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PARENTERAL PRODUCTS
A. SOLUBILIZATION
Solubilization is a very important subject in the field of pharmacy for the
preparation of solutions from sparingly soluble drugs.
This concept is even more important for preparing parentral and ophthalmic
solutions. Solubilization can be achieved by several approaches including:
1. Salting in (Hydrotropy) where salts of organic acids such as sodium or
potassium citrate, acetate, benzoate …etc are used to increase the solubility
of non-electrolyte.
2. Complex formation where a third substance other than the sparingly soluble
drugs and the solvent is added to form a soluble complex.
3. Surface active agents above their critical micelle concentration where the
water insoluble drugs are enclosed inside the hydrophobic core of the
formed submicroscopic micelles.
B. ISOTONIC SOLUTION
When a solvent passes through a semipermeable membrane from a dilute solution
into a more concentrated one with the result that the concentrations tend to become
equalized, the phenomenon is known as osmosis. The pressure responsible for this
phenomenon is called osmotic pressure, and it proves to be caused by, and to vary
with the number of the solute particulate in solution.
1. If the solute is a non-electrolyte, its solution will contain only molecules,
and the osmotic pressure of the solution will vary only with the
concentration of the solute.
2. If, on the other hand, the solute is an electrolyte, its solution will contain
ions, and the osmotic pressure of the solution will vary not only with the
concentration but also with the degree of dissociation of the solute.
Obviously then, substances that dissociate have a relatively greater number
of particles in solution and should exert a greater osmotic pressure than
could undissociated molecules.
Like osmotic pressure, the other colligative properties of solutions, namely, vapor
pressure; boiling point, and freezing point, depend upon the number of particles in
solution. These properties, therefore, are related, and a change in any of them will
be accompanied by corresponding changes in the others.
It is generally agreed that many solutions to be mixed with body fluids should have
the same osmotic pressure, in other words, should be made isotonic with those
fluids for greater comfort, efficacy, and safety. Solutions of lower osmotic pressure
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than that of a body fluid are hypotonic, whereas those having a higher osmotic
pressure are hypertonic.
Blood and the fluids of the eye and nose have so far been principally concerned in
this matter, and of these the pharmacist is most likely to be asked to make
ophthalmic solutions, isotonic with lachrymal fluid.
The calculations involved in preparing isotonic solutions may be made in terms of
data related to the colligative properties of solutions.
METHODS OF CALCULATION:
1. Freezing – Point Depression Method:1. The freezing point depressions of a number of drug solutions determined
experimentally or theoretically are given in table 1.
2. When one gram molecular weight of any non-electrolyte, that is a substance
with negligible dissociation such as boric acid is dissolved in 1000 g of
water, the freezing point of the solution is about 1.86⁰C below the freezing
point of pure water.
3. By simple proportion, therefore, we may calculate the weight of any nonelectrolyte that should be dissolved in each 1000 g of water if the solution is
to be isotonic with the body fluids.
1. Preparation of isotonic solution of non-electrolyte:
Boric acid, for example, has a molecular weight of 6l.8, and hence (in theory) 61.8
g in 1000 g of water should produce a freezing point depression of 1.86⁰C.
Therefore,
℃
61.8 𝑔
1.86
=
0.52 ℃
𝑥𝑔
𝑥 = 17.3 𝑔
In short, 17.3 g of boric acid in 1000 g of water, having a weight-in-volume
strength of approximately 1.73%, should make a solution isotonic with lachrymal
fluid.
2. Preparation of isotonic solution of electrolyte:
Since osmotic pressure depends on the number of particles, substances that
dissociate have a tonic effect that increases with the degree of dissociation and the
greater the dissociation, the smaller the quantity required to produce any given
osmotic pressure.
If we assume that sodium chloride in weak solutions is about 80% dissociated, then
each 100 molecules yield 180 particles, or 1.8 times as many particles as are
yielded by 100 molecules of a non- electrolyte. This dissociation factor, commonly
symbolized by the letter “i”, must be included in the proportion.
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Summary Table of Isotonic Values *
Substance
Alcohol, dehydrated
Aminophylline
Ammonium chloride
Amphetamine sulfate (Benzedrine sulfate)
Antipyrine
Antistine hydrochloride (Antazoline hydrochloride)
Apomorphine hydrochloride
Ascorbic acid
Atropine sulfate
Aureomycin hydrochloride
Barbital sodium
Benadryl hydrochloride (Diphenhydramine hydrochloride)
Boric acid
Butacaine sulfate (Bulyn sulfate)
Bafileine
Calleine and sodium benzoate
Calcium chloride.2H2O
Calcium gluconate
Calcium lactate
Camphor
Chloramphenicol (Chloromycetin)
Chlorobutanol (Chloretone)
Cocaine hydrochloride
Cupric sulfate.5H2O
Dextrose.H2O
Dibucaine hydrochloride (Nupercaine hydrochloride)
Emelina hydrochloride
Ephedrine hydrochloride
Ephedrine sulfate
Epinephrine bitartarate
Epinephrine hydrochloride
Ethylhydrocupreine hydrochloride (Optochin)
Ethylmorphine hydrochloride (Dionin)
Eucatropine hydrochloride (Euphthalmine hydrochloride)
Fluorescein sodium
Glycerin
Homotropine hydrobromide
Lactose
Magnesium sulfate.7H2O
Menthol
Meperidine hydrochloride (Demerol hydrochloride)
Mercuric chloride (Mercuric bichloride)
Mercuric cyanide
Mercuric succinimide
Methacoline chloride (Mecholyl chloride)
Methamphetamine hydrochloride (Desoxyephedrine
hydrochloride)
Melycaine hydrochloride
Mild silver protein
Morphine hydrochloride
Morphine sulfate
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M
E
V
∆T1%
Liso
46.07
456.46
53.50
368.49
188.22
301.81
312.79
176.12
694.82
544
206.18
291.81
61.84
710.95
194.19
147.03
448.29
308.30
152.23
323.14
177.47
339.81
249.69
198.17
379.92
553.56
201.69
428.53
333.29
219.66
376.92
385.88
327.84
376
92.09
356.26
360.31
246.50
156.26
283.79
271.52
252.65
396.77
195.69
0.70
0.17
1.08
0.22
0.17
0.18
0.14
0.18
0.13
0.11
0.29
0.20
0.50
0.20
0.08
0.25
0.51
0.16
0.23
0.20
0.10
0.24
0.16
0.18
0.16
0.13
0.10
0.30
0.23
0.18
0.29
0.17
0.16
0.18
0.31
0.34
0.17
0.07
0.17
0.20
0.22
0.13
0.15
0.14
0.32
23.3
5.37
36
7.3
5..7
6.0
4.7
6.0
4.3
3.7
10.0
6.6
16.7
6.7
2.7
8.7
17.0
5.3
7.7
6.7
3.3
8.0
5.3
6.0
5.3
4.3
3.3
10.0
7.7
6.0
9.7
5.7
5.3
6.0
10.3
11.3
5.7
2.3
5.7
6.7
7.3
4.3
5.0
4.8
10.7
0.41
0.10
0.64
0.13
0.10
0.11
0.08
0.11
0.07
0.06
0.29
0.34
0.29
0.12
0.05
0.79
0.30
0.09
0.14
0.12
0.06
0.14
0.09
0.11
0.09
0.08
0.06
0.18
0.14
0.11
0.17
0.10
0.09
0.11
0.18
0.20
0.10
0.04
0.10
0.12
0.12
0.08
0..09
0.08
0.19
1.9
4.6
3.4
4.8
1.9
3.2
2.6
1.9
5.3
3.5
3.5
3.4
1.8
8.4
0.9
4.4
4.2
4.2
1.8
1.9
2.5
3.2
2.6
1.9
2.9
3.3
3.6
5.8
3.5
3.7
3.8
3.6
3.5
6.9
1.8
3.6
1.7
2.5
1.8
3.7
2.1
2.2
3.3
3.7
185.69
0.37
12.3
0.22
4.0
292.82
375.84
758.82
0.20
0.18
0.15
0.14
6.7
6.0
5.0
4.8
0.12
0.11
0.09
0.088
3.4
3.3
6.2
Substance
Neomycin sulfate
Neostigmine bromide (Prostigmine bromide)
Nicotinamide
Penicillin G potassium
Penicillin G procaine
Penicillin G sodium
Phenacaine hydrochloride (Holocaine hydrochloride)
Phenobarbital sodium
Phenol
Phenylephrine hydrochloride (Neosynephrine hydrochloride)
Physostigmine salicylate
Physostigmine sulfate
Pilocarpine nitrate
Potassium acid phosphate (KH2PO4)
Potassium chloride
Potassium iodide
Privine hydrochloride
Procaline hydrochloride
Quinine hydrochloride
Quinine and urea hydrochloride
Scopolamine hydrobromide (Hyoscine hydrobromide)
Silver nitrate
Sodium acid phosphate (NaH2PO4.H2O)
Sodium benzoate
Sodium bicarbonate
Sodium bisulfite
Sodium borate.10H2O
Sodium chloride
Sodium iodide
Sodium nitrate
Sodium phosphate, anhydrous
Sodium phosphate.2H2O
Sodium phosphate.7H2O
Sodium phosphate.12H2O
Sodium propionate
Sodium sulfite, exsiccated
Streptomycin sulfate
Strong silver protein
Sucrose
Sulfacetamide sodium
Sulfadiazine sodium
Sulfamerazine sodium
Sulfanilamide
Sulfathiazole sodium
Tannic acid
Tetracaine hydrochloride (Pontocaine hydrochloride)
Tetracycline hydrochloride
Pyribenzamine hydrochloride
Urea
Zinc chloride
Zinc phenolsulfonate
Zinc sulfate.7H2O
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M
E
V
∆T1%
Liso
303.20
122.13
372.47
588.71
356.38
352.85
254.22
94.11
203.67
413.46
648.45
271.27
136.13
74.55
166.02
246.73
272.77
396.91
547.48
438.32
169.89
138.00
144.11
84.00
104.07
381.43
58.45
149.92
85.01
141.98
178.05
268.08
358.21
96.07
126.06
1457.44
342.30
254.25
272.27
286.29
172.21
304.33
300.82
480.92
291.83
60.06
139.29
555.84
287.56
0.11
0.22
0.26
0.18
0.10
0.18
0.20
0.24
0.35
0.32
0.16
0.13
0.23
0.43
0.76
0.34
0.27
0.21
0.14
0.23
0.12
0.33
0.40
0.40
0.65
0.61
0.42
1.00
0.39
0.68
0.53
0.42
0.29
0.22
0.61
0.65
0.07
0.08
0.08
0.23
0.24
0.23
0.22
0.22
0.03
0.18
0.14
0.30
0.59
0.62
0.18
0.15
3.7
6.0
8.7
6.0
3.3
6.0
5.3
8.0
11.7
9.7
5.3
4.3
7.7
14.2
25.3
11.3
7.7
7.0
4.7
7.7
4.0
11.0
13.3
13.3
21.7
20.3
14.0
33.3
13.0
22.7
17.7
14.0
9.7
7.3
20.3
21.7
2.3
2.7
2.7
7.7
8.0
7.7
7.3
7.3
1.0
6.0
4.7
7.3
19.7
20.3
6.0
5.0
0.06
0.11
0.15
0.11
0.06
0.11
0.11
0.14
0.20
0.18
0.09
0.08
0.14
0.25
0.45
0.20
0.16
0.12
0.08
0.14
0.07
0.19
0.24
0.24
0.38
0.36
0.25
0.58
0.23
0.39
0.31
0.25
0.17
0.13
0.36
0.38
0.04
0.05
0.05
0.14
0.14
0.14
0.13
0.13
0.02
0.11
0.08
0.17
0.35
0.37
0.11
0.09
3.2
1.9
3.9
3.5
3.8
3.3
3.6
1.9
3.5
3.9
5.0
3.7
3.4
3.3
3.3
3.3
3.4
3.3
7.4
3.1
3.3
3.2
3.4
3.2
3.7
9.4
3.4
3.4
3.4
4.4
4.4
4.6
4.6
3.4
4.8
6.0
1.6
3.4
3.8
3.9
2.2
3.9
3.2
4.0
3.8
2.1
5.1
5.9
2.5
* M is the molecular weight of the drug.
E is the sodium chloride equivalent of the drug
V is the volume in ml isotonic solution that can be prepared by adding water to 0.3
of the drug (the weight of drug in 1 fluid ounce of a 1% solution).
ΔTf1% is the freezing point of a 1% solution of the drug.
Liso is the molar freezing point depression of the drug at a concentration
approximately isotonic with blood and lacrimal fluid
The values in the abovementioned table have been obtained from the data of
Hammarlund and Pedersen- Bjergaard, J. Am. Pharm. Assoc Pract. Ed.19, 39,
1959; ibid set. Ed, 47, 107, 1958, and other sources. The values vary somewhat
with concentration, and those in the table are for 1 to 3% solutions of the drugs in
most instances. A complete table of E and ΔTf values is found in the Merck index,
9th Edition, Merck, rahway. Nj. 1978.
Isotonic solution of sodium chloride (molecular weight, 58.5) is calculated as:
1.86 ℃ 𝑥 1.8 58.5 𝑔
=
0.52 ℃
𝑥𝑔
𝑥 = 9.09 𝑔
Hence, 9.09 g of sodium chloride in 1000 g of water should make a solution
isotonic with blood or lachrymal fluid. Actually, a 0.90% (w/v) sodium chloride is
taken to be isotonic with the body fluids.
a. The value of "i" for many medicinal salts has not been experimentally
determined. Some salts (such as zinc sulfate, with only some 40%
dissociation and an i value therefore of 1.4) are exceptional.
b. but most medicinal salts approximate the dissociation of sodium chloride in
weak solutions, and if the number of ions is known we may use the
following values, lacking better information.
Non-electrolytes and substances of slight dissociation: 1.0
Substances that dissociate Into 2 ions:
1.8
Substances that dissociate into 3 ions:
2.6
Substances that dissociate into 4 ions:
3.4
Substances that dissociate into 5 ions:
4.2
3. Adjusting the Isotonicity of Hypotonic Solutions:
Example:
How much sodium chloride is required to render 100 ml of a 1% solution of
apomorphine hydrochloride isotonic with blood serum?
Solution:
From the previous table, it is found that a 1% solution of the drug has a freezing
point lowering of 0.08⁰C. To make this solution isotonic with blood, sufficient
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sodium chloride must be added to reduce the freezing point by an additional 0.44⁰C
(0.52 - 0.08). In the freezing point table, it is also observed that a 1% solution of
sodium chloride has a freezing point lowering of 0.58. By the method of
proportion,
1% 0.5 8℃
=
𝑥
0.44 ℃
𝑥 = 0.76%
Thus 0.76% sodium chloride will lower the freezing point the required 0.44 o and
will render the solution isotonic. The solution prepared by dissolving 1.0 g of
apomorphine hydrochloride and 0.76 g of sodium chloride in sufficient water to
make 100 ml of solution.
2. Sodium Chloride Equivalent Method:
The sodium chloride equivalent, of a drug is the amount of sodium chloride that
has the same Osmotic effect as 1 gram of the drug. The sodium chloride
equivalents E for a number of drugs are listed in the previous table.
Calculations for determining the amount of sodium chloride or other inert
substance to render a solution isotonic simply involve:
a. Multiplying the quantity of each drug in the prescription by its sodium
chloride equivalent.
b. Calculating the amount of sodium chloride that renders the whole
prescription volume isotonic.
c. Subtract the value in step (a) from that in step b give the amount of sodium
chloride must be added.
d. If the isotonicity is to be adjusted with some other inert substance the
calculated NaCl amount in the previous step is converted to the inert
substance using its NaCl equivalent value.
Example:
A solution contains 1.0 g ephedrine sulphate in volume of 100 ml. What quantity
of sodium chloride must be added to make the solution isotonic? How much
dextrose would be required for this purpose?
Solution:
The quantity of the drug is multiplied by its sodium chloride equivalent E, giving
the weight of sodium chloride to which:
1. The quantity of drug is equivalent in osmotic pressure to:
1.0 g x 0.23 = 0.23 g of NaCl
2. The total sodium chloride required for isotonicity is 0.9 g/100 ml (the
prescription volume).
3. The amount of NaCl required to be added to adjust the isotonicity of the
prescription:
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0.9 - 0.23 = 0.67 g of NaCl must be added.
If one desired to use dextrose instead of sodium chloride to adjust the tonicity, the
quantity would be estimated by setting the following proportion. Since the sodium
chloride equivalent of dextrose is 0.16.
1 𝑔 𝑑𝑒𝑥𝑡𝑟𝑜𝑠𝑒
𝑥
=
0.16 𝑔 𝑁𝑎𝐶𝑙
0.67 𝑔 𝑁𝑎𝐶𝑙
𝑥 = 4.2 𝑔 𝑑𝑒𝑥𝑡𝑟𝑜𝑠𝑒
3. White-Vincent Method:
1. This method involves the addition of water to the drugs to make an isotonic
solution.
2. Followed by the addition of an isotonic or isotonic -buffered diluting vehicle
to bring the solution to the final volume. Stimulated by the need to adjust the
pH in addition to the tonicity of ophthalmic solutions, White and Vincent
developed a simplified method for such calculations.
The derivation of the equation is best shown as follows:
Suppose that one wishes to make 30 ml of a 1% solution of cocaine hydrochloride
isotonic with body fluid.
* First, the weight of the drug W is multiplied by sodium chloride equivalent E:
0.3 g x 0.16 = 0.048 g.
This is the quantity of sodium chloride osmotically equivalent to 0.3 g of cocaine
hydrochloride.
* Second it is known that 0.9 g of sodium chloride, when dissolved in enough
water to make 100 ml, yields a solution that is isotonic. The volume V of isotonic
solution that can be prepared from 0.048 g of sodium chloride in obtained by
solving the proportion:
0.9 𝑔
0.048 𝑔
=
100 𝑚𝑙
𝑉
100
𝑉 = 0.048 𝑥
0.9
𝑉 = 0.048 𝑥 111.1
𝑉 = 5.3 𝑚𝑙
The quantity 0.048 is equal to the weight of drug W multiplied by the sodium
chloride equivalent E:
.: V = W x E x 111.1
In which V is the volume in ml of isotonic solution that may be prepared by
mixing the drug with water. 111.1, represents the volume in ml of isotonic solution
obtained by dissolving 1 g of sodium chloride in water.
The problem may be solved in one step as follows:
V = 0.3 x 0.16 x 111.1 = 5.3 ml
7
* In order to complete the isotonic solution, enough isotonic sodium chloride,
another isotonic solution, or an isotonic-buffered diluting solution is added to make
30 ml of the finished product.
When more than one ingredient is contained in an isotonic preparation, the
volumes of isotonic solution, obtained by mixing each drug with water, are
additive.
Example:
Make the following solution isotonic with lachrymal fluid.
Phenacaine hydrochloride
0.06 g
Boric acid
0.30 g
Sterilized distilled water
QS
Solution:
V = (0.06 x 0.2) + (0.3 x 0.50) x 111.1 = 18 ml
The drugs are mixed with water to make 18 ml of an isotonic solution, and the
preparation is brought to a volume of 100 ml by an isotonic diluting solution.
4. The Sprowls Method:
It is a simplification of the method of White and Vincent. The equation (V = W x E
x 111.1) was used to construct a table of values of V when the weight of the drug
W was fixed to 0.3 g (the quantity of a drug per fluidounce of a 1 % solution). The
volume V of isotonic solution that can be prepared by mixing 0.3 g of a drug with
sufficient water may be computed for drugs commonly used in ophthalmic and
parentral solutions (see the table). The primary quantity of isotonic solution is
finally brought to the specified volume with the desired isotonic or isotonicbuffered diluting solutions.
8
PROBLEMS
1. What proportion of procaine hydrochloride will yield a solution isotonic with
blood plasma?
F.P.D of 1% W/V solution of procaine HCL is
0.122.
F.P.D of a 1% W/V solution of NaCl is
0.576
2. Find the proportion of sodium chloride required to render a 1% solution of
cocaine hydrochloride isotonic with blood plasma F.P.D of 1% solution of cocaine
HCl is 0.09.
3. Find the proportion of sodium chloride required to render a 1.5% solution of
procaine hydrochloride isotonic with blood plasma F.P.D a 1% W/V solution of
procaine HCl is 0.122.
9
4. Find the amount of sodium chloride necessary to be included in 100 ml of 0.3
per cent solution of zinc sulfate so that, on dilution with an equal quantity of water,
it will be isotonic with lachrymal secretion. F.P.D of a 1% solution of zinc sulfate
is – 0.086.
5. A 1 fluidounce solution contains 4.5 grains of silver nitrate. How much sodium
nitrate must be added to this solution to make it isotonic with nasal fluid? Assume
nasal fluid as an isotonic value of 0.9 gram of NaCl/100ml.
10
6. How much boric acid should be used in compounding the following prescription
to render it isotonic with lachrymal fluid?
Rx
Holocaine hydrochloride
1%
Chlorobutanol
0.5%
Distilled water ad
60 ml
7. Give a formula for 8 ounce of a solution containing 1/8 grain of morphine
hydrochloride in 5 minims, rendered isotonic with blood plasma using sodium
chloride. For the purpose of comparison, this problem should be worked out by all
methods.
11
8. Rx
Ephedrine sulfate
Sodium chloride
Distilled water ad
Make isotonic solution.
How many grains of
prescription?
gr. iv
q.s.
℥i
sodium chloride should be used in compounding the
9. How much sodium chloride should be used in compounding the following
prescription?
Rx
Dionin
1/2%
Scopolamine hydrobormide
1/3%
Sodium Chloride
q.s
Distilled water ad
30.0 ml
12
10. How much sodium chloride should be used in compounding the following
prescription?
Rx
Cocaine HCl
0.6 g
Eucatropine HCl
0.6 g
Chlorobutanol
0.1 g
Sod. Chloride
q.s
Distilled Water ad
30 ml
13