Wypych Handbook of Solvents

14.19.2.5.6 Color

A coalescing agent should be colorless, to prevent discoloration of the product.

14.19.2.5.7 Coalescing efficiency

The effectiveness of a coalescing agent is based upon the MFFT test.

14.19.2.5.8 Incorporation

A good coalescing agent should be capable of addition during any stage of paint manufacture. Any particular coalescing agent may need premixing prior to addition with varying amounts of the water and surfactant used in the paint stage.

14.19.2.5.9 Improvement of physical properties

A good coalescing agent can provide a significant improvement in scrub resistance, stain resistance, flexibility and weatherability.

14.19.2.5.10 Biodegradability

A good coalescing agent should exhibit acceptably rapid biodegradation quickly.

14.19.2.5.11 Safety

The use of the coating system requires that the nature of the coalescing agent should permit use in the domestic environment. The suitability of such a material is therefore obviously dependent on its toxicity, flash point, vapor pressure and VOC classification.

14.19.2.6 Comparison of coalescing solvents

From the above, it may readily be seen that AB type coalescing solvents give the best performance in use. These are the high molecular weight esters and ester alcohols. Other species have some of the benefits of these materials but have side effects, which render them less suitable. Minimization of the quantity used tends to be a key financial issue, as well as offering the best environmental option. In virtually all cases, the efficiency of the AB group in application is so marked, that they have become the industry standards. Several other properties, perhaps less important, than efficiency must then be considered when selecting between these.

These products are usually used in enclosed spaces, where product odor will be vital for acceptance to the consumer. The dibasic esters are virtually odor free. For legislative reasons, a solvent not classified as a VOC will be of definite benefit, given the current attitude to organics in consumer products. Again, the dibasic esters have initial boiling points considerably above the VOC threshold of 250°C.

The stability of the product towards hydrolysis is also a significant factor in the selection of the optimum coalescing agent. Effectively, this parameter determines the storage stability of the product. Again, dibasic esters, particularly those produced from higher molecular weight alcohols appear to have advantage.

The efficiency of the AB group of coalescents towards almost all polymer types has already been mentioned. For styrene-acrylics and vinyl acetate - Veova copolymers, the diesters have a significant edge in performance compared with other members of that group. This advantage is shown in the reduction in amount required to attain a particular MFFT or the actual MFFT for a given addition level.

Coasol manufactured by Chemoxy is the blend of di-isobutyl esters of the dibasic acids; adipic, glutaric and succinic. These acids are produced as a by-product in the production of adipic acid in the manufacture of Nylon 6,6. The ratio of the acids is 15-25% adipic,

50-60% glutaric, 20-30% succinic. Esterification using isobutanol is then performed and the product is isolated following distillation. Coasol was introduced in the early part of last decade as a coalescing agent to the aqueous based coatings industry.

Coasol has excellent coalescing properties and is compatible with virtually all paint systems. It has very low vapor pressure at ambient temperature which ensures excellent plasticization throughout the film forming and drying process. Its extremely low odor also significantly improves the general view that aqueous systems have unpleasant odors. This is almost always as a result of the coalescing solvent. Its resistance to hydrolysis allows its use in a wide variety of formulations, including those, which require adjustment of pH to basic conditions.

It rapidly biodegrades, both aerobically and anaerobically, since, as an ester, it is readily attacked by ubiquitous bio-species. Finally, its toxicological profile is virtually benign, so in use it can be handled with confidence in most working environments. Its properties are summarized in Table 14.19.2.1.

Table 14.19.2.1. Properties of Coasol

14.19.2.7 RECENT ADVANCES IN DIESTER COALESCING SOLVENTS

We have also prepared the di-isopropyl esters of the higher adipic content stream. This has a vapor pressure similar to that of Coasol, but is slightly more water soluble. Finally, we have manufactured di-isopropyl adipate, which has the highest boiling point, the lowest vapor pressure and the lowest water solubility of all of this range of products. These preparations were undertaken to add to repertoire of products to suit the diverse requirements of the formulators of aqueous based systems.

In virtually all cases, the dibasic esters gave a significant improvement in efficiency in reducing the MFFT for a given quantity of additive. The attempts are made to offer a tailor made solution to each individual polymer system employed in the development of aqueous based systems. The dibasic esters of the AGS acids group offer the opportunity for fine tuning, with the added advantage of low odor, low toxicity and “excellent” VOC status.

14.19.2.8 Appendix - Classification of coalescing solvents

14.20 PETROLEUM REFINING INDUSTRY

George Wypych

ChemTec Laboratories, Inc., Toronto, Canada

The US petroleum refining industry generates sales of over $140 billion with only about 200 plants. It employs 75,000 people. About 90% of the products used in US are fuels of which 43% is gasoline. Figure 14.20.1 illustrates how the products breakdown. The process is described in detail in Chapter 3. Emissions of hydrocarbons to the atmosphere occur at almost every stage of the production process. Solvents are produced in various processes and they are also used to extract aromatics from lube oil feedstock, deasphalting of lubricating base stocks, sulfur recovery from gas stream, production of solvent additives for motor fuels such as methyl tert-butyl ether and tert-amyl methyl ether, and various cleaning operations. Emissions to atmosphere include fugitive emissions of the volatile components of crude oil and its fractions, emissions from incomplete combustion of fuel in heating system, and various refinery processes. Fugitive emissions arise from thousands of valves, pumps, tanks, pressure relief valves, flanges, etc. Individual leaks may be small but their combined quantity results in the petrochemical industry contributing the largest quantity of emissions and transfers.

Tables 14.20.1 and 14.20.2 give solvent releases and transfers data for the petroleum refining industry. Transfers are small fraction of releases which means that most wastes are processed on-site.

In addition to emissions to atmosphere, some plants have caused contamination of ground water by releasing cooling and process water.

One or several active compounds (DS) are prepared by organic synthesis, extracted from vegetable, animals, micro-organisms or obtained by biotechnology. The DS is generally associated in the product with several excipients of chemical, mineral or biological in nature either as monomers or as polymers.

The goal is to formulate a processable DP stable over the time and allowing the active substance to be released in vitro and in vivo. Obviously the formulation is designed in relation to the route of administration:

•oral route solid dosage forms (e.g., tablets, capsules, etc.) drinkable solutions etc.

•ORL route (nasal solutions, spray)

•local route (suppositories, transdermal systems, eye-drop formulation, spray)

•intravenous and intramuscular route (injectable solution, lyophilizate, etc.)

At practically every step of the manufacture of the drug substance and the excipients, solvents including water are utilized. This is equally true for the preparation of the pharmaceutical formulations.

Ideally we would like to have available a universal stable solvent, ultrapure, non-toxic and which does not affect the solutes. This is an old dream of the alchemists who searched for a long time for the “Alkahest” or “Menstruum universal” as it was named by Paracelsus.1

The fact that a solvent is not a totally inert species allows it to play an important role in chemical equilibria, rates of chemical reactions, appearance of new crystalline forms, etc. and consequently contributes to the great wealth of compounds which the chemists are able to produce.

But of course, there are drawbacks in using solvents. Because there are not totally inert they may favor the formation of undesirable impurities in the intermediates of synthesis and in the DS. Regarding the manufacture of the DP, the solvents, including water, may induce either polymorphic transformations or formation of solvates (hydrates) which, after drying, could lead to a desolvated solvate with quite different physical properties impacting potentially either positively or negatively on the DP performance.2

Another crucial aspect which deserves to be discussed, is the notion of purity. Impurities present in solvents could have an impact on the stability of drugs, for example, or on the crystallization process.

Last, but not least, the toxicological aspects should be taken into account. Numerous solvents show different kinds of toxicity and this should be a matter of concern in relation to the health of workers exposed to them.3 But ultimately residual solvents still present in the DS and DP have to be assessed and systematically limited.

We are now going to consider several aspects of the use of solvents in the manufacture of drug substances (DS) and drug products (DP) including their quality (purity) and influence on the quality, stability and physico-chemical characteristics of pharmaceutical products.

The issue of residual solvents in pharmaceutical products will be considered in Chapter 16.2 and will focus amongst other things on the corresponding ICH Guideline.4

can have by contract an access to the DS Mater File or because there is a compendial monograph giving occasionally some indications (e.g., search for benzene in carbomers).

As a consequence of the ICH Guideline Q3C4 dealing with the residual solvents in pharmaceutical products (see Chapter 16.2), the use of solvents of class I (solvents to be avoided) like benzene is no more possible. It is known that carbopol resins (carbomer), used to modify the rheology of polar systems and as a binder in sustained release tablets, were up to now polymerized in benzenic medium. In the current quality of poloxamers it was possible to retrieve up to 1000 ppm of benzene. The ICH limit being 2 ppm, it was impossible to achieve this goal. The manufacturers have consequently developed new polymerization media6 containing either ethyl acetate alone or a mixture of ethyl acetate and cyclohexane, the first one belonging to class III (no safety concern), the second one belonging to class II (ICH limit 3880 ppm).

14.21.1.2.1.2 Criteria of purity

This is a difficult matter. Purity in chemistry is an ideal concept referring to a situation where a product consists of one type of molecules only. This is a theoretical situation which can only be EXPERIMENTALLY approached more or less closely.7

The purity of a product is a relative notion and is dependant on the analytical methods used and their performances. More practically the quality finally chosen for a solvent will depend on the specific use for which this solvent is intended to be utilized.8

A solvent is considered sufficiently pure if it does not contain impurities able in nature and in quantity to interfere on the admissible quality of the product in the manufacture of which it participates.7

14.21.1.2.1.3 Solvents as reaction medium

In this case the solvents should have a range between the melting point and the boiling point as extended as possible and a good thermal and chemical stability. The purity should be of good degree but could depend on the step considered of the global synthesis.

As an example let us consider the case of the dimethylformamide (DMF).5 If it is used in reactions evolving in anhydrous media, it will be mandatory to control the level of water at the ppm level. The specification regarding the water content will be of course loosened if the DMF in the chemical step considered is used in conjunction with water as reaction media.

We will see further that solvents contain actually a lot of chemical impurities which could be reactive vis a vis the main molecule undergoing the chemical reaction and leading to additional impurities other than those coming from the mechanism of reaction itself.

14.21.1.2.1.4 Solvents for crystallization

They should be carefully chosen in such a way that they show a high solubility at high temperature and a low solubility at low temperature of the substance to be crystallized or recrystallized.

Of course the solvent should be absolutely inert and of the highest achievable purity for at least two reasons:

•The first one being identical to the one mentioned for solvents as reaction media: possibility to produce other impurities.

•The second one being linked to the crystallization process itself. It is well known that the presence of impurities whatever the origin could have serious effects on the nucleation and growth process. We will tell a little bit more about that further in the text.