10. Mass Transport andert Dissolution.pptx

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1. Mass transport and dissolution 1

2. Introduction Substances are routinely transported (received and delivered) across the cell plasma membranes. These substances include compounds, liquids, nutrients, hormones and other signaling molecules, and waste products . Transport into and out of cells can be one of two ways Passive transport or Active transport 2

3. A . Passive transport I nvolves movement of substances that does not require energy ( ATP) Substances move from an area of higher concentration to lower concentration (down or with their concentration gradient) Types of passive transport include simple diffusion facilitated diffusion and osmosis 3

4. Passive Transport 1. Diffusion through a membrane A membrane is defined as a physical barrier that separates two or more regions The transport of drug molecules through a non-porous membrane occurs by diffusion Diffusion is the process where by a solute moves from a region of high concentration to one of low concentration 4

5. M = amount of drug (material) dissolved (usually mg or mmol ) t = time (seconds) D = diffusion coefficient of the drug (cm 2 /s) A = surface area of membrane (cm 2 ) K = oil/water partition coefficient h = thickness of the liquid film C 1 - C 2 = concentration gradient where C 1 is the concentration of drug at donor side of membrane and C 2 is the concentration of drug in the membrane at receptor side. 5

6. Diffusion model for Fick’s Law. 6

7. Probably the most widely used laws of diffusion are known as Fick’s first and second laws. Fick first law involving steady-state diffusion (where dc/ dx does not change) is derived from the following expression for the quantity of material (M) flowing through a cross section of a barrier (S) in unit time (t) expressed as the flux (J): J = dM /( Sdt ) Under a concentration gradient (dc/ dx ), Fick’s first law can be expressed thus where J is the flux of a component across a plane of unit area, C1 and C2 are the concentrations in the donor and receptor compartments, h is the membrane thickness, and D is the diffusion coefficient (or diffusivity) 7

8. Schematic Representation of Monolithic (matrix) Diffusion Controlled Drug Delivery Device 8 Schematic Representation of reservoir Diffusion Controlled Drug Delivery Device 1. Diffusion Controlled System (a) Reservoir Type (b) Matrix Type 2. Dissolution Controlled Systems (a) Encapsulation Dissolution Controlled Systems (b) Matrix Dissolution Controlled Systems Pharmaceutical Significance of diffusion

9. 2 . Osmosis spontaneous movement of a solvent from a solution of lower solute concentration to a solution of higher solute concentration through an ideal semipermeable membrane, which is permeable only to the solvent but impermeable to the solute 9

10. 10 Water Penetration Controlled Systems (a) Swelling Controlled System (b) Osmotically Controlled Release Systems Device approach...

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12. Pharmaceutical significance of osmosis Osmotic pressure controlled drug delivery system Drug may be osmotically active, or combined with an osmotically active salt (e.g., NaCl ). Semi-permeable membrane usually made from Cellulose acetate. Drug is pumped out continuously because of osmotic pressure gradient. More suitable for hydrophilic drug Provides zero order release 12

13. B. Active Transport The energy-dependent movement of compounds across membranes most often against their concentration gradient involves the reversible binding of the molecule with a carrier 13

14. Dissolution of particles Dissolution is a process in which a solid substance solubilizes in a given solvent i.e. mass transfer from the solid surface to the liquid phase. Dissolution is the rate limiting step in bio-absorption for drugs of low solubility Rate of dissolution is the amount of drug substance that goes in solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. 14

15. Theories of Drug Dissolution Diffusion layer model/Film Theory :- It involves two steps :- Solution of the solid to form stagnant film or diffusive layer which is saturated with the drug Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this is rate determining step in drug dissolution. 15

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17. II. Danckwert’s model/Penetration or surface renewal Theory Dankwert takes into account the eddies or packets that are present in the agitated fluid which reach the solid-liquid interface, absorb the solute by diffusion and carry it into the bulk of solution. These packets get continuously replaced by new ones and expose to new solid surface each time, thus the theory is called as surface renewal theory. 17

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19. The Danckwert’s model is expressed by equation Where, m = mass of solid dissolved Gamma ( γ ) = rate of surface renewal 19 dC dt = dm dt = A (Cs- Cb ) . D γ V

20. In the dissolution of particles of drug, the dissolved molecules diffuse away from the individual particle body An expression to describe this, derived from Fick equations, is known as the Noyes It can be written as follows: Where C is the concentration of drug dissolved at time t, M is the mass of solute dissolved in time t, D is the diffusion coefficient of the solute in solution S is the surface area of the exposed solid, V is the volume of solution, h is the thickness of the diffusion layer, Cs is the saturation solubility of the drug, and C is the concentration of solute in the bulk phase at a specific time, t. 20

21. It is common practice to use sink conditions in which C does not exceed about 20% of the solubility of the drug being investigated. Under these conditions, the expression simplifies to dC / dt = (DSCs/ Vh ) and incorporating the volume of solution (V), the thickness of the diffusion layer (h), and the diffusivitycoefficient (D) into a coefficient k (to take into account the various factors in the system), the expression becomes dC / dt = kSCs As the factors are held constant, it becomes apparent that the dissolution rate of a drug can be proportional to the surface area exposed to the dissolution medium. 21

22. Factors affecting Drug Dissolution A. Factors relating to the physicochemical properties of drug Solubility- Solubility plays important role in controlling dissolution from dosage form. From Noyes-Whitney equation it shows that aqueous solubility of drug determines its dissolution rate. 22

23. Particle size and effective surface area of the drug – Particle size and specific surface area are inversely related to each other. i.e. reduction in size generally increases the specific surface area of particles Thus particles having small dimensions will tend to increase the rate of solution 23

24. iii. Polymorphism and amorphism When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as Polymorphism . Stable polymorphs has lower energy state, higher M.P. and least aqueous solubility. Metastable polymorphs has higher energy state, lower M.P. and higher aqueous solubility Amorphous form of drug which has no internal crystal structure represents higher energy state and greater aqueous solubility than crystalline forms. 24

25. E.g.- amorphous form of novobiocin is 10 times more soluble than the crystalline form. Thus, the order for dissolution of different solid forms of drug is – amorphous > metastable > stable iv. Salt form of the drug Dissolution rate of weak acids and weak bases can be enhance by converting them into their salt form. With weakly acidic drugs, a strong base salt is prepared like sodium and potassium salts of barbiturates and sulfonamides. With weakly basic drugs, a strong acid salt is prepared like the hydrochloride or sulfate salts of alkaloidal drugs . 25

26. v. Hydrates/solvates The stoichiometric type of adducts where the solvent molecules are incorporated in the crystal lattice of the solid are called as the solvates. When the solvent in association with the drug is water, the solvate is known as hydrate. The organic solvates have greater aqueous solubility than the nonsolvates . E.g. – chloroform solvates of griseofulvin is more water soluble than their nonsolvated forms 26

27. Factors relating to the dosage forms Pharmaceutical excipients – Vehicle, Diluents, Lubricants, Binders, Surfactants, colorants ii. Manufacturing processes Method of granulation – Wet granulation Direct compression Generically identical tablet and capsule products, manufactured by different pharmaceutical manufacturers, were found to exhibit significant differences in dissolution rates for their active ingredients The drug-regulatory agencies and compendial authorities to institute the dissolution test as a legal requirement for most solid dosage forms. 27