Self-Emulsification of Vegetable Oil-Nonionic ... - ACS Publications

18 Self-Emulsification of Vegetable Oil-Nonionic Surfactant Mixtures A Proposed Mechanism of Action 1

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Mark G. Wakerly, Colin W. Pouton, Brian J. Meakin, and Frank S. Morton Downloaded by UNIV OF ARIZONA on January 11, 2013 | http://pubs.acs.org Publication Date: June 5, 1986 | doi: 10.1021/bk-1986-0311.ch018

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School of Pharmacy and Pharmacology, University of Bath, United Kingdom R.P. Scherer Ltd., Blagrove, Swindon, United Kingdom

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Binary mixtures of some commerical nonionic surfactants and vegetable oils have been screened for their ability to emulsify under conditions of gentle agitation. Such mixtures may have potential use as pharmaceutical drug delivery systems. The system Tagat TO, an ethoxylated glycerol tri-oleate and Miglyol 812, a medium chain triglyceride, has been studied in detail for its ability to form stable, submicron-droplet oil-in-water emulsions. Ternary phase studies have revealed a specific region of lamellar liquid crystal dispersed in the isotropic phase of solubilised water. The occurrence of this dispersion phase correlates with good self-emulsifying performance from the binary mixture. The observed self-emulsification is considered to be a result of aqueous penetration into the liquid crystal aided by mechanical dispersion of the resulting emulsion. Soft gelatin capsules containing oily solutions of drugs, such as sedatives, vitamins and steroidal hormones, are used as oral dosage forms for medicinal products. Such drug delivery systems can have therapeutic advantages over tablets or powder-filled hard gelatin capsules; in particular the slow drug dissolution step often encountered with lipophilic drugs can be avoided (l 2). This can lead to better control of drug absorption from the gastro-intestinal tract and hence improvement in the effectiveness of the medicinal product (3-5). If the lipophilic drug is presented in an o i l - i n water emulsion further enhancement of bioavailability can be achieved (6J. However water-containing vehicles cannot be filled into soft gelatin capsules due to the hydrophilic nature of the gelatin shell which absorbs water thus dehydrating and eventually disrupting the emulsion structure (I). Consequently we are studying surfactant-oil solutions which exhibit the phenomenon of self-emul sif ication as a method of achieving emulsions in the gastro-intestinal tract which are derived from soft gelatin encapsulated formulations. f

0097-6156/86/0311-0242$06.00/0 © 1986 American Chemical Society In Phenomena in Mixed Surfactant Systems; Scamehorn, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

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Vegetable Oil-Nonionic Surfactant Mixtures

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S e l f - e m u l s i f i c a t i o n i s the formation of an emulsion from o i l and water by weak mechanical shear f o r c e s . I n v i v o such l e v e l s of agitation would be provided by the digestive m o t i l i t y of the stomach and intestine (8). Reiss has calculated that the free energy of o i l water mixing w i l l be negative i f the i n t e r f a c i a l tension i s l e s s than 10"3 Nm" , and at about 10"^ Nm" emulsion d r o p l e t s of diameter approximately 0.3 μη w i l l form (11). Such systems are described as being s p o n t a n e o u s l y - e m u l s i f y i n g (9 10). S y s t e m s w h i c h have i n t e r f a c i a l tensions of the order of 10"^ Nm" w i l l emulsify readily although not spontaneously and are c l a s s i f i e d as s e l f - e m u l s i f y i n g . For both s e l f - and spontaneous e m u l s i f i c a t i o n the presence of added s u r f a c e a c t i v e m a t e r i a l s i s n o r m a l l y r e q u i r e d (12.). The r a t i o n a l e behind t h i s study necessitated the use of materials with p o t e n t i a l l y acceptable t o x i c i t y c h a r a c t e r i s t i c s when ingested o r a l l y . The choice of s u r f a c t a n t was t h e r e f o r e r e s t r i c t e d to the ethoxylated nonionic type which are l i k e l y to have acceptable t o x i c i t y p r o f i l e s ( H ) and o i l s were derived from vegetable sources. 1

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Downloaded by UNIV OF ARIZONA on January 11, 2013 | http://pubs.acs.org Publication Date: June 5, 1986 | doi: 10.1021/bk-1986-0311.ch018

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Experimental Materials. A l l materials were used as received from the suppliers. Nonylphenol ethoxylates (Synperonics) were obtained from Cargo Fleet Chemical Company Ltd, England. Alcohol ethoxylates (Marlipals) were obtained from Huls (UK) L t d . F a t t y a c i d e t h o x y l a t e s (Leeks) were obtained from Leek Chemicals L t d , England. Tween 85 was o b t a i n e d from A t l a s Chemical I n d u s t r i e s (UK) L t d . Tagat TO was s u p p l i e d by Th. Goldschmidt AG, Germany. Vegetable o i l s were M i g l y o l 812 supplied by Dynamit Nobel (UK) Ltd and Arachis o i l supplied by Evans Medical Ltd, England. A l l water was single d i s t i l l e d using a l l glass apparatus. Methods. I n i t i a l l y a range of d i f f e r e n t n o n i o n i c s u r f a c t a n t - o i l m i x t u r e s c o n t a i n i n g 30$ w/w s u r f a c t a n t were screened f o r t h e i r a b i l i t y to s e l f - e m u l s i f y i n water at 25 and 37°C. Gentle a g i t a t i o n was provided by a g l a s s s t i r r e r as d e s c r i b e d by Pouton (UL). The e f f i c i e n c y of s e l f - e m u l s i f i c a t i o n was assessed s u b j e c t i v e l y on a scale of 1 to 5 (bad to excellent) by v i s u a l observation. Emulsion p r e p a r a t i o n under c o n t r o l l e d Q Q ^ j t i o n s , Those systems which appeared t o e m u l s i f y e f f i c i e n t l y were s t u d i e d f u r t h e r by p a r t i c l e size analysis of the emulsions formed by s e l f - e m u l s i f i c a t i o n under agitation conditions considered to be a reasonable simulation of the in. vivo s i t u a t i o n (8). Mixtures containing between 5 and 70$ w/w surfactant were examined over the temperature range 25 to 50°C. A c o n c e n t r a t i o n of 0.04$ v/v of b i n a r y l i p o p h i l i c m i x t u r e was achieved by the following method. 10 μΐ of s e l f - e m u l s i f i a b l e mixture was delivered from an Agla micrometer syringe i n t o 25 ml of d i s t i l l e d water i n a 30 ml Pyrex glass tube f i t t e d with a ground glass stopper. A l l materials were pre-equilibrated to the appropriate temperature. The tubes were immersed i n a t h e r m o s t a t t e d shaking waterbath (+ 0.1°C) and rocked h o r i z o n t a l l y through 2.5 cm at a r a t e of 40 o s c i l l a t i o n s per minute f o r 10 minutes unless otherwise stated. The concentration of the resulting emulsions was such that droplet s i z e determinations could be performed without d i l u t i o n .

In Phenomena in Mixed Surfactant Systems; Scamehorn, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.


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PHENOMENA

IN M I X E D S U R F A C T A N T

SYSTEMS

A n a l y s i s o f Mean Emulsion Droplet Diameter (MEDD). Two techniques were used t o measure the MEDD of the s e l f - e m u l s i f i e d systems. Low angle l a s e r l i g h t d i f f r a c t i o n (Malvern model 3600E with small volume s t i r r e d c e l l ) was used f o r emulsions with droplet d i s t r i b u t i o n s above 1 μη. The majority of determinations were carried out over the range 1-120 /im. Samples were a n a l y s e d immediately a f t e r p r e p a r a t i o n . Q u a s i - e l a s t i c l i g h t s c a t t e r i n g (QELS, Malvern model 4600 photon correlation spectrometer) was used f o r i n v e s t i g a t i o n s of submicron d i s p e r s i o n s and measurements were made 24 hours a f t e r preparation. The MEDD of such submicron emulsion systems has been shown t o be u n a l t e r e d by storage f o r 7 days (14). For both t e c h n i q u e s t h r e e separate emulsion samples were examined. Each sample was determined i n t r i p l i c a t e by l a s e r d i f f r a c t i o n and i n q u i n t r i p l i c a t e by QELS. MEDD v a l u e s are expressed as mean v a l u e s o f a l l data + standard error. E q u i l i b r i u m Phase Behaviour. Phase s t u d i e s were performed u s i n g approximately 10 g samples of o i l - s u r f a c t a n t mixture d i l u t e d s e q u e n t i a l l y by the weighed a d d i t i o n of water. The i n i t i a l b i n a r y mixture contained 5-7 0$ w/w s u r f a c t a n t a t 5$ i n t e r v a l s . Phase boundaries were determined to + 0.5$ water. The ternary mixtures i n Pyrex g l a s s tubes f i t t e d w i t h PTFE l i n e d caps were e q u i l i b r a t e d t o the r e q u i r e d temperature (20-65 ± 0.1°C) f o r 2 hours and then thoroughly mixed f o r 5 minutes using a Fisons o r b i t a l whirlimixer. The tubes were then r e t u r n e d t o the waterbath and l e f t u n d i s t u r b e d for 48 hours before i d e n t i f i c a t i o n of the phase type using a crossed polarised viewer and an o p t i c a l microscope. Results and Discussion Qualitative data obtained by v i s u a l assessment of s e l f - e m u l s i f i c a t i o n at 25 o r 37°C (Table I) show that the unsaturated e s t e r - t y p e s u r f a c t a n t s e x h i b i t b e t t e r s e l f - e m u l s i f y i n g behaviour than t h e e q u i v a l e n t s a t u r a t e d e t h e r types w i t h both o i l s . These data a l s o show t h e phenomenon i s not d i r e c t l y r e l a t e d t o the h y d r o p h i l e l i p o p h i l e b a l a n c e (HLB) o f t h e s u r f a c t a n t . The e s t e r t y p e s u r f a c t a n t s probably show b e t t e r behaviour due t o m o b i l i t y of the l i q u i d - l i k e oleate chains i n these surfactant molecules. However , of the m a t e r i a l s screened , the Tagat T 0 - M i g l y o l 812 and Tween 85M i g l y o l 812 m i x t u r e s showed the best behaviour and the former was chosen as a model commercial system f o r more d e t a i l e d study. The o i l , M i g l y o l 812 i s a f r a c t i o n a t e d t r i g l y c e r i d e c o n t a i n i n g m a i n l y c a p r y l i c (Cg, 50-65$) and c a p r i c ( C , 45-30$) saturated carboxylic acid residues. Tagat TO i s an e t h o x y l a t e d (25 moles per molecule) t r i g l y c e r i d e of commercial o l e i c acid (65$ o l e i c with the remainder mainly myristic C , p a l m i t i c C-^, s t e a r i c C-^o and l i n o l e i c Cig:2 bonds). The surfactant has a negligible bulk water s o l u b i l i t y (23); however , the ethylene oxide condensation r e a c t i o n used t o manufacture t h e s u r f a c t a n t r e s u l t s i n a d i s t r i b u t i o n of p o l y o x y e t h y l e n e r e s i d u e s . T h i s means some of the c o n s t i t u e n t s o f the m i x t u r e w i l l be s u f f i c i e n t l y hydrophilic to be water soluble. 1 0

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Table I. Qualitative Screening of Surfactant-Oil Mixtures f o r SelfEmulsifying Behaviour at 25 and 37°C. (S) Denotes Suspended Material i n Binary Mixture. Self-emulsifying Behaviour Miglvol 812 Arachis O i l 25°C T7°C 25°C 37°C

Surfactant

HLB

Ethers Nonylphenol (5) Ethoxylate Nonylphenol (6) Ethoxylate Nonylphenol (8) Ethoxylate Nonylphenol (9) Ethoxylate Nonylphenol (10) Ethoxylate Stearyl (5) Ethoxylate Stearyl (10) Ethoxylate Dodecyl (9) Ethoxylate

10.5 10.9 12.3 12.8 13.3 9.7 12.9 14.2

1 2 2 3 3 1 Ks) 1

1 1 2 2 2 1 KS) 1

-2

-1

1 1

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Esters Polyoxyethylene (6.8) mono-oleate Polyoxyethylene (13.6) di-oleate Polyoxyethylene (9.1) mono-oleate Polyoxyethylene (13.6) mono-oleate Polyoxyethylene(25)sorbitan t r i - o l e a t e Polvoxvethvlene( 25) glycerol t r i - o l e a t e

10.1 10.2 11.3 13.3 11.0 11.3

1 2 3(S) 2(S) 5 5

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1 1 2 1 4 3

1 2(S) 2(S) 5 5

1 1 2 1 4 L·

MEDD A n a l y s i s . The p a r t i c l e size-surfactant concentration p r o f i l e s obtained by laser d i f f r a c t i o n analysis of the s e l f - e m u l s i f i e d Tagat T 0 - M i g l y o l 812 m i x t u r e s a r e shown i n F i g u r e 1. At a s e l f emulsification temperature of 30°C the p r o f i l e shows three regions. Between 5 and 15Î surfactant there i s l i t t l e change i n measured MEDD with increasing surfactant concentration. Values obtained f o r MEDD i n t h i s region were however misleading due t o the gross i n s t a b i l i t y of these lower surfactant concentration emulsions. The creaming rate of d r o p l e t s g r e a t e r than a p p r o x i m a t e l y 100 yum was so r a p i d that although p a r t i c l e s i z e d e t e r m i n a t i o n was c a r r i e d out immediately a f t e r formation, these large droplets were excluded from detection and consequent MEDD evaluation. Microscopical examination of these crude emulsions showed t h a t o i l d r o p l e t s i n excess of 500 pm were present. A reduction i n the measured MEDD on repeated analysis also c o n f i r m e d t h e i n s t a b i l i t y o f t h e s e samples. I n c r e a s i n g the s u r f a c t a n t c o n c e n t r a t i o n from 15 t o 30$ r e s u l t e d i n emulsions of improved s t a b i l i t y (region 2). Replicate analysis of these samples gave reproducible results but e x c e s s i v e creaming s t i l l occurred on overnight storage. The reduction i n the MEDD i n t h i s second region probably r e s u l t e d from i n c r e a s e d i n t e r f a c i a l s t a b i l i s a t i o n by the w a t e r s o l u b l e s u r f a c e a c t i v e components a s t h e s u r f a c t a n t concentration was raised. Above 30$ surfactant the MEDD apparently reached a minimum value of 1-2 pm. T h i s t h i r d r e g i o n was a f u n c t i o n of the lower d e t e c t i o n l i m i t of t h e apparatus. Table I I shows t h a t the p r o p o r t i o n of emulsion d r o p l e t s below 3 and 1 jum i n c r e a s e d as the s u r f a c t a n t concentration increased. The data emphasize the marked reduction i n emulsion droplet size which occurred above 30$ w/w surfactant.


P H E N O M E N A IN M I X E D S U R F A C T A N T S Y S T E M S


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Figure 1. Effect of Binary Mixture Surfactant Concentration and S e l f - E m u l s i f i c a t i o n Temperature on Emulsion Droplet Size f o r the Miglyol 812-Tagat TO System as Determined by Laser D i f f r a c t i o n . Bars Represent Standard Errors.


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Table I I . P r o p o r t i o n of Emulsion D r o p l e t s below 3 and 1 jum as a Function of Increasing Surfactant Concentration of the Binary Mixture Tagat TO - M i g l y o l 812 as Measured by Laser D i f f r a c t i o n a t a S e l f Emulsification Temperature of 30°C.


Percentage Surfactant i n Binary Mixture (w/w) 5 10 15 20 25 30 35 40

Percentage by Weight of Emulsion DroDlets below size 3 Aim 1 urn 0.1 6 0.4 6 5 0.3 12 3 8 48 39 95 50 99 99 61

At t h e s e l f - e m u l s i f i c a t i o n temperature of 40°C ( F i g u r e 1) a s i m i l a r p r o f i l e was obtained and again three d i s t i n c t regions were identified, however MEDD were l a r g e r a t a l l s u r f a c t a n t concentrations. This i s attributable to a reduction i n the degree of hydrogen bonding of the oxyethylene groups with water (16). This i n t u r n reduces the e f f e c t i v e HLB of the s u r f a c t a n t and r e s u l t s i n weaker i n t e r f a c e s t a b i l i s a t i o n , and hence l a r g e r emulsion droplets form (17). Reducing the self-emul s i f i c a t i o n temperature to 25°C had the opposite effect on the e f f e c t i v e HLB of the surfactant r e s u l t i n g i n improved emulsion s t a b i l i t y and hence smaller MEDD. However, the i n s t a b i l i t y of l a r g e r droplets s t i l l affected the measured MEDD at the lower surfactant concentrations. The r e s u l t s obtained from QELS examination of emulsions formed from b i n a r y m i x t u r e s c o n t a i n i n g 35$ or more Tagat TO are shown i n f i g u r e s 2 and 3. F i g u r e 2 i n d i c a t e s t h a t the MEDD-surfactant c o n c e n t r a t i o n p r o f i l e s are of a s i m i l a r c h a r a c t e r f o r a l l s e l f e m u l s i f i c a t i o n temperatures studied (25-50°C) exhibiting a minimum MEDD at about 50-55$ Tagat TO. Self-emul s i f i c a t i o n at 30°C yielded e m u l s i o n s w i t h t h e l o w e s t MEDDs ; t h e minimum MEDD b e i n g approximately 100 nm at 52.5$ surfactant i n the binary mixture. At t h i s temperature a l l b i n a r y m i x t u r e s c o n t a i n i n g 35-52.5$ Tagat TO e x h i b i t e d good, r a p i d s e l f - e m u l s i f i c a t i o n . The time r e q u i r e d t o attain droplet size equilibrium at 30°C was l e s s than 10 seconds a t 35$ surfactant increasing to about 120 seconds a t 52.5$ s u r f a c t a n t . Above t h i s c o n c e n t r a t i o n s e l f - e m u l s i f i c a t i o n c h a r a c t e r i s t i c s deteriorated. Equilibrium times increased markedly , reaching about 20 minutes a t 70$ surfactant. This was accompanied by an increase i n MEDD and a doubling of the polydispersity. Figure 2 also shows that b e t t e r r e p r o d u c i b i l i t y of t h e formed e m u l s i o n i n terms of MEDD occurred p r i o r t o and i n the r e g i o n of the minimum. At 30°C, MEDD v a l u e s obtained w i t h 40-55$ s u r f a c t a n t had a r e l a t i v e standard d e v i a t i o n o f about + 2$; a t 60$ Tagat TO t h i s f i g u r e i n c r e a s e s t o about + 4$. Reproducible c o n t r o l of p a r t i c l e s i z e i s an important feature i n the potential of s e l f - e m u l s i f y i n g mixtures f o r oral drug delivery.

American Chemical Society Library 1155 16th St., N.W. In PhenomenaWashington, in Mixed Surfactant Scamehorn, J.; D.C.Systems; 20036 ACS Symposium Series; American Chemical Society: Washington, DC, 1986.

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500

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40

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1

50 Percentage Binary

1—

60 of

Tagat

70 TO

in

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Figure 2. Effect of Binary Mixture Surfactant Concentration and S e l f - E m u l s i f i c a t i o n Temperature on Emulsion Droplet Size f o r the M i g l y o l 812-Tagat TO System as Determined by QELS. Bars Represent Standard Errors.



Figure 3. Effect of S e l f - E m u l s i f i c a t i o n Temperature on Emulsion Droplet Size f o r the Miglyol 812-Tagat TO System as Determined by QELS. Bars Represent Standard Errors.


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F i g u r e 3 i l l u s t r a t e s the e f f e c t of temperature over the range 25-50°C on the MEDD of the r a p i d l y s e l f - e m u l s i f y i n g systems (

Self-Emulsification of Vegetable Oil-Nonionic ... - ACS Publications

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