Parenteral Products

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 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 non- electrolyte 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,

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.

Summary Table of Isotonic Values *

Isotonic solution of sodium chloride (molecular weight, 58.5) is calculated as:

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.

1. 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.
2. 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 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,

Thus 0.76% sodium chloride will lower the freezing point the required 0.44o 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:

1. Multiplying the quantity of each drug in the prescription by its sodium chloride equivalent.
2. Calculating the amount of sodium chloride that renders the whole prescription volume isotonic.
3. Subtract the value in step (a) from that in step b give the amount of sodium chloride must be added.
4. 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

1. The total sodium chloride required for isotonicity is 0.9 g/100 ml (the prescription volume).
2. The amount of NaCl required to be added to adjust the isotonicity of the prescription:

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.

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:

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

* 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 isotonic-buffered diluting solutions.

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 is0.576

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.

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.

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 ad60 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.

8. Rx

Ephedrine sulfate gr. iv

Sodium chloride q.s.

Distilled water ad ℥ i

Make isotonic solution.

How many grains of sodium chloride should be used in compounding the prescription?

9. How much sodium chloride should be used in compounding the following prescription?

Rx

Dionin 1/2%

Scopolamine hydrobormide1/3%

Sodium Chloride q.s

Distilled water ad 30.0 ml

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

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