Liquid Dosage Forms
Solutions: Liquid preparation that contain one or more chemical substances dissolved in a suitable solvent or mi
of mutually miscible solvents. May be oral, otic, ophthalmic, and topical.
Colligative properties
- Relative lowering of vapor pressure (Raoult's law)
- Elevation of boiling point
- Depression of freezing point
- Osmotic pressure: Water flows through the semipermeable membrane to dilute the alcohol solution, until t
force of gravity pulling down on the column of this solution balances the osmotic pressure, pushing the w
through the membrane
- Physical changes that result when adding solute to solvent
o The properties depend on how many solute particle are present, and the solvent amount
o The properties do not depend on the type of solute, but rather the solvent type employed
Rules of solubility
- What is the maximum concentration to which a solution can be prepared with that agent and solvent?
o Attractive forces: are responsible for molecules to come together
o Repulsive forces: prevent molecule interaction and possible destruct them from coming together
Important for two forces balance. Two forces should be equal the potential energy between two molecules
at minimum have a stable preparation.
o Dipolar molecules: negative polar and positive polar can contribute forces to solutions as well
o Hydrogen bonding:
Hydrogen atoms move in close to electronegative atoms (F, O, N).
Hydrogen bonds exist also with Esters, Carboxylic acids, Aldehydes, and Polypeptides.
- How to improve solubility conditions? What options are available to pharmacists?
o Different solubilizing agents
o Different chemical salt form of medicinal agent
o Alteration of the pH of a solution
o Partial or whole substitution of a solvent
** Always add solute into solvent – be able to overcome any forces that keep solute interaction intact, don’t want
solute-solute or solvent-solvent
Example: 1g of iodine granules in 3,000 mL (0.03% iodine)
Alternative: dissolve in Potassium Iodide, Sodium Iodide
Iodine Topical Solution, USP (contains 2% iodine, 2.4% sodium
iodide)
- for inorganic molecules
o If cation and anion of an ionic compound are monovalent, solute-solute attractive forces are easily
overcome (i.e., NaCl, LiBr, KI).
o Same is true if one of the two ions in an ionic compound is monovalent (i.e., BaCl2, MgI2)
, o If both the cation and anion are multivalent, the solute-solute interaction may be too great to overcome ( i
CaSO4, BaSO4) This results in POOR WATER SOLUBILITY
o Ammonium and quaternary ammonium salts are water soluble
o Phosphates, Carbonates, Silicates, Borates, and Hypochlorite are water insoluble (except for their alkali m
salts and ammonium salts).
- for organic molecules
o Molecules having one polar functional group is sufficient to solubilize chain lengths consisting of 5 carbon
o Molecules having branched chains are more soluble than corresponding straight-chain compounds
o Water solubility decreases with increase in molecular weight
o Increased structural similarity between solute and solvent = increased solubility (remember: “like dissolves
like”)
Terms used to describe solubility: When the exact solubility is not known (or has yet to be determined), gene
expressions of relative solubility may be used.
Very Soluble <1
When you said something is soluble, you talk Freely Soluble 1-10
about the solvent required for 1 part of solute. Soluble 10-30
When go from very soluble to insoluble, require Sparingly Soluble 30-100
more and more water to be able to dissolve of the Slightly Soluble 100-1000
same concentration of the drug substance Very Slightly Soluble 1000-10000
Practically Insoluble or Insoluble>10000
- Factors influencing solubility:
o Temperature:
□ “Positive heat of solution” – if you have the particular drug compound where the addition of heat w
actually assist the facilitate solution preparation, the drug will dissolve in the particular solvent
solution. If heat can assist the drug substance to get into solution, that drug substance has positive
heat of solution. Not all drugs are benefit from the heat.
o pH of the solution:
□ Weak acids or weak bases – do not want to adjust pH outside comfortable range if ophthalmic, if w
to inject into blood, be careful cause it may become precipitated.
o Physical agitation:
□ Extent to which solvent passes over solute – the more able shaking or agitating, increase the
possibilities solute get into the solvent
o Particle size:
□ Finer the powder, greater the surface area, the more rapid dissolving process
- Beneficial considerations
o Salts of organic compounds are more soluble in water compared to their organic base counterparts.
o Organic bases are more soluble in organic solvents
- “Like dissolves like”: Solvents having chemical structures most similar to the solute will most likely dissolve it
o For i.e., organic compounds are more soluble in organic solvents compared to in water
o One exception is if organic compound has polar functional group
o Polar groups are: OH, CHO, COH, CHOL, CH2OH, COOH, NO2 and SO3H
o In general, halogen atoms decrease solubility
o Because of an increase in MW without proportionate increase in polarity
, Solvents for liquid preparations
- Alcohol, USP: Ethyl Alcohol, ethanol, C2H5OH (internal and external)
o A primary solvent for many organic compounds
o When mixed with water = hydroalcoholic mixture
o Alcohol USP is 94.9% to 96.0% C2H5OH by volume, when determined at 15.56 °C
o 15.56 °C (U.S. government standard temp. for alcohol determinations).
o Dehydrated Alcohol, USP contains not less than 99.5% C2H5OH.
o For drugs not soluble in water alcohol is preferred as a suitable alternative due to its miscibility in water a
ability to dissolve many water insoluble agents.
□ For e.g., Drug agents, flavorants, antimicrobial preservatives.
o When alcohol content is too much, glycerin and glycols can be used to reduce total amount of alcohol needed.
o FDA proposed for manufacturers of OTC oral drug products
□ For children < 6 years of age alcohol limit is 0.5%
□ For children 6 to 12 years of age, limit is 5%
□ For children over 12 years of age & adults limit is 10%
- Diluted alcohol (internal and external)
o Prepared by mixing equal parts of alcohol USP with purified water
o Since liquids tend to contract during mixing the final volume is generally 3% less than what otherwise sho
be expected.
□ For example, if 50 mL of each component is combined the result is 97 mL.
o Dilute alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes and preparations
- Rubbing alcohol (external only)
o Rubbing alcohol contains about 70% ethyl alcohol by volume, remaining is water, denaturants (with or
without color additives and perfume oils and stabilizers).
o To discourage oral ingestion each 100 mL must contain not less than 355mg of sucrose octa-acetate (or
mg of denatonium benzoate) which has a bitter taste.
o Internal Revenue Service- U.S. Treasury Department, the denaturant employed is called Formula 23-H
□ 8 Parts (by volume) of acetone
□ 1.5 Parts (by volume) of methyl isobutyl ketone
□ 100 parts (by volume) of ethyl alcohol
** Product is volatile and flammable, should be stored in tight container remote from fire
- Glycerin, USP (Glycerol) (internal and external)
o A clear syrupy liquid with a sweet taste
o Miscible in water and in alcohol
o Glycerin is naturally viscous, but can be made less viscous by heating
o Can be used as a preservative or stabilizer
o Can also be used for internal applications in addition to external use
- Isopropyl rubbing alcohol (external)
o Isopropyl rubbing alcohol, ~70% isopropyl alcohol. Remaining components are water (with or without
colorants), stabilizers and perfumes.
o Used externally as *rubefacient and soothing rub vehicle for topical purposes.
o To prepare diabetic needles and syringes for hypodermic injections of insulin, a commercially available ~9
isopropyl rubbing alcohol is used also.
** A rubefacient is a substance for topical application that produces redness of the skin e.g. by causing dilation o
capillaries and an increase in blood circulation”
Solutions: Liquid preparation that contain one or more chemical substances dissolved in a suitable solvent or mi
of mutually miscible solvents. May be oral, otic, ophthalmic, and topical.
Colligative properties
- Relative lowering of vapor pressure (Raoult's law)
- Elevation of boiling point
- Depression of freezing point
- Osmotic pressure: Water flows through the semipermeable membrane to dilute the alcohol solution, until t
force of gravity pulling down on the column of this solution balances the osmotic pressure, pushing the w
through the membrane
- Physical changes that result when adding solute to solvent
o The properties depend on how many solute particle are present, and the solvent amount
o The properties do not depend on the type of solute, but rather the solvent type employed
Rules of solubility
- What is the maximum concentration to which a solution can be prepared with that agent and solvent?
o Attractive forces: are responsible for molecules to come together
o Repulsive forces: prevent molecule interaction and possible destruct them from coming together
Important for two forces balance. Two forces should be equal the potential energy between two molecules
at minimum have a stable preparation.
o Dipolar molecules: negative polar and positive polar can contribute forces to solutions as well
o Hydrogen bonding:
Hydrogen atoms move in close to electronegative atoms (F, O, N).
Hydrogen bonds exist also with Esters, Carboxylic acids, Aldehydes, and Polypeptides.
- How to improve solubility conditions? What options are available to pharmacists?
o Different solubilizing agents
o Different chemical salt form of medicinal agent
o Alteration of the pH of a solution
o Partial or whole substitution of a solvent
** Always add solute into solvent – be able to overcome any forces that keep solute interaction intact, don’t want
solute-solute or solvent-solvent
Example: 1g of iodine granules in 3,000 mL (0.03% iodine)
Alternative: dissolve in Potassium Iodide, Sodium Iodide
Iodine Topical Solution, USP (contains 2% iodine, 2.4% sodium
iodide)
- for inorganic molecules
o If cation and anion of an ionic compound are monovalent, solute-solute attractive forces are easily
overcome (i.e., NaCl, LiBr, KI).
o Same is true if one of the two ions in an ionic compound is monovalent (i.e., BaCl2, MgI2)
, o If both the cation and anion are multivalent, the solute-solute interaction may be too great to overcome ( i
CaSO4, BaSO4) This results in POOR WATER SOLUBILITY
o Ammonium and quaternary ammonium salts are water soluble
o Phosphates, Carbonates, Silicates, Borates, and Hypochlorite are water insoluble (except for their alkali m
salts and ammonium salts).
- for organic molecules
o Molecules having one polar functional group is sufficient to solubilize chain lengths consisting of 5 carbon
o Molecules having branched chains are more soluble than corresponding straight-chain compounds
o Water solubility decreases with increase in molecular weight
o Increased structural similarity between solute and solvent = increased solubility (remember: “like dissolves
like”)
Terms used to describe solubility: When the exact solubility is not known (or has yet to be determined), gene
expressions of relative solubility may be used.
Very Soluble <1
When you said something is soluble, you talk Freely Soluble 1-10
about the solvent required for 1 part of solute. Soluble 10-30
When go from very soluble to insoluble, require Sparingly Soluble 30-100
more and more water to be able to dissolve of the Slightly Soluble 100-1000
same concentration of the drug substance Very Slightly Soluble 1000-10000
Practically Insoluble or Insoluble>10000
- Factors influencing solubility:
o Temperature:
□ “Positive heat of solution” – if you have the particular drug compound where the addition of heat w
actually assist the facilitate solution preparation, the drug will dissolve in the particular solvent
solution. If heat can assist the drug substance to get into solution, that drug substance has positive
heat of solution. Not all drugs are benefit from the heat.
o pH of the solution:
□ Weak acids or weak bases – do not want to adjust pH outside comfortable range if ophthalmic, if w
to inject into blood, be careful cause it may become precipitated.
o Physical agitation:
□ Extent to which solvent passes over solute – the more able shaking or agitating, increase the
possibilities solute get into the solvent
o Particle size:
□ Finer the powder, greater the surface area, the more rapid dissolving process
- Beneficial considerations
o Salts of organic compounds are more soluble in water compared to their organic base counterparts.
o Organic bases are more soluble in organic solvents
- “Like dissolves like”: Solvents having chemical structures most similar to the solute will most likely dissolve it
o For i.e., organic compounds are more soluble in organic solvents compared to in water
o One exception is if organic compound has polar functional group
o Polar groups are: OH, CHO, COH, CHOL, CH2OH, COOH, NO2 and SO3H
o In general, halogen atoms decrease solubility
o Because of an increase in MW without proportionate increase in polarity
, Solvents for liquid preparations
- Alcohol, USP: Ethyl Alcohol, ethanol, C2H5OH (internal and external)
o A primary solvent for many organic compounds
o When mixed with water = hydroalcoholic mixture
o Alcohol USP is 94.9% to 96.0% C2H5OH by volume, when determined at 15.56 °C
o 15.56 °C (U.S. government standard temp. for alcohol determinations).
o Dehydrated Alcohol, USP contains not less than 99.5% C2H5OH.
o For drugs not soluble in water alcohol is preferred as a suitable alternative due to its miscibility in water a
ability to dissolve many water insoluble agents.
□ For e.g., Drug agents, flavorants, antimicrobial preservatives.
o When alcohol content is too much, glycerin and glycols can be used to reduce total amount of alcohol needed.
o FDA proposed for manufacturers of OTC oral drug products
□ For children < 6 years of age alcohol limit is 0.5%
□ For children 6 to 12 years of age, limit is 5%
□ For children over 12 years of age & adults limit is 10%
- Diluted alcohol (internal and external)
o Prepared by mixing equal parts of alcohol USP with purified water
o Since liquids tend to contract during mixing the final volume is generally 3% less than what otherwise sho
be expected.
□ For example, if 50 mL of each component is combined the result is 97 mL.
o Dilute alcohol is a useful hydroalcoholic solvent in various pharmaceutical processes and preparations
- Rubbing alcohol (external only)
o Rubbing alcohol contains about 70% ethyl alcohol by volume, remaining is water, denaturants (with or
without color additives and perfume oils and stabilizers).
o To discourage oral ingestion each 100 mL must contain not less than 355mg of sucrose octa-acetate (or
mg of denatonium benzoate) which has a bitter taste.
o Internal Revenue Service- U.S. Treasury Department, the denaturant employed is called Formula 23-H
□ 8 Parts (by volume) of acetone
□ 1.5 Parts (by volume) of methyl isobutyl ketone
□ 100 parts (by volume) of ethyl alcohol
** Product is volatile and flammable, should be stored in tight container remote from fire
- Glycerin, USP (Glycerol) (internal and external)
o A clear syrupy liquid with a sweet taste
o Miscible in water and in alcohol
o Glycerin is naturally viscous, but can be made less viscous by heating
o Can be used as a preservative or stabilizer
o Can also be used for internal applications in addition to external use
- Isopropyl rubbing alcohol (external)
o Isopropyl rubbing alcohol, ~70% isopropyl alcohol. Remaining components are water (with or without
colorants), stabilizers and perfumes.
o Used externally as *rubefacient and soothing rub vehicle for topical purposes.
o To prepare diabetic needles and syringes for hypodermic injections of insulin, a commercially available ~9
isopropyl rubbing alcohol is used also.
** A rubefacient is a substance for topical application that produces redness of the skin e.g. by causing dilation o
capillaries and an increase in blood circulation”
