pencils DDS pharmaceutical preformulation

preformulation stage of drug development

among the most important physiochemical properties to determine are:

1. water solubility

2. lipid solubility

3. stability

water solubility

drug must be soluble enough to dissolve in body fluids

lipid solubility

drug must be lipophilic enough to cross membranes “lipid bilayer”

crystal habit

description of the outter appearance of a crystal

take home crystals

diff crystal types represent diff molecular arrangements

amorphous 

w/out distinct crystaline structure (no repeating arrangements RANDOM arrangement, w/no crystal lattice

amorphous arrangement

more soluble due to there lack of molecular arrangement and their water interactions

importance of understanding the solid form: melting point

mp is the function of strength of molecular interactions

importance of understanding the solid form: dissolution

the form of a drug in a solid state and their dissolution shows which have weaker interactions and through these weak interactions they will dissolve better

importance of understanding the solid form: bioavailability 

the function of drug dissolution can change w/diff forms 

importance of understanding the solid form: flow properties

dosage properties… important for dosage uniformity

importance of understanding the solid form: solid state solubility

hygroscopicity- tendency of a substance to take up atmospheric moisture

polymorphism

capacity for appearing in many forms

diff properties of polymorphs 

molecules w/in diff polymorphs interact differently forms possessing molecules w/weaker molecular interactions are metastable 

metastable

unstable transient but relatively long lived state of chemical or physical system that will change over time to a more stable form

take home metastable polymorphs

metastable polymorphs are generally more soluble than their more stable counter parts bc of weaker interactions

chloramphenicol polymorph B

form B is more metastable which means it is more water soluble

solvates 

crystal containing solvent molecules w/in crystal lattice 

hydrate

water is part of crystal lattice

solvate solubility

changes in hydrate form can affect solubility

hydrates are generally less soluble then their anhydrous counterparts

dissolution differs between hydrates & anhydrous

anhydrous (solvate) dissolution 

an anhydrous is better for dissolution leading to better bioavailability

melting behavior

melting behavior of the solid is studied during preformulation

detecting polymorphs through melting behavior

diff polymorphs have diff melting points

particle flow

studied during preformulation bc it affects several processes mixing/pouring powders, efficient manufacture or tabs & caps, and stratification

stratification 

process of arranging in layers 

diff particles in the mix have diff flow properties and it leads to problems in drug uniformity

drug dissolution

drug must be in solution to be absorbed and to cause an effect

solution

homogenous mix of two or more substances

solubility (amount dissolved per volume)

concentration of a solute (drug) in a saturated solution of that solute at a given temperature

HIGH TEMP= INCREASED SOLUBILITY

solids dissolve 

process of dissolution involves the relocation of a solute molecule from an environment where it is surrounded by identical molecules in a cavity in a liquid where it becomes surrounded by molecules that are not identical to the solute 

nature of solvent

“like dissolves like”

the more alike the crystal is w/the solvent it is trying to dissolve in the more readily it’ll dissolve

ex: more polar crystaline molecules are more likely to dissolve in water

MOST IMPORTANT SOLVENT IS WATER

factors governing the solubility of a solid in a water

nature of solid

nature of solute

take home amorphous solid & metastable crystal

amorphous solid & metastable crystal are more soluble than their more stable counterparts bc of looser molecular arrangement

hydrophilic substituents 

hydrophilic substituents can form hydrogen bonds w/ water and therefore make a drug more water soluble

hydrophilic substituents cont 

-CHO hydrophilic

-COOH slightly hydrophilic  

-COO- very hydrophilic

-NH2 hydrophilic

-NH3+ very hydrophilic

-OH very hydrophilic

hydrophilic substituents and size 

large lipophilic molecules can have very low solubility 

estradiol (corticosteroid)

despite 2 hydroxyl groups, the size & back bone of estradiol decreases solubility

ionization state of the solute

ionization is one of the most important physiochemical properties as it affects water & lipid solubility

ionization effects dosage formulation, & ADME processes

ionization & ionizable groups

most drugs have ionizable groups: most are either weak bases, weak acids, or amphoteric

WEAK: less able to donate (acid) or accept (base) a proton

weak base ionization 

99.9% of the drug will be ionized at 3pH units below the pka 

weak acid ionization

99.9% of the drug will be ionized at 3pH units above the pka

salts and methods of altering the solubility of a solid in a liquid

salt formation is a very common method of altering a drugs properties close to 50% are drug salts

general process of salt formation 

ionized drug forms an ionic interaction w a counterion in a solvent containing a SA or SB

salt is crystalized from solvent  

take home drug salts 

strong bases used to fully ionize drugs

salt formation can be used to decrease/increase a drugs solubility

salt formation to decrease a drugs solubility

a solid drug (in suspension) is more chemically stable than drug molecules in solution

chemical breakdown generally occurs to drug molecules in solution

chemical exposed to what will degrade it

salt formation to increase drug solubility

greater ionic dissociation of drug molecules

in the crystal, ionized drug & the counterion form a crystal lattice

phenytoin 

phenytoin is very slightly soluble in water, phenytoin sodium is soluble in water 

phenytoin sodium for IV injection 

ampicillin

ampicillin is slightly soluble in water, ampicillin sodium is very soluble in water

ampicillin good oral

ampicillin sodium good for IV injection

prodrug is an approach to altering the solute

synthetic derivative of a drug that is transformed in vivo to liberate an active drug molecule

prodrug ester linkage 

most prodrugs are created using an ester linkage 

cleaved in vivo w/help of esterases 

prodrugs may be synthesized for a variety of purposes

biopharmaceutical or pharmacological purposes

biopharmaceutical or pharmacological purposes

absorption-

prolonged action- prodrug- prolong action- make lipophilic for IM injections

pharmaceutical purposes

taste, stability, & solubility

prodrugs to alter solubility- a decrease in solubility is an increase to lipophilicity

better tasting

better tasting is less soluble bc it is in suspension (e.g., for kids)

taste making= drugs must be in solution to interact w/taste bud chemoreceptors 

bypasses gastric degradation

erythromycin in crystals “suspension” does not degrade in acidic conditions as much

better absorption

better absorption of medication = more lipophilic

to increase solubility (create more water soluble pro drug for injection)

phosphate group is added to create a phosphate-ester derivative

phosphate esters- in vivo phosphate ester linkage are cleaved by phosphotases 

phosphate groups 

the phosphate group is very polar, it is added to things to make them more polar= MORE WATER SOLUBLE 

take home on buffers

buffers are often employed to adjust the pH to optimize a drugs solubility/stability

cosolvents

solvents used in combination to increase a solutes solubility by bringing down the polarity of the solvent

use of cosolvents to reduce the polarity of water so that the polarity matches the polarity of the drug to get it go into injection

take home on water

water is the universal solvent

solubilizing agents

surfactants & cyclodextrins classified as nonsolvent chemicals… used to help solubilize drug

surfactants

surfactants are amphiphilic molecules that have the tendency to accumulate (adsorb) at the interface between two phases

rate of dissolution of a solid in a liquid

dissolution of poorly water soluble drugs- can be the rate limiting step for absorption

noyes whitney equation 

describes the dissolution rate of a solid in a liquid 

noyes whitney: total surface area of the undissolved solid

the size of solid particles is important bc the smaller it is the greater the exposed surface area is

noyes whitney: conc of solute in the bulk liquid

taking a med with a glassful of water makes a difference in how fast something dissolves because you increase the volume and are decreasing the conc

noyes whitney: dissolution rate constant

the thickness of the stagnant boundary layer can be decreased by agitation “shaking”

diffusion coefficient of solute in the dissolution medium can be decreased by an increase in liquid viscosity

partition phenomena microorganisms

important for some antibiotics

partition phenomena plastic

plastics for drugs that absorb into IV sets

partition coefficient 

the measurement that explains how the drug is in two phases P & NP

measuring a drugs PC is one of the most important methods of determinings a drugs lipophilicity… THINK LARGER P = MORE LIPOPHILIC (NONIONIZED) (NON POLAR)

effect of ionization on P

non ionized form of a drug is less polar and is MORE LIPOPHILIC=LARGER P

partition coefficient and GI tract

the PC is studied over a range of pHs similar to what is found in the GI tract bc we want to predict absorption of unionized drug at diff GI sites 

ionization is an equilibrium process

when nonionized drug is absorbed, some remaining ionized drug becomes nonionized BALANCE

“EQUILIBRIUM RESTABLISHES ITSELF”

the surface area of the absorption site is often more important

surface area of the absorption site is important bc a lot of it occurs in the duodenum and jejunum high surface area in the small intestines

neurotoxicity & penicillin

neurotoxicity due to increased passage through BBB toxicity seen only in @ risk pts