RX 421 Exam 1

Physicochemical Factors

  • Aqueous solubility: A critical factor for drug formulation determining how well a drug dissolves in water.

  • Dissolution rate: Influences how quickly a drug becomes available for absorption.

  • Partition coefficient: A measure of a drug's hydrophilicity vs lipophilicity, essential for absorption and bioavailability.

  • Permeability: Concerns how easily a drug passes through cellular membranes.

  • Ionization constant: Impacts the solubility and bioavailability of drugs in different pH environments.

  • Crystallinity & Polymorphism: Different forms of a drug can have various properties affecting dissolution and stability.

  • Particle size, morphology, surface area: Smaller particle sizes often enhance dissolution rates and absorption.

  • Density and porosity: Derived properties that influence the performance of dosage forms.

  • Melting point: Determines thermal stability and solubility characteristics of solids.

  • Hygroscopicity: The ability of a substance to absorb moisture from the environment, affecting stability.

  • Chemical stability: The drug's ability to maintain its chemical integrity over time.

Van’t Hoff Equation

  • X: Solubility of solute in mole fraction.

  • ΔHf: Heat of fusion for the solute.

  • T0: Melting point of solid solute (Kelvin).

  • T: Absolute temperature of the solution.

  • Y: Activity coefficient, reflecting how real solutions deviate from ideal behavior.

Customizing Dissolution Rate for Unique Products: Ambien CR

  • t1/2 of zolpidem tartrate: 2.8 hours.

  • Combination release dynamics:

    • 2-layer tablet: one immediate release (IR) layer and one slow-release layer.

    • Dosage: 12.5 mg for adults, 6.5 mg for elderly.

Permeability in Drug Delivery

  • Importance of Passive Diffusion: Most drugs utilize passive diffusion; thus permeability is crucial.

  • Key Determinants:

    • Lipophilicity, polarity, and molecular size.

    • Biological membrane nature has a lesser effect.

Barriers to Oral Drug Delivery

  • Poor solubility and dissolution.

  • Absorption barriers:

    • Intestinal barrier.

    • Other physiological barriers (e.g., blood-brain barrier).

  • Pre-systemic metabolism: Including hepatic barrier challenges.

  • Excretion challenges.

Intestinal Barrier Notes

  • Molecule Size: Determines absorbability; larger molecules face challenges.

  • Enzymatic Degradation:

    • Variability in degradation rates across the GI tract:

      • Duodenal region differs from ileum and colon.

  • Absorption Mechanisms:

    • Passive diffusion vs active transport (transporters).

    • Efflux Transporters: Their activity varies within different GI regions.

  • Local metabolism in enterocytes: Predominantly by CYP3A4.

Hepatic Barrier Notes

  • Phase I and Phase II Enzymes: Critical for drug metabolism.

  • Efflux Transporters:

    • Located on the bile canicular membrane, transport metabolites out of hepatocytes.

    • Metabolic enzyme functions are often coupled with efflux activity.

  • Double Jeopardy or Revolving Door Theorems: Describe the interdependence of drug metabolism and excretion mechanisms.

Important Considerations in Dosage Form Design

  • Physical and Chemical Properties of the Drug:

    • Includes particle size, solubility, dissolution rates, partition coefficients.

  • Biopharmaceutical Considerations:

    • Impact of drug properties and administration route on absorption.

  • Therapeutic Considerations:

    • Targets specific patient populations, clinical conditions, and potential drug interactions.

Patient-Centric Drug Product Design

  • Patient Characteristics:

    • Age, pharmacokinetics/dynamics, physical abilities, socioeconomic factors, comorbidities, polypharmacy.

  • Drug Substance Elements:

    • Solubility, permeability, morphology, dosing impact.

  • Product-Related Characteristics:

    • Route of administration, dosage form, strength, dosing regimen, stability, packaging.

Semaglutide Injection (Ozempic)

  • Drug Type: Glucagon-like peptide 1 (GLP-1) analogue.

  • Administration: Once weekly subcutaneous injection.

  • Effects: Delays gastric emptying, aids in weight loss, lowers hypoglycemia risk.

Mechanism of Rybelsus

  • Tablet Action: Erodes in the stomach, releasing SNAC to neutralize gastric pH.

  • SNAC Functionality:

    • Increases gastric membrane permeability without disrupting tight junctions.

    • Induces semaglutide to a monomeric state for better absorption.

Target Product Profile for Elderly & Pediatric Populations

  • Elderly Patients:

    • Design for ease of swallowing, handling, patient adherence, and minimal excipient burden.

  • Pediatric Patients:

    • Consider appearance, dosage forms, palatability, safety, dosing flexibility.

Pediatric Population Ranges

  • Preterm Newborn.

  • Term Newborn: 0–27 days.

  • Infants and Toddlers: 28 days to 23 months.

  • Children: 2–11 years.

  • Adolescents: 12–16 or 18 years.

Oral Solid Dosage Forms for Children

  • Types:

    • Chewable tablets.

    • Effervescent tablets.

    • Orodispersible tablets (ODTs).

    • Multiparticulates/granules.

Solutions and Suspensions

  • Solutions:

    • Homogenous dispersion of solute in solvent; molecular interaction occurs.

  • Suspensions:

    • Dispersions of insoluble drug particles; require shaking before use for dosage accuracy.

    • Typical particle sizes are 0.5-3 µm.

Advantages of Solutions as Oral Dosage Forms

  • Easier to swallow than solids.

  • More rapid absorption leads to quicker therapeutic onset.

  • Reduced dose variation risk.

  • Flexibility in dosing is particularly beneficial for pediatric usage.

Limitations of Solutions as Oral Dosage Forms

  • Stability challenges; prone to hydrolysis.

  • Risk of microbial growth in aqueous solutions.

  • Patient ability to accurately dispense doses can vary.

  • Unpleasant taste issues are typically more noticeable in liquid forms.

Compounding Solutions Starting Points

  • Physicochemical Properties of API: Solubility, ionization, and particle size.

  • Stability of Formulations: Needs assessment of pH impact and hydrolysis risk.

  • Understanding Patient Population: Tailor formulations to suit pediatrics and elders.

Steps in Compounding Oral Solutions

  • Solubilize the Drug: Select appropriate solvent.

  • Optimize Stability: Consider adding preservatives.

  • Enhance Organoleptic Properties: Improve patient acceptability through flavor and color adjustments.

Choice of Solvent for Solutions

  • Water: Most common solvent; USP states purified water must be used.

  • Drug Concentration: Keep below saturation points to prevent precipitation.

Strategies for Low Aqueous Solubility Drugs

  • Utilize Cosolvents.

  • Adjust pH levels of formulations.

  • Select suitable drug salts.

  • Use surfactants for solubilization.

  • Formulate as a suspension instead of a solution.

Cosolvents and Their Mechanism

  • Mixing organic solvents with water increases solubility of the organic solute.

  • Relations of solvent to solute enhance solubility through 'like dissolves like'.

Example of Cosolvent Pharmaceutical Preparations

  • Phenobarbital Elixir: A hydroalcoholic solution.

  • Sulfamethoxazole-trimethoprim: Mixed formulation using propylene glycol and water.

Composition of Phenobarbital Elixir

  • Ingredients: Phenobarbital, orange oil, propylene glycol, alcohol, sorbitol solution, colorants, purified water.

Precautions of pH Manipulation

  • Stability Considerations: Products can degrade based on pH.

  • Compatibility: Ensure formulation components work together well.

  • Acceptability: Be aware of potential membrane irritation at extreme pHs (ideal range 4-7).

Common Oral Liquid Vehicles

  • Examples: Aromatic elixir, simple syrup, Ora-sweet, Ora-sweet SF, sorbitol 70% w/w.

Excipients Used in Oral Pharmaceutical Solutions

  • Include: Cosolvents, buffers, surfactants, sweeteners, flavoring agents, coloring agents, viscosity enhancers, preservatives, anti-oxidants.

Types of Sweeteners

  • Nutritive Sweeteners: Sucrose, fructose, dextrose (caloric sources).

  • Non-Nutritive Sweeteners: Sugar alcohols (sorbitol, xylitol), artificial sweeteners (saccharin, aspartame).

Sucrose Overview

  • Attributes: Pleasant taste, high aqueous solubility, and enhances viscosity.

  • Cautions: Avoid in diabetes, hereditary fructose intolerance, and per long-term dental health concerns.

Sugar Alcohol Sweeteners (Sorbitol, Xylitol)

  • Absorption: Monosaccharides poorly absorbed; may lead to osmotic diarrhea, especially in children.

  • Recommendations: Dilute sorbitol to ≤ 50% w/v to mitigate side effects.

Artificial Sweeteners

  • Saccharin: 500 times sweeter than sucrose; avoid in sulfonamide allergies.

  • Aspartame: 150-200 times sweeter; should be avoided by phenylketonuria patients.

Viscosity Control in Solutions

  • Utilize hydrophilic polymers:

    • Non-Ionic Polymers: Methylcellulose, hydroxyethylcellulose, polyvinyl pyrrolidone.

    • Ionic Polymers: Sodium carboxymethylcellulose, sodium alginate.

Preservatives Considerations

  • Should be safe and effective:

    • Compatible with other formulation ingredients, used at non-toxic concentrations, and sufficiently soluble in the medium.

Commonly Used Preservatives in Oral Solutions

  • Parabens: E.g., methylparaben, propylparaben; effective in low concentrations.

  • Organic Acids: E.g., benzoic acid, sorbic acid; effective within specific pH ranges.

    • Effectiveness contingent upon maintaining drugs in acidic forms (e.g., free acid forms).

Preventing Oxidation in Formulations

  • Deaeration: Use deaerated water or purge with nitrogen.

  • Antioxidants: Additives like ascorbic acid; they help prevent oxidative degradation.

  • Chelating Agents: Ex. EDTA; bind trace metals that catalyze oxidation.