Terms, Definitions, Compounding, & USP

What are the three stages of drug discovery and approval?

Preclinical, Clinical, and NDA Review

Approximately how long does the ‘Preclinical’ stage of drug discovery/approval take?

~3-6 years

What is the ‘Preclinical’ stage of drug discovery composed of?

Formulation animal test, animal study of safety, efficacy, and pharmacokinetics (PK)

What is the ‘Clinical’ stage of drug discovery composed of?

Phase 1, Phase 2, Phase 3

Approximately how long does the ‘Clinical’ stage of drug discovery/approval take?

~6-7 years

Approximately how long does the ‘NDA Review’ stage of drug discovery/approval take?

~1 year

What does ‘FDA’ stand for?

Food and Drug Administration

What does ‘NDA’ stand for?

New Drug Application

What does ‘ANDA’ stand for?

Abbreviated New Drug Application

What does ‘IND’ stand for?

Investigational New Drug Application

What does ‘INADA’ stand for?

Investigational New Animal Drug Application

What does ‘SNADA’ stand for?

Supplemental New Drug Application

What does approval of an NDA by the FDA signify?

Signifies a rigorous review and authorization, allowing the drug to be marketed legally and proving it to be safe and effective for its intended use.

What characteristics of a New Drug Application (NDA) must be assessed before FDA approval?

Formulation, Influence of pharmaceutical ingredients/container, Manufacturing/Processing Conditions, Packaging components, Conditions of storage, Anticipated conditions of shipping/duration/conditions of pharmacy shelf-life and patient use

What are the differentiating factors for brand drugs versus generic drugs?

Has a patent, high price, marketing name (e.g. Tylenol)

What are the differentiating factors for generic drugs versus brand drugs?

No patent, low price, chemical name (e.g. Acetaminophen)

What sections are included in a ‘package insert’?

Important safety information, indications & usage, dosage and administration, dosage strengths/forms, contraindications, warnings & precautions, adverse reactions, drug interactions, use in specific populations, drug abuse & dependence, overdosage, description, clinical pharmacology, nonclinical toxicology, clinical studies, supply/storage/handling instructions, patient counseling information

What is the definition of ‘Pharmaceutics’?

The general area of study concerned with the formulation, manufacturing, stability, and effectiveness of pharmaceutical dosage forms.

What is the definition of ‘Active Pharmaceutical Ingredient (API)’?

The biologically active components of a drug product

What is the definition of ‘Pharmaceutical Excipients’?

The inactive components of a drug product

What is the definition of ‘Pharmaceutical Formulation’?

The systematic process of designing, developing, and optimizing compositions comprising APIs and excipients to produce a final medicinal product suitable for administration.

What is the definition of ‘Drug Product’?

The finished dosage form of a drug

What is the definition of ‘Preformulation’?

The process of characterization of physicochemical (and some biological) properties of an API before formulation into a dosage form (tablets, capsules, solution, or injections)

What are the benefits of ‘Preformulation’ studies before actual product formulation begins?

Reduction of drug development costs

Decreased product’s time to the market

What do ‘Preformulation’ studies usually consist of?

Physicochemical properties, biopharmaceutical considerations, therapeutic considerations

What is the definition of polymorphism in the formulation process?

The property of having more than one crystalline form/and or amorphous form

Approximately one-third of all organic compounds exhbit?

Polymorphism

Polymorphs of the same organic compound typically exhibit what different physical properties?

Solubilities, melting points, infrared spectra

What is the effect of low pH (e.g. acidic) on solubility and permeability for weak acids and bases?

Weak acids more permeable

What is the effect of high pH (e.g. basic) on solubility and permeability for weak acids and bases?

Weak bases more permeable

What is the correlation with solubility and permeability?

High solubility → Low permeability

Low solubility → High permeability

What is the correlation with lipophilicity and membrane permeability?

High lipophilicity → High membrane permeability

Low lipophilicity → Low membrane permeability

What characteristics are associated most with polar drugs?

Charged/ionized, hydrophilic, lower permeability

What characteristics are associated most with nonpolar drugs?

Uncharged/unionized, lipophilic, higher permeability

How does particle size affect dissolution rate?

Smaller particle size → Faster dissolution rate

Larger particle size → Slower dissolution rate

What is the ‘Partition Coefficient’ (LogP)?

Serves as a representation of substance distribution between two immiscible (heterogeneous) phases.

What is the threshold for a ‘low’ LogP?

< 0

What is the threshold for a ‘high’ LogP?

> 3

What characteristics are associated with a drug with low LogP?

Low lipophilicity, higher affinity for aqueous phase, low solubility in lipid environment

What characteristics are associated with a drug with high LogP?

High lipophilicity, Higher affinity for lipid phase, Low solubility in aqueous phase

What is the LogP threshold for an ideal drug candidate?

1-3

What are the three most important mechanisms responsible for drug degradation?

Oxidation, Hydrolysis, Photodegradation

What best defines an oxidation reaction?

Loss of electrons, often involving a reaction with oxygen

What best defines a hydrolysis reaction?

Breakdown of a molecule due to reaction with water.

What best defines a photodegradation reaction?

Chemical breakdown due to exposure from light (e.g. UV)

What are the five types of stability concerns associated with drugs and drug products?

Physical, Chemical, Microbiological, Therapeutic, Toxicological

What traits are often associated with physical stability of drug products?

Changes in color/odor/taste, precipitation, phase separation

What traits are often associated with chemical stability of drug products?

Chemical integrity, labeled potency, degradation by hydrolysis, oxidation, or photolysis, loss of active pharmaceutical ingredient (API), formation of degradation products

What traits are often associated with microbiological stability of drug products?

Growth of bacteria, fungi, or mold in multi-dose containers, breakdown of preservatives, contamination during storage or use.

What traits are often associated with therapeutic stability of drug products?

Loss of pharmacological activity, changes in bioavailability/absorption

What traits are often associated with toxicological stability of drug products?

Harmful byproducts during degradation, unexpected adverse effects due to impurities

What is the purpose of stability testing of drugs, excipients, and drug products?

Provide evidence on how the quality of a drug product varies with time under the influence of a variety of environment factors.

What environmental factors are often used in stability testing of drug products?

Temperature, humidity, oxidation, light intensity, microbial exposure

What is the purpose of accelerated stability testing?

Predict the long-term stability of a drug product under normal storage conditions by exposing it to more extreme conditions.

In accelerated stability testing, how long will a drug product will remain stable?

~6 months

What is the typical process that occurs during accelerated stability testing?

Store drug at elevated temperature, collect drug samples periodically and determine quantity decomposed, determine decomposition rate constant at various temperature, prepare an Arrhenius plot and extrapolate the plot to room temperature to determine decomposition at room temperature.

What best defines ‘Expiration Date’?

The specific date printed on the packaging after which the manufacturer no longer guarantees full potency or safety.

What variable is used to define ‘Shelf-Life’?

t_shelf

What is the typical threshold for shelf-life (t_shelf)?

90% or 0.9

What best defines shelf life?

The time period during which a drug product is expected to remain stable and effective, based on stability data.

What differentiates bulk powder from divided powder?

Packaged in quantities greater than needed for a single dose, appropriate for low potency products. The patient/caregiver must measure the appropriate dose.

What are some medication classes that come as a bulk powder formulation?

Antacids, laxatives, and medicated powders for external application

What differentiates divided powder from bulk powder?

Divided into individual dosing units, often placed on small pieces of paper that are folded to enclose the medication (simple bond paper, vegetable parchment, glassine, or waxed paper). Require skill and experience for accurate dividing and packaging of individual doses.

What advantages do solid dosage forms provide over solution dosage forms?

Easy to identify, store, and transport

Convenient handling → Better patient compliance

Varibale dosage strengths possible through scoring

What reactions do solid dosage forms provide better protection from compared to solution dosage forms?

Oxidation and Hydrolysis

What is the chemical composition of effervescent granules?

Citric acid + tartaric acid + sodium bicarbonate

What is the main benefit for use of effervescent granules?

Masks undesirable taste for saltiness/bitterness, provides a pleasant vehicle for certain drug products

What is the main goal/function of effervescent tablets/granules?

Liberate carbon dioxide (CO₂) when mixed with water

In effervescent granules, what is the ratio of citric acid to tartaric acid?

1:2

What are the two ways to prepare effervescent?

Dry/Fusion and Wet Methods

What are some examples of effervescent granule drugs?

Sennakot Granules, Zantac 25

What best defines the ‘dry/fusion method’ in effervescent compounding?

Mixing the ingredients (acid and base) without adding any water, using the small amount of moisture in citric acid monohydrate to initiate a slight reaction that helps bind the powders together.

What best defines the ‘wet method’ in effervescent compounding?

Use of a small amount of a non-aqueous solvent (like alcohol or isopropanol) to wet and bind the powders, avoiding a premature acid-base reaction since no water is added.

What are some key points associated with the ‘dry/fusion method’ in effervescent compounding?

No external water is added.

Requires heat.

Suitable only for citric acid monohydrate, not anhydrous form.

What are some key points associated with the ‘wet method’ in effervescent compounding?

Uses non-aqueous solvent.

No heating needed.

Safer for heat-sensitive ingredients.

What best defines ‘Extended Release’ (ER) formulations?

Releases the active drug at a predetermined rate over an extended period; allows at least a two-fold reduction in dosing frequency

What are some advantages to ER formulations?

Reduced dosing frequency, reduction in blood level fluctuations, lower healthcare costs/side effects, higher patient compliance

What are the two types of diffusion-controlled systems?

Monolithic/Matrix and Reservoir

What best defines a ‘Monolithic/Matrix’ diffusion-controlled system?

Drug dispersed homogeneously through an inert polymer matrix. Drug in outer layer exposed to aqueous solution dissolved and diffuses out of the matrix.

What are some advantages associated with a ‘Monolith/Matrix’ diffusion-controlled system?

Easier to produce, can deliver high molecular weight compounds

What best defines a ‘Reservoir’ diffusion-controlled system?

Characterized by a core of drug surrounded by a polymeric membrane. Nature and thickness of the membrane determine the rate of release of drug from the system.

What are some advantages associated with a ‘Reservoir’ diffusion-controlled system?

Zero order delivery possible, release rate variable with polymer type and thickness

What are the most commonly used classes of excipients (inactive ingredients)?

Disintegrants, Binders, Diluents, Preservatives, Lubricants

What best defines the function of disintegrants?

Facilitate the breakup of tablets in contact with water in the gastrointestinal tract.

What best defines the function of binders?

Add cohesiveness to powders, thereby providing necessary bonding to form granules.

What best defines the function of diluents?

Increase bulk formulation

What best defines the function of preservatives?

Microbial growth prevention

What best defines the function of lubricants?

Reduce friction between materials during tablet manufacturing.

What are some examples of disintegrants?

Starch derivatives, alginic acid, sodium starch glycolate

What are some examples of binders?

Gelatin, starch, methylcellulose, acacia, polyvinylpyrrolidone

What are some examples of diluents?

Lactose, anhydrous lactose, spray-dried lactose, kaolin, mannitol, sorbitol, starch

What are some examples of preservatives?

Parabens, sodium benzoate, benzyl alcohol, chlorhexidine

What are some examples of lubricants?

Stearic acid salts (e.g. Mg-stearate, Ca-stearate)

What are the six types of tablets?

Enteric-coated, Sublingual, Chewable, Chewable-dispersible, Effervescent, Rapidly Dissolving

What medications use enteric-coated tablets?

Ecotrin, Prilosec, Ibuprofen, E-mycin

What medications use sublingual tablets?

Nitrostat, Suboxone, Saphris

What medications use chewable tablets?

Tums, Mylanta, Singulair, Risperdal

What medications use chewable-dispersible tablets?

Coartem, Augmentin, Zentel

What medications use effervescent tablets?

Alka-Seltzer, Berocca, Disprin, Cebion Effervescent

What medications use rapidly dissolving tablets?

Claritin Reditabs, Zofran, Maxalt