Growup Pharma

B Pharmacy Sem 4: Pharmaceutical Organic Chemistry III

By /

B Pharmacy Sem 4: Pharmaceutical Organic Chemistry III

Subject  2: Physical Pharmaceutics II

1. Interfacial Phenomena & Surface Chemistry (Adsorption, Surface Tension, Wettability)
2. Colloidal Dispersions (Theory, Stability of Lyophilic & Lyophobic Systems)
3. Emulsions & Suspensions (Types, Preparation, Characterization & Stability Testing)
4. Rheology of Pharmaceutical Systems (Flow Behavior, Viscosity Measurements)
5. Diffusion & Dissolution Phenomena (Fick’s Laws, Dissolution Testing Methods)
6. Stability of Dosage Forms (Physical, Chemical, Microbial; Accelerated Stability Studies)

Table of Contents

 

Unit 1: Interfacial Phenomena & Surface Chemistry

This unit examines the behavior of molecules at interfaces and surfaces, focusing on adsorption, surface tension, and wettability—and how these properties influence formulation, stability, and performance of pharmaceutical products.

1.1 Fundamentals of Interfaces

1.1.1 Definition of Interface

  • Region of contact between two immiscible phases (solid–liquid, liquid–air, liquid–liquid).

  • Molecular environment at the interface differs from the bulk: unsatisfied intermolecular forces, altered entropy.

1.1.2 Gibbs’ Thermodynamics

  • Gibbs Surface Excess (Γ): Amount of substance adsorbed per unit area at interface.

  • Gibbs Adsorption Isotherm:

    dγ=−∑iΓidμi \mathrm{d}\gamma = -\sum_i \Gamma_i\,\mathrm{d}\mu_i

    – Relates changes in surface tension (γ) to chemical potential (μ) and surface excess of each component.

1.2 Adsorption

1.2.1 Types of Adsorption

  • Physical (Physisorption):

    • Reversible, weak van der Waals forces.

    • Multilayer possible at high pressure/concentration.

  • Chemical (Chemisorption):

    • Strong, specific chemical bonds (covalent or ionic).

    • Generally monolayer; often irreversible.

1.2.2 Adsorption Isotherms

  • Langmuir Isotherm (monolayer chemisorption):

    Γ=Γ∞KC1+KC \Gamma = \frac{\Gamma_\infty\,K\,C}{1 + K\,C}

  • Freundlich Isotherm (heterogeneous surfaces, physisorption):

    Γ=KFC1/n \Gamma = K_F\,C^{1/n}

1.2.3 Pharmaceutical Implications

  • Drug–Excipient Interactions: Adsorption of active molecules onto carriers (e.g., silica, talc) affects release.

  • Protein Adsorption: Protein binding to container surfaces can lead to loss of potency or immunogenic aggregates.

  • Surface Coatings: Use of surfactants to block unwanted adsorption (e.g., polysorbate on vial walls).

1.3 Surface Tension

1.3.1 Definition & Origin

  • Work required to increase the surface area of a liquid by one unit.

  • Arises from net inward cohesive forces on surface molecules.

1.3.2 Measurement Methods

  • Drop Weight/Volume: Mass or volume of dripping drop relates to γ.

  • Wilhelmy Plate: Force on a plate immersed at the interface measures γ.

  • Du Nouy Ring: Torque needed to detach a ring from the liquid surface.

1.3.3 Surface-Active Agents (Surfactants)

  • Structure: Amphiphilic molecules with hydrophilic head and hydrophobic tail.

  • Critical Micelle Concentration (CMC): Concentration above which micelles form, and γ reaches a plateau.

  • Classification:

    • Anionic (e.g., sodium dodecyl sulfate)

    • Cationic (e.g., cetyltrimethylammonium bromide)

    • Nonionic (e.g., Tween 80)

    • Zwitterionic (e.g., lecithin)

1.3.4 Role in Formulations

  • Emulsification: Lower γ between oil–water phases to form stable droplets.

  • Wetting Agents: Reduce surface energy to enhance powder wetting or tablet disintegration.

  • Solubilization: Micellar solubilization of poorly water‑soluble drugs.

1.4 Wettability

1.4.1 Contact Angle & Young’s Equation

  • Contact Angle (θ): Angle between tangent to liquid drop and solid surface.

    • θ < 90°: Wetting (hydrophilic surface)

    • θ > 90°: Non‑wetting (hydrophobic surface)

  • Young’s Equation:

    γSV=γSL+γLVcos⁡θ \gamma_{SV} = \gamma_{SL} + \gamma_{LV}\cos\theta

    – Relates solid‑vapor (γ_SV), solid‑liquid (γ_SL), and liquid‑vapor (γ_LV) tensions.

1.4.2 Factors Influencing Wettability

  • Surface Roughness: Wenzel and Cassie–Baxter models describe roughness effects.

  • Chemical Heterogeneity: Mixed surface chemistries alter local γ_SL.

  • Temperature & pH: Can change both γ_LV and surface energy of solids.

1.4.3 Pharmaceutical Applications

  • Tablet Coating: Wettability of coating solution on tablet core affects film uniformity.

  • Powder Wet Granulation: Adequate wetting of granulating fluid ensures uniform agglomerates.

  • Implant & Device Biocompatibility: Wettability of biomaterials influences protein adsorption and cell adhesion.

1.5 Integration in Drug Development

1.5.1 Surface Modification Techniques

  • Plasma Treatment: Alters surface energy to improve wettability or reduce adsorption.

  • Self‑Assembled Monolayers: Tailored surface chemistry for specific drug–surface interactions.

1.5.2 Analytical Characterization

  • Atomic Force Microscopy (AFM): Topography and adhesion forces at sub‑nanometer resolution.

  • X‑ray Photoelectron Spectroscopy (XPS): Chemical composition of surface layers.

1.5.3 Stability & Performance

  • Control of interfacial properties critical for emulsion creaming, tablet dissolution, and sterile formulation integrity.

1.6 Key Points for Exams

  1. Define & Derive: Explain Gibbs adsorption isotherm and derive Young’s equation.

  2. Isotherm Application: Given adsorption data, fit to Langmuir vs. Freundlich models.

  3. Surfactant Behavior: Sketch γ vs. log [C] plot, indicate CMC, and discuss micelle role in solubilization.

  4. Contact Angle Measurement: Describe how to measure θ and interpret wettability for a powder.

  5. Formulation Design: Propose a surfactant system to stabilize an oil‑in‑water emulsion for intravenous lipid emulsion.

Unit 2: Colloidal Dispersions (Theory, Stability of Lyophilic & Lyophobic Systems)

An exhaustive study of colloidal systems—their classification, methods of preparation, stabilization mechanisms, characterization techniques, and pharmaceutical applications.

2.1 Definitions & Classification

2.1.1 Colloid & Dispersion

  • Colloid: A system in which particles of one substance (1 nm–1 µm) are dispersed throughout another without settling under gravity.

  • Dispersion Medium: Continuous phase (liquid, solid, or gas) in which the colloidal particles are suspended.

  • Dispersed Phase: The colloidal particles themselves.

2.1.2 Classification by Phase

Dispersed PhaseDispersion MediumSystem NameExample
SolidGasAerosol (smoke)Soot particles in air
LiquidGasAerosol (fog)Water droplets in air
SolidLiquidSolGold sol, colloidal silver
LiquidLiquidEmulsionOil‑in‑water (O/W) cream
GasLiquidFoamShaving cream
GasSolidSolid foam (porous)Pumice
LiquidSolidGelGelatin, hydrogel
SolidSolidSolid solColored gemstones

2.1.3 Lyophilic vs. Lyophobic Colloids

  • Lyophilic (“solvent‑loving”): Strong affinity between dispersed phase and medium; spontaneous formation, reversible; high stability.

    • Examples: gelatin sol in water, starch sol.

  • Lyophobic (“solvent‑hating”): Weak affinity; require special stabilizers; low stability, irreversibility on dilution.

    • Examples: gold sol, sulphur sol.

2.2 Preparation of Colloids

2.2.1 Dispersion Methods

  • Milling/Micronization: Mechanical breakup of coarse particles (e.g., high‑shear mills for nanosuspensions).

  • Ultrasonication: Cavitation‑induced fragmentation of droplets or particles.

2.2.2 Condensation Methods

  • Chemical Reduction: Metal salts → metal nanoparticles (e.g., gold sol via citrate reduction).

  • Chemical Precipitation: Controlled addition of reagents to form insoluble colloidal precipitate (e.g., alumina sol).

  • Emulsification: High‑pressure homogenization to create droplets in nano‑/micro‑emulsions.

2.3 Stability Mechanisms

2.3.1 Electrostatic Stabilization

  • Electrical Double Layer (EDL): Charged colloidal surface attracts counter‑ions, forming a stern layer + diffuse layer.

  • Zeta Potential (ζ): Potential at the slipping plane; |ζ| > ±30 mV typically indicates stable dispersion due to repulsion.

  • DLVO Theory: Balance of van der Waals attraction (V_A) and electrical repulsion (V_R); total interaction

    Vtotal=VA+VR. V_{\text{total}} = V_A + V_R.

    Energy barrier prevents particle aggregation if sufficiently high.

2.3.2 Steric Stabilization

  • Mechanism: Adsorbed or grafted polymers/ligands on particle surface produce entropic repulsion when layers overlap.

  • Examples: PEGylated liposomes, Pluronic F‑68 stabilized nanoparticles.

2.3.3 Electrosteric Stabilization

  • Combines electrostatic and steric effects (e.g., polyelectrolyte coatings such as chitosan).

2.4 Characterization of Colloidal Dispersions

2.4.1 Particle Size & Distribution

  • Dynamic Light Scattering (DLS): Measures Brownian motion to infer hydrodynamic diameter.

  • Laser Diffraction: Angle‑dependent scattering to determine size distribution.

2.4.2 Surface Charge

  • Electrophoretic Light Scattering: Determines zeta potential from electrophoretic mobility.

2.4.3 Stability Testing

  • Sedimentation & Creaming: Centrifugation or visual observation over time.

  • Turbidity & Light Transmission: Changes indicate aggregation or flocculation.

  • Viscosity Measurements: Rheometer to detect increases due to network formation.

2.5 Pharmaceutical Applications

2.5.1 Parenteral Nanosuspensions

  • Poorly soluble drugs formulated as stabilized nanosuspensions (e.g., paclitaxel) to enhance bioavailability.

2.5.2 Liposomes & Lipid Nanoparticles

  • Lyophilic colloids: Phospholipid vesicles for targeted drug delivery (Doxil®, siRNA vaccines).

2.5.3 Emulsions for IV Nutrition

  • O/W emulsions of soybean oil with egg phospholipid stabilizers (Intralipid®) to deliver lipids.

2.5.4 Inhalation Aerosols

  • Liquid aerosols (nebules) and dry‑powder colloidal particles for pulmonary delivery.

2.6 Key Points for Exams

  1. Define & Distinguish: Differentiate lyophilic and lyophobic colloids in terms of spontaneity, stability, and reversibility.

  2. Explain DLVO: Sketch V_total vs. interparticle distance, showing primary and secondary minima and the energy barrier.

  3. Zeta Potential: Describe how you would measure and interpret ζ for a new nanoparticle formulation.

  4. Preparation Choice: Given a hydrophobic drug, propose a method to prepare a stable nanosuspension for IV use, including stabilizers.

  5. Characterization: List three analytical techniques for particle size and two for surface charge or stability, explaining their principles.

Unit 3: Emulsions & Suspensions (Types, Preparation, Characterization & Stability Testing)

A thorough exploration of two fundamental dispersed‑phase systems—emulsions (liquid‑liquid) and suspensions (solid‑liquid)—covering their definitions, classifications, formulation strategies, analytic techniques, and stability considerations.

3.1 Definitions & Distinctions

3.1.1 Emulsions

  • Definition: Heterogeneous systems of two immiscible liquids (oil and water) where one is dispersed as droplets within the other.

  • Continuous Phase vs. Dispersed Phase: The medium in which droplets are suspended (e.g., water in oil‑in‑water emulsions).

  • Thermodynamic Instability: Tend toward phase separation; kinetically stabilized by emulsifiers.

3.1.2 Suspensions

  • Definition: Coarse dispersions of insoluble solid particles (1 µm–100 µm) within a liquid medium.

  • Sedimentation Prone: Governed by Stokes’ law; require suspending agents to retard settling.

3.2 Classification

3.2.1 Emulsions

TypeDispersed PhaseContinuous PhaseExample
O/WOilWaterCreams, lotions
W/OWaterOilWater‑in‑oil cold creams
MultipleW/O/W or O/W/OAlternate layerControlled release emulsion

3.2.2 Suspensions

  • Flocculated: Particles loosely aggregated—form a network that slows sedimentation; redispersible.

  • Deflocculated: Particles settle as a hard cake—difficult to redisperse.

3.3 Preparation Methods

3.3.1 Emulsions

  1. High‑Shear Homogenization: Rotor–stator devices reduce droplet size to 0.1–10 µm.

  2. Ultrasonic Emulsification: Cavitation generates intense local shear for sub‑micron droplets.

  3. Phase Inversion Temperature (PIT): Nonionic surfactants invert oil/water affinity by temperature cycling.

  4. Spontaneous Emulsification: Mixing surfactant/oil blends with water under controlled composition yields fine droplets.

3.3.2 Suspensions

  1. Wet Milling (Media Milling): Grinding with beads to achieve desired particle size (100 nm–10 µm).

  2. Sonication: Breaks aggregates; less effective for primary particle size reduction.

  3. Spray Drying & Reconstitution: Dry powder formation with protective matrix; rehydrated before use.

3.4 Formulation Components

3.4.1 Emulsifiers & Surfactants

  • Role: Lower interfacial tension; form interfacial film around droplets.

  • Selection Criteria: HLB value (Hydrophilic–Lipophilic Balance) guides O/W vs. W/O choice.

3.4.2 Suspending Agents

  • Polymers: Cellulose derivatives (methylcellulose, HPMC) increase viscosity.

  • Clays & Gums: Bentonite, xanthan gum form gel‑like networks.

  • Osmotic Modifiers: Glycerin, sorbitol to adjust density and slow sedimentation.

3.4.3 Co‑solvents & pH Modifiers

  • Improve wetting of solids or solubility of emulsifier; adjust zeta potential in suspensions.

3.5 Characterization Techniques

3.5.1 Droplet/Particle Size & Distribution

  • Laser Diffraction: Measures droplet size distribution (emulsions) and particle size (suspensions).

  • Dynamic Light Scattering: For sub‑micron emulsions or nanosuspensions.

3.5.2 Zeta Potential

  • Electrophoretic Mobility: Indicator of colloidal stability; |ζ| > 30 mV favor stability against aggregation.

3.5.3 Rheological Properties

  • Viscosity Profiles: Newtonian vs. non‑Newtonian (pseudoplastic, thixotropic) behavior measured with rotational rheometers.

3.5.4 Microscopy & Imaging

  • Optical/Polarized Light: Visual droplet/particle morphology, floc structure.

  • Cryo‑TEM/SEM: High‑resolution imaging of nanoscale droplets or particles.

3.6 Stability Testing & Mechanisms of Instability

3.6.1 Emulsions

  • Creaming & Sedimentation: Stoke’s law–driven droplet rise/fall; accelerated by centrifugation.

  • Coalescence: Film rupture between droplets → droplet growth; measured by change in droplet size over time.

  • Ostwald Ripening: Diffusive transfer of dispersed phase from small to large droplets; driven by Laplace pressure differences.

  • Phase Inversion: Change from O/W to W/O (or vice versa) under stress or compositional shifts.

3.6.2 Suspensions

  • Sedimentation Rate: Monitored volumetrically; described by Stokes’ equation:

    v=2(ρp−ρm)gr29η v = \frac{2(\rho_p – \rho_m)g\,r^2}{9\eta}

  • Caking vs. Flocculation: Flocculated systems resist caking; deflocculated form hard sediment.

  • Redispersibility Tests: Number of inversions or minutes of shaking to fully resuspend.

3.7 Pharmaceutical Applications

  • Topical Creams & Lotions: O/W emulsions for drug delivery and cosmetic appeal.

  • Intravenous Lipid Emulsions: Parenteral nutrition; drug solubilization for IV administration.

  • Oral Suspensions: Pediatric formulations; antibiotics (e.g., amoxicillin suspension).

  • Ophthalmic Suspensions: Controlled release in the eye; particle size critical (<10 µm).

3.8 Key Points for Exams

  1. Define & Compare: Emulsions vs. suspensions; flocculated vs. deflocculated suspensions.

  2. Formulation Design: Select appropriate surfactant (HLB) for an O/W emulsion containing a lipophilic drug.

  3. Instability Mechanisms: Explain Ostwald ripening with a schematic of droplet size change.

  4. Analytical Choice: Recommend techniques to monitor droplet size, zeta potential, and rheology over shelf‑life.

  5. Case Study: Propose a stabilizing strategy for a nanosuspension of a poorly soluble API, including milling method and choice of polymer.

Unit 4: Rheology of Pharmaceutical Systems (Flow Behavior & Viscosity Measurements)

An in‑depth investigation into the flow and deformation behavior of pharmaceutical formulations—covering rheological principles, flow classifications, viscosity measurement techniques, mathematical models, and formulation implications.

4.1 Fundamental Concepts in Rheology

4.1.1 Definition of Rheology

  • Science of deformation and flow of matter under applied stress or strain.

  • Critical for predicting processing behavior (mixing, pumping) and end‑use performance (sprayability, spreadability).

4.1.2 Stress, Strain & Rate

  • Shear Stress (τ): Force per unit area parallel to the material surface (τ = F/A).

  • Shear Rate (γ̇): Rate of change of strain; velocity gradient between layers (γ̇ = dv/dy).

  • Viscosity (η): Ratio of shear stress to shear rate (η = τ/γ̇).

4.2 Flow Classifications

4.2.1 Newtonian Fluids

  • Behavior: Constant viscosity regardless of shear rate.

  • Examples: Water, simple syrup, low‑molecular‑weight solvents.

4.2.2 Non‑Newtonian Fluids

  • Shear‑Thinning (Pseudoplastic): Viscosity decreases with increasing shear rate.

    • Pharma Examples: Polymer solutions (HPMC gels), injectable polymeric suspensions.

  • Shear‑Thickening (Dilatant): Viscosity increases with shear rate.

    • Examples: High‑solid suspensions at certain concentrations.

  • Thixotropic Systems: Time‑dependent shear‑thinning; viscosity decreases under constant shear and recovers on rest.

    • Examples: Paints, certain creams.

  • Rheopectic Systems: Time‑dependent shear‑thickening; rare in pharmaceuticals.

4.3 Rheological Models & Parameters

4.3.1 Newton’s Law

τ=ηγ˙ τ = η \;γ̇

4.3.2 Power‑Law Model (Ostwald–de Waele)

τ=Kγ˙n τ = K γ̇^n

  • K: Consistency index (apparent viscosity at γ̇ = 1 s⁻¹).

  • n: Flow behavior index

    • n < 1: Pseudoplastic

    • n = 1: Newtonian

    • n > 1: Dilatant

4.3.3 Bingham Plastic Model

τ=τ0+ηpγ˙ τ = τ_0 + η_p γ̇

  • τ₀: Yield stress (minimum stress to initiate flow).

  • η_p: Plastic viscosity.

  • Applications: Toothpaste, concentrated suspensions.

4.3.4 Herschel–Bulkley Model

τ=τ0+Kγ˙n τ = τ_0 + K γ̇^n

  • Combines yield stress and power‑law behavior for more complex fluids.

4.4 Instrumentation & Measurement Techniques

4.4.1 Rotational Rheometers

  • Cone‑and‑Plate: Constant shear rate; measures torque to determine τ vs. γ̇.

  • Parallel Plate: Adjustable gap for sample thickness control; ideal for gels and semi‑solids.

  • Brookfield Viscometer: Spindle rotation at set speeds; reports apparent viscosity.

4.4.2 Capillary Viscometers

  • Ostwald/U‑tube: Gravity‑driven flow through capillary; viscosity from flow time.

  • Applications: Polymer solution viscosity (HPMC concentration determination).

4.4.3 Falling‑Ball Viscometer

  • Measures terminal velocity of ball in fluid; relates to viscosity via Stokes’ law.

4.4.4 Oscillatory Rheometry

  • Dynamic Testing: Applies small sinusoidal strain; measures storage modulus (G′) and loss modulus (G″).

    • G′ (Elastic Modulus): Energy stored (solid‑like behavior).

    • G″ (Viscous Modulus): Energy dissipated (liquid‑like behavior).

  • Frequency Sweeps: Characterize viscoelastic spectrum; gel strength and stability.

4.5 Pharmaceutical Implications of Rheology

4.5.1 Processing & Manufacturing

  • Mixing & Pumping: Viscosity dictates equipment selection and energy requirements.

  • Filling & Coating: Controlled rheology ensures uniform dosage and film thickness.

4.5.2 Dosage Form Performance

  • Ointments & Creams: Spreadability and retention on skin depend on yield stress and thixotropy.

  • Suspensions: Optimal viscosity prevents rapid sedimentation yet allows easy pourability.

  • Inhalation Suspensions: Low viscosity for nebulization but sufficient suspension stability.

4.5.3 Patient Acceptability

  • Oral Suspensions: Palatability and ease of swallowing linked to mouth‑feel (viscosity profile).

  • Ophthalmic Solutions: Low shear viscosity ensures ease of drop formation; mucoadhesion relates to viscoelasticity.

4.6 Data Interpretation & Rheograms

4.6.1 Flow Curve (τ vs. γ̇)

  • Identify Newtonian plateau, shear‑thinning regions, yield stress intercept.

4.6.2 Viscosity Curve (η vs. γ̇)

  • Determine pseudoplastic or dilatant behavior from slope.

4.6.3 Oscillatory Plots (G′, G″ vs. Frequency)

  • Sol–Gel Transition: Crossover point where G′ = G″ indicates gel strength.

4.7 Key Points for Exams

  1. Define Terms: Distinguish between shear stress, shear rate, viscosity, yield stress.

  2. Model Application: Fit given flow data to Newtonian, power‑law, and Bingham models; calculate K, n, τ₀.

  3. Instrument Selection: Recommend a rheometer type for evaluating a topical cream vs. a dilute polymer solution.

  4. Interpret Rheograms: Given a viscosity vs. shear‑rate plot, classify flow behavior and predict formulation performance.

  5. Formulation Adjustment: Propose rheology modifiers to convert a shear‑thinning gel into a thixotropic cream with desired spreadability.

Unit 5: Diffusion & Dissolution Phenomena (Fick’s Laws & Dissolution Testing Methods)

An exhaustive examination of molecular transport processes in pharmaceutical systems—covering diffusion theory, quantitative laws, experimental measurement of dissolution, and their critical role in drug release and bioavailability.

5.1 Fundamentals of Diffusion

5.1.1 Definition

  • Diffusion: Spontaneous movement of molecules from regions of higher concentration to lower concentration due to random thermal motion.

5.1.2 Types of Diffusion

  • Molecular (Fickian) Diffusion: Governed by concentration gradients in homogeneous media.

  • Interstitial Diffusion: Occurs in porous matrices or gels.

  • Knudsen Diffusion: In very small pores where molecule–wall collisions dominate.

  • Convective Transport: Bulk movement superimposed on diffusion (e.g., stirring, blood flow).

5.2 Fick’s Laws of Diffusion

5.2.1 Fick’s First Law

  • Describes steady‑state diffusion (flux constant over time).

  • Mathematical Form:

    J=−D∂C∂x J = -D\,\frac{\partial C}{\partial x}

    – J: Diffusive flux (amount per unit area per unit time)
    – D: Diffusion coefficient (cm²/s)
    – ∂C/∂x: Concentration gradient

5.2.2 Fick’s Second Law

  • Describes non‑steady‑state diffusion (flux and concentration vary with time).

  • Mathematical Form:

    ∂C∂t=D∂2C∂x2 \frac{\partial C}{\partial t} = D\,\frac{\partial^2 C}{\partial x^2}

  • Solutions depend on geometry and boundary conditions (e.g., slab, cylinder, sphere).

5.2.3 Factors Affecting D (Diffusion Coefficient)

  • Temperature (T): D ∝ T/η (η = viscosity of medium).

  • Molecular Size & Shape: Smaller solutes diffuse faster.

  • Medium Properties: Viscosity, porosity, tortuosity in gels or tissues.

  • Obstruction & Tortuosity: In polymeric matrices or mucus layers.

5.3 Dissolution Phenomena

5.3.1 Definition

  • Dissolution: Mass transfer process by which solid drug dissolves into a solvent, forming a saturated solution at the solid–liquid interface.

5.3.2 Noyes–Whitney Equation

  • Relates dissolution rate to surface area, solubility, and diffusion:

    dMdt=DAh(Cs−C) \frac{dM}{dt} = \frac{D\,A}{h}\,(C_s – C)

    – dM/dt: Mass dissolved per unit time
    – A: Surface area of solid
    – h: Thickness of diffusion layer
    – C_s: Solubility (saturated concentration)
    – C: Bulk concentration

5.3.3 Modified Models

  • Hixson–Crowell Cube‑Root Law (changes in surface area):

    M01/3−Mt1/3=kHCt M_0^{1/3} – M_t^{1/3} = k_{HC}\,t

  • Weibull & Korsmeyer–Peppas Models for controlled‑release systems.

5.4 Experimental Dissolution Testing

5.4.1 Apparatus & Methods (USP Standards)

ApparatusDescriptionTypical Use
I (Basket)Basket rotated at controlled RPM, drug-filled capsules.Capsules & sustained‑release tabs
II (Paddle)Paddle stirs dissolution medium over tablet bed.Immediate‑release tablets
III (Reciprocating Cylinder)Gentle dip movement, open systems.Dosage forms with friable matrices
IV (Flow‑Through Cell)Continuous flow of medium through cell.Poorly soluble drugs & OSD forms
V & VI (Paddle & Basket over Discs)Discs of transdermal patches.Transdermal & ODTs

5.4.2 Test Parameters

  • Medium Composition: pH, surfactants to mimic gastric/intestinal fluids.

  • Temperature: 37 ± 0.5 °C to simulate body conditions.

  • Agitation Rate: 50–100 RPM for paddle; affects h (diffusion layer).

  • Sampling & Analysis: UV‑Vis spectrophotometry or HPLC for concentration determination.

5.5 Data Analysis & Interpretation

5.5.1 Dissolution Profiles

  • Plot % drug dissolved vs. time; compare to specification (e.g., Q ≥ 80% in 30 min).

  • Lag Time & t₅₀/t₉₀: Time to dissolve 50%/90% of dose—key quality attributes.

5.5.2 Release Kinetics Modeling

  • Determine kinetic order (zero, first) or fit to Higuchi (t^½ dependence) for matrix systems:

    Mt=kHt1/2 M_t = k_H \, t^{1/2}

5.5.3 Biorelevance & IVIVC

  • In Vitro–In Vivo Correlation: Predict plasma profiles from dissolution data; Level A, B, C correlations.

  • Biowaivers: Using dissolution equivalence to waive in vivo bioequivalence studies for BCS Class I/III drugs.

5.6 Pharmaceutical Implications

5.6.1 Formulation Design

  • Particle Size Reduction: Increases A in Noyes–Whitney, speeds dissolution.

  • Use of Solubilizers & Surfactants: Enhances C_s by micellar solubilization.

  • Matrix & Coating Technologies: Controls h and surface exposure for sustained release.

5.6.2 Quality Control & Regulatory

  • Dissolution Specifications: Batch release criteria; discriminatory to detect formulation changes.

  • Stability-Indicating Testing: Ensures no change in dissolution with aging.

5.6.3 Clinical Relevance

  • Oral Absorption: Rate‑limited vs. solubility‑limited drugs; strategies for Biopharmaceutics Classification System (BCS) Class II compounds.

  • Modified‑Release Products: Achieve targeted plasma profiles through diffusion‑controlled matrices.

5.7 Key Points for Exams

  1. Derive & Apply: Show derivation from Fick’s first law to Noyes–Whitney equation.

  2. Calculate D: Given experimental data, compute diffusion coefficient in a polymer gel.

  3. Design Experiment: Specify dissolution apparatus choice and method parameters for a weakly basic drug with pH‑dependent solubility.

  4. Model Fitting: Fit % release data to zero‑order, first‑order, and Higuchi models; interpret best fit.

  5. IVIVC Concept: Explain Level A correlation and its regulatory importance for a BCS Class I tablet.

Unit 6: Stability of Dosage Forms (Physical, Chemical, Microbial & Accelerated Stability Studies)

A comprehensive examination of the factors that affect the shelf‑life and integrity of pharmaceutical products, covering physical, chemical, and microbial degradation pathways, stability testing protocols, and strategies to ensure product quality over time.

6.1 Overview of Stability

6.1.1 Definition & Importance

  • Stability: Ability of a dosage form to maintain its identity, strength, quality, and purity throughout its shelf life.

  • Regulatory requirements (ICH Q1A(R2)) mandate stability data for expiry dating and storage conditions.

6.1.2 Types of Degradation

  1. Physical: Changes in appearance, phase, dissolution, or mechanical properties.

  2. Chemical: Breakdown of active pharmaceutical ingredients (APIs) or excipients via hydrolysis, oxidation, photolysis, etc.

  3. Microbial: Contamination leading to growth of bacteria, yeast, or mold, compromising safety and efficacy.

6.2 Physical Stability

6.2.1 Manifestations

  • Appearance: Color change, precipitation, crystal growth, caking in suspensions/emulsions.

  • Mechanical: Tablet hardness variation, friability increase, capsule brittleness.

  • Phase Separation: Creaming, coalescence in emulsions; sedimentation in suspensions.

6.2.2 Influencing Factors

  • Temperature: Affects solubility, polymorphic transitions, viscosity.

  • Humidity: Promotes hydration, hydrolysis, and microbial growth.

  • Light Exposure: Can induce photodegradation or discoloration.

  • Packaging: Barrier properties (moisture, oxygen, light) critical to protect formulation.

6.2.3 Assessment Methods

  • Visual Inspection: Colorimetric scales, turbidity measurements.

  • Microscopy: Polarized light for polymorph identification; particle analysis in suspensions.

  • Thermal Analysis: DSC/TGA for phase transitions and moisture content.

6.3 Chemical Stability

6.3.1 Common Chemical Degradation Pathways

  • Hydrolysis: Cleavage of esters, amides, lactones; acid/base‑catalyzed.

  • Oxidation: Radical or electron‑transfer processes; catalyzed by metals or peroxides.

  • Photolysis: UV/visible light–induced bond cleavage or rearrangement.

  • Polymerization/Isomerization: API structural changes affecting activity.

6.3.2 Kinetics of Degradation

  • Zero‑Order: Rate independent of concentration:

    Ct=C0−k0t C_t = C_0 – k_0 t

  • First‑Order: Rate proportional to concentration:

    ln⁡Ct=ln⁡C0−k1t \ln C_t = \ln C_0 – k_1 t

  • Arrhenius Equation: Temperature dependence of rate constant:

    k=A e−Ea/(RT) k = A \, e^{-E_a/(RT)}

6.3.3 Stability-Indicating Methods

  • Chromatography: HPLC/UPLC with photodiode array to separate API from degradation products.

  • Spectroscopy: UV‑Vis, FTIR for monitoring specific chromophores or functional groups.

  • Mass Spectrometry: LC‑MS for structural elucidation of degradants.

6.4 Microbial Stability

6.4.1 Contamination Risks

  • Source: Raw materials, equipment, water, personnel.

  • Routes: Intrinsic (raw API) vs. extrinsic (processing environment).

6.4.2 Preservation Strategies

  • Preservatives: Parabens, benzalkonium chloride—broad‑spectrum efficacy; compatibility with formulation.

  • Aseptic Processing: Sterile filtration and filling for parenterals.

  • Packaging: Tamper‑evident closures, antimicrobial coatings.

6.4.3 Testing Protocols

  • Microbial Limit Tests: Total aerobic microbial count; specified pathogens (E. coli, S. aureus).

  • Sterility Tests: Membrane filtration or direct inoculation (USP <71>).

  • Preservative Efficacy Test: Challenge organisms over 28 days; log‐reduction criteria.

6.5 Accelerated Stability Studies

6.5.1 Purpose & Design

  • Predict long‑term stability by storing at elevated stress conditions (temperature, humidity).

  • ICH conditions:

    • Zone I & II: 25 °C/60% RH → long‑term; 40 °C/75% RH → accelerated.

    • Zone III & IV: Varied tropical conditions (e.g., 30 °C/65% RH).

6.5.2 Data Analysis

  • Extrapolation: Use Arrhenius plot (ln k vs. 1/T) to estimate shelf‑life at 25 °C.

  • Shelf‑Life Assignment: Time until API retains ≥ 90% of label claim.

  • Stress Testing: Expose to extreme pH, light, oxidation to identify degradation pathways.

6.5.3 Container-Closure Integrity

  • Testing: Dye ingress, vacuum decay, microbial ingress under stress.

  • Significance: Ensures barrier function over product life.

6.6 Formulation Strategies for Enhanced Stability

6.6.1 Physical Stabilization

  • Use of Antioxidants: Ascorbic acid, BHT for oxygen‑sensitive APIs.

  • pH Adjustment & Buffers: Maintain optimal pH to minimize hydrolysis.

  • Lyophilization: Remove water for parenterals; protect labile proteins with cryoprotectants.

6.6.2 Chemical Protection

  • Complexation: Cyclodextrins to shield labile moieties.

  • Prodrug Approach: Mask reactive functional groups, regenerate API in vivo.

6.6.3 Microbial Safeguards

  • Aseptic Fill: Clean‐room classifications, HEPA filtration.

  • Single‑Dose Packaging: Eliminates need for preservatives.

6.7 Key Points for Exams

  1. Define & Differentiate: Physical vs. chemical vs. microbial degradation with examples.

  2. Kinetic Calculations: Determine t₉₀ and shelf‑life from first‑order degradation data at multiple temperatures.

  3. ICH Guidelines: Outline stability study design per ICH Q1A(R2) for a tablet intended for tropical markets.

  4. Stability-Indicating Method: Describe development and validation of an HPLC assay that separates API and its major degradant.

  5. Formulation Solutions: Propose a strategy to enhance the stability of an oxidation‑prone liquid formulation.

Related Posts

0 0 votes
Article Rating
Subscribe
Notify of
guest
0 Comments
Oldest
Newest Most Voted
Inline Feedbacks
View all comments
Scroll to Top