The fundamental property of surfactants is their tendency to accumulate at interfaces, such as solid-liquid (suspension
), liquid-liquid (emulsion
), or liquid-vapor (foam
Surface-active agents possess both water-soluble and oil-soluble characteristics. The dual solubility of the surfactants makes them able to exhibit unique properties. If a compound is completely water soluble or completely oil soluble, it will not collect at the interface; instead, it will dissolve in the medium in which it is soluble. It is the nonpolar group that allows the compound to be partially oil soluble and the polar group that allows the compound to be partially water soluble.
Another important characteristic of surfactants is their capacity to lower surface or interfacial tension. Surface tension of a liquid is the force that opposes the expansion of the surface area of that liquid. Interfacial tension is similar to surface tension; however, one important difference is the location at which the tension occurs. Interfacial tension takes place at the interface of the two immiscible liquids, whereas surface tension takes place between the liquid surface and the air. Electrostatic or molecular forces are responsible for surface and interfacial tension. These forces are the reason for the mutual attraction of molecules for one another. Many molecules, although electrically neutral, have an uneven distribution of electrical charge, thus giving them polarity, or a negative or positive center of electricity. These negative and positive centers of electricity create the electrostatic forces within molecules.
The molecules in a liquid possess electrostatic forces, giving rise to intermolecular attraction. This attraction between “like” molecules is caused by cohesive forces
. Adhesional forces
occur because of the molecular attraction between the liquid’s surface and the liquid molecules. The net result of the adhesional forces and the cohesive forces at the interface of two immiscible liquids is known as interfacial tension
. If the cohesive forces, which tend to hold the liquid molecules together, are stronger than the adhesional forces, which tend to pull the surface of the molecules apart, the interfacial tension will be high and the two liquids will not mix. To lower the interfacial tension between two immiscible liquids, the interface between the two liquids must be altered by some means. This may be accomplished by adding a substance that is
capable of orienting itself between the liquid layers. On collection of a surface-active substance at the interface, there is a reduction of interfacial tension. These surface-active compounds are called emulsified agents
, which help to hold together two immiscible liquids, forming a water-in-oil or an oil-in-water emulsion.
A representation of the structure of surfactant monomers and associated classification based on their overall charge (nonionic, anionic, cationic, and amphoteric). Also shown (right) are examples of micelles or aggregates of surfactants and the locations of solubilizates in spherical micelles. A, Ionic surfactant (solubilized molecules in this case have no hydrophilic groups). B, Nonionic surfactant (with polar solubilizate). Based on Zografi et al1
Stearic acid is an example of a surface-active compound. When stearic acid is placed in water, the molecules will collect at the surface. The molecules cannot go beyond the surface because the hydrophobic (or lipophilic groups) are insoluble in the water. Because of the dual-solubility characteristics of stearic acid molecules, they are adsorbed on the surface of the liquid and then are able to lower the surface tension of water. When the water and petrolatum are mixed, they have an interfacial tension of 57 dynes/cm. With the addition of a drop of stearic acid to water alone, the acid collects at the surface, with its polar groups projected in the water and its nonpolar groups oriented in an outward direction. The interfacial tension between the stearic acid and the water is 15 dynes/cm. When liquid petrolatum is added to the water-stearic acid mixture, the interfacial tension still remains at 15 dynes/cm. The monomolecular layer of the stearic acid between the liquid interface serves to lower the interfacial tension from 57 dynes/cm to 15 dynes/cm.
Another fundamental property of the surface-active agents is that in solution, they tend to form micelles or aggregates (see Figure 21.1
). The different types of micelles formed by surfactants are shown in Figure 21.2
. Micelle formation, or micellization
, reduces the free energy of the system by decreasing the hydrophobic surface area exposed to water. The surfactant molecules behave differently when present in micelles compared with free monomers in solution. Micelles are a reservoir for surfactant molecules, usually in their monomer
(single molecule) form. The ability of the surfactant molecules to lower surface interfacial tension and dynamic phenomena, such as wetting and foaming, is governed by the concentration of free monomers in solution. Micelles are generated at low surfactant concentration in water. The concentration at which micelles start to form is called the critical micelle concentration
(CMC) and is an important characteristic for each surfactant. Table 21.1
lists the CMC and micellar aggregation numbers for the three most common types of surfactants: anionic, cationic, and nonionic (with the values recorded in water at room temperature).
The global surfactants market was estimated to be approximately $43 million in 2017 and is projected to rise to approximately $66 million by 2025. The classification of surfactants is typically made on the basis of the charge of the hydrophilic (polar) group. There are four major classes of surfactants (in order of decreasing, estimated volume demand):
A. Anionics (approximately 40%)
B. Nonionics (approximately 30%)
C. Cationics (approximately 20%)
D. Amphoterics or zwitterions (<10%)
The anionic group, which consists of alkaline salts of fatty acids, is by far the largest group used by consumers
in the form of soaps. Commercially, soaps are prepared by saponification of animal fats, vegetable oil, coconut oil, palm oil, or natural fatty acid glycerides in caustic solution. The soaps, in addition to their cleaning and detergent characteristics, are used in the pharmaceutical industry for their ability to solubilize compounds. They also act as wetting agent for solid dosage forms and emulsifying agent in emulsion formation. Monovalent soaps (Na+
) will give oil-in-water emulsions. Divalent soaps (Ca2+
), due to their poor water solubility, will produce waterin-oil emulsions. The triethanolamine salts of fatty acids will give an oil-in-water emulsion. The synthetic anionic surfactants of commercial importance in this category include the following: alkyl sulfate, alkyl ether sulfate, alkyl benzenesulfonate, alkyl xylenesulfonate, dialkyl sulfosuccinate, alkyl phosphate, alkyl ether phosphate, alkyl ether carboxylate, and others.
Examples of different types of micelles. A, Spherical micelle of an anionic surfactant. B, Spherical micelle of a nonionic surfactant. C, Cylindrical micelle. D, Lamellar micelle. E, Reverse micelle of an anionic surfactant in oil. Based on Zografi et al1
The nonionic group is a major class of surfactants used widely throughout the pharmaceutical industry as a result of its low toxicity, good compatibility, and excellent stability in biologic systems. The most widely used compounds are the polyoxyethylene sorbitan fatty acid esters, which are found in both internal and external pharmaceutical formulations. The polar group in this category is a polyether or polyhydroxy oxyethylene unit attached to a fatty alcohol, fatty acid, or fatty amide moiety. These compounds can be water insoluble or quite water soluble, depending on the degree of ethoxylation. Ethoxylated surfactants can be tailor-made with regard to the average number of oxyethylene units added to a specific fatty alcohol. Representative commercially available nonionic surfactants include fatty alcohol ethoxylate, fatty acid ethoxylate, fatty amide ethoxylate, fatty amine ethoxylate, alkyl glucoside, sorbitan alkanoate (SpanTM), ethoxylated sorbitan alkanoate (TweenTM), alkylphenol ethoxylate (IgepalTM CO, Nonoxynol-9 or -11). The ethers offer an advantage over the esters in that they are quite resistant to alkaline or acidic hydrolysis. Nonionic surfactants are compatible with all other classes of surfactants and have been used as stabilizers, wetting agents, dispersants, detergents, and emulsifiers.
The interfacial properties of nonionics are greatly influenced by the polarity or nonpolarity of the system. As a result of the importance of polarity, a system was developed to assign a hydrophilic-lipophilic balance (HLB) number to each surfactant. The HLB value is the percentage weight of the hydrophilic group divided by 5 to reduce the range of values. On a molar basis, a 100% hydrophilic molecule (polyethylene glycol) would have a value of 20. The Atlas Powder Company3
devised the HLB number system for nonionic surfactants used as emulsifying agents (Table 21.2
developed an HLB scale, which is a numeric scale that extends from 1 to approximately 50. There is a relationship between the different applications of surfactants and the HLB range (Table 21.3
), and there are methods available to calculate the HLB value of new surface-active agents. Table 21.4
provides examples of how to calculate the HLB value of
nonionic emulsifying blends to form an oil-in-water or a water-in-oil emulsion and thus to assign an HLB number. The hydrophilic groups on the surfactant molecule make a positive contribution to the HLB number, and the lipophilic groups exert a negative effect. There are several members of this class of surfactants, like nonoxynol-9, with spermaticidal and some disinfecting activity (eg, against human immunodeficiency virus [HIV] and some bacteria associated with sexually transmitted diseases).5
Nonionic nonoxynol-9 can stabilize quaternary ammonium compound (QAC; types of cationic surfactant) formulations because nonionics are not sensitive to hard water. The hard-surface disinfecting activity of QACs is potentiated by the nonionics, such as nonoxynol-9. It is well documented that ethoxylated surfactants do support bacterial growth and deactivate preservatives,6
such as the parabens. Although they are predominantly used for cleaning applications, they are not widely used as disinfecting agents. They can demonstrate some bactericidal activity and are sometimes used in combination with other biocides as preservatives, demonstrating some bacteriostatic, fungistatic, and sporistatic activities. Further discussion of nonionic surfactants are outside the scope of this chapter.
TABLE 21.1 Critical micelle concentrations (CMCs) and micellar aggregation numbers of various surfactants in water at room temperature
Sodium octant sulfonate
Sodium decane sulfonate
Sodium dodecane sulfonate
Sodium lauryl sulfate
Sodium lauryl sulfates
Sodium di-2-ethylhexyl sulfosuccinate
Octaoxyethylene glycol monododecyl ether
Dodecaoxyethylene glycol monododecyl ether
Decaoxyethylene glycol mono-p,t-octylphenyl
ether (octoxynol 9)
a Interpolated for physiologic saline, 0.154 M NaCl.
b At 55°C instead of 20°C.
Cationic surfactants arise due to a cationic charge on the nitrogen atom. Although phosphonium and sulfonium cationic surfactants exist,7
this chapter primarily addresses the QACs with antimicrobial activity. This class of surfactants is hydrolytically stable and shows higher aquatic toxicity than most other classes; however, newer “soft” QACs, which were considered more environmentally friendly, have replaced dialkyl QACs as textile softening agents. They contain an ester or amide moiety in their hydrocarbon chain. Devinsky and coworkers,8
using quantitative structure-activity relationships (QSAR) methods, give a good correlation of biologic activity (minimum inhibitory concentration or MIC) and lipophilicity, which is characterized by CMC and the length of the alkyl chain (Table 21.5
). This topic is discussed later in this chapter. Several molecules in this class of soft
QACs have good antimicrobial activity and low systemic toxicity. Compared with “hard” counterpart benzalkonium bromide (dimethyldodecylbenzylammonium bromide, with an oral median lethal dose [LD50
] 410 mg/kg), the amides and the esters differ significantly (eg, LD50
for compound no. 4 = 976 mg/kg, whereas compound no. 15 = 1450 mg/kg orally in mice) (see Table 21.5
). It was concluded that “soft” QACs are two to three times less toxic than benzalkonium bromide based on LD50
comparison. When the ester or the amide groups within a “soft” QACs are hydrolyzed, the surface activity of the QAC is lost, and so is its antimicrobial efficacy. As a result, the biodegradation order was proposed as ester, QAC >> amide >>>> benzalkonium bromide (the most resistant to biodeterioration); however, the “soft” QACs had limited application as commercial antimicrobials. Instead, they are mostly used as hair- and skin-conditioning agents in personal care industries and as fabric softeners in textile and paper industries.
TABLE 21.2 Approximate hydrophilic-lipophilic balance (HLB) values for emulsifying agents
Generic or Chemical Name
Propylene glycol monostearate
Glycerol monostearate (non-self-emulsifying)
Propylene glycol monolaurate
Glyceryl monostearate (self-emulsifying)
Polyethylene glycol 400 monostearate
Sodium lauryl sulfate
TABLE 21.3 Relationship between HLB range and surfactant application
W/O emulsifying agents
O/W emulsifying agents
Abbreviations: HLB, hydrophilic-lipophilic balance; O/W, oil-in-water emulsion; W/O, water-in-oil emulsion.
TABLE 21.4 Hydrophilic-lipophilic balance group numbers
N (tertiary amine)
Ester (sorbitan ring)
Hydroxyl (sorbitan ring)
The amphoteric (or zwitterionic) surfactants contain both an anionic and a cationic charge on the same molecule. An amphoteric surfactant is pH dependent and can therefore be either cationic, zwitterionic, or anionic. A change in pH of an amphoteric surfactant will change its charge and naturally affects its properties like detergency, wetting, and foaming. At the isoelectric point, the physiochemical properties of these amphoterics resemble that of nonionic surfactants. Above and below the isoelectric point, there is a gradual shift toward anionic and cationic character, respectively. The amphoterics have excellent dermatologic properties and show low eye and skin irritation.
These properties are well suited for use in shampoos and other personal care products. They are compatible with all other classes of surfactants, and they are stable in acidic and basic environments. Under strong alkaline conditions, betaines retain their surfactant properties. The most common commercial representatives of amphoteric surfactants are betaine (alkyldimethyl ammonium acetate from chloroacetic acid and alkyldimethylamine), alkyldimethylamine oxide (made by reaction of alkyldimetylamine with hydrogen peroxide), amidobetaine (made from fatty acid reaction with N,N-dimethylpropane-1,3 diamine, followed by reaction with chloroacetic acid), and alkyl imidazoline (synthesized by reaction of a fatty acid with aminoethanolamine, followed by treatment with chloroacetic acid). By far, the most widely used betaine is cocoamidopropyl betaine (under many trade names). It is used by many surfactant manufacturers, such as betaine C (TEGOTM; Evonik Goldschmidt Chemical Co, Mapleton, Illinois), cocamidopropyl betaine (LexaineTM C, Inolex, Philadelphia, Pennsylvania; AmphosolTM CA, Stepan, Northfield, Illinois; MirataineTM BET C-30, Rhône-Poulenc, Collegeville, Pennsylvania; EmpigenTM BS, Albright & Wilson, Oldbury, United Kingdom; CaltaineTM C-35, Pilot Chemical Co, Houston, Texas; MackamTM 35-HP, McIntyre Group Ltd, University Park, Illinois), and oleamidopropyl betaine (LonzaineTM C; Lonza, Walkersville, Maryland).
The amphoteric surfactants are also widely used in formulations due to their surfactancy and often low associated irritation, such as a foam booster, antistatic agents, and as shampoos, but also are reported to have some antimicrobial activity. They are both used for preservative (bacteriostatic and fungistatic) and disinfectant activity (bactericidal and fungicidal) at low concentrations,9
including the yeast Pityrosporum ovale
(associated with dandruff and formulations used for dandruff treatment).10
TABLE 21.5 Antimicrobial activity and critical micelle concentrations of quats
—log Cka (mol/dm3)
MIC × 106(mol/dm3)
Abbreviations: MIC, minimum inhibitory concentration; NH, nitrogen-hydrogen.
a From conductivity measurements.
b Benzyldodecyldimethylammonium bromide.
c Not included into calculations of regression equations.
QUATERNARY AMMONIUM ANTIMICROBIAL COMPOUNDS
The quaternary nitrogen moiety is an essential component for many biologically active compounds. The QACs play an important role in the living process. From vitamins (vitamin B complex and thiamine) to carboxylase enzymes, which participate in the carbohydrate metabolism, to choline, which is involved in the transmethylation reaction of fat metabolism, and to acetylcholine, a mediator in the transmission of nerve impulses all play a fundamental function. There are at least four types of physiologic actions11
associated with QACs: (1) curare-like (curaremimetic or curareform) action, a muscular paralysis with no involvement of central nervous system or heart, produced by D-tubocurarine chloride used to induce muscular relaxation during surgery; (2) muscarinic-nicotinic action, which is a direct stimulation of smooth muscles and is a primary transient stimulation and secondary persistent depression of sympathetic and parasympathetic ganglia; (3) ganglia-blocking action; and (4) neuromuscular blockade. Table 21.6
illustrates the chemical structures of representative compounds responsible for these physiologic actions.
TABLE 21.6 Examples of quaternary structures with physiological actions
d-Tubocurarine chloride USP
Medicinal chemists, using the principle of structureactivity relationships (SARs), have synthesized many QACs that will mimic certain biologic effects.12
Thus, a complex structure of D-tubocurarine chloride can be reduced to a much simpler decamethonium structure, a neuromuscular-blocking agent. Hexamethonium acts as a ganglionic blocker by preventing the receptor from responding to acetylcholine. The decamethonium is too long to fit the ganglionic receptor but acts as a neuromuscular blocker by preventing the binding of acetylcholine to muscle endplate receptors. When the number of carbon atoms separating the quaternary nitrogens is increased above 12 carbons, the autonomic nervous activity disappears and the compounds become surface active and antimicrobial; however, there are exceptions to this rule, as discussed later in the case of bis-quaternary and polymeric QACs, where two and four carbon atoms separate the quaternary nitrogen, and the products have antimicrobial properties.
Although there are many stages in the historical development of quaternary ammonium antimicrobials, there is general agreement on at least two truly historical milestones. The first is the work of Jacobs and coworkers, which examined structure, preparation, and antimicrobial activity.13
A number of papers published in 1915 described the preparation of various different series of the quaternary ammonium salts of hexamethylenetetramine.14
In 1916, the antimicrobial activity of many of these synthesized QACs and additional derivatives were described.13
In these publications, they related structure to antimicrobial activity. Although some reviews have challenged this work as the earliest investigations of QACs, their preeminence is assured by their quality, quantity, and treatment, which included antimicrobial activity and correlation between structure and antimicrobial activity. The only valid criticism may be the fact that some of the antimicrobial activity observed may be due to the release of formaldehyde from hexamethylenetetramine. Methenamine mandelate United States Pharmacopeia (USP) is still used as an antibiotic for urinary tract infection, acting by releasing formaldehyde in an acid medium.2
During the 1920s, additional information was published on the bacterial activity of quaternary derivatives of pyridine, quinoline, and other ring structures23
as well as QACs of acylated alkylene diamines.26
By 1935, with the demonstration of the antibacterial activity of long-chain quaternary ammonium salts, the second and most important milestone in the development of antimicrobial QACs took place.27
The improved bactericidal activity that occurred when a large aliphatic residue was attached to the quaternary nitrogen atom established the practicability and utility of these compounds, first in medicine and later in many other applications. This important disclosure stimulated research in the synthesis and antimicrobial testing of QACs, with the consequent frequent publications and patents up to the present. After Domagk’s discovery of the biocidal properties of cationic surface-active agents, several generations of structurally variable quaternary ammonium antimicrobials of commercial importance were developed.
The first generation was the standard benzalkonium chloride (BAC) of specific alkyl distribution, namely, C12
, 40%; C14
, 50%; and C16
, 10%. Another version of equally commercially successful alkyl distribution in the benzalkonium series is C12
, 5%; C14
, 60%; C16
, 30%; C18
, 5% as shown in Table 21.7
. The official USP recognized BAC as a pharmaceutical aid (antimicrobial preservative). The USP specification for the C12
homologues components was 70% minimum of the total alkylbenzyldimethyl ammonium chloride content. This broad specification does not always give the most efficacious product. The major determining factor for biocidal efficacy is the HLB of the products. The peak for biocidal activity of the homologue series is illustrated on Table 21.8
, with a carbon chain of 14 offering the best activity.28
Modifications in the first-generation QACs by substitution of the aromatic ring hydrogen with chlorine, methyl, and ethyl groups resulted in the second generation of the substituted benzalkonium compounds. Of this group, the product with commercial significance was the alkyldimethylethylbenzyl ammonium chloride under the trade name BTC 471 with alkyl distribution C12, 50%; C14, 30%; C16, 17%; and C18, 3%. Another product with antimicrobial activity in this group was alkyldimethyl-3,4-dichlorobenzyl ammonium chloride under the trade names of Tetrosan 3,4D and Riseptin with same alky distribution as previously described.
But by far, the greatest commercial significance was with third generation of QACs, the dual quats, initially developed in 1955 under the trade name BTC 2125M. This product was a mixture of equal proportions of alkyldimethylbenzyl ammonium and alkyldimethylethylbenzyl ammonium chlorides of specific alkyl distribution, as shown in Table 21.7
. This combination of BAC with alkyl distribution (C12
, 5%; C14
, 60%; C16
, 30%; C18
, 5%) and alkyldimethylethylbenzyl ammonium chloride with alkyl distribution (C12
, 68%; C14
, 32%) is BTC 2125M, with claimed antimicrobial performance against vegetative bacteria. This synergistic combination of the third generation of quaternaries not only had an increased biocidal activity but also reduced the acute oral LD50
from 0.3 g/kg of BAC to an acute oral LD50
of 0.750 g/kg for BTC 2125M. The third generation of dual QACs offered improved biocidal activity, stronger detergency, and a relatively lower level of toxicity. In the early 1950s, the nonionic detergents were being developed with far greater cleaning power than natural soaps. The compatibility of QACs with nonionic detergents resulted in superior formulations that helped overcome the environmental factors, such as hard water, anionic residues of soap, and proteinaceous soils, which were found to weaken their effectiveness.34
A continual change and improvement in advancing and broadening the spectrum of biocidal activity enabled disinfectants to work under the most adverse conditions and produced safer, more economic products. In 1965, another technologic development, catalytic amination of long-chain alcohols, made commercially feasible the production of dialkylmethyl amines, which in turn can be quaternized with methyl chloride to give us the twin-chain quats, the fourth generation of quaternaries antimicrobials with high performance, unusual properties, and tolerances.35
The twin-chain quats, such as dioctyl dimethyl ammonium bromide and didecyldimethyl ammonium bromide, were first introduced by the British Hydrological Corporation for the British food industry (DECIQUAM 222).37
These products displayed outstanding bactericidal performance, unusual tolerance for anionic surfactants, protein loads, and hard water, and even low-foaming characteristics. Table 21.9
illustrates the bactericidal activities and pseudomonicidal, fungicidal, and hard-water tolerance (HWT) of five of the most active twin-chain
quats of 20 as measured by the official Association of Official Analytical Chemists (AOAC) procedure.36
The product of choice in this series was C8
DMAC because of its superior water solubility and bactericidal activity; however, the odd number chain C9
DMAC is an equally active product, although its commercial feasibility was not explored at that time because of high cost of the odd carbon chain alcohols. Several odd carbon chain alcohols have been offered in commercial quantities. The concept of synergistic combination in the dual quats has been applied to twin-chain quats dialkyldimethyl ammonium chlorides (dioctyl, 25%; didecyl, 25%; octyldecyl, 50%)
was combined with BACs (R = C12
, 40%; C14
, 50%; C16
, 10%). A 60:40 blend of the previously mentioned quaternaries proved superior to the individual components tested by the AOAC use-dilution test (Official Methods of Analysis of the AOAC
This newer blend of quaternaries represents the fifth generation of QACs. The blend remained active under the most hostile conditions, was less toxic and less costly, and provided more convenient disinfectants.
TABLE 21.7 Commercial antimicrobial quaternary ammonium compounds
R1 = C12, 40%; C14, 50%; C16, 10%
R1 = C12, 5%; C14, 60%; C16, 30%; C18, 5%
BTC 835, BTC 824
BTC 50 USP
Variquat 50 MC
Substituted benzalkonium chlorides
R2 = C12, 50%; C14, 30%; C16, 17%; C18, 3%
R2 = C12, 68%; C14, 32%
Dioctyl 25%, didecyl 25%, octyldecyl 50%
BTC 818, BTC 812
N-(3-chloroallyl) hexaminium chloride
Procter & Gamble
Rohm and Haas
Rohm and Haas
Effect of length of carbon chain on bactericidal activity: bactericidal testa
Staphylococcus aureus #6538
Salmonella typhosa #6539
Pseudomonas aeruginosa #15 442
aMinimum concentration that kills in 10 min but not in 5 min in ppm.
TABLE 21.9 Antimicrobial activity of twin-chain quaternary ammonium compounds
Abbreviation: HWT, hard-water tolerance.
In the 1980s, the toxicity of QACs underwent scrutiny by the US Environmental Protection Agency (EPA) and other US regulatory agencies. The safety of the biocides in general received a greater priority over efficacy. A new class of biocides, the polymeric quaternaries, has emerged; these are less toxic than the standard BACs and less powerful than the dual quats or twin-chain quats. The polymeric quaternaries are milder and have found applications in pharmaceuticals as preservatives.39
The polymeric quaternary ammoniums are polyelectrolytes, representing the sixth generation of QACs. They are generally considered milder and safer than all other classes based on LD50
More recently, other synergistic combinations, considered the seventh generation of quaternary, consisted of blends of bis-quats and polymeric quaternary (polyionenes). These offered excellent antimicrobial activity against oral flora bacteria, namely Bacteroides gingivalis
, Actinomyces viscosus
, and Streptococcus mutans
at 1 to 5 ppm in pharmaceutically accepted polymer formulations.40
These results required further testing to confirm safety and true synergism in this series of polymeric quaternaries with bis-quats blends, and a subsequent series of patents claiming antimicrobial, low-toxicity, blend composition of bis-QACs and polyvinylpyrrolidone.40