Solid Dispersion PDF

Solid Dispersion Code: PHC 413 Course Name: Physical Pharmacy Prof Dr Wong Tin Wui Non-Destructive Biomedical and Pharmaceutical Research Centre/Faculty of Pharmacy Universiti Teknologi MARA 1 YouTube Video https://www.youtube.com/watch?v=9e1kaRN...

Solid Dispersion Code: PHC 413 Course Name: Physical Pharmacy Prof Dr Wong Tin Wui Non-Destructive Biomedical and Pharmaceutical Research Centre/Faculty of Pharmacy Universiti Teknologi MARA 1 YouTube Video https://www.youtube.com/watch?v=9e1kaRN7fqQ https://www.youtube.com/watch?v=fjbhgfCVpbI https://www.youtube.com/watch?v=a3h5arV_5L0 https://www.youtube.com/watch?v=s4vtL6GenG4 Textbook Pharmaceutics: The Science of Dosage Form Design. Michael E Aulton. Churchill Livingstone. Introduction The bioavailability of poorly water-soluble drugs is often limited by their dissolution rate. Conventional methods for reducing particle size and increasing specific surface area for dissolution are: Trituration Grinding Ball milling Fluid energy micronization Controlled precipitation. Current approaches: coprecipitate and melt for reducing particle size to molecular level. 3 Definition Solid dispersion is a dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion), solvent, or melting-solvent method. Method of Preparation 1. Fusion technique 2. Cosolvent technique 4 Melting or Fusion Method A physical mixture of a drug and a water-soluble carrier is heated until it is melted. The melt is solidified rapidly in ice bath under vigorous stirring, pulverizing or atomizing, and then sieving. Trigger 1 Advantages: ? Disadvantages: ? 5 Cosolvent Method Cosolvent is a solvent employed to dissolve the drug and carrier of which the carrier itself is also a solvent for the drug. Single or mixture of cosolvents may be used. Choice of cosolvent and rate of removal. Trigger 2 Advantages: ? Disadvantages: ? 6 Classification of Solid Dispersion 1. Simple eutectic mixture 2. Solid solution 3. Glass solution and glass suspension 4. Amorphous precipitation in crystalline carrier 5. Compound and complex formation 6. Combination of any 7 Simple Eutectic Mixture Rapid solidification of fused melt of two components. Intimately blended physical mixture of two crystalline components. Eutectic mixture has a lower melting point than those of the pure components. Complete liquid miscibility. Negligible solid-solid solubility. Example: paracetamol-urea, griseofulvin-succinic acid. 8  TB MELT TEMPERATURE TA MELT + MELT + SOLID A SOLID B TE E SOLID A + SOLID B A B (100%) COMPOSITION (100%) Simple binary phase diagram with eutectic formation. E is the eutectic point. 9 Amorphous Precipitations in a Crystalline Carrier Similar to simple eutectic mixture except that the drug is precipitated in an amorphous form. Cooling propensity. Example: sulfathiazole-urea. 10 Solid Solution Two components crystallize together in a homogeneous one- phase system. Drug in solid solution is reduced to its molecular size. Solid solution achieves a faster drug dissolution rate than the corresponding eutectic mixture. Types of solid solution 1. Continuous or discontinuous 2. Substitutional or interstitial 11 Solid Solution a) Continuous solid solution Two components are miscible in solid state in all proportions. b) Discontinuous solid solution Some solid state solubility can be expected for all two- component systems. Discontinuity occurs at extremes of composition. 12 Solid Solution a) Substitutional solid solution Drug molecules substitute carrier molecules in crystal lattice. Molecular size of the two components should not differ by more than 15%. b) Interstitial solid solution Drug molecules occupy the interstitial spaces in the carrier lattice. Drug molecule diameter should be less than 0.59 times that of the carrier molecule. Volume of drug should be less than 20% of the carrier molecule. 13 Solid Solution Example: digitoxin-PEG 6000, methyltestosterone-PEG 6000, prednisolone acetate-PEG 6000, hydrocortisone acetate-PEG 6000. SUBSTITUTIONAL INTERSTITIAL Schematic diagram of substitutional and interstitial solid solutions. Red symbol represents solute; yellow symbol represents solvent. 14 Glass Solution and Suspension Glass solution refers to a homogeneous glassy system in which a drug dissolves in the glassy carrier. Glass suspension refers to a mixture in which precipitated drug particles are suspended in glassy carrier. Glassy state is characterized by transparency and brittleness below glass transition temperature. Glasses do not have sharp melting point. They soften progressively on heating. The lattice energy, which represents the barrier to dissolution, is much lower in glass solution than in solid solution. Examples of carrier: citric acid, PVP, PEG, dextrose, sucrose. 15 Compound and Complex Formation Two substances form a molecular compound. Soluble or insoluble complex. Example: Digoxin-hydroquinone exhibits high dissolution rate. Phenobarbital-PEG with reduced rate of dissolution. 16 Trigger 3 Which solid dispersion is expected to induce the fastest drug dissolution? 17 Mechanism of Increased Dissolution Rate 1. Reduction of particle size Particle size of drug is reduced to a minimum level in glass solution, solid solution and amorphous dispersion. Dissolution rate is enhanced due to an increase in specific surface area for dissolution and matrix solubilization. 2. Solubilization effect Carrier material, as it dissolves, may have a solubilization effect on drug through the formation of soluble complex or / and micelle. 3. Wettability and dispersibility The carrier material may have an enhancing effect on wettability and dispersibility of drug in dissolution medium. 18 Mechanism of Increased Dissolution Rate 4. Metastable form Formation of metastable dispersion with reduced lattice energy would result in faster dissolution rate. Amorphous drug and polymorph. 19 Trigger 4 What are the contributing factors that enhance drug dissolution rate of a solid dispersion system? 20 Selection of A Carrier Criteria of carrier for increasing drug dissolution rate: 1. Freely water-soluble with intrinsic rapid dissolution property. 2. Non-toxic and pharmacologically inert. 3. Low cost and ready availability. 4. Heat stable with a low melting point. 5. Soluble in a variety of cosolvents and pass through a vitreous state upon cosolvent evaporation. 6. Able to increase aqueous solubility of drug. 7. Chemically compatible with drug and not form a strongly bonded complex with drug. 21 Selection of A Carrier 1. Sugar: Dextrose, sucrose, galactose, sorbitol 2. Acid: Citric acid, succinic acid 3. Polymer: Polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), hydroxypropylmethylcellulose 4. Surfactant: Span, tween, poloxamer 5. Others: Urea Single or combination Matrix may be coated with enteric polymer e.g. hydroxypropylmethylcellulose phthalate 22 Trigger 5 What are the advantages of a solid dispersion in drug delivery application? 23 Trigger 6 What are the disadvantages of a solid dispersion in drug delivery application? 24