Exam 1 Dosage Forms

solution

a mixture of 2 or more components that form a single phase that is homogenous down to the molecular level
* most pharmeceutical solutions contain multiple ingredients
* there can be be multiple solutes and solvents
* the resulting solution is completely liquid

solvent

is a drug carrier that carries the drug to the patient
* aka vehicle

solutes

molecules dissolved in the solvent
*excipients buffers, antimicrobial preservative, flavors, etc

API

active pharmaceutical ingredient

Drug Particle

a solid with a particular size and surface area

Is the drug dissolved or undissolved when there are many drug molecules "stuck" together?

undissolved

Drug molecule

has a molecular weight
* a single drug molecule dissolved in a solvent is a dissolved drug

Dissolution

the process by which a solid solute enters a solution
* it is the transfer of ions from the solid state into the solution

What factors affect dissolution?

temperature, co-solvents, stirring

Rate of Dissolution (ROD)

how much a drug is dissolved over a fixed amount of time

What is the Rate of Dissolution measured in?

Mg/min (amount/time)

solubility

the analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent
*extent=how much is dissolved

What is solubility measured in?

Mg/mL (amount/volume)

What are the 2 main importances of solubility?

1. drug absorption
2.maximum dose

Drug Absorption

a drug molecule must be in solution in order to move across the biological membranes and/or bind to receptors

maximum Dose

Drugs must have a high enough solubility for the selected dosage form
* if the solubility is not high enough, the dose can be limited

Saturation solubility

a solution containing the maximum amount of solute that can dissolve in the solvent
*additional solute will not dissolve
*undissolved solute may present as Cs

What does saturation solubility tell pharmacists?

maximum dose of the drug

What are the 4 factors that affect saturation solubility

1. temperature: important for storage and shipping
2. pressure: atmosphere; cannot be controlled without an autoclave
3. solvent
4. other solute molecules that are in the solution
* solvent will interact with the other molecules which reduces the amount of solvent available to interact with the drug

What are the 3 steps in solubility interactions?

1. solute-solute
2. solvent-solvent
3. solute-solvent

Step One: Solute-Solute

the removal of solute molecule from solid solute
* requires energy
* the greater the interaction between solute molecules, the tighter they are held in the solid state and more difficult to dissolve

Step Two: Solvent-Solvent

the separation of solvent molecules to create a cavity for solute
* requires energy
*creates solute-solvent contacts

Step Three: Solute-Solvent

the insertion of the solute molecule into the cavity created in the solvent
*releases energy
* the attraction between the solute and solvent are very important in this step as strong solute-solvent interactions favor solubility

unsaturated solution

contains a solute below the limits of its solubility at a given temperature and pressure
*the bulk solution is often unsaturated
*if the drug is not very soluble, the dose may be hard to deliver as a solution

Are most pharmaceutical systems saturated or unsaturated?

unsaturated

super saturated

when the solute concentration in a solution is greater than its equilibrium solubility
*usually there is no undissolved solute present
*is the solution in which the solubility limit of the solute has been exceeded at a given temperature and pressure

Dissolution

when a solid absorbs energy to become liquid (1) and then dissolves to become a solution (2)

1. removal of solute molecule from solid solute and separation of solvent molecules to create a cavity
2. insertion of solute molecules into the cavity created in the solvent

Heat of Solution

the amount of heat absorbed or released when 1 mol of solute dissolves in 1 Liter of solvent (usually water)
* takes energy for the water molecules to pull on a solute, causing it to separate. Energy is then released when the water molecules are attracted to and bond to a solute.

What determines if dissolution will be endothermic or exothermic?

the energy balance

Endothermic dissolution

Less energy is released when water bonds to the solute than it takes to separate the solute
* Temperature decreases (surroundings get cooler)

Exothermic dissolution

More energy is released when water bonds to the solute than it takes to separate the solute
* Temperature increases (surroundings get warmer)

Temperature Independent Dissolution

when heat is neither released or absorbed
*solubility is not affected by temperature changes

What are the 5 factors affection solubility at temperature and pressure?

1. molecular size
2. boiling point of pure solvent and melting point of pure solute
3. chemical substitutions on the solute molecule
4. solid state characteristics
5. solvent characteristics

(1) Molecular size

* need to create solute-solvent contacts
*the larger molecules require larger cavities and a greater number of solvent contacts
*** solubility decreases as a molecule gets bigger and increases as a molecule gets smaller

(2) Boiling point of pure solvent and melting point of pure solute

*measures of the strength of "interaction" within the respective pure compounds
*the higher the melting point of the solute, the lower the solubility
*** more thermodynamically stable---> more energy to solubilize the solute
*the lower the melting point of the solute, the higher the solubility
*** less thermodynamically stable--->less energy to solubilize the solute

Does aqueous solubility increase or decrease with increasing boiling and melting point?

decreases

Does aqueous solubility increase or decrease with decreasing boiling and melting point?

increases

(3) Chemical Substitutions

*affect the solubility of molecules in water by altering the interaction the solute molecule has with water molecules
* ionization of substituents increase solubility
* position of substituents can influence solubility
*polarity of compounds

(4) Polarity of Compounds

*typically contain several functional groups
*the proportion of polar and non-polar groups determine overall polarity
* structures are often optimized to make drugs somewhat soluble in a polar and non-polar environment

What are the 2 functions of polar functional groups?

1. hydrogen bonding with water (hydrophillic)
2. increase aqueous solubility

What are the 2 functions of non-polar functional groups?

1. decrease aqueous solubility
2. be able to cross biological membranes (lipophillic)
* ex -Cl and -CH3

Crystalline solid State

Atoms are arranged in regular repetitive pattern
•Crystal lattice•Long range order
•Defined physical properties-- Example: sharp melting point
•Higher chemical stability --> higher melting points and lower solubility
•Exhibits polymorphism
•Most drugs

Amorphous Solid State

Disordered arrangements of molecules with weak interactions between atoms
• No distinguishable crystalline lattice
• Short range order
•Poorly defined physical properties• Example: no defined melting point so soften at a wide variety of temperatures
•Lower chemical stability --> faster dissolution and higher solubility
•Less physical stability --> crystallize overtime over time when stressed

What are the 2 classes for marketed amorphous products?

1. API's - only a few• accolate, ceftin, accupril, viracept
2. Amorphous: cresamet, Gris-Peg, Isoptin, Kaletra, Sproanox

Crystalline Polymorphs

Solids with more than one crystalline form
•Chemically identical but have different physical properties (MP, solubility, etc.)
•Unstable crystalline forms exhibit a faster dissolution rate than stable crystalline forms
• As stability increases, bioavailability decreases
•Chloramphenicol palmitate has 3 polymorphs

What are the 3 polymorphs?

1:stable
2.metastable
3.unstable - too unstable to be used in a pharmaceutical dosage form

solvate

drug and solvent molecules associated with one another to produce a crystal

Hydrate

solvate with water as the solvent
* The greater the degree of solvation, the lower the solubility and dissolution rate as compared to the anhydrous form
*Adding more water to a crystal structure makes it more stable
**Example: dihydrate is more stable than monohydrate

solvent

Like dissolves like --> compounds are more likely to dissolve in solvents with similar chemical properties

polar

Large dipole moments
• High dielectric constants
• Water or miscible with water

Non-polar

Low dipole moments
• Small dielectric constants
• Not miscible with water
• Examples: hydrocarbons, oils, lipids

Semi-Polar

Intermediate dipole moment
• Intermediate dielectric constant
• Miscible with water

Solvent: Dosage From Considerations

Oral: GIT (stomach, small intestine, large intestine, and colon)
** Aqueous based products: water
Injections: muscle, subcutaneous fat
**Nonaqueous based products: vegetable oil
Topical
**Nonaqueous based products: mineral oil, petrolatum

Water as a Polar Solvent

Primary interactions that allow solutes to dissolve in water:
• Ion-dipole interactions
• Van der Waals Forces
• Dipole-dipole interactions
• Dipole-induced dipole interactions
• Hydrogen bonds

Non-Polar Solvent

Hydrophobic interactions: van der Waals forces •Hydrophobic compounds will not dissolve in water to any great extent
•Hydrophobic effect = repel water
•Compounds that dissolve in nonpolar solvents are called lipophilic
•Immiscible with water

Semi-Polar Solvent

Solvents that exhibit strong dipole but do not have a strong hydrogen bonding activity
•Fall between water (polar) and lipids (nonpolar)
•Capable of dissolving both polar and nonpolar substances
***Example: alcohols have a lower dielectric constant and exhibit a greater affinity toward dissolving neutral compounds than water
•Miscible with both water and some lipids
•Used as co-solvents: mix of solvents with different polarities to enhance solubility in water
** alcohols are the most common

Co-solvent system

Water is the solvent of choice
•Drugs/excipients with limited solubility and/or limited stability in water require the addition of a co-solvent
•Mix co-solvents with water to dissolve nonpolar drugs
•Biocompatible small alcohols and polyhydroxyl liquids overcome the solubility and stability issues
•Form three component homogeneous system (solution)

What are the three component homogeneous system (solution)?

1. Ethanol: most common
* enhances the solubility of alkaloids, glycosides, essential oils, resins
2. Glycerin and propylene glycol
* Cosolvents for salts, vegetable acids, enzymes (pepsin), carbohydrates, gums, and some natural products
3. Isopropyl alcohol
* External uses (lotions and liniments)

What are the 2 different types of solubility?

1. Intrinsic aqueous solubility = So
*Includes only non-electrolytes and unionized acids and bases
* Unionized form of acids = HA
* Unionized form of weak bases = NH2
*Equilibrium constant
2. Observed solubility = St
* Saturation solubility
* Unionized and ionized drug
* pH dependent

Intrinsic aqueous solubility = So

S0 is dependent on the chemical structure of the drug without the complication of ionization
•S0 is always measured at a pH where the compound is entirely unionized use a buffer
•Same as P
•Concentration of a saturated solution of the compound in water at a given temperature.
Drug solid ---> Drug solution
•Further addition of solid drug will not change the concentration of drug in solution

What are the 4 Factors Affecting Intrinsic Aqueous Solubility?

1. drugs chemical and solid states structure
2. temperature
* as temp increases So increase
3. determined solvent
4. not very practical

Pharmacokinetics

the study of what the body does to the drug
** movement of any drug going into, through, and out of the body (ADME).

PharmacoKINETICS

essentially means movement; study of forces acting on mechanisms.

ADME

absorption, distribution, metabolism, excretion

Pharmacodynamics

The study of what the drug does to the body; refers to how the drug works and how it exerts its power on the body.
**fancy term for drug efficacy and toxicity

'dynamo'

refers to energy or power

What are the 3 things that Pharmacodynamics focuses on?

1. receptor binding
2. post-receptor effects
3. chemical interactions

Bioavailibility

The extent a substance or drug becomes completely available to its intended biological destination(s); Measure of the rate and fraction of the initial dose of a drug that successfully reaches either the site of action or the bodily fluid domain from which the drug's intended targets have unimpeded access.
***Fraction of the active form of a drug that reaches systemic circulation unaltered. (This definition assumes 100% of the active drug that enters systemic circulation will successfully reach the target site)
**** Bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation

What is the bioavailability when a drug is administered via IV?

100%
***when a medication is administered via routes other than IV, its bioavailability is generally lower than that of IV due to Intestinal endothelium absorption and First Pass Metabolism/First pass effect/pre-systemic metabolism

first pass effect

Phenomenon of drug metabolism whereby the concentration of a drug (specifically when administered orally) is greatly reduced before it reaches the systemic circulation
• It's the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall

What are the 2 sites in which the first pass effect may take place?

1. liver
***This first pass through the liver greatly reduce the bioavailability of the drug.
2. gut

Why is dissolution important?

A drug must be in solution to diffuse across biological membranes
- drug absorption

What is a liquid solution?

a homogeneous solution that is comprised of a solvent and a solute.
* The resulting solution is completely liquid, meaning there is no precipitated material throughout the solution. - molecules in solution- no "particles"

Can there be multiple solutes and solvents?

yes

Cmax

Maximum plasma concentration of a drug.

AUC

area under the curve, represents the extent of drug absorption or the quantity of a drug that appears in the bloodstream following administration

T 1/2

• Time needed to clear 50% of a drug from the plasma
• Frequency of administration for effect

Cmin

minimum effective plasma concentration
* the plasma concentration is low which will result in the next dose needing to be taken

MTC

Maximum therapeutic concentration - at which the greatest therapeutic effect of a drug is achieved

MEC

maximum effective concentration

Dissolve

to cause a solute to pass into a solution.
- a solid going into a liquid phase
- dissolving = dissolution

Diffusion Layer Model

* If dissolution is favored a substance is said to be soluble in that solvent.
* If dissolution is not favored a substance it is said to be insoluble in that solvent.
****A compound or molecule may be soluble in one solvent yet insoluble in another.

Rate of Dissolution (ROD)

How fast a molecule moves into solution (dissolves)

What Equation describes the rate of dissolution?

Noyes-Whitney equation

Rate of Dissolution is Directly related to

* if one of these terms increases the rate of dissolution increases proportionally
* Surface Area of the Drug Particle
• Diffusion Coefficient
• Solubility of the drug in the stagnant/diffusion layer

Rate of Dissolution Inversly

if h increases the rate of dissolution decreases proportionally

What 3 factors affect Surface Area of the Drug = A

1. Size of the particle
*** Surface area is inversely related to particle size
**Decrease particle size-->Increase surface area ->Increase rate of dissolution
2. Dispersibility of powder in dissolution medium
***Disintegration and deaggregation
***If solids forms a cohesive mass, the surface area available for dissolution is reduce
3. Porosity of the solid particles- can increase surface area

What will dissolve faster? A sugar cube or loose sugar

loose sugar as it is in more of a powder form

micronize

Decreasing the average diameter of a solid material's particle size down to microns (μm) in size

Diffusion Coefficient = D

k = Boltzmann Constant
T = absolute temperature
η = viscosity of the dissolution medium
r = radius of the spherical molecule ("particle")

Saturation Solubility = Cs

Dissolution rate is directly proportional to the saturation solubility of the drug in the stagnant layer

When you have a high Cs is there a faster or slower Rate of Dissolution?

faster

T or F: Diffusion (D) through the stagnant layer is a concentration gradient driven process

true

Does the pH vary as it moves through the GI Tract?

yes

Are weak acids and bases pH dependent dissolution?

yes
*poorly soluble weak bases must dissolve rapidly in the stomach solubility decreases as it moves through the GIT
*poorly soluble weak acids solubility increases as it moves through GIT

Concentration Gradient = Cs-Cb

relatively very, very small as compared to Cs
*** Cb = 0
• Dissolution rate is directly proportional to the saturation solubility of the drug in the stagnant layer
***high Cs = faster rate of dissolution
- Diffusion through the stagnant layer is a concentration gradient driven process

What does Saturation Solubility in Dissolution Media = Cs depend on?

1. Salt form
2. Complexation
**** Chelates• Calcium drug interactions
3. absorption
**** crystalline vs amorphous

Is salt faster absorbed due to faster dissolution?

Yes, salt is faster absorbed due to faster dissolution = more effective

Where does Acidic salt form of a weak base drug dissolve the most rapidly?

GI and Intestinal fluid

What type of anion is strongly acidic in the diffusion layer around the particle ensure the pH in the layer is lower than the bulk pH (gastric or intestinal)

Cl anions