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Required HLB Determination of Some Pharmaceutical Oils in Submicron

Emulsions

Article  in  Journal of Dispersion Science and Technology · June 2012

DOI: 10.1080/01932691.2011.584800

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 Journal of Dispersion Science and Technology, 33:816–820, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0193-2691 print=1532-2351 online
DOI: 10.1080/01932691.2011.584800

Required HLB Determination of Some Pharmaceutical

Oils in Submicron Emulsions
T. Schmidts, P. Schlupp, A. Gross, D. Dobler, and F. Runkel
Technische Hochschule Mittelhessen, University of Applied Science, Institute of Bioprocess
Engineering and Pharmaceutical Technology, Giessen, Germany

Different calculations of the hydrophilie-lipophilie balance (HLB) value of Sorbitan fatty acid
ester are discussed in literature. Influence on the required HLB value of ethyl oleate was inves-
tigated using several emulsifier blends: Span 80/Tween 20, Oleth-3/Steareth-20, Oleth-5/
Steareth-20, Oleth-3/PEG-40-Stearate. The calculations of the HLB value of Span 80 have a
bearing influence on the determination of the required HLB value. The postulated transferability
of the determined required HLB value by the Tween 20/Span 80 system compared to other emul-
sifier systems is depending on the used equation. Additionally, the required HLB values of the
Downloaded by [Aston University] at 08:17 04 September 2014

pharmaceutical oils coco-caprate/caprylate and cetearyl isononanoate were determined empiri-

cally by preparing submicron emulsions.
Keywords HLB, required HLB, Sorbitan oleate, submicron emulsion

1. INTRODUCTION development. Two of these major parameters are the

Submicron emulsions (SMEs) are oil-in-water emulsions,
which have a mean droplet size that usually ranges between
100 and 500 nm.[1] Compared to microemulsions, favorably
smaller amounts of emulsifiers are needed for stabilization.
However, SMEs also possess, as a result of the ingredients
and their small droplet sizes, good penetration properties
for active ingredients.[2–4] The interest in the development
of formulations as targeting systems for dermal drug
administration is continuously growing. Especially, carrier
systems below one micrometer have been of particular
interest for the last decade and allow enhanced drug trans-
port into and through the skin compared to conventional
formulations.[5–7] In particular, drug carrier systems are
developed empirically. These empirical procedures are
often extremely time-consuming, since especially systems
with small droplet sizes require a well-defined ratio of the
ingredients.[8,9] Therefore, it is of great importance to
incorporate the physicochemical properties of the selected
constituents in an early stage of the formulation
Received 4 April 2011; accepted 19 April 2011.
The authors would like to thank the Hessen State Ministry of
Higher Education, Research and the Arts for the financial sup-
port within the Hessen Initiative for Scientific and Economic
Excellence (LOEWE-Program) and the Federal Ministry of
Economics and Technology, Central Innovation Programme
(ZIM).
Address correspondence to F. Runkel, Technische Hochschule
Mittelhessen–University of Applied Science, Institute of Biopro-
cess Engineering and Pharmaceutical Technology, Wiesenstr. 14,
35390 Giessen, Germany. E-mail: Frank.Runkel@kmub.thm.de
hydrophilie-lipophilie balance (HLB) value of the emulsi-
fiers and, determined by experiments and the required
HLB value of the oil phase. Using these parameters, the
number of experiments can be reduced early during the for-
mulation screening stage.[10–13]
The HLB system was first introduced by Griffin and
serves to characterize nonionic emulsifiers.[14] Griffin allo-
cated nonionic emulsifiers a nondimensional numerical
value, which is either calculated or determined experimen-
tally.[10] Additionally, each oil or oil phase to be emulsified
can be allocated a so-called required HLB value and this is
determined empirically. The required HLB value specifies
the optimum HLB value of an oil or oil phase for pro-
ducing the best possible emulsion regarding stability and
dispersity.[14,15]
The conventional way to determine the required HLB of
oil is the Griffin approach using an emulsifier blend, com-
monly Span 80 and Tween 20. Therefore, various emulsions
are produced with emulsifier blends of Span 80 and Tween 20
in different ratios, covering a certain HLB range, and are
observed in respect of their separating properties.[14] An
accelerated investigation of the separating characteristics
can be expedited using centrifugation.[16] Furthermore,
droplet size analysis constitutes a new approach to determine
the required HLB of an oil or oil phase.[11,12,17] Here, the
required HLB is defined as the HLB of the emulsifier
mixture, were the smallest droplet size of the dispersed oil is
obtained.
Two different equations for working out the HLB value
of sorbitan fatty acid esters (e.g., Span) are described in the

816
 REQUIRED HLB DETERMINATION OF SOME PHARMACEUTICAL OILS 817

literature.[10,13] which results in unequal HLB values. TABLE 1

Griffin’s[10] calculation of the HLB value for polyhydric Emulsifiers and their HLB valuea
alcohol fatty acid esters (equation 1) based on chemical y

classification numbers. INCI HLB value

Polysorbat 20 16.7
y
Sorbitan oleate 6.8 =4.3
 
S
HLB ¼ 20
1 ÿ Oleth-3 6.6
A
½1Š Oleth-5 9.0
S saponification value of the ester
Steareth-20 15.3
A acid value of the acid PEG-40-Stearate 16.7
a
Pasquali[13] presents an alternative calculation for the HLB HLB values obtained by the manufacturer.

Calculated by Pasquali.[13]
value (Equation (2)) using the theoretical molecular weight 
Determined by Griffin.[10]
of the emulsifier. y
Manufacturer’s specifications.

ðMrmonoester ÿ Mracid Þ
20
HLBMonoester ¼ 2.2. Preparation of Submicron Emulsions
Mrmonoester
SMEs, 100 g per sample, containing 15% (w.=wt) of an
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Mrmonoester relative molecular mass of the the monoester
Mracid relative molecular mass of the acid
½2Š
The two approaches for calculating the HLB value of
sorbitan fatty acid esters leads to different HLB values
for e.g., Span 80, 4.3[10] and 6.8.[13] Since the HLB of the
emulsifier are the basis of the required HLB determination,
this might falsify the required HLB determination of an oil
phase. Especially, due to the common used emulsifier blend
of Span and Tween might constitute a problem for the
transferability of the determined required HLB to other
emulsifier systems. Therefore, the aim of this study was
to verify this difficulty by the investigation of the required
HLB of ethyl oleate by using various mixtures of emulsi-
fiers including the Tween=Span system. The droplet size
approach was applied. Subsequently, the required HLB
values of two oils and an oil mixture were determined
empirically, listed in the European Pharmacopoeia, as it
was not yet published. Additionally, short-term stability
of selected formulations was performed.
2. MATERIALS AND METHODS
2.1. Materials
The oils coco-caprate=caprylate (Cetiol LC), cetearyl
isononanoate (Cetiol SN) were a gift from Cognis GmbH,
Germany. Ethyl oleate and the emulsifiers Sorbitan oleate
(Span 80), Oleth-3, Oleth-5, Steareth-20 and PEG-40-
Stearate were supplied by Croda GmbH, Germany. Poly-
sorbate 20 (Tween 20) was donated by Fagron GmbH,
Germany (Table 1). The preservatives methyl-4-hydroxy-
benzoate and propyl-4-hydroxybenzoate were obtained
from Caelo GmbH, Germany. All reagents are listed in
the European Pharmacopoeia.
oil or a mixture thereof, 79% (wt=wt) of preserved water
(containing 0.025% propyl-4-hydroxybenzoate and 0.075%
methyl-4-hydroxybenzoate) and a mixture of two emulsi-
fiers with a total blend concentration of 6% (wt=wt), were
produced. The required amount of the emulsifier blend
was dispersed under magnetically stirring (300 rpm) in the
oil phase at 70 C for about 10 minutes. The aqueous phase
was also heated and stirred using similar conditions. Then,
the aqueous phase was quickly added to the oil phase and
the emulsions were prepared using a rotor-stator homoge-
nizer (Heidolph DIAX 600, Heidolph GmbH, Germany) at
24000 rpm for 60 seconds.
For the determination of the required HLB of the oils or
the oil blend, a series of emulsions with various HLB values
of the emulsifier blend, were prepared by mixing the emul-
sifiers in different required ratios according to Equation
(3).[14]
n
X
HLBblend ¼ xi
HLBi
i¼1
½3Š
xi massðorweightÞ fraction of surfactant i
HLBi HLB value of the emulsifier
2.3. Droplet Size Analysis
Droplet size analysis was performed using laser diffrac-
tometry (Mastersizer S, Malvern Instruments, UK). The
Sauter diameter D [3.2] was determined since this para-
meter is frequently used to determine droplet size distri-
bution. It is defined as the diameter of a droplet that has
the same volume=surface area ratio as that of the whole
volume=total surface area of a droplet population in an
emulsion.[1] Additionally, SMEs with droplet sizes below
300 nm were analyzed by dynamic light scattering (High
Performance Particle Sizer, Malvern Instruments, UK)
 818 T. SCHMIDTS ET AL.
due to the detection limit of the Mastersizer S. The
Z-average also known as the ‘‘cumulants mean’’ is
presented. Droplet size measurements were done 24 h after
SME production and at day 30 stored at room tempera-
ture. Furthermore, the amount of creaming of the SMEs
was established optically.
3. RESULTS AND DISCUSSION
3.1. HLB Value of Sorbitan Fatty Acid Ester
One purpose of pharmaceutical emulsion development
is to achieve stable systems. As various parameters can
influence the stability, it is often an empirical development.
A key factor for the emulsion development is the selection
of the appropriate emulsifier or emulsifier blend. Therefore,
the HLB value of emulsifiers is a crucial tool to decrease the
experimental work (time and effort). Once determined the
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required HLB of the oil, the impact of the chemical class
of the emulsifier or emulsifier blend can be studied. Cus-
tomarily, the required HLB of oils is determined by mixing
different portions of two emulsifiers of known HLB, com-
monly Span 80 and Tween 20, and several emulsion within
a range of HLB values are produced.
Two approaches for calculating the HLB value of sorbi-
tan fatty acid esters are described in the literature, which
leads to different HLB values, for example, Span 80,
4.3,[10] and 6.8.[13] The influence of this disparity on the
required HLB determination was investigated using ethyl
oleate. Following the conventional way to determine the
required HLB of oils using Span and Tween as emulsi-
fiers,[14] submicron emulsions using the oil ethyl oleate
and emulsifier blends of Span 80 and Tween 20 in different
ratios, representing various HLBs, are produced. Further-
more, in order to proof the discrepancy, the following
emulsifier systems were used: Oleth-3=Steareth-20, Oleth-
3=PEG-40 stearate and Oleth-5=Steareth-20, since at these
chemical classes of emulsifiers, Griffin’s way of HLB deter-
mination matches to the HLB determination by the
approach of Pasquali. Figure 1 shows the dependency of
the droplet size on the HLB of the emulsifier blends.
Due to the two approaches for calculating the HLB of
Span 80, there is a shift of about two units, 8.1 for Griffin
and 9.8 for Pasquali, in the determined required HLB of
ethyl oleate (Table 1). As the required HLB value of the
oil might be transferrable to other emulsifier systems, the
obtained required HLB value were compared to other
emulsifier blends leading to required HLB values of ethyl
oleate between 10.6 and 11.5. Thus, the calculated HLB
of Span 80 of 6.8 by Pasquali seems to be the more crucial
one. Negligible deviation among the systems might be
caused by the purity grade of the emulsifiers. These results
are in accordance with the determined required HLB of
11.3 for ethyl oleate by Wang[17] and the specification of
FIG. 1. Droplet size of the SME (ethyl oleate) as a function of the
HLB. (&) Oleth-5=Steareth-20, (~) Oleth-3=Steareth-20, (.) Oleth-3=
PEG-40-Stearate, () Tween 20=Span 80 (HLB 4.3), and (^) Tween
20=Span 80 (HLB 6.8); n ¼ 1.
the manufacturer (Croda GmbH, Germany), required
HLB of 11.0. These results show that the use of a required
HLB value determined by the Span=Tween emulsifier sys-
tem have to be handle with care if the Griffin equation
was used. The HLB range for a stable SME may be situ-
ated in a very narrow array for certain emulsifier system
and thus the transfer to other emulsifier systems leads to
probably false results.
The droplet size of the different emulsifier systems
increased from Oleth-5=Steareth-20 < Oleth-3=Steareth-
20 < Span 80=Tween 20  Oleth-3=PEG-40-Stearate at the
required HLB value of ethyl oleate 10.8  0.8. Thus, at
the required HLB value of the oil, the droplet size can be
adjusted by the selection of the chemical classes of emulsi-
fier system.
3.2. Determination of Required HLB of Some
Pharmaceutical Grade Oils
The required HLB of two oils, coco-caprate=caprylate
and cetearyl isononanoate, both listed in the European
Pharmacopoeia, were investigated. The same emulsifier
systems were used. The Tween=Span system was calculated
by the equation of Pasquali since this is well in accordance
with the other emulsifier systems regarding the required
HLB value of the oil.
Figures 2A and 2B show the dependency of the droplet
size on the HLB of the emulsifier blends. With respect of
the four emulsifier systems investigated, a required HLB
value of 9.1  0.4 (cetearyl isononanoate) and 9.3  0.4
(coco-caprate=caprylate) was determined. The outlier of
the required HLB of 5.7 (coco-caprate=caprylate with
Oleth-3=PEG-40-Stearate) is caused by the curve pro-
gression due to the available HLB range. Again, the
 REQUIRED HLB DETERMINATION OF SOME PHARMACEUTICAL OILS 819

droplet size of the different emulsifier systems increased

from Oleth-5=Steareth-20 < Oleth-3=Steareth-20 < Span
80=Tween 20  Oleth-3=PEG-40-Stearat with both oils.
This seems to be related to the deviation in the HLB values
of the two emulsifiers used in the blend (Table 2). With
ascending difference between the HLB values of the two
emulsifiers of the blend, the droplet size is increasing. Great
deviation cause weakening of the oil-in-water interfacial
layer due to insufficient interaction between the two emul-
sifiers.[18] Further factors influencing the constitution of the
interfacial layer can be the chain length of side chains and
double bonds in the side chains of the emulsifiers.[17] Both,
optimum HLB value and the selected emulsifier system,
affect the emulsions characteristics. Nevertheless the stab-
ility over the time has to be proven.

3.3. Stability
Possible alterations of emulsions over time, such as
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coalescence, creaming or sedimentation might lead to a

FIG. 2. Droplet size of the SME’s as a function of the HLB. (A)
cetearyl isononanoate and (B) coco-caprate=caprylate; (&) Oleth-5=
Steareth-20, (~) Oleth-3=Steareth-20, (.) Oleth-3=PEG-40-Stearate and
(^) Tween 20=Span 80 (HLB 6.8); n ¼ 1.
breakdown of the emulsion. Coalescence can be deter-
mined by droplet size measurement. According to Stokes’
equation sedimentation and creaming occur because of a
difference in density between the external and inner phases
and the droplet sizes of the dispersed phase of an emulsion.
Creaming, the floating of the oil droplets, is a reversible
alteration of an emulsion that cannot determined by drop-
let size measurement. A small droplet size is needed to pre-
vent creaming. Thus, correct adjustment of the HLB value
is important. Since creaming and sedimentation are revers-
ible phenomena, coalescence is the most crucial alteration
regarding formulation stability.
To determine the short time stability a selection of
SMEs containing the oils coco-caprate=caprylate, cetearyl
isononanoate, or ethyl oleate as well as a mixture thereof
were investigated using the emulsifier system Span 80=
Tween 20. Results presented in Figure 3 shows no

TABLE 2
Required HLB values of the oilsa
Coco-caprate= Cetearyl
Ethyl oleate caprylate isononanoate
Deviation of the HLB
Emulsifier blend rHLB R2 rHLB R2 rHLB R2 value of the emulsifier blend

Oleth-3=Steareth-20 11.5 0.95 9.0 0.99 8.7 0.99 8.7

Oleth-3=PEG-40-Stearate 10.6 0.95 5.7 0.98 8.9 0.97 10.1
Oleth-5=Steareth-20 11.3 0.97 9.7 1.00 9.6 0.98 6.3
Tween 20=Span 80 (HLB ¼ 6.8) 9.8 0.96 9.3 0.95 9.0 0.95 9.9
Tween 20=Span 80 (HLB ¼ 4.3) 8.1 0.97 8.5 0.95 7.0 0.94 —
Required HLB (mean value) 10.8  0.8 9.3  0.4 9.1  0.4 —
a
The required HLB of the oil was determined by the calculation of the minimum point of the polynomial second order.

This value was excluded for determination of the mean value.

Required HLB values determined with HLB 4.3 of Span were excluded for determination of the mean value.
 820 T. SCHMIDTS ET AL.
FIG. 3. Results of the droplet size measurements of SMEs stabilized
with Span 80=Tween 20. (.) coco-caprate=caprylate, (~) cetearyl isono-
Downloaded by [Aston University] at 08:17 04 September 2014
nanoate, (&) ethyl oleate and (^) oil mixture of the three oils (1:1:1).
Filled symbols ¼ day 1 and opened symbols ¼ day 30 (n ¼ 3).
FIG. 4. Creaming depending on the HLB value. Cetearyl isononano-
ate stabilized with Span 80=Tween 20 at day 30. Arrows denote the level of
creaming.
significant changes in droplet size after one month among
the investigated SME. Nevertheless, reversible creaming
was observed beyond the required HLB range. The extent
of creaming was dependent on the HLB value of the emul-
sifier blend. Figure 4 shows exemplary the influence of the
present HLB value on the amount of creaming. The SMEs
close to the required HLB value (1) exhibited no cream-
ing. The greater the difference between the present emulsi-
fier HLB value and the required HLB value of the oil, the
greater was the amount of creaming.
4. CONCLUSION
In summary, it was able to be demonstrated that pub-
lished HLB values lead to inaccurate assumptions when
required HLB values are determined. The established
HLB value of 4.3 of Span 80 leads to incorrect required
HLB values. The HLB of 6.8 for Sorbitan oleate published
by Pasquali[13] seems to be more crucial. According to the
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results, this value should be taken as the basis for required
HLB determination.
The postulated transferability of the determined requi-
red HLB value using the system of Tween 20 and Span
80 compared to other emulsifier systems is depending on
the used equation. Additionally, this was confirmed by
the empirical determination of the required HLB values
by preparing submicron emulsions of the pharmaceutical
oils coco-caprate=caprylate and cetearyl isononanoate. It
was shown that the droplet size of the submicron emulsion
systems developed this way is able to be regulated by
altering the HLB value by approximately 1 unit of the
calculated required HLB values, thereby creating stable
emulsions. Particle size measurement proved to be a suit-
able method for the determination of the required HLB
value.
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