Professional Documents
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Use of Nonaqueous Solvents in Parenteral Products
Use of Nonaqueous Solvents in Parenteral Products
Use of Nonaqueous Solvents in Parenteral Products
Sciences
OCtObef"1963 volume 52, number 10
Review Article
Use of Nonaqueous Solvents in Parenteral Products
By A. J. SPIEGEL and M. M. NOSEWORTHY
HE PRACTICE OF incorporating naturally oc- jedion, and the solvent must remain fluid over a
Tcurring nonaqueous solvents such as fixed fairly wide temperature range. It is advantage-
oils and glycerin in pharmaceuticals has been ous if the solvent has a sufficiently high boiling
Common for many years. Water is always the point to allow heat sterilization. Additional
solvent of choice. However, when it is not considerations are water and body fluid misci-
possible for physical or chemical reasons (such as bility, the degree of flammability, availability,
limited solubility and hydrolytic reactions) to source of supply, and constant purity.
use a wholly aqueous system, nonaqueous sol- Obviously, no such individual solvent presently
vents aid the formulator in developing stable, exists. Thus, the selection of a nonaqueous
convenient parenteral dosage forms. A paren- solvent for a parenteral vehicle is a compromise
teral solution avoids the disadvantages inherent among the many influencing factors. The ad-
in suspensions, such as nonuniform dosage, cak- vent of modem chemical technology has pro-
ing, and possible slow release of the medicament duced many new synthetic solvents in addition to
when it is not desired. the naturally occurring ones.
A formulator encounters many problems once This review presents the toxicity, chemical and
he determines that an aqueous system is un- physical properties, and applications of some of
satisfactory. The chosen solvent must be non- the more commonly used nonaqueous solvents,
toxic, nonirritating, and nonsensitizing. It also as well as some specialized and rarely used sol-
must exert no pharmacologic activity of its own, vents in pharmaceutical formulations.
nor adversely affect the action of the medica-
ment. There are reported instances in which a FIXED OILS
solvent potentiated the activity of the medica-
The U.S.P. (1) recognizes the use of fixed oils as
ment necessitating a change of dosage level.
parenteral vehicles. Fixed oils are mainly mix-
This will be discussed in greater detail later in
tures of esters of unsaturated fatty acids which
this review.
are fluid at 20°. The fluidity is generally due to
In addition to being pharmacologically accept-
the presence of the oleic acid esters of glycerin.
able, the chemical and physical properties of the
The most commonly used fixed oils are corn oil,
solvent must be taken into account. Thus, the
cottonseed oil, peanut oil, and sesame oil (2).
ideal solvent should not be affected by acids or
Castor oil and olive oil have been used occasion-
alkalies and it should be generally stable under
ally. While the toxicities of vegetable oils are
normal conditions of pharmaceutical use. The
relatively low, some patients exhibit allergic re-
viscosity must be such as to allow for ease of in-
actions to specific vegetable oils. Therefore,
Received from the Pharmaceutical Research and Develop when such oils are used as vehicles, the label must
ment Depart.mrmt, Chas. Pker & Co.. Inc., Brooklyn, N. Y.
Presented in part at the Fourth Annual National Industnal state the specific oil contained in the product.
Pharmaceutical Research Conference, Land @Lakes, Wis.,
June 1862. Fixed oils have been known to cause undesirable
917
918 Joitrnal of Pharmaceutical Sciences
local tissue reactions, such as cysts, foreign-body cept that i t is less viscous, is a superior solvent,
granulomas and, occasionally, nerve injury. and is more rapidly absorbed by the tissues (7).
The requirements for fixed oils to be used in Unlike untreated sesame oil, ethyl oleate remains
parenteral products are specified in the U.S.P. (1). clear a t 5 O , but it has the disadvantage of dis-
The use of fixed oils is limited because of the low coloring on standing.
solubility of most drugs in these solvents. Since There are indications of increased hormone
these oils are not miscible with water, dissolved activity when ethyl oleate is used in place
drugs may exhibit a sustained-release effect with of sesame oil as a parenteral hormone vehicle.
a possible diminution of absorption. Aqueous Studies by Dekanski and Chapman (8) demon-
insolubility also precludes the use of fixed oils in strated improved intensity and duration of ac-
unemulsified intravenous products. tion of testosterone phenylpropionate and tes-
Cottonseed oil has been used in intravenous fat tosterone propionate in ethyl oleate over that of
emulsions administered to surgical patients as the same androgens in sesame oil.
reported by Lehr and co-workers (3) and a com-
merical product is available, ISOPROPYL MYRISTATE
Drugs which are incorporated in oils are mainly
The use of isopropyl myristate as a vehicle for
the steroid hormones, dimercaprol, calciferol,
parenteral injections has been reported by
and menadione. Since fixed oils contain un-
Platcow and Voss (9). I t is an oil miscible, water
saturated fatty acids, oxidative changes take
immiscible, chemically stable substance, not
place which may necessitate the use of oil soluble
susceptible to rancidity and having a specific
antioxidants such as propyl gallate, butylated
gravity of 0.852 (10). I t consists mainly of
hydroxyanisole, butylated hydroxytoluene, and
isopropyl myristate and a small amount of
tocopherols.
isopropyl esters of other saturated fatty acids.
A list of the official U.S.P. (1) and N.F. (4)
Acute toxicity studies indicate a very low order
parenteral solutions using fixed oils as solvents of toxicity, but attempts to establish an LDso in
is given in Table I.
mice failed when dosages equivalent to 100
ml./Kg. did not affect the test animals. Isopropyl
~.--OPPICIAL
TABLE INJECTIONS
IN OIL
myristate shows a very low degree of irritability
Desoxycorticosterone acetate U.S.P. and exhibits no sensitizing properties in rabbits
Dimercaprol U.S.P. and guinea pigs following topical and parenteral
Estradiol benzoate U.S.P.
Estradiol cyclopentylpropionate N.F. administration. In experiments on ovariec-
Estradiol dipropionate U.S.P. tomized rats it compared favorably with sesame
Estrone U.S.P.
Progesterone U.S.P. oil as a repository vehicle for estrogens (9). The
Tcstosterone propionate U.S.P. external pharmaceutical use has been evaluated
Diethylstilbestrol dipropionate N.F. by Donovan, et al. ( l l ) , who found it a useful
Menadione N.F.
intermediate solvent for the incorporation of
phenol, cocaine, resorcinol, and salicylic acid into
A typical intramuscular formula for a testos- liquid petrolatum.
terone propionate oil solution, 50 mg./ml., is
(5) B E N Z n BENZOATE
Gm./1000 ml.
Benzyl benzoate (12) is a colorless, oily liquid
Testosterone propionate 5o.n
Benzyl alcohol 21 .o with a pleasant aromatic odor. It has a specific
Sesame oil 869.0 gravity of 1.118, boils at 3 2 3 O , and is insoluble
in water or glycerin, but is miscible with alcohol,
Since sesame oil becomes turbid on cooling, a
chloroform, ether, and fixed oils. Its structural
“winterized” or treated oil should be used, so
formula is
that the oil remains clear when cooled to So.
ETHYL OLEATE
50% was the highest used. The author (65) also turbances (74), and weight loss (75). Hanke (76)
has given an excellent review of the physiologic
established that stability of barbiturates dissolved
in pure propylene glycol and polyethylene glycol action of glycerin.
400 was very good, and that a lowering of pH in There are, however, references to its use in
alcohol solutions decreases the rate of deteriora- human parenteral therapy. No toxic effects
tion. were noted after the administration of very small
The use of 10% polyethylene glycol 300 as a amounts of glycerin by intra-arterial administra-
solubilizing agent for a 2.5 mg./ml. injection of tion in the treatment of elephantiasis (77).
reserpine has been reported by Leyden, et al. (66). Sloviter (78, 79) reported that the intra-
Commercial reserpine products containing 10- venous administration of solutions containing 5y0
30% PEG 300, as well as 25% PEG 400, are glycerin to experimental animals and to man
available. caused no toxic or other undesirable effects.
Higuchi and Lach (67) reported that although Humans were given intravenously 50 Gm. of
pentobarbital and barbital have little or no glycerin in a liter of solution which also con-
tendency to complex with polyethylene glycols, tained 50 Gm. of glucose and 9.0 Gm. of sodium
phenobarbital forms stable and stoichiometric chloride. No disturbances of cardiorespiratory
molecular compounds with these macromolecular or central nervous system function occurred, and
substances. Analysis indicates that one pheno- no significant hemolytic effects occurred.
barbital molecule is bound by two ethylene oxide Sloviter (78,79) further stated that the previously
units of the polyether chain. They have also reported toxic effects of parenterally administered
shown that phenolic compounds are bound by the glycerin were not observed, and that there were
polyethers in the same manner, the higher molec- indications that these toxic effects were due to the
ular weight polymers exhibiting greater complex- osmotic disturbances produced by the injection
ing tendency than those of lower degrees of poly- of solutions of high glycerin concentrations. In
merization. Several organic acids, such as the dog, the rapid injection of a concentrated
salicylic acid and p-hydroxybenzoic acid, are solution produced a transient drop in blood pres-
only weakly bound. sure which the author believed to be due to a
An erythromycin ethyl succinate intramuscular peripheral vasodilating effect. It was also sug-
product in a PEG vehicle is available, as is a gested that intravenously administered glycerol
secobarbital parenteral product in a 50% PEG may be useful as a nutritional agent as well as for
vehicle. The specific PEG used was not indicated a solvent in preparations of drugs for intravenous
in either case. administration (79).
Large parenteral doses cause convulsant and
GLYCERIN paralytic symptoms through direct action on the
central nervous system. The blood corpuscles
Glycerin (68) is a clear, viscous, high-boiling are also laked, probably caused by an osmotic
liquid, which is miscible with water and alcohol effect as previously mentioned. The glycerin re-
and is a good solvent for many compounds. It is mains for a time, unabsorbed, and in high concen-
hygroscopic and will absorb several times its tration a t the site of injection, and the corpuscles
weight of water under conditions of high humidity. are probably laked during their passage through
Glycerin tends to supercool rather than crystal- this area (69).
lize at lower temperature; its aqueous solutions Lachaux (80) states that aqueous solutions of
resist freezing. up to 30% glycerin are well tolerated intra-
The toxicity (69) is low with oral administra- muscularly. Absorption is good and there is rapid
tion. No deleterious effects were observed in dilution by the body fluids.
man with 110 Gm. of glycerin per day for 50 Latven and Molitor (44)determined the intra-
days. Normal growth and reproduction occurred venous and subcutaneous toxicity in white mice.
in rats with 41% of glycerin added to the food Their results are shown in Table VII.
for 40 weeks, and in dogs with 35% added for 50
weeks. Drill (70) reports the oral LDhoin rats for TABLE VII.-ACUTE TOXICITY OF GLYCERIN
undiluted glycerin to be 25 Gm./Kg. and the
intravenous LDK,is 5 to 6 Gm./Kg. Min. Non-
There appears to be some controversy regard- LDo LDm LDiw Dose
Sympt. Sympt.
Dose
ing the use of glycerin in parenterals, as in- Subcutaneous,
dicated by reports that its administration to ml./Kg. 8 . 0 10.0 12.0 8 . 0 7.0
animals has caused hemoglobinurea (71, 72), Intravenous,
ml./Kg. 5 . 0 6 . 0 7 . 0 3.0 2.0
hypotension (73, 74) and central nervous dis-
924 Journal of Pharmaceutical Sciences
Krause and Cross (81) have found that the in 1895, has commanded little or no interest in
solubility of phenobarbital in alcohol was en- chemistry or medicine even though it is avail-
hanced by the addition of glycerin. The maxi- able commercially. Today, it is one of the most
mum solubility of phenobarbital in alcohol- widely used nonaqueous solvents.
glycerin mixtures was reached at a level of 80% Propylene glycol, 1,2-propanediol, is a viscous
alcohol and 20% glycerin. hygroscopic liquid with a specific gravity of
Linde (65), in his work on sodium salts of 1.036. It freezes at -59' and boils at 188' and
barbiturates, found that glycerin has considerably is miscible with water, acetone, and chloroform,
lower stabilizing properties than propylene but is immiscible with fixed oils. Under ordinary
glycol, polyethylene glycol, and alcohol. conditions it is very stable but at high tempera-
Husa and Jatul (82) found that after heating a tures it is oxidized t o propionaldehyde, lactic
sodium phenobarbital solution in 50% glycerin acid, pyruvic acid, and acetic acid (85,86).
for 30 minutes at 115', deterioration was 8% com- The toxicity of propylene glycol has been ex-
pared to 9% in pure water solution. tensively studied (44, 84, 87-91). Seidenfeld and
The U.S.P. (1) allows the use of glycerin in in- Hanzlik (84) reported the intravenous minimum
jections of deslanoside and digitoxin. A com- fatal dose for white rats to be 1.68 Gm./Kg. and
mercial product of deslanoside contains 15% for rabbits, 5.25 Gm./Kg. The intramuscular
glycerin. minimum fatal dose was 14.7 Gm./Kg. for rats
ETHANOL and 7.5 Gm./Kg. for rabbits. Mice are more
sensitive to propylene glycol (92) and have a
Ethanol (alcohol), ethyl alcohol, finds occa-
lower toleration for this solvent. The LDMfor
sional use in parenteral products, particularly the
mice by intraperitoneal injection was found t o be
digitalis glycosides. A commercial digitoxin
9.7 Gm./Rg. (92). The subcutaneous and intra-
preparation for intramuscular or intravenous
venous LDjo for mice was reported to be 18.5
use contains 49% alcohol. This produces pain on
Gm./Kg. and 8.0 mg./Kg., respectively (44).
intramuscular administration. The U.S.P. (1)
The action of propylene glycol on the central
states that such a product can contain 5-50y0
nervous system in dogs is similar to that of ethyl
alcohol. A digoxin preparation containing 10%
alcohol ; however, its activity is about one-third
alcohol, as allowed by the U.S.P., may be used for
that of ethyl alcohol (93).
intramuscular or intravenous administration. A
Brittain and D'Arcy (94) reported that intra-
deslanoside product containing 7.4% alcohol is
venous injections of propylene glycol in saline solu-
also available.
tion up to 50y0 in rabbits had no effect on the red
Alcohol injected subcutaneously causes con-
blood cell count, packed cell volume, hemoglobin,
siderable pain followed by anesthesia. If injec-
or total white blood cell count. There was, how-
tion is made close to nerves, neuritis and nerve
ever, an increase in the number of circulating
degeneration may occur. Injection in or near
polymorphs and a decrease in the lymphocytes.
nerves is deliberately used to cause anesthesia in
Blood clotting time was markedly decreased.
the treatment of severe pain. The intravenous
Heine, et at. (95), have given several formulas
anesthetic dose is 2-3 ml. of %yoalcohol/Kg.
illustrating the use of propylene glycol in the
(83). preparation of barbiturate solutions for intra-
Latven and Molitor (44) have reported the
muscular or intravenous use
LDa in mice to be 1973 mg./Kg. intravenously,
and 8285 mg./Kg. subcutaneously.
Sterile Solution of Sodium Pentobarbital
A commercial hydrocortisone intravenous 0.150 Gm./ml.
product contains 5Oy0 alcohol. Mephensin in- Sodium pentobarbital 15.0 Gm.
jection B.P. (1958) contains 25% alcohol, its Benzyl alcohol 2.0 ml.
formula is mephenesin 10 Gm.; alcohol (95%) 25 Propylene glycol 60.0 ml.
Water for injection, to make 100.0 ml.
ml. ; propylene glycol 15 ml.; and water, pyrogen-
free, to make 100 ml. Sterile Solution of Sodium Amobarbital
0.250 Gm./ml.
The formula for digoxin injection B.P. (1960 Sodium amobarbital 25.0 Gm.
Supplement) is digoxin 25 mg.; alcohol (80%) Benzyl alcohol 2.0 ml.
12.5 ml.; propylene glycol 40 ml.; citric acid 75 Propylene glycol 60.0 ml.
Water for injection, to make 100.0 ml.
mg.; sodium phosphate 0.45 Gm.; and water,
pyrogen-free to make 100ml. Sterile Solution of Sodium Phenobarbital
0.150 Gm./ml.
PROPYLENE GLYCOL Sodium phenobarbital 15.0 Gm.
Seidenfeld and Hanzlik (84) in 1932 stated Benzyl alcohol 2.0 ml.
Propylene glycol 60.0 ml.
that propylene glycol, which was first described Water for injection, to make 100.0 ml.
Vol. 52, No. 10, October 1963 925
Brass (96) prepared a quinidine formulation for Mehta and Drommond (106) determined the sta-
intramuscular use composed of 10.0 Gm. of bility of various medicaments in propylene glycol
quinidine hydrochloride and 75.0 ml. of propylene after storage at 25'.
glycol. This solution showed no signs of dis- Marcus and Taraszka (107) reported that the
coloration or crystallization over a period of 6 specific hydrogen ion-catalyzed degradation of
months. When injected in man, the evidence chloramphenicol in solutions containing up to
of the action of quinidine is detectable in 15 min- 50% (v/v) of propylene glycol was qualitatively
utes and persists for approximately 2 hours. similar to degradation in purely aqueous systems.
Gluck, et al. (97), tested a 20% solution of The reactions remain pseudo-first order with re-
quinidine sulfate in propylene glycol for its local spect to chloramphenicol and the direct depend-
irritant effects by intramuscular injection and ence of the rate upon acid concentration is main-
for its action on the auricle in auricular fibrilla- tained. Their results show that it is unwise to as-
tion and flutter. The results indicated negligible sume that replacement of all or a portion of the
local reaction and a dose response similar to that water in a vehicle will always enhance the sta-
obtained with oral administration-peak effect bility of the active ingredient.
being reached in an average of about 3 hours, Huttenrauch (108) has shown that propylene
about half of the effect wearing off in about 8 glycol enhances the stability of L-ascorbic acid in
hours, and the effect disappearing completely in tests run for 120 weeks at room temperature.
24 hours or less. Weinstein, et al. (log), reported that oxytetra-
The use of propylene glycol as a vehicle for the cycline intramuscular solution in propylene glycol
intravenous administration of desoxycorticos- was well tolerated and produced prompt, pro-
terone acetate in a concentration of 10 mg./ml. longed, satisfactory blood levels. A 250 mg./-
has been discussed by McGavack and Vogel (98). 2 ml. oxytetracycline intramuscular formula
Since this compound crystallizes out when diluted would be
with water, a technique is reported whereby the
preparation is injected slowly, not to exceed Oxytetracycline 250 mg.
Lidocaine 2%
a rate of 2.5 ml. per minute. This assures its Magnesium chloride, hexahydrate 6%
rapid dilution and prevents the formation of any Sodium formaldehyde sulfoxylate 0.5y0
acicular precipitate. Ethanolamine 4.270
Propylene glycol 67%
Ganz and co-workers (99) have studied the in- Water 16.870
tramuscular administration of digoxin in 40%
propylene glycol and 10% ethanol in patients This formula is stable for 2 years a t room tem-
with auricular fibrillation and reported satis- perature. Without the use of propylene glycol,
factory results. the stability is of 2-day duration only.
The comprehensiveuse of propylene glycol is re- Hanson (110) compared the amount of tissue
viewed in articles by Parisi (loo), Gialdi and reaction produced by subcutaneous and intra-
Baruffini (101), Brown (102), and Heine, et ul. muscular injections of a number of parenteral
(95). preparations of broad-spectrum antibiotics. The
Gershenfeld and W i t h (103) investigated the smallest amount of tissue reaction was produced
use of propylene glycol as a solvent for iodine by propylene glycol solutions of oxytetracycline.
and suggested that iodine 2% and sodium iodide
2.4% in distilled water containing 25 to 50% 1,3-Bu"E GLYCOL
propylene glycol would be a suitable formula.
Linde (65) reported that the stability of bar- 1,3-Butylene glycol, 1,3-butanediol, is a color-
biturates dissolved in pure or diluted propylene less, viscous liquid having a specific gravity of
glycol was satisfactory. 1.005, a boiling point of 204O, and is soluble in
Peterson and Hopponen (104) determined the water and alcohol (111). It is possible to modify
solubility of phenobarbital in propylene glycol- the effect of drugs by choosing the proper solu-
alcohol-water systems. The solubility reached bilizing agent. In this manner, we can cause an
a maximum at a 50% d u r e of propylene glycol increase or decrease in the effect of a drug.
and alcohol. Propylene glycol, loo%, dissolves Bornmann, et al. (112), demonstrated that 1,3-
more phenobarbital than 100% alcohol. Upon butylene glycol can prevent the toxic reactions of
Addition of water to the solvents, the solubility pentamethylenetetrazol. It was also shown that
falls off more quickly with propylene glycol than the action of morphine hydrochloride, meperidine
with alcohol. hydrochloride, and methadone hydrochloride in
Propylene glycol was found to potentiate the 1,3-butyleneglycol, as compared to aqueous solu-
preservative action of the parabens (105). tions, gave stronger and more prolonged effects
926 Journal of Pharmaceutical Sciences
(26) Spiegelberg H.
in a shorter time. Thus, by the use of this sol- Studer. A., ArEncimiffel-jiorsch., Schlapfer R Zbinden, G., and
6 , i.5(1$56).
vent, the dose may be lowered and undesirable (27) “Merck Index,’’ op. riI., p. 368.
(28) Davis. K., and Jenner, P. M., Toxicol. Appl. Phnr-
side effects eliminated. macol.. 1. 576(1959).
(29) Horn, H. J., ibid., 3, 12(1961).
Bornmann and Loeser ( I 13) reported on the use (30) Hammer H.F. U. S. pat. 2 980 584(1961).
(31) Graham ’1). M.’ U. S. pat. 2’990’333(1961).
of propylene glycol and 1,3-butylene glycol as (32) Glenn, E. M., U. S. pat. 3,0&5,145(1962).
solvents for meprobamate. The 1,3-butylene P’an, (33) Hammer,,H. F., Dumas, K. J., English, A. R.. and
S. Y., “Antibiotics Annual 19.58-1959 ” Med3cal En-
glycol preparation was found to be slightly more cyclopedia, Inc.. New York, N. Y., 1959, p. i44.
(34) Ciba Ltd.. Brit. pat. 886,996(1862).
toxic than the propylene glycol product, but both (35) Weiss, A. J., Mancall, E. L., Koltes, J. A,, White,
J. C.. and Jackson. L. G . . Sciqnce, 136, 151(1902).
were suitable as solvents for the drug. (38) Personal communication.
(37) Neumann, H.. and Viehmann. P.. Arsneimittel-
Bornmann (114-116) in his review of glycol Forsch.. 9, 711(1959).
(38) Dimmling. T., ibid., 9, 755(1959).
toxicity, stated that 1,3-butylene glycol had ..-, -lhid
IXR\ -.._.. -11.
-,4- 2-,
1 1.-R.,6-l \,.
(40) Seeliger, F., ibid.. 10, 423(1900).
a slight acute as well as a slight chronic toxicity. (41) Hupe, R.. Med. Klin. (Munich). 56, 1456(1961).
The LD50 suhcutaneously in mice is 16.51 d./- (42) Neumann. H.. Viehmann. P.. and Hafer.. H...U. S.
pat. 2,990,331( m i ) .
Kg. and in rats is 20.06 ml./Kg. (43) “Merck Index,’’ 09. cat., p. 432.
(44) Latven, A. R., and Molitor, H., J. Pharmacd. Ex-
ptl. Therap.. 65, 89(1939).
SUMMARY (4.5) Richter, H., U. S. pat. 2,822,316(1958).
(46) Richter, H., Ger. pat. 947,335(1956).,
(4’7!Browning, E., “Toxicity of Industnal Organic Sol-
A large number of organic solvents are currently vents, Chemical Publishing Co., Inc., New York, N. Y..
1953, p. 315.
available to the pharmaceutical formulator The (48) “Merck Index,” op. cit., p. 425.
three most commonly used nonaqueous solvents (49) Browning, E., o p . __..)
=. 212
ril n
(50) Smyth, H. F., (:arpenter, C. P.. and Weil. C. S..
are fixed oils, propylene glycol, and the poly- THIS JOURNAL, 39,34g(ia50j.
(51) “Carbowax, Polyethylene Glycols for Pharmaceuti-
ethylene glycols. The remaining solvents dis- cals and Cosmetics,” Union Carbide Chemicals Co., New
York. N. Y.. 1959.
~
cussed are of minor importance and are used only (g2) Carpenter, C. P., and Shaffer,C. B., THISJOURNAL,
in specific instances.
11. .
- - , 2711952)
- . ...-,.
(53) Smyth. H. F., Carpenter, C. P.. and Shaffer, C. B.,
ibid.. 34, 172(1945).
The use of nonaqueous solvents in parenteral (54) ShatTer, C. B., and Critchfield, F. H.. ibid., 36, 152
products offers greater latitude in the formula-
tion of new dosage forms. Such solvents, how-
ever, should be used only if a definite need is
established. It must be recognized that any
formulation containing a nonayueous solvent is
potentially a new entity and must he adequately
tested.
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\__--,_
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