Solutions

Question 1

what is solution

Answer 1

A solution is a homogeneous one-phase system consisting of two or more components.
Solvent: Phase in which the dispersion occurs
Solute: Component which is dispersed as small molecules or ions in the solvent

Types of solutions: aqueous or non-aqueous

Question 2

concentration of solute

Answer 2

concentration is usually well below its saturation solubility in order to avoid the possibility of drug ppt out of the solvent as a result of temperature changes during storage and use

Question 3

advantage of soluton

Answer 3

• the drug is already dissolved in the solvent system, hence DRUG ACTION CAN BE RAPID, allowing their use in emergencies, e.g. the use of adrenaline solution, as an injection, for the treatment of anaphylaxis
• when drug absorption is required prior to drug action, for example, following oral administration, the drug in a solution is already in a molecular form and thus, AVAILABLE FOR ABSORPTION
• solutions provide DOSE UNIFORMITY, and specific volumes of the liquid solutions that can be measured accurately; this allows a range of different doses to be easily administered
• oral solutions are EASILY SWALLOWED and are beneficial for patients for whom swallowing may be difficult, e.g. children and older people.
• solutions are EASIER TO MANUFACTURE compared to other dosage forms.

Question 4

Disadvantage of solution

Answer 4

• many drugs are inherently UNSTABLE, and instability is increased when a drug is present in solution, i.e. as molecules. The solution formulation is therefore not feasible for certain drugs. For other drugs, stability can be enhanced by optimizing the formulation
• many drugs are POORLY SOLUBLE in water. Their formulation as a solution is CHALLENGING
• liquids are BULKY and less easy for the patient to carry, for example, the daily dose, compared to solid dosage forms. Liquids are also more EXPENSIVE to TRANSPORT , which increases the medicine’s cost. The packaging of pharmaceutical solutions requires materials of higher quality

Question 5

Types of solutions:

Answer 5

aqueous or non-aqueous

Question 6

Aqueous solution

Answer 6

Water is the most widely used solvent for aqueous solutions.

The quality of water required depends on the type of preparations to be made

a) Potable water
b) Purified water BP
c) Water for Injection BP
d) Water free from carbon dioxide or air

Question 7

portable water

Answer 7

for oral/external solution that are not intended to be sterile

normally not used for the manufacture of solution or extemporaneous compounding as it contains dissolved substances which could interfere with the formulation, for example, reduce drug solubility and stability.

Question 8

purified water

Answer 8

to prepare non-parenteral solution

purified from tap water by distillation, ion exchange or reverse osmosis.

Question 9

water for injection BP

Answer 9

purified from purified water to remove pyrogen

Question 10

most drug are not completely dissolved at normal storage temperature
various methods employed to increase apparent solubility includes

Answer 10

Cosolvency 
pHcontrol 
Solubilization 
Complexation 
Chemical modification 
Particle size control

Question 11

cosolvency

Answer 11

used to increase water solubility of drugs which do not contain ionizable group(s) and whose solubility can thus not be increase by ph adjustment.

The solubility of a weak electrolyte or non-polar compound in water can be improved by the addition of a water-miscible solvent in which the compound is also soluble.
Vehicles used in combination to increase the solubility of a drug are called cosolvents.
The solubility of a drug is generally affected by the dielectric constant of the solvent system.

Ideally,suitable blends should possess values of dielectric constant between 25 and 80.
The choice of suitable cosolvents is limited for pharmaceutical use.
Examples: Co-trimoxazole+Propyleneglycol+Water Paracetamol + Alcohol + Propylene glycol + Syrup Betamethasone valerate+Isopropanol+Water

Question 12

typically a linear increase in cosolvent fraction results in log increase in drug solubility

Answer 12

typically a linear increase in cosolvent fraction results in log increase in drug solubility

Question 13

non-polar drug are poorly soluble in water.

cosolvency do what ?

Answer 13

need to lower polarity by adding liquid eg water-miscible organic liquid with a low polarity.

Question 14

pH control

Answer 14

If a drug is either a weak acid or a weak base, its degree of ionization and consequently its solubility are influenced by the pH of the solution.
This is expressed by the Henderson-Hasselbalch equation.
In controlling the solubility of a drug in this way, it must be ensured that the chosen pH does not conflict with other product requirements.

weak acid are ionized when ph increase
weak base are ionized when ph decrease

Question 15

solubilization

Answer 15

The solubility of a drug in water can be improved by the addition of a surfactant.
The concentration of surfactant used should be above its critical micellar concentration –>micellarsolubilization However,a large excess of surfactant is undesirable. Hydrophilic surfactants with HLB values above 15 are useful solubilizing agents.

Question 16

Factors that affect the choice of solubilizing agents:

Answer 16

Toxicity and irritancy
Miscibility with solvent system
Compatibility with other components
Odour and taste

Examples:
Fat-soluble vitamins+Polysorbates
Iodine+Macrogol ethers
Steroids+Polyoxyethylated castoroil Cresol+chloroxylenol+potassium soaps of fatty acids

A combination of cosolvent and solubilizing agent may be employed to improve solubility
Examples:
VitaminA+Polysorbate80+Glycerol Chloroxylenol+Potassium ricinoleate+ethanol+ terpineol

the amount of surfactant used should not be excessive due to its potentially harmful effects

Question 17

determination of minimum concentration of surfactant for solubilization of drug

Answer 17

A series of vials, each consisting of the solvent with a constant concentration of the surfactant is prepared.
Different amounts of the drug are added to the vials and the optical density of the mixtures determined.
The maximum drug concentration(MDC) that produces a clear solution is obtained from the graph.

Using the same procedure, the MDC values of different concentration of the surfactant are determined
A plot of MDC vs surfactant concentration is constructed
The minimum surfactant concentration can be determined from this plot.

Question 18

Complexation

Answer 18

this involves the interaction of a poorly soluble drug with a soluble material to form a soluble complex.

complex formation should be easily reversible as most complexes are macromolecules which tend to be inactive

example
iodine + PVP
salicyclates + xanthines

cyclodextrins

Question 19

cyclodextrins

Answer 19

for complexation
Cyclodextrins (CDs) are non-reducing cyclic glucosebased oligosaccharides, comprising a variable number of D-glucose residues linked by α-(1,4) glycosidic linkages. The three most important CDs are alpha, beta and gamma cyclodextrins which consist o 6, 7 and 8 D-glucopyranosyl units, respectively, arranged in a ring. Three-dimensionally, CDs can be visualized as a hollow truncated cone.
The interior cavity of cyclodextrins is apolar, while their exterior is hydrophilic.
The hydrophilic exterior results in CDs being soluble in water. Concurrently, the less polar interior can accommodate non-polar drug molecules via non-covalent interactions, thereby allowing the nonpolar drug to be ‘hidden’, enabling it to be molecularly dispersed in water. Thus, drug inclusion within CDs effectively increases their aqueous solubility.

Each cyclodextrin molecule can form complexes with one or more drug molecules. Drug-CD complexes can also self-associate, and the water-soluble structures formed can further solubilize the drug through non-inclusion complexation. Upon administration, for example orally, of a solution containing a drug-CD complex, the drug can be released from the CD molecule and the free drug can then be absorbed through the gastrointestinal tract.

Question 20

Chemical modification

Answer 20

This involves synthesis of soluble salts of the drug.
The soluble salt which may not have any activity is converted back to the active base in the biological system.
Examples:
Sodium phosphate salts of hydrocortisone, prednisolone and betamethasone
Sodium succinate salt of chloramphenicol

Question 21

particle size reduction

Answer 21

The size and shape of very small particles (<1 micron) can affect their solubility.

particle size is commonly reduced by milling.

this method is less commonly employed to improved solubility.

Question 22

Non aqueous solution

Answer 22

The solvents used are non-aqueous in property.

they are employed for various reasons:

1) to prepare solutions of drugs which are unstable in water
2) to prepare intramuscular injections of drugs for depot therapy.

The solvents are classified as fixed oil of vegetable origin, alcohol, polyhydric alcohols, mineral oils and other.

Question 23

Fixed oils of vegetable origin

Answer 23

E.g. almond oil, arachis oil, olive oil, corn oil, soya oil, castor oil, cottonseed oil, sesame oil, coconut oil.

Used in the formulation of injections, eye-drops, liniments and oral preparations.

Oily Phenol Injection BP (almond oil)
Dimercaprol Injection BP (arachis oil)
Methyl Salicylate Liniment BP (arachis oil) Physostigmine Oily Eye-drops BP (castor oil)

Tasteless and odourless fixed oils are used for oral preparations.
Fractionated coconut oil is used as a solvent for phenoxymethylpenicillin

Question 24

what are fixed oils of vegetable origin typically used for

Answer 24

Used in the formulation of injections, eye-drops, liniments and oral preparations.

Question 25

Alcohol

Answer 25

Ethanol For internal and external use. More commonly employed in low concentration, as a cosolvent with water in the formulation of aqueous solutions for oral and parenteral use. ``` Industrial methylated spirit Ethanol with 5% methanol as a denaturant For external use. Isopropanol For external use ```

Question 26

Polyhydric alcohols

Answer 26

Commonly used as a cosolvent with water in the formulation of injections. Glycerol For internal and external use. E.g. Phenol Ear Drops BPC 1973 Propylene glycol For internal and external use (include otic soln) E.g. Digoxin Injection BP, Phenobarbitone Injection BP, Chloramphenicol Ear Drops BP Polyethylene glycols of low molecular weight For internal and external use. E.g. Erythromycin Ethylsuccinate Injection BP Dipropylene glycol, diethylene glycol, ethylene glycol Used in the formulation of external preparations for veterinary and horticultural use.

Question 27

Mineral oils

Answer 27

Liquid paraffin For internal and external use. Limited use as a solvent in pharmaceutical preparations because of its oily and tacky nature. Vegetable oils are generally preferred. More often employed in the formulation of emulsions.

Question 28

Not for internal use

Answer 28

Xylene Common solvent for ear drops Ethyl ether Cosolvent with alcohol in some collodions More commonly used for extraction of crude drugs Isopropyl myristate, isopropyl palmitate More commonly used in cosmetics Dimethylsulphoxide, dimethylformamide, dimethylacetamide Mainly used in veterinary products Kerosene Solvent for insecticides

Question 29

can prevent [o] by purging soln with N2 and create a N2 headspace within the container.

Answer 29

can prevent [o] by purging soln with N2 and create a N2 headspace within the container.

Question 30

additives

Answer 30

buffer colours sweetening agent flavours and fragrances

Question 31

Buffers

Answer 31

E.g.carbonates,citrates,gluconates, lactates,phosphates,tartrates and borates

Question 32

Colours

Answer 32

These are employed to improve attractiveness and to enable easy identification of products. The stability of the colour may be affected by pH,ultraviolet radiation and presence of oxidizing or reducing agents. It should be ensured that the colour chosen is acceptable in the country in which the product is to be sold. A colour may be known by different names. E.g.Amaranth is also known as Bordeaux S, CI Food Red 9 and CI Acid Red 27. 2 types natural and synthetic

Question 33

Types of colour

Answer 33

1) natural colours - Show variation in chemical composition and are less stable. However, they are more widely accepted. classified into carotenoids, chlorophylls, anthocyanins and others 2) Synthetic colours - also known as coal tar dyes - give brighter colours and are more stable - eg Na salt of sulphonic acids.

Question 34

Sweetening agents

Answer 34

two types 1) natural E.g.sucrose, fructose, sorbitol, mannitol, glycerol, xylitol, hydrogenated glucose syrup, isomalt,honey and liquorice 2) Artificial Intense sweeteners (<0.2%) Tendency to impart bitter or metallic after taste. E.g.saccharin, aspartame, acesulfame potassium, thaumatin

Question 35

Flavours and fragrances

Answer 35

Flavours are employed to made oral products more palatable while fragrances improve the appeal of the products. In some cases, the additive serves as a flavouring agent as well as a fragrance. These may be obtained from natural or synthetic sources. E.g. fruit juice, aromatic oils, herbs and spices. There is a strong association between the use of a product and its flavour/fragrance.

Question 36

isotonicity modifiers

Answer 36

to adjust the tonicity of large volume soln for parenteral and ophthalmic use

Question 37

Density modifiers

Answer 37

To adjust density of spinal anaesthetics