Compendial Standards for Drug Quality

Compendial Standards

• Define acceptable articles at the time of use
• Establishment of drug names and requirements for identity, strength, quality, purity, packaging, storage, and labeling
• Solid oral dosage forms of drugs are used most frequently in drug therapy.
• Compendial requirements for solid dosage forms concern quality standards
• Standards are set by pharmacopeias such as USP and Ph. Eur.

Purpose of Compendial Standards

• Establishes minimum quality requirements for drug substances and products
• Aims to ensure consistency, purity, potency, and overall quality
• Legally recognized in many countries

Key Compendia

• United States Pharmacopeia (USP)
• European Pharmacopoeia (Ph. Eur.)
• Japanese Pharmacopoeia (JP)

Quality Attributes and Tests

• Identity ensures the correct active pharmaceutical ingredient (API) is present
• Uses spectroscopic techniques (IR, UV), chromatography (HPLC), and chemical tests
• Assay (Potency) determines the quantity of API in the dosage form
• Primarily uses HPLC
• Uniformity of Dosage Units ensures each unit contains the correct amount of API

Tests

• Content uniformity measures API content of individual units, verifies even distribution,
• Weight variation measures weight of individual units and the degree to which weights differ

Dissolution

• Process in which a solid substance solubilizes in a given solvent
• Rate of Dissolution measures the amount of drug that goes into solution per unit time, releases the API, crucial for assessing bioavailability
• Standardized dissolution apparatus and conditions
• Not performed in sustained release tablet preparation; directly undergo Dissolution because of the low rate of dissolution
• Deaggregation is the further breakdown into even smaller particles

Basic Theories

• Diffusion Layer Model (Film Theory) involves two steps:
• Solution of the solid to form a stagnant film or diffusive layer that is saturated
• Diffusion of the soluble solute from the stagnant layer to the bulk of the solution
• Steps 1 which is usually rapid
• Step 2 is slow and rate determining
• Danckwert’s Model (Penetration or Surface renewal Theory)
• Ruled out the existence of stagnant layer
• There is a turbulence of dissolution medium where there is a formation of eddies/water pockets in the dissolution media
• Turbulence in the dissolution medium exists at the solid/liquid interface
• Interfacial Barrier Model (Double barriers or Limited solvation Theory)
• Proposes that dissolution rate is limited by the interactions at the solid-liquid interface, where a high activation energy barrier hinders spontaneous dissolution

Noyes-Whitney Equation

• Earliest equation to explain the rate of dissolution when the process is diffusion controlled
• dC/dt = K (Cs-Cb)
  • k = Dissolution rate constant (first order),
  • Cs = Concentration of drug in the stagnant layer/ stagnant concentration,
  • Cb = concentration of drug in the bulk of the solution at time t.

Disintegration

• Measuring the time it takes for a solid dosage form to break apart in a liquid medium
• Sufficient disintegration of tablets conducive to rapid dissolution of drugs, improves bioavailability
• Relevance for tablets and capsules
• Three major mechanisms of tablet disintegration:
  • Swelling of the disintegrant overcomes adhesion forces, causing fragmentation
  • Porosity and capillary action (wicking) enhance fluid penetration and rupture
  • Deformation by elastic deformation/release of energy upon contact with water
• Purity limits the presence of impurities

Tests

• Related substances: Detecting and quantifying impurities.
• Residual solvents: Measuring the levels of solvents used in manufacturing.
• Microbial testing: Testing for the presence of harmful microorganisms.
• Hardness/Friability (for Tablets)
• Measure mechanical strength and ability to withstand handling and transportation
• Hardness measures the force needed to break a tablet, while friability assesses its resistance to abrasion and breakage

Moisture Content

• Also known as "Moisture Content"
• Critical quality attribute, impacts product stability, shelf-life, and overall quality
• Measures the amount of water present in the dosage form
• Excessive moisture can impact stability
• Packaging and Labeling requires packaging materials and labeling information
• Ensuring product stability and proper use
• Factors influencing compendial requirements
• Type of solid dosage form, routes of administration, drug substance properties, manufacturing process

Importance of Compendial Compliance

• Patient safety is ensuring patients receive safe and effective medications
• Regulatory compliance means meeting requirements of regulatory agencies like the FDA
• Product quality is maintaining consistent product quality throughout the shelf life

Liquid Dosage Form

• Semi-solid dosage (SSD) forms are a type of medication that is neither solid nor liquid
• Applied to skin, mucosa, cornea, tissue, membrane.
• SSD forms have oil and water phases
• Has a continuous or external phase and a dispersed, or internal phase
• Active ingredients can be dissolved in one or both phases

Continuous Phase (External Phase)

• Substance that forms the "background" or the "carrying" medium
• Phase that surrounds the dispersed phase, called "continuous"
• Dispersed Phase (Internal Phase) is broken up and spread throughout
• Examples include emulsion (oil-in-water) or (water-in-oil) and suspension (solid in liquid)
• Benefits of Semi-Solid for external use, Reduced side effects, avoiding first-pass effect, and controlled release

Significance Terms

• Solution is a homogenous mixture with drug fully dissolved
• Suspension has undissolved particles and requires shaking
• Emulsion is an oil and water mix, stabilized.
• Elixir is sweetened, hydroalcoholic solution.
• Syrup has high sugar concentration
• Tincture is an alcoholic extract

Preparation of Liquid Dosage Forms

• By dissolving the active drug substance in an aqueous or nonaqueous solvent, or by suspending the drug in an appropriate medium or by incorporating it into oil/water phases.
• Assaying liquid dosage preparations measures the concentration of the active pharmaceutical ingredient (API) within the liquid formulation
• Common Assay Methods:
  • High-Performance Liquid Chromatography (HPLC) separates, identifies, and quantifies components in a liquid mixture, versatile, accurate
  • Gas Chromatography (GC) analyzes volatile compounds, it's used to determine the concentration of APIs or residual solvents
  • Spectrophotometry (UV-Vis) measures the absorption of ultraviolet or visible light by a substance, used for quantifying APIs
  • Titration involves reacting the API with a titrant to quantify API
  • Atomic Absorption Spectroscopy (AAS) determines the concentration of metallic elements, when testing for trace metal contamination