FDA Journal of
`
`Science and
`
`Technology
`
`I Pharmaceutical
`
`Number 2 _
`
`1995
`
`March / April
`
`Volume 49
`
`APOTEX 1041, pg. 1
`
`APOTEX 1041, pg. 1
`
`

`

`March—April 1995
`
`V01. 49, No. 2
`
`FDA Journal of
`
`Pharmaceutical Science and Technology
`EDITOR:
`Joseph B. Schwartz
`
`Philadelphia College of Pharmacy & Science
`600 South 43rd Street
`
`Philadelphia, PA 19104-4495
`Phone: (215) 596-8590
`STAFF: Susan M. McCoy, Henrietta Zimm
`
`
`CIRCULATION OFFICE:
`PDA, Inc.
`7500 Old Georgetown Rd
`Suite 620
`Bethesda, MD 20814
`Phone: (301) 986-0293
`
`ADVERTISING / CIRCULATION : Margaret Wanca
`Phone: (301) 986-0293
`
`ADVISORY BOARD
`
`Michael Akers, Eli Lilly and Co.
`Frederick J. Carleton
`
`Patrick DeLuca, University ofKentucky
`Barry Garfinkle, Merck Sharp & Dohme
`Michael Groves, University ofIllinois
`Joseph Robinson, University of Wisconsin
`Theodore Roseman, Baxter Healthcare
`
`1995 OFFICERS AND DIRECTORS
`
`Chairman:
`
`Clarence A. Kemper, Ph.D.
`Chairman-Elect: Raymond Shaw, Jr., Ph.D.
`Henry K Kwan, Ph.D.
`Secretary:
`Treasurer:
`Raymond Gabler, Ph.D.
`
`'
`
`James E. Akers, Ph.D.
`Joyce Aydlett
`Floyd Benjamin
`Peter T. Bigelow
`Joyce L. DeYoung, Ph.D.
`R. Michael Enzinger, Ph.D.
`John Geigert, Ph.D.
`Martin W. Henley
`Kunio Kawamura, Ph.D.
`Robert Morrissey, Ph.D.
`, Terry E. Munson
`Robert Myers
`Jean A. LaDouceur
`
`President: Edmund M. Fry
`
`PDA Journal of Pharmaceutical Science & Technology
`(ISSN 1076-397X) is published bimonthly by the PDA, Inc.,
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`‘ Printed in the USA.
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`Formerly the
`“Journal of Parenteral Science and Technology”
`
`Copyright—FDA, Inc. 1995
`ISSN 1076-397X
`
`The FDA, Inc. and‘its editor assume no responsibility
`for the statements and opinions advanced by contribu-
`tors. Views expressed in the editorials are those of the
`author and do not necessarily represent the oflicial
`
`position of FDA, Inc.
`
`APOTEX 1041, pg. 2
`
`APOTEX 1041, pg. 2
`
`

`

`RESEARCH ARTICLE
`
`Particle Size Reduction of Emulsions by Formulation Design-11:
`Effect of Oil and Surfactant Concentration
`
`GURMUKH D. CHANANA* and BHOGI B. SHETHt
`
`Parenteral Medications Laboratories, Department of Pharmaceutics, University of Tennessee, Memphis, Tennessee
`
`ABSTRACT: The objective of this study was to investigate the effect of the concentration of surfactant and oil on
`particle size reduction and stability of oil-in-water emulsion formulations containing polyhydroxy alcohols.
`Emulsions were prepared using an emulsifier system consisting of Tween 80® and Span 80® with 5%, 10%, 15%
`and 20% soybean oil and containing 50% w lw of either propylene glycol (PG) or glycerol (GLY) in the external
`phase. At each oil concentration, four emulsions were formulated with increasing surfactant concentration to
`provide emulsions with surfactant to oil ( S I 0) ratios of 0.1, 0. 2, 0.3 and 0. 4. Three parameters were evaluated,
`particle size reduction, particle size stability upon dilution, and viscosity. It was found that increase in S I 0 ratio
`resulted in substantial decrease in particle size in all cases. But there was a difference in the particle size reduction
`pattern between PG and GLY. Increase in oil concentration at the same S I 0 ratio caused particle size reduction
`for emulsions with PG but not for emulsions with GLY. The reduction in particle size was also greater for
`emulsions containing PG. Further, particle size of emulsions containing PG was found to be stable over 24 hours
`after dilution. However, a slight increase in particle size was observed in emulsions containing GLY. It was also
`found that the viscosity of emulsions increased with an increase S I 0 ratio as well as the concentration of the oil.
`
`Introduction
`
`The use of oil-in-water emulsions as drug delivery
`systems has been widely recognized, and considerable
`research has been focused on emulsions in recent years.
`These systems can be used for the delivery of poorly
`water-soluble drugs via the parenteral route (1). The
`typical method of preparation of intravenous 0 IW
`emulsions requires the use of high shear. or high energy
`equipment (2-4). An alternate method for particle size
`reduction is by formulation design. In this method, a
`fourth component, referred to as the cosurfactant, is
`added to emulsion formulations to achieve a decrease in
`particle size (5, 6).
`In a previous study, we reported on the effect of the
`addition of glycerol (GLY) and propylene glycol (PG)
`on particle size reduction of oil-in-water emulsions of
`soybean oil (7). These polyhydroxy alcohols appeared to
`act as cosurfactants when added at concentrations
`ranging from 30% to 70% in the external phase, causing
`a substantial reduction in the particle size. The mini(cid:173)
`mum particle size obtained in the study was approxi(cid:173)
`mately 2.0 ,_..,m. However, the particle size of emulsions
`intended for intravenous administration needs to be
`below 1 ,_..,m (8).
`Therefore, it was an objective of this study to investi(cid:173)
`gate if further particle size reduction could be achieved
`
`Received November 22, 1993. Accepted for publication September 16,
`1994.
`* Present Address-American Drug Development Inc., 9100A Yellow
`Brick Road, Baltimore, MD 21237.
`t Author to whom correspondence should be addressed: 38163.
`
`by either decreasing the amount of oil or increasing the
`amount of surfactant. Soybean oil emulsions were formu(cid:173)
`lated containing 50% w lw GL Y or PG in the external
`phase. This was the concentration of polyhydroxy alco(cid:173)
`hol at which maximum particle size reduction was
`observed (7). Emulsions were prepared containing in(cid:173)
`creasing oil concentration as well as increasing surfac(cid:173)
`tant concentration. The parameters evaluated were
`particle size reduction, particle size stability upon dilu(cid:173)
`tion, and viscosity. Particle size stability was evaluated in
`emulsions diluted with commonly used Large Volume
`Parenteral Solutions (L VPs ).
`
`Materials and Equipment
`
`Glycerol ( GL Y) and propylene glycol (PG) were
`obtained from J. T. Baker (Phillipsburg, NJ). Soybean
`oil was obtained from Croda Inc. (Mill Hall, PA).
`Polyoxyethylene sorbitan monooleate (Tween 80®) and
`sorbitan monooleate (Span 80®) were obtained from
`Emulsion Engineering, Inc. (Sanford, FL). Sterile Wa(cid:173)
`ter for Injection, USP (SWFI) was obtained from Abbott
`Laboratories (North Chicago, IL), 10% Mannitol Injec(cid:173)
`tion, USP was obtained from American McGaw (Irvine,
`CA) and 0.9% Sodium Chloride Injection was obtained
`from Travenol Laboratories Inc. (Deerfield, IL). A
`single lot of each material was used in preparation of all
`emulsions. Equipment used to make emulsions in~
`eluded: propeller mixer, Model RW 20 DZM, (Ika(cid:173)
`Werk, Germany), and homogenizer, Model Omni 2000,
`(Omni International, CT). Particle size was determined
`with a Horiba Particle Size Analyzer, Model CAPA 700,
`(Horiba Corporation, Irvine, CA). Viscosity was mea-
`
`Vol. 49, No. 2 I March-April1995
`
`71
`
`APOTEX 1041, pg. 3
`
`

`

`sured using a Brookfield Cone and Plate Viscometer,
`Model DV-11, (Brookfield Engineering Laboratories,
`Stoughton, MA).
`
`5
`
`4
`
`No Polyhydroxy Alcohol
`in External Phase
`
`--o-- GL Y Emulsions
`--..- PG Emulsions
`
`Methods
`
`In a study reported previously, it was found that the
`emulsifier blend with HLB value of 8.0 gave the most
`stable emulsion (7). It was also found that emulsifier
`concentration of 2% w /w (10 percent of the oil phase)
`gave the minimum particle size. Increase in emulsifier
`concentration beyond 2% w /w did not result in further
`decrease in the particle size of the emulsion. Therefore,
`this concentration of the emulsifier blend, correspond(cid:173)
`ing to surfactant to oil (S/0) ratio of 0.1, was chosen as
`the minimum concentration used in this study. Formula(cid:173)
`tions with higher surfactant concentrations were pre(cid:173)
`pared to provide emulsions with,S/0 ratios ranging from
`0.1-0.4.
`We had also reported that the particle size of soybean
`oil decreased with an increase in polyhydroxy alcohol
`concentration in the external phase (7). It was found
`that poly hydroxy alcohol level of 50% w /w in the
`external phase caused maximum reduction in particle
`size. The particle size of emulsions containing 50% w /w
`of either GLY or PG was found to be approximately 2.0
`J.Lm. Therefore, this level of polyhydroxy alcohol was
`selected.
`A stable base 0 /W emulsion without any poly hydroxy
`alcohol was first formulated. This base emulsion was
`formulated to contain 20% w /w soybean oil and a
`surfactant system consisting of an emulsifier blend of
`35% Tween 80® and 65% Span 80®. The amount of
`emulsifier blend used was 10% of the oil phase, giving an
`S/0 ratio of 0.1. The procedures used in formulation
`development have been previously described (7). Four
`
`TABLE I
`Formulations Prepared to Study the Effect of Surfactant and
`Oil Concentrations on the Particle Size and Viscosity of
`Emulsions Containing Propylene Glycol or Glycerol
`
`Surfactant Concentration (% w/w of oil phase)
`
`Figure 1-Effect of surfactant concentration on the particle size of
`0/W emulsions with 20% w/w soybean oil.
`
`series of emulsions were prepared with this emulsifier
`blend containing 5%, 10%, 15% and 20% w/w oil,
`respectively. For each series of emulsions, four formula(cid:173)
`tions were prepared at each oil concentration with
`increasing amounts of the emulsifier blend. The increase
`in emulsifier concentration was designed to provide S/0
`ratios of 0.1, 0.2, 0.3 and 0.4, respectively. Table I shows
`the sixteen emulsions prepared for this investigation.
`The method of preparation of emulsions was as follows:
`the oil phase containing the surfactants, heated to 60°C,
`was added to aqueous phase (50% w /w poly hydroxy
`alcohol solution) heated to 60oC and mixed with the
`homogenizer at 30,000 rpm for 5 minutes. Particle size
`determination of the emulsions was carried out within
`24 hours after their preparation. The procedure used in
`the particle size determination has been described
`previously (7).
`The investigation of particle size stability of admix(cid:173)
`tures of emulsions with L VPs was done with 20%
`soybean oil emulsion at two S/0 ratios of 0.1 and 0.4,
`respectively. The following procedure was used: the
`sample tube containing the emulsion was gently inverted
`10 times to get a homogeneous sample. A sample of 2
`
`Ingredient Concentration, % w /w
`
`Soybean Tween
`Oil
`SO®
`
`Span PGn or
`GLYh Water
`SO®
`
`3
`
`Surfactant
`to Oil (S/0)
`Ratio
`0.1
`
`0.2
`
`0.3
`
`0.4
`
`5
`10
`15
`20
`5
`10
`15
`20
`5
`10
`15
`20
`5
`10
`15
`20
`
`0.17
`0.35
`0.50
`0.70
`0.35
`0.70
`1.05
`1.40
`0.50
`1.05
`1.60
`2.10
`0.70
`1.40
`2.10
`2.80
`
`0.33
`0.65
`1.00
`1.30
`0.65
`1.30
`1.95
`2.60
`1.00
`1.95
`2.90
`3.90
`1.30
`2.60
`3.90
`5.20
`
`47.25
`47.25
`45.50
`45.50
`41.75
`41.75
`39.00
`39.00
`47.00
`47.00
`44.00
`44.00
`41.00
`41.00
`38.00
`38.00
`46.75
`46.75
`. 43.50
`43.50
`40.25
`40.25
`37.00
`37.00
`46.50 . 46.50
`43.00
`43.00
`39.50
`39.50
`36.00
`36.00
`
`a Propylene Glycol.
`b Glycerol.
`
`72
`
`i:
`3-
`0
`>
`
`= :0
`::E
`
`'1.1
`
`SlQ RDtiQ
`
`-o- 0.2
`
`--o- 0.4
`
`----- 0.1
`---- 0.3
`" ~ =
`<====
`
`0
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`Oil Concentration (% w/w)
`Figure 2-E.ffect of surfactant and oil concentrations on the particle
`s1ze of soybean oil emulsions containing 50% w /w glyc-
`erol.
`
`PDA Journal of Pharmaceutical Science & Technology
`
`APOTEX 1041, pg. 4
`
`

`

`3
`
`2
`
`e
`
`~
`0
`;...
`0
`
`= tG :a
`
`Cll
`~
`
`S/0 Ratio
`
`• 0.1
`• 0.3
`
`D 0.2
`
`0 0.4
`
`o+---~----~--~----~--~--~
`0
`10
`20
`30
`
`Oil Concentration (% w/w)
`Figure 3-Effect of surfactant and oil concentrations on the particle
`size of soybean oil emulsions containing 50% w /w propyl(cid:173)
`ene glycol.
`
`grams of this emulsion was added to 18 grams of the
`LVP solution to make a 1:10 dilution. The particle size
`was measured before dilution, immediately after dilu(cid:173)
`tion, and 1 hour, 6 hours and 24 hours after dilution. The
`LVPs used were Sterile Water for Injection (SWFI),
`10% Mannitol Solution and 0.9% Sodium Chloride
`Injection. These solutions are commonly used in the
`preparation of intravenous admixtures.
`Viscosity values of emulsions and of aqueous solutions
`corresponding in composition to the respective external
`phase of each emulsion were also determined. The
`viscosity measurements were made with a Brookfield
`Model DV II cone and plate viscometer at 25°C.
`
`Results and Discussion
`
`Effect of Increasing Surfactant Concentration ( S I 0 ratio)
`
`The effect of increasing surfactant concentration, with
`a corresponding increase in the S/0 ratio, on the
`particle size reduction of emulsions containing 20% w /w
`oil is shown in Figure 1. The effect of 50% w /w
`polyhydroxy alcohol concentration on the particle size
`
`can also be noted in Figure 1. The effect of increasing
`S I 0 ratio on particle size at four concentrations of oil is
`given in Figure 2 for emulsions with GL Y and in Figure
`3 for emulsions with PG. It is evident that increasing the
`S/0 ratio caused further decrease in particle size.
`Increasing the S/0 ratio from 0.1 to 0.4 resulted in a
`four-fold decrease in the particle size. The particle size
`of emulsions with GLY decreased from about 2.1 J.Lm to
`about 0.5 J,Lm. The particle size reduction effect is
`similar, but more pronounced, for emulsions with PG.
`It was found that particle size reduction to below 1 J.Lm
`could be achieved by increasing the surfactant concentra(cid:173)
`tion above a critical surfactant concentration (CSC) for
`emulsions containing PG or GL Y. The CSC required for
`emulsions with 50% w /wPG and 20% w /w oil was found
`to occur at a surfactant concentration at 0.2 S/0 ratio.
`The CSC required for emulsions with 50% w /w PG and
`lower oil concentrations was at surfactant concentra(cid:173)
`tions corresponding to 0.3 S/0 ratio. On the other hand,
`the esc was at 0.3 s I 0 ratio for all oil concentrations
`for emulsions with 50% w /w GL Y. This indicates that
`PG acts as a more effective cosurfactant than GL Y at
`the higher oil concentration.
`Several theories on the reduction of particle size and
`formation of microemulsions due to the addition of
`cosurfactant have been proposed (9-14). Two of the
`predominant theories include reduction of interfacial
`tension (9-14) and solubilization of oil in surfactant
`micelles (15). The addition of polyhydroxy alcohols in
`the external phase can cause changes in the interfacial
`properties, since the surface tensions of both PG ( 40.1
`dynes/em) and GLY (63.4 dynes/em) are considerably
`lower than that of water (72.8 dynes/em) at 20°C. It is
`likely that the interfacial tensions of polyhydroxy alcohol
`solutions (that make up the external phase) and the oil
`will be significantly lower than between water and oil.
`Hence, it is likely that the predominant factor in the
`reduction of particle size is the lower interfacial tension.
`This mechanism is also supported by other studies
`reported for microemulsions. Prince (13) proposed that
`the formation of small droplets in microemulsions was in
`part due to a reduction in the interfacial tension of oil
`and water, in the presence of a cosurfactant. Rucken(cid:173)
`stein and Chi (14) also explained the formation and
`stability of microemulsions using the surface tension
`
`TABLE II
`Particle Size Stability of Emulsions Containing Propylene Glycol After Dilution with Large Volume Parenteral Solutions
`
`10% Mannitol
`
`0.9% Sodium Chloride Injection
`
`Sterile Water For Inj. (SWFI)
`
`Particle Size, Median-Dvol (f.Lm) ± SDa
`
`A
`
`Time
`Before dilution
`After dilution
`After 1 hour
`After 6 hours
`After 24 hours
`
`A
`A
`B
`B
`1.8 ± 1.3
`0.6'± 0.6
`1.8 ± 1.3
`0.6 ± 0.6
`1.8 ± 1.3
`1.4 ± 1.0
`1.2 ± 0.9
`0.4 ± 0.4
`1.6 ± 1.1
`0.4 ± 0.5
`1.4 ± 1.2
`1.4 ± 1.0
`0.4 ± 0.4
`1.6 ± 1.0
`0.4 ± 0.4
`1.4 ± 1.2
`1.5 ± 1.2
`0.4 ± 0.3
`0.4 ± 0.4
`1.6 ± 1.2
`1.5 ± 1.3
`1.5 ± 1.1
`0.4 ± 0.3
`1.1 ± 0.7
`0.4 ± 0.4
`A: Emulsions containing S/0 ratio of0.1. B: Emulsions containing S/0 ratio of 0.4. Emulsions contained 20% oil and 50% propylene glycol in the
`external phase.
`a Standard Deviation. The particle size of three separate samples was measured for each emulsion.
`
`B
`0.6 ± 0.6
`0.4 ± 0.4
`0.4 ± 0.4
`0.4 ± 0.4
`0.4 ± 0.4
`
`Vol. 49, No. 2 I March-April1995
`
`73
`
`APOTEX 1041, pg. 5
`
`

`

`TABLE Ill
`Particle Size Stability of Emulsions Containing Glycerol After Dilution with Large Volume Parenteral Solutions
`
`Particle Size, Median-Dvol (f.Lm) ± SDa
`
`10% Mannitol
`
`0.9% Sodium Chloride Injection
`
`Sterile Water For lnj. (SWFI)
`
`Time
`Before dilution
`Mter dilution
`Mter 1 hour
`Mter 6 hours
`After 24 hours
`
`A
`2.4 ± 1.3
`2.8 ± 1.7
`2.5 ± 1.8
`2.6 ± 1.8
`2.6 ± 1.5
`
`B
`0.6 ± 0.6
`0.8 ± 1.0
`0.8 ± 1.2
`0.8 ± 1.0
`0.9 ± 1.0
`
`A
`2.4 ± 1.3
`2.7 ± 1.6
`2.6 ± 1.5
`2.6 ± 1.3
`2.6 ± 1.3
`
`B
`0.6 ± 0.6
`0.8 ± 0.9'
`0.8 ± 1.0
`0.7 ± 0.9
`0.8 ± 1.3
`
`A
`2.4 ± 1.3
`2.2 ± 1.4
`2.7 ± 1.5
`2.6 ± 1.4
`2.6 ± 1.4
`
`B
`0.6 ± 0.6
`1.1 ± 1.1
`1.0 ± 1.3
`1.5 ± 1.3
`1.1 ± 1.2
`
`A: Emulsions containing S/0 ratio of 0.1. B: Emulsions containing S/0 ratio of 0.4. Emulsions contained 20 percent oil and 50 percent glycerol in
`the external phase.
`a Standard Deviation. The particle size of three separate samples was measured for each emulsion.
`
`lowering concept, including the dispersion entropy of
`the droplets and the reduction of chemical potential of
`· the surfactant 'and the cosurfactant in the bulk phase by
`adsorption at the interface. It is thought that the
`mechanism of particle size reduction due to addition of
`the polyhydroxy alcohol should be similar. Decrease in
`the interfacial tensions between oil and aqueous solu(cid:173)
`tions of polyhydroxy alcohols have been reported by
`Magdasi and Frank (16).
`The decrease in particle size observed, with an in(cid:173)
`crease in the surfactant concentration, may also be the
`result of more surfactant being available to stabilize the
`increased interfacial area created during the mixing
`process. In the absence of polyhydroxy alcohol, much
`more energy may be required to create a similar increase
`in the interfacial area due to a higher interfacial tension.
`The differences observed in the effects of PG and
`GL Y on the reduction of particle size may be due to the
`nature of the polyhydroxy alcohols. PG is dihydroxy
`alcohol with a significantly lower surface tension ( 40
`dynes/em), while GLY is a trihydroxy alcohol with a
`surface tension of 63.4 dynes/em. Hence, it is possible
`that the interfacial tension between the oil and aqueous
`solution of PG may be lower than that between the oil
`and aqueous solution of GL Y. Also, the fewer number
`of hydroxyl groups in PG may result in an increased
`presence of PG at the interface that may also result in
`increased hydrogen bonding with the polar regions of
`the surfactants.
`
`Effect of Oil Concentration
`
`It was observed that there was a difference in the
`effect of oil concentration on particle size reduction of
`the emulsions containing PG and GL Y. This is shown in
`Figure 2 for emulsions containing GLY as cosurfactant
`and in Figure 3 for emulsions containing PG. In emul(cid:173)
`sions containing GLY as the cosurfactant, the particle
`size remained essentially similar at all S I 0 ratios. But
`particle size decreased with an increase in the oil
`concentration at all S I 0 ratios in emulsions containing
`PG. These results also indicate that PG acts as a better
`cosurfactant than GLY. It is unlikely that the reduction
`in particle size observed was due to solubilization of the
`oil in sudactant and polyhydroxy alcohol because both
`PG and GL Y are immiscible with fixed oils.
`
`Effect of Dilution on Particle Size Stability
`
`The particle size stability of emulsions upon dilutions
`with selected L VPs is shown in Tables II and III. The
`emulsions with S/0 ratio of 0.1 and 0.4 were selected for
`the study. It was found that emulsions containing PG
`were very stable, showing no increase in particle size. A
`slight increase in particle size was observed for emul(cid:173)
`sions with GL Y. Thus, the differences in the effect of PG
`and GLY can also be seen in particle size stability
`results. These results also indicate that PG is a better
`cosurfactant than GL Y. The differences in the stability
`of the emulsion droplets also indicate an increased
`presence of PG at the interface due to possible increase
`in hydrogen bonding with the polar regions of the
`surfactants.
`
`Effect on Emulsion Viscosity
`
`Measurements were made of the viscosity of emul(cid:173)
`sions and the corresponding external aqueous phase.
`Solutions containing 50% of the polyhydroxy alcohol
`and amounts of Tween 80® corresponding to the concen(cid:173)
`trations in the respective emulsions were prepared as
`samples representative of the external phase. These
`results are shown in Figures 4 and 5. The viscosity of
`
`Soybean Oil Conrentratjon (% w/w)
`
`- - - 5%
`-o- 10%
`--o- 15%
`----- 20%
`
`30
`
`20
`
`10
`
`~
`g.
`~
`.t>
`·;
`Q
`Col
`
`til ;;
`
`0+---~-,--~--~--~~~~---r--~~
`0.0
`0.1
`0.3
`0.4
`0.2
`0.5
`
`S/0 Ratio
`Figure 4-Effect of surfactant to oil (S/0) ratio on the viscosity of
`soybean oil emulsions containing 50% w/w propylene
`glycol.
`
`74
`
`PDA Journal of Pharmaceutical Science & Technology
`
`APOTEX 1041, pg. 6
`
`

`

`30
`
`20
`
`10
`
`,-.,
`
`Ill =-~
`
`~
`'iil
`Q
`u
`
`Ill >
`
`Soybean Oil Cone. (% w/w)
`
`--- 5%
`
`-o- 10%
`
`•
`
`Soybean Oil Concentration (% w/w)
`
`--- 5%
`
`-o- 10%
`-o-
`--.-
`
`30
`
`,-.,
`Ill
`=..
`~ 20
`~
`·~
`Q
`u
`
`Ill >
`= Q
`10 = e
`'iil
`
`1';1:;:1
`
`o+---~--r-~~~--~--~--~--~--~~
`0.0
`0.1
`0.4
`0.2
`0.3
`0.5
`S/0 Ratio
`Figure 5-Effect of surfactant to oil (S/0) ratio on the viscosity of
`soybean oil emulsions containing 50% w /w glycerol.
`
`0+------------r----~----~------~--~
`5.0
`5.5
`6.5
`6.0
`External Phase Viscosity (cps)
`Figure ?-Relationship between the external phase viscosity and
`viscosity of emulsions with 50% w /w propylene glycol.
`
`emulsions was affected by the concentration of oil as
`well as surfactant. The viscosity of emulsions increased
`with an increase in surfactant concentration as might be
`expected, but the effect was relatively modest at lower
`concentrations of oil and surfactant.
`The viscosity increase was substantially higher for
`emulsions containing 20% w /w oil than for emulsions
`with lower oil concentrations. In addition, the emulsions
`with GL Y had higher viscosities than corresponding
`emulsions with PG at 20% w /w oil concentration. This
`effect was more pronounced at S/0 ratios of 0.3 and 0.4.
`A similar pattern was also observed for the viscosities of
`the corresponding aqueous external phase formulations.
`The viscosity of the solution containing GL Y was consis(cid:173)
`tently higher than the viscosity of the PG solutions above
`Tween 80® concentration of 1% w /w. This concentra(cid:173)
`tion of Tween 80® corresponds to the amount of- this
`surfactant required to provide S/0 ratios of 0.3 and
`higher. This viscosity effect is thought to be due to
`increase in the total amount of hydrophilic surfactant in
`the emulsion. These findings are similar to results
`
`30
`
`Soybean Oil Concentration (% w/w)
`
`- - 5%
`--o- 10%
`-o- 15%
`----- 20%
`
`o+---~----.---~--~----~--~--~~~
`5.5
`6.5
`6.0
`5.0
`7.0
`External Phase Viscosity (cps)
`
`Figure 6-Relationship between the external phase viscosity and
`viscosity of emulsions with 50% w/w glycerol.
`
`reported in an earlier studies (7). The relationship
`between the viscosity of emulsions and the viscosity of
`the external phase is shown in Figures 6 and 7.
`
`Conclusions
`
`Further reduction in the particle size (below 1 1-1m) of
`emulsions containing GL Y and PG can be achieved with
`increase in surfactant concentration relative to the
`amount of oil above a minimum level referred to as the
`critical surfactant concentration ( CSC). The value of
`esc can be expressed in terms of the surfactant to oil
`(S/0) ratio for emulsions. This reduction in particle size
`is thought to be a result in the decrease of interfacial
`tension of oil and water. The lower S/0 ratio required to
`reach the CSC for emulsions with PG and 20% w /w oil
`suggest that PG is more effective as a cosurfactant than
`GLY. The particle size stability upon dilution of the
`emulsions also shows that PG is a better cosurfactant
`than GLY. It also indicates that the interfacial film of·
`droplets of emulsions containing PG remains strong and
`does not coalesce. The increase in emulsion viscosity
`with an increase in S/0 ratio is largely due to the
`increase in total amount of hydrophilic surfactant.
`
`References
`
`1. R. A. Prankerd and V. J. Stella, "The use of oil-in-water emulsions
`as a vehicle for parenteral drug administration," J. Parenter. Sci.
`Techno!. 44 (3), 139-149 (1990).
`2. D. M. Lidgate, R. C. Fu, and X. X. Fleitman, "Using a microfiuid(cid:173)
`izer to manufacture emulsions," BioPharm., 28-33 (Oct. 1989).
`3. D. M. Higgins and D. M. Skauen, "Influence of power on quality
`of emulsions prepared by ultrasound," J. Pharm. Sci., 61 (10),
`1567-70 (1972).
`4. J. B. Boyett and C. W. Davis, "Injectable emulsions and suspen(cid:173)
`sions," Pharmaceutical Dosage Forms: Disperse Systems, (H. A.
`Lieberman, M. M. Reiger, G. S. Banker, eds.), 2, 379-414 (1989).
`5. A. Jayakrishnan, K. Kalaiarasi, and D. 0. Shah, "Microemulsions:
`evolving technology for cosmetic applications," J. Soc. Cosmet.
`Chern., 34, 335-350 (1984).
`6. H. N. Bhargava, A. Narurkar, and L. M. Lieb, "Using microemul(cid:173)
`sions for drug delivery," Pharm. Techno!., 46-54 (March 1987).
`7. G. D. Chanana and B. B. Sheth, "Particle size reduction of
`emulsions by formulation design-I: effect of polyhydroxy alco(cid:173)
`hols," J. Parenter. Sci. Techno!. 47(3), 130 (1993).
`
`Vol. 49, No. 2 I March-April 1995
`
`75
`
`APOTEX 1041, pg. 7
`
`

`

`8. P. P. DeLuca and J. C. Boylan, "Formulation of small volume
`parenterals," Pharmaceutical Dosage Forms: Parenteral Medica(cid:173)
`tions, (K. E. Avis, L. Lachman, and H. A. Lieberman, eds.) 1, 174
`(1984).
`9. T. P. Hoar and J. H. Schulman, "Transparent water-in-oil disper(cid:173)
`sions: the oleopathic hydro-micelle," Nature, 152, 102-103, (1943).
`10. J. H. Schulman and D. P. Riley, "X-ray investigation of the
`structure of transparent oil-water disperse systems. I," J. Colloid
`Sci., 3, 383-405 (1948).
`11. J. H. Schulman and J. A. Friend, "Light scattering investigation of
`the structure of transparent oil-water disperse systems. II," J.
`Colloid Sci., 4, 497-509 (1949).
`
`12. S. E. Friberg and R. L. Venable, Encyclopedia of Emulsion
`Technology, (Becher, P., ed.), Marcel Decker, Inc. New York, 3
`(1988).
`13. L. M. Prince, "A theory of aqueous emulsions, I. Negative interfa(cid:173)
`cial tension at the oil/water interface," J. Colloid lntetface Sci., 23,
`165 (1967).
`14. E. Ruckenstein and J. Chi, "Stability of microemulsions," J. Chern
`Soc., Faraday Trans. 2 (71), 1690 (1975).
`15. K. Shinoda and S. E. Friberg, Emulsions and Solubilization,
`Wiley-Interscience Publication, New York, 7 (1984).
`16. S. Magdassi and S. G. Frank, "Formation of oil in glycerol/water
`emulsions," J. Disp. Sci. Techno!., 7 (5), 599-612 (1988).
`
`76
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`PDA Journal of Pharmaceutical Science & Technology
`
`APOTEX 1041, pg. 8
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`