Wypych Handbook of Solvents

Option 2

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.

16.2.5 CONCLUSIONS

Those who have worked for many years in pharmaceuticals will have observed continuous progress in standards of Quality and Control in manufacturing.

Solvents including water are still used in almost every step of the elaboration of a drug product. Their residues could be detrimental for the processability and stability of the pharmaceutical products and the safety of patients. At the end of this millennium it can be said that the testing and control of RS has been thoroughly assessed and is based on robust and sensitive techniques, for which the limitations are known, resulting in a sound strategy accepted almost everywhere in the world.

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17.1.2 WATER

17.1.2.1 Solubility

One of the most important properties of an organic solvent is its solubility in water. The greater a compound's solubility, the more likely that a solvent or a solvent-containing waste will dissolve into water and become part of the hydrological cycle. Hence, water solubility can affect the extent of leaching of solvent wastes into groundwater, and the movement of dissolved solvent into rivers and lakes. Aqueous solubility also determines the efficacy of removal from the atmosphere through dissolution into precipitation. The solubility of solvents in water may be affected by temperature, salinity, dissolved organic matter, and the presence of other organic solvents.

17.1.2.2 Volatilization

Solvents dissolved in water may volatilize into the atmosphere or soil gases. A Henry's Law constant (KH) can be used to classify the behavior of dissolved solvents. Henry's Law describes the ratio of the partial pressure of the vapor phase of an ideal gas (Pi) to its mole fraction (Xi) in a dilute solution, viz.,

In the absence of measured data, a Henry's Law constant for a given solvent may be estimated by dividing the vapor pressure of the solvent by its solubility in water (Si) at the same temperature;

A KH value of less than 10-4 atm-mol/m3 suggests that volatilization would probably not be a significant fate mechanism for the dissolved solvent. The rate of volatilization is

more complex, and depends on the rate of flow, depth, and turbulence of both the body of water and the atmosphere above it. In the absence of measured values, there are a number of estimation techniques to predict the rate of removal from water.8

17.1.2.3 Degradation

The disappearance of a solvent from solution can also be the result of a number of abiotic and biotic processes that transform or degrade the compound into daughter compounds that may have different physicochemical properties from the parent solvent. Hydrolysis, a chemical reaction where an organic solvent reacts with water, is not one reaction, but a family of reactions that can be the most important processes that determine the fate of many organic compounds.9 Photodegradation is another family of chemical reactions where the solvent in solution may react directly under solar radiation, or with dissolved constituents that have been made reactive by solar radiation. For example, the photolysis of water yields a hydroxyl radical:

Other oxidants such as peroxy radicals (RO2r) and ozone can react with solvents in water. The subject of photodegradation is treated in more detail under atmospheric processes (17.1.4).

Biodegradation is a family of biologically mediated (typically by microorganisms) conversions or transformations of a parent compound. The ultimate end-products of biodegradation are the conversion of organic compounds to inorganic compounds associated with normal metabolic processes.10 This topic will be addressed under Soil (17.1.3.3).

17.1.2.4 Adsorption

Adsorption is a physicochemical process whereby a dissolved solvent may be concentrated at solid-liquid interfaces such as water in contact with soil or sediment. In general, the extent of adsorption is inversely proportional to solubility; sparingly soluble solvents have a greater tendency to adsorb or partition to the organic matter in soil or sediment (see Soil, 17.1.3.2).

17.1.3 SOIL

17.1.3.1 Volatilization

Volatilization from soil may be an important mechanism for the movement of solvents from spills or from land disposed solvent-containing wastes. The efficacy and rate of volatilization from soil depends on the solvent's vapor pressure, water solubility, and the properties of the soil such as soil-water content, airflow rate, humidity, temperature and the adsorption and diffusion characteristics of the soil.

Organic-solvent vapors move through the unsaturated zone (the interval between the ground surface and the water-saturated zone) in response to two different mechanisms; convection and diffusion. The driving force for convective movement is the gradient of total gas pressure. In the case of diffusion, the driving force is the partial-pressure gradient of each gaseous component in the soil air. The rate of diffusion of a solvent in bulk air can be described by Fick's Law, viz.,