# Formulating at pH 4-5: How Lower pH Benefits the Skin and Formulations

Ever since Johnson & Johnson introduced its “pH 5.5” product range, which is in fact formulated at a pH of 5.5, consumers have come to know that the pH of the skin is 5.5—or at least they believe it should be. However, reports in the literature suggest that the pH of skin is lower, more on the order of 4.7. This review discusses the meaning of pH and how it is measured on human skin; which processes regulate the natural skin surface pH; and what processes are regulated by natural skin pH. It then describes the importance of this acidic pH for normal skin homeostasis, what factors cause deviations from natural skin pH, and finally discusses the implications of a pH lower than the generally assumed level of 5.5 for the formulator of cosmetic products.

## pH, Natural Skin pH and How to Measure It

Most individuals will have come across pH for the first time during their secondary education, learning that it was the -10log of the concentration of hydrogen ions in an aqueous solution. Water was described as a molecule that could dissociate into H+ ions and OH- ions according to the reaction:
H2O    H+ + OH-            Eq. 1
and its equilibrium was determined by the dissociation constant of water, Kw. The value of Kw was the product of the concentrations of the two ions; i.e., Kw = [H+]∙[OH-] = 10-14. In neutral water, the concentration of H+ ions equaled that of OH- ions, and both are therefore 10-7 M, corresponding to a pH and pOH of 7. Scientifically, it is probably more correct to write the above equation as:

2 H2O    H3O+ + OH-        Eq. 2

but this does not change the principle. The pH is the -10log of the concentration of H+ or H3O+ ions. University-level chemistry lectures, however, have revealed that this is not quite the case. pH is not -10log [H+] or -10log [H3O+] but rather -10log {H+} or -10log {H3O+}; where {H+} and {H3O+} refer to the activity of hydrogen and hydronium ions, respectively; and where the relationship between activity and concentration is given as:

{H3O+} = γw•[H3O+]          Eq. 3

where γw is the activity coefficient. In an ideal solution, the activity and concentration of a species are identical—i.e., γw = 1; but most solutions are non-ideal and γw < 1, particularly in solutions that contain strong electrolytes. Therefore, in most practical cases, it is the environment in which a hydrogen ion is situated that determines its activity. It is thus important to examine from where the hydrogen ion comes to study its immediate environment and how it can be measured.

## pH on the Surface

The so-called acid mantle of human skin is composed of different chemical species with different origins that can be exogenous and endogenous.1,2 These include:
•        Exogenous substances such as metabolic by-products of bacteria;
•        Substances that are made within the body but are excreted to the skin surface, such as the α-hydroxy acids, lactic acid and butyric acid, that are naturally present in eccrine sweat; and acidic lipids such as cholesterol sulfate and free fatty acids from the sebaceous gland that break down into other products and change the pH of skin—although the acidity of fatty acids is often overestimated. The lactic acid is argued to diffuse back into the skin and so to acidify the superficial layers of the stratum corneum (SC);2
•        Endogenous filaggrin-related and other metabolic breakdown products, such as urocanic acid and pyrrolidone carboxylic acid, that are components of the natural moisturizer factor (NMF); and
•        Endogenous H+ generated from cellular transporters such as the nonenergy-dependent Na+/H+ exchanger.

Öhman and Vahlquist2 investigated the pH gradient of normal human skin during tape stripping. Prior to any tape strips being taken, the skin surface pH measured 4.5 ± 0.2 (n=7) that, despite the small sample size, is in line with later and much more extensive studies such as those of Lambers et al.3 who concluded that the natural skin pH is 4.7 based on extrapolation of pH values obtained before (5.12 ± 0.56; n=330) and after (4.93 ± 0.45; n=330) test subjects refrained from showering or applying cosmetic products for
24 hr. Segger et al.4 found a mean value of 4.9 ± 0.4 (n=222) after a 1-min water rinse administered 24 hr prior to the skin pH measurement and without any further contact with water or topical preparations. Note how similar the two 24-hr values are.

## pH: Delving Deeper

Thus far, the skin surface has been examined; now this essay will delve deeper. Approximately 80–120 tape strips were used by Öhman and Vahlquist to remove the SC on the forearm and with linear progression, the overall pH rose from 4.5 to 7. Based on this observation, the researchers hypothesized that a relationship exists between pH and the quantity of these chemical species as a function of depth in the epidermis, as illustrated in Figure 1a.

Interestingly, in 1998 this was only a hypothesis but in 2001 the concentration profile of lactate in skin was shown by confocal Raman microspectroscopy to act as predicted (see Figure 1b).5 Recently, the same scientists were able to measure the concentrations of urocanic acid and its conjugated salt independently via confocal Raman microspectroscopy. Because the ratio between the concentrations of an acid [HA] and its conjugated salt [A-] is determined only by the pKa of the acid and the local pH, the researchers could work out the local pH after having assessed the ratio between [HA] and [A-] as a function of depth, using the Henderson-Hasselbach equation:

pH = pKa + log ([A-]/[HA])      Eq. 4

The pH profile obtained in this manner and measured in vivo noninvasively inside human skin on a male subject is shown in Figure 2.

The measurement was taken on the palm of the hand, close to the thumb, where the SC is significantly thicker (approx. 150 μm) than on the forearm (approx. 15μm).

It can be seen that the pH in skin increased dramatically due to the application of this extremely alkaline solution but that skin surface values remained reasonable. This suggests that acidification, in addition to an inside-out acidification process, takes place from the outside inwards, for instance, by the inward migration of lactic acid. Almost one day later, the levels were still elevated. It is interesting to note that the data from confocal Raman microscopy was in agreement with that obtained by tape stripping—there was first a tendency to a more acidic pH just below the skin surface, before the gradual increase toward neutrality in the viable epidermis (see Figure 1a).

Most cosmetic scientists, however, will only have used the flat glass electrode to measure the acidity of the skin’s surface. pH values recorded in a semi-hydrophobic environment such as the SC should be interpreted with care. Öhman states: “We do not know whether surface pH actually reflects the hydrogen concentrations of intercellular water, or if it represents the combined acidity of exposed corneocytes, lipids and water-soluble compounds.”6

His caution is shared by Parra and Paye.7 For the specific requirements of skin surface pH measurements, a planar electrode was developed with one unit containing the active and the reference electrode. A schematic overview of such a glass electrode is shown in Figure 3,8 illustrating that the skin pH electrode is similar to other H+-sensitive glass electrodes, apart from the flat surface that is to be placed on the skin. Its use is relatively simple but Parra and Paye deal more with variability caused by subjects than by the improper use of the equipment or the wrong choice of experimental conditions.7

One important, practical step in measuring skin pH is dipping the measuring electrode in distilled water and then drying it with a filter paper, leaving the surface wet but avoiding an excessive amount of water,9 and storing it properly between measurements.7 The reason for this may be that the water needs to create the aqueous environment in which the water-soluble acids can dissolve. The measuring electrode is then placed on the skin for a period of approximately 10 sec with slight pressure. Measurement with one of the latest skin pH-metersa is initiated, for example, by pressing a button on the side of the probe handle, which immediately displays the results. This short measuring time avoids occlusive effects on the skin.10

## Variations in pH Surface Measurements

The main causes for variability in surface skin pH are as follows:
Age:1, 9, 11 The skin surface pH of both full-term infants and premature infants is less acidic than that of children and adults (around 6.5) but acidifies rapidly in the first two weeks with a similar time course in both term and premature infants. Thereafter, pH appears to be relatively constant, at least from childhood through to age 70. Skin surface pH rises significantly in adults near or older than 70 years of age.

Gender and race:9,12 Here, the literature is not consistent, as both higher and lower skin pH values have been reported in women. Based on the fact that the studies finding women to have higher skin pH values are from the late 1930s, and on the fact that it only recently became known that the time period between last product application (including water) and measurement is crucial, one would be inclined to adhere to the view of Ehlers who concluded that females have lower skin surface pH values than men.12 Even there, however, the mean values are 5.80 (men) and 5.54 (women) and the values keep decreasing in both genders, suggesting that the 12-hr time span between last product application of soap, detergents and/or cosmetics and measurement was still too short, or there could be circadian rhythms in skin surface pH.

With respect to race, again, the literature is contradictive. African-American skin has been found to have a lower as well as a higher skin pH.
Body site:9,12 Most studies have been performed on the volar forearm with the lowest values detected closest to the wrist, in the area called the wristwatch zone; this area should be avoided since the values there are noted to be significantly lower in men, for reasons that are not yet clear.12 No differences have been found between right and left arms and again, different results can be found due to the influence of the dominant arm. Throughout the whole body, skin pH seems to be reasonably constant apart from the moister skin surfaces such as the axilla and the groin area where the pH is elevated.

Circadian rhythm: Yosipovitch et al. 13
detected circadian rhythms of skin pH on the shin and forearm but not on other body sites. For the majority of subjects, the maximal values were obtained at all body sites in the afternoon, between 2 pm and 4 pm, and the minimum in the evening, around 8 pm.
Relative peak to trough differences were found to be statistically significant
(p < 0.05) and were as follows: forehead 5.29/4.93; forearm 5.44/4.87; upper back 5.5/5.14; and shin 5.5/4.8.

Whether this is truly a circadian rhythm is still open for discussion. Burry et al.14 debate that it could also be due to a circadian rhythm of the sweat gland. At the deep end of the sweat gland, sweating begins as the result of active excretion of salts such as sodium, potassium, chloride and bicarbonate, which subsequently osmotically attract water. Higher up in the gland, many of these salts are re-absorbed so that a dilute sweat is secreted onto the surface of the skin. At higher sweat rates, less bicarbonate can be re-absorbed,
leaving the sweat more alkaline. As with skin surface pH measurements, there are conflicting reports as to what point overall body sweat rates are the highest throughout the day.

Water and topical product application: The work performed by Lambers et al.3 clearly demonstrates that the time between product application and skin surface pH measurement is crucial. Four hours after rinsing with tap water—most tap water is alkaline, especially hard water—the pH values have just returned to their starting values. For soaps, which are typically alkaline, these times are even longer and more than 6 hr are required to reach the initial values (see Figure 5). However, to address whether the starting value of approximately 5.25 was also the natural skin surface pH, the researchers looked at time effects in a different way. They found that the greater the deviation from this unknown natural value, the steeper the decline and they could mathematically derive the natural skin surface pH value not influenced by product application, resulting in a pH of around 4.7. Since most cosmetic products have pH values around 6, this means consumers are constantly changing the pH of their skin.

## Skin Surface pH for Healthy Skin

The above discussion suggests that skin surface pH is variable. While the variance between races, sexes and age is relatively small, and there might be differences with circadian rhythms, the greatest variance in skin surface pH values is probably caused by daily hygiene routines, in line with Parra and Paye who claim that topical products and the temporary effect of skin washing are the main contributors to skin pH fluctuations.7 It is therefore of importance to ask the question whether these changes in skin surface pH matter or not. This section discussed processes within human skin that are influenced by local skin pH, namely: skin barrier maintenance, skin moisturization and microbiological colonization.

Skin permeability barrier maintenance: Hachem et al.15 summarize the reasons why an acidic pH is useful for skin barrier repair. Barrier recovery is delayed when acutely disrupted skin sites are immersed in neutral pH buffers, whereas barrier abnormalities brought about via blocking the non-energy dependent sodium-proton exchanger16—mentioned previously as one of the reasons for an acidic pH in the skin—can be overruled by co-exposure of the inhibitor-treated sites to an acidic skin surface pH buffer. The acidic pH is critical for barrier homeostasis for two reasons: first, because two ceramide-synthesizing enzymes have low pH optima; and second, because a low pH helps to promote the 13-nm long periodicity phase17 necessary for barrier formation. In short, an acidic pH creates a stronger barrier.

Skin moisturization: Skin moisturization is a complex process involving many enzymes that degrade pro-
filaggrin and filaggrin to a series of chemicals that form the SC natural moisturizing factor (NMF). This cascade of events generates urocanic acid, which plays a role in acidifying the SC but more importantly creates the optimal conditions for proper desquamation. Corneocytes are held together by corneo-
desmosomes that need to degrade properly for cells to slough off one by one. Currently, several serine, cysteine and aspartic enzymes are believed to be involved in this process, namely the serine proteases hK7 or kallikrein 7, formerly known as SC chymotryptic enzyme (SCCE); hK5 or kallikrein 5, formerly known as SC tryptic enzymes (SCTE); cathepsin L-2, formerly known as SC thiol protease (SCTP); cathepsin E; and the aspartic protease cathepsin D.
hK7 and hK5 are neutral to alkaline-optimal enzymes whereas the latter ones are acidic-optimum enzymes.18 If the pH of the outer layers of the SC is raised to neutral or alkaline levels, the enhanced activity of the serine proteases will lead to accelerated corneodesmosome degradation, which negatively impacts SC integrity and cohesion.19

A recent article profiling the serine protease activities in human SC concluded that all serine proteases showed a distinct gradient on the forearm with the highest activity in the outermost layers of the SC,20 where under normal conditions the pH is too acidic for optimal enzyme activity. The pH gradient in the skin carefully controls all these processes and while not all details are yet known or understood, it is beyond any doubt that skin with a low surface pH will have a better barrier and be better hydrated, as illustrated by the studies of Wilhelm and Maibach21 and Lambers et al.3 A lower skin surface pH correlates with a better resistance against SLS-induced irritant dermatitis,3, 21
whereas subjects with skin pH < 5.0 show statistically significant less scaling
and higher hydration levels than subjects
with skin pH > 5.0.3

Microbiological colonization: One of the issues that emerges repeatedly when studying the scientific literature on skin surface pH is the increased defense against invading bacteria in an acidic rather than a neutral or alkaline environment. For instance, while Propionibacteria grows well at pH 6.0 to 6.5, growth slows at pH 5.5. Staphylococcus aureus grows best at pH 7.5 but continues to proliferate slowly at pH 5.0 to 6.0. The acidic pH of the SC restricts colonization by pathogenic flora and encourages the persistence of normal microbial flora.9

The same consideration also is apparent from the title of the article of Lambers et al.: “Natural skin surface pH is on average below 5, which is beneficial for its resident flora.” The authors state that, “skin has a mutualistic symbiotic relationship with its microflora: the human skin provides the right biotope for the resident flora, while the resident flora in turn strengthens humans’ defense by prevention of the colonization of harmful bacteria, as well as playing a role in the acidification of the skin.”3 In fact, the natural skin surface pH creates an environment in which the resident flora (mainly Staphylococci, Micrococci, Corynebacteria and Propionibacteria) can grow while the growth of transient flora (such as the well-known species Escherichia coli,
S. aureus and Pseudomonas aeruginosa) is inhibited.

This natural skin pH indeed is important. Hartmann describes an interesting observation made on 26 healthy volunteers when their arms were occluded for a period of 3 days and the skin pH and skin flora were measured before application, immediately after removal of an occlusive dressing, and 24 hr thereafter. The skin pH increased from 4.9 to 7.1 and subsequently decreased to 5.2, whereas the number of Staphylococci and Corynebacterium species increased five and four logs, respectively, and was still elevated by two logs 24 hr after occlusion.22

The most obvious conclusion is that the higher skin pH favors the growth of these microorganisms as stated above but these findings could also be explained by the fact that an acidic skin pH keeps the resident bacterial flora attached to the skin, whereas a more alkaline pH (8–9) promotes its removal from the SC.3 So in traditional sampling methods such as detergent scrubs, there may not only be more bacteria present on the skin, but they also will detach more easily.

The above discussion aims to illustrate that many normal physiological processes are facilitated by an acidic skin surface pH. If the normal acidic pH of the skin is raised by applying alkaline treatments or genetically or chemically blocking acidifying mechanisms, barrier recovery kinetics and skin barrier functions are reduced. It should be realized that skin pH is not the only factor influencing this whole cascade, since it is heavily intertwined with other gradients over the thickness of the SC such as the water and the calcium gradients. Maintaining an acidic environment on the skin surface, however, supports natural skin care.

## Consequences for the Cosmetic Formulator

While the preceeding discussion represents the scientific progress of almost a decade since the last review of skin pH in this publication,23 cosmetic formulators might be asking themselves the very justifiable question whether this new knowledge has any consequence for their work. This section will give some practical examples of the impact of lowering the pH of cosmetic products by roughly one unit.

Recommendations of skin care formulations: Based on the understanding that a skin surface pH of below 5 is beneficial for human skin, one would anticipate that most topical formulations, pharmaceutical or cosmetic, are formulated at pH values at least below 5. In order to check whether this is indeed the case, an analysis was made of 425 formulations that were recently published in the skin care formularies published in Cosmetics & Toiletries magazine in the period between 2002–2008.24–30 This analysis included creams, lotions, cleansers, scrubs and miscellaneous product forms but excluded sun care and hair care formulations. Of the 425 formulations considered, only 106 (25%) mentioned a pH value to which their formulation should be adjusted, 9 of which only advised to change pH as needed without stating a desired pH value. The results of this analysis are shown in Figure 6.

The two formulations that were formulated in the pH range 3.5–4 both contained organic acids as the active ingredient such as alpha hydroxy acids, which are known to be more effective at a lower pH because of the increased skin penetration of the active ingredient.31 There may be other reasons such as formulation stability for formulating at specific pH levels but the main point here is clear: Even the latest and newest formulations that suppliers of cosmetic materials have published over the years do not take the recent developments of the importance of skin pH for skin biology into account. Only eight of them were formulated around the preferred pH value of 4.5, corresponding to 7.5% of the formulations with a recommended pH value, and only 1.9% of all formulations analyzed.

Enhanced efficacy by lowering pH: This is relevant in particular for organic acids such as lactic acid. Its penetration into the SC is enhanced for a series of closely related reasons: a) the polarity of the acid (e.g., lactic acid) is more compatible with that of the SC than the polarity of the dissociated anion (e.g., lactate) is, which will favor the partitioning of the acid into the SC; b) the permeability coefficients of charged species are, on average, 10,000-fold smaller than of their uncharged equivalents; and c) the aqueous solubility of an acid is, on average, significantly lower than that of its conjugated anion, which will increase the driving force for diffusion into the SC. In the case of AHAs, these differences are so extreme that they are all formulated at a low pH. Whether this needs to be done for all acids depends on the dissociation constant (the pKa) of the acid, as well as its aqueous solubility.

Apart from via increasing skin penetration, efficacy also can be enhanced by formulating at a lower pH. A lower pH on its own already presents a less favorable environment for bacterial growth, as described. In addition, preservatives such as benzoic acid and sorbic acid, which have not yet received bad press, are more active at a lower pH since their pKas are 4.2 and 4.8, respectively. Similarly, preservative boosters such as 1,2-diols, for example pentylene glycol, 1,2-hexanediol, caprylyl glycol and decylene glycol, among others, are more effective at a lower pH. An example is shown in
Figure 7 illustrating o/w-emulsions with 0.6% 1,2-hexandiol (and) 1,2-octanediol at pH 5, 7 and 9 that were each challenged with five usual pathogenic strains.

The best preservation was obtained at the lowest pH, especially for Aspergillus niger, but also for Candida albicans.

Enhanced chemical stability below pH 5: Although raw materials will vary, maintaining the chemical stability of the active ingredient could be another reason for formulating around this natural skin surface pH of 4.7. A well-known pH- sensitive cosmetic raw material is ascorbic acid (a 3,4-dihydroxy-5H-furan-2-on). It very much prefers a lower pH range, just like dihydroxyacetone, a tanning agent. Actives with similar sensitive structures include those based on hydroxyphenol derivatives. Therefore, plant extracts containing polyphenols usually also exhibit a better color stability at a lower pH.

Yet another example is phenylethyl resorcinol,b a skin toning agent. This material was incorporated at 0.5% in aqueous ethanolic solutions, which were buffered at pH 4, 5, 7 and 9, and stored at room temperature. Color measurements were performed on phenylethyl resorcinol measuring the L*a*b* color space before and after 7 and 28 days. The Δb* values (color change relative to t = 0) were used to measure discoloration. Figure 8 shows the effect of pH in samples all containing 0.5% phenylethyl resorcinol in 20% ethanol and 0.15% disodium EDTA. Since a lower pH is ultimately better for skin, as has been shown, formulators should not hesitate to formulate at a low pH to benefit from alternative preservation systems or to improve the stability of acid stable actives.

## Conclusion

Considering the wealth of knowledge available suggesting that the natural skin pH is significantly lower than 5.5, namely around 4.7, it is surprising that the majority of cosmetic products are still formulated at values of around 6. On one hand, the industry is using active ingredients to help improve the quality of skin, yet on the other hand, sub-optimal cream bases are being used. If the base of a skin care formulation is chosen such that it not only feels right but also does not disturb the natural pH level, effective products can be created. Formulations with a pH of about 4.7 are beneficial for the skin as they maintain or even fortify the skin barrier and support the natural skin flora. At the same time, a pH of 4.0 to 5.0 helps reduce the use of preservatives and stabilizes many cosmetic active ingredients.

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