Limits for residual solvents

Solvents of class 1 (see Table 16.2.3) should not be employed. However, if then-use is unavoidable in order to produce a significant therapeutic advance, then their levels should be restricted as shown in Table 16.2.3, unless otherwise justified. 

Solvents of class 2 (see Table 16.2.4). Two options are available when setting limits for class 2 solvents. 

The concentration limits in ppm stated in Table 16.2.4 1] by assuming a product mass 

It is not considered necessary for each component of the medicinal product to comply with the limits given in option 1. The PDE in terms of mg/day as indicated in Table 16.2.4 can be used with the known maximum daily dose and equation [16.2.1] to determine the concentration of residual solvent allowed in the medicinal product. Option 2 may be applied by adding the amounts of RS present in each of the components of the pharmaceutical formulation. The sum of the amounts of solvent per day should be less than that given by the PDE. 

Solvents with low toxic potential solvents of class 3 (see Table 16.2.5) may be regarded as less toxie and of lower risk to human health. It is considered diat amounts of these RS of 50 mg per day or less (corresponding to 5000 ppm or 0.5 % under option 1) would be acceptable without justification. Higher amounts may be acceptable provided they do not have a negative impact on the processability and the stability of the pharmaeeutical product. 

Solvents for which no adequate toxicological data was found (Table 16.2.6). These solvents can be used in the manufacture of drug substances, excipients and drug products, but the manufacturer should supply justification for residual levels of these solvents in pharmaceutical products. 

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The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) [40] has adopted impurities guidelines for residual solvents that prescribe limits for the amount of residual solvents allowed. 

Bicchi and Bertolino [193] analyzed a variety of pharmaceuticals for residual solvents. Samples were equilibrated directly or dissolved in a suitable solvent with a boiling point higher than that of the residual solvent to be determined. Equilibration conditions were 90 or 100°C for 20 min. A Perkin-Elmer HS-6 headspace sampler was used. The chromatographic phase chosen was a 6 x Vs in. column packed with Carbopack coated with 0.1% SP 1000. Residual ethanol in phenobarbital sodium was determined by a direct desorption method. An internal standard, /-butanol, was used. Typically, 0.44% of ethanol was detected (compared to a detection limit of 0.02 ppm). The standard deviation of six determinations was 0.026. Pharmaceutical preparations which were analyzed by the solution method included lidocaine hydrochloride, calcium pantothenate, methyl nicotinate, sodium ascorbate, nicotinamide, and phenylbutazone. Acetone, ethanol, and isopropanol were determined with typical concentrations ranging from 14 ppm for ethanol to 0.27% for acetone. Detection limits were as low as 0.03 ppm (methanol in methyl nicotinate). 

Styrene monomer concentration in foods packaged in 31 different PS-containing food packages and contact materials averaged 224 mg/kg with two products having concentrations between 800 and 1500 mg/kg, well above the sensory threshold limits (Baner, 2000). Strict specifications for styrene monomers as well as for residual solvents, toluene, and odor and taint transfer for supplier materials should be set (Huber et al., 2002). 

Residual solvent contents, water contents, residue on ignition contents, and process-related impurities below their method determination limit of quantitation (LOQ) or below 0.05%, whichever is the greater, are generally not included in the calculation. The LOQ should be 0.05% or less for residual solvents, water contents, and process-related impurity contents and 0.1% for residue on ignition contents. 

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. ... 

Each batch of finished active pharmaceutical ingredient must meet established specifications for quality, purity, identity, and potency, including, where applicable, specifications for tests and limits for residues of solvents and other reactants. 

Many excipients are extracted from or purified by the use of organic solvents. These solvents are normally removed by drying the moist excipient It is important that excipient specifications include tests and limits for residues of solvent. 

GC is the most commonly used technique for residual solvent and organic volatiles analysis in API and has also found application where trace level detection of analytes is required. An airborne monitoring method for SB-202026-A (8) was required and due to the low occupational exposure limit (OEL) for this molecule it was necessary to be able to quantify (8) in solutions at 100ngml . This was achieved readily using a 1 microhtre splitless injection. 

If we eonsider the official limits reported on Table 15.2.3.5 for residual solvent contents, we can note that the concentration of chloroform in meprobamate spherical crystals is much higher than the limit allowed in any dr5dng conditions. Due to its inherent toxicity, this solvent should be avoided in the recrystallization process of meprobamate. The solvent... 

The FDA has pubhshed methods for the deterrnination of residual solvents in spice extracts such as oleoresins and has limited the concentrations of those specific solvents that are permitted. Chlorinated hydrocarbons and benzene have been almost completely removed from use as extracting solvents in the United States their use continues overseas where toxicity regulations are less stringent. The presence of pesticides or herbicides in spices is rigidly controHed by the FDA. 

Recovery of DNAPL is a very slow process that is alfected by those factors encountered with LNAPL (i.e., relative permeability, viscosity, residual hydrocarbon pool distribution, site-specific factors, etc ). Dissolution of a DNAPL pool is dependent upon the vertical dispersivity, groundwater velocity, solubility, and pool dimension. Dispersivities for chamolid solvent are estimated for a medium to coarse sand under laboratory conditions on the order of 1(L3 to 1(H m. Thus, limited dispersion at typical groundwater velocities is anticipated to be slow and may take up to decades... 

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