relation to the drug molecule. In the simplest case, residual quantities of a solvent used at some step in the process chemistry can become an impurity in the drug product. A recent, very extensive publication to which the interested reader is referred, listed the proton and carbon NMR chemical shifts of a large number of potential solvent impurities in a number of commonly employed NMR solvents [22]. There have also been several reviews on the topic of residual solvents in pharmaceuticals [23, 24]. 

Since products (1) and (2) contain a considerable amount of solvent (60-100%), they are loaded directly into the kneader together with the solvent, kneaded for 1-2 hr and filtered in a press in which the die is replaced by a steel plate with circular openings, approximately 1 mm dia. Since there is less ether in the residual solvent in the powder than is primarily used for its manufacture, the solvent added to the waste products should be richer in ether (approximately 70% by weight of ether and 30% by weight of alcohol). 

Examples of the application of headspace extraction are flavors in food products, volatile organic compounds in soils, and residual solvents in pharmaceutical products [33, 34]. The main advantages of headspace extraction are minimal sample preparation and the possibility for direct introduction of headspace gas into the gas chromatograph. 

Currently, the SCF technology has a widespread utility ranging from food processing to pharmaceutical applications. The use of SCFs such as CO2 is proving to be environmentally benign and economical, with the added advantage of reduced residual solvents in food and pharmaceutical products. 

The analytical chemistry and regulatory aspects of residual solvents in pharmaceutical products have been reviewed in detail by Witschi and Doelker and B Hymer.f Both of these reviews discuss the central role of GC-based analytical methods for this application. Also of note is the review by Dwivedi. ... 

Witschi, C. Doelker, E. Residual solvents in pharmaceutical products. Acceptable limits, influences on physicochemical... 

For safety reasons, the pressure is set in such a way that the temperature is 5°C below the melting point of the product. On an hourly basis, the freeze-dryer automatically uses a drain valve to allow the pressure within the system to drop. A simultaneous fall in product temperature is indicative of the presence of frozen solvent that should thus be extracted during the sublimation or primary drying step. Detecting any residual solvent in this way avoids the risk of the product melting down. Before the desorption step is started, this pressure control cycle is repeated until no further drop in product temperature is observed. 

Majority of nanoliposome manufacture techniques either involve utilisation of potentially toxic solvents (e.g. chloroform, methanol, diethyl ether and acetone) or high shear force procedures. It has been postulated that residues of these toxic solvents may remain in the final liposome or nanoliposome preparation and contribute to potential toxicity and influence the stability of the lipid vesicles (35-38). Although there are methods to decrease the concentration of the residual solvents in liposomes (e.g. gel filtration, dialysis and vacuum), these are practically difficult and time-consuming procedures. In addition, the level of these solvents in the final formulations must be assessed to ensure the clinical suitability of the products (39). Therefore, it would be much preferable to avoid utilisation of these solvents in nanoliposome manufacture, which will also bring down the time and cost of preparation especially at the industrial scales. 

The product is usually removed from the filter when the exit rate of wash is judged to be sufficiently slow, or when the amount of residual solvents in the solvent-wet product has decreased to the desired level. The filter cake is... 

This guideline was drafted as a joint working group exercise between experts from both the analytical chemistry and the toxicology fields. Residual solvents in pharmaceuticals are defined as the organic volatile chemicals that are used or produced in the manufacture of drug substances or excipients or in the preparation of drug products. 

The guideline applies mainly to drug substances and excipients, because if the levels of residual solvents in those materials are controlled, then the levels in drug products made from them are defined. The exception is when a solvent is used in the manufacturing process for a drug product, for example, the solvent-based film coating of tablets. In this case, a specification for the solvent must be set for the drug product. 

The RESS process, without the use of a cosolvent, is very attractive and probably the most easily managed supercritical process. Unfortunately many molecules are not soluble in pure SCCO2, and these require the use of a cosolvent. However, such an addition makes the RESS process less favorable, since it loses its main advantage of being system free of organic solvent. Any residual solvent in the product must be removed. 

Further studies in this direction [79, 80] suggested the following possible causes of poor reproducibility of data and systematic errors (1) the presence of residual solvent in the test sample (2) the wide range of pyrolysis temperatures (3) contamination of the equipment by sample residues and residual products of previous pyrolyses and (4) widely differing sample sizes. To obtain reproducible results one should give equal attention to all stages sample preparation, pyrolysis and GC analysis. 

Most often, this sequence leads to final products similar to those that occur under photochemistry. As the secondary electrons lose energy, they become therm ali zed and may have themselves attached either to specific molecules (thus forming molecular ions) or to the residual solvents in the resist film in the form of solvated electrons. ... 

The second part of this handbook (Chapters 14-25) is devoted more to the industrial use of solvents. Formulating with solvents applied in a broad range of industrial areas such as biotechnology, dry cleaning, electronic industry, food industry, paints and coatings, petroleum refining industry, pharmaceutical industry, textile industry, to mention only a few, is extensively described in Chapter 14. Standard and special mefriods of solvent detection and solvent analysis as well as the problem of residual solvents in various products, particularly in pharmaceutical ones, are the topics of Chapters 15 and 16. 

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