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Drug release and dissolution

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Drug release and dissolution

  1. 1. + Drug release and dissolution
  2. 2. + USP Disintegration Apparatus Drug release and dissolution
  3. 3. + Video…
  4. 4. + The five types of dosage forms that can be characterized by release in vitro 1. Solid oral dosage forms 2. Rectal dosage forms such as suppositories 3. Pulmonary (lung delivery) dosage forms ( orally inhaled products) 4. Modified-release dosage forms 5. Semisolid products such as ointments, creams,and transdermal products.
  5. 5. + Drug release and dissolution
  6. 6. + Drug release and dissolution
  7. 7. + SUPAC (Scale Up Post Approval Change) guidances Drug release and dissolution Biopharmaceutics Classification System (BCS)
  8. 8. +  Drug Product: A drug product is a finished dosage form (e.g., tablet and capsule) that contains a drug substance, generally, but not necessarily in association with one or more other ingredients (21 Code of Federal Regulations 314.3(b)).  Drug Substance: An active ingredient that is intended to furnish pharmacologic activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure of any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 Code of Federal Regulations 314.3(b)). Drug release and dissolution
  9. 9. +  Drug release is the process by which a drug leaves a drug product  Immediate release drug products allow drugs to dissolve with no intention of delaying or prolonging dissolution or absorption of the drug  Delayed release is defined as the release of a drug at a time other than immediately following administration. (Enteric Coated)  Enteric Coated: Intended to delay the release of the drug (or drugs) until the dosage form has passed through the stomach. Enteric-coated products are delayed-release dosage forms.  Repeat action two single doses of medication; one for immediate release; another one for modified release  Targeted release drug release directed toward isolating or concentrating a drug in a body region, tissue or site of absorption or for drug action Drug release and dissolution
  10. 10. +  Extended-release products are formulated to make the drug available over an extended period after administration.  Prolonged-release dosage forms Prolonged-release dosage forms are modified-release dosage forms showing a slower release of the active substance(s) than that of a conventional-release dosage form administered by the same route. Equivalent term: extended-release dosage form.  Pulsatile release involves the release of finite amounts (or pulses) of drug at distinct time intervals that are programmed into the drug product.  Modified-Release Dosage Forms: Dosage forms whose drug-release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate- release dosage form OR Modified-release dosage forms are preparations where the rate and/or place of release of the active substance(s) is different from that of a conventional- release dosage form administered by the same route.  Modified-release dosage forms include both delayed and extended-release drug products  controlled release includes extended-release and pulsatile-release products. Drug release and dissolution
  11. 11. + 1. Immediate release (IR) 2. Sustained Release (SR) 3. Sustained Action (SA) 4. Extended Release (ER) 5. Long Acting (LA) 6. Prolong Action (PA) 7. Controlled Release (CR) 8. Timed Release (TR) Drug release and dissolution
  12. 12. +
  13. 13. + Osmotically Controlled Systems
  14. 14. + Dissolution Dissolution Dissolution refers to the process by which a solid phase (e.g., a tablet or powder) goes into a solution phase such as water. It is the process for which drug molecules leave the boundary surrounding the dosage form and diffuses into the dissolution media.
  15. 15. + Drug release and dissolution
  16. 16. +
  17. 17. + Different controlled release systems Time of release Cumulative release Diffusion controlled release Zero order (linear) release Burst like release Pulsatile release Lag followed by Burst release
  18. 18. + Mechanism aspects of Oral drug delivery formulation 1.Dissolution : 1.Matrix 2.Encapsulation 2.Diffusion : 1.Matrix 2.Reservoir 3.Combination of both dissolution & diffusion. 4.Osmotic pressure controlled system
  19. 19. + Dissolution controlled systems  In dissolution controlled systems, the rate controlling step is dissolution.  The drug is embedment in slowly dissolving or erodible matrix or by coating with slowly dissolving substances  There are basically two types of dissolution devices Controlled Release Systems Encapsulation dissolution controlled system Matrix dissolution controlled system Soluble drug Slowly dissolving matrix Soluble drug Slowly dissolving or erodible coat
  20. 20. + Controlled Release Systems Diffusion controlled systems  Diffusion systems are characterized by release rate of drug is dependent on its diffusion through inert water insoluble membrane barrier.  There are basically two types of diffusion devices. (I)Reservoir devices (II)Matrix devices
  21. 21. + Dissolution & Diffusion Controlled Release system  Drug encased in a partially soluble membrane.  Pores are created due to dissolution of parts of membrane.  It permits entry of aqueous medium into core & drug dissolution.  Diffusion of dissolved drug out of system. Insoluble membrane Pore created by dissolution of soluble fraction of membrane Entry of dissolution fluid Drug diffusion Controlled Release Systems
  22. 22. + Controlled Release Systems Osmotic pressure controlled system
  23. 23. Swelling vs. Erosion Diffusion controlled systems and / or Dissolution & Diffusion Controlled Release system Dissolution controlled systems Controlled Release Systems
  24. 24. +  Drug dissolution and release commonly fall into two groups:  zero-order release and first-order release.  Typically in the pharmaceutical sciences, zero-order release is achieved from non-disintegrating dosage forms such as topical or transdermal delivery systems, implantable depot systems, or oral controlled release delivery systems oral osmotic tablets matrix tablets with low-soluble drugs Drug release and dissolution
  25. 25. zero-order release tKQQt 00  where Q is the amount of drug released or dissolved (assuming that release occurs rapidly after the drug dissolves) Q0 is the initial amount of drug in solution (it is usually zero), and K0 is the zero-order release constant. tKQt 0 “Constant” release is defined in this context as the same amount of drug release per unit of time
  26. 26. First-order release. Kt Q Q eQQ tkt t   )ln( 0 0 Where Qt is the amount of drug released or dissolved Q0 is the initial amount of drug in the device and K is the First-order release constant.
  27. 27. + Absorption depends some what on 1- The rate of disintegration of the dosage forms 2- Deaggregation of the granules 3- More importance is the dissolution rate of the solid drug. Frequently, dissolution is the limiting or rate-controlling step in the absorption of drugs with low solubility Dissolution
  28. 28. Mathematical model for drug dissolution Noyes-Whitney equation
  29. 29. + Chemical photography of drug release Mathematical model for drug dissolution Noyes-Whitney equation
  30. 30.  The equation describes the rate of release of the drug from its solid state. )( )( CCs Vh DS dt dC CCs h DS dt dM   M: mass of solute dissolved in time t. D: is the diffusion coefficient. S: is the surface area of dissolution. (concentration of a saturated solution) h: is the diffusion layer thickness Cs: is the solubility of drug in the dissolution medium. C: is the concentration of drug in the bulk. V: is the volume of solution. dC/dt is the dissolution rate, Mathematical model for drug dissolution Noyes-Whitney equation
  31. 31. + An aqueous diffusion layer or stagnant liquid film of thickness h exists at the surface of a solid undergoing dissolution. This thickness, h, represents a stationary layer of solvent in which the solute molecules exist in concentrations from Cs to C h Cd DSK dt dM h CrCd DSK dt dM   
  32. 32. +
  33. 33. Cs Vh DS dt dC Cs h DS dt dM C    0 Mathematical model for drug dissolution Noyes-Whitney equation )( )( CCs Vh DS dt dC CCs h DS dt dM   Under sink conditions C<<<<CS the equation becomes Cs V S K dt dC KSCs dt dM   h D K  K dissolution rate constant
  34. 34. Calculate the dissolution rate of a hydrophobic drug having the following physicochemical characteristics: surface area = 2.5 x 103 cm2 saturated solubility = 0.35 mg/mL (at room temperature) diffusion coefficient = 1.75 x 10-7 cm2/s thickness of diffusion layer = 1.25 μm [Note: need to convert to cm, so 1 μm = 1 x 10-4 cm and 1.25 x 10-4 cm] conc of drug in bulk = 2.1 x 10-4 mg/mL Noyes-Whitney equation Example: )( CCs h DS dt dM      sec/22.1 1025.1 101.235.0105.21075.1 4 437 mg x xxx dt dM     
  35. 35. +  A preparation of drug granules weighing 5.5 gm and having a total surface area of 2800 cm2 is allowed to dissolve in a 500 ml of water at 25oC. After the first minute, 0.76 gm have dissolved. The saturation solubility (Cs) of the drug is 15 mg/ml. a) Calculate the dissolution rate constant (K = D/h) case 1 dM/dt =KS (Cs-Ct) = (0.000336 cm /sec)(5000 cm2)(15- 1.52 mg/ml) dM/dt = 22.646mg/sec case 2 dM/dt =KS (Cs) = (0.000302 cm /sec)(5000 cm2)(15mg/ml) dM/dt = 22.65 mg/sec case 1: not sink condition dM/dt =KS (Cs-Ct) dM/dt =0.76gm / 60 seconds = 0.01267 gm/sec X 1000= 12.67 mg/sec S = 2800 cm2 Cs = 15 mg/ml Ct = 0.76 gm / 500 ml = 0.00152 gm/ ml X 1000 = 1.52 mg/ml 12.67 mg/sec = K (2800 cm2) (15 mg/ml - 1.52 mg/ml) K = 0.000335cm /sec 500 ml is the volume of stomach case 2 : In the case of sink condition dM/dt =KS Cs 12.67 mg/sec = K (2800 cm2) x15 mg/ml K = 0.000302cm /sec b) If the diffusion layer thickness (h) is 0.005 cm, calculate the diffusion coefficient (D). K = D/h D = K X h case 1 D = 0.000335 cm /sec X 0.005 cm = 1.6 X10-6 cm2/ sec case 2 D = 0.000302 cm /sec X 0.005 cm = 1.6 X10-6 cm2/ sec c) Suppose that surface area was increased to 5000 cm2, what would be the dissolution rate.
  36. 36. +  When surface area is 2800 cm2: dM/dt = 12. 67 mg/sec  When surface area is 5000 cm2: dM/dt = 22.65 mg/sec  Surface area: leads to increase dissolution rate. How to utilize Noyes Whitney equation to enhance solubility: dM/dt =(D/h)S (Cs-Ct) 1) Increase surface area by decreasing particle size. Effective surface area is area in direct contact with water. Reduced particle size leads to increased surface area leading to increased effective surface area and increased solubility. 2) Mechanical stirring leads to reduced diffusion layer thickness
  37. 37. +  Derivation of equations Noyes-Whitney it was assumed that h and S were constant But this is not the case.  The static diffusion layer thickness is altered by the force of agitation at the surface of the dissolving tablet  The surface area, S, obviously does not remain constant as a powder, granule, or tablet dissolves, and it is difficult to obtain an accurate measure of S as the process continues.
  38. 38. +  Applies for dissolution of powder drugs:  Assumptions:  Spherical particles.  Shape remains spherical during dissolution.  All particles have the same size. (uniform size) Mathematical model for drug dissolution Hixson-Crowell cube root equation
  39. 39. +   kCs d M k tMM t 23 1 0 3 1 3 1 0   M0: original mass of drug particles Mt: mass of drug particles remaining at time t κ: cube rate dissolution constant k= D/ h Mathematical model for drug dissolution Hixson-Crowell cube root equation
  40. 40. + 2 4 rr radius and surface area and if the radius is reduced by dr, the volume change is 3 3 4 rV  drrdV 2 4 drrNdV 2 4 For N particles The surface area of N particles is 2 4 rNS  the infinitesimal mass change Noyes–Whitney law, KSCsdtdM  drug's density multiplied by the infinitesimal volume change, ρ dV, can be set equal to dM KSCsdtdV   Substituted S and dV KCsdtrNdrrN 22 44   KCsdtdr   t KCs rr   0 Integration dt KCs dr tr r   00 
  41. 41. + t KCs rr   0 the cube root dNM 3 1 3 1 6                Volume of a spherical particle 3 6 1 dV  Mass for N particles 3 6 dNM    d =2r     kCs d MkC N tMM S t 22 6 3 1 0 3 1 3 1 3 1 0               Equations 1 t tkC NMM s t                        2 6 3 1 3 1 3 1 0
  42. 42. + the estimated time for complete dissolution, τ (i.e., when r = 0) DCs r 2 2 0  Dissolution time
  43. 43. + Example (1) A specially prepared tolbutamide powder of fairly uniformly sized particles with a diameter of 150 μm weighed 75 mg. Dissolution of the drug was determined in 1000 mL of water at 25°C as a function of time. Determine the value of κ, the cube-root dissolution rate constant, at each time interval and calculate the average value of κ. M0 1 3 - Mt 1 3 =kt
  44. 44. + In clinical practice, diazepam injection (a sterile solution of diazepam in a propylene glycol– ethanol–water cosolvent system) is often diluted many fold with normal saline injection. An incipient precipitation of diazepam occurs invariably upon addition of saline followed by complete dissolution within 1 min upon shaking. DCs r 2 2 0   Example (2)
  45. 45. + More Complex Models of Dissolution: Convective Diffusion
  46. 46. +  Release of water soluble and poorly soluble Drugs  Drugs are dispersed homogeneously throughout the matrix of an erodible tablet  Drug release from ointment base.  Diffusion of dispersed solid drug. Mathematical model for drug dissolution Higuchi (Equation)
  47. 47. +  The drug is assumed to dissolve in the polymer matrix and to diffuse out from the surface of the of the device  As the drug released, the distance for diffusion becomes increasingly greater  The boundary that forms between the drug and empty matrix therefore recedes into the tablet as drug is eluted
  48. 48. +
  49. 49. + Mathematical model for drug dissolution Higuchi (Equation)   2 1 2 tCCADQ SS   2 1 2 2 1         t CCAD dt dQ SS A>>>>Cs  2 1 2 tADCQ S 2 1 2        t ADC dt dQ S dQ/dt the rate of drug released per unit area Cs is the solubility or saturation concentration of drug in the matrix A is the total concentration dissolved and undissolved, of drug in the matrix. OR Total amount of drug in a unit volume of the matrix OR The initial drug concentration Q amount of the drug release in time t per unit area D, the diffusion coefficient of the drug in the matrix
  50. 50. + Release from Granular Matrices: Porosity and Tortuosity   2 1 2        tCCADQ SS   Sink condition OR A>>>>Cs 2 1 2        tADCQ S   dQ/dt the rate of drug released per unit area Cs is the solubility or saturation concentration of drug in the matrix A is the total concentration dissolved and undissolved, of drug in the matrix. OR Total amount of drug in a unit volume of the matrix Q amount of the drug release at time t per unit area D, the diffusion coefficient of the drug in the matrix; ε is the porosity of the matrix and τ is the tortuosity of the capillary system,
  51. 51. +  Porosity is the fraction of matrix that exists as pores or channels into which the surrounding liquid can penetrate  Tortuosity is introduced to this equation to account for an increase in the path length of diffusion due to branching and bending of the pores as compered to shortest ‘straight –through’ pores  Tortuosity tends to reduce the amount of drug release in a given interval of time
  52. 52. + T(hr) Concent. Drug release mg/ml 0 0 2 0.42 4 0.59 6 0.74 8 0.876 10 0.98 2 1 tQ  The dissolution in 500 ml water data are found in the table below. 0 100 200 300 400 500 600 0 1 2 3 4 5 6 7 8 9 10 mgdrrugrelease t (hr) Amount drug release Mg (in 500ml) Qt 0 210 295 370 438 490 T^(1/2) 0.000 1.414 2.000 2.449 2.828 3.162 K mg*^(1/2)/hr 148.4924 147.5 151.0519 154.8564 154.9516
  53. 53. + T(hr) Concent. Drug release mg/ml Amount drug release Mg (in 500ml) Qt T^(1/2) K mg*^(1/2)/hr 0 0 0 0.000 2 0.42 210 1.414 148.4924 4 0.59 295 2.000 147.5 6 0.74 370 2.449 151.0519 8 0.876 438 2.828 154.8564 10 0.98 490 3.162 154.9516 2 1 tQ  The dissolution in 500 ml water data are found in the table below. 0 100 200 300 400 500 600 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 mgdrugrelease t (hr)^(1/2)
  54. 54. + Mathematical model for drug dissolution zero-order release tKQt 0 first-order release. Kt Q Q eQQ tkt t   )ln( 0 0 Noyes-Whitney equation )( )( CCs Vh DS dt dC CCs h DS dt dM   tMM t  3 1 3 1 0 Hixson-Crowell cube root equation Higuchi (Equation)   2 1 2 tCCADQ SS 2 1 ktQ    2 1 2 SS CCADk 
  55. 55. + 55
  56. 56. + T(hr) Qt Drug release mg 0 0 1 10.02 2 19.8 3 28.78 4 38.54 5 49.05 6 58.78 7 67.99 8 78.12 9 88.04 10 97.58 KtQt  hrmgK /749.9 7 24.68 29 8.1904.88     0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 t(hr) Qtmgdrugrelease K= (Qt)/t Mg/hr 10.02 9.90 9.59 9.64 9.81 9.80 9.71 9.77 9.78 9.76 K=9.78 Mg/hr Average Mathematical model for drug dissolution zero-order release equation
  57. 57. + tMM t  3 1 3 1 0 Mathematical model for drug dissolution Hixson-Crowell cube root equation T(hr) Concent. Drug release mg/ml 0 0 2 0.159 4 0.288 6 0.39 8 0.468 10 0.528 3 1 3 1 0 tMM  A 0.625 g af paracetamol powder was dissolved in 1000 ml of water. The dissolution data are found in the table below. 0 100 200 300 400 500 600 0 2 4 6 8 10 12 mgdrugrelease t( hr) Average K= 0.397 Amount drug release Mg / 1lt Wt 0 159 288 390 468 528 Amount of undissolved drug Mt=625-Wt 0 466 337 235 157 97 0.000 0.797 1.591 2.379 3.155 3.955 K mg*^(1/3)/hr 0 0.399 0.398 0.396 0.394 0.396

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