Ch4- Lec4- Gen. Consideration in Dosage form Design Flashcards
Dosage forms may be used to improve drug action
•Dosage forms are administered in combination with one or more non-active agents to serve a variety of pharmaceutical functions
•Drug + Receptor Drug-Receptor Complex–
Pharmacologic Response
Dosage form: Improving target specificity
•Dosage forms can be used to optimize delivery of drugs to specific areas
–The more you know about the drug and its intended target, the more options you have available to deliver drug to target site
Characteristics of the ideal dosage form
•The final dosage form should be
–Biocompatible
–Drug and Dosage form should be compatible
–Formulation should be
–Stable
–Easily administered
–Safely administered
–Efficacious
Other reasons for why we need dosage forms?
•To provide protection from destructive chemical influences
•To provide protection from gastric pH
•To address offensive taste or odors
•To provide liquid preparations
•To control the rate of drug release
•To improve drug action
•To provide for insertion into body’s orifices
General concerns
•Match dosage form with appropriate illness
•Select dosage forms to address patient-specific needs
•For children less than 5 years of age the liquid dosage forms for oral route of administration is best
•To assist the elderly with self-medication procedures
Preformulation considerations
•Physical Description
•Microscopic examination
•Melting point depression
•The phase rule
•Particle size
•Polymorphism
–Crystal
–Amorphous
•Solubility
–Solubility and Particle size
–Solubility and pH
•Dissolution
•Membrane Permeability
•Diffusion
–Ficks Law
•Partition Coefficient
•Pharmaceutical Ingredients & Excipients
•Reaction rates
–Zero order reactions
–First order reactions
Physical Description
•Majority of drugs are in solid form
–Crystalline or amorphous constitution
•Chemical properties:
–Structure, form, and reactivity
•Physical Properties:
–Particle size, crystalline structure, melting point and solubility
•Biologic Properties:
–Ability to get to site of drug action and elicit response
Solid >liquid>gas
Microscopic Examination
•Is the appropriate site of
drug action targeted?
•Gives indication of
particle size for finished
Pharmaceuticals
•Some idea of stability
of dosage form
Particles are sized directly, and individually, rather than grouped statistically
Melting Point Depression
•Low melting point drugs soften during a processing step where heat is generated
•The melting point can be used to determine purity
–DSC = Differential Scanning Calorimetry
–Measures thermal phase behavior, and can be used to determine purity of a given drug substance. How??
Melting Point
•Mp Pure A = 124 ºC
•Mp Contaminated A (5% B) = 95-115 ºC
•Used for determining:
–Determination of purity
–Solid drug + Solid pharmaceutics ingredients
DSC
•How do you use it?
–Sample chamber:
Contains dosage form without the drug
–Experimental chamber: Contains dosage form with drug
• This is a thermogram for the melting of lipids used to prepare dosage forms.
• Thermogram: A plot of the energy absorbed as the temperature of the system is raised. For e.g., the peak is caused by the absorption of energy required to melt the lipid bilayer
Phase diagram
•A phase diagram (aka~ temperature-composition diagram) “reveals the melting point as a function of composition of two or
three component systems”
•The phases are non-solid and solid
•When a substance is added to either one of these phases (that is Pure A or Pure B), the melting temperature of the pure component(s) decrease.
•Minimum melting point = EUTECTIC POINT
Particle Size
•Physical and chemical properties of drug substances are affected by particle size distribution
–Drug dissolution rate
–Bioavailability
–Content uniformity
–Sedimentation
–Textures
Polymorphism
•Represents 1/3 rd of all organic compounds
•Different physicochemical properties of drug
–Non crystalline (or amorphous)
–Crystalline (crystal structure)
“The energy required for a molecule of drug to escape from a crystal is much greater than the energy required to escape from an amorphous powder”
THEREFORE,
Amorphous form of drug is more soluble than the crystal form
Polymorphism: examples
•Antibiotic substances
–Novobiocin
–Chloramphenicol
are inactive in crystal form but active in the amorphous form
- *then**
- *Absorption from GI tract is rapid in amorphous form**
•Crystal drugs can be more active due to better stability over amorphous state
–Penicillin G
•Its crystal form results in a better therapeutic response
Solubility and particle size
•“Drug must possess some aqueous solubility to be considered effective” see page 100
•Relatively insoluble compound can lead to incomplete absorption
•Solubility can be increased by chemical modification
•Solubility is determined by an ‘equilibrium solubility’ method.
–Excess of drug is placed in a solvent and shaken at a constant temperature until an equilibrium is obtained.
–This is done to determine the degree of solubility
Solubility and pH
•pH: Measure of a substances acidity
•The pH can be adjusted to enhance solubility.
•Not all drugs can benefit from adjustments to pH.
–“For example weak acids and strong bases require significant changes in pH that are outside the physiological limits.
•When manipulation of pH is not an option due to physiological issues, the following can be used,
–Co-solvents:
–Micronization:
–Dispersion:
–Emulsion:
Dissolution
•Dissolution: The time it takes for a drug to dissolve in fluids at the absorption site.
•Dissolution is the rate limiting step in the absorption process
–Absorption rate will ↑ with ↓ in particle size
–Dissolution will ↑ with ↑ in solubility, ex., highly soluble salt of parent drug
–Dissolution can influence duration of therapeutic effect
Diffusion
•Most drugs undergo transport by simple diffusion, whether in the cytoplasm or interstitial fluid environment
•Fick’s law of diffusion (simple passive diffusion)
–Transfer of drugs from an area of high conc. (C1) to an area of low conc. (C2).
–dQ/dt = DA/h (C1- C2)
–Formula symbols: dQ/dt = rate of drug diffusion; D = diffusion coefficient for drug; A = surface area a cross which transfer occurs; h = thickness of the region through which diffusion occurs
Membrane Permeability
•Drugs must cross biological membranes to exert a biologic response
–Lipid soluble drugs have little problem
–Lipid insoluble drugs require additional assistance
What about special challenges caused by the overexpression of highly specialized features on cellular surfaces?
Membrane Permeability 2
•“Everted intestinal sac”
–Used to evaluate absorption characteristics of drug substances
–How does it work?
–A piece of intestine is removed from an intact animal, everted, filled with drug to be tested and degree and rate of passage of drug through membrane is determined
»-Normally used to study active and passive transport
Partition Coefficient
•Optimal balance between water and lipid solubility
P = Conc. of drug in octanol/
Conc. of drug in water
Octanol (hydrophobic environment)
Water (Aqueous environment)
27
When is the partition coefficient useful?
•When recovering antibiotics from fermentation broth
•When extracting drugs from biologic fluids for therapeutic monitoring
•Absorption of drugs from dosage forms (ointments, suppositories etc..)
•Study of distribution of flavoring oils between oil and water phases of emulsions
How is the partition coefficient measured?
•Shake a known amount of drug in a flask containing a measured amount of water and octanol.
•Phosphate buffer (pH 7.4) is used to mimic physiological pH. This also corrects for the ratio of [conjugated base]/[acid] found in vivo.
•The amount of drug in one or both of the phases is determined by HPLC (or by some other quantitative analytical approach).
Pharmaceutics Ingredients and Excipients
•One or more inactive agents are used to prepare final dosage forms
–Flavors, and sweeteners: improve taste
–Colorants: enhances appearance
–Preservatives: prevent microbial growth
–Stabilizers: prevent decomposition
–Diluents or fillers: to increase bulk
–Binders: improves adhesive properties
–Anti-adherents/ or lubricants: smooth coating
–Disintegrating agents: promotes tablet breakup
See page 128-132 for examples of each
Reaction rates
•Since drug therapy is a dynamic process, the time it takes for a reaction to occur is important in terms of development of drug products, and drug behavior.
•Rate of reaction: Actual speed of velocity at which the dynamic process occurs
•Drug Some Product, or Some Outcome
–Drug decomposition
–Drug dissolving in H20 to give solution
–Drug absorption
–Drug metabolism
Zero order reactions
•In this reaction rate the rate is a constant, and thus does not change with time.
•The term ko is the zero order reaction rate
•The amount of drug removed over any given period of time is a constant,
• = -kot + C0 use to calculate zero order reaction rates
First-Order Reactions
•This a reaction rate that depends on the concentration of only one reactant.
•Rate of reaction is initially fast when the concentration (C) is large; as C decreases the reaction slows as the reaction proceeds
•The higher the concentration of drug the faster the rate process
•Most reactions dealing with pharmaceutical products follow this process
•lnc = -kt + lnC 0 use to calculate first order reaction rates
The amount of drug removed each year decreases with time, but percentage or the fraction removed over this period of time remains constant
•Dosage forms are administered in combination with one or more non-active agents to serve a variety of pharmaceutical functions
•Drug + Receptor Drug-Receptor Complex–
Pharmacologic Response
Dosage forms may be used to improve drug action
•Dosage forms can be used to optimize delivery of drugs to specific areas
–The more you know about the drug and its intended target, the more options you have available to deliver drug to target site
Dosage form: Improving target specificity
•The final dosage form should be
–Biocompatible
–Drug and Dosage form should be compatible
–Formulation should be
–Stable
–Easily administered
–Safely administered
–Efficacious
Characteristics of the ideal dosage form
•To provide protection from destructive chemical influences
•To provide protection from gastric pH
•To address offensive taste or odors
•To provide liquid preparations
•To control the rate of drug release
•To improve drug action
•To provide for insertion into body’s orifices
Other reasons for why we need dosage forms?
•Match dosage form with appropriate illness
•Select dosage forms to address patient-specific needs
•For children less than 5 years of age the liquid dosage forms for oral route of administration is best
•To assist the elderly with self-medication procedures
General concerns
•Physical Description
•Microscopic examination
•Melting point depression
•The phase rule
•Particle size
•Polymorphism
–Crystal
–Amorphous
•Solubility
–Solubility and Particle size
–Solubility and pH
•Dissolution
•Membrane Permeability
•Diffusion
–Ficks Law
•Partition Coefficient
•Pharmaceutical Ingredients & Excipients
•Reaction rates
–Zero order reactions
–First order reactions
Preformulation considerations
•Majority of drugs are in solid form
–Crystalline or amorphous constitution
•Chemical properties:
–Structure, form, and reactivity
•Physical Properties:
–Particle size, crystalline structure, melting point and solubility
•Biologic Properties:
–Ability to get to site of drug action and elicit response
Solid >liquid>gas
Physical Description
•Is the appropriate site of
drug action targeted?
•Gives indication of
particle size for finished
Pharmaceuticals
•Some idea of stability
of dosage form
Particles are sized directly, and individually, rather than grouped statistically
Microscopic Examination
•Low melting point drugs soften during a processing step where heat is generated
•The melting point can be used to determine purity
–DSC = Differential Scanning Calorimetry
–Measures thermal phase behavior, and can be used to determine purity of a given drug substance. How??
Melting Point Depression
•Mp Pure A = 124 ºC
•Mp Contaminated A (5% B) = 95-115 ºC
•Used for determining:
–Determination of purity
–Solid drug + Solid pharmaceutics ingredients
Melting Point
–Sample chamber:
Contains dosage form without the drug
–Experimental chamber: Contains dosage form with drug
• This is a thermogram for the melting of lipids used to prepare dosage forms.
• Thermogram: A plot of the energy absorbed as the temperature of the system is raised. For e.g., the peak is caused by the absorption of energy required to melt the lipid bilayer
DSC
•How do you use it?
•A phase diagram (aka~ temperature-composition diagram) “reveals the melting point as a function of composition of two or
three component systems”
•The phases are non-solid and solid
•When a substance is added to either one of these phases (that is Pure A or Pure B), the melting temperature of the pure component(s) decrease.
•Minimum melting point = EUTECTIC POINT
Phase diagram
•Physical and chemical properties of drug substances are affected by particle size distribution
–Drug dissolution rate
–Bioavailability
–Content uniformity
–Sedimentation
–Textures
Particle Size
•Represents 1/3 rd of all organic compounds
•Different physicochemical properties of drug
–Non crystalline (or amorphous)
–Crystalline (crystal structure)
“The energy required for a molecule of drug to escape from a crystal is much greater than the energy required to escape from an amorphous powder”
THEREFORE,
Amorphous form of drug is more soluble than the crystal form
Polymorphism
•Antibiotic substances
–Novobiocin
–Chloramphenicol
are inactive in crystal form but active in the amorphous form
- *then**
- *Absorption from GI tract is rapid in amorphous form**
•Crystal drugs can be more active due to better stability over amorphous state
–Penicillin G
•Its crystal form results in a better therapeutic response
Polymorphism: examples
•“Drug must possess some aqueous solubility to be considered effective” see page 100
•Relatively insoluble compound can lead to incomplete absorption
•Solubility can be increased by chemical modification
•Solubility is determined by an ‘equilibrium solubility’ method.
–Excess of drug is placed in a solvent and shaken at a constant temperature until an equilibrium is obtained.
–This is done to determine the degree of solubility
Solubility and particle size
•pH: Measure of a substances acidity
•The pH can be adjusted to enhance solubility.
•Not all drugs can benefit from adjustments to pH.
–“For example weak acids and strong bases require significant changes in pH that are outside the physiological limits.
•When manipulation of pH is not an option due to physiological issues, the following can be used,
–Co-solvents:
–Micronization:
–Dispersion:
–Emulsion:
Solubility and pH
•Dissolution: The time it takes for a drug to dissolve in fluids at the absorption site.
•Dissolution is the rate limiting step in the absorption process
–Absorption rate will ↑ with ↓ in particle size
–Dissolution will ↑ with ↑ in solubility, ex., highly soluble salt of parent drug
–Dissolution can influence duration of therapeutic effect
Dissolution
•Most drugs undergo transport by simple diffusion, whether in the cytoplasm or interstitial fluid environment
•Fick’s law of diffusion (simple passive diffusion)
–Transfer of drugs from an area of high conc. (C1) to an area of low conc. (C2).
–dQ/dt = DA/h (C1- C2)
–Formula symbols: dQ/dt = rate of drug diffusion; D = diffusion coefficient for drug; A = surface area a cross which transfer occurs; h = thickness of the region through which diffusion occurs
Diffusion
•Drugs must cross biological membranes to exert a biologic response
–Lipid soluble drugs have little problem
–Lipid insoluble drugs require additional assistance
What about special challenges caused by the overexpression of highly specialized features on cellular surfaces?
Membrane Permeability
•“Everted intestinal sac”
–Used to evaluate absorption characteristics of drug substances
–How does it work?
–A piece of intestine is removed from an intact animal, everted, filled with drug to be tested and degree and rate of passage of drug through membrane is determined
»-Normally used to study active and passive transport
Membrane Permeability 2
•Optimal balance between water and lipid solubility
P = Conc. of drug in octanol/
Conc. of drug in water
Octanol (hydrophobic environment)
Water (Aqueous environment)
27
Partition Coefficient
•When recovering antibiotics from fermentation broth
•When extracting drugs from biologic fluids for therapeutic monitoring
•Absorption of drugs from dosage forms (ointments, suppositories etc..)
•Study of distribution of flavoring oils between oil and water phases of emulsions
When is the partition coefficient useful?
•Shake a known amount of drug in a flask containing a measured amount of water and octanol.
•Phosphate buffer (pH 7.4) is used to mimic physiological pH. This also corrects for the ratio of [conjugated base]/[acid] found in vivo.
•The amount of drug in one or both of the phases is determined by HPLC (or by some other quantitative analytical approach).
How is the partition coefficient measured?
•One or more inactive agents are used to prepare final dosage forms
–Flavors, and sweeteners: improve taste
–Colorants: enhances appearance
–Preservatives: prevent microbial growth
–Stabilizers: prevent decomposition
–Diluents or fillers: to increase bulk
–Binders: improves adhesive properties
–Anti-adherents/ or lubricants: smooth coating
–Disintegrating agents: promotes tablet breakup
See page 128-132 for examples of each
Pharmaceutics Ingredients and Excipients
•Since drug therapy is a dynamic process, the time it takes for a reaction to occur is important in terms of development of drug products, and drug behavior.
•Rate of reaction: Actual speed of velocity at which the dynamic process occurs
•Drug Some Product, or Some Outcome
–Drug decomposition
–Drug dissolving in H20 to give solution
–Drug absorption
–Drug metabolism
Reaction rates
•In this reaction rate the rate is a constant, and thus does not change with time.
•The term ko is the zero order reaction rate
•The amount of drug removed over any given period of time is a constant,
• = -kot + C0 use to calculate zero order reaction rates
Zero order reactions
•This a reaction rate that depends on the concentration of only one reactant.
•Rate of reaction is initially fast when the concentration (C) is large; as C decreases the reaction slows as the reaction proceeds
•The higher the concentration of drug the faster the rate process
•Most reactions dealing with pharmaceutical products follow this process
•lnc = -kt + lnC 0 use to calculate first order reaction rates
The amount of drug removed each year decreases with time, but percentage or the fraction removed over this period of time remains constant
First-Order Reactions
