PHYS 1107 Lecture Notes - Lecture 11: Phenobarbital, Electric Charge, Carboxylic Acid
Solutions
Definition – a homogenous one-phase (only one distinguishable system) system consisting
of the solvent and the solute.
Solutions as an oral dosage form
Advantages:
Liquids absorb faster as drug is already in solution
Easier to drink than swallow
Compounded liquids can be adjusted for dosage amount very easily
Problems:
Measuring out how much liquid is taken for each dose is subject to accuracy of
measuring instrument (tablets are fixed and easy)
Less chemical (liquid state of matter is less stable than solid) and microbial (moisture
promotes this) stability
Solubility of the drug
Important issues to consider:
Solubility
Stability
Compatibility between API and additives (to aid dissolution, suit savoury standards
etc.)
Bioavailability
Type of Formulations – A) Aqueous solutions, B) Non-aqueous solutions
A. Aqueous solutions:
Approaches to enhance aqueous solubility
1. pH adjustment
2. Cosolvency
3. Micellar solubilisation
4. Complexation
5. Chemical Modification
6. Others: nanoparticles, log S/So = 2 γV /2.303 RTr,
where r is particle radius (S is the solubility of the nanoparticles, So the solubility of the large
particles, γ the surface tension of the particles, V the molar volume, R the gas constant, T
the absolute temperature)
1. pH adjustment
Ka For a weakly acidic drug:
DH (solid) ↔ DH (solution) ↔ D ̄ + H+
[D ̄] = [DH] Ka / [H+]
The total amount of drug ST = [DH] + [D-] (free drug + ionized drug)
= [DH] + Ka[DH]/[H+]
Similarly for a weak base [DOH], ST= [DOH] + [D-] (free drug + ionized drug)
= [DH] + (Kb[DOH]/[H+])/Kw
Example: What must be the pH of an aqueous formulation be to give a 10mg/ml solution of a
weakly acidic drug of M.W. 200, [DH] = 0.001M, Ka 1 x 10-5? (answer 6.7)
ST = 10mg/ml -> 0.01g/200gmol-1 x 1000ml = 0.05M
0.05M = 0.001M + (1 x 10-5 x 0.001M)/[H+]
[H+] ~=~ 10-6.7
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Criteria for Selection of a Buffer for Liquid Formulations
1. pH
2. buffer capacity
3. Non-toxic
4. Compatibility
Preparation of Pharmaceutical Buffer Solutions:
Based on HA ↔ A ̄ + H+
USES HENDERSON-HASSELBACH EQUATION :D
1. choose a weak acid, HA, having a pKa ~ pH at which the buffer is to be used
2. calculate the ratio of [A-]/[HA] to obtain the desired pH
3. decide the concentration of [HA] and [A ̄] to obtain the desired buffer capacity (higher
concentrations = more buffering capacity, kind of intuitive)
4. measure the pH (confirmation)
2. Cosolvency
Definition – a phenomenon in which a solute is more soluble in a mixture of solvents than in
a single solvent alone. (must be miscible in water)
The role of dielectric constant of solvents:
Dielectric constant is a solvent property related to the amount of energy required to separate
two opposite charges in the solvent as compared to a vacuum. (Cation + anion)
Inclusion of cosolvent such as alcohol and propylene glycol decrease the dielectric constant
Water - 78, Alcohol - 48, glycerol - 70
a. Lowers the degree of dissociation of the drug
b. Raises the solubility of the un-ionised drug
For aqueous formulations the cosolvent must be miscible.
The solubility of the drug in the cosolvent should be higher. (If it is not higher it is an anti-
solvent - promotes precipitation).
Some common cosolvents are
Ethanol, glycerin, propylene glycol, sorbitol and syrup.
The choice is limited by toxicity.
Examples of enhancing solubility by co-solvents:
Propylene glycol and water for co-trimoxazole Alcohol,
propylene glycol and syrup for paracetamol in elixir
(source: The Theory and Practice of Industrial Pharmacy, 2nd ed, Lachman et al, p. 545)
Phenobarbital solubility 1 g in 1 L (H2O), 1 g in 8 mL (EtOH), Pk1 7.3, PK2 11.8
Remember!! Two opposing forces! Suppression of Ionized form and Solubility of Unionized form!
First suppress ionized form (done by ethanol instead of ethanol dissolving unionized form)
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Then when fully suppressed ethanol can start dissolving the unionized form which increases
total dissolved drug conc.
Solutions
Definition – a homogenous one-phase (only one distinguishable system) system consisting
of the solvent and the solute.
Solutions as an oral dosage form
Advantages:
Liquids absorb faster as drug is already in solution
Easier to drink than swallow
Compounded liquids can be adjusted for dosage amount very easily
Problems:
Measuring out how much liquid is taken for each dose is subject to accuracy of
measuring instrument (tablets are fixed and easy)
Less chemical (liquid state of matter is less stable than solid) and microbial (moisture
promotes this) stability
Solubility of the drug
Important issues to consider:
Solubility
Stability
Compatibility between API and additives (to aid dissolution, suit savoury standards
etc.)
Bioavailability
Type of Formulations – A) Aqueous solutions, B) Non-aqueous solutions
A. Aqueous solutions:
Approaches to enhance aqueous solubility
1. pH adjustment
2. Cosolvency
3. Micellar solubilisation
4. Complexation
5. Chemical Modification
6. Others: nanoparticles, log S/So = 2 γV /2.303 RTr,
where r is particle radius (S is the solubility of the nanoparticles, So the solubility of the large
particles, γ the surface tension of the particles, V the molar volume, R the gas constant, T
the absolute temperature)
1. pH adjustment
Ka For a weakly acidic drug:
DH (solid) ↔ DH (solution) ↔ D ̄ + H+
[D ̄] = [DH] Ka / [H+]
The total amount of drug ST = [DH] + [D-] (free drug + ionized drug)
= [DH] + Ka[DH]/[H+]
Similarly for a weak base [DOH], ST= [DOH] + [D-] (free drug + ionized drug)
= [DH] + (Kb[DOH]/[H+])/Kw
Example: What must be the pH of an aqueous formulation be to give a 10mg/ml solution of a
weakly acidic drug of M.W. 200, [DH] = 0.001M, Ka 1 x 10-5? (answer 6.7)
ST = 10mg/ml -> 0.01g/200gmol-1 x 1000ml = 0.05M
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Document Summary
Definition a homogenous one-phase (only one distinguishable system) system consisting of the solvent and the solute. Liquids absorb faster as drug is already in solution. Compounded liquids can be adjusted for dosage amount very easily. Measuring out how much liquid is taken for each dose is subject to accuracy of measuring instrument (tablets are fixed and easy) Less chemical (liquid state of matter is less stable than solid) and microbial (moisture promotes this) stability. Compatibility between api and additives (to aid dissolution, suit savoury standards etc. ) Type of formulations a) aqueous solutions, b) non-aqueous solutions: aqueous solutions: Dh (solid) dh (solution) d + h+ The total amount of drug st = [dh] + [d-] (free drug + ionized drug) Similarly for a weak base [doh], st= [doh] + [d-] (free drug + ionized drug) Example: what must be the ph of an aqueous formulation be to give a 10mg/ml solution of a weakly acidic drug of m. w.
