dr. rer. nat. rebaz h. ali - wordpress.com. rer. nat. rebaz h. ali 1/3/2017 pharmaceutical...
TRANSCRIPT
University of Sulaimani School of Pharmacy
Dept. of Pharmaceutics
Dr. rer. nat. Rebaz H. Ali
1/3/2017 Pharmaceutical Compounding I 1
1/3/2017 Pharmaceutical Compounding I 2
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
1/3/2017 Pharmaceutical Compounding I 3
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.
1/3/2017 Pharmaceutical Compounding I 4
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.
1/3/2017 Pharmaceutical Compounding I 5
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.
1/3/2017 Pharmaceutical Compounding I 6
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
1/3/2017 Pharmaceutical Compounding I 7
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
1/3/2017 Pharmaceutical Compounding I 8
Outlines
• Introduction
• Expression of solubility
• Factors affecting the solubility
• Solvents for pharmaceutical use
• Dissolution rate
• Pharmaceutical solutions and excipients
• Official solutions
• Ophthalmic solutions
1/3/2017 Pharmaceutical Compounding I 9
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
1/3/2017 Pharmaceutical Compounding I 10
Outlines
• Introduction
• Expression of solubility
• Factors affecting the solubility
• Solvents for pharmaceutical use
• Dissolution rate
• Pharmaceutical solutions and excipients
• Official solutions
• Ophthalmic solutions
1/3/2017 Pharmaceutical Compounding I 11
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
)
1/3/2017 Pharmaceutical Compounding I 12
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
1/3/2017 Pharmaceutical Compounding I 13
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.
1/3/2017 Pharmaceutical Compounding I 14
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 ?
1/3/2017 Pharmaceutical Compounding I 15
Outlines
• Introduction
• Expression of solubility
• Factors affecting the solubility
• Solvents for pharmaceutical use
• Dissolution rate
• Pharmaceutical solutions and excipients
• Official solutions
• Ophthalmic solutions
1/3/2017 Pharmaceutical Compounding I 16
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.
1/3/2017 Pharmaceutical Compounding I 17
Outlines
• Introduction
• Expression of solubility
• Factors affecting the solubility
• Solvents for pharmaceutical use
• Dissolution rate
• Pharmaceutical solutions and excipients
• Official solutions
• Ophthalmic solutions
1/3/2017 Pharmaceutical Compounding I 18
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.
1/3/2017 Pharmaceutical Compounding I 19
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 ↑
1/3/2017 Pharmaceutical Compounding I 20
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
1/3/2017 Pharmaceutical Compounding I 21
Outlines
• Introduction
• Expression of solubility
• Factors affecting the solubility
• Solvents for pharmaceutical use
• Dissolution rate
• Pharmaceutical solutions and excipients
• Official solutions
• Ophthalmic solutions
1/3/2017 Pharmaceutical Compounding I 22
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.
1/3/2017 Pharmaceutical Compounding I 23
Pharmaceutical solutions
Route of administration Requirements
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.
1/3/2017 Pharmaceutical Compounding I 24
Pharmaceutical solutions
Route of administration Requirements
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
1/3/2017 Pharmaceutical Compounding I 25
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
1/3/2017 Pharmaceutical Compounding I 26
Outlines
• Introduction
• Expression of solubility
• Factors affecting the solubility
• Solvents for pharmaceutical use
• Dissolution rate
• Pharmaceutical solutions and excipients
• Official solutions
• Ophthalmic solutions
1/3/2017 Pharmaceutical Compounding I 27
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.
1/3/2017 Pharmaceutical Compounding I 28
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.
1/3/2017 Pharmaceutical Compounding I 29
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.
1/3/2017 Pharmaceutical Compounding I 30
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.
1/3/2017 Pharmaceutical Compounding I 31
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.
1/3/2017 Pharmaceutical Compounding I 32
Outlines
• Introduction
• Expression of solubility
• Factors affecting the solubility
• Solvents for pharmaceutical use
• Dissolution rate
• Pharmaceutical solutions and excipients
• Official solutions
• Ophthalmic solutions
1/3/2017 Pharmaceutical Compounding I 33
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.
1/3/2017 Pharmaceutical Compounding I 34
Ophthalmic solutions
• 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.
1/3/2017 Pharmaceutical Compounding I 35
Ophthalmic solutions
• 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%.
1/3/2017 Pharmaceutical Compounding I 36
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
1/3/2017 Pharmaceutical Compounding I 37
Thank you for your attention!