session 03
session 03
By Mr. Abou
A. Isotonic Solutions.
•Osmosis
Initial level of solution at time 0
Solution
Water (solvent)
Semi-permeable membrane
At time = 0
It should be noted that if a red blood cell is immersed in water, the water moves through the cell membrane
into the cell, resulting in swelling and frequently bursting of the cell (haemolysis)
o The solvent (water) moves through the semi-permeable membrane from region of lower solute
concentration (water) to a region of higher solute concentration (cell)
On the other hand, if a red blood cell is immersed in an aqueous solution containing higher solute
concentration than the fluid in cell, water moves out of the cell causing shrinking or wrinkling of the cell
(plasmolysis)
o Again the solvent moves through the semipermeable membrane of the cell from region of lower solute
concentration (cell) to region of higher solute concentration (the surrounding aqueous solution)
In an effort to reduce pain or irritation which may accompany the administration of a solution which come
into contact with tissues or blood, many of such solutions are made isotonic.
Blood and fluids of the eye, nose and bowel are of critical concern to the pharmaceutical personnel in the
manufacture and use of preparations to be mixed with these biological fluids, which include ophthalmic
(eye), nasal (nose), parenteral (injection) and some enema (rectal) preparations
Preparation of Isotonic Solutions
•Calculations involving solutions iso-osmotic with blood and lachrymal fluids are usually based on:
o Freezing point data
o Molecular concentration
o Sodium chloride equivalent
o Graphical methods based on vapor pressure and freezing point determinations
•
•Only the first three methods will be discussed.
Calculations Based On Freezing Point Data
Colligative properties of solutions are independent of the nature of the dissolved substances, they depend
only on the number of ultimate units into which the substances breaks up in solution.
These units may be;
o Molecules – in case of substances which do not ionize
o Ions – when substances ionize completely
o Mixtures of molecules and ions – when the substances ionize partially.
The two colligative properties of interest are osmotic pressure and freezing point depression. These being
proportional to the number of units present in the solution, are proportional to one another, and the
measurement of another is therefore an indirect measurement of the other.
Determination of depression of freezing point is simpler and more accurate than direct measurement of
osmotic pressure and is therefore used to compare osmotic pressure.
The temperature at which blood plasma and tears freeze is -0.52 0C. The dissolved substances which they
contain depress the freezing point (of water) to 0.52 0C below that of water, and any other solution which
freezes at -0.520C will have the same osmotic pressure as blood plasma and tears.
Examples:
o A 1% of solution of procaine HCl freezes at -0.122 0C in order to render this solution isotonic, an adjusting
substance must be added to reduce the F.P to -0.52 0C. The proportion of adjusting substance required is that
which will produce a solution with a F.P of -0.398 0C (-0.52 - -0.1220C).
o As a general statement, the proportion of adjusting substance required is that which will lower the freezing
point by -0.520C minus the F.P depression of an unadjusted solution.
o The F.P of solutions of the same substance, provided they are fairly dilute and not very unequal in strength
are proportional to their strength.
o Thus the F.P of 0.5% w/v solution of procaine HCl may be taken as -0.061 0C i.e. half that of 1% solution
(i.e. -0.1220C /2 = -0.0610C).
•
The general formula for calculation of solutions to be rendered iso-osmotic on the blood serum therefore becomes:
% w/v of adjusting substance = 0.52 - a
b
Where;
a = figure representing the F.P depression of an unadjusted substance
b = figure representing the F.P depression of a 1% w/v solution of the adjusting
substance.
Each solute exerts its effect on the F.P independent of other items. Hence, if two or more substances are present, a = the
sum of their depressions.
Examples:
1. What concentration of procaine HCl will yield a solution iso-osmotic with blood plasma? The freezing point depression
of 1% w/v procaine HCl solution is -0.1220C.
0.52 - a
b
a= 0.00
b= -0.122
0.52-0.00 = 4.26% w/v
0.122
OR
-0.122 + X = -0.52
X = -0.52 + 0.122
= -0.398
1% w/v ………… -0.122
X w/v …………. -0.398
X = 3.26 % w/v
1% w/v + 3.26 w/v = 4.26% w/v
2. Find the concentration of NaCl required to render a 1.5% w/v solution of procaine HCl iso-osmotic with
blood plasma. The F.P depression of a 1% w/v solution of procaine HCl is -0.122 0C and that of sodium chloride
is -0.5760C.
0.52 - a
B
a = 0.183 1%w/v …….. -0.122 0C
b = 0.576 1.5%w/v ……. X
0.52 – 0.122 x 1.5/1 X = -0.183
0.56 0.52 – 0.183 = 0.585%W/V.
= 0.585%w/v 0.576
3. Rx. Ephedrine sulphate 1%
Chlorobutol 0.5%
Sodium chloride q.s
Distilled water to 25 ml
How many mg of sodium chloride should be used in preparing the isotonic solution? 140mg
F.P depressions:
Ephedrine sulphate = 0.13
Chlorobutol = 0.14
4. Calculate the amount of sodium chloride required to make 200ml of an injection containing 2% w/v
methoxamine hydrochloride iso-osmotic with blood plasma.
Given F.P depression of methoxamine HCl 1% = 0.150 0C
NaCl solution 1% = 0.5760C
0.764 g
5. Ephedrine HCl 0.25g
Chlorobutol 0.125g
Dextrose q.s
Purified water to 25ml
Make isotonic solution.
Sig. nasal drops
How many grams of dextrose should be used in compounding the prescription?
Given F.P depression ephedrine HCl 1% = 0.1650C
Chlorobutol 1% = 0.1380C
Dextrose solution 1% = 0.1010C
0.708 g
Calculations Based on Molar Concentrations:
It has been established that at standard/normal temperature and pressure (stp), a solution containing one gram
molecule of a non-ionizing solute in 22.4litres has an osmotic pressure of 1 atmosphere.
Then, it follows that, a solution containing one gram molecules in 1 litre (1 molar solution) will have an osmotic
pressure of 22.4 atmospheres, i.e. V1P1 = V2P2, P2 = (V1P1) ÷ V2
Osmotic pressure of blood plasma and lachrymal secretions is approximately 6.7 atmospheres. Therefore
molarity of the fluid is 6.7 ÷ 22.4 = 0.299 = 0.3.
1mole/litre (molar solution) = 22.4 atm.
X mol/L = 6.7 atm.
6.7atm. x 1mol/L = 0.3M
22.4 atm.
Consequently, a 0.3M solution of any non-ionizing solute will be iso-osmotic with blood plasma and tears.
Examples:
1. Find the concentration of anhydrous dextrose needed to produce a solution iso-osmotic with blood plasma.
The molecular wt. of dextrose anhydrous is 180.
W = 0.3 x M
W = conc g/L = 0.3 x Mwt.
W = conc in g/L, M = Mwt of a substance
W = 0.3 x 180 = 54g/L
W= (54/1000) x 100% = 5.4%w/v (the BP uses 5%w/v)
2. Find the concentration of boric acid required to produce a solution iso-osmotic with lachrymal secretion. Mwt
of boric acid is 62 (it is practically non-ionizing)
W = conc of boric acid = 0.3 x M
= 0.3 x 62
= 18.6g/L
= 1.86%w/v
NB: An ionizing substance will give a greater osmotic pressure than non-ionizing substance of equal weight
depending on the degree of dissociation into ions.
If a solute ionizes in solution this is assumed to be complete and the following formula is used:
W = 0.3 x M
N
Where,
M = Mwt of the solute
W = conc required in g/L
N = number of ions produced from each molecules of a solute assuming complete
dissociation.
Example:
Find the concentration of NaCl required to produce a solution iso-osmotic with blood plasma/serum. The Mwt
of NaCl is 58.5 and it dissociates into two (2) ions.
W = 0.3 x M
N
W = g/L
M = 58.5
N=2
W = 0.3 x 58.5 = 8.775 g/L
2
W= 8.8 g/L = 0.88 %w/v = 0.9 %w/v
(The BP uses 0.9%w/v, normal saline)
•Solutions that are not iso-osmotic are adjusted by adding a suitable substance such as NaCl, dextrose, etc. to
produce a total concentration of solutes equivalent to 0.3M of a non-ionizing solute.
The calculations involve three steps:
i. The effective molar concentration (EMC) of the medicament(s) is found/calculated including due allowance
for ionization if necessary.
ii. This EMC is subtracted from 0.3 to obtain the EMC of the adjusting substance.
iii. The latter is converted to g/L, again allowing for ionization if necessary.
•If the original solution contains two or more medicaments, the EMC for each is determined and the sum of
these is subtracted from 0.3 to obtain the EMC of the adjusting substance.
•
Examples:
Find the conc of dextrose required to make 0.12% solution of NaCl iso-osmotic with blood plasma.
i. EMC of NaCl
As NaCl ionizes, the formula becomes W = 0.3M
N
Substituting C (representing the EMC of the medicament for 0.3
(0.12 x 1000 / 100 = 1.2g/L)
W = 1.2g/L, M = 58.5, N = 2
1.2g/L = C x 58.5
2
C = 2.4g/L = 0.041
58.5
ii. The EMC of adjusting substance (dextrose)
0.3 – 0.041
EMC = 0.259
Example:
The F.P depression of 1% ascorbic acid solution is 0.1050C
The F.P depression of 1% NaCl solution is 0.5760C
Sodium chloride equivalent of ascorbic acid = 0.1050C
0.5760C
= 0.18
Since the F.P depression of many medicaments is not proportional to the solute concentration, the NaCl equivalents in the table have usually been calculated
for several concentrations i.e. 0.5%, 1%, 2%, 3%, and 5%, and the one nearest to the strength of the medicament that requires adjustment is used.
To find the concentration of NaCl to render a solution of a given medicament iso-osmotic with body fluids:
Look upon the table of the NaCl equivalents for the strength of solution nearest to the strength of the
medicament in the preparation
Multiply this by the strength of the medicament
Subtract the result from 0.9% (conc of NaCl iso-osmotic with blood plasma)
The difference is the strength of NaCl necessary to adjust the solution to iso-osmoticity.
i.e.
% of NaCl required = 0.9% - (% of medicament x NaCl equivalent of the medicament)
TABLE: SODIUM CHLORIDE EQUIVALENTS
Examples:
1. Calculate the % of NaCl required to render 0.5% potassium chloride solution iso-osmotic with blood plasma.
% of NaCl required = 0.9% - (0.5 x 0.76)
= 0.9 - 0.38
% of NaCl required = 0.52%
When adjustment is made with a substance other than NaCl, first, calculate the % of NaCl and then divide the
answer by the NaCl equivalent of the chosen adjusting substance.
2. Calculate the % of anhydrous dextrose required to render a 1% solution of ephedrine HCl iso-osmotic with body fluids.
2. Calculate the % of NaCl needed to make an injection containing morphine sulphate 1%,
hyoscine HBr 0.04% and sodium metabisulphate 0.1% iso-osmotic with blood plasma.
3. Rx.
Cocaine HCl 0.6g
Eucaptropine 0.6g
Chlorbutol 0.1g
Boric acid q.s
Purified water a.d 30 Ml
Make isotonic solution for the eye
How many grams of boric acid should be used in compounding the prescription?
Given: sod. Chloride equivalent
Cocaine HCl = 0.16
Eucaptropine = 0.18
Chlorbutol = 0.24
Boric acid = 0.52
4. Rx.
Ephedrine sulphate 0.5%
Tetracycline HCl 0.5%
Dextrose q.s
Purified water ad 30mL
On the basis of 40% dissociation, 100 particles of zinc sulfate will yield:
40 zinc ions
40 sulfate ions
60 undissociated particles
or 140 total particles
Because 140 particles represent 1.4 times as many particles as were present before dissociation, the dissociation (i) factor is
140 = 1.4, answer.
100
2. Zinc chloride is a 3-ion electrolyte, dissociating 80% in a certain concentration. Calculate its dissociation (i) factor.
On the basis of 80% dissociation, 100 particles of zinc chloride will yield:
80 zinc ions
80 chloride ions
80 chloride ions
20 undissociated particles
or 260 total particles
Because 260 particles represents 2.6 times as many particles as were present before dissociation, the dissociation (i) factor is
260 = 2.6, answer.
100
To calculate the NaCl equivalents of substance:
Example:
1. Papaverine hydrochloride (Mwt. 376) is a 2-ion electrolyte, dissociating 80% in a given concentration. Calculate its sodium chloride equivalent.
Because papaverine hydrochloride is a 2-ion electrolyte, dissociating 80%, its i factor is 1.8.
2. Calculate the sodium chloride equivalent for glycerin, a nonelectrolyte with a molecular weight of 92.
Glycerin, i factor = 1.0
58.5 x 1.0 = 0.35, answer.
1.8 92
3. Calculate the sodium chloride equivalent for Timolol maleate, which dissociates into two ions and has a molecular weight of 432.2
Timolol maleate, i factor = 1.8
58.5 x 1.8 = 0.14, answer.
1.8 432
Note: most medicinal salts approximate the dissociation of sodium chloride in weak solutions. If the number of ions is known, we may use the
following values, lacking better information:
Nonelectrolytes 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
The procedure for the calculation of isotonic solutions with sodium chloride equivalents may be outlined as follows:
Step 1. Calculate the amount (in grams) of sodium chloride represented by the ingredients in the prescription. Multiply the amount (in grams) of
each substance by its sodium chloride equivalent.
Step 2. Calculate the amount (in grams) of sodium chloride, alone, that would be contained in an isotonic solution of the volume specified in the
prescription, namely, the amount of sodium chloride in a 0.9% solution of the specified volume. (Such a solution would contain 0.009 g/mL.)
Step 3. Subtract the amount of sodium chloride represented by the ingredients in the prescription
(Step 1) from the amount of sodium chloride, alone, that would be represented in the specific volume of an isotonic solution (Step 2). The answer
represents the amount (in grams) of sodium chloride to be added to make the solution isotonic.
Step 4. If an agent other than sodium chloride, such as boric acid, dextrose, or potassium nitrate, is to be used to make a solution isotonic, divide
the amount of sodium chloride (Step 3) by the sodium chloride equivalent of the other substance.
•Examples:
1. How many grams of sodium chloride should be used in compounding the following prescription?
Rx. Pilocarpine Nitrate 0.3 g
Sodium Chloride q.s.
Purified Water ad 30 mL
Make isotonic. sol.
Sig. For the eye.
Step 1. 0.23 x 0.3 g = 0.069 g of sodium chloride represented by the pilocarpine nitrate
Step 2. 30 x 0.009 = 0.270 g of sodium chloride in 30 mL of an isotonic sodium chloride solution
Step 3. 0.270 g (from Step 2)
-0.069 g (from Step 1)
0.201 g of sodium chloride to be used, answer.
1. How many grams of boric acid should be used in compounding the following prescription?
Rx. Phenacaine Hydrochloride 1%
Chlorobutanol 1
⁄ 2%
Boric Acid q.s.
Purified Water ad 60mL
Make isoton. sol.
Sig. One drop in each eye.
The prescription calls for 0.6 g of phenacaine hydrochloride and 0.3 g of chlorobutanol.
Step 1. 0.20 x 0.6 g = 0.120 g of sodium chloride represented by phenacaine hydrochloride
0.24 x 0.3 g = 0.072 g of sodium chloride represented by chlorobutanol
Total: 0.192 g of sodium chloride represented by both ingredients
Step 2. 60 x 0.009 = 0.540 g of sodium chloride in 60 mL of an isotonic sodium chloride sol.
Step 3. 0.540 g (from Step 2)
- 0.192 g (from Step 1)
0.348 g of sodium chloride required to make the solution isotonic
But because the prescription calls for boric acid:
Step 4. 0.348 g ÷ 0.52 (sodium chloride equivalent of boric acid) = 0.669 g of boric acid to be used, answer.
Activity 3.2: Individual Assignment
1. How many grams of potassium nitrate could be used to make the following prescription isotonic?
Rx. Sol. Silver Nitrate 60ml, 1:500 w/v
Make isoton. sol.
Sig. For eye use. 0.86 g
2. How many grams of sodium chloride should be used in compounding the following prescription?
Rx. Ingredient X 0.5
Sodium Chloride q.s.
Purified Water ad 50mL
Make isoton. sol.
Sig. Eye drops.
0.32 g
A. Electrolyte Solutions:
Milliequivalents
Millimoles
Milliosmoles
•
•Intro:
The molecules of chemical compounds in solution may:
o remain intact as molecules, or
o they may dissociate into particles known as ions, which carry an electric charge.
•
Substances that are not dissociated in solution are called nonelectrolytes, e.g. Urea and dextrose
Substances with varying degrees of dissociation are called electrolytes, e.g. sodium chloride
Electrolyte ions in the blood plasma include:
Cations Anions
Na+ Cl-
K+ HCO3-
Ca++ HPO4- -
Mg++ SO4- -
organic acids(-)
protein(-)
Electrolytes in body fluids play an important role in
Maintaining the acid-base balance in the body
controlling body water volumes and
regulating body metabolism
•
Electrolyte preparations are used in the treatment of disturbances of the electrolyte and fluid balance in the
body.
In clinical practice, they are provided in the form (dosage forms) of
oral solutions and syrups,
dry granules intended to be dissolved in water or juice to make an oral solution,
oral tablets and capsules and,
when necessary, as intravenous infusions.
Milliequivalents (mEq)
A chemical unit, the milliequivalent (mEq), is now used by clinicians, physicians, pharmacists, and manufacturers to express the
concentration of electrolytes in solution.
This unit of measure is related to the total number of ionic charges in solution, and it takes note of the valence of the ions. i.e., it is a unit
of measurement of the amount of chemical activity of an electrolyte.
Under normal conditions, blood plasma contains 154 mEq of cations and an equal number of anions
The total concentration of cations always equals the total concentration of anions. Any number of milliequivalents of Na+, K+, or any
cation+ always reacts with precisely the same number of milliequivalents of Cl-, HCO 3- - or any anion-.
For a given chemical compound, the milliequivalents of cation equals the milliequivalents of anion equals the milliequivalents of the
chemical compound.
A milliequivalent represents the amount, in milligrams, of a solute equal to 1⁄1000 of its gram equivalent weight, taking into account the
valence of the ions.
The gram equivalent weight of an ion – is the ionic weight (the sum of the atomic weights of elements in an ion) in grams divided by the
valence of that ion.
The mEq is one thousands part of the gram equivalent weight and is therefore the same figure in milligrams (mg)
• 1mEq = ionic wt in mg
• Valency
The milliequivalent expresses the chemical activity or combining power of a substance relative to the activity of 1 mg of hydrogen.
Thus, based on the atomic weight and valence of the species, 1 mEq is represented by 1 mg of hydrogen, 20 mg of calcium, 23 mg of
sodium, 35.5 mg of chlorine, 39 mg of potassium, and so forth.
Ion Ionic wt Gram equivalent wt=ionic wt ÷valency Wt of 1mEq (in mg)
Na+ 23 23 23
K+ 39 39 39
Ca++ 40 20 20
Cl- 35.5 35.5 35.5
HCO3- 61 61 61
HPO4- - 96 48 48
CATIONS ANIONS
K+ Na+ Mg2+ Cl- HPO42-
30 30
10 10
10 10
5 5
= 55 = 55
To convert quantities expressed in mEq per litre into weighable quantities, the following formulae may be
used, whereby
• W = the mg of the salt containing 1mEq of the required ion
• E = the number of mEq per litre
Soln.
Wt of NaCl = W x E = 70 x 58.5 = 4095mg = 4.095g
KCl = W x E = 2 x 74.5 = 149mg = 0.149g
CaCl2.2H2O = W x E = 4 x 73.5 = 294mg = 0.294g
I.e. g/L = W x E
1000
Hence the formula becomes
Sodium Chloride 4.095g
Potassium Chloride 0.149g
Calcium chloride 0.294g
Water for inj. to 500mL
2. Express the following formula as %w/v
Rx. Na+ 147mEq
K+ 4mEq
Ca++ 4mEq
Cl- 155mEq
Water of inj. to 1 litre
Soln.
Conversion eqn. = W x E
10,000
%w/v NaCl = 58.5 x 147 = 0.860g = 0.860%w/v
10,000
KCl = 74.5 x 4 = 0.0298g = 0.030g = 0.030%w/v
10,000
CaCl = 73.5 x 4 = 0.0294g= 0.029%w/v
10,000
Formula becomes,
Sodium chloride 0.860%w/v
Potassium chloride 0.030%w/v
Calcium chloride 0.029%w/v
Water for inj. to 1 litre
To convert %w/v tp mEq per litre, the number of g per 100ml (C) is converted to mg per litre by multiplying by
10,000. This divided by the weight (W) in mg of the salt containing 1mEq, will give the number of mEq per litre.
Or, by rearranging the formula for conversion
%w/v = W x E
10,000
Hence, C = W x E , W x E = C x 10,000
10,000
E = C x 10,000
W
• Example;
Express 0.9%w/v sodium chloride solution in mEq per litre.
E = C x 10,000
W
= 0.9 x 10,000 = 153.85mEq = 154mEq
58.5
Note
When the unit of mEq is used, it can be seen that the total number of cations exactly balances the total number
of anions and it is clear that if a disorder arises in the body, the aim of formulating the preparations for the
treatment will be to restore this balance as closely as possible.
• Average Normal Composition Of Blood Plasma Electrolytes In mEq/L
CATIONS mEq/L ANIONS mEq/L
Na+ 142 Cl- 103
K+ 5 HCO3 27
Ca++ 5 HPO4- - 2
Mg++ 3 SO4- - 1
Organic acids - 6
Proteins - 16
= 155mEq/L = 155mEq/L
The table also shows that the cation Na+ can balance all the inorganic anions thus indicating its great
importance in the body.
Adjustment to isotonicity with blood plasma on
milliequivalents:
It will be clear from the table above that a solution isotonic with blood plasma contains 155mEq each of cations and anions. I.e. it has an ionic conc of 310mEq per litre.
Thus provides a further method for calculating the adjustment required to make the solution isotonic with blood plasma.
The equation used is
b = 310 – a
Where, a = number of mEq per litre of medicament present
b = number of mEq per litre of adjusting substance
Example;
Calculate the amount of NaCl required to adjust a solution containing 40mEq each of K+ and Cl- ions per litre to isotonicity with blood plasma.
Soln.
A solution containing 40mEq of K+ and 40mEq of Cl- provides a total of 80mEq of cations and anions (total ionic conc)
b = 310 – a
b= 310 – 80
b= 230mEq each of Na+ and Cl-
230mEq will be provided by 115mEq Na+ and 115mEq Cl-.
The formula for the solution will be
KCl = 74.5 x 40 = 2980mg =2.98g
NaCl = 58.5 x 115 = 6727.5mg = 6.73g