PDD Cumulative Final Notes
Lecture 1: Introduction
Learning Objectives
1. Identify major dosage forms
2. Explain physicochemical principles relevant to dosage forms
3. Comparison of different dosage forms with specific reference to: reason for use, physical
form, stability/mechanisms for instability, bioavailability, patient acceptance
- Pharmaceutics: formulation, manufacturing, stability, effectiveness of pharmaceutical
dosage forms
- Consideration of dosage forms
Therapeutic considerations: systemic use, emergency use, age (young
children/elderly)
- Excipients: pharmaceutical ingredients in dosage form other than active agent
Solubility: solvents, surfactants
Palatability: sweeteners
Stability: antimicrobials, antioxidants
Others: diluents-safe/convenient delivery of accurate dosage, binders, lubricants,
disintegrating agents
Lecture 2: Drug Release/Dissolution
Learning Objectives
1. Define: dissolution, solubility
2. Explain mechanism of dissolution
3. Understand how different factors influence dissolution
4. Describe biopharmaceutical classification system
5. Apply knowledge of dissolution and biopharmaceutical classification to predict how drugs
might behave in different conditions
- Dissolution: compound goes from solid into solution in a solvent
Prior to absorption
Rate limiting step in absorption
Can affect onset, intensity, duration of response
1. Interfacial reaction: drug dissolves at surface of solid, forming thin film (S=Csat)
2. Concentration gradient develops-high drug conc in diffusion layer, low conc in
bulk solvent
Passive diffusion: mass of drug moving out into surrounding area- Dissolution rate:
DA(S-C)/h
i. h= thickness of diffusion layer, C=conc drug in bulk solution, (S-
C)=concentration gradient, S=drug solubility, S=Csat,
- Fick’s Law of passive diffusion: J=dm/dt=-Ddc/dx
J: flux, dc/dx: concentration gradient
, - Factors influencing dissolution:
Particle size/surface area
Viscosity of diffusion layer (food increases viscosity-decreases D)
Use of parent substance salt or salt w lower solubility
Temperature (influences D and conc of drug in diffusion layer)
Agitation, GI motility
pH of medium, pKa of drug
solubility
rate of removal of solute from medium
MW of drug
- Solubility: amount of solute that dissolves in given solvent volume at temp and p
Extent of dissolution under certain conditions
S=solubility at pH, T (mg/mL)
S0=saturation solubility of unionized drug
A solution that dissolves 3.3% or more of a solute is considered soluble
Partitioning of Drugs and Distribution
Biopharmaceutical Classification System of Active Pharmaceutical Ingredients
- I: high solubility, high permeability
, Dissolve rapidly, rapidly transverse gut wall
- II: low solubility, high permeability
Dissolve slowly, rapid transverse of gut wall
Formulation approaches to improve dissolution rate to enhance F
- III: high solubility, low permeability
Dissolve rapidly, poorly permeably across gut wall
Formulation approaches to improve permeability to enhance F
- IV: low solubility, low permeability
Dissolve slowly, poorly permeable across gut wall
Cannot be given PO
Formulation approaches: prodrug, lipid based drug delivery
Pharmaceutical Solutions
Learning Objectives
1. Compare/contrast 3 types of pharmaceutical dispersions
2. Describe advantages/disadvantages of formulating a drug as solution
3. Describe solvent systems used in solutions
4. Describe how aq solubility of API in solution can be augmented w cosolvents, pH
optimization, complexation
5. Understand importance of taste masking for pediatric patients
6. Describe taste making technologies currently in use/under dev for solutions
7. Understand MOA of commonly used preservatives, how their activity relates to other
excipients
8. Describe how antioxidants and chelators protect APIs in solutions
9. Explain purpose of viscosity enhancers
- True solutions: two or more component mixture, homogenous molecular dispersion
Solutes <1nm, not large enough to scatter light, 1 phase
- Colloidal dispersion: particles 1-500 nm, scatter light, may appear visibly turbid
i. Lyophilic: particles have affinity for dispersion medium
ii. Lyophobic: particles lack affinity for dispersion medium
iii. Association colloids: self-association of amphiphilic solutes that form colloid
above certain conc (micelle formation above CMC)
- Coarse dispersion: particles >500 nm, scatter light, appear cloudy
i. Solid in liquid coarse dispersion: suspension
ii. Liquid in liquid coarse dispersion: emulsion
- Advantages of solutions:
i. More easily admin PO for swallowing
ii. Drug already dissolved, readily absorbed, potentially increase F over solid PO
forms
iii. Taste masking
- Disadvantages of solutions
i. Unsuitable for chemically unstable agents in presence of water
, ii. Poor drug solubility could prohibit formulation (but techniques to deal w this)
iii. Expensive to ship/bulky, inconvenient for PT carrying and use
Components of Pharmaceutical Solution
- API, solvent/vehicle, cosolvents, buffers, complexing agents, tastemasking agents,
preservatives, rheology (viscosity) enhancers, antioxidants, chelators, colorants
Solvent Systems
- Water: preferred, common, solid residue <1mg/100mL purified water
- Aromatic water: saturated aq solution of volatile oil
Oil triturated w talc, mixed w purified water 500x volume oildissolves in water,
filtered
- Alcohol/oil: aq solutions cannot be formulated
i. Alcohol: ethanol, glycerol
ii. Oils: peanut, corn
Improving Aq solubility
- Optimize pH: done w buffer system, API more soluble in ionized state
i. APIs w ionizable groups within ph2-8 good candidates for pH optimization
ii. Common buffer systems: acetate (3.7-5.6), citrate (3-6.2), phosphate (5.8-8)
K= [Drug]solution/[Drug]solid =S0 intrinsic solubility
- Make a salt
- Add a cosolvent: addition of water miscible organic solvent to reduce polarity of aq
system helps solubilize non polar/non ionized drugs and unionized components of
ionizable drugs
i. Ethanol, PEG, PEO, propylene glycol, glycerol
- Complexation: CDs (cyclic oligosaccharides from starch)-3 general classes by
increasing size-alpha, beta, gamma-derivatives by attaching R groups to backbone
Lecture 1: Introduction
Learning Objectives
1. Identify major dosage forms
2. Explain physicochemical principles relevant to dosage forms
3. Comparison of different dosage forms with specific reference to: reason for use, physical
form, stability/mechanisms for instability, bioavailability, patient acceptance
- Pharmaceutics: formulation, manufacturing, stability, effectiveness of pharmaceutical
dosage forms
- Consideration of dosage forms
Therapeutic considerations: systemic use, emergency use, age (young
children/elderly)
- Excipients: pharmaceutical ingredients in dosage form other than active agent
Solubility: solvents, surfactants
Palatability: sweeteners
Stability: antimicrobials, antioxidants
Others: diluents-safe/convenient delivery of accurate dosage, binders, lubricants,
disintegrating agents
Lecture 2: Drug Release/Dissolution
Learning Objectives
1. Define: dissolution, solubility
2. Explain mechanism of dissolution
3. Understand how different factors influence dissolution
4. Describe biopharmaceutical classification system
5. Apply knowledge of dissolution and biopharmaceutical classification to predict how drugs
might behave in different conditions
- Dissolution: compound goes from solid into solution in a solvent
Prior to absorption
Rate limiting step in absorption
Can affect onset, intensity, duration of response
1. Interfacial reaction: drug dissolves at surface of solid, forming thin film (S=Csat)
2. Concentration gradient develops-high drug conc in diffusion layer, low conc in
bulk solvent
Passive diffusion: mass of drug moving out into surrounding area- Dissolution rate:
DA(S-C)/h
i. h= thickness of diffusion layer, C=conc drug in bulk solution, (S-
C)=concentration gradient, S=drug solubility, S=Csat,
- Fick’s Law of passive diffusion: J=dm/dt=-Ddc/dx
J: flux, dc/dx: concentration gradient
, - Factors influencing dissolution:
Particle size/surface area
Viscosity of diffusion layer (food increases viscosity-decreases D)
Use of parent substance salt or salt w lower solubility
Temperature (influences D and conc of drug in diffusion layer)
Agitation, GI motility
pH of medium, pKa of drug
solubility
rate of removal of solute from medium
MW of drug
- Solubility: amount of solute that dissolves in given solvent volume at temp and p
Extent of dissolution under certain conditions
S=solubility at pH, T (mg/mL)
S0=saturation solubility of unionized drug
A solution that dissolves 3.3% or more of a solute is considered soluble
Partitioning of Drugs and Distribution
Biopharmaceutical Classification System of Active Pharmaceutical Ingredients
- I: high solubility, high permeability
, Dissolve rapidly, rapidly transverse gut wall
- II: low solubility, high permeability
Dissolve slowly, rapid transverse of gut wall
Formulation approaches to improve dissolution rate to enhance F
- III: high solubility, low permeability
Dissolve rapidly, poorly permeably across gut wall
Formulation approaches to improve permeability to enhance F
- IV: low solubility, low permeability
Dissolve slowly, poorly permeable across gut wall
Cannot be given PO
Formulation approaches: prodrug, lipid based drug delivery
Pharmaceutical Solutions
Learning Objectives
1. Compare/contrast 3 types of pharmaceutical dispersions
2. Describe advantages/disadvantages of formulating a drug as solution
3. Describe solvent systems used in solutions
4. Describe how aq solubility of API in solution can be augmented w cosolvents, pH
optimization, complexation
5. Understand importance of taste masking for pediatric patients
6. Describe taste making technologies currently in use/under dev for solutions
7. Understand MOA of commonly used preservatives, how their activity relates to other
excipients
8. Describe how antioxidants and chelators protect APIs in solutions
9. Explain purpose of viscosity enhancers
- True solutions: two or more component mixture, homogenous molecular dispersion
Solutes <1nm, not large enough to scatter light, 1 phase
- Colloidal dispersion: particles 1-500 nm, scatter light, may appear visibly turbid
i. Lyophilic: particles have affinity for dispersion medium
ii. Lyophobic: particles lack affinity for dispersion medium
iii. Association colloids: self-association of amphiphilic solutes that form colloid
above certain conc (micelle formation above CMC)
- Coarse dispersion: particles >500 nm, scatter light, appear cloudy
i. Solid in liquid coarse dispersion: suspension
ii. Liquid in liquid coarse dispersion: emulsion
- Advantages of solutions:
i. More easily admin PO for swallowing
ii. Drug already dissolved, readily absorbed, potentially increase F over solid PO
forms
iii. Taste masking
- Disadvantages of solutions
i. Unsuitable for chemically unstable agents in presence of water
, ii. Poor drug solubility could prohibit formulation (but techniques to deal w this)
iii. Expensive to ship/bulky, inconvenient for PT carrying and use
Components of Pharmaceutical Solution
- API, solvent/vehicle, cosolvents, buffers, complexing agents, tastemasking agents,
preservatives, rheology (viscosity) enhancers, antioxidants, chelators, colorants
Solvent Systems
- Water: preferred, common, solid residue <1mg/100mL purified water
- Aromatic water: saturated aq solution of volatile oil
Oil triturated w talc, mixed w purified water 500x volume oildissolves in water,
filtered
- Alcohol/oil: aq solutions cannot be formulated
i. Alcohol: ethanol, glycerol
ii. Oils: peanut, corn
Improving Aq solubility
- Optimize pH: done w buffer system, API more soluble in ionized state
i. APIs w ionizable groups within ph2-8 good candidates for pH optimization
ii. Common buffer systems: acetate (3.7-5.6), citrate (3-6.2), phosphate (5.8-8)
K= [Drug]solution/[Drug]solid =S0 intrinsic solubility
- Make a salt
- Add a cosolvent: addition of water miscible organic solvent to reduce polarity of aq
system helps solubilize non polar/non ionized drugs and unionized components of
ionizable drugs
i. Ethanol, PEG, PEO, propylene glycol, glycerol
- Complexation: CDs (cyclic oligosaccharides from starch)-3 general classes by
increasing size-alpha, beta, gamma-derivatives by attaching R groups to backbone
