DFDS EXAM 1

Solubility

measure of maximum amount of substrate that will dissolve in a liquid

pH, temperature and particle size significantly affect

What is Pharmaceutics

The art, science, and tech of dosage form design + preparing and dispensing drugs and medicinal agents

Drug

General term for agent intended for use in the diagnosis, mitigation, treatment, cure, or prevention of disease in humans or in other animals

Excipients

Inactive ingredients used in the preparation of dosage forms

Formulation

Process in which different chemical substances, including the active drug are combined to make final drug product (drug + excipient)

Drug Product

Final, marketed combination of API, and usually other inactive ingredients

Dosage Form

Drug products in the form in which they are marketed for use (tablets, capsules, solutions, etc); combination of APIs and excipients

Drug Substance

API (Active Pharmaceutical Ingredient)

Used with excipients to formulate drug product

Impurity

Any component present in the excipient, drug substance, or drug product that is not the desired product, a product-related substance, or excipient

Prescription Drug

Human Drug that is not safe for use exept for under surpervision of licensed medical practicioner

United States Pharmacopeia (USP)

Published in 1820

Set standards for the majority of drugs

National Formulary (NF)

Initially developed to include drugs omitted by USP

Merged with USP in 1975

New Drug Process (Discovery + Approval)

Gene/ Genome Sequencing —> Target Discovery —> Lead Discovery —> Pre-Clinical —> Clinical Phase I —> Clinical Phase II —> Manufacturing —> Distribution

Gene/Genome Sequencing

Building a library of gene/ protein sequences to study for information; initial drug discovery phase

Target Discovery

Identifying proteins/mRNA/ regulatory pathways expressed in a disease in body

Lead Discovery

Discover drug molecules that affect (inhibit/ activate) the target gene, protein, or pathway

Natural Compound Library Screening

Random screening of compounds for biologic activity; uses in vitro cell culture models or enzyme systems for testing

Relatively Fast

In Silico Screening

Biological experiments conducted on computer

Calculate affinity + use In Silico tools to simulate binding of candidate molecules to target and estimate likelihood of successful interaction

Rational Drug Design

Requires knowledge of 3D structure of active site; computer is used to design a drug with a specific structure to bind to the active site; designing drug specially for molecule

Combinatorial Chemistry

Combining different chemical building blocks in many combinations to make a large number of related chemical compounds

High throughput-screening (HTS) provides the most promising substances

Lead Optimization: ADMET

Absorption (passes GI tract into bloodstream)

Distribution (gets to target tissue)

Metabolism (don’t want it to be readily metabolized)

Excretion (not readily secreted)

Toxicity (not toxic to other cells/ tissues)

FDA

Food and Drug Administration

Responsible for drug approval

Ensures drug is safe and effective

CDER

Center For Drug Evaluation and Research

Approves small-molecule drugs

Determines OTC/prescription status

CBER

Center for Biologics Evaluation and Research

Approves biologics (genetic material) drugs

Pre-Clinical

Biologic tests of toxicity and efficacy of therapy

Drug is tested on mice, rats, and monkeys

Plans of dosage form as well

IND

Investigational New Drug

post Pre-Clinical Phase

animal studies —> IND —> FDA reviews all preclinical testing and plans for clinical testing to determine is drug is safe to move to human trials —> FDA response time = 30 days

Clinical Phase I

Main purpose: Assessing safety

Healthy volunteers take drug (20-100)

~70% drugs move on to next stage

Clinical Phase II

Main Purpose: Effectiveness

Impaired patients take drug (100-1000)

~33% of drugs move on

Clinical Phase III

300-3000 health impaired patients; globally tested

weigh benefit/risk relationship of drug

~25-30% move on

Identify other effective uses and alter labeling information

NDA

New Drug Application

Filed if clinical trials demonstrate drug safety and theraputic effectiveness*

After Clinical Phase III*

Filed to gain permission to market drug product in US

Review clock (time to get response): 180 days; can be extended

Phase IV Post Market Surveillance/ Commercialization

Collecting data to potentially reveal additional side effects, drug interactions, unexpected adverse effects, new theraputic uses, need for additional dosage strengths

Practice Pharmacists are responsible to report adversities to FDA

Reasons for Failure in New Drug Development

1) Efficacy

2) Animal Toxicity

3) Adverse Effects

4) Commercial, Pharmacokinetics (not circulating enough), miscellanous

Pre-formulation

Phsiochemical characterization of API

foundation of developing formulations to avoid problems in the later stages of drug development

Solubility

Measure of the maximum amount of substance that will dissolve in a liquid (at a constant temperature)

pH, temperature and particle size significantly affect

Solubility Definition

Very Soluble (VS) >1000

Freely Soluble (FS) 100-1000

Soluble 33-100

Sparingly Soluble (SPS) 10-33

Slightly Soluble (SS) 1-10

Very Slightly Soluble (VSS) 0.1-1

Practically Insoluble (PI) >10.000

VS —> FS —> S —> SPS —> SS —> VSS —> PI

Increased water solubility

Increased polar groups (polar ♡ polar)

Increased branching (more molecular interactions)

Salts of weak acids and bases

More Co-solvents in solvent

Decreased aqueous solubility

Increasing carbon molecules

Increasing molecular weight

Weak Acids and Bases as solvents

Predict solubility of a weak acid in stomach

Low solubility

Predict solubility of a weak bases in stomach

High solubility

Weak acid in high pH (basic environment)

High solubility

Weak acid in low pH (acidic environment)

Low solubility

Weak base in high pH (basic environment)

Low solubility

Weak base in low pH (acidic environment)

High solubility

Partition Coeffcient (K)

K=C1/C2

concentration of drug in lipophilic solvent/ concentration of drug in hydrophilic solvent

ratio determines whether drug is lipophilic or hydrophiliic

Lipophillic phase/ solvent

n-octanol or chloroform

Higher Lipid/Water Partition Coefficient

Greater the rate of transfer across the membrane

Increasing the polarity by increasing ionization

Decrease the lipid/ water partition coefficient

(higher denominator)

Decreasing the polarity by increasing ionization

Increase the lipid/ water partition coefficient

Permeability Coefficient

P = Dk/h

D= diffusion coefficient

k = partition coefficient

h = thickness of membrane

Dissolution Rate

The time it takes a drug to become soluble/ dissolve

Often become rate-limiting step

Crystalline Physical Form

Uniform, highly ordered and well-defined arrangement of atoms; definite lattice structure

Cube-esque

more stable less soluble

Amorphous Physical Form

Random, loose arrangment of atoms/ molecules in a shapeless structure

Powder-esque

Less stable but more soluble

Dissociation Constant

Measure of extent of ionization (dissociation) of drug

Dependent on pH

Higher Ionization

Favors water solubility

Lowers membrane permeability

Lower Ionization

Lowers solubility

Favors membrane potential

Ideal Drug

High water solubility

High membrane permeability

Relationship between particle size and specific surface area

Inverse Relationship

The smaller the particles, the larger the surface area

Smaller particle size is ideal for drug bc it absorbs easier

Easier drug processing (shape)

Spherical/ oval powders (minimum surface area> needle-shaped

Pharmaceutical Ingredients for a tablet; Diluents/ Fillers

Increases bulk of formulation

Pharmaceutical Ingredients for a tablet; Binders

causes adhesion of powerdered drug and pharmaceutical ingredients; glues with pressure

Pharmaceutical Ingredients for a tablet; Lubricants

assists in smoothening of tableting process

prevents sticking when tablet-making-machines get hot

Pharmaceutical Ingredients for a tablet; Disintegrating agents

promotes tablet break-up after administration (GI tract)

Which of the following is the most accurate example of target discovery?

a. inhibition of a required protein

b. looking for proteins or protein modifications associated with a disease

c. activation of a required protein

d. stimulation of a protein modification

b. looking for proteins or protein modifications associated with a disease

Which of the following is an example of a dosage form?

a. API

b. drug substance

c. solution

d. corn starch

c. solution

The USP and NF are examples of…

a. gene editing tools

b. clinical trial designs

c. drug discovery databases

d. drug standard references

d. drug standard references

Which of the following accurately differenciates In Sillico screening vs. Rational drug design

a. biological experiments conducted on a computer

b. estimate the likelihood of successful interaction

c. 3D structure of the target is required

d. random screening of several thousand molecules

d. random screening of several thousand molecules

What is the FDA’s primary role in drug approval?

a. manufacturing regulation

b. drug safety and effectiveness evaluation

c. marketing authorization for cosmetics

d. patent filing for new drugs

b. drug safety and effectiveness evaluation

Which of the following approaches will increase the solubility of a poorly water-soluble drug

a. using the crystalline form of the drug

b. using the linear chain structure of the drug

c. using the branched chain structure of the drug

d. using the base form of the drug

c. using the branched chain structure of the drug

Which of following factors will increase the permeability of a drug?

a. decreasing the polarity of the drug

b. increasing the polarity of the drug

c. decreasing the diffusion coefficient of the drug

d. decreasing the partition coefficient of the drug

a. decreasing the polarity of the drug

Which factor primarily determines a drug’s ability to penetrate biological membranes?

a. melting point

b. partition coefficient

c. particle size

d. excipient compatibility

e. permeability

e. permeability

Absorption is important because

Distribution, metabolism, and excretion follow

can take place after the administration of the drug

Diffusion

mass transfer of molecules via random molecular motion + associated with forces such as a concentration gradient

Passive Diffusion

passage of drug molecules through a membrane that behaves inertly;

driven by concentration gradient existing across membrane

high drug concentration to low

Ficks First Law of Diffusion

The rate of diffusion or transport across a membrane is proportional to the drug concentration on both sides of membrane

-dc/dt =PC1

Rate of Diffusion

dependent on drug concentration

Magnitude of P (permeability coefficient) is dependent on

diffusion coefficient of the drug

thickness + absorption of membrane (h)

partition coefficient

Major site for drug absorption via passive diffusion

villi and microvilli in small intestines duodenum

More permeable form of drug (cell membrane)

Unionized

Determines ionized/ ionized form of drug

pKa

Type of molecule that requires specialized transport mechanisms

lipid insoluble (polar molecules)

large molecules

Facilitated Diffusion

need concentration gradient (high —> low); no energy used

membrane has special protein channels with hydrophilic passages for ions and molecules

carrier protein is highly specific

Active Tranport

Against the concentration gradient

Low to high concentration

occurs via transport molecules; very specific to molecules

one cell contains many transporter proteins