The Impact of Formulary Components on Antimicrobial Products



The Impact of Formulary Components on Antimicrobial Products


Peter A. Burke

José A. Ramirez



Many applications of antimicrobials use the antimicrobial agent or precursor in its pure form (eg, ethylene oxide sterilization, chlorination of potable water) or incorporated into a suitable solvent or matrix at the point of use (eg, most preservatives and antimicrobials used in the impregnation of manufactured materials). However, most products used for topical applications or for the disinfection of environmental surfaces (which includes the US Environmental Protection Agency [EPA]-defined categories of sanitizer, disinfectant, and sterilant) are complex chemical mixtures designed to meet multiple product performance specifications demanded by the user. These include, besides the required biocidal efficacy levels, properties such as product toxicity (oral, ocular, dermal, inhalation, etc), cleaning efficacy, ease of use, cost in use, desired aesthetic characteristics (eg, foaming, scent, visual appearance), shelf life, etc. Many times, it is the nature of the chemical matrix into which an active antimicrobial is formulated—the formulation—that provides a manufacturer with certain competitive advantages over other participants in the marketplace.

In this chapter, references are made to a number of chemically functional materials that comprise a formulated antimicrobial product. The terms presented in Table 6.1 are used extensively in the following pages to describe such materials and are defined therein for clarity of discussion.

This chapter focuses on the formulation of antimicrobial actives into finished products. As alluded to earlier discussion, attention is drawn toward topical or environmental disinfection applications, with treatment limited to the more relevant antimicrobial actives for those applications as examples of the importance of formulation. Preservative application and formulation vary in complexity and are highly dependent on the desired product features and performance specifications. Preservation system selection and formulation have to not only meet the desired preservation specifications, but also not alter or negatively affect other important product properties such as appearance, color, odor, rheology, and other relevant mechanical, physical, chemical, or electrical properties inherent to the commercialized product or material. For an extended treatment on preservation systems, the reader is referred to the relevant chapters in this book.


SYNERGISM, ANTAGONISM, AND ADDITIVE EFFECTS

Fundamental concepts in formulation science are those of synergism, antagonism, and additivity. Multiple references exist defining these, including in the specific context of antimicrobial and pharmaceutical formulations.2,3,4 Limiting ourselves to the practical descriptions of the term as used in this context, a mixture is said to exhibit additive effects when its overall performance can be expressed as a linear combination of the individual effects of the components. In other words, the overall effect can be predicted by simple addition of the individual component effects (ie, additivity). On the other hand, a mixture is said to exhibit synergy when the observed effect is greater than the additive effect. Mathematically speaking, higher order (nonlinear) positive interactions between components contribute to an additional effect beyond the linear, additive one. In contrast, antagonism pertains to diminished overall effect from the mixture as compared to the individual components. This could be due to negative linear interactions between species, negative nonlinear (higher order) effects between components, or both. It is noted that these concepts apply not only to the combination of antimicrobial species but also to the combination of antimicrobial species with “inert” components. It is also important to note that the “effect” on which synergism, antagonism, or additivity is measured can not only be antimicrobial activity (eg, log reduction of viable organisms) but also irritation profile, shelf life/stability, odor, or any other relevant product feature.









TABLE 6.1 Definition of key formulation terms employed in this chaptera









































Ingredient


Functionality


Examples


Biocide, antimicrobial


Destruction or prevention of microbial subsistence and/or reproduction


QACs, aldehydes, phenolics, alcohol, peroxygens, halogens, etc


Solvent


Organic molecules, for the most part polar in nature and mostly containing at least an oxygen atom; employed for dissolving hydrophobic substances in water; also used in some cases to improve detergency, streaking, or improve drying rates


Short-chain alcohols (eg, ethanol, isopropanol), alkylene glycols, glycol ethers


Surfactants/emulsifiers


Surface active agents typically comprising a hydrophobe-lipophobe pair structure; used to impart detergency, lower surface tension, emulsify insoluble species, impart or reduce foaming


Sodium lauryl sulfate, linear alkylbenzene sulfonates, ethoxylated alcohols, betaines


Thickeners


A substance used to increase the viscosity of a formulation


Polyethylene glycols, polysaccharides (eg, pectin, gums, alginates)


Chelating or sequestering agents


Compounds that bind dissolved metals (such as calcium, magnesium, iron, copper, etc); used for reducing ill effects of hardness in water on biocide and detergency action and reducing transition metal-aided decomposition of peroxygens and halogens


Ethylenediamine, EDTA, EGTA, MGDA, GLDA, HEDP


Alkali or acid


pH stabilization to desired specification for optimal performance


Alkalis (NaOH, KOH, silicates); acids (organic acids, H2SO4, H3PO4, HCl, etc)


Buffer


Maintaining pH over time and increasing alkalinity


Disodium phosphate


Corrosion inhibitor


Reducing the corrosion rates and protecting metal surfaces


Nitrates, phosphates, molybdates, triazoles


Abbreviations: EDTA, ethylenediaminetetraacetic acid; EGTA, ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid; GLDA, glutamate diacetate; H2SO4, sulfuric acid; H3PO4, phosphoric acid; HCl, hydrochloric acid; HEDP, 1-hydroxyethane 1,1-diphosphonic acid; KOH, potassium hydroxide; MGDA, N-(1-carboxylatoethyl)iminodiacetate, methylglycinediacetic acid; NaOH, sodium hydroxide; QACs, quaternary ammonium compounds.


a Adapted from McDonnell.1


With this in mind, some of the more relevant approaches to formulation with the key antimicrobial material types are discussed further in this chapter. Because it would be impossible to delve into the almost boundless field of formulation science in antimicrobial products, the material presented here is considered a starting point for formulators—the critical, need-to-know, basic principles that enable the reader to plan a formulation approach, devise a registration strategy, or gain a better understanding of the makeup of an existing product.


HALOGENS

Various halogen compounds have been widely used for over a century and a half. The main classes of chemistries are chlorine, bromine, and iodine compounds that are very effective antimicrobials at low concentrations. For instance, iodophors have been used in household settings for the disinfection (or sanitization) of the toilet bowl water at concentrations in the part per billions to react biocidally with gram-negative bacteria in potable water like Escherichia coli.5

Chlorine is not normally distributed in nature but is found in a salt form as either sodium, potassium, calcium or magnesium. Iodine was first used in medical treatment of wounds as Lugol solution (USP XXIII) or tincture of iodine.6 Bromine has been used in a solid released form from hydantoin compounds like 1-bromo-3-chloro-5,5 dimethylhydantoin forming active bromine and chlorine active species. These hydantoin compounds have been effectively used for years in swimming pool sanitization.7

Different approaches have been employed depending on the active selected (chlorine, bromine, or iodine) to formulate an effective industrial antimicrobial product with specific commercial end points as the product’s goal. These approaches include the following methods:



  • Direct liquid or gas injection


  • Slow dissolving granular or tablet mixtures forms


  • Two parts in situ formation of the active to maximize active stability


  • Tincture of iodine solution for skin and wound treatment

The formulation is always specific to the intended use of the antimicrobial product. Uses are broad in this
category because halogens are used for very diverse applications such as drinking water disinfection, sterilization, and wound treatment as well as medical devices, to list just a few examples. Thus, the formulation type coupled with packaging or method of application strategy is rigorously considered at project initiation depending on the market need and industry regulations to be served. The pharmaceutical and medical device applications have much stricter guidelines and antimicrobial requirements. This fact drives different consideration from a concentration perspective as well as toxicity (including ecotoxicity) profile relating to excipient ingredients. This section focuses on formulating halogen-based products for general and some specific applications.

Working with halogen compounds can be very challenging because they are naturally very reactive from a pure chemical perspective and many times are toxic in pure chemical form. Chlorine is a green gas that can react quickly with organic materials in an exothermic reaction that is hard to control. Additionally, this reactive nature makes these agents effective at low concentrations but leads to shorter stability profiles once the active ingredient is dosed into the area for disinfection. The finished formulated product must carefully define the best method of application to the point of antimicrobial action. Many chlorine, bromine, and iodine products are relatively unstable once placed in water or the environment requiring treatment. For instance, hypochlorous acid, a major active entity in many chlorination products used to disinfect swimming pool water, has a very rapid degradation profile once in the water, which is influenced by pH, salts, organic materials, and divalent cations. If the pH of the solution is maintained at 2 to 3, it provides a greater release of hypochlorous acid and longer period of activity. However, this pH is not appropriate for pool chlorination due to the irritancy potential to eye and skin to the humans using this water for exercise. Thus, the pH must be balanced against other important product requirements rather than just antimicrobial efficacy. The impact of pH effect on hypochlorous acid is depicted in Figure 6.1. Therefore, the specific concentration of the active needs to be adjusted to permit application at a suitable pH to achieve the goal. Nevertheless, because less than 1 ppm of hypochlorous acid is typically sufficient for disinfection of the water, there is a lot of potential formulation range to optimize the product to achieve the end point requirements.

To maximize the performance, many factors other than just pH need to be factored in the final formulation or delivery system. Antimicrobial efficacy needs to consider the calcium and magnesium concentrations found as hard water salts in water to prevent any effect of these divalent cations causing active reduction or neutralization. These factors, coupled with the concentrations of organic compounds in the water source, need to be accounted for to minimize the negatively catalyzing agents to hypochlorous acid.






FIGURE 6.1 Relationship between hypochlorous acid (HOCl) and hypochlorite ion (OCl) concentration as a function of pH. Adapted from Baker.8 Copyright © 1959 American Water Works Association. Reprinted by permission of John Wiley & Sons, Inc.

Bromine compounds and iodine in the form of iodophors (iodine-releasing polymers; see following discussion) all have stability challenges centering around the active nature of the antimicrobial agent in the environment resulting in shorter half-lives of the active in solution. Of course, iodine solutions or iodine-releasing compounds have a classic brownish color that needs to be dealt with from an end product perspective because it will discolor clothing, skin, etc, that contact these compounds.

In the case of solid or crystalline compounds releasing halogens, the products are formulated to maximize storage shelf life by mixing the powders under low humidity conditions and using binding agents that have limited chemical interactions with the hydantoin compounds. For example, ethylene oxide-propylene oxide (EO-PO) block copolymers permit very slow release of active ingredients into the application site.5 Most of these products are in tablet form, being made using a Mainstay 10- to 20-ton tablet press after appropriate granularization by a Fitz Mill or equivalent to achieve the desired particle size and density. Iodophor liquid active agents have been
incorporated using similar method of manufacture with some additional steps to reduce humidity.

Some halogen forms have superior stability, especially those that are in granular or powder form such as 1-bromo-3-chloro-5,5-dimethylhydantoin or calcium isocyanuric acid, which are presented in tablet form. These solid forms of chlorine-releasing compounds have excellent shelf life until at the point of use. The ability to present these products as solids permits a long-term stability profile. These types of products have been used in swimming pool sanitizers, toilet bowl sanitizers, medical device disinfectants, and general disinfecting agents for various water sources and are commercially sold in granular or tablet form. For instance, hydantoin tablets are commonly used for hot tub sanitization on a weekly basis due to the slow release technology.

Generally, for chlorine and bromine solution products, the first and most important stabilizing consideration is maintaining liquid formulations at higher pH. The maintenance of higher pH will reduce the rate of decomposition and loss of active agent. The formulation manufacturing needs to have high-quality water with rigid control of ionic contaminants. The presence of transition metals (such as iron, cobalt, and copper) and hardness factors (calcium, magnesium) will increase the rate of degradation of active.9 Thus, chelating agents such as ethylenediaminetetraacetic acid (EDTA) or phosphonates incorporated as an additive in the formula will enhance the stability of the active agent as a function of time. For instance, hypochlorous acid will want to chemically react to form chloramines, chlorides, or chlorates. These compounds typically have lesser or no antimicrobial properties (see chapter 15).

Iodine is a very toxic compound if ingested or absorbed percutaneously, so it is formulated specifically to minimize these negative factors while maintaining its excellent antimicrobial activity. Iodophors are formed to achieve this goal, such as in the use of povidone-iodine complexes. The iodine is reacted by incorporation into a carrier molecule such as polyvinylpyrrolidone (PVP), which has very low toxicity profile. The PVP had been used in the past as a potential blood substitute, having neglectable toxicity.10 This combination has been used for many years in wound healing formulations designed to either reduce or prevent infection by various skin microorganisms on abraded skin or burns. Povidone-iodine complexes have been used in the healing of burned skin for decades without any significant negative impact on the patient or users (see chapter 16).

There are a number of compounds with potential to contribute to the inherent properties of halogens, increasing antimicrobial efficacy while minimizing their negative oxidative properties. As mentioned earlier, pH, by itself, is a synergistic agent to halogens. Thus, the mere control of pH can dramatically improve antimicrobial activity under constant conditions. Agents that control the pH provide the active agent a more active efficacy per unit and greater stability profile presenting greater microbial reaction. This profile is seen most easily under difficult microbial conditions such as in the presence of bacterial endospores, which are intrinsically more resistant naturally to halogens than vegetative microorganisms. Various surfactants or other surface-active agents act as synergists with halogens as well. Anionic surfactants are most effective due to their low pH tolerance. Thus, alkylbenzene sulfonates, alkyl sulfates, and alkyl phosphonates are good formulary compounds that provide positive benefits to halogens in solution. Some nonionic surfactants can be used but are much more difficult to formulate with many side interactions that negatively impact the halogen antimicrobial effectiveness. Nevertheless, their ability to increase wettability and reduce the interfacial surface tension of solutions to be able to suspend soil particles at low concentrations impart important benefits for removal of soiled surface particles permitting greater antimicrobial activity because of the combination with cleaning activity.

Finally, cationic and amphoteric surfactants have also been used in formulated products; however, the superior effects observed with anionic surfactants makes the use of these alternative agents less likely in practice. Hence, most standard nonspecific application formulas usually contain an anionic or nonionic surfactant as a preferred cleaning agent.

Other common compounds found in halogen-containing formulations begin with high-quality water without ionic characteristics (ie, deionized water). Second, solvents are used as cosolvents as well for cleansing and solubility factors. Thus, other than water, common solvents include short-chain alcohols such as methanol, ethanol, and isopropanol. Other solvents used are glycol ethers for solubility and freezing point depression and benzyl alcohol to provide wettability and detergency properties. Examples of general formulations such as an iodine-based, toilet bowl-sanitizing tablet and a chlorine-releasing, extruded lavatory sanitizing block are provided in Table 6.2.


ALCOHOLS

Alcohols have been used for many years as antimicrobial agents and are perhaps the oldest biocidal active still in use. They are known to have been used as early as 131-201 ad as a wound treatment and cleaning aid. In the late 1870s, Koch studied these agents and suggested they were ineffective, at least with relevance to Bacillus anthracis spores. This finding, although correct, did not reflect the agent’s action on vegetative cells on which it has been proven to be very efficacious. By 1888, Furbringer12 was recommending alcohol as a hand disinfectant for surgeons, which has remained a potential use even today.









TABLE 6.2 Examples of halogen formulations


























































Ingredient


Concentration (%)


US 4,911,8595


Calcium sulfate dihydrate


59.8


Calcium sulfate anhydrous


10.0


Fumed silica


4.0


Iodophor (Biopal NR-20)


8.5


Polyvinylpyrrolidone-iodine complex (povidone)


5.7


Dye (acid blue #9)


5.0


Polyethylene oxide polymer (Polyox 60K)


2.0


Polyethylene glycol (PEG 4500)


5.0



100.0


US 5,449,47311


Sodium dodecylbenzene sulfonate


52.0


Chloramine T


31.5


Neodol 91 (alcohol ethoxylate)


8.0


Polybutene


4.0


Perfume


0.5


Volatile silicone oil


4.0



100.0


As a group, alcohols have played an active role over the years as either a disinfectant or an antiseptic. The broad-spectrum antimicrobial activity against both gram-positive and gram-negative bacteria, fungi, and viruses made the common alcohols of ethanol and isopropanol widely used agents for many years. The mode of action is thought to be a combination of protein degradation and cell membrane disruption (see chapter 19). Nevertheless, unlike antibiotics but like most chemical disinfectants, alcohols are considered nonspecific antimicrobials from a pure mechanistic perspective. Because they have been in use for many years in hospitals settings, it can be speculated if the microbial flora is becoming resistant to these agents and require reformulation with either other antimicrobial agents or compounds to prevent this effect. Studies to date do not show any marked resistance to alcohols especially at the use concentrations used for either disinfectants or antiseptics. Both Willie and Wigert13 showed minimal resistance profiles and, more importantly, reversal of any developed resistance with termination of alcohol exposure.

Alcohols are typically used in concentrations of 70% to 80% to be effective, which can often limit their use for surface disinfection in comparison to other available antimicrobials. There are many factors such as toxicity, ecology, and general cleansing properties that often favor other formulations. The use of alcohols for submersion of a limited number of medical devices is still performed but is limited in scope. By submerging the device for 10 minutes in 70% to 80% alcohol, disinfection can be achieved. However, the use of alcohols for general environmental surface disinfection is often limited because these formulations are poor cleaners and evaporate rapidly, preventing sufficient contact time for biocidal activity. However, it should be noted that simple aqueous dilutions of alcohol are still used with great effectiveness against vegetative bacteria.

The high concentration requirement (more than 70% ethanol or isopropanol) is a potential cost disadvantage and leaves little room for synergistic compound incorporation or for improvement in the cleansing properties in surface disinfectant products. Simple alcohols diluted in water are widely used as a surface disinfectant without necessary formulation to gain effectiveness for this application and because they are not registered disinfectants no further improvement will occur. Despite this, examples can include combinations of alcohols and formulations with oxidizing agents (such as hydrogen peroxide or peracetic acid) (see chapter 19). In contrast, the majority of alcohol and alcohol formulations have been used significantly in wound healing, skin degerming, and antiseptic waterless hand washes. Alcohols have been very widely used in skin treatments for medical procedures. Therefore, the majority of this review focuses on the formulation of skin care products using alcohols as an antiseptic.

Skin has a normal microbial flora natural for each individual depending on the area of anatomical skin, which can harbor both transient and pathogenic organisms that can infect disrupted (abraded) skin (see chapters 42 and 43). Alcohol application to the skin limits these organisms from colonizing the skin by reducing the entire microbial population, part of which may include very low numbers of pathogenic organisms such as methicillin-resistant Staphylococcus aureus. The alcohol formulation itself has an optimal concentration of 95% for maximum effectiveness.14 However, to balance cost, safety risks, and ultimate antimicrobial effectiveness, a 70% concentration has been found to be very efficacious with excellent results for many years in hospitals and other health care facilities.

The use of alcohols in hospitals as prophylactics against cross-contamination and infection has prompted the use of waterless agents every time a health care professional or visitor enters the patient area or tends to the patient. These measures have been effective in helping to prevent the spread of health care-acquired infections from one patient to another via the health care worker. Thus, the alcohol disinfection or washing of hands assists in the potential hand-to-hand contact resulting in limited but potentially dangerous cross-contamination of hospital pathogens among patients.15

To achieve effective formulations for this application, the alcohols have been incorporated into gels and foam
products. A variety of polymers are used to achieve this gelling effect such as Carbopol®.16 The use of this polymer permits the user to dispense and rub together their hands without alcohol loss from running off the skin surface to the floor presenting a hazard. This is important because the hands need to be vigorously rubbed together to entirely cover the skin surface of the hand. This treatment can result in improved antimicrobial efficacy, some claiming to be in excess of a 5 log reduction of bacteria under certain test conditions.17

In the United States, the US Food and Drug Administration (FDA) regulates these products from a regulatory perspective relative to toxicity and efficacy. These antiseptics were initially regulated under the tentative final monograph of 1976. However, this monograph has been under careful review by FDA to examine the toxicity requirement of these products for future use and registration with FDA for use in the United States. This review will take an extended period of time between government requirement and generation of industry-based data to depict the toxicity profile in modern toxicology methods. The criteria for acceptance of these products is thus still under flux regarding toxicity at the time of writing. These regulatory decisions will potentially have a significant impact relative to formulary practice.

One of the main concerns from health care professionals using these products multiple times per day is the irritancy and sensitization potential of the products. Hence, formulators have focused on this point to ensure the emollient nature of the product provide a less irritating formulation while not reducing the efficacy profile. Various humectant components have been incorporated into formulae to achieve a gentler product for multiple use applications. A basic moisturizing agent is a glycerin-like compound that provides this property to the alcohol-based formulation. The most simplistic formulary action can be the mere reduction in alcohol content from 60% to 70%, which reduces cost with minimal-if any-effect on antimicrobial efficacy. This formulary consideration affects efficacy by reduction of evaporation, providing while greater contact time of active. The added water provides very basic moisturizing benefits. Of course, there are many complex chemistries that can be used for these moisturizing purposes depending on the formula properties.

Finally, the regulations often require these antiseptics to have reduced microbial skin population (eg, after 10 successive hand washes), which retard microbial repopulation. Alcohols by themselves are not substantive in nature to skin, and hence, other formulary constitutions are often added to achieve this goal. This typically includes the addition of a low concentration of another biocide, such as chlorhexidine gluconate (CHG) or triclosan (Figure 6.2). The bisphenol triclosan is one of many ingredients that has shown to be substantive to skin at low concentration making this compound useful for this purpose. This compound has been found to be effective for this use due to not only its substantive properties but also its traditionally considered low toxicity and rare sensitization potential. These properties have led to the incorporation of this compound like others in medicated soap, hand antiseptic products, antiperspirants, deodorants, and dentifrices. The CHG is being used widely today in comparison to other compounds for residual effect due to both antimicrobial efficacy with excellent toxicity and environmental profile. However, recent evidence would suggest concerns on the safety of triclosan, particularly in nonessential applications such as routine handwashing in the general public.18 These include human toxicity impacts, environmental bioaccumulation and persistence potential, effects on natural microbiomes, and development of bacterial tolerance mechanisms as well as cross-resistance to antibiotics.19 In certain situations, this has led to banning the use of triclosan and indeed other similar antimicrobials in certain applications (such as antimicrobial soap-based products by the FDA).17 For further reviews of this subject, see McDonnell.1






FIGURE 6.2 Example of biocides (top, triclosan, and bottom, chlorhexidine) used in combination with alcohols to provide substantivity to skin.

In conclusion, alcohol-containing waterless hand gels have been shown effective in reducing the potential for cross-contamination leading to hospital-acquired infections. Until safer and more effective agents are developed, alcohol-containing formulations will be used in hand washes to protect patients from cross-contamination in the hospital setting. The formulation of alcohol-containing antiseptics can be modified to improve efficacy, as well as to address any toxicity concerns to patients and health care workers, or ecology concerns to provide the desired efficacy but limiting environmental impact.


PHENOLICS

Phenolics, in particular coal tar compounds, have been used as early as 1815 for antimicrobial purposes. The first medical application of phenol itself as an antimicrobial was by Lister20 in 1867 as a wound dressing treatment and
surgical antiseptic solution. Most phenolic compounds today are synthetically derived as pure actives substances (see chapter 20). Alkylated phenol homologs are very effective agents, and generally, as the number of methylene groups increases in substitution, the antimicrobial potency increases likewise. A few phenolic compounds are presented in Figure 6.3 to demonstrate the variation in molecular structure.






FIGURE 6.3 Examples of antimicrobial phenolic compounds.

Phenolic disinfectants compounds have been used since the early 19th century, and today, at least 10 million pounds of active are used in various biocidal applications.21 The most common phenolic derivatives used in health care applications are ortho-phenylphenol (OPP) (2-phenylphenol); ortho-benzyl, para-chlorophenol (OBPCP); and 4-tert-amylphenol.

Several approaches are possible to formulate industrial or hospital-grade disinfectant products containing a phenolic compound or blended compounds as the active agents. The formulations are based on the use of the active against the organisms required to be eradicated by the location such as a hospital versus the use in industrial settings (such as in food or general housekeeping). Hence, many factors need to be considered when formulating the component parts with varying interaction with the phenolic compounds to either enhance or synergize activity. Phenolics are generally more effective in acidic solutions. Hence, the inclusion of soaps and emulsifiers is required to make the phenols more soluble while maintaining a balance of pH necessary for optimal efficacy. As the pH increases in solution, the phenol is converted to sodium or potassium phenate that is less active. Therefore, using the correct combination of soap and phenolic compound at a given pH can increase the antimicrobial potential. The phenates themselves can act as a solubilizing agent for the phenol. Fully formulated phenolic disinfectants take into consideration the use of cosolvents, pH adjustment, surface active agents, and chelation agents, which will maximize the efficacy potential when used in unison.

Most phenolic disinfectants concentrates are formulated for dilution to 400 to 1400 ppm at use. These formulations are used as broad-spectrum disinfectants that possess vegetative, viricidal, and tuberculocidal activity but are not sporicidal generally. Phenolic dispersions have been made in natural soaps, but this is not recommended due to the effect of hard water salts that readily precipitate calcium and magnesium soaps when diluted. Most modern synthetic soaps can be easily diluted in 400 ppm of hard water without any clarity issues while maintaining its antimicrobial activity. Surfactants are used to solubilize the active ingredient while providing cleansing properties as well as solvating the soils present in the environment for formula effectiveness.

Of the various classes of surfactant ingredients, only the anionic class is generally used in the formulation of phenolic disinfectant products. Wallhausser22 has reported that alkane sulfonates as solubilizing agents are very effective solvents with phenolic compounds. Nonionic surfactants can inactivate the antimicrobial properties of phenolics. The use of cationic surfactants (such as quaternary ammonium compounds [QACs]) has been reported as being used in some specific applications but are generally considered incompatible with phenolic disinfectants. Synergy has been reported with certain quaternary compounds.23 The theory is that the QAC reduces the surface tension to such a degree that solution falls below the critical micelle concentration permitting more phenol to interact at the cell membrane. Anionics are the mainstay for surfactants used for cleansing, wettability, and solubilization of phenolic compounds with agents such as dodecylbenzene sulfonates commonly used. This type of compound provides good solvent action while not affecting the antimicrobial potency of the phenolic compound when diluted to the use dilution during application.

Furthermore, other cosolvents are used to formulate the final phenolic disinfectant product such as alcohols, glycol ethers, and propylene glycol. These cosolvents permit greater incorporation of the agent at various pH’s while maintaining the antimicrobial potency with limited decline of active. Hence, the use of various agents to aid in the incorporation of phenolics is critical for formulation maximization. The selection of detergents, builders, cosolvents, and appropriate chelating agents will greatly improve the formula.

Stability of phenolic disinfectants is generally good provided no interaction with incompatible ingredients incorporated in error. It is important to have a long-term stability profile of the phenolic agent as a function of time with a minimum of 1 year with a goal of 2 years of acceptable shelf life. Thus, negative interacting compounds such as nonionic surfactants should be carefully screened with the specific phenolic compound via assays to maintain long-term disinfectant stability (shelf life). Examples of a few phenolic formulation used commercially are shown in Table 6.3.









TABLE 6.3 Examples of formulated commercialized phenolic formulationsa















































































































































































































































Ingredient


F1


F2


F3


F4


F5


F6


F7


F8


F9


F10


F11


OPP


15


18


18


15


15


15


7.5


14


14


14


5


4-Chloro, cyclopentylphenol


6


7



5.9


6



2.9






4-Chloro, 2-benzylphenol




7




6.3



7.5


8.5




4-Tert-amylphenol





2.5



2.5


1.25


2.0


2.0



0.8


2,4-Dichloro, 3,5-dimethylphenol











12


4.7


Alkyldiphenyloxide disulfonate (45%)


7


8.5


8.5


4.5


6.5


4.5


4.5


8.1


6.8


6.8


4.5


Sodium lauryl sulfate


3





3.5


4.0


1.0



2.1




Dodecylbenzene sulfonate



1.5


1.5


2.0







2.0



NTA











1.0



EDTA


3.3


3.3


3.3


3.3


2.5


0.8


0.4


1.0


1.0



1.0


Sodium hydroxide


3.0


3.5


3.7


3.6


3.3


3.2


1.4


3.0


2.6


2.8


1.4


Isopropanol


10


10


10


5



10


10


10




5


Hexylene glycol








5.0



10




Sodium sulfite



0.5


0.5


0.5


0.5


0.5


0.25


0.6


0.6


0.5


0.5


Sodium xylene sulfonate











4



Perfume



0.3


0.4


0.3


0.3


0.3


0.2




0.2



Dye



.002


.002


.001


.001


.001


.001




.001



Abbreviations: EDTA, ethylenediaminetetraacetic acid; F, formula; NTA, nitrilotriacetic acid; OPP, ortho-phenylphenol.


a Data from Winicov and Schmidt.24

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