Lecture 3: Formulation and API Flashcards
Drug product performance
-ability of drug to elicit therapeutic response and stay in a safe range during dosage
-no toxic response
-described by pharmacokinetics and parmacodynamic processes
Goal of Formulations
-transfer a new therapeutic compound
-develop reproducible dosage form
-release from dosage form must balance the way body processes medicine
reproducible
-refers to each dosage form containing same amount of drug
-refers to same performance in the body
Drug blood level vs time graph
- Absorption: increase up to Cmax, Tmax (2hoursish)
- slow decrease through distribution, metabolism, excretion
AUC= area under the curve
Disposition phase of drug
distribution, metabolism, excretion
Elimination phase of drug
metabolism and excretion
Dosage form controls
-absorption, dissolution, degradation in intestinal tract
Body controls
metabolism, distribution, excretion
Drug upon Administration
Intestinal tract (dosage form controls) –> portal vein –> liver (metabolism) –> blood –> peripheral tissues (distribution), perfused tissue, and urine (excretion)
Absorption rate
-MUST BALANCE DISPOSITION
-begins declining as disposition starts to increase
-Kabs
Kabs defined by
-drug properties
-excipient/composition of formulation
-physiological barriers between GI tract and systemic circulation
Margin of Safety
-goal of dosage form design
-area between pharma and toxicology
Drug discovery: Assessing translation
-finding chemistries that can mitigate disease
-driven by receptor binding
-druggability and developability
Druggability
-binding and “drug-like” properties favorable for product translation
Developability
assessment to characterize if new molecules can be formulated
Druggability stages
- discovery
- Assess ability to bind to drug target
- in vivo models used to assess
Developability stages
- refers drug performance
- incorporates factors like solubility/dissolution
- incorporates formulation factors related to ADME/T
Druggable genome
-genes that encode disease related proteins that can be modded by drugs
-includes differentially regulated drugs
-vary in intensity upon comparative analysis
Healthy vs sick gene expression
-this contrast can yield genes that may serve as targets for drug design
Druggable targets
mostly disease genes
Druggable gene identification
via pharmacogenomic methods
Druggable proteins
-proteins that can bind drug-like compounds with affinity < 10mM
-compound must be able to modulate the protein
Druggable proteins identification
-via genes of disease-related proteins that be modulated by drugs
Druggable pharmacophore
-druggable genes converted to proteins via in silico methods
Druggable pharmacophore identification
binding cavities
Pharmaceutically tractable genome
-genes that encode proteins that can be targeted by smaller compounds, antibodies, and therapeutic proteins for pharmaceutical use
Drug candidate to tractable gene + protein associated with disease
= mitigated disease yay
Pharmacophore drug design
-proteins associated with disease modeled to find binding pockets
-drugs fitting these pockets generated
-chemicals can be made to optimize drug binding
Pharmacophore drug design applications
-virtual screening
-de novo design
New chemical entities (NCE)
-generated to fit a pharmacophore
-characterization to assess drugability
Good druggable entities
-do not equal a good potential to be translated
ADMET
T is toxicity
Developability
-centers on evaluating properties that will be used to generate a working formulation
Pharmacokinetics and pharmacodynamics
-main indicators of safe and efficacious use
-do NOT vary across patient populations
Goal of Drug Delivery
Drug + vehicle
-vehicle has selected properties to overcome barriers and transport it from administration site
Formulation design considerations (performance factors)
-physicochemical properties of the drug
-properties and composition of formulation
-biological factors (ADMET)
-MUST be properly balanced
Performance
-drug response and therapeutic range
-lack toxicity
-function of the drug
Physicochemical Properties of the Drug
that Affects Absorption
-solubility
-drug stability in solution
-lipophilicity
-molecular size/shape
-pKa of groups
-physical state of drug
-SLIDE 31
Solubility depends on
-molecular structure
-physical state
-composition of solvents
-measurement methods
solid physical state
amorphous, crystalline, polymorphic
liquid physical state
predissolved in solvent
Composition of solvents
-types
-cosolvent %s
-solution components (salts, ions, lipids, ets)
-pH and temp
Measurement Methods
-equilibration time
-detection method
Partition Coefficient
-ratio of concentrations in two immiscible solvents (octanol and water)
-Ko/w = Coct / Cwater
pH-partition hypothesis
-permeability transport depends on the fraction of unionized drug at intestinal pH
-for drugs absorbed by passive, transcellular mechanism
solubility and partition coefficient
-as Ko/w increases, solubility decreases
-formula SLIDE 34
pH and pKa
-important in determining absorption of weak acids vs weak bases
Cell membrane structure
-lipid bilayer with lipid and protein molecules
protein to lipid ratio in the GI tract
1:7 ??
-octanol:water partitioning not accurate predictor of physiological conditions
Organelle pH
-differences in extracellular and intracellular values affect transport
-can trap molecule in a cell
Overcome effects of pH partition hypothesis
-functionalize the compound-change pKa
-prodrug strategy
-salt selection
-drug delivery system
prodrug strategy
-modifiy charged moiety
-modify molecule to be recognized by transporter
Salt selection
-ion pairing effective in improving permeation
-form can alter unionized fraction
Polar Surface Area (PSA)
-solvent accessible surface area (SASA) provided by O, N, H
-good estimate of H bond potential
-does NOT account for charges
Poor absorption/permeation when:
-more than 5 H bond donors
-more than 10 H bond acceptors
-MW over 500
-MlogP over 4.15 (ClogP over 5)
