Munson 2

Drug Product Performance

= function of drug, the formulation, and the body

• ability of drug to elicit therapeutic response

• ability of drug to stay in a safe therapeutic range during dosing

• non-toxic and effective

The Goal of Formulation

• transfer new, promising therapeutic compound + develop reproducible dosage form

• going from small batches to being created in large batches

• release from dosage forms has to balance how the body processes medicine

define reproducible

• each dosage form containing same amount of drug

• same performance in body 

define absorption rate (k_abs)

 drug properties, excipient/drug composition, physiological barriers between GI tract and systemic circulation

What is the Typical Blood Level vs Time Curve used for?

accessing performance and reproducibility 

as absorption begins declining, diposition begins to ______

increase

Druggability refers to

• discovery stage

• assesses the ability to bind to the drug target

• vivo models used to assess (tested within animals or humans)

Developability refers to

• drug product performance

• factors like biorelevant solubility and dissolution

• formulation factors related to ADME/T incorporated

define Druggable genome

genes that encode disease-related proteins that can be modulated by drug-like molecules

• subset of genomes that express proteins that bind to drug-like molecules

define Druggable protein

proteins that can bind drug-like compounds with binding affinity below 10 mM

druggable genes are identified by _______ methods

pharmacogenetics

Why are new chemical entities generated?

to fit a pharmacophere

What do new chemical entities demonstrate?

assess the ability for each agent to act like a drug aka druggability

• candidates that perform best advance

What two indicators are used to test dafe and efficacious use?

Pharmacokinetics and Pharmacodynamics

Drug formulation should consider…

• physicochemical properties of drug

• physicochemical properties and composition of formulation

• biological factors that influence performance (ADME and Toxicity)

How are dosage forms able to reach a clinic?

be properly balanced

Physicochemical drug properties that affect absorption

• solubility

• drug stability in solution

• lipophilicity

• molecular size and shape

• pKa of ionizable groups

• physical state of drug (amorphous, crystalline, polymorphism, etc)

Solubility depends on… 

• molecular structure

• physical state

• composition of solvents

• measurement methods

Physical state

solid: amorphous, crystalline, polymorphic form

liquid: predissolved in a solvent

Composition of solvent

• type of solvent

• co-solvent percentages

• solution components (salts, ions, lipids)

• pH, temperature

Measurement mehtods

• equilibrium time

• detection method

Partition coefficient

ratio of concentrations in two immiscible solvents (eg: octanol and water)

pH-Partition hypothesis

for drugs absorbed by a passive, transcellular mechanism

• permeability depends on fraction of unionized drug at intestinal pH

generally, as K_o/w increases, solubility _____

decreases

Different _____ and ______ pHs can affect drug transport

extracellular and intracellular

How do you functionalize the compound?

changing its pKa

What is prodrug strategy

• modify the charged moeity

• modify the molecule to be recognized by a transporter

What is salt selection?

• ion pairing effective in improving permeation

• salt form may alter unionized fraction

Define excipients

inert ingredients that are added to therapeutically active compounds to improve appearance, bioavailability, stability, palatability

Cellulose-based excipients

microcrystalline cellulose (MCC), SMCC, HPMC, ethylcellulose

Sugar-based excipients

surcrose, lactose, mannose

Synthetic polymer excipients

polyvinyl pyrrolidone (PVP), polyethylene oxide (PEO)

How is excipient compatibility tested?

• binary or formulation blends

• binary or formulation blends with 10-20% w/w water

• suspension/solution of excipients and drug

• mechanical stress (milling drug)

Solid Dosage Form Requirements

• content uniformity (every tab has approx. 85-115% API)

• stable shelf life of 2 years

• cannot break into smaller pieces