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University of Sulaimani School of Pharmacy

Dept. of Pharmaceutics

Dr. rer. nat. Rebaz H. Ali

1/3/2017 Pharmaceutical Compounding I 1


Outlines

• Introduction

• Expression of solubility

• Factors affecting the solubility

• Solvents for pharmaceutical use

• Dissolution rate

• Pharmaceutical solutions and excipients

• Official solutions

• Ophthalmic solutions

• References

• Sprowls' American Pharmacy: An Introduction to Pharmaceutical Techniques and Dosage Forms

• Pharmaceutics: The Science of Dosage Form Design, M. E. Aulton.

• Pharmaceutical dosage forms and drug delivery systems by Ansel


Introduction

• A solution is one phase system of two or more substances which are chemically

different and they completely mixed with each other and a physically homogenous

system results.

• The component that determines the phase of the solution is termed the

solvent and usually constitutes the largest proportion of the system.

• The other components are termed solutes, and these are dispersed as molecules

or ions throughout the solvent, i.e. They are said to be dissolved in the solvent.


Introduction

• Solutes other than the medicinal agent (API) are usually present in orally

administered solutions like coloring, flavoring, sweetening agent and stabilizer.

• The transfer of molecules or ions from a solid state into solution is known as

dissolution.

• System consisting of two liquids which are miscible with each other, such as alcohol

and water, the term soluble and solvent are interchangeable.

• The solute–solute forces and the solvent–solvent forces should be breaked to

achieve the solute– solvent attraction.


Introduction

• The extent to which the solute dissolves at a given temperature and saturated

solution obtained is called solubility of the solute in the solvent.

• When a saturated solution is in contact with excess solute and the temperature is

raised, more of the solute will dissolve. If such a solution is filtered and cooled to the

original temperature it often will retain the extra solute that is dissolved at the higher

temperature. The resulting solution is called super-saturated solution.


Introduction

Advantages of solutions

• Rapid onset of action

• It provides dose uniformity

• It is convinent to patients

• Easy manufacturing

Disadvantages of solutions

• Many drugs are unstable

• Many drugs are poorly soluble

• Liquids are bulky

• Difficult to be carried and handling

• Difficult and expensive transportation


Types of solutions

Types of solutions Liquid in

liquid

Miscible

Homogeneous system is formed irrespective to the proportions, like alcohol and water

Miscible in certain ratio

Homogeneous system is formed at certain proportion, like liquefied phenol and water

Immiscible Practically insoluble at any proportion, like oil and water

Gas in liquid

* Solubility of gas is proportional to the pressure at constant temperature.

* With increased temperature solubility of gas in liquid decreased.

Solid in liquid


Outlines

• Introduction









Expression of solubility

• Solubility could be expressed in various ways

• Quantity per quantity; mg/mL, g/L

• Percentage; % w/w, % w/v and % v/v

• Parts; g/mL

• Molarity; mol/L (of solution)

• Molality, mol/kg (of solvent)

• The approximate solubility of official substances are indicated by the use of the

following descriptive terms:

Descriptive terms Parts of solvent required for 1 part of solute

Very soluble Less than 1

Freely soluble 1 to 10

Soluble 10 to 30

Sparingly soluble 30 to 100

Slightly soluble 100 to 1000

Very slightly soluble 1000 to 10000

Practically insoluble More than 10000


Outlines

• Introduction









Factors affecting the solubility of solids in liquids

1. Temperature: rise in temperature will lead to an increase in the solubility of a solid

with a positive heat of solution.

Solu

bili

ty (

kg p

er k

g o

f w

ater

)


Factors affecting the solubility of solids in liquids

2. Molecular structure of the solute: solute dissolves best in a solvent with similar

chemical properties (like dissolves like).

• Polar solutes dissolve in polar solvents.

• Non-polar solutes dissolve in non-polar solvents.

3. Nature of solvent: using cosolvents such as ethanol or propylene glycol, which

are miscible with water and which act as better solvents for the solute.

• E.g. the aqueous solubility of metronidazole is about 10 mg / mL and with

cosolvents increased to 50 mg/1 mL


Factors affecting the solubility

4. Crystalline structure:

• Polymorphs: are different crystalline form of the same substance

• Amorphous: is the absence of the crystalline structure, which has higher

solubility than its crystalline form.

Crystal Amorphous

5. pH: solubility of weakly acidic drug decreased as pH of the solution decreased.


Factors affecting the solubility

6. Effect of other substance: the solubility of slightly soluble electrolyte is reduced by

the addition of a second salt which contains a common ion.

• NaCl is added to a saturated solution of silver chloride, some of AgCl

precipitates.

• When the solubility of a nonelectrolyte is decreased by addition of electrolyte,

the phenomenon is called as salting out;

• if it is increased, the effect is described as salting in.

7. Solubilizing agent.

How to determine the solubility of a solid ?


Outlines

• Introduction









Solvents for pharmaceutical use

Alcohol (ethyl alcohol-ethanol)

• Next to water, alcohol is the most useful solvent in pharmacy

• Alcohol, USP, is 94.9% to 96.0% C2H5OH by volume (i.e., v/v)

• Dehydrated Alcohol, USP, also called absolute alcohol, contains not less than 99.5%.

• It may acts as preservative

Glycerin USP, Glycerol

• Glycerin is a clear syrupy liquid with a sweet taste.

• It is miscible with both water and alcohol.

• As a solvent, it is comparable with alcohol, but because of its viscosity, solutes are

slowly soluble in it unless it is rendered less viscous by heating.


Outlines

• Introduction









Dissolution rate

Dissolution stages: • An interfacial reaction that results in the liberation

of solute molecules from the solid phase. • The solute molecules must migrate through the

boundary layers surrounding the crystal to the bulk of the solution.

• Noyes-Whitney equation was developed to define the dissolution from a single spherical particle.

𝑑𝑚

𝑑𝑡=𝐷𝐴(𝐶𝑠 − 𝐶)

ℎ

• Sink condition: the volume of the dissolution

medium is so large that C is not allowed to exceed 10% of the value of Cs.


Factors affecting the dissolution rate

• Particle surface area: with ↓ particle size, surface area ↑→ dissolution rate ↑

• Temperature: with ↑ T → dissolution rate ↑

• Volume of the dissolution medium: with ↑ volume (sink condition) → dissolution rate ↑

• Thickness of the boundary layer: with ↑ agitation → boundary layer ↓ → dissolution rate ↑

• Diffusion coeffient:

• With ↓ size of the molecule → diffusion coeffient ↑ → dissolution rate ↑

• With ↓ viscosity of the medium → diffusion coeffient ↑ → dissolution rate ↑


Measurement of dissolution rate

List of the Official Dissolution Apparatus and their uses

Sr. No Official name Main features of the apparatus Uses

1. USP Apparatus 1 Basket Tablets, capsules, Floating dosage forms

2. USP Apparatus 2 Paddle Tablets, capsules, enteric forms

3. USP Apparatus 3 Reciprocating cylinder Extended release drug product

4. USP Apparatus 4 Flow through cell Implants, powders, suspensions

5. USP Apparatus 5 Paddle over disk TDDS

6. USP Apparatus 6 Cylinder TDDS

7. USP Apparatus 7 Reciprocating disk Extended release drug products


Outlines

• Introduction









Pharmaceutical solutions

Route of administration Requirements

Oral They are swallowed Oral cavity Like mouthwash and gargle Topical, skin/hair/Nail Those applied for the skin either for local or systemic effect Otic Used for local effect Used as ear was softener, anti-infective, analgesic

• It should be palatable by the patients→ flavoring, coloring, sweetening agent.

• Solutions have a higher viscosity than water. • The dose is usually in multiples of 5 mL

• It should be palatable • It should not be swallowed • Used for local effect

• It should spread easily and smoothly. • Formulation must adhere to site of application,

without being tacky or difficult to remove.

• Non-aqueous vehicles are used when as ear-wax removal.

• No need to be isotinc • Glycerin could be used to increase viscosity.




Ocular Used for local or systemic effect Nasal For local or systemic effect Pulmonary They are administered by pMDI or by nebulizer for local or systemic effect Rectal Enemas are usually used for local or systemic effect

• It should be sterile. • Multidose should contains preservative • It would be better to be isotonic and has a pH as

physiological fluid.

• Usually they are isotonic • Flavoring and sweetening agent sometime are used!

• pMDI is a dissolved drug in a liquified propellent (triflouromonoflouroethane)

• Microenema (1-20 mL) • Macroenema 50 mL or more • Macroenema should be warmed before use.




Vaginal Used for local Parenteral It refers to the injectable route of administration

• Sometime include excipient to adjust pH

• They must be sterile • For IV it should be aqueous • For IM or SC it could be aqueous or non-aqueous • Large volume should be isotonic • It would be better to have pH close to that of

physiological fluid


Excipients used for pharmaceutical solution

Excipients Examples

Co-solvent Flavoring agents Coloring agents Sweeteners Antimicrobial preservatives Isotonicity adjuster Viscosity enhancer

• Ethanol, glycerol, propylene glycol

• Vanilla, raspberry, orange oil, lemon oil

• Cherry, amaranth

• Sucrose, sorbitol, mannitol, saccharin sodium

• benzalkonium chloride, benzyl alcohol, chlorobutanol, parabens (methyl, propyl, butyl)

• Sodium chloride, potassium chloride, mannitol, dextrose

• HPMC, HEC, Povidon


Outlines

• Introduction









Official solutions

Official solutions prepared by SIMPLE SOLUTION

Official name Strength Category or use(s) comments

Amaranth solution 1% Coloring agent Imparts red color to clear liquid preparation

Diphenoxylate HCl and atropine sulphate

2.5mg diphenoxylate and 0.025 atropine in each 5ml

Antidiarrheal Atropine sulfate is added to minimize the addiction potential of diphenoxylate.

Ephedrine sulfate 3% ephedrine and 0.5% chlorobutanol in an isotonic solution

Adrenergic For use on mucous membranes of the nose, it should be diluted with an equal volume of isotonic sodium chloride solution.

Gentian violet 1% gentian violet in hydroalcoholic (10%) solution

Topical local anti-infective

Used topically in undiluted form in infections caused by gram positive bacteria or by certain parasitic fungi.

Povidone iodine 5, 7.5, 10 and 30% solutions of povidone-iodin equivalent to 0.5, 0.75, 1 and 3% of available iodine

Local anti-infective Used topically for the preoperative disinfection of the skin, and as a general microbicide.


Official solutions

Iodine solution 2% iodine and 2.4% sodium iodide in aqueous solution

Local anti-infective Used as a skin and surgical disinfectant.

Strong iodine solution 5% iodine and 10% potassium iodide in an aqueous solution

Source of iodine Commonly known as Lugol's solution. Administered internally for systemic effect of iodine, the usual dose is 0.3ml diluted with water or milk, three times a day.

Naphazoline HCl 0.05 and 0.1% Vasoconstrictor Used to relieve congestions and swelling of nasal mucosa due to colds. Hay fever and other allergic conditions

Sodium cyclamate and sodium saccharin

6% sodium cyclamate and 0.6% sodium saccharin in aqueous solution

Non-nutritive sweetener

In sweetening power each 0.9ml is equivalent to about 2 tsp. of sugar.


Official solutions

Tolnaftate 1% in polyethylene glycol 400

Antifungal Used topically in the treatment of superficial fungus infections of the skin

Xylometazoline HCL (otrivin)

0.05 and 0.1% Adrenergic Used topically for the relief of nasal congestion

Official oral solutions prepared from DRY POWERS BY RECONSTITUTIONS

Sodium cloxacillin 125mg per 5ml Antibacterial. Reconstituted solution should be stored under refrigeration, unused portions should be discarded after 14 days

Solution prepared by CHEMICAL REACTIONS

Formaldehyde Prepared by oxidation of methyl alcohol in the presence of catalysts.

Disinfectant; for disinfection of inanimate objects, in full strength or as a 10% solutions

Commonly known as Formalin and formaol. An ingredient of embalming fluids.

Hydrogen peroxide

Prepared by the decomposition of barium peroxide with phosphoric acid or diluted sulfuric acid, or by the hydrolysis of per-sulfuric acid.

Topical anti-infective; used for cleaning of wounds and suppurative areas.

Capable of liberating 10 times its volume of oxygen; hence, its called 10 volume peroxide.


Outlines

Solutions prepared by simple solutions with STERILIZATION

Anticoagulant Heparin Sterile solution of 75.000 units of sodium heparin in sodium chloride injection

Anticoagulant for storage of whole blood

30ml of the solution should be used for each 500ml of whole blood

Ringer's solution Isotonic solution of 8.6% sodium chloride, 0.3% potassium chloride and 0.33% of calcium chloride in purified water

Irrigation solution; a physiologic salt solution which is used as a solvent for medicinal substances which are to be applied topically to delicate tissues.

Solution is not to be used for parenteral administration or in preparations to be used parenterally

Sodium chloride Solution 0.9% sodium chloride in purified water

Isotonic vehicle, used as a solvent for medications that are intended to be applied topically

Non sterilized should not be used for parenteral administration or irrigation that may result in absorption of the solution into blood.


Outlines

Official solutions prepared from tablets

Official name Strength Use Comment

Halazone 4mg Disinfectant; for the sterilization of drinking water, 1 or 2 tablet per liter of water.

The tablet should be labeled to indicate that they are not intended to be swallowed.

Potassium permanganate

60, 125, and 300 mg

Topical anti-infective. Applied topically to the skin and mucous membranes as a 0.004 to 1% solution or in a wet dressing

Solution of the tables has a deep violet-red color when concentrated and a pink whine highly diluted, since potassium permanganate is incompatible with organic materials such as might be present in tap water only distilled water should be used in preparing solution of it.


Outlines

• Introduction









Ophthalmic solutions

Ophthalmic solutions are sterile, free from foreign particles, and specially prepared for

instillation in the eye.

Drugs are administered to the eye for local effects such as miosis, mydriasis, and

anesthesia, or to reduce intraocular pressure in treating glaucoma.

• Requirements of ophthalmic solutions

• Antimicrobial preservative:

• for multi-dose container, an antimicrobial preservative must be included in the

formulation. E.g . Benzalkonium chloride, chlorhexidine, chlorobutanol and

methylparaben.



• Sterile: Sterility is defined as the absence of viable microbial contamination.

Autoclaving the final container is the preferred method of sterilizing ophthalmic

solution.

• Isotonic: ideally it should be isotonic (0.9% w/v NaCl), but eye can tolerates 0.6 % to

1.3% w/v NaCl.



• Antioxidant: The use of plastic bottles, which allow gases to permeate through the

container, will be particularly susceptible to oxidative degradation.

• EDTA 0.1% and sodium bisulfite 0.1%.

• pH: the eye can tolerate preparations over a range of pH values 3.5 to pH 9.

However, it is preferable to formulate as close to physiological pH values as possible

(pH 7.4).

• Viscosity: increased viscosity of ophthalmic solutions offers prolonged contact with

the tissue, thus possibly enhancing the penetration and therapeutic effect of the

drug. Thickening agent like MC and HPMC 0.5- 2.5%.


Ophthalmic solution

Official solutions prepared by SIMPLE SOLUTION WITH SERILIZATION –OPHTHALMIC SOLUTIONS

Official name Commercial name Use(s), comment

Antazoline phosphate Antisitine Antihistamine, used for symptomatic relief of certain condition of the eye resulting from allergies

Atropine sulfate Ophthalmic anticholinergic, produces mydriasis and cycloplegia

Dexamethasone sodium phosphate

Decadron Glucocorticoid, used in various forms of conjuctivites, lid allergies and other inflammatory conditions of the eye.

Phenylpherine HCl Neo-synephrine Adrenergic; used for its vasoconstrictor and mydriatic actions.

Neomycin sulphate, polymyxin B, and Gramixidin

Neosporin Local anti-infective


Thank you for your attention!

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