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Effect of a model lipophilic compound on the phase behavior of hydrophilic self-

micro-emulsifying lipid formulations

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Effect of a model lipophilic compound on the phase behaviour of

hydrophilic self-micro-emulsifying lipid formulations
NaserM.Y. Hasan*1, 2
1 School of
Pharmacy, Taif University, SaudiArabia
2 Department of Pharmacy and Pharmacology, TheUniversity of Bath, UK

Received on:19-08-2016; Revised on: 16-09-2016; Accepted on: 05-10-2016

ABSTRACT
Background: There has been growing interest in the self-emulsifying lipid technology in recent years as an approach to improve
the oral bioavailability of poorly water-soluble compounds. Nonetheless, for the design of successful lipid formulations with a
potential to maximize the bioavailability of lipophilic drugs, key elements in the lipid composite in relation to the physicochemical
state of drug after dispersion needs to be optimized. Methods: In this study, various lipid formulations were optimized for oil-in-
water micro-emulsion drug delivery systems. The effect of Ibuprofen (a model lipophilic drug) on the emulsification behavior of
these systems was also investigated by constructing ternary phase equilibrium diagrams using dynamic phase behavior study
method. Results and Discussion: Optimum self-micro-emulsifying systems were obtained by using oil blends of {Miglyol
812/Imwitor 308} at ratio of 5:5 in the case of Cremophor RH40 and 4:6 for Tagat S2 or Tagat S Ternary phase equilibrium
diagrams reveal extended regions of L2 phase when no drug was added to the lipid mixtures. However, in the case of lipid
formulations containing Ibuprofen at 100mg/g, small limited areas of L2 phase was observed which suggests that the drug can
interfere in the mechanistic processes of emulsification. Conclusion: In order to design successful self-micro-emulsifying lipid
systems, pre-formulation studies which affect the performance of resultant dispersions of these systems with and without drug
should be carried using suitable emulsification media.

KEY WORDS: SMEDDS; SEDDS; Phase behavior studies; Poorly water-soluble drugs; Cremophor RH40

1. INTRODUCTION
There has been growing interest in the field of self-emulsifying lipid SEDDS (Self-emulsifying drug delivery systems) are isotropic mixtures
technology in recent years as an approach to improve the oral of oils (triglycerides), and/ or co-surfactant (mixed glycerides) and
bioavailability of poorly water-soluble compounds. After the advent non-ionic surfactants which upon gentle agitation spontaneously
of Neoral® (Cyclosporine A,immunosuppressive agent) in 1995 by emulsify in water producing fine oil in water (o/w) dispersionsof
Novartis, Sandoze back then, lipid-based delivery systems have droplets <5µm5. On the other hand, Self-micro-emulsifying drug
gained considerable research attention. Hence, many pharmaceutical delivery systems (SMEDDS) contain in the lipid mix hydrophilic
products using SEDDS or SMEDDS were introduced to the market components such as, hydrophilic surfactants (HLB >12) and/ or
including,Targretin® (Bexarotene, Ligand), Norvir® (Ritonavir, hydrophilic co-solvents systemswhich when mixed with water under
Abbott), Agenerase®(Amprenavir, GlaxoSmithKline), Rocaltrol® gentle agitation can produce an almost clear o/w microemulsion of
(Calcitriol, Roche), Aptivus® (Tipranavite, BoehringerIngelheim), oil droplets with diameters between 5 and 140nm 6 . These
Lipirex® (Fenofibrate, Sanofi-Aventis)1-3 and Avodart®(Dutasteride, systems,based on various physicochemical factors such as; the
GlaxoSmithKline)4. hydrophilicity of the oil mixture, particle size of the resultant
dispersion and the formulation digestibility were classified into type
*Corresponding author. I, II, III and IV7-8. Hydrophilicity of the lipid mixture increases by
Dr. Naser M.Y. Hasan moving from type 1 lipid class system to type 4. An archetypal example
School of Pharmacy,
of a Type III system is the reformulation of cyclosporine A as
Taif University,
SaudiArabia. Neoral® 9. Type IV formulations do not contain natural lipids and
represent the most hydrophilic formulations. An example of a Type
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IV formulation is the current capsule formulation of the HIV protease a gift.Simulated Gastric Fluid (SGF) without pepcin; 2.4g NaCl and
inhibitor amprenavir (Agenerase®) which contains TPGS as a 7ml HCl/1000ml water. All water used was Mili Q water.
10
surfactant and PEG 400 and propylene glycol as co-solvents . There
is an obvious trend amongst formulation scientists to opt for Type 2.2. Methods
IV class formulations as these systems have high solubilization
capacity to drugs. Yet, due to hydrophilic nature of Type IV lipid 2.2.1. Miscibility profiles for lipid mixtures
class carriers may render lipophilic drugs susceptible to crystallization Regions of mutual miscibility of various lipidformulations
in the GIT lumen after dispersion, as these carriers tend to lose their containingvarious surfactants thatrepresent different HLB values
solvent capacity during emulsification process. Dynamic of drug were determinedusing ternary phase diagrams. Miscibility diagrams
precipitation from the various types of lipid class systems ofMiglyol 812 (source oil), Imwitor 308 (co-surfactant) and various
highlighting the role of oil (source triglyceride and/or mono- surfactants including; Cremophor RH 40,Tagat S2 and Tagat S were
diglycerides) in the lipid matrix in preventing drug crystallization constructed.Formulations of two grams which represent
after dispersion in the aqueous media was thoroughly investigated variouspercentages of oils, co-surfactants and surfactants onthe
by Hasan et al 11-12
. ternary phase diagrams were weighed in 20 mlglass test tubes and
then tops were wrapped withcling film. Mixtures were placed in a
Nonetheless, for the design of successful lipid formulations with a water bath at 50ºC for 2 minutes before lipid components
potential to maximize the bioavailability of lipophilic drugs, key werethoroughly vortexed. Mixtures were then kept for 24-48 hours in
elements in the lipid composite in relation to the physicochemical an oven set up at 25°C before visualassessment. Samples that
13
state of drug after dispersion needs to be optimized . This process displayed two or more phases weredescribed as immiscible systems.
includes; determination of drug solubility in the lipid matrix, Mixtures which formed a continuoussingle phase were classified as
controlling factors which influence the hydrophilicity of the lipid miscible formulations.
vehicle such as type of oil, oil-cosurfactant ratio, type of surfactant
and the inclusion of hydrophilic co-solvent. Also, it is important to 2.2.2. Self-Emulsification profiles of lipid mixtures
investigate the effect of drug on the emulsification performance of Mixtures of oils, co-surfactants andsurfactants were accurately
weighed into glass test tubes and then wrapped bycling film followed
these systems in suitable media simulating the physiological
by votrexing. Test tubes were held at 50°C in a thermostated water
conditions of the GI tract. In this study, various lipid formulations
bath held for 2 minute before lipid mixtures were thoroughly vortexed.
were optimized for oil-in-water micro-emulsion drug delivery systems.
Lipid formulations were then left toequilibrate over night in an oven
The effect of Ibuprofen (a model lipophilic drug) on the emulsification
set up at 25°C. Emulsions were prepared under conditions of
behavior of these systems was also investigated by conducting
gentleagitation at a controlled temperature of 37°C. Anamount of 1g
phase behavior studies. of each lipid mixture was introducedinto either 100ml of distilled
water or media simulating gastrointestinal fluids (SGF) in a 500-ml
2. MATERIALS AND METHODS glass beaker. Emulsification was carried out under agitation simulating
in vivo situation. Agitation was provided by gentleshaking on a
2.1. Materials mechanical shaker at 100 oscillationsper min for 15 minutes. Visual
Miglyol 812, medium chain triglyceride, (C8/C10 mono/diglycerides) assessment ofresulting dispersions was carried out and systemswhich
and Imwitor 308 were supplied by CondeaChemie GmbH. Tagat produced clear micro-emulsions wereidentified as SMEDDS while
S2(PEG-(20)-glyceryl stearate) and Tagat S(PEG-(30)-glyceryl milky turbid emulsions were denoted as SEDDS.
stearate)were supplied by Goldschmidt AG, Germany. The fatty acid
2.2.3. Phase behavior Study
distribution in Miglyol 812 according to the manufacturer is: caprylic
Phase behavior study was carried out using dynamic method. Pseudo-
(C8): 50-65%, capric (C10): 30-45%, caproic (C6):<2% and Lauric acid
ternary diagrams were constructed by blending oil mixtures of
C12: <3%. Imwitor 308 is approximately a 9:1 mixture of C8/C10 mono/
{Miglyol 812/Imwitor 308} at ratios of 5:5 or 4:6 with increasing
diglycerides with 1% free glycerol. Cremophor RH 40 (PEG-(40)-
concentrations (10-90% w/w) of either Cremophor RH40 or Tagat S2,
hydrogenated castor oil) and Ibuprofen were supplied by BASAF as
respectively. Demineralized water was then sequentially added at

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5% w/w intervals into the oil mixture under agitation. Systems were blends of {Miglyol 812/Imwitor 308} at ratio of 4:6 at Tagat S2 or
then allowed to equilibrate at 37°C for few minutes. The addition of Tagat S concentrationsof 30% w/w, see linen AB depicted on figures2
water was continued until phase change was observed. Phases were and 3. This suggests that the emulsification performance of lipid
identified as isotropic L2 (oil-based liquids) or L1 (aqueous-based composites containing Cremophor RH40 is relatively better than using
liquids), liquid crystalline phases (LC) and multiphasic turbid mixtures Tagat S2 or Tagat S in the oil mi. This might be due to variations in
(L1+L2). The phase behavior was also carried out in lipid mixtures the HLB values and packing parameters of these non-ionic
containing Ibuprofen at 100mg/g. surfactants.The molecular packing parameter Pc is defined as vo/alo,
where vo and lo are the volume and the length of the surfactant tail
3. RESULTS AND DISCUSSION and a is the surface area per molecule. The expected aggregate shapes
in relation to surfactant critical packing parameter are as follows;
3.1. Effect of surfactants hydrophilicity on emulsification behavior 0 <vo/alo< 1/3 for sphere, 1/3 <vo/alo< 1/2 for cylinder, and 1/2 <
of lipid systems vo/alo< 1 for bilayer22. Chemical structure of Cremophor RH40 exhibits
For the design of successful lipid formulations, three key constituents triple-tailed surfactant molecule while Tagat S or S2 is single-tailed,
must be optimized which include; type of oil, co-surfactant and see figure 4 for chemical structures. This suggests that Cremophor
surfactant. There is a consensus amongst researchers11,14-19 that the RH40 has relatively high Pc values(0.5 - 1) in comparison to either
use of MCT as source of oil in SEDDS or SMEDDS enhances Tagat S or S2 (> 0.5). Therefore, Cremophor RH40 would possibly
emulsification process of these systems as opposed to using LCT. form flexible bilayer aggregates while in the case of Tagat S or S2
Nonetheless, this does not preclude the importance of using LCT in spherical or cylindrical aggregates are favored.
the lipid composite in enhancing bioavailability of highly lipophilic
drugs of log P> 5; as in the case of probucoal20 and danazol21.
Co-surfactants are considered polar oils generally composed of Immiscible 2-phases
medium chain mono- and diglyceridescontaining small proportions
of un-esterified glycerol. Co-surfactants with high monoglyceride Self-emulsifying
content such as Imwitor 308, 312 and 191 have high HLB values (i.e.
more polar) and may form liquid crystalline states which render Self-microemulsifying [Clear]
them more susceptible to the ionic strength and temperature of the
medium. It is thought that co-surfactants can stabilize the interface
by penetrating into the void spaces among surfactant molecules in
the surfactant film around the oil droplet and hence lowering the
interfacial tension and increasing the interfacial fluidity13. Nonionic
surfactants are normally used in oral self-emulsifying lipid.
Emulsification efficiency of surfactants is verily controlled by the
average HLB value and the empirical chemical structure of the
B
surfactant. Polyoxyethylene hydrogenated caster oil derivatives have
relatively shown relativelyhigher solubilization capacity to the oil
composite and emulsification efficiency during aqueous dispersion.

Figure 1 shows the emulsification profile of blends composed of

Miglyol 812 (source of oil), Imwitor 308 (co-surfactant) and
Cremophor RH40 (non-ionic surfactant). Extended area of SMEDDS
was observed which suggests the robustness of this lipid composite A
at minimal concentrations of surfactants. Optimum self-micro- Imwitor 308
emulsifying systems were obtained by using oil blends of {Miglyol
812/Imwitor 308} at ratio of 5:5 at Cremophor RH40 concentration of Figure 1: Ternary phase diagram of Miglyol 812/Imwitor 308-
20% w/w, see line AB depicted on figure 1. On the other hand, Cremphor RH40 depicting various areas of emulsification
replacing Cremophor RH40 in the lipid mix with either Tagat S2 performance of representative oil mixtures. 1 g of each mixture was
(figure 2) or Tagat S (figure 3) though has produced good SMEDDS introduced into100ml of Milli-Q water and emulsified at 37°C for
area yet, still relatively less than SMEDDS area which is observed in 15 minutes by gentle agitation. Line A-B represents formulations
the case of lipid mix containing Cremophor RH40. Furthermore, of {Miglyol/Imwitor} at ratio of 5:5 with increasing concentration
Optimum self-micro-emulsifying systems were obtained by using oil
of Cremophor.

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Immiscible 2-phases

Self-emulsifying

Self-microemulsifying [Clear]

Figure 4: Chemical structures of (a) Cremophor RH40 (PEG-(40)-

hydrogenated castor oil); x + y + z = 40 (b) Tagat S2 or S (PEG-(20/
30) glycerol stearate; x + y + z = 20 or 30.
Imwitor 308 A
3.2. Effect of medium ionic strength on the emulsification behavior
Figure 2: Ternary phase diagram of Miglyol 812/Imwitor 308- of lipid systems
TagatS2 depicting various areas of emulsification performance of The luminal environment in the proximal GI tract varies considerably
representative oil mixtures. Line A-B represents formulations of with site and meal ingestion. Hence, it is essential to consider the
{Miglyol/Imwitor} at ratio of 4:6 with increasing concentration of use of several different sets of emulsification conditions to evaluate
Tagat S2. the dissolution behavior of the oil formulations with and without
drugs. The United States Pharmacopoeia23 denotes Simulated Gastric
Fluid (SGF) to simulate dissolution in the stomach. SGF simulates pH
conditions in the fasted stomach.

Generally, electrolytes present in the emulsification media, as the

variation in temperature, can affect emulsification performance of
lipid formulations. The preferential aqueous solubility of the
surfactant is shifted to the oil phase due to salting out effect and
thus inducing phase separation. This effect, however, can be averted
B by using surfactants with relatively high HLB values. Any reduction
of the surfactant hydrophilicity incurred by electrolytes will not be
sufficient to induce phase separation.The self-emulsifying system
initially investigated by Pouton16,24 which is composed of Tween 85-
Miglyol 812 was shown to be influenced by the electrolytes present
in the emulsification media. On the other hand, the Tagat TO-Miglyol
812 system produced by Wakerly25-26,was shown to be capable of
A forming submicron emulsions with no effect of the medium ionic
Imwitor 308 strength on the self-emulsification process. This resistance to the
Figure 3: Ternary phase diagram of Miglyol 812/Imwitor 308-Tagat salting out effect of electrolytes present in the emulsification media
S depicting various areas of emulsification performance of is probably due to the fact that the non-ionic surfactant Tagat TO
representative oil mixtures. Line A-B represents formulations of has a relatively higher HLB value than Tween 85, or due to the
{Miglyol/Imwitor} at ratio of 4:6 with increasing concentration of chemistry variations of the two aforementioned surfactants.
Tagat S.
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Furthermore, the self-micro-emulsifying system developed by 3.3. Effect of a model lipophilic drug on the phase behavior of
Hasan13 which is composed of Miglyol 812-Imwitor 988-Tagat To lipid systems
was susceptible to the effect of the electrolytes present in the In the design of successful lipid formulation with maximum drug
emulsification media. As Imwitor 988 is polar oil, it causes depressions absorption, the effect of the drug on the emulsification process has
in phase inversion temperature PIT and also lossof surfactant’s to be investigated. The exact physical state of the drug during the
affinity for the aqueous phase due to electrolytes present in the various stages of the emulsification process has to be highlighted
media. This can induce phase separation and thus significant increase using static or dynamic phase behavior methods. The mechanistics
in droplet diameter13. This is clearly illustrated in table 1 which shows of self-micro-emulsifying lipid formulations after aqueous dispersion
the effect of ionic strength of dispersion media (SGF versus water) involve the following dynamic intermediate phases; L2 phase (clear
on the emulsification behavior of various lipid mixtures, containing w/o micro-emulsion)  L1 + L2 phase (turbid emulsion phase)  LC
non-ionic surfactants with varying degree of hydrophilicity. In the (liquid crystalline phase)  L1 phase (clear w/o micro-emulsion).
case of lipid mixtures containing Cremophor RH40 (HLB 14-16) or, Depending on the hydrophilicity of oil mix, amount of co-surfactant
Tagat S (HLB 16.4), the emulsification performance has shown high and surfactant, L1 + L2 or Lc phase might not appear on the phase
resistance to the effect of temperature or electrolytes present in the behavior map and thus the initial L2 phase could pass through L1
emulsification media vis clear micro-emulsionswere obtained after phase on progressive dilution with water. The former rout of
dispersion in either water or SGF media at all surfactant emulsification might be quintessential for the bioavailability
concentrations. On the contrary, for formulations containing Tagat enhancement of highly lipophilic drug such as Danazol (Log P 4.5).The
S2 (HLB 15), ionic strength of the media has dramatically influenced formation of turbid emulsion phase (L1 + L2 phase) throughout
emulsification performance. Emulsification of lipid mixtures containing emulsification process may prevent crystallization of drug in the
30 to 40% w/w Tagat S2 in SGF media has produced turbid lumen of the gut as the drug will be sequestered in the oil phase
emulsionsin comparison to the optically clear dispersions in water. minimizing direct contact with external aqueous phase. Another
This effect, however, was retarded in the case of using Tagat S2 at important factor which improves bioavailability of highly lipophilic
higher concentrations of e” 50 %w/w. Therefore, it is essential to use drugs is the use of lipids composed of long-chain triglycerides (LCT).
sufficient amount of surfactants with relatively high HLB values in LCT stimulates the formation of lipoproteins, which facilitates their
order to avert salting out effect of electrolytes present in the lymphatic transport27. On the other hand, the dynamic transformation
emulsification media. In this case, any reduction of the surfactant from L2 L1 phase without passing through intermediatory phases
hydrophilicity incurred by electrolytes will not be sufficient to induce on progressive dilution with watermight be essential for
phase separation. bioavailability enhancement of intermediate lipophilic drugs of
Table 1: The effect of emulsification media on the emulsification log P < 2.5 such as Ibuprofen.
performance of various lipid mixtures.SGF: Simulated Gastric Fluid,
EM: Emulsion (turbid dispersion) and ME: Microemulsion (opti- Figures 5 and 7 depict 3D representation of the equilibrium phases
cally clear dispersion). resulting from the progressive dilution of water of lipid system
Surfactant 30% 40% 50% composed of either {Miglyol 812/Imwitor 308} (5:5)-CremophorRH40
Concentration Resultant dispersion in various media
or {Miglyol 812/Imwitor 308} (4:6)-Tagat S2, respectively. At least 20
% w/w of Cremophor RH40 (Fig 5) or 30 % w/w of Tagat S2 (Fig 7) is
Lipid
needed in the lipid mix to produce o/w microemlusion. On the hand,
Formulations
at least 40% w/w of either Cremophor RH40 or Tagat S2 is required to
Water SGF Water SGF Water SGF obtain all the way through clear dispersions (L2  L1) on the
progressive addition of water. Nonetheless, the inclusion of Ibuprofen
{Miglyol/Imwitor} ME ME ME ME ME ME at 100mg/g lipid has transformed phase behavior map on interaction
{5/5} / with water for both systems as shown in figures 6 and 8. In comparison
Cremophor RH40 to the lipid systems without drug (Fig 5 and 7), small limited areas of
L2 phase was observed, see figures 6 and 8. Besides, the appearance
{Miglyol/Imwitor} ME ME ME ME ME ME of new intermediate phases L1+L2 and/or LC phases resulting from
{4/6} / the progressive dilution with water before final clear o/w
Tagat S microemlusion is obtained.This suggests that the drug can interfere
in the mechanistic processes of emulsification by blocking charge
transfer during dispersion of the formulation. On the hand, at least
{Miglyol/Imwitor} ME EM ME EM ME ME
50% w/w of either Cremophor RH40 or Tagat S2 is needed respectively
{4/6} /
in both systems (Figs 6 and 8) for LC intermediate phases to appear
Tagat S2

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Turbid mixtures (L1+L2)

Liquid Cr ystalline phases (LC)

Clear dispersions (L2 / L1)

Figure 7: 3D representation of the equilibrium phase behaviour for

{Miglyol 812/Imwitor 308} (4:6)-Tagat S2 with no drug resulting
from the incremental addition of water.

Figure 5: 3D representation of the equilibrium phase behaviour for

{Miglyol 812/Imwitor 308} (5:5)-CremophorRH40 with no drug
resulting from the incremental addition of water.

Figure 8: 3D representation of the equilibrium phase behaviour for

{Miglyol 812/Imwitor 308} (4:6)-Tagat S2 with 10% ibuprofen re-
sulting from the incremental addition of water.
on the phase behavior map during dilution with water. Furthermore,
at least 70 % w/w of Cremophore RH40 is needed to cause L1+L2
phase to disappear from phase behavior map in comparison to using
50% w/w Tagat S2, see Figs 6 and 8. It is thought that the appearance
of L1+L2intermediate turbid phase during emulsification process
which takes place in the stomach might be detrimental to the
Figure 6: 3D representation of the equilibrium phase behaviour for bioavailability enhancement of poorly water soluble drugs.
{Miglyol 812/Imwitor 308} (5:5)-Cremophor RH40 with 10% Nonetheless, the formation of LC clear lyotropicmesophases might
Ibuprofen resulting from the incremental addition of water. form sustained release systems.
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4. CONCLUSION 7. Pouton CW. Lipid Formulations for oral administration of

In order to design successful self-micro-emulsifying lipid systems, drugs: non-emulsifying, self-emulsifying and “self-
pre-formulation studies which affect the performance of resultant microemulsifying” drug delivery systems. Europ J Pharm
dispersions of these systems with and without drug should be carried Sci., 2000; 11(2): S93-S98.
using suitable emulsification media.It appears that drugs can interfere 8. Pouton CW. Formulation of poorly water-soluble drugs for
in the mechanistic processes of emulsification by blocking charge oral administration: physicochemical and physiological
transfer during dispersion of the formulation. issues and the lipid formulation classification system, Europ
J Pharm Sci., 2006; 29: 278-87.
5. ACKNOWLEDGMENT 9. Pouton CW. Key issues when formulating hydrophobic
I am grateful to Dr. Stephen Moss and Prof. Colin Pouton for their drugs with lipids. Bulletin Technique Gattefossé, 1999.
endless support, guidance and encouragement throughout this 10. Suman K, Chandrasekhar P, BalajiS.Approaches for the
project. I am also grateful to the Department of Pharmacy and development of solidself-emulsifying drug delivery systems
Pharmacology at Bath University for providing a good atmosphere anddosage forms. Asian J Pharm Sci.,2009;4(4):240-253.
and excellent facilities of research. I am also thankful to Capsugel for 11. Hasan NMY, HayajnehFM, KhaleelMA, AlharthiSA.,
their sponsorship and to Goldschmidt (Germany), BASF Corporation, Shahada HM, Almalki HF. Development of Potential Self-
CondeaChemie (Hüls), Gattefossé and Croda who have been microemulsifying Lipid Formulation for the Oral
providing us with the excipients needed. Finally, my sincere Administration of Curcumin. Int J Adv Pharm Biol Chem.,
gratefulness goes to the school of Pharmacy at Taif University for 2015; 4(3): 590-602.
the excellent friendly, socially and scientifically environment they 12. Hasan MYN. Self-micro-emulsifying lipid formulations to
endeavor to provide. This is a full publication based on an abstract improve the bioavailability of poorly water-soluble drugs.
(poster presentation) presented at BPC in 2005 in Manchester, UK. PhD thesis, University of Bath, 2004.
13. Hasan N.M.Y., Role of medium-chain fatty acids in the
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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.10 Issue 10 October 2016 647-654

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