No. 5
`
`V
`
`»A
`
`(chem. Pharm. Bull.
`23(5 )l085——-l090(197E'>)
`
`11085
`
`Upc‘ 547, 93,03
`
`Solubilization of Steroids by Multiple co-(Solvent Systems
`
`YIE W. 'CH1EN1’ and HOWARD J. LAMBERT
`
`Biogbkzwmaceutios Section Product Development Department Searle Labomtm/z'es1>
`
`(Received September 27, 1974)
`
`The aqueous solubility of steroids was exponentially increased following the addition
`of a co-solvent. A theoretical equation was derived to describe the relationship between
`the amount of drug solubilized and the volume fraction of co-solvent incorporated. Both
`single and multiple co-solvent systems followed the derived relationship.
`
`Introduction
`
`In the practice of pharmaceutical formulation, the challenge of improving the solubility
`of many poorly soluble drugs, e.g., steroids, in solution dosage forms is common. To solve
`such problems, scientists often incorporate one or more co-solvents with distilled water to
`overcome the poor aqueous solubility.
`at
`Ethanol, propylene glycol, and several members of the polyethylene glycol polymer
`‘series, e.g., polyethylene glycol 400, represent the limited number of co-solvents that are both
`useful and generally acceptable in the formulation of aqueous liquids”.
`In addition, Spiegal
`and Noseworthyi” in their review of nonaqueous solvents used in parenteral products, also
`suggested a number of co-solvents, such as 2,2-dimethyl—l,3-dioxolane—4—methanol (Solketal),
`dimethylacetamide, glycerol formal, glycoiurol,
`'N-(,8—hydroXyethyl)-lactarnide, and ethyl
`lactate.
`
`There have been several reports dealing with the systematic investigation of drug solubility
`and solvent composition.2=‘-‘*7’ Observations to date indicate that the solubility of many
`drugs and druglike substances in binary aqueous systems is enhanced exponentially by the
`addition of a co-solvent.“
`
`Past experiences in our laboratories with solution dosage formulation indicated that the
`semilogarithmic ‘relationship of drug solubility to co~solvent composition was followed not
`only in binary aqueous systems containing a single co-solvent, but also in the systems
`containing 2 or more different co-solvents.
`In this paper, the authors will report their obser-
`vations on the dependency of steroid solubility on the concentration of single, binary, and/or
`ternary co~solvents, and will present a theoretical analysis on the semilogarithmic relationship
`of drug solubility to co—solvent concentration.
`
`Experimental
`
`K Materialsg———SC-9376, SC—4640, SC—11800, and SC-25152 (Fig. 1) (Searle‘Laboratories, Skokie, Illinois),
`propylene glycol, polyethylene glycol 400, 2,2-dimethyl—1,3—dioxo1ane—4-methanol, and N,N-dimethylacet—
`amide (Matheson Coleman Bell Co., Norwood, Ohio) and 95 % ethanol for medical use were utilized as obtained.
`
`.
`1) Location: Skokie, Illinois 60076, U.S./1.
`2) L. Lachman, )H.A. Lieberman, and ].L. Kanig, “The Theory and Practice of Industrial Pharmacy,”
`Lea & Febiger, Philadelphia, 1970, Chapter 15.
`I
`‘
`v
`3) A.J. Spiegel and M.M. Noseworthy, ]. Phmm. Sci, 52,» 917 (1963).
`4) S.H. Yalkowsky, G.L. Flynn, and G.L. Amidon, ]. Pharm. Sci, 61,1983 (1972).
`5) A.N. Parnta and S.A. Irani, J. Phawm. So2'., 54, 1334 (1965),
`.
`' 6) W.G. Gorman and G.D.’Ha11, J. Pharm. Soil, 53, 1017 (1964).
`7) KS. Lin, J. Anschel, and C.j. Swartz, Bull. Parememl Drug Assoc., 25, 40 (1971).
`
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`

`

`
`
`(1086 Vol. 23 (#1975)
`
`'7j1§k':1,renteral quality distilled water was prepared and used for the preparation of 0-80_%: vco—so1vent—wa‘ter
`combinations. Absolute methanol (spectroquality, ].T. Baker Chemical, Cleveland, Ohio) was”emp1oyéd
`for the dilution of filtered drug solutions to an appropriate concentration for spectrophotometric measurement.
`
`0
`
`H3-cOҤ
`
`0
`‘
`3
`l
`“
`_
`SC 93'76'('canre'nQne‘)
`
`_
`
`.
`
`‘
`
`.
`
`s_c:11‘8do
`f
`';
`sc;i4a4o~
`',(ethyr'1odi(>l'_diacetatfi)
`H
`(inor‘ethi_ndrone)
`.
`V
`2:552 ,
`1. Molecular Structures of the Steroids investigated
`
`'
`
`The methodology reported earliersl was adopted here with minor
`Determination of Drug Solubility
`mo,difications,to~ avoid the possible hydrolysis of SC-9376 and SC-25152 after‘4,8-hour equilibration at 37°.
`Excess drug solid was equilibrated with 10 ml of a co—solvent—vvater combination at 37° for 2 hours with
`constant shaking.
`V Aftercooling to room temperature, the over-saturated drug solution was quickly [filtered
`through a filter holder (millipore) containing" a glass fiber membrane (Reeve"Angel). The filtered ‘drug
`solution was diluted 10 to 4000 times with methanol to an appropriate drug concentration and then read
`spectrophotometrically. The magnitudeof the absorbance at the A max was used to calculate the amount
`of a drug solubilized in a given solvent system. The filtered solution‘ of ethynodiol diacetate (SC-1 1800)
`was subjected to acidic hydrolysis” before dilution.
`V
`i
`'
`
`Results and Discussions '0
`
`,
`
`In nonideal‘solutions,9> the solubility of a d’rug“(CW) in pure Water system is defined by ..
`
`log Cw = —
`
`__ASW
`2.303RT
`
`(Tm—:r) + log W
`
`0
`
`"
`
`(1)
`
`Also, the solubilities of this drug, (CA, CB, or CX) in pure systems of co—solvent A, B, or
`may be defined in the same way:
`"
`
`~
`
`ASA
`log or = ———<Tm—T> + low
`V
`2.303122“.
`. AS
`log C3 = _ (Tm—T) + log 7),;
`
`.
`
`a
`
`*
`
`.
`
`.
`
`0
`
`(2)
`
`' log Cx = — (T¢—T) +‘ log 31;;
`
`A
`
`_
`
`_
`
`(3) A
`
`(4)
`
`where ASW, ASA, AS3, and A5,; are the entropies of thedrug species in the pure solvent systems
`and yw, 32A, 92],, and 3/X are the corresponding activity coefficients ; Tm is the drug melting point;
`. and T‘ is the temperature of the system investigated.
`(
`»
`In a nonideal multiple solvent system containing f, fraction of co—solvent A, f,, fraction
`bf co—solvent B, fx fraction of co-solvent X, and [1——(fA +f,, +fx)] fraction of water, the apparent
`solubility (CA, B, X) of the same drug species may be expressed as
`log C1_;,»a,x = fw log Cw _+ fA log CA +._fs.1og CB + fx16§Cx
`’ _
`‘
`= log Cw + mag C,;——log Cw) +_ fg(1og Ci;—.—log-Cw).
`+fx(]ogCx_1og Cw)
`,
`,
`,
`,1
`g
`V
`
`(53)
`
`V
`
`,
`
`V
`
`.
`
`‘
`
`V
`
`_
`
`-g
`
`(
`
`(Sb)
`
`_
`8) Y.VV. Chien, H.]. Lambert, and D.E. ‘Grant‘,’.v Phm/ml Soil, 63.,
`9) A.N. Martin, “Physical 'Pharmacy,”.»Lea. & Febiger, Philadelphia‘,"19§0,: Chapter 14.
`
`,
`
`NII—Electronic Library Service
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`|nnoPharma Exhibit 10980002
`
`

`

`No, .5
`
`~-
`
`—
`
`1087'
`
`since
`
`p
`(AspJ“’ASA) +1og—::—
`log CA - log Cw =
`(4Sw‘—ASB> + log 33$.
`log cg — log C, =
`(AS:,';—ASx) + log gt:
`log Cx —— log CW =
`Substituting Eqs. (6), (7), and (8) into (51.-b) gives
`(9)
`10%: CA,B,X =10g Cw, + 8AfA,+ safis + exfx
`where the slopes (e,(, 33, and ex) of the sernilogarithmic relationship between the drug solubility
`(CA, B, X) and the composition of co—solvent (f,,, f,,, and fx) are defined by:
`
`(6) ‘
`(7);
`(8)i
`
`1
`
`eA= ;_7;3;R:2;(Asw¥AsA)+1og‘.:)’.:.
`
`(Asw~Asg))+g1og;’—:
`813 =
`_ (Tm“T) A
`__AS‘
`1
`_7’_3_C_
`ax— 2.303RT( Sw
`x)+ og yw
`
`(10)
`
`(11)
`
`.'
`
`(12)
`
`.'.
`
`I
`
`.
`
`_
`
`Eqs. (10) to (12) point out that the magnitudes of the slopes (3,, 83, and ex) are determined by
`the difference in entropies, (AS,,—ASA), (AS,,~ASB), and (ASWj——ASx), respectively,the ratio
`of the activity coefficients ()2,/yw, y,,/)/,, and yx/7/W and the difference between the melting
`point temperature (Tm) and the temperature of the system studied (T).
`Eq. (9) indicates that the solubility -of a drug species in a given multiple co—solvent system
`(CA, B, x,) is exponentially related to the volume fractions of co-solvents (A, B, and X) added.
`In the case of a ternary system containing a fixed (fA) of co—solvent A and a varying fraction
`(fx) of co—solvent X, Eq.
`(9)) may be simplified. Since fB=:0, the apparent drug solubility
`(CA, X) in such a ternary system is:
`
`log CA,-x = log Cw + €AfA + exfx
`
`(13)
`
`When using a binary system, (only one co—so1vent),vEq. (13) may be further simplified to
`log Cx = log CW -5- exfx
`V
`M
`T (14)
`An equation similar to Eq. (14) was reported previously by Yalkowsky, et all“ to describe
`the solubility of alkyl p—aminobenzoates in propylene glycol~water systems.
`The experimental evidence for the dependence of drug solubility upon co—solvent composi-
`tion in a binary system (Eq. 14:) is demonstrated in Fig. 2, where the solubility of poorly soluble
`steroids, e.g., progestins (SC—1180O and SC—464:0) as well as anti—mineralcorticoid drugs (SC-9376
`and 8025152), is exponentially enhanced as the volume fraction of polyethylene glycol 400
`co—solvent increases. The molecular structures of the four synthetic steroids investigated
`were shown earlier in Fig. 1.
`.
`_
`,
`Eq., (14) was also followed in binary systems_containing either ethanol, propylene glycol,
`solketal (2,2-d.imethyl—1,3-dioxolane-4-methanol), or dimethylacetamide. For example, the
`solubilization of canrenone by ethanol, propylene glycol, and PEG 400 is illustrated in Fig. 3,
`A common ordinate intercept, which was equivalent to the actual aqueous solubility (Cw)
`of canrenone (8.1 X 10*5M) measured independently, was obtained. The relative efficiency
`on the solubilization of canrenone by these five co-solvents is tabulated in Table I in order
`of solubilizing efficiency. Ethanol is the most effective solubilizer and polyethylene glycol
`400 is least effective.
`,
`'
`v
`I.
`‘_
`.
`f.
`;.
`‘
`,
`The validity of Eq.
`(13) in a ternary system containing a fixed (fA) Volume fraction of
`co—solvent A and a varying fraction (fx) of co—solvent X is denionstratedby the data-:in‘Fig..4=-.
`In this experinient, the incorporation 'of«a fixed concentration (19 or 28.5% v/v), of ethanol
`
`NII—Electronic Library Service
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`
`

`

`1088
`
`Vol. 23 (1975)
`
`6><10”2
`
`4x10"
`
`1o*2~
`
`<
`5’:
`O
`5 10-9
`at
`,3
`
`>>
`L‘ 10*
`O
`
`U)
`
`10‘5
`
`V
`
`1-0
`
`0-3
`0-5
`0-4
`’ 0-2
`0
`‘Volume fraction of polyethylene
`glywl 400
`Solubiliéation of some Synthe_
`Fig 2
`tic Steroids by the'Addition of Poly-
`ethylene Glycol
`
`keys: Q SC-11800, O SC-4640, I SC-9376, and
`D 5025152
`
`
`
`E 10"? I
`E
`:
`_ 5
`G
`£3
`15' I0”
`“a
`
`‘.5
`.2
`
`10~4
`
`‘ 5><10‘5____._
`0
`
`0.8
`0.6
`0.4
`0.2
`Volume‘ fraction of co-solvent
`
`;
`1.0
`
`’
`
`_
`
`Fig. 3. Semilogarithmic Relationship
`between the Concentration of Cante-
`none (moles/liter) solubilized and the
`Volume Fraction of a Single co-
`Solvent
`
`'
`_
`A common intercept at 8.1 X 10--"M was observed,
`keys: 0 ethanol, 0 propylene glycol, and Q
`polyethylene glycol 400
`
`TABLE I. The Solubilization of Canrenone by the Binary
`Systems Containing a Single co-Solvent and Water
`
`Solubilizers
`
`Ethanol
`Solketal
`-
`_) Propylene‘ glycol
`V
`Dimethylacetamide L
`Polyethylene glycol 400’
`
`.
`
`ex“)
`
`4,75
`3.97
`3.42
`3.21
`2.93
`
`a) axis the slope of the log Cx as. fx profiles as defined in Eq. (14).
`
`substantially enhanced the magnitude of the intercept (from log CW to log CW+eAfA) (compare
`Eqs; 14 with 13); but, the linear relationship of log CA, X to fx was still followed and the magni-
`tude of the slope (ex) stayed about the same (aX=8.34 to 3.43).
`‘ When’ a fixed concentration of a third co~solvent, e.g., solketal (20% V/V) or dimethyl-
`acetamide (20% v/v) T was incorporated into mixtures of ethanol—propylene glycol—water,
`the solubility of canrenone was enhanced. The linearity of log CA, B, X to the volume fraction
`of propylene glycol (as expected from Eq.
`(9)) was still observed. Following the addition
`of 20% V/V of either dimethylacetamide or solketal (Fig 5) the intercept (at zero concentration
`‘of propylene glycol) was significantly increased from log CW +3AfA (Eq. 13) to log CW —l—eAfA+aBfB
`(Eq. 9). The effectlof addition of a third solubilizer on the magnitude of both the intercept
`(log Cw—|—aAfA+eBfB) and the slope (ex) of the log CA, B, X vs.fW profiles are found in Table II.
`Along with the increase in the intercept, the slopes were slightly minimized due to the addition
`or a third co-solvent. This may be due to the change in the entropy and activity coefiicient
`of the resultant solution. The predictive value of Eq.
`(9')
`is demonstrated in Table III.
`
`NII—Electronic Library Service
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`|nnoPharma Exhibit 1098.0004
`
`

`

`3><1o-I
`
`1089
`
`I-L
`
`..o
`
`J.
`
`~
`
`
`
`Solubilityofcanrenone(moles/liter)
`
`
`
`M
`
`I—
`
`,9
`
`_
`10-4’
`1'.o
`0.8
`0.6
`0.4
`0,2‘
`M1050
`Volume fraction of propylene glycol
`I
`Fig. 5. Semilogarithmic Relationship
`between the Concentration of Canre-
`
`none (moles/liter) solubilized and the
`Volume Fraction of Propylene Glycol
`in a Three co-Solvent Aqueous System
`
`keys’ 0 P‘°PY1e“e 31Y°°1 31°“: C P1115 9-5%
`ethanol and 20% dimethylacetamide, I plus 19%
`ethanol and 20% dimethylacetamide, and Q plus
`19% ethanol and 20% solketal
`
`N0. 5:
`
`e><1o'*
`
`N
`
`
`
`
`
`F-4 9
`
`Solubilityofcanrenone(moles/liter) 3e\*
`
`—4—
`..
`;/
`1°C
`5X10’5f 0
`Volume fraction of propylene glycol
`
`‘
`
`Fig. 4. Semilogarithmic Relationship
`between the Concentration (moles/
`liter) of Canrenone solubilized and the
`Volume Fraction of Propylene ‘Glycol
`in a Two co-Solvent Aqueous System
`
`keys: 0 propylene glycol alone, 0 plus 19% v/v
`of ethanol, and Q plus 28.5% v/v of ethanol
`
`TABLE II. Effect of the Addition of Third co-Solvent on the Intercept
`and Slope Values of log CA,a,x vs. fx Profiles (Eq. 9)
`
`co—Solvent combinations
`
`# 1
`
`# 2
`
`# 3
`
`Propylene glycol
`Propylene glycol
`Propylene glycol
`Propylene glycol
`Propylene glycol
`
`—
`19.0% ethanol
`9.5% ethanol
`19.0% ethanol
`19.0% ethanol
`
`——
`——
`20% DMA
`20% DMA
`20% solketal
`
`Intercept
`(MX 103)
`
`0,081
`0.80
`2.06
`7.00
`13.80
`
`Slope
`
`3,42
`3.43
`3.00
`2.39
`2.08
`
`The product of the slope (is) (obtained from the solubilization of canrenone with individual
`co—solVents) an.d the Volume fraction (f’s) used was employed to estimate the expected can-
`renone solubility in multi—co—solvent systems. The agreement of the observed solubility
`with that calculated is good. The small deviation of the observed solubility from the estimated
`value (low ratio, ca. 0.76) may be due to the slight decline in slope (Table II) observed after
`the incorporation of a third co-solvent.
`The use oi? multiple co-solvent combinations to enhance steroid solubility is an improve—
`ment over solubilization with a high volume fraction of a single co-solvent. For example,
`55% ethanol, or 77% propylene glycol, or 87% polyethylene glycol 4100 was required in order
`to effectively solubilize 3.25>< 10“2M of canrenone in aqueous solution. The use of high co-
`solvent concentrations may unfavorably affect the desired viscosity, and the esthetic accepta-
`bility of the resultant formulations. On the other hand, this drug concentration (3.25 X 1O"2M)
`was achieved with a multiple co-solvent system containing either 9.5% ethanol—20% dimethyl-
`acetamide—40% propylene glycol or 19% ethanol—20% solketal—18% propylene glycol.
`In
`
`NII—Electronic Library Service
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`
`

`

`1090
`
`Vol. 23 (1975)
`
`TABLE III. Agreement between,Calculated and Observed Canrenone Solubility
`
`
` Iin Multiple co—Solvent Systems ‘
`
`log’?
`I
`Multiple
`co—Solvent systems“)
`CA, 3, x")
`‘
`Calculated“
`Observed
`
`
`Canrenone ‘solubility ;(M X 102)
`
`Ratio”)
`
`M
`
`1.368
`40%
`Propylene glycol
`0 . 451
`9. 5%
`Ethanol
`0.642
`20%
`DMA”
`2.461
`SUIW .
`g
`-A 1.368:
`Propylene glycol
`40%
`0 . 903
`Ethanol
`19%
`0.642
`DMAe>
`20%
`3 2.91.3
`SUM
`'
`1.368
`Propylene glycol
`40%
`I 0.903
`Ethanol
`19%
`O . 794
`Solketal
`20%
`
`V 3.065 11.61 9.61 ASUM 0.83
`
`
`2.89
`
`'
`
`3.25
`
`1.12
`
`8.18
`
`6.125
`
`0.76
`
`
`
`
`
`
`
`I
`a) Q5. of distilled Water is added to make 100%
`1))
`calculated from Table I by multiplying the slope (is) with volume fraction (f) for each cosolvent used
`c)
`ratio of observed solubility over calculated Value
`'
`d)
`autilogarithmic of log CA,g,x
`e ) dimethylacetamide
`
`practice, any number of combinations may be blended depending on specific formulation
`requirements and the physico—chemical properties of the drug. Finally, the use of a multiple
`co-solvent system may prevent the occurence of undesirable toxicity which may result from
`the use of a high volume fraction of a single co—solvent.
`
`Appreciation is extended to Ms. Dianne M. Jefferson for her
`Acknowledgements and Addresses
`technical assistance and to Ms. Susan M. Justi for manuscript preparation.
`
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`
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