Diffusion and Dissolution (1).pptx.......

Integrated pharmaceutical

1. UNIT-5: Diffusion and Dissolution 1 BY:FANTAHUN M.

2. Outline Introduction Diffusion Osmosis Fick’s laws of diffusion Dissolution In-vitro dissolution testing models Diffusion Controlled drug Delivery system Dissolution and Diffusion Controlled drug Delivery system Osmotic controlled drug delivery system 2 BY:FANTAHUN M.

3. Introduction Diffusion can be defined as a process by which molecules transfer spontaneously from a region of higher concentration to a region of lower concentration. Diffusion governs the transport of the great majority of drugs across various biological barriers after administration . The theory of diffusion has been used: investigating the mechanism of drug transport applied to the design and development of various sustained release 3 BY:FANTAHUN M.

4. Cont,… The molecules that migrate from one location to another are termed as diffusants , called permeants or penetrants The medium in which the diffusant migrates is called the diffusional barrier . The concentration gradient is the concentration profile of the diffusant in the diffusional barrier . 4 BY:FANTAHUN M.

5. Cont,… The number of molecules that diffuse through a unit area of the diffusional barrier in a given time is termed as flux, J. Fig. 1 Schematic representation of a diffusion system: concentration gradient in a cross section of diffusional barrier 5 BY:FANTAHUN M.

6. Mass transport : Molecular or ionic solution involves transfer of mass from a: solid to a fluid , eg: Solid + solvent = solution fluid to a fluid , eg: Liquid + heat = vapour Dissolution Process of conversion of solute to liquid solution 03/08/2024 6 BY FM Solute + Solvent Dissolution Molecular or ionic solution

7. Factors that influence diffusion rates: Distance Molecular Size Temperature Steepness of concentrated gradient Membrane surface area 7 BY:FANTAHUN M.

8. Drug Transport S ystem Various nutrients like Carbohydrates, Amino acids, Vitamins and drugs are transported and absorbed into the blood by various mechanisms across semi permeable membrane. Passive diffusion Facilitated transport Active transport 8 BY:FANTAHUN M.

9. Passive Diffusion Major process for absorption of more than 90% of drugs. Diffusion follows Fick’s law : The drug molecules diffuse from a region of higher concentration to a region of lower concentration till equilibrium is attained. Rate of diffusion is directly proportional to the concentration gradient across the membrane. 9 BY:FANTAHUN M.

10. Cont,… Factors affecting Passive diffusion: Diffusion coefficient of the drug Related to lipid solubility and molecular wt. Thickness and surface area of the membrane Size of the molecules 10 BY:FANTAHUN M.

11. Cont,.. Certain characteristic of passive diffusion can be generalized . Down hill transport Greater the surface area & lesser the thickness of the membrane, faster the diffusion. Equilibrium is attained when the concentration on either side of the membrane become equal . 11 BY:FANTAHUN M.

12. Carrier Mediated T ransport M echanism Involves a carrier which binds reversibly with the solute molecules to be transported to yield the carrier solute complex. W hich transverses across the membrane to the other side where it dissociates to yield the solute molecule The carrier then returns to its original site to accept a fresh molecule of solute. 12 BY:FANTAHUN M.

13. Facilitated Transport This mechanism involves the driving force as concentration gradient. In this system, no expenditure of energy is involved (down-hill transport ). Example of passive facilitated diffusion is the gastro-intestinal absorption of vitamin B12. 13 BY:FANTAHUN M.

14. Active Transport The driving force is against the concentration gradient Since the process is uphill, energy is required E.g . Pyrimidine transport system – absorption of 5 FU L-amino acid transport system – absorption of methyldopa and levodopa 14 BY:FANTAHUN M.

15. Osmosis Movement of water Across a selectively permeable membrane Down its concentration gradient Toward the solution containing the higher solute concentration Continues until water concentrations and solute concentrations are the same on either side of the membrane 15 BY:FANTAHUN M.

16. Cont,… 16 BY:FANTAHUN M.

17. Significance of Osmosis Water soluble drug can be released from its reservoir such as osmotic pump by osmosis Formation of Osmotic Pump Water soluble osmotically active drug or drug blended with osmotically active diluent is formulated into a tablet that is coated with cellulose triacetate barrier that serve as semipermeable membrane The membrane is permeable only to water Ingresses of water in addition to dissolving drug, create osmotic pressure[OP] OP then forces drug release via pump orifice The release rate is proportional to rate of drug fluid ingress from git 03/08/2024 BY FM 17

18. 03/08/2024 BY FM 18 semipermeable membrane Orifice drug Gastriintestinal fluid

19. Membrane T ransport Types of membrane Impermeable membrane - membrane through which nothing can pass Freely permeable membrane - any substance can pass through it Selectively permeable membrane - permits free passage of some materials and restricts passage of others Plasma membrane is selectively permeable 19 BY:FANTAHUN M.

20. Cont,… Diffusion through lipid bilayer Non polar, hydrophobic substances diffuse through lipid layer; these are “lipid soluble” or lipophilic substances. Diffusion through channel proteins hydrophilic and charged solutes diffuse through channel proteins; these are lipid insoluble or lipophobic (fat fearing) substances. 20 BY:FANTAHUN M.

21. Diffusion via a Membrane Drug molecules in solution spontaneously diffuse from a region of high chemical potential to one of low chemical potential 03/08/2024 BY FM 21 C h C l X Membrane C= concentration X= Membrane thickness

22. Fick’s Laws of Diffusion Fick described diffusion of molecules in quantitative terms The quantitative description of diffusion through a given unit area, expressed as follows is called Fick’s first law . D is the diffusion coefficient, or diffusivity dC/dx is the concentration gradient 22 BY:FANTAHUN M.

23. Cont,… The rate of movement of drug is directly proportional to the diffusion coefficient, surface area and conc. gradient and inversely proportional to the thickness of the membrane. These factors combine into Fick’s law of diffusion . Where; dq/ dt is the rate of diffusion 23 BY:FANTAHUN M.

24. Cont,… D (cm2/sec) is the diffusion coefficient related to permeability A (cm2) is the surface area C (g/cm3) is the concentration X (cm) is the thickness of the membrane 24 BY:FANTAHUN M.

25. Cont,… In most instances, D, A and x are constants. Therefore, these factors can be combined into a single constant P, permeability constant, or coefficient . Therefore the rate of net transport (diffusion) across the membrane then becomes 25 BY:FANTAHUN M.

26. Non Steady S tate and steady state Diffusion Non steady state diffusion refers to a diffusion process in which the concentration of diffusion in a given space is a function of time or the concentration of diffusant in the diffusional barrier varies with time . In this case, one should use Fick’s second law to study the diffusion process. 26 BY:FANTAHUN M.

27. Cont,… When the amounts of diffusant enter and leave the given space at the same rate , the concentration of the diffusant in the given volume is a constant . The concentration in the given space is independent of time. The diffusion process that meets this condition is considered a steady state diffusion . 27 BY:FANTAHUN M.

28. Distribution or Partition C oefficient Distribution or partition coefficient is a measure of the ability of a compound to distribute in two immiscible phases . The partition phenomenon is of paramount importance for the diffusion across skin and other epithelia. Many pharmaceutical processes based on the partition principles. absorption from the gastrointestinal tract after oral administration extraction and isolation of pure drugs after synthetic manufacturing or from crude plant sources, 28 BY:FANTAHUN M.

29. Cont,… The ability of drugs to penetrate a biological membrane has been evaluated using its partition in an octanol and water system. When a drug is placed in an immiscible system composed of octanol and water , the drug distributes in each solvent and eventually reaches equilibrium 29 BY:FANTAHUN M.

30. Cont,… The ratio of drug concentration in each phase is termed its distribution coefficient or partition coefficient (K) Expressed as: The mobility of a substance in a diffusional barrier is determined by: the physicochemical properties of the diffusant the diffusional barrier temperature . 30 BY:FANTAHUN M.

31. Diffusion through membrane 31 Donor Compartment High concentration of penetrant molecules (solute) Receptor Compartment C d C 1 C 2 C r h Thickness of Barrier BY:FANTAHUN M.

32. Significance of Diffusion Drug release by diffusion[reservoir system, matrix system] Drug absorption & distribution 03/08/2024 BY FM 32

33. Drug release by diffusion[reservoir system, matrix system] Release of drug from a delivery system such as reservoir or matrix involves both dissolution & diffusion Drugs absorbed from site of absorption such as GI mucosa, skin, vagina, buccal cavity, etc by diffusion. Example : Erodible table D 03/08/2024 BY FM 33 Dissolution Diffusion Blood Drug molecule Drug substance

34. B. Drug absorption & distribution Drug absorption from extravasscular absorption sites into systemic circulation occurs by diffusion across biologic membranes 03/08/2024 BY FM 34 Passive transport lipoidal pathway Passive transport aqueous pathway Lumen Aqueous boundary layer Biomembrane Blood (Sink) Physical model for passive diffusion of drugs from intestinal lumen through biomembrane

35. Sink C onditions In most pharmaceutical systems, the concentration of drug in the receptor side (Cr) is significantly lower than at the donor side. For instance, when a transdermal patch is applied to the skin, the concentration of drug inside the skin at any time will be very low compared with the concentration in the patch. This is because the drug in the skin is absorbed continuously into the blood stream, transported to the active site, and eliminated from the body . 35 BY:FANTAHUN M.

36. Cont,… When the concentration C r is approximately zero, this state is defined as the sink condition . Sink conditions occur when the rate of exit of drug from a compartment is much greater than the rate of entry. Thus, there is no accumulation of drug in the compartment. This conditions are analogous to a sink, where the rate of exit of water through drain is much greater than the rate of entry from the tap and thus there is no accumulation of water in the sink. 36 BY:FANTAHUN M.

37. Sink Conditions... Conditions where drug concentration on one side of the membrane is significantly low as compared to its concentration on other side, i.e, C h >>> C l . Thus, Fick’s first low is reduced as follow: 03/08/2024 BY FM 37 Rate of diffusion = dM = - DAC h dt x

38. Sink... Diffusion coefficient [D] Surface area of membrane [A] Concentration gradient[ C h - C l ] Membrane thickness[x] BY:FANTAHUN M. 38

39. Lag T ime and Burst E ffect Lag time is the time required by the drug to saturate the tissue/membrane before it is absorbed into the blood stream. The lag time effect is observed typically in systems when they first contact the skin or mucosal tissue The release is slightly different because of the time required to saturate the membrane (lag-time effect) or the initial rapid release of drug (burst effect) from presaturated membranes 39 BY:FANTAHUN M.

40. Cont,… The lag time effect is dependent on the thickness of the membrane and the diffusion coefficient of the drug. The burst effect is observed in systems whose rate controlling membrane is presaturated with the drug. The burst effect is also dependent on the thickness of the membrane and diffusion coefficient . 40 BY:FANTAHUN M.

41. Lag time and burst effects Lag time : Time elapsed for administered drug to have its onset of action Example: Enteric-coated tablets 03/08/2024 BY FM 41 Lag time Plasma drug concentration Time

42. DISSOLUTION Dissolution is the process by which drug molecules are librated from a solid phase and enter into a solution phase. If particles remain in the solid phase once they are introduced into a solution, a pharmaceutical suspension results. 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. 42 BY:FANTAHUN M.

43. Cont,… Disintegration Dissolution Dissolution Deaggregation Dissolution 43 Tablet Granules Fine particles Drug in solution BY:FANTAHUN M.

44. Solubility & Dissolution Solubility of a compound depends on physicochemical properties of solute & solvent, temperature, pressure & pH of the solution. It is determined under specific experimental conditions. Thus, solubility is intrinsic property of drug substance Can be altered only by chemical modification of drug molecule Dissolution is extrinsic material property Can be influenced by various chemical, physical or crystallographic means such as complexation, particle size, surface properties, solid-state modification, or solubilization enhancing formulation 03/08/2024 BY FM 44

45. Mass Transfer T heory of Drug D issolution An aqueous diffusion layer or stagnant liquid film of thickness h exists at the surface of solid undergoing dissolution. Beyond the diffusion layer, at x greater than h , mixing occur in the solution, and the drug is found at a uniform concentration C , throughout the bulk phase There is a change in drug concentration with distance across diffusion layer Diffusion of the soluble solute from the stagnant layer to the bulk of the solution is rate determining step in drug dissolution. 45 BY:FANTAHUN M.

46. Cont,… 46 BY:FANTAHUN M.

47. Cont,… The rate at which a solid dissolves in a solvent was proposed in quantitative terms by Noyes and Whitney in 1897 . The equation can be written as: or M is the mass of solute dissolved in time t dm/ dt is the mass rate of dissolution (mass/time) D is the diffusion coefficient of the solute in solution 47 BY:FANTAHUN M.

48. Cont,… S is the surface area of the exposed solid h is the thickness of the stagnant layer Cs is the concentration of drug in the stagnant layer (diffusion layer) Cb is the concentration of drug in the bulk layer 48 BY:FANTAHUN M.

49. Modified Noyes- whitney’s Equation- Where , D = diffusion coefficient of drug. A = surface area of dissolving solid. Kw/o= water/oil partition coefficient of drug. V = volume of dissolution medium. h = thickness of stagnant layer. ( C s – C b )= conc. gradient for diffusion of drug. 49 BY:FANTAHUN M.

50. Cont,… This is first order dissolution rate process, for which the driving force is concentration gradient . This is true for in-vitro dissolution which is characterized by non-sink conditions . The in-vivo dissolution is rapid as sink conditions are maintained by absorption of drug in systemic circulation i.e. Cb=0 and rate of dissolution is maximum. The dissolution rate is constant under sink conditions and follows zero order kinetics. 50 BY:FANTAHUN M.

51. Factors Affecting Drug Dissolution Factors relating to the physicochemical properties of drug Solubility Particle size and effective surface area of the drug Polymorphism and amorphism Salt form of the drug Hydrates/solvates 51 BY:FANTAHUN M.

52. Cont,… Factors relating to the dosage forms . Pharmaceutical excipients Vehicle, Diluents Lubricants, Binders Manufacturing processes Method of granulation Compression Force Intensity of packing of capsule contents 52 BY:FANTAHUN M.

53. In-Vitro D issolution T esting M ethods Dissolution testing-official in pharmacopeias Quantify the extent of release of drug Routinely used by quality control and research and development Quality control evaluate batch consistency P rediction of drug release 53 BY:FANTAHUN M.

54. Classification There are basically three general categories of dissolution apparatus Beaker methods Open flow-through compartment system Dialysis concept 54 BY:FANTAHUN M.

55. Beaker Methods Rotating basket a pparatus(Apparatus1). It is basically a closed-compartment , beaker type apparatus. Rotating paddle a pparatus (Apparatus 2 ). Here, basket is replaced with a stirrer . The r eciprocating cylinder method (Apparatus 3 ) This method adopts the USP disintegration “basket and rack” assembly for the dissolution test. The disks are not used. 55 BY:FANTAHUN M.

56. Cont,… 56 BY:FANTAHUN M.

57. Diffusion Controlled Drug Delivery system Polymers function as physical barriers to drug transport and hence control the rate of release of a drug when administered orally . G enerally , diffusion controlled systems are of two types: reservoir devices matrix devices. 57 BY:FANTAHUN M.

58. Reservoir Systems Drug release is believed to involve the following processes: Water , gastric juices, or intestinal juices penetrate the coating and the drug dissolves to produce a saturated solution the drug diffuses though the polymeric coating The release of solutes from polymeric drug delivery systems are based on Fick’s laws of diffusion . The membrane can be made of wax, polyethylene, polypropylene, and ethylcellulose. 58 BY:FANTAHUN M.

59. Cont,… The drug is located at the centre of the dosage form, constituting the “ reservoir” or “ drug depot” The drug reservoir can be a drug solid particles, dispersion of fine insoluble drug or a concentrated drug solution in a liquid- or solid-type dispersing medium . 59 BY:FANTAHUN M.

60. Cont,… 60 BY:FANTAHUN M.

61. Matrix S ystems A matrix (monolithic) device consists of an inert polymeric matrix in which a drug is uniformly distributed . Fine powder can also be homogenously mixed with polymer 61 BY:FANTAHUN M.

62. Cont,… Dissolved Drug: When the system is a homogeneous matrix containing a dissolved drug, the release can be described by a solution to Fick’s second law of diffusion. Dispersed Drug: If a drug is dispersed as a solid in the homogeneous matrix ( monolith) instead of being completely dissolved, the release kinetics are altered. The derivation of the release rate expression is based on Fick’s first law of diffusion. Higuchi developed a model for the analysis of a homogeneous polymer matrix containing a suspended drug. 62 BY:FANTAHUN M.

63. Osmotic Controlled D rug R elease This type of delivery device has a semipermeable membrane that allows a controlled amount of water to diffuse into the core of the device filled with a hydrophilic component. A water-sensitive component in the core can either dissolve or expand to create osmotic pressure. push the drug out through a small delivery orifice. 63 BY:FANTAHUN M.

64. Cont,… 64 BY:FANTAHUN M.

65. Cont,… The main advantage of the osmotic pump system is constant release rate can be achieved. The release rate of the device is affected by: the amount of osmotic agent, surface area and thickness of semipermeable membrane, the size of the hole. 65 BY:FANTAHUN M.

66. Dissolution and Diffusion Controlled Systems In this system, the drug forms the core, which is surrounded by a partially water-soluble polymer. Drug release is triggered by the dissolution of the water-soluble part of the polymer membran e. achieved by incorporating water-soluble additives in the polymer coating. When placed in an aqueous environment, the water-soluble additives (often called pore-formers) in the polymer coating dissolve to leave pores. 66 BY:FANTAHUN M.

67. Cont,… 67 BY:FANTAHUN M.

68. Dialysis In a healthy person kidney acts as crude filter removing toxic waste products[creatinine, urea] from the body while retaining such essential components as blood cells , plasma proteins & fats in the body’s natural homeostatic balance. This process is called ‘ ultrafiltration process ’ If renal function is impaired, water & electrolyte balance is disturbed , toxic waste products build up in the blood & patient suffer from fluid overload . Under this conditions, an artificial method called dialysis that allow ultrafiltration to take place is adopted 03/08/2024 BY FM 68

69. Dialysis... It refers to passage of solute together with solvent across biological membrane or artificial semipermeable membrane[made of cellophane or nitrocellulose] or S eparation process based on unequal rates of passage of solutes & solvent through microporous membranes Semipermeable membrane allows separation of a mixture of blood & dialysis fluid As dialysis fluid passes over the membrane, it removes water & waste products from the blood restoring homeostatic balance 03/08/2024 BY FM 69

70. Dialysis Solution Has electrolyte concentration similar to normal extracellular fluid Prepared as concentrate solution to be diluted with water prior to use Its composition include Na, K, Ca, Mg, & chloride ions and HCO3 - [from lactate or acetate] Glucose is added to dialysis solution to achieve necessary osmotic effect during dialysis Note : Haemodialysis solutions need not be sterile as dialysis membrane within dialysis machine is microbial proof 03/08/2024 BY FM 70

71. Haemodialysis is used in treating kidney malfunction to rid blood of metabolic waste products while preserving high-molecular-weight components of the blood Patient’s blood is passed over the dialyser [sterile disposable dialysis membrane] that allows solutes to be exchanged b/n the blood & dialysis fluid Pressure is applied to blood to induce ultrafiltration process Dialysis machines have programmed cycles to allow dialysis to be achieved as quickly & efficiently as possible Note : Osmosis & dialysis are spontaneous processes 03/08/2024 BY FM 71