Medicines 1 - Dissolution (Basic ppt) PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Dissolution (I, II) Course: Masters in Pharmacy (MPharm), BSc Advanced Therapeutic Technologies Module: Medicines 1 Lecturer: Dr Sam Maher LEARNING OUTCOMES 1. Explain the process of dissolution 2. Describe...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Dissolution (I, II) Course: Masters in Pharmacy (MPharm), BSc Advanced Therapeutic Technologies Module: Medicines 1 Lecturer: Dr Sam Maher LEARNING OUTCOMES 1. Explain the process of dissolution 2. Describe the factors that influence dissolution according to Noyes-Whitney Equation 3. Outline the physiological, physicochemical and formulation factors that influence dissolution 4. Recall how diffusion can influence dissolution (controlled release) 5. DISSOLUTION OF SOLIDS Dosage forms that present the drug in solid form such as tablets and capsules or incompletely dissolved forms such as suspensions must dissolve to release drug for absorption DISSOLUTION (RATE OF SOLUTION) INTRINSIC DISSOLUTION RATE: Is the rate of transfer of molecules or ions from a solid state into homogenous molecular dispersion per unit time and unit surface area is known. INTERFACIAL REACTION MIGRATION  DISSOLUTION: INTERFACIAL REACTION COHESION Vs ADHESION SOLUTE REMOVAL FROM CRYSTAL CREATION OF A CAVITY CAVITY INSERTION  DISSOLUTION: MIGRATION Dissolved molecules are transferred into the bulk solution by diffusion through a static solvent layer around the remaining undissolved particles Static boundary layer of liquid at solid-liquid interface This step is frequently the rate limiting step controlling the rate and extent of absorption DISSOLUTION: MIGRATION  MATHEMATICS OF DISSOLUTION Dissolution is governed by the Noyes-Whitney equation dm/dt Rate of solution (mass dissolved per unit time) A surface area of solid Cs-C Concentration difference across the boundary layer K1 Diffusion coefficient (symbol D also used) h Thickness of the boundary layer  FACTORS INFLUENCING DISSOLUTION RATES OF SOLIDS IN LIQUIDS TERM IN NOYES WHITNEY AFFECTED BY Surface area (A) Size of the solid particles ↑ A ↑ rate of solution Disintegration of solids Particle porosity Saturation solubility (Cs) Temperature ↑ Cs ↑ rate of solution Nature of the dissolution medium Molecular structure of the solute Crystalline form of solid Presence of other compounds Solute conc. in solution at time t (C) Volume of dissolution medium ↓ C ↑ rate of solution Removal of drug (e.g. absorption) Diffusion coefficient (K1) Viscosity ↑ K1 ↑ rate of solution Temperature Molecular diameter Thickness of the boundary layer Degree of agitation ↓ h ↑ rate of solution DISSOLUTION AND DRUG ABSORPTION Drugs with water solubility of < 0.01mg/mL will typically demonstrate dissolution rate limited absorption Rapid dissolution for a dosage form is defined as >85% dissolution dissolved within 30 minutes in a 900mL dissolution medium volume at 37ºC Many factors influence dissolution and therefore many factors influence the rate at which drugs are absorbed which influences efficacy and safety  DISSOLUTION AND SINK CONDITIONS If the solute is removed from the dissolution environment at a faster rate than solution (Or C < 10% Cs). Hence Cs – C ≈ Cs This is referred to as sink conditions KINETICS OF DISSOLUTION LIMITATIONS OF NOYES WHITNEY Noyes-Whitney assumes that dissolving particles remain constant throughout the dissolution, which is not common for particulates in tablets, capsules and suspensions delivered orally because their size reduces upon dissolution True only for zero order release (sink conditions) PHYSIOLOGICAL FACTORS INFLUENCING IN VIVO DISSOLUTION OF TABLET DOSAGE FORMS GI fluid volume and co-administered fluids Fasted or fed state Surfactant concentration micelle diffusivity Residence time and mixing (motility patterns) Disease state Diet (alcohol, other medicines) FLUID VOLUME AVAILABLE FOR DRUG DISSOLUTION THE GI TRACT SITE FLUID VOLUME Oral cavity 0.9-1.1mL Stomach 118mL Small intestine 212mL Large intestine 187mL Rectum 2-3mL PHYSICOCHEMICAL FACTORS INFLUENCING IN VIVO DISSOLUTION OF ORAL DOSAGE FORMS Solubility – Log P – Melting point – Physical form (salt, hydrate, solvate, crystalline or amorphous) – pKa D (Mw) Particle size Physical behaviour (rheological properties) Wettability FORMULATION FACTORS INFLUENCING IN VIVO DISSOLUTION OF DOSAGE FORMS Dosage form (tablet, capsule, suspension, emulsion) Particle size (processing) Release properties (IR, SR, DR, CR) Excipient composition – Surfactants – Binders – Lubricants – Disintegrants – Solubility enhancers – Granulating agents IN VITRO DISSOLUTION TESTING: WHY? Prediction of in vivo dosage form behaviour – New innovator product – Bioequivalence testing Regulatory approval Manufacturing (Quality Control) CONTACT INFORMATION Sam Maher Lecturer in Pharmaceutics RCSI School of Pharmacy Royal College of Surgeons in Ireland 1st Floor Ardilaun House Block B 111 St Stephen’s Green, Dublin 2, Ireland T: 01-402-2362 E: [email protected]