Increased shelf-life of fosphenytoin: Solubilization of a degradant, phenytoin, through complexation with (SBE)(7m)-β-CD

Article abstract of DOI:10.1021/js980041h

Fosphenytoin, a water-soluble prodrug of phenytoin, degrades primarily to phenytoin at pH values <8 during long term storage; phenytoin readily precipitates when formed from fosphenytoin due to its limited aqueous solubility. The objective of this study was to develop stable formulations of fosphenytoin in the pH range of 7.4-8.0 by inhibiting the phenytoin precipitation through complexation with a parenterally safe cyclodextrin, (SBE)(7m)-β-CD. Phase solubility studies at 25 °C revealed that phenytoin could be effectively solubilized by (SBE)(7m)-β-CD both in the presence and absence of 80.6 mg/mL fosphenytoin (as its dihydrate). The binding constants for the phenytoin/cyclodextrin complex were found to be 1073 and 792 M^-1 at pH 7.4 and pH 8.0, respectively. Because of the competitive inclusion between fosphenytoin and phenytoin with (SBE)(7m)-β-CD, the extent of solubilization of phenytoin was lower, as expected, in the presence of fosphenytoin than in the absence of fosphenytoin, even though the binding constants for the fosphenytoin/cyclodextrin complex were relatively small (41-45 M^-1). Initial rates were used to follow the production of phenytoin from fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50 °C in the presence of 0.03 or 0.06 M (SBE)(7m)-β-CD. It was projected from the solubility of phenytoin and the kinetic information that fosphenytoin shelf lives as high as nine years at 25 °C and pH 7.4 in the presence of 60 mM of (SBE)(7m)-β-CD might be possible while longer shelf lives might be possible at pH 8.

Full text of DOI:10.1021/js980041h

Increased Shelf-Life of Fosphenytoin: Solubilization of a Degradant,
Phenytoin, through Complexation with (SBE)7m-â-CD
†,‡
,†
SHINJI NARISAWA AND VALENTINO J. STELLA*
Contribution from Department of Pharmaceutical Chemistry and Higuchi Biosciences Center for Drug Delivery Research,
The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047.
Received January 27, 1998. Accepted for publication May 6, 1998.
Abstract 0 Fosphenytoin, a water-soluble prodrug of phenytoin,
degrades primarily to phenytoin at pH values <8 during long term
storage; phenytoin readily precipitates when formed from fosphenytoin
due to its limited aqueous solubility. The objective of this study was
to develop stable formulations of fosphenytoin in the pH range of
7.4−8.0 by inhibiting the phenytoin precipitation through complexation
with a parenterally safe cyclodextrin, (SBE)7m-â-CD. Phase solubility
studies at 25 °C revealed that phenytoin could be effectively solubilized
by (SBE)7m-â-CD both in the presence and absence of 80.6 mg/mL
fosphenytoin (as its dihydrate). The binding constants for the
phenytoin/cyclodextrin complex were found to be 1073 and 792 M-1
at pH 7.4 and pH 8.0, respectively. Because of the competitive
inclusion between fosphenytoin and phenytoin with (SBE)7m-â-CD,
the extent of solubilization of phenytoin was lower, as expected, in
the presence of fosphenytoin than in the absence of fosphenytoin,
even though the binding constants for the fosphenytoin/cyclodextrin
complex were relatively small (41−45 M-1). Initial rates were used
to follow the production of phenytoin from fosphenytoin. Zero-order
kinetics were observed under all conditions investigated. Phenytoin
production rates were followed at 25, 37, and 50 °C in the presence
of 0.03 or 0.06 M (SBE)7m-â-CD. It was projected from the solubility
of phenytoin and the kinetic information that fosphenytoin shelf lives
as high as nine years at 25 °C and pH 7.4 in the presence of 60 mM
of (SBE)7m-â-CD might be possible while longer shelf lives might be
possible at pH 8.
Figure 1sChemical structures of phenytoin and fosphenytoin.
such as 5,5-diphenyl-glycinamide, 5,5-diphenyl-4-imidazo-
lidinone, and hydantoic acid species, are claimed.7 These
degradants are more water soluble than phenytoin. There-
fore, to avoid phenytoin precipitation during the long-term
storage, the pH of the commercial product of fosphenytoin
is adjusted to these higher values despite greater intrinsic
stability around pH range 8.0. However, at the higher pH
values refrigeration storage is required. To develop a
stable fosphenytoin injection around physiological pH with
a shelf life of at least two years at 25 °C, it would be
necessary to solubilize the poorly soluble degradant, pheny-
toin, to prevent possible precipitation from solution during
long-term storage.
Cyclodextrins (CDs) have been reported to be effective
for increasing the aqueous solubility, stability, and bio-
availability of drugs.8-10 In addition to natural CDs (R-,
â-, and γ-CDs), various types of modified CDs have been
developed to improve on the physical, chemical, and safety
properties of the natural CDs. A sulfobutyl ether deriva-
tive with and average degree of substitution of seven,
sodium salt, termed (SBE)7m-â-CD or Captisol (Figure 2)
is an anionically charged cyclodextrin with greater solubil-
ity in water than the parent material, â-cyclodextrin.
Recently it was reported that (SBE)7m-â-CD could increase
aqueous solubility of various neutral and charged drugs
and has been shown to have greater safety after parenteral
administration.11-14
The objective of this work, therefore, was to examine the
possibility of developing a stable formulation of fospheny-
toin at or near physiological pH, 7.4 or 8.0, by using
(SBE)7m-â-CD to solubilize phenytoin produced from the
degradation of fosphenytoin. The concept is illustrated in
Scheme 1. Phase solubility analysis was used to determine
the amount of (SBE)7m-â-CD necessary to solubilize pheny-
toin in the presence of fosphenytoin. Initial rate, acceler-
ated temperature studies, as well as studies at 25 °C were
then used to project shelf lives under a variety of condi-
tions.
Introduction
Fosphenytoin (Figure 1; 3-(hydroxymethyl)-5,5-diphe-
nylhydantoin, phosphate ester, disodium salt) is a parenter-
ally useful prodrug form of phenytoin recently approved
by the FDA. Phenytoin is a sparingly water-soluble (20-
25 µg/mL), weakly acidic (pKa 8.3) drug.1 The advantages
of fosphenytoin over sodium phenytoin2 have been recently
documented.1 Fosphenytoin has also been shown to be
useful after intramuscular administration3 and to avoid
second peak phenomena after intravenous injection.4
Although the maximum stability of fosphenytoin appears
to be around pH values of 7.5-8.0, the pH of the com-
mercially available fosphenytoin injection is adjusted to
values greater than 8.5. The principle chemical degrada-
tion products of fosphenytoin around physiological pH are
phenytoin, formaldehyde, and inorganic phosphate5,6 as
well as some other minor products. On the other hand, at
pH values greater than 8, various ring-opened degradants,
* To whom correspondence should be addressed. Tel: 785-864-3755.
Fax: 785-749-7393. E-mail: stella@smissman.hbc.ukans.edu.
† The University of Kansas.
Experimental Section
‡ Current address: Pharmaceutics Research Laboratory, Tanabe
Seiyaku Co., Ltd., 16-89 Kashima 3-chome Yodogawa-ku, Osaka 532,
J apan.
Ma ter ia lssFosphenytoin, isolated as its dihydrate, was syn-
thesized according to the method developed by Varia et al.15 The
final material, as a 80.6 mg/mL aqueous solution contained about
926 / Journal of Pharmaceutical Sciences
S0022-3549(98)00041-0 CCC: $15.00
Published on Web 06/05/1998
© 1998, American Chemical Society and
Vol. 87, No. 8, August 1998
American Pharmaceutical Association

late matter and for sterility purposes. The ampules were stored
in a temperature-controlled water bath at 25 °C or ovens at 37,
50, and 60 °C and periodically removed and analyzed for phenytoin
content. Sampling times were adjusted according to expected
reactivities at differing temperatures. The concentration of
phenytoin in ampules versus time was quantitated to determine
the initial rates of phenytoin production. In all cases, phenytoin
production followed apparent zero-order kinetics with linear
correlation coefficients of >0.99. Over the time range studied, the
loss of fosphenytoin was negligible. Another earlier eluting peak
was also quantitated and compared to phenytoin production,
results not presented here. At pH 8.0, this peak had a HPLC peak
area comparable to that of phenytoin while at pH 7.4 phenytoin
was the major degradant peak observed. All results are presented
as the average of duplicate runs.
P h a se Solu bility Stu d iessExcess phenytoin solid was added
to 1 mL of Tris buffer solutions in the presence (80.6 mg/mL) or
absence of fosphenytoin dihydrate as a function of various amounts
of (SBE)7m-â-CD (0.00-0.08 M). After sonication and mixing by
a vortex mixer, the phenytoin-suspended solutions were placed
in a shaking, temperature-controlled water bath for at least 5 days
at 25 °C. After equilibration, checked by periodic sampling, the
suspensions were filtered through a membrane filter (Acrodisc,
PVDF 0.2 µm, Gelman). The filtrate was isolated and diluted with
HPLC mobile phase, and the concentration of phenytoin was
determined by HPLC. This work was performed in duplicate.
Figure 2sChemical structure of (SBE)7m-â-CD.
Results and Discussion
P h en ytoin Solu bility in th e P r esen ce of F osp h en -
ytoin sTo predict the time when phenytoin could precipi-
tate from fosphenytoin samples, phenytoin solubility was
measured in the absence and presence of fosphenytoin at
25 °C. The fosphenytoin concentration of 80.6 mg/mL (75
mg/mL anhydrous fosphenytoin) was the same as the
commercial product. The solubility of phenytoin was 18.1
µg/mL in the absence of fosphenytoin, and 49.8 µg/mL in
the presence of fosphenytoin at a pH 7.4. At pH 8.0, the
solubility of phenytoin was 27.5 µg/mL in the absence of
fosphenytoin, and 61.9 µg/mL in the presence of fospheny-
toin. The slightly higher solubilities at pH 8.0 relate well
to the pKa value of 8.06-8.33 for phenytoin.18 The solubil-
ity of phenytoin is elevated in the presence of fosphenytoin
probably through micellar solubilization or complex forma-
tion.19,20 The possibility that fosphenytoin may form as-
sociative species was not addressed in this paper.
P h a se Solu bility Stu d iessPhenytoin was found to
interact with â-CD.21 Figure 3 shows the phase solubility
diagrams for phenytoin with (SBE)7m-â-CD at 25 °C in the
presence or absence of 80.6 mg/mL of fosphenytoin in 0.02
M Tris buffer solution at pH values 7.4 (Figure 3a) and
8.0 (Figure 3b), respectively. All phase solubility diagrams
are AL-type, according to the classification of Higuchi et
al.,22 suggesting 1:1 phenytoin /(SBE)7m-â-CD complex
formation at both pH values. No evidence in this or other
studies supported the presence of higher order complexes
although AL-type diagrams only confirm that the interac-
tion is first order with respect to ligand. Since fosphenytoin
can compete with phenytoin for (SBE)7m-â-CD binding, the
solubility enhancement in the presence of fosphenytoin, as
expected, was lower than that in the absence of fospheny-
toin.
Scheme 1
20 µg/mL of phenytoin as an impurity. The synthesis and
characterization procedures for (SBE)7m-â-CD have been described
elsewhere.16,17 HPLC grade methanol was obtained from Fisher
Scientific (Pittsburgh, PA). Tris(hydroxymethyl)aminomethane
HCl (Trizma hydrochloride, Sigma Chemical Co., St. Louis, MO)
and tris(hydroxymethyl)aminomethane (Trizma base, Sigma Chemi-
cal Co.) were used for preparation of Tris buffer solutions. All
other chemicals were reagent grade. All glassware was washed
with purified water and 70% (w/v) ethanol, followed by drying at
90 °C for at least 24 h before use. Double distilled water was used
throughout.
P h en ytoin An alysissReversed-phase HPLC analysis of pheny-
toin was carried out using a Shimadzu 6A-HPLC pump (Shimadzu
Corp., Kyoto, J apan), a Shimadzu SPD-6A UV detector (Shimadzu
Corp.), a Shimadzu CR601 integrator (Shimadzu Corp.), and a
Rheodyne injector (Rheodyne, Berkeley, CA) fitted with a 20 µL
loop. A reversed phase column (150 × 4 mm, Phenyl Hypersil, 5
µm particle size) was used for the analysis at 50 °C, and phenytoin
was quantitated at UV 254 nm. The mobile phase consisted of
35% (v/v) methanol and 65% (v/v) of aqueous potassium phosphate
monobasic solution (25 mM) adjusted to pH 3.8 with phosphoric
acid. When the flow rate was 1.1 mL/min, the retention times of
fosphenytoin and phenytoin were 4 and 11 min, respectively.
Ch em ica l Sta bility Stu d iessThe chemical stability of fos-
phenytoin was investigated in 0.02 M tris buffer solutions at pH
values of 7.4 and 8.0. Fosphenytoin concentration (as its dihy-
drate) was 80.6 mg/mL. This is equivalent to 75 mg/mL anhydrous
fosphenytoin and on a mole basis, equivalent to 50 mg/mL sodium
phenytoin. At pH 7.4, reactions were run in the presence of 0 and
60 mM (SBE)7m-â-CD, while at pH 8.0, reactions were run in the
presence of 0, 30, and 60 mM (SBE)7m-â-CD. The solutions were
filtered through a 0.2 µm membrane filter (Disposal Sterile Syringe
Filter, cellulose acetate membrane, 25 mm, Corning Glass Works,
NY) before filling into 1 mL glass ampules (prescored funnel top
ampule, Fisher Scientific, Pittsburgh, PA) to remove fine particu-
This phenomena is illustrated in Scheme 2. The binding
constant for the phenytoin/(SBE)7m-â-CD complex, K1, can
be calculated by the slope and intercept of the data from
Figure 3 (absence of fosphenytoin) according to eq 1.22
K1 ) slope/intercept/(1 - slope)
(1)
K2, the binding constant for the fosphenytoin/(SBE)7m
-
â-CD complex, can be calculated according from eqs 2 and
Journal of Pharmaceutical Sciences / 927
Vol. 87, No. 8, August 1998

Table 1sBinding Constants for Phenytoin and Fosphenytoin at 25 °C
with (SBE)7m-â-CD
binding constant (M-1)
pH 7.4
pH 8.0
phenytoin/(SBE)7m-â-CD (K )
1073
45
792
41
1
fosphenytoin/(SBE)7m-â-CD (K )
2
Table 2sPhenytoin Production Rates in Different Formulations and at
Various Temperatures of Fosphenytoin
rate (µg/mL/day)
pH
temp °C
0 mM CD
30 mM CD
60 mM CD
7.4
7.4
7.4
7.4
8.0
8.0
8.0
8.0
25
37
50
60
25
37
50
60
0.160
−
−
111.8
0.083
0.634
−
−
−
−
−
0.133
0.993
21.37
−
0.075
0.562
13.82
−
0.088
0.600
14.43
−
67.20
values of x and substituting into eq 3 allows one to estimate
K2 for each Lt concentration. Some assumptions are made
in performing this calculation. These include that So′ is
constant and the same in the presence and absence of CD,
tris buffer components do not interact with the CD, only
1:1 complexes are formed, and that the CDs do not disrupt
any associative species.
The estimated values of K1 and K2 at pH values 7.4 and
8.0 are listed in Table 1. The K1 value at pH 8.0 was found
to be smaller than at pH 7.4. An explanation for this
observation is that a fraction of phenytoin at pH 8.0 is in
its anionic form18 (see earlier discussion), and anionically
charged drugs interact weakly with (SBE)7m-â-CD.12 K2 was
found to be much smaller than K1 at both pH levels,
consistent with the dianionic nature of fosphenytoin at both
pH values. Earlier work from this laboratory12 showed
weaker interaction of anionically charged drugs with
(SBE)7m-â-CD presumably due to Coulombic repulsion.
P h en ytoin P r od u ction a t p H Va lu es 7.4 a n d 8.0s
On the basis of solubility analysis, and initial projection
of phenytoin production from a preliminary study at 60 °C
(results included in Table 2) in the absence of (SBE)7m-â-
CD, 60 mM (SBE)7m-â-CD was chosen as the desired CD
concentration at pH 7.4 while 30 mM and 60 mM concen-
trations where chosen for pH 8.0. In hindsight, lower levels
may have been possible but initial stability data obtained
at 60 °C overestimated phenytoin production rates at lower
temperatures.
Figure 3sPhase solubility diagram for phenytoin in the presence of increasing
(SBE)7m-â-CD concentration pH 7.4 and pH 8.0 in the absence (b) or presence
(9) of 80.6 mg/mL fosphenytoin (as its dihydrate).
Figures 4 shows typical plots of initial phenytoin produc-
tion profiles versus time at 37 °C. At all temperature
conditions investigated, phenytoin production followed
similar pseudo zero-order kinetics; phenytoin is produced
linearly at all temperatures and CD concentrations and at
both pH values. Since the concentration of fosphenytoin
(80.6 mg/mL as its dihydrate, 180 mM) is higher than that
of (SBE)7m-â-CD (0, 30 or 60 mM) and because the binding
of fosphenytoin to (SBE)7m-â-CD is weak (see Table 1),
(SBE)7m-â-CD appeared to only minimally influence the
phenytoin production rate; there was a trend to greater
stability with increasing (SBE)7m-â-CD concentration, sug-
gesting that fosphenytoin was more chemically stable at
the complex compared to its free form. Apparent phenytoin
production rates under all conditions investigated are
summarized in Table 2.
Scheme 2
3 as follows:
K1 ) (St - So′)/(St - (St - So′))/(Lt - (St - So′) - x)
(2)
K2 ) x/(St′ - x)/(Lt - (St - So′) - x)
(3)
where the various terms are defined in Scheme 2. Since
K1 is easily calculated from the phase solubility diagram
in the absence of fosphenytoin and the other terms in eq 2
are either known or are determined experimentally, x can
be calculated for variations in Lt. Using the calculated
Figure 5 shows Arrhenius plots for phenytoin production
rate from fosphenytoin. The apparent energy of activation,
928 / Journal of Pharmaceutical Sciences
Vol. 87, No. 8, August 1998

Table 3sProjected Shelf Lives at 25 °C of Fosphenytoin Based on
Phenytoin Production Rates and Solubility in the Presence and
Absence of (SBE)7m-â-CD
solubility criteria
stability criteria
(SBE)7m-â-CD phenytoin
phenytoin
concentration
(nM)
concn
shelf lifea
(years)
concn
shelf lifeb
(years)
pH
(µg/mL)
(µg/mL)
7.4
7.4
8.0
8.0
8.0
0
60
0
30
60
49.8
450.8
61.9
274.4
475.5
0.9
9.3
2.0
8.5
17.4
−
230
−
230
230
−
4.7
−
7.2
8.4
a Time to exceed phenytoin solubility at the stated pH and concentration
of added (SBE)7m-â-CD. b Time to exceed the concentration of phenytoin
equivalent to 0.5% production of phenytoin from 80.8 mg/mL fosphenytoin
(as its dihydrate).
Figure 4sProduction of phenytoin from the degradation of fosphenytoin at
37 °C in 0.02 M Tris buffer solution. Key: (b), pH 7.4/60 mM (SBE)7m-â-CD;
(4), pH 8.0/without (SBE)7m-â-CD; (2), pH 8.0/30 mM (SBE)7m-â-CD; (9),
pH 8.0/60 mM (SBE)7m-â-CD.
phenytoin solubility in the presence and absence of (SBE)7m
-
â-CD and 0.5% phenytoin production. Since 80.6 mg/mL
of fosphenytoin dihydrate is equivalent to 50 mg/mL of
sodium phenytoin or 46 mg/mL of phenytoin, 0.5% pheny-
toin production corresponds to the productions of 230 µg/
mL phenytoin from 80.6 mg/mL fosphenytoin. When 60
mM (SBE)7m-â-CD was used, phenytoin should not pre-
cipitate for over two-years at 25 °C at either pH value; the
most apparent stable formulation, which is a combination
of pH 8.0 and 60 mM of (SBE)7m-â-CD concentration,
suggested that phenytoin precipitation should not occur for
at least 17 years if maintained at 25 °C. Using the 0.5%
phenytoin production as the shelf life cutoff criteria, greater
than two year shelf lives was also possible. Obviously, the
amount of (SBE)7m-â-CD could be adjusted to meet other
phenytoin production criteria. These results clearly indi-
cate that physically stable formulations of greater than two
years at 25 °C of fosphenytoin in the pH range 7.4-8.0
should be possible.
Figure 5sArrhenius plots for phenytoin production rates from fosphenytoin
degradation. Key: (O), pH 7.4/60 mM (SBE)7m-â-CD; (4), pH 8.0/30 mM
(SBE)7m-â-CD; (0), pH 8.0/60 mM (SBE)7m-â-CD; (b), pH 7.4/without (SBE)7m-
â-CD; (2), pH 8.0/without (SBE)7m-â-CD; s, regression line for pH 7.4; ----,
regression line for pH 8.0.
References and Notes
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Del. Rev. 1996, 19, 311-330.
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Ea, values were found to be 38.9 kcal/mol for pH 7.4 and
39.5 kcal/mol for pH 8.0. These values are higher than
those reported previously; 30.8 kcal/mol, and are also
higher than Ea values reported from most other drug
degradation studies (10-30 kcal/mol).23 Possible explana-
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Acknowledgments
This work was supported by Kansas Technology Enterprise
Corporation through the Centers of Excellence program.
J S980041H
930 / Journal of Pharmaceutical Sciences
Vol. 87, No. 8, August 1998