PHCY503: Week 1 Materials

API/Drug substance

the active chemical component; pharmacologically active; identified by its common chemical name

Excipients

Non-API components aded to perform specific product functions, such as coatings, colors, flavors, preservatives, and vehicles

Dosage form

the physical form in which the product is presented or administered (tablet, capsule, solution, suspension, gel, patch, powder)

Drug product

the finished deliverable unit that a patient receives and uses, combining the API(s) and excipients

Why is the drug product not the same thing as the API?

API: therapeutic potential through engagement of the target

(can't work doesn't equal doesn't work)

Why must the drug product enable useful API exposure?

Must solve physical delivery challenges by presenting the API in a stable unit that releases API with useful exposure in a real patient

What is product readiness in the Product-to-exposure journey?

Drug product's stability, usability, and capability of delivering a reliable dose

What does API Release / Availability refer to in the Product-to-exposure journey?

Whether the solid drug disintegrates, dissolves, or releases

What is meant by Entry / Access in the Product-to-exposure journey?

Whether the API is introduced via a specific route and can bypass biological barriers

What does Exposure at relevant site mean in the Product-to-exposure journey?

The active API reaches the target location in sufficient amount, rate, duration, and consistency.

What is target engagement and response in the Product-to-exposure journey?

Refers to the API binding its molecular target (receptors, enzymes) to drive a biological response

Use effectiveness, safety, and adherence/use to explain why drug product performance matters for patient care.

Effectiveness: Evaluates whether useful Exposure occurred at the relevant target site to achieve the desired clinical outcome

Safety: Evaluates whether unnecessary, excessive, or unintended exposure was created elsewhere in the body

Adherence / Use: Evaluates whether the patient can successfully handle, store, administer, and use the drug product as intended

Explain exposure as a condition that helps make the target engagement and response possible.

An API cannot engage its target unless it physically reaches the target site in an appropriate patter

Evaluates where, how much, how quickly, how long, and how reliably active API becomes available at the target site

Differentiate intrinsic molecular properties of an API from physical and chemical conditions the API encounters

intrinsic: individualized to the API molecule itself (MW, pH, etc)

Conditions encountered: physical and chemical variables in the drug product or biological environment surrounding the API

Predict polarity, acid/base character, charge, H-bonding, or lipophilicity from carboxylic acid.

supports weak-acid behavior; deprotonates to carry a negative charge, increasing aqueous compatibility

Predict polarity, acid/base character, charge, H-bonding, or lipophilicity of amine / tertiary amine.

supports weak-basic behavior; accepts a proton to become positively charged

Predict polarity, acid/base character, charge, H-bonding, or lipophilicity phenol / hydroxyl

Contributes polarity and hydrogen-bonding interaction capability with water

Predict polarity, acid/base character, charge, H-bonding, or lipophilicity amide

contributes polarity and hydrogen bonding capability

Predict polarity, acid/base character, charge, H-bonding, or lipophilicity aromatic / hydrocarbon-rich regions

contributes lipophilicity, favoring non-polar lipid-like environments

Predict polarity, acid/base character, charge, H-bonding, or lipophilicity quaternary ammonium

carries a permanent postive charge across ordinary pH conditions

Predict the predominant protonation state of an ionizable API from pH relative to pKa

pH < pKa: high hydronium concentration forces the protonated form to predominate

pH > pKa: low hydronium concentration forces the deprotonated form to predominate

Predict how ionization state affects aqueous solubility and lipid-like partitioning.

Ionized forms (A-, BH+): interact strongly with polar water molecules, favoring greater aqueous solubility

Non-ionized forms (HA, B): lack formal charge penalties, favoring more favorable lipid-like partitioning across biological membranes

Differentiate log P and log D as descriptors of lipid-water partitioning

log P (partition coefficient): describes the intrinsic partitioning of only the uncharged, non-ionized API form between lipid and water phases; its an intrinsic constant unaffected by pH

log D (distribution coefficient): describes the distribution of both ionized and non-ionized API species at a specified pH; it reflects the actual species population at that pH

Explain why the log D of an ionizable API change with pH

changing surrounding pH alters the relative population ratio of ionized versus non-ionized API according to the pH-versus-pKa relationship

How does aqueous solubility affect API availability?

Aqueous solubility supports API release and availability by allowing dissolution in aqueous body fluids.

What role does lipid-like partitioning play in API access?

Lipid-like partitioning supports entry and access by facilitating passive permeation across biological lipid membranes.

What is the relationship between aqueous availability and passive membrane access?

Improving aqueous availability can reduce passive membrane access, and vice versa.

What log P range provides an optimal balance for small-molecule APIs?

An intermediate log P range provides an optimal balance between availability and passive barrier access for small-molecule APIs.

Explain stability along the P2E

Product readiness: Asks whether the drug product remains suitable, physically and chemically intact, and performs as intended during storage and use before administration

Explain solubility along the P2E

API Release / Availability: Describes the thermodynamic equilibrium capacity of an API (how much can dissolve at saturation)

Equilibrium

Explain Dissolution along the P2E

API release / availability: describes a time-dependent kinetic rate process (how fast does solid API enter over time)

kinetic rate

Explain Diffusion along the P2E

Entry / Access: describes the spontaneous mass movement of dissolved solute molecules through a fluid, medium, or tissue down a concentration gradient

Explain Flux along the P2E

Entry / Access: quantifies the rate of diffusive mass transfer per unit of barrier surface area

Why are drug product readiness and stability prerequisites for reliable API release and Exposure?

Chemical or physical instability during storage reduces the amount of intact, active API or alters product properties

Changes occurring before administration results in variable/unsafe exposure in the patient

How does hydrolysis affect drug product stability?

cleavage of vulnerable ester/amide bonds by water is accelerated by humidity or improper sealing

How does oxidation affect drug product stability?

chemical degradation driven by atmospheric oxygen or free radicals

How does photodecomposition affect drug product stability?

cleavage or isomerization of light-sensitive APIs triggered by UV/light exposure

How does temperature affect drug product stability?

increases thermal molecular motion and frequency of productive collisions, directly increasing the chemical degradation rate

What is the difference between solubility and dissolution?

Solubility is an equilibrium amount that answers how much API can be dissolved under temperature and fluid conditions

Dissolution is a time-dependent rate process that answers how fast does the API enter solution

Dissolution is a rate because solid particles must break down

Interpret the Noyes-Whitney relationship

Surface Area (A): increasing total solid-liquid surface area increases dissolution rate

Concentration driving force (Cs-Cb): a larger gradient increases dissolution rate

Diffusion-layer thickness (h): thicker layer surrounding the particle decreases the dissolution rate

Explain why reducing particle size can increase dissolution rate without changing intrinsic API equilibrium solubility

micronization increases the total solid-liquid interface surface area

greater surface area accelerates the rate of dissolution

intrinsic equilibrium is a thermodynamic property

Interpret Fick-type relationships

Concentration Gradient: a steeper concentration difference increases diffusive flux

Barrier thickness/ path length: a thicker physical barrier creaters a longer path, decreasing diffusive flux

Molecular mobility / diffusion coefficient: higher mobility within the barrier matrix increases flux

Available area: larger barrier surface area increases total amount of API transferred/unit time

What would be the reasoning to choose Advil Liqui-gels vs tablets?

Liqui-Gels present pre-solubilized ibuprofen inside a capsule and achieve earlier API availability and faster acute pain relief

What would be the reason to use READI-CAT 2 barium sulfate?

extremely low solubility is intentionally utilized because the delivery goal is the GI without systemic absorption or toxicity

Define biological product (biologic)

Complex therapeutic material including proteins, mAbs, peptides, nucleic acids, vaccines, etc. that are produced by living host cells or biological systems

Differentiate biologics from small-molecule drugs

Molecular size: biologics are large macromolecules while conventional drugs are small molecules

Structural complexity: biologics possess fragile tertiary/quaternary 3D folding and post-translational modifications

Characterization and heterogeneity: small molecules are well-defined identical chemical structures while biologics exist as a population of micro-heterogenous species

Stability & Manufacturing: biologics are highly sensitive to thermal and physical shear stress (risking denaturation and aggregation) and depends entirely on biological cell-culture manufacturing

Explain how recombinant DNA or cell-based manufacturing links the biological system, process conditions, and product quality attributes

Recombinant DNA technology inserts the coding gene into living host cells to synthesize the protein

Because living cells perform synthesis and post-translational processing, bioreactor conditions and purification steps directly dictate the final products quality attributes

Explain "the process is the product" of biologic manufacturing and quality control

a complex biologic cannot be fully defined or duplicated as a single identical chemical species

Exact host cell system, manufacturing conditions, purification steps, and quality controls define the final product itself

What is an NDA?

Original approval pathway for small-molecule drugs

What is a BLA?

Biologics license application, original approval pathway for biological products

Whats an ANDA?

abbreviated new drug application, generic pathway for small-molecule drugs

What is the FDA orange book?

Resource for approved drug products and therapeutic equivalence ratings

What is the FDA purple book?

Resource for approved biological products, biosimilarity ratings, and interchangeable designations

What is the evidence standard for generic drugs?

approved by demonstrating chemical structural identity and pharmacokinetic bioequivalence (Cmax and AUC 90% CI within 80-125%

What is the evidence standard for biosimilars?

totality of evidence to prove high similarity with no clinically meaningful difference

What is biosimilarity?

confirms the product is highly similar to the reference biologic with no clinically meaningful difference in safety, purity, or potency

What is interchangeability?

a higher FDA designation meeting biosimilar standards plus switching studies; interchangeable biologic may be substituted at the pharmacy level for reference product, subject to state pharmacy laws

Predict how instability of biologics can affect exposure, safety, or reliability

Aggregation and immunogenicity: physical stress or temperature spikes cause unfolding --> protein aggregates --> immune recognition and anti-drug antibody formation --> increases immunogenicity risk --> neutralizes efficacy

Storage: requires cold-chain refrigeration and protection from light/shaking

Explain why biologics require spacial handling and parenteral delivery

4 oral barriers (GI tract): acidic gastric acid (denaturation), digestive proteases (enzymatic cleavage), mucus hydrogel layer (trapping), and the intestinal epithelium (paracellular size cutoff)

Parenteral to avoid and get good exposure

Patient use consequences: cold-chain handling, allowing drug to warm to room temp, avoid shaking, review autoinjector/syringe technique to prevent user error

Explain surface tension and surfactant behavior at interfaces

water molecules in bulk liquid experience forces; molecules at an interface experience net attractive pull, creating surface or interfacial tension

Classify surfactants by connecting to amphiphilic structure to function

Surfactants are amphiphilic molecules with hydrophilic heads and hydrophobic tails

accumulate at interfaces; alignment disrupts cohesive water interactions, lowering surface and interfacial tension

Classify Surfactants by charge

Anionic: negatively charged head group

Cationic: positively charged head group

Nonionic: uncharged polar head group

Zwitterionic: carries both positive and negative formal charges

Describe the endogenous surfactant: Bile Salts

synthesized in the liver, emulsify dietary lipids and fats in intestinal lumen into droplets, enable enzymatic digestion and absorption

Describe the endogenous surfactant: Pulmonary surfactant dipalmitoyl-phosphatidylcholine (DPPC)

DPPC abdsorbs to the air-water interface of lung alveoli, polar head groups in water and hydrophobic facing alveolar air

Drastically reduces alveolar surface tension, preventing lung collapse and reducing work of breathing

Describe the endogenous surfactant: surfactant protein-A

reduces surface tension at the cornea-ear interface in the eye and serves as a circulating biomarker for lung injury and pathology

Explain micelle formation and CMC

At low concentrations, surfactants exist at individual monomers

[S] inc --> interface because saturated

Beyond CMC (critical micelle concentration), additional monomers aggregate into micelles

What are the driving forces of micelle formation?

Hydrophobic effect: release of ordered water molcules cause a favorable increase in entropy

What are the opposing forces?

Electrostatic charge repulsion between ionic head groups, concentration gradients, and brownian thermal motion

What is micellar solubilization?

highly insoluble, lipophilic drugs partition into the hydrophobic core via "like dissolves like," creating clear, stable micellar solution

Analyze how surfactant structure and solution conditions affect CMC and micellar size.

hydrophobic tail length: inc length, inc lipophilicity, dec CMC and inc micelle size

hydrophilic head group: nonionic surfactants have lower CMC than ionic, inc head size, inc hydrophilicity, inc CMC

Counterions: weakly hydrated counterions adsorb onto micelle surfaces, dec head-group repulsion, micelle size inc with counterion MW

Electrolyte: adding electrolytes dec CMC and inc micelle size

What is HLB?

hydrophilic-lipophilic balance; an empirical scale calculated from percentages of hydrophilic vs lipophilic groups on surfactant molecule

Explain the different HLB values.

HLB 1-3: Highly hydrophobic/oil-soluble; used as antifoaming agents or for reverse micelles.

HLB 3-6: Hydrophobic; used as Water-in-Oil (W/O) emulsifiers (e.g., Sorbitan monooleate / Span 80, HLB 4.3).

HLB 7-9: Water dispersible; used as wetting and spreading agents (e.g., Sorbitan monolaurate / Span 20, HLB 8.6).

HLB 8-16: Hydrophilic; used as Oil-in-Water (O/W) emulsifiers (e.g., Soy lecithin, HLB 8.0).

HLB 13-15: Hydrophilic; used as detergents.

HLB 15-18: Highly hydrophilic/water-soluble; used as solubilizing agents for insoluble APIs

What are the size classifications for dispersions?

Molecular dispersion: particle size < 1nm

Colloidal dispersion: particle size 1-1000 nm (micelles, microemulsions)

Coarse dispersion: particle size > 1000 nm (macro-emulsions)

What are the dosage form types?

Emulsion: 2-phase system of immiscible liquids (O/W, W/O)

Suspension: insoluble solid drug dispersed in liquid vehicle

Gel: water-insoluble 3D crosslinked polymer network, swells in solvent

Aerosol: solid or liquid drug particles in gas vehicle

Foam: gas bubbles dispersed and trapped within liquid or solid continuous phase

Creaming

instability mechanism

density-driven upward movement of dispersed droplets (reversible upon gentle shaking)

Flocculation

instability mechanism

clumping or clustering of droplets without merging of internal liquid cores (reversible)

Coalescence

instability mechanism

merging of small droplets into larger due to film failure (irreversible)

Breaking

instability mechanism

Complete phase separation into distinct, un-emulsified oil and water layers (irreversible)

Ostwald Ripening

solute dissolves from smaller particles and diffuses onto larger droplets/particles, causing small droplets to shrink and disappear while large droplets grow (irreversible)

Use Stokes' law to calculate settling rates

particle radius (r): reducing particle size reduces settling rate

density difference: minimizing density difference between particle and fluid vehicle reduces settling rate

Medium viscosity: increasing continuous phase vehicle inversely reduces settling rate

Apply storage and handling conditions that maintain formulation stability

Must be protected from extreme storage temperatures

Above 35-37C accelerates coalescence

Freezing breaks the emulsifying phospholipid film (separation when thawing)

Distinguish Newtonian and non-Newtonian Flow

Newtonian: fluid viscosity remains constant regardless of applied force

Non-Newtonian: viscosity changes with applied shear:

- Pseudoplastic (Shear-thinning): viscosity decreases as shear rate inc

- dilatant (shear-thickening): viscosity inc as shear rate inc

Relate viscosity to injectability and protein crowding

concentrated protein/monoclonal antibody formulations exhibit exponential viscosity increases at high concentrations due to molecular crowding

adding viscosity-reducing excipients limits intramolecular antibody interactions, lowering viscosity to ensure comfortable SC injection

Cremophor EL (Taxol) conventional delivery

solubilized polyethoxylated castor oil in ethanol

drawbakcs: severe vehicle hypersensitivity, non-linear PK, DEHP plasticizer leaching from IV bags, low maximum tolerated dose

Genexol-PM micellar delivery

paxlitaxel encapsulated in polymeric micelles comosed of amphiphilic diblock copolymers

Benefits: eliminates vehicle hypersensitivity, permits standard IV tubing, reduces toxicity, raises MTD

Evaluate the advantages and tradeoffs of liquid formulations for different patient populations

Advantages: patients with swallowing difficulties and allow flexible, weight-based dosing

Tradeoff: higher risks of physical instability, chemical degradation, and shorter shelf-lives compared to dry powders

What is hydrogels drug solubility and LogP information?

consists of a 3D polymer network swelling in an aqueous phase; optimal for water-soluble, hydrophilic drugs (LogP < 0)

What is organogel drug solubility and LogP information?

consists of a polymer network containing an organic/non-aqueous solvent; optimal for poorly water-soluble, lipophilic drugs (LogP >0)

Prevent sedimentation in suspensions

micronize drug particle radius, add suspending/viscosity-modifying agent, or adjust vehicle density

Prevent electrostatic powder trapping in inhaler spacers

washing plastic spacers with dilute detergent leaves microscopice film that dissipates static electricity, preventing powder from clinging to spacer walls and restoring fine-particle lung deposition

Describe how the components and design of oral dosage forms contribute to product readiness, API release, and patient

Oral dosage forms combine the active API with functional excipients (binders, distintegrants, lubricants, coatings)

Design choices ensure product readiness (chemical instability, physical integrity, dose uniformity)

Control API release (disintegration and dissolution in GI fluids)

Facilitate patient use (manageable unit size, palatability, swallowing convenience)

Explain how particle shape and flowability influence product readiness.

Spherical, uniform particles flow smoothy, ensuring dose unifomrity

Irregular or needle-shaped particles flow poorly, causing tablet weight variation and dose variability

Explain how solid-state form influences product readiness

Amorphous forms lack a rigid crystal lattice, dissolving faster and achieving higher apparent solubility than stable crystalline polymorphs

Explain how formulation-related alter oral bioavailability and systemic exposure

particle size/surface area, crystal polymorph, welling agents, salt forms, and disintegration/dissolution rates

Explain how patient-related factors alter oral bioavailability and systemic exposure

Gastric emptying rate, GI fluid pH across segments, intestinal transit time, food effects, GI luminal enzymes, and hepatic first pass metabolism

What is immediate-release oral dosage forms?

a dosage form that is designed to dissolve rapidly in GI contents without delaying release kr>> ka

Biological membrane absorption is rate-limiting

What is modified-release oral dosage form?

a dosage form that is designed so the drug release is the rate-limiting step kr << ka

formulation controls pharmacokinetic clock, flattening peak-to-trough fluctuations

How is relative bioavailability used to compare drug products and their resulting exposure?

compares the rate and extent of systemic availability between two non-IV oral formulations

How is bioequivalence used to compare drug products and their results exposure?

confirms that a test formulation and reference product show no significant difference in the rate and extent of availability at the site of action (FDA requires 90% CI for both AUC and Cmax to fall between 80% and 125%

How does particle size and shape influence powder flow, dose uniformity, reliable dosing, and exposure using micromeritics principles?

Micromeritics evaluates particle size, shape, and surface area

Spherical particles minimize inter-particle friction, promoting uniform powder flow into tablet dies

Poor flowability creates weight variation between tablets, propagating forward into variable API dose delivery and exposure