Formulating for Better Efficacy

Formulating for Better 

Efficacy 

Prof. Dr. Johann W. Wiechers 

Independent Consultant for Cosmetic Science 

JW Solutions, Gouda, The Netherlands 

Visiting Professor at The School of Pharmacy University 

of London, London, UK 

Technical Advisor Cosmetics & Toiletries

The answer to better efficacy is simple, 

don’t you think? 

2

The answer to better efficacy is simple, 

don’t you think? 

3

Can technology provide better answers 

in financially challenging times? 

4

“Formulating for Better Efficacy” is a 

structured approach to formulation 

design 

1. Selection of the drug / active ingredient 

2. Selection of the emollient 

3. Selection of the emulsifier 

4. Selection of adjuvants 

5



design 





6

Step 1: Can my drug / active penetrate 

the skin in sufficient amounts? 

Select only drugs/ actives that: 

- MW < 1000, ideally



Calculate the permeability coefficient using the 

Potts – Guy equation: 

log k p (cm/sec) = 

- 6.3 + 0.71·log K oct/water - 0.0061·MW 

Potts, R.O., and Guy, R.H., Predicting skin permeability, Pharm. Res. 9 

(1992) 663-669 

8



Input = J ss 

= k p · ΔC 

Output = Cl · C T 

C 

T 

= 

k 

p 

⋅ ΔC 

Cl 

Delivery gap = MEC / C T 

, ideally ≤ 100 

9



design 





10

An emollient serves two important 

functions related to skin delivery 

High absolute solubility of the drug in the 

formulation to ensure that enough is present to 

reach minimal effective concentrations at target 

site 

Low relative solubility of the drug in the 

formulation, relative to that in the stratum corneum 

to ensure a good driving force for the drug to 

penetrate the stratum corneum 

11

“Formulating for Efficacy” optimises 

these two contradictory requirements… 

High absolute solubility in formulation: 

polarities drug and formulation the same 

Low relative solubilities in formulation: 

more soluble in stratum corneum than in formulation, 

therefore: 

polarities drug and stratum corneum the same 

polarities drug and formulation different 

How to cope with such contradiction? 

12

“Formulating for Efficacy” identifies the 

optimal ‘polarity’ of your formulation 

Optimal polarities of formulation 

solubility 

penetrant 

driving force 

penetrant 

more 

hydrophilic 

-PPG 

polarity 

penetrant 

+ PPG 

more 

lipophilic 

13

PPG stands for the penetrant polarity 

gap… 

…and is the difference in “polarity” between drug 

and stratum corneum 

The bigger the PPG, the smaller the skin delivery 

Both optimized formulation polarities are equally 

good from a delivery point of view 

Optimized polarity of formulation can be calculated: 

polarity of formulation = polarity of penetrant ± 

penetrant 

polarity 

gap 

14

You need a few more novel definitions 

to be able to work with this… 

PI: 

RPI: 

Polarity Index 

A company-proprietary polarity index 

but encompassing much more than 

only polarity 

Relative Polarity Index 

Difference in PI between drug and 

formulation components such as 

emollients 

PPG: Penetrant Polarity Gap 

Difference in PI between drug and 

stratum corneum 

15

Now, let’s start to get to “Formulate for 

Efficacy”… 

An emollient with a small RPI… 

…will have a high solubility of your drug in the formulation 

An emollient with a large RPI… 

…will have a low solubility of your drug in the formulation and 

will increase the partitioning of your drug into skin 

Three-step plan: 

Step 1: Maximize solubility by selecting a 

primary emollient Small(est) RPI 

Step 2: Maximize partitioning by selecting a 

secondary emollient Large RPI 

Step 3: Mix in right proportions to obtain ideal 

formulation phase 

16

What I am doing in the schematic representation 

of “Formulating for Efficacy”? 

Optimal polarities of formulation 

solubility 

penetrant 

driving force 

penetrant 

more 

hydrophilic 

-PPG 

polarity 

penetrant 

+ PPG 

more 

lipophilic 

17

First, you need some RPI values when 

Formulating for Efficacy… 

…using 

25 

octadecenedioic acid as an example 

Solubility (% w/v) 

Arlamol E 

Arlamol HD 

20 

Estasan 3575 

Estol 1512 

15 

Estol 1526 

Estol 1540 

Estol 3609 

10 

Pripure 3759 

Prisorine 2021 


5 



0 


0 2 4 6 8 10 Prisorine 3515 

Relative Polarity Index (RPI) 

18

In Table form, selection of your 

emollients might actually be easier… 

INCI name 

Calculated RPI value 

Glycerin 24.9 

Propylene glycol 17.5 

Dipropylene Glycol 11.8 

Ethanol 11.8 

Glyceryl stearate 2.8 

Glyceryl Isostearate 2.8 

Triethylhexanoin 3.7 

Caprylic/capric triglyceride 3.7 

Propylene Glycol Isostearate 0.75 

Pentaerythrityl Tetraisostearate 4.6 

Isopropyl Myristate 4.5 

Isopropyl Isostearate 4.8 

Ethylhexyl palmitate 5.1 

Ethylhexyl isostearate 5.2 

Isostearyl Isostearate 5.8 

Vegetable Squalane 8.8 

2 

1 

19

In this way, we get a skin delivery 

optimised formulation 



Octadecenedioic acid 2.0 

Steareth-21 5.0 


Glycerin 4.0 

Xanthan gum 0.2 

Phenoxyethanol (and) Methylparaben (and) 

Propylparaben (and) 2-bromo-2-nitropropane-1,3-diol 0.7 

Aqua ad 100.0 

20

We had already used and tested 

another formulation 

Caprylic/Capric triglyceride 10.0 

Glyceryl stearate SE 3.0 



Cetyl alcohol 2.0 


Glycerin 3.0 

Benzoic acid 0.2 

2-Amino-2-methyl-1-propanol, to pH 5.5 

qs 

Aqua ad 100.0 

21

Pig skin was dermatomed to 400µm and 

the two formulations were applied 

A or B 

Pig skin 

22

After 24 hours, the application area 

was split in three separate layers 

A or B 

tapes 

skin 

transdermal 

Pig skin 

23

Using this strategy enhances the skin 

delivery… 

15 

Dioic Acid Delivery (μg/cm 2 ) 

10 

5 

3.5-fold 

Tapes 

Skin 

Transdermal 

0 

Formulation not 

optimised for delivery 

Delivery optimised 

formulation 

24

…and therefore also the efficacy of this 

skin whitening molecule 

2.5 

ΔL-value (relative to wk 0) 

2 

1.5 

1 

0.5 

0 

0 2 4 6 8 

3.2-fold 

p < 0.05 

Time (weeks) 

Study 1 (2% non-FFE) 

Study 2 (2% FFE) 

25

Using FFE, you can even lower the 

dose without loss of efficacy… 






Glycerin 4.0 


Phenoxyethanol (and) Methylparaben (and) Propylparaben 

(and) 2-bromo-2-nitropropane-1,3-diol 0.7 

Aqua ad 100.0 

7.5 

1.5 

1.0 

26

Using FFE, you can even lower the 

dose without loss of efficacy… 

2.5 

3.9-fold 

ΔL-value (relative to wk 0) 

2 

1.5 

1 

0.5 

p < 0.002 

0 

0 2 4 6 8 

Time (weeks) 

Study 1 (2% non-FFE) Study 2 (2% FFE) Study 3 (1% FFE) 

27

Formulating for Efficacy has therefore 

three types of benefits… 

MICMAC 

Concentration delivered at target site 

A 

B 

C 

Minimum effective concentration 

A. Create efficacy 

B. Enhance efficacy 

C. Reduce concentration 

Concentration in formulation 

= non skin delivery-optimized formulation 

= skin delivery-optimized formulation 

28

Emollients determine the extent of skin 

delivery 

…because they influence the thermodynamic 

activity of the active ingredient 

…because they determine the absolute solubility 

of the active ingredient 

29



design 





30

Four formulations were prepared for 

the skin delivery studies 

A B C D 

Octadecenedioic Acid 2.0 2.0 

Propagermanium 0.5 0.5 

Propylene Glycol Isostearate 15.0 15.0 15.0 15.0 

Triethylhexanoin 3.0 3.0 3.0 3.0 

Steareth-21 5.0 5.0 


Sorbitan Stearate (and) Sucrose Cocoate 5.5 5.5 

Glycerin 4.0 4.0 4.0 4.0 

Xanthan gum 0.2 0.2 0.4 0.2 

Preservative 0.7 0.7 0.7 0.7 

Aqua 69.1 69.6 70.4 71.1 

31

Two contained the lipophilic active 

ingredient octadecenedioic acid 

A B C D 








Glycerin 4.0 4.0 4.0 4.0 

Xanthan gum 0.2 0.2 0.4 0.2 


Aqua 69.1 69.6 70.4 71.1 

32

Two contained the hydrophilic active 

ingredient propagermanium 

A B C D 








Glycerin 4.0 4.0 4.0 4.0 

Xanthan gum 0.2 0.2 0.4 0.2 


Aqua 69.1 69.6 70.4 71.1 

33

Formulations A and C contained a non 

LX-inducing emulsifier system 

A B C D 








Glycerin 4.0 4.0 4.0 4.0 

Xanthan gum 0.2 0.2 0.4 0.2 


Aqua 69.1 69.6 70.4 71.1 

34

Microscopy of these formulations does 

not show liquid crystals 

Formulation A 

35

Formulations B and D contained a LXinducing 

emulsion system 

A B C D 








Glycerin 4.0 4.0 4.0 4.0 

Xanthan gum 0.2 0.2 0.4 0.2 


Aqua 69.1 69.6 70.4 71.1 

36

Polarised light microscopy does reveal 

liquid crystals 

Formulation B 

37

Skin penetration experiments show the 

effects of the LX emulsifiers… 

A, B, C or D 

tapes 

skin 

transdermal 

Pig skin 

38

Lipophilic: Transdermal delivery 

increased with LX formulations 

Dioic Acid Delivery (μg/cm 2 ) 

16 

14 

12 

10 

8 

6 

4 

2 

0 

Formulation 

A 

LX 

Formulation 

B 

Total delivery 

the same but 

more 

transdermal 

Tapes 

Skin 

Transdermal 

39

Total delivery increased with the Total delivery 

hydrophilic penetrant 

has increased 

but transdermal 

still low 

Propagermanium Delivery (μg/cm 2 ) 

35 

30 

25 

20 

15 

10 

5 

0 

Formulation 

C 

LX 

Formulation 

D 

Tapes 

Skin 

Transdermal 

40

LX emulsions enhance both dermal 

and transdermal delivery 

But in different ways! 

more transdermal delivery of lipophilic 

penetrant = faster delivery 

more dermal delivery of the hydrophilic 

penetrant = more delivery 

How to explain this scientifically? 

41

Hydrophilic active ingredients 

remained trapped in LX structures 

a: hydrophobic part 

b: trapped water 

c: hydrophilic part 

d: bulk water 

e: oil 

Longer residence time = more penetration 

42

LX systems may influence packing of 

skin barrier lipids 

more permeable for 

all penetrants 

enhanced 

transdermal 

delivery for both 

polarities 

Pilgram et al, JID 117 (2001) 710-717 

43

Emulsifiers determine the rate of skin 

delivery… 

…because of possible influence on skin lipid 

packing 

Much more experimental data needed before 

general rules can be established 

44



design 





45

Another possibility to increase skin 

penetration is to change the polarity of 

the stratum corneum 

2 formulations with and without 10 % dimethyl 

isosorbide based on: 

3.0 

5.0 

1.0 

0.5 

4.0 


Triethylhexanoin 

Steareth-21 

Steareth-2 

Propagermanium 

Glycerin 


Phenoxyethanol (and) Methylparaben (and) 

46

DMI makes the stratum corneum more 

compatible with the active ingredient 

Propagermanium delivery 

(% applied dose) 

50 

45 

40 

35 

30 

25 

20 

15 

10 

5 

~2-fold 

Tape Strips 

Skin 

Transdermal 

0 

Formulation without 

DMI 

Formulation with DMI 

47

Let me explain this using RPI 

terminology... 

PI values: 

Skin (~ n-butanol) estimated at 0.8 

DMI = -1.6 

Water-soluble actives < 0 

Theory: 

DMI penetrates skin 

raises PI of skin making it more compatible with PI of 

water-soluble actives 

in essence, a reduction of the PPG 

fast penetrating molecules like DMI, PG and TC 

48

Summarizing, one can easily formulate 

for better efficacy and save money 

Use your brains before you use your hands 

Throw away your standard / preferred prototype 

formulations 

Finding MICMAC only worthwhile for expensive 

drugs / actives or high volume products 

Scope and validity of this 

approach can be calculated 

49

Formulating for Better Efficacy

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