Residual solvents level

Residual solvent level If solvents are used for tablet coating, the residual solvent level will need to be determined. 

Excipient impurity profiles and how to evaluate this important aspect of excipient manufacture, particularly in light of the International Conference on Harmonization (ICH) guidance published in 1999, also are addressed. Care must also be taken that residual solvent levels do not exceed those prescribed in the ICH Guidance for Residual Solvents published in 1999. Solvents are divided into three classes ... 

ICH Q3C guides in determining, on a safety basis, acceptable residual solvent levels for intake by use of the term permitted daily exposure (PDE). This Guidance classifies residual solvents used in the synthesis and processing into four categories. The Guidance recommends that Class I solvents be avoided. These include benzene, carbon tetrachloride, 1,2-dichloromethane, 1,1-dichloroethane, and 1,1,1-trichloroethane. Table 2 is an example from the list of Class II solvents that should be limited because of their inherent toxicity either by calculation of concentration (PPM) or by PDE. 

An additional broad area of utilization of GC is the determination of residual solvents (organic volatile impurities). The solvents allowed for use in the synthesis and manufacture and their respective residual limits have been addressed by the ICH. Tests for residual solvents should be conducted whenever production or purification processes may result in the presence of such solvents. This mandates that residual solvents be determined in drug substances. For drug products, residual solvent levels may be calculated from the levels in the ingredients used to produce the drug product unless class 1 (to be avoided) or class 2 (to be limited) solvents are used in the manufacture of the drug substance, excipients, or drug product. ... 

A tablet-coating investigation was conducted to evaluate the effect of spray rate, inlet air temperature, and atomization air pressure on the six-hour dissolution and residual solvent levels of coated tablets. The goal was to find conditions which maximized the dissolution and minimized the residual solvents of the coated tablets. 

The kinetic approach has been used in the study of pharmaceuticals to some extent, although there remains some uncertainty with regard to the reliability and predictive power of the data obtained from such modeling. Chapter 5 contains more details in this respect. Finally, the technique may be used to study both conventional and controlled release dosage forms, as a means of assessing residual solvent levels and as a means of understanding solvent binding. Overall, TGA remains a simple,... 

The most important extraction technique nowadays is simple solvent extraction. The traditional solvent for extraction was benzene, but this has been superseded by other solvents because of concern over the possible toxic effects of benzene on those working with it. Petroleum ether, acetone, hexane and ethyl acetate, together with various combinations of these, are typical solvents used for extraction. Recently, there has been a great deal of interest in the use of carbon dioxide as an extraction solvent. The process is normally referred to as super-critical carbon dioxide extraction but, in fact, the pressures employed are usually below the critical pressure and the extraction medium is sub-critical, liquid carbon dioxide. The pressure required to liquefy carbon dioxide at ambient temperature is still considerable and thus the necessary equipment is expensive. This is reflected in the cost of the oils produced, but carbon dioxide has the advantage that it is easily removed and there are no concerns about residual solvent levels. 

Acceptable residual solvent levels can be achieved in biomaterials processed using organic solvents scCOj is completely non-toxic and solvent residues are simply not an issue [35]. 

The co-solvent system that has been most extensively evaluated was the tert-butanol/water combination. The tert-butanol possesses a high vapor pressure, freezes completely in most commercial freeze-dryers, readily sublimes during primary drying, can increase sublimation rates, and has low toxicity. This co-solvent system is being used in the manufacture of a marketed injectable pharmaceutical product. When using this solvent system, both formulation and process control required optimization to maximize drying rates and to minimize residual solvent levels at the end of drying. 

G Needham. Formulation and processing factor affecting residual solvent levels in TBA/water formulations. Freeze-Drying of Pharmaceuticals and Biologicals, Breckenridge, CO, August 1-4, 2001. 

Selection of an evaporation method that produces ASD with acceptable residual solvent levels... 

Permissible residual solvents Level of residual solvents must be controlled based on the International Conference on Harmonization (ICH) solvent classification guidance permissible daily limit (1CHQ3 Guidance 2009). In addition, the impact on the Tg of the amorphous product and stability of the amorphous form must be considered. 

Typical residual solvent levels of the rubber pellets is <0.3 % by weight. The solvent vapours coming from the vent domes of the extruder are compressed and condensed. The vent domes operate between almost atmospheric (first vent) down to 60 mbar (last vent). 

When the supercritical fluid and drug solution make contact, a volume expansion occurs leading to a reduction in solvent capacity, increase in solute saturation, and then supersaturation with associated nucleation and particle formation. A number of advantages are claimed by using this platform technology (6), such as particle formation from nanometers to tens of micrometers, low residual solvent levels in products, preparation of polymorphic forms of drug, etc. 

In each case the solvent can be chosen to be gaseous under ambient conditions. If this is done, nearly all the solvent will automatically be expelled from the product when the latter comes to ambient pressure. This is a distinct advantage over normal liquid extraction processes, much of the energy requirement for which can lie in the separation of the product from the solvent (a specific example of this is given in section 5.6). This is particularly true where the product is to be used for human consumption since residual solvent levels then have to meet the stringent food standards described in section 2.2. 

Very low residual solvent levels can readily be obtained without the use of elevated temperatures. 

Near-critical extraction is not yet a separation method of universal applicability but it does deserve careful consideration in many situations, for example as a step within an existing high pressure process or as a replacement for existing solvent extraction processes, particularly where non-polar or slightly polar solvents are at present used. The near-critical process has the advantage that solvent removal from the product is virtually complete and not expensive in energy. This aspect may become particularly important in the food industry where permitted residual solvent levels are liable to reexamination. 

Table 1. Measured Residual Solvent Levels for a Series of Spin-Coated...

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