University of Sulaimani Pharmacy College 3 rd level Pharmaceutical Compounding Solution containing non volatile substance Dr. Hiba Hani
q Objectives Ø Simple solution definition Ø Types of solution Ø Rate of solution Ø Factors effecting on the solubility Ø Expression of solution Ø Solvents for pharmaceutical uses Ø Pharmaceutical solutions and excipients Ø Official solutions Ø Ophthalmic solution Ø Ophthalmic solution requirements
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
Simple solution liquid pharmaceutical preparation consists of one or more chemical substances dissolved in a suitable solvent or mixture of solvents in one phase system physically homogeneous Example: addition of sucrose to water produces a single phase system
In other words: solution the dissolved substance(s) is completely & permanently dissipated throughout the liquid (one phase) True solution
v Main Constituents of Solution 1. Solvent(s): one or a mixture of miscible liquids and usually constitutes the largest proportion of the system 2. Solute(s): and these are dispersed as molecules or ions throughout the solvent, i.e. They are said to be dissolved in the solvent
v Solutes other than the medicinal agent (API) are usually present in orally administered solutions solubilizing agent colorants and/or flavoring agent preservatives thickening agent and others
The transfer of molecules or ions from a solid state into solution is known as dissolution When a solute dissolves, the solute solute intermolecular forces and the solvent solvent intermolecular forces should be break to achieve the solute solvent attraction The solubility of pure chemical substances at a given temperature and pressure is constant
Steps of solid going into solution Step 1: hole open in the solvent Step 2: molecule of the solid breaks away from the bulk Step 3: the solid molecule is enter into the hole in the solvent
q Advantages of solutions ü ü ü ü ü young children and some adults have difficulty in swallowing tablets and capsules more quickly effective than tablets, which must disintegrate and solubilized before absorption uniform dosage is certain (contrast suspension, emulsion, capsules and other dosage form) it is convenient to patients easy manufacturing
q Disadvantages of solutions ü many drugs are unstable ü many drugs are poorly soluble ü liquids are bulky to carry around ü unpleasant taste sometimes can be difficult to mask ü a spoon is needed to administer the dose ü accidental breakage of the container results in complete and messy loss of the contents
There are many classifications of pharmaceutical solutions based on their composition or medicinal use v Pharmaceutical solutions according to medicinal use as: oral solution, injection, mouth wash, drops, spray, gargle...etc. v Solid in water is the most widely used in pharmaceutical preparations
Types of solutions 1. Solution of liquid in liquid a. miscible: homogeneous system is formed irrespective to the proportions, like alcohol and water, acetone and water b. miscible in certain ratio: homogeneous system is formed at certain proportion, like liquefied phenol and water, ether and water c. immiscible: practically insoluble at any proportion, like oil and water
q Solubility of gas in liquid a. solubility of a gas is very nearly proportional to the pressure if the temperature remains constant according to Henry s law. ex: Carbon dioxide + water Ø directly proportional to remain constant pressure if temperature
b. solubility of a gas is also influenced by temperature; as the temperature is raised the solubility of a gas in a liquid decreases. Ø Inverse proportional to Temperature therefore gaseous solutions should be stored in a cool place.
Ex. Solubility of carbon dioxide in water twice soluble at 0 C as it is at 20 C
3. Solutions of solids in liquid Most true solutions which are pharmaceutical interests represent solid in liquid solution - Water+ sodium chloride
Saturated and supersaturated solutions When an excess of a solid shake with a liquid for a period of time max. amount dissolve & solvent saturated by solute saturated solution at a given temp. At this saturated solution (contain an excess of solute if temp. raised more solute dissolve then filtered & cooled to the original temp. It will retain the extra solute that dissolve at the higher temp. super-saturated solutions
Rate of solution dissolves in a solvent. how quickly a solute ü It depend on: 1. size (inverse proportional): increase in surface area will increase the rate of solution 2. agitation 3. temperature (direct proportional)
How you determine the solubility of a substance? - by preparing a saturated solution of it at a specific temperature and determining by chemical analysis the amount of chemical dissolved in a given weight of solution
Relative terms of solubility as in USP The solubility of substance may be expressed as: no. of ml of a solvent required to dissolve 1g of the solute at 25 C. Descriptive terms Very soluble Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble Practically insoluble Parts of solvent required for 1 part of solute Less than 1 From 1 to 10 From 10 to 30 From 30 to 100 From 100 to 1000 From 1000 to 10000 More than 10000
q Factors affecting on the solubility of solids in liquids 1. temperature 2. effect of molecular structure 3. effect of ph on solubility 4. effect of other substances 5. crystalline structure 6. nature of solvent 7. solubilizing agent
1. Temperature generally, the solubility of a solid or liquid can increase or decrease as temperature increases depending on whether the dissolution reaction is exothermic or endothermic. If the process of solution: - Endothermic reaction temp. more of solute go into solution (This is the most common situation where an increase in temperature produces an increase in solubility for solids) - Exothermic reaction solubility temp of the solute. - If heat neither absorbed nor release solubility is not effected by variation in temperature.
2. Effect of molecular structure on solubility q solute dissolves best in a solvent with similar chemical properties (like dissolves like) hence the more nearly solute and solvent molecular structure better solubility polar solutes dissolve in polar solvents non-polar solutes dissolve in non-polar solvents q Selectivity of solvent action depend on ability of the solvent: ü to overcome certain forces which hold the atoms of the solute together and ü to act as the solute-solvent binding force
q Examples u An electrovalent compound as sodium chloride placed with water (solvent) water molecular orient themselves at Na & Cl ions with sufficient energy to overcome the force which holds the ions in the crystal of NaCl and solvate them.
Also the substituents affect on solubility Ex. non-polar groups such as CH 3 and Cl are hydrophobic and impart low solubility.
3. Effect of ph on solubility - most of the organic medicinal agent are either weak acids or weak bases - these drugs are react with strong bases or strong acids to form water soluble salts Ø organic medicinal agents that are weak acid as: 1. barbiturate drugs (phenobarbital & pentobarbital) 2. sulfonamides drugs (sulfadiazine & sulfacetamide) ü ü these and other weak acids form water soluble salts in basic solution solubility of weakly acidic drug decreased as ph of the solu6on decreased
Example: Solubility of weak acid in water ph add base Ex. solubility of phenobarbital in water at 25C is about 1.25 g/1l at ph 5.5 While solubility of phenobarbital sodium in water at 25C is about 1000 g/1l at ph 9.3
Ø The weak bases including: 1. alkaloids (atropine, codeine, and morphine) 2. antihistamines (diphenylhydramine) 3. local anesthetics (tetracaine) ü all of them not very water soluble but they are soluble in acidic solutions
Example: solubility of weak base in water ph add acid Ex. solubility of atropine in water at 25c is about 2.2g/1L at ph>10. While: solubility of atropine sulfate in water at 25c is about 2500g/1L at ph 5.4.
4. Effect of other substances on solubility q The solubility of a substance also may depend on the types and concentrations of other substances in solution. ü ex 1. solubility of slightly soluble electrolyte by adding second salt contain common ion If adding NaCl to saturated solution of AgCl AgCl ppt. some of
ü ex 2. water solubility of nonelectrolyte either or by addition of electrolyte If: a. solubility of nonelectrolyte salting out b. solubility of nonelectrolyte salting in
5. Crystalline structure: Polymorphs: have the same chemical structure but different physical properties, such as solubility, density, hardness, and compression characteristic Amorphous: is the absence of the crystalline structure, which has higher solubility than its crystalline form.
6. Nature of solvent: like dissolves like when two substances are similar they can dissolve in each other ü polar solutes dissolve in polar solvents ü non-polar solutes tend to dissolve in nonpolar solvents ü ionic compounds are more soluble in a polar solvent than in a non-polar solvent
u Examples
Solvents for pharmaceutical uses: selection of the proper solvent for a given solute is important v structural similarity is significant and important v choice of suitable solvent depend on many factors as toxicity, volatility and stability and others
q Aqueous (polar): is the most commonly used solvent in the preparation of pharmaceutical products: it is, ü nontoxic ü palatable ü easy to product ü non expensive ü can dissolve a wide range of substances q Co-solvent can be used to enhance the solvent properties of water and render the solutes more soluble in the aqueous media: e.g. alcohol, glycerin & propylene glycol
Purified Water ü it is water obtained by distillation, ion exchange treatment, reverse osmosis, or other suitable process ü it is more free of solid impurities than drinking water, when evaporated to dryness, it must not yield more than 0.001% of residue, thus its 100 times more free of solids than drinking water ü good solvent most inorganic salts & many organic compounds. ü useful vehicle for many pharmaceutical preparations due to its miscibility with other solvents, as alcohol & glycerin.
Alcohol ü Ethyl alcohol, ethanol ü most useful solvent in pharmacy ü Alcohol USP, 94.9% to 96.0% C 2 H 5 OH by volume (i.e., v/v) ü together with water it forms a hydro-alcoholic mixture that dissolves both alcohol-soluble and watersoluble substances ü good solvent for many organic substances (natural, synthetic) ü alcohol can be used with other solvent such as glycerin, to reduce the amount of alcohol required
Polyethylene glycol (PEG) ü have a wide variety of average molecular weights, the higher the number the higher m.wt. ü PEG 600 & below tends to be liquids at room temperature ü can be used for oral, topical or parenteral preparations ü generally considered as non toxic and non irritant
Glycerin ü clear syrup liquid with a sweet taste ü it is miscible both with water & alcohol ü good solvent for tannins, phenol and boric acid ü 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
Propylene glycol Ø viscous liquid, miscible with water, acetone, alcohol & chloroform but immiscible with fixed oils Ø use dissolve many essential oils and is frequently substituted for glycerin in modern pharmaceutical preparations Carbon tetrachloride Ø very slightly soluble in water Ø miscible with organic solvents Ø use dissolves fats & oil
Pharmaceutical solutions and excipients
Route of administration Oral They are swallowed Requirements It should be palatable by the patients flavoring, coloring, sweetening agent. 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 softener, antiinfective, & analgesic 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. Glycerin could be used to increase viscosity.
Route of administration Requirements Ocular 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. Nasal For local or systemic effect Rectal Enemas are usually used such as decongestants and allergy treatments are used Microenema (1-20 ml) Macroenema 50 ml or more
Vaginal Sometime include excipient to adjust ph Parenteral It refers to the injectable route of administration They must be sterile It would be better to have ph close to that of physiological fluid
Official solutions: liquid preparations that contain one or more soluble chemical substances dissolved in liquid solvents
q Formulation considerations Ø what is the physical nature of the solute (solid or liquid) Ø what is the required solvent(s), aqueous, organic or a mixture of both? Ø what is the solubility of the solute in the solvent? Ø what is the solubility of the solute in the solvent, preferably across a range of PH values?
Ø what is the solubility at the stated storage condition? Ø what is the stability of the drug in solution? Ø what are the required solution strength? Ø are there any other additives and what are their functions? - examples: colorants, flavours, stabilizers, preservatives. etc
Ophthalmic solution q ophthalmic solutions are ü sterile ü free from foreign particles ü prepared for instillation in the eye q drugs are administered to the eye: Ø either for local effects such as miosis, mydriasis, and anesthesia Ø or to reduce intraocular pressure in treating glaucoma
Glaucoma
Ophthalmic solutions require to be: 1. sterile 2. preservation 3. isotonic 4. antioxidant & stabilizers (if required) 5. ph 6. viscosity
1. Sterile q defined as the absence of microbial contamination q contaminated ophthalmic formulations eye infections blindness q autoclaving the final container (120C for 20-30 min) preferred method of sterilizing ophthalmic solution q in general, all ophthalmic products would be terminally sterilized in the final packaging
2. Preservation v ophthalmic solutions may be packaged in multiple-dose containers when intended for - individual use of one patient and - ocular surfaces are intact v each solution must contain a suitable substance(s) prevent the growth of, or to destroy, the M.O. introduced accidentally the containers are opened during use
q preservative examples 1. phenylethyl alcohol 0.5% 2. chlorobutanol 0.5% 3. benzalkonium chloride 0.01% q ophthalmic solutions that are intended for surgical use must be: ü sterile ü not contain any preservative ü should be packaged in the single-use disposable containers
3. Isotonic: should be isotonic with the lacrimal fluid (i.e.., exert an osmotic pressure equal to that of tear fluid, generally agreed to be equal to 0.9% NaCl) to avoid discomfort & irritation but the eye can tolerate isotonicity values as low as that of a 0.6% NaCl solution and as high as that of a 1.3% NaCl solution without causing discomfort Ex. commonly tonicity adjusting ingredients include : NaCl, KCL, buffer salts, and others
4. Antioxidant & stabilizers q Some drugs can be chemically degraded by oxidation if present in the formulation antioxidant should be added Example ü EDTA 0.1% & sodium bisulfite 0.1% q Stabilizers are ingredients added to a formula to decrease the rate of decomposition of the active ingredients
5. ph ideally, every product would be buffered to a ph of 7.4 (the normal physiological ph of tear fluid) ph plays an important role in therapeutic activity, solubility, stability and comfort to the patient where the eye can tolerate preparations over a range of ph values 3.5 to ph 9
v additionally, many drugs are chemically unstable at ph levels approaching 7.4. o for these reasons, the buffer system should be selected nearest to ph 7.4 v not cause - precipitation of the drug or - deterioration
6. Viscosity increased viscosity of ophthalmic solutions prolonged contact with the tissue - enhancing the penetration - enhancing therapeutic effect of the drug thickening agent as, methylcellulose & hydroxyl propyl methyl cellulose