Dissolution Test(Ver26.0).pptx

Presentation for Dissoloution

1. Dissolution Theory & Method (Ver. 24.0) Introduction to Dissolution Test Theory of Dissolution Interpretation of data derived from dissolution profile Dissolution test method & apparatus

2. Introduction to Dissolution Test Theory of Dissolution Interpretation of data derived from dissolution profile Dissolution test method & apparatus

3. 3 Definition of Dissolution test

4. 4 dissolution Steps of Solid Dosage Forms

5. 5 dissolution Steps of Solid Dosage Forms

6. 6 Roles of in vitro dissolution testing in pharmaceutical drug development

7. 7 Characteristics of the in vitro dissolution profiles Characteristics of the in vitro dissolution profiles are influenced by the characteristics of API, excipients, drug product, and mechanics of the dissolution system, media composition in the dissolution vessel, the analytical methods, and the specifications.

8. Introduction to Dissolution Test Theory of Dissolution Interpretation of data derived from dissolution profile Dissolution test method & apparatus

9. 9 Theory of Dissolution

10. 10

11. 11 Theory of Drug Dissolution

12. Diffusion Layer Model/Film Theory This is the simplest and the most common theory for dissolution. Process of dissolution of solid particles in a liquid, in the absence of reactive or chemical forces, consists of two consecutive steps: Solution of the solid to form a thin film or layer at the solid/liquid interface called as the stagnant film or diffusion layer which is saturated with the drug; this step is usually rapid Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this step is slower and is therefore the rate-determining step in drug dissolution. 12

13. 13 h Diffusion Layer Model/Film Theory Cs

14. 14 Diffusion Layer Model/Film Theory

15. 15 Diffusion Layer Model/Film Theory

16. 16 Diffusion Layer Model/Film Theory

17. 17 Fick’s laws of diffusion

18. 18 What is diffusion 확산 (Diffusion) : 원자 움직임에 의한 물질 이동 (Mass transport) Mechanisms Gases & Liquids ; 랜덤한 움직임 ( 브라운 운동 ) 고체 (Solids) ; 공공 확산 (vacancy diffusion) / 침입형 확산 (interstitial diffusion)

19. 19 What is diffusion 분산계수 (D) membrane 의 종류에 따라 결정되는 고유 값 해당 재질에 대해 단위 면적 (1㎠), 단위 시간 (1 초 ), 단위 두께 (1cm) 조건에서 얼마나 많은 양이 이동했는지 측정된 것이기 때문에 단위는 ㎠ /s 얇든 두껍든 단위 두께에 대한 값이니 같은 재질의 membrane 이라면 항상 같은 값 투과상수 (P) 물질이 membrane 을 통과하여 분산되는 정도가 어느 정도인지 다루는 값 분산계수와 공통점이 있지만 , 분산계수와 달리 막의 두께에도 영향을 받는다는 차이점 단위 면적 , 단위 시간에 대한 물질의 이동량을 측정한 것이라서 두께가 두꺼워지면 그 양이 줄어듬 ( 단위 : cm/s) 분배계수 (K) 서로 거의 섞이지 않는 두 상 ( 예 : 물 (A) / 기름 (B) 대해 두 물질에 다 녹는 제 3 의 물질 (C) 를 가해줬을 때 C 의 농도가 A 와 B 각각에서 어떤 값을 갖는지 구해서 그 비를 구한 것 K = CA/CB

20. 20 What is diffusion

21. 21 확산의 속도 및 양은 어떻게 정량화 할 수 있을까 ?

22. 22 확산의 속도 및 양은 어떻게 정량화 할 수 있을까 ?

23. 23 Noyes & Whitney Equation & 1 st Ficks Law

24. The earliest equation to explain the rate of dissolution when the process is diffusion controlled and involves no chemical reaction was given by Noyes and Whitney: dc/dt = dissolution rate of the drug k = dissolution rate constant (first order) Cs = concentration of drug in the stagnant layer (also called as the saturation or maximum drug solubility ) C b = concentration of drug in the bulk of the solution at time t. Equation was based on Fick's second law of diffusion. Noyes & Whitney Equation 24 d c /dt = k (C s - C b )

25. Nernst and Brunner incorporated Fick‘s first law of diffusion and modified the Noyes-Whitney’s equation to: D = diffusion coefficient (diffusivity) of the drug A= surface area of the dissolving solid K w/o = water/oil partition coefficient of the drug considering the fact that dissolution body fluids are aqueous. ※ Since the rapidity with which a drug dissolves depends on the Kw/o, it is also called as the intrinsic dissolution rate constant [It is a characteristic of drugs] V = volume of dissolution medium. h = thickness of the stagnant layer. (C s – C b ) = concentration gradient for diffusion of drug. Nernst and Brunner Equation (Modified Noyes-Whitney Equation) 25 d c /dt = ADK o/w (C s - C b ) / V h

26. 26 Nernst and Brunner Equation (Modified Noyes-Whitney Equation)

27. Equation represents first-order dissolution rate process, the driving force for which is the concentration gradient (Cs – Cb). Under such a situation, dissolution is said to be under non-sink conditions. This is true in case of  in vitro  dissolution in a limited dissolution medium. Dissolution in such a situation slows down after sometime due to build-up in the concentration of drug in the bulk of the solution. The  in vivo  dissolution is always rapid than  in vitro  dissolution because the moment the drug dissolves; it is absorbed into the systemic circulation. ☞ C b  = 0, and dissolution is at its maximum. ☞ Under  in vivo  conditions, there is no concentration build-up in the bulk of solution and hence no retarding effect on the dissolution rate of the drug ☞ Cs >> Cb and  sink conditions  are maintained. ☞ Under sink conditions, if the volume and surface area of solid are kept constant, then equation reduces to: where K incorporates all the constants in equation Equation represents that the dissolution rate is constant under sink conditions and follows zero-order kinetics i.e. yields a linear plot Drug Solubility and Dissolution Rate 27 d C /dt = K

28. 28 For example, a preparation of drug particles weighing 550 mg and having a total surface area of 0.28 × 104 cm 2 was allowed to dissolve in 500 mL of water at 37°C. Assuming that analysis of bulk dissolution sample showed that 262 g had dissolved after 10 min, if the saturation solubility of the drug in water is 1.5 mg/mL at 37°C, k can be calculated as follows: Calculation Example

29. 29 The dissolution rate constant is related to the diffusion constant of the drug through the solvent (D) and the diffusion layer thickness (h): k = D/h Therefore, if the diffusion layer’s thickness could be estimated, the diffusion coefficient of the drug can be calculated. Thus, if the diffusion layer’s thickness were 5 × 10 –3 cm, the diffusion coefficient (D) would be given by: 0. 0201 cm/min = D / (5 × 10 −3 cm) D = 0. 0201 cm/min × 5 × 10 −3 cm = 1.01×10 −4 cm 2 / min Calculation Example

30. 30 Factors influencing dissolution rate

31. 31 Factors influencing dissolution rate Drug solubility The greater the drug solubility, the greater the drug’s dissolution rate. This is evident in the Noyes–Whitney equation. The solubility and dissolution rates of acidic drugs are low in acidic gastric fluids, whereas the solubility and dissolution rates of basic drugs are high. Similarly, the solubility and dissolution rates of basic drugs are low in basic intestinal fluids, whereas those of acidic drugs is high. 2. Viscosity (of the dissolving medium) The greater the viscosity of the dissolving liquid, the lower the diffusion coefficient of the drug and hence the lower the dissolution rate. Viscosity of the dissolving bulk medium and/or the unstirred layer on the surface of the dissolving formulation can be affected by the presence of hydrophilic polymers in the formulation, which dissolve to form a viscous solution. In vivo, the viscosity may be affected by the food intake.

32. 32 Factors influencing dissolution rate 3. Diffusion layer’s thickness The greater the diffusion layer’s thickness, the slower the dissolution rate. The thickness of the diffusion layer is influenced by the degree of agitation of the dissolving medium, both in vitro and in vivo. Hence, an increase in gastric and/or intestinal motility may increase the dissolution rate of poorly soluble drugs. For example, food and certain drugs can influence gastrointestinal (GI) motility. 4. Sink conditions Removal rate of dissolved drugs by absorption through the GI mucosa and the GI fluid volume affect drug concentration in the GI tract.

33. 33 Factors influencing dissolution rate 5. pH (of the dissolving medium) The drug dissolution rate is determined by the drug solubility in the diffusion layer surrounding each dissolving drug particle. The pH of the diffusion layer has a significant effect on the solubility of a weak electrolyte drug and its subsequent dissolution rate. The dissolution rate of a weakly acidic drug in GI fluid (pH 1–3) is relatively low because of its low solubility in the diffusion layer. If the pH in the diffusion layer could be increased, the solubility exhibited by the weak acidic drug in this layer (and hence the dissolution rate of the drug in GI fluids) could be increased.

34. 34 Factors influencing dissolution rate 6. Particle size and surface area An increase in the specific surface area (surface area per unit mass) of a drug in contact with GI fluids would increase its dissolution rate. Generally, the smaller a drug’s particle size, the greater its specific surface area and the higher the dissolution rate. However, particle size reduction may not always be helpful in increasing the dissolution rate of a drug and hence its oral bioavailability. Porosity of drug particles plays a significant role. -Thus, smaller particles with lower porosity may have lower surface area com pared with larger particles with greater porosity. - The dissolution rate depends on the effective surface area, which includes the influence of particle porosity . In some cases, particle size reduction may cause particle aggregation, thus reducing the effective surface area. - To prevent the formation of aggregates, small drug particles are often dispersed in PEG, PVP, dextrose, or surfactants such as polysorbates.

35. 35 Factors influencing dissolution rate 7. Crystalline structure Amorphous ( noncrystalline ) forms of a drug may have faster dissolution rate compared with the crystalline forms . Some drugs exist in a number of crystal forms or polymorphs. These different forms may have significantly different drug solubility and dissolution rates. Dissolution rate of a drug from a crystal form is a balance between the energy required to break the intermolecular bonds in the crystal and the energy released on the formation of the drug–solvent intermolecular bonds. ☞ Stronger crystals may have lower intrinsic dissolution rate. b. Intrinsic dissolution rate reflects the dissolution rate of a drug crystal or powder normalized for its surface area. It is expressed in terms of mass per unit time per unit surface area. Drug forms that have higher intrinsic dissolution rate are expected to have higher dissolution rates. c. The greater strength of a crystalline polymorph, sometimes evident by its high melting point and sometimes by the rank order, correlates with its lower intrinsic dissolution rate.

36. 36 Factors influencing dissolution rate 8. Temperature An increase in temperature leads to greater solubility of a solid, with positive heat of the solution. Heat of solution indicates release of heat on dissolving. Positive heat of solution is indicative of a greater strength of solute–solvent bonds formed (which release energy) compared with the solute–solute bonds broken The solid will therefore dissolve at a more rapid rate if the system is heated. 9. Surfactants Surface-active agents increase the dissolution rate by (a) lowering the interfacial tension, which lowers the contact angle of the solvent on the solid surface and increases wetting of the drug particle and penetration of the solvent inside the dosage form (b) increasing the saturation solubility of the drug in the dissolution medium. Surfactants such as SLS and Tween 80 are frequently used to achieve sink conditions and rapid dissolution during in vitro dissolution method development .

37. 37 Factors affecting in vitro dissolution rates of solids in liquids

38. Influence of Some Parameters on Dissolution Rate of Drug 38

39. Introduction to Dissolution Test Theory of Dissolution Interpretation of data derived from dissolution profile Dissolution test method & apparatus

40. 40 Schema of the current strategy in a dissolution data comparison by the EMA and FDA guidelines

41. 41 Frequently used mathematical models to describe the drug dissolution profiles

42. 42 Frequently used mathematical models to describe the drug dissolution profiles Zero-order Model M t : Amount of drug released in the time t K : zero-order release rate constant First-order Model M ∞ : Maximum amount of drug which can be released from a dosage form in infinite time K 1 : First-order release rate constant Weibull model kw : Constant of Weibull model β : Parameter characterizes the shape of the exponential curve Korsmeyer–Peppas model K KP : Constant of Korsmeyer–Peppas model Higuchi model K H : Constant of Higuchi model Hixson–Crowell model M’t : Drug amount in a dosage form in the time t K HC : Constant of Hixson–Crowell model Hopfenberg model K HP : Constant of Hopfenberg model.

43. Introduction to Dissolution Test Theory of Dissolution Interpretation of data derived from dissolution profile Dissolution test method & apparatus

44. Classification of Dissolution Test 44

45. 45 List of the Official Dissolution Apparatus and their uses

46. 46 Rotating basket type apparatus-Apparatus I Paddle type apparatus-Apparatus II Reciprocating cylinder type apparatus-Apparatus III Flow-through cell type apparatus- Apparatus IV Paddle over disk type apparatus- Apparatus V Cylinder type apparatus- Apparatus VI Reciprocating disk type apparatus- Apparatus VII Classification of dissolution test Basket Type apparatus- Apparatus I Paddle Type apparatus- Apparatus II Flow-through cell type apparatus- Apparatus III Vs Types of dissolution test apparatus as per BP: Types of dissolution test apparatus as per USP:

47. 47 Classification of of dissolution test apparatus

48. 48 Classification of of dissolution test(USP)

49. Summary of Dissolution Test Method 49

50. 50 It is commonly referred to as a rotating basket since it smoothly rotates and its speed complies with USP recommendations. It consists of a cylindrical basket (capacity of up to 1000 ml) which is held by a motor shaft (made of stainless steel), and the shape is semi-hemispherical at the bottom. The sample is placed in the basket, which rotates up to 100 rpm in a circular flask filled with dissolution medium. The entire flask is immersed in a constant bath temperature at 37°C. The apparatus-1 is generally preferred for capsules, suppositories, and for dosage forms that float or disintegrate slowly (delayed-release). Rotating basket (USP Apparatus 1)

51. 51 Paddle type is the most widely used dissolution apparatus. It consists of specially coated paddles which reduces the disturbance due to stirring. The paddle vertically comes in contact with the bottom of the shaft and is connected to a motor that rotates at a set speed. The sample (tablet/caplet/capsule) is placed in a dissolving flask with a circular bottom to reduce the turbulence of the dissolution medium. Its operating motor speed is usually at 40 and the operating temperature is  37 o C. Paddle type (USP Apparatus 2)

52. 52 This apparatus is based on the disintegration tester and more suitable for extended-release, chewable tablets. It consists of a set of cylindrical, flat-bottomed glass outer vessels, and a set of glass reciprocating inner cylinders. Fittings and screens are made of stainless steel and other suitable materials that fit the tops and bottoms of the reciprocating cylinders. Reciprocating cylinder (USP Apparatus 3)

53. 53 The flow-through method allows the system to be set into two types as an open system and a closed system. It consists of a reservoir for the dissolution medium and a pump that pumps the medium through the test sample-holding cell. The medium is maintained at operating temperature 37°C with flow rates ranging from 4 to 16 ml/min and up to the six samples can evaluate. The flow through the cell apparatus is used to evaluate modified-release dosage or is typically employed for low-dose medication. Flow-through cell (USP Apparatus 4)

54. 54 It consists of a shaft and a disc assembly that can hold the sample so that the surface can be leveled with a paddle. It is most commonly used for transdermal delivery systems that are attached to a stainless steel disc, which is then placed directly on the bottom of the vessel, under the paddle . Paddle over the disk (USP Apparatus 5)

55. 55 The cylinder type apparatus is used for testing transdermal patches. It consists of a stainless steel cylinder which is used to hold the sample. Generally that sample is mounted on to cuprophan. The sample is placed inside the cylinder and will be extracted from the outside into a water bath. Rotating cylinder (USP Apparatus 6)

56. 56 The reciprocating disc equipment is suitable for small dosages and is ideal for controlled release formulations, and dosage forms that requiring a change of media. It consists of a motor and drives assembly that turns the system vertically and also consists of a volumetrically calibrated solution. A flat-bottomed cylinder-shaped vessel with a volume capacity of up to 200 ml is used in this apparatus. Reciprocating disk (USP Apparatus 7)

57. USP I / USP II 57

58. 58 TYPICAL DISSOLUTION PARAMETER OVERVIEW USP APPARATUS 1 AND 2

59. 59 Paddle Method(USP 1) Vs Basket Method (USP 2)

60. USP III Method 60

61. 61 Summarization USP Apparatus 3 (reciprocating cylinder) is a very versatile device for the in vitro assessment of release characteristics of solid oral dosage forms, because it enables the product to be subjected to different dissolution media and agitation speeds in a single run. A brief history and a description of this system are presented, along with its applications in the development of immediate and modified release products and in the simulation of fasted and fed states using biorelevant media. Furthermore, a comparison is made with the basket and paddle apparatus, especially highlighting the superior hydrodynamics of USP apparatus 3 , since the results are not sensitive to factors such as the presence of sample collection probes or air bubbles in the dissolution medium.

62. 62 Bioavailability and, consequently, the therapeutic effects of orally-administered medicinal products depend on the dissolution of the active ingredient in gastrointestinal fluids, as well as its permeation through the membrane of the luminal mucosa. Where the absorption process is rapid, dissolution may be the stage that controls the introduction of the drug into the bloodstream This, in turn, led to universal recognition that the dissolution test is indispensable in the development, quality assurance and post-marketing authorization modifications of solid oral dosage forms Furthermore, in the context of the Biopharmaceutics Classification System (BCS), the dissolution test, together with bioavailability studies, has become an essential tool for the establishment of an in vitro-in vivo correlation (IVIVC) (FDA, 2000). With regards to the apparatuses used in the dissolution test, the basket apparatus (USP apparatus 1) was the first to be adopted by the U.S. Pharmacopeia in1970, while the paddle apparatus (USP apparatus 2) was recognized in 1978, as the result of ongoing developments in the area and a growing interest in matters related to dissolution Introduction of USP3 ( I )

63. 63 However, research in the field of modified release dosage forms has indicated that, in order to obtain a correlation between in vitro dissolution results and the bioavailability of these products (in vitro-in vivo correlation), it would be essential for the pH, composition, ionic strength, viscosity and agitation speed of the medium to be sequentially altered during the dissolution test, thus simulating passage of the product through the gastrointestinal tract. With the purpose of addressing this issue, a group of researchers from the University of London, headed by Professor A.H. Beckett, developed the reciprocating cylinder method In the 1970s, Professor Beckett’s team used the rotating bottle method in order to assess the dissolution profiles of extended-release products, which presented important advantages over the basket and paddle apparatuses, especially with regards to hydrodynamics and the possibility of using the pH gradient . However, the method was extremely labor-intensive and there were limitations with regards to automatization of the system Introduction of USP3 ( II )

64. 64 Thus, the reciprocating cylinder apparatus was conceived, with a design based on the capsule and tablet disintegration device, associating the hydrodynamics of the rotating bottle method with the facility for exposing the dosage form to different dissolution media and agitation speeds , in a device that could be automated. This proposal was incorporated into the U.S. Pharmacopeia in 1991 as USP apparatus 3, making it an alternative to USP apparatuses 1 and 2 for the assessment of dissolution characteristics of products that consist of solid oral modified-release dosage forms ☞ Considering the importance of assessing the dissolution of solid oral modified- release dosage forms with the reciprocating cylinder, the purpose of this study is to discuss the applications of this apparatus on the assessment of in vitro release of solid oral dosage forms and to establish a comparison between aforementioned system and the basket and paddle apparatuses Introduction of USP3 ( III )

65. 65 DESCRIPTION OF RECIPROCATING CYLINDER APPARATUS ( I ) The main components of the reciprocating cylinder apparatus are internal cylinders, external cylinders, metallic agitation rods and the heating bath . Each unit of the dosage form is inserted into an internal cylinder, consisting of a glass tube closed at both ends with plastic caps containing a screen , which is made of nylon or stainless steel The internal cylinders are coupled to metallic rods that undertake the immersion and emersion movements (reciprocating action) within the dissolution vessel, which is called the external cylinder. This vessel is very different from the one used for the basket and paddle methods because, besides its distinctive cylindrical format and flat bottoms, it has a capacity of only 300 mL. Besides the standard 300 mL vessels , other vessels for specific applications are also available, with 100 mL and 1,000 mL capacities . An anti-evaporation system is deployed over the vessels in order to avoid alterations in the volumes of the dissolution medium during the assay

66. 66 DESCRIPTION OF RECIPROCATING CYLINDER APPARATUS ( II ) The heating bath contains dissolution vessels arranged in lines; temperature of the medium is maintained at 37 ºC. Each horizontal line consists of 7 vessels, 6 for the product and the seventh may be used for the standard solution , in systems in which the quantification stage is automated, or even to contain the replacement medium, in the event that this procedure is adopted after the collection of samples. The internal cylinders remain in each line of vessels, in reciprocal movement, for pre-programmed times and intensities (dips per minute or “ dpm ”) in the apparatus. During emersion, the agitation system rises until the screen in the lower cover touches the dosage form, which separates from the screen and floats freely in the dissolution medium when the stirring system activates . After the programmed period, the rods rise until the internal cylinders are positioned over the vessels, where they remain for a pre-established timeframe so that the dissolution medium can drain. Then the rods move to the following line, submerging again and the reciprocating actions begin anew

67. 67 DESCRIPTION OF RECIPROCATING CYLINDER APPARATUS ( III ) The system contains six lines of vessels, but if a larger volume of dissolution medium is necessary to ensure sink conditions, it may be programmed so that, after the cylinders move along the sixth line, they return to the first, where the medium must be replaced. The time the internal cylinders remain in each line of vessels as well as the pH, the composition, ionic strength and agitation speed of the dissolution medium may be selected, according to physiological conditions and, accordingly, it is possible to simulate the passage of the product through the gastrointestinal (GI) tract. Samples are collected throughout the test in order to quantify the drug released and the dissolution profiles are traced after calculating the cumulative percentage of drug dissolved. ☞ Amount of drug released from the dosage form at the end of the test will correspond to the sum of percentages quantified in all the vessels covered

68. 68 Reciprocating cylinder apparatus (USP 3/USP7) Internal cylinder and its top and bottom caps Internal cylinder coupled to the rod inside the external cylinder (vessel). DPM (dips per minute) emersion immersion

69. 69 Reciprocating cylinder apparatus (USP 3/USP7) Schematic representation of fluid-flow past a tablet in the inner cylinder of USP Apparatus III Schematic representation of the free-stream velocity past a tablet when agitated using USP Apparatus III

70. 70 Reciprocating cylinder apparatus (USP 3/USP7)

71. 71 Schematic representation of apparatus and its six lines of vessels Each containing a dissolution medium with a different pH value, by way of example, simulating the passage of the product through the gastrointestinal (GI) tract Test Medium ST Medium pH, ionic Strength, viscosity , agitation speed of medium

72. 72 Reciprocating cylinder apparatus (USP 3/USP7)

73. 73 Reciprocating cylinder apparatus (USP 3/USP7)

74. 74 Reciprocating cylinder apparatus (USP 3/USP7)

75. 75 APPLICATIONS FOR MODIFIED-RELEASE SOLID ORAL DOSAGE FORMS

76. 76 Modified-release dosage forms offer therapeutic advantages over conventional release mechanisms due to the use of advanced technologies and excipients with special characteristics, and they are thus capable of generating a specific dissolution profile. However, the complexity that they present and the necessity for in vivo performance to be predictable and reproducible means development becomes more complex APPLICATIONS FOR MODIFIED-RELEASE SOLID ORAL DOSAGE FORMS ( I )

77. 77 One issue to be considered is the time that these products remain in the GI tract, which is greater compared to the immediate-release forms , since the latter undergo rapid disaggregation when they come in contact with an aqueous medium As a result of the greater exposure time, the performance of extended-release products is more susceptible to mechanical forces and physicochemical conditions of the luminal environment Since the reciprocating cylinder method enables these conditions to be simulated, it is reasonable to suppose that this apparatus is more efficient than the basket and paddle methods in predicting the in vivo performance of extended-release dosage forms APPLICATIONS FOR MODIFIED-RELEASE SOLID ORAL DOSAGE FORMS ( II )

78. 78 One fundamental condition for the development of dissolution methodologies is the suitable selection of the pH of the medium , since this affects drug solubility. These methodologies involve mostly weak acids or bases When modified-release products are tested in apparatus 3, it is possible to simulate the different environments to which the dosage forms are subject when they pass through the GI tract These conditions can be assessed by employing different buffer solutions with or without surfactants APPLICATIONS FOR MODIFIED-RELEASE SOLID ORAL DOSAGE FORMS ( III )

79. 79 Vs Dissolution profile representing a hypothetical extended-release formulation using USP apparatus I in a pH 6.8 buffer solution Dissolution profile representing a hypothetical extended-release formulation using apparatus III under different pH conditions (1.2, 4.5, 6.8, 7.2 and 7.5) APPLICATIONS FOR MODIFIED-RELEASE SOLID ORAL DOSAGE FORMS ( IV )

80. 80 Vs Hypothetical dissolution profile of a gastro-resistant formulation using USP apparatus I in a pH 6.8 buffer Hypothetical dissolution profile of a gastro-resistant formulation using USP apparatus III in three different media (pH 1.2, 4.5 and 6.8) APPLICATIONS FOR MODIFIED-RELEASE SOLID ORAL DOSAGE FORMS ( V )

81. 81 USP Dissolution Test III ; SIMULATION OF FASTED AND FED STATES

82. 82 Besides its use in the development of dosage forms, the dissolution test has become an important tool in assessing the performance of formulations under conditions very close to those encountered in the human gastrointestinal (GI) tract However, in order to achieve this, the assays must be outlined and executed in conditions different from those usually employed and described in Pharmacopoeias, both in terms of the equipment used and in the composition of dissolution media, such that they simulate the nutritional state of the patient ☞ Dressman et al. (1998) suggest alterations to the composition of dissolution media so that they can correspond better to fasted and fed states. This is the beginning of the use of the so-called biorelevant media; i.e., dissolution media with compositions that are similar to the conditions encountered in the GI tract Factors such as pH, buffer capacity, presence of surfactants and enzymes, volume of fluid present in the GI tract and hydrodynamics, must be taken into account when it comes to a biorelevant dissolution medium. SIMULATION OF FASTED AND FED STATES ( I )

83. 83 Another important issue involves the mechanical forces and the degree of agitation to which the product is exposed in the GI tract, in the form of intestinal motility and pressure on the stomach, duodenum and jejunum. It is particularly critical in the case of dosage forms that are subject to erosion, such as hydrophilic matrices Although it may be difficult to select the agitation intensity that best mimics in vivo conditions, it is common to use 5-15 dips per minute ( dpm ) to simulate the fasted state and 30-40 dpm for the fed state, thus representing the greater turbulence within the stomach Furthermore, inert spheres of varying densities may be added in order to simulate interaction with solid food particles in movement With regards to the composition of the dissolution media, several approaches may be used to simulate the presence of foodstuffs in the GI tract. SIMULATION OF FASTED AND FED STATES ( II )

84. 84 Biorelevant dissolution media constitute a very interesting tool, because they are more capable of simulating drug delivery throughout the GI tract, in both the fasted and fed state , and they are now used very frequently Besides pH and volume, these types of dissolution media take into account other characteristics such as osmotic concentration, the presence of enzymes and surface tension, as a means of best mimicking especially the conditions in the small intestine, including the presence of bile salts SIMULATION OF FASTED AND FED STATES ( II )

85. USP III Vs USP VII Method 85

86. USP III Method 86

87. 87 Apparatus 3 and 7 are both reciprocating systems and allow for the testing of samples in multiple vessels. Apparatus 3 and 7 This ability allows for: pH profiling Programmable dip speeds at each interval Programmable interval time Flexibility allows for closest in vivo/in vitro modeling

88. 88 Agitation in these systems comes from dipping within the vessel, rather than through a stirred media approach Agitation

89. 89 Apparatus 3 and 7 look very similar Apparatus 3 Apparatus 7

90. 90 Basic Components of the Reciprocating Cylinder Apparatus The Reciprocating Cylinder Apparatus has 6 or 7 inner sample tubes, which mechanically traverse six rows of corresponding, media-filled outer tubes. Temperature 37 ± 0.5 ℃ Dip rate (DPM) ± 5% of set speed Stroke Distance 10.0 ± 0.1 cm Bottom screen Method specific Top screen Method specific (optional ) Physical Parameters and Tolerances

91. 91 Reciprocating Cylinder

92. 92 USP Apparatus 3 Reciprocating Cylinder Useful for : • Extended-release testing • Tablets • Capsules • Beads • pH change in different rows

93. 93 USP Apparatus 3

94. 94 Comparison of Systems

95. 95 History of the USP Apparatus 3 As knowledge of therapeutic performance of drugs increased, more sophisticated formulations became available. Modified Release : • Timed Release • Extended Release • Positioned Release • Controlled Release • Delayed Release In the 1970s, Professor Arnold Beckett and many workers in the field used the rotating bottle method (NF XII 1965-XIV 1975) to evaluate pellets and other solid dosage forms.

96. 96 As research progressed, it became apparent that a system would have to sequentially alter a variety of dissolution conditions in order to achieve an in vitro – in vivo correlation. • pH • Molarity • Anions • Cations • Viscosity • Buffers • Surface Active Agents • Degree of Agitation History of the USP Apparatus 3

97. 97 When you operate the Reciprocating Cylinder Apparatus you program the agitation rate as dips per minute (DPM) for the inner tubes When the inner tube elevates, the bottom mesh moves upward to make contact with the sample When the inner tube lowers, the sample leaves the mesh and floats freely within the tube The resulting agitation creates a moving medium. The Reciprocating Cylinder Apparatus Creates a Moving Medium

98. 98 Factors for USP Apparatus 3 Type of product Volume of medium Number of rows Mesh size Medium in each row Dip speed per row Residence time per row

99. 99 Typical Products Tested

100. 100 Media Volume Considerations Each of the outer tubes is usually filled with 250 mL of medium Because there are 6 rows of outer tubes, 6 x 250 mL or 1500 mL of medium can be used in a single dissolution test If the proper conditions are not achieved with 1500 mL of medium, rows can be refilled and the tester can be programmed to return to the first row and continue Traditionally, after the required time interval, the medium in each tube was made up to volume and then analyzed giving one result per row Today, automation of the sampling and/or analysis is common so that multiple measurements can be made in each row.

101. 101 Mesh Size Considerations Mesh size should be chosen in the same way a basket is selected: Retain undissolved API product Allow for maximum flow

102. 102 Media Considerations Media Considerations Media usually related to in vivo fluids, and will range in pH from pH 1.1~ pH 7.5 in early method development work Delayed Release may utilize 2 different media (pH ~1.1 and pH 6.8 ~ 7.5) Media Considerations(Surfactants) If surfactants are used, regardless of speed, foam will occur and lead to lost volume and a mess Use of an anti-foaming agent such as simethicone is recommended

103. 103 Typical Conditions for Extended-Release Testing

104. 104 Achieving Fasted and Fed States To simulate a fasted state, dip the product in the first row for one hour To simulate a fed state, dip the product in the first row for four hours and for one hour in the second row The appropriate dipping times for the other rows depends on whether a 12 or 24 hour product is being analyzed The dip speeds for each row should be set to 10 or 15 DPM except in the fed state (first row pH 1.5 for four hours) when the dipping rate should be increased to 30 or 40 DPM to simulate stomach turbulence The fed state can also include inert beads of mixed density to represent moving particles of food

105. USP VII Method 105

106. 106 USP Apparatus 7 Also known as the “ Alza Apparatus”, USP Apparatus 7 has evolved to handle not only transdermal apparatus but other modified release products

107. 107 Typical volume is 50 mL through 75 mL Operational minimum around 25 mL Modifications have been made to accommodate 300 mL vessels Extended release tablets, capsules, transdermal, osmotic pumps, beads, arterial stents. Small volume App. 7 400-DS also available USP Apparatus 7 Temperature 32 or 37 ± 0.5 ℃ Dip rate : 5~40 DPM Stroke Distance 2 cm Holder Method specific

108. 108 Reciprocating Holder

109. 109 Note on Apparatus 7 Holders

110. 110 USP Apparatus 7 Solid Oral Dosage Forms

111. 111 Pointed Rod holder

112. 112 Spring Holders Utilized for capsule shaped osmotics and non-disintegrating products Choose Spring Holder the same way you size a capsule shell 5 sizes, centered and off-centered Titanium “bird cage” basket, and 40 or 50 mesh minibaskets are also options

113. 113 Transdermal Holders Holders utilized with a patch and an appropriate membrane material Membrane secured by o-rings Cylinder accommodates largest patches 5 flat disk sizes available, 2 angled disks

114. 114 Medical Device Holders Medical device hook used for stents, pacemaker leads, etc Basket holders also used to contain implants as well Other modified holders are known to exist as well

115. 115 400-DS Small Volume Apparatus 7 The 400-DS was designed to meet the challenges associated with the testing of combinatorial products: Small Volume Low Evaporative Loss Automated Sampling Automated Media Replacement Bathless Regulatory Compliance Small footprint

116. 116 USP Apparatus 7 Volumes 1 day Dissolution media containing alcohols/some organics Product is non-disintegrating

117. 117 Applications of the 400-DS Apparatus 7 Drug Coated Stents Pacemaker leads Catheters Transdermals Other Medical Devices Novel Dosage Forms Micronized powders

118. 118 Variety of Holders Available

119. 119 Contact Lens/Woven Material Holder

120. 120 Small volumes: 5 mL or 10 mL dissolution cells can use from 3 mL to 12 mL media for testing Bathless: heater jackets provide stable temperature control for extended run times Automated media replacement: Integrated fluidics module provides total media replacement with up to four different types of media Negligible evaporation: <0.2% volume per 24 hrs ensures reliable results even for long test runs Integrated autosampler: samples 1 mL – 4 mL from dissolution cells into sealed vials for analyses Agilent 400-DS: Key Features and Benefits ( I )

121. 121 Smaller size: Occupies about 35% less space on a lab bench compared to traditional Apparatus 7 Automation of convenience and throughput : One instrument can run 13 test samples (two sets of six, plus a standard or control) and 400-DS software running on a single PC can control up to four instruments (up to 52 test samples) Regulatory Compliance: 400-DS is a compendial Apparatus VII and the software is compliant with 21 CFR Part 11 guidelines for electronic records ※ CFR : Code of Federal Regulations[ 미국 연방 규정집 ] Agilent 400-DS: Key Features and Benefits ( II )

122. USP IV Flow-Through Cell Method 122

123. 123 Capsules and Pellets

124. 124 In the Flow-Through Method, the test sample is located in a small volume cell through which media is pumped at a temperature of 37 °C. The eluate is filtered upon leaving the cell and then can be analyzed directly or collected in fractions to calculate the percent drug release Dissolution Testing according to the Flow-Through Method

125. 125 Open Loop Configuration Originally designed for poorly soluble compounds where more than the compendial USP 1, 2 and 3 media volumes was required, the Flow-Through Cell system has always been linked to “optimal sink conditions” allowing for complete flexibility in terms of media volume required In the “open loop” configuration, fresh media crosses the dosage form Samples are collected as fractions within a defined time interval, analyzed on-line by a UV-Vis spectrophotometer or a fiber optic probe The total amount of media is determined by the flow rate This means that the influence of poor sink conditions on the test can be avoided altogether by using larger volumes of media without the need for solubilizing agents In an open loop configuration, the total media volume used can be infinite

126. 126 In the open loop configuration, it is also possible to change the type of media that passes through the flow cell after predefined time intervals Using the MS47 media selector, media is automatically switched to draw from a different source Up to 3 different medias can be programmed Biorelevant Dissolution Media can also be used depending on filter performance This feature is useful for performing IVIVC studies where the dosage form naturally passes through the different pH of the digestive tract within sink conditions Studies have shown improved correlations due in part to maintaining sink conditions as well as differing hydrodynamics in the Flow-Through Cell It is also useful for enteric coated products, modified release and extended release products Unlike the USP Apparatus 1, 2 and 3 methods where a physical removal of the dosage and change to a new media can be cumbersome and tedious, USP 4 maintains temperature control and dosage integrity even on disintegrating and light sensitive formulations The Flow- Through Method is the only method that allows for Piston Pump a media change on a suspension and a powder. Open Loop Configuration

127. 127 Open system off-line with splitter, fraction collector and media selector Open Loop Configuration

128. 128 In a closed system, the Flow Through Method is conducted much like USP Apparatus 1 and 2 where a fixed volume of media circulates across the dosage form Samples can be taken a predetermined time by an autosampler, read by an on-line UV or a fiber optic probe Results of drug dissolved are expressed as a cumulative dissolution curve Closed systems are ideal for dosage forms where solubility and sink conditions are optimal in a volume range from 50 ml to 2 L. USP 4 offers another possible way to compare results with traditional 250 ml, 500 ml, 900 ml, 1 L, 2 L paddle, baskets and USP 3 methods This method also provides advantages over other USP methods such as different hydrodynamic and mixing effects eliminating the coning or dead zones seen in USP 1 and 2 as well as sampling issues and sample introduction effects . Closed Loop Configuration

129. 129 As a direct result of low dose formulations such as drug eluting stents, implants, coated medical devices, injectables, and microspheres, the USP 4 method has evolved to fulfill even lower media volume testing Within the medical device field, the term dissolution has been replaced by “elution” where the amount of drug released from a polymer coating or drug depot is measured These drug amounts are often so low that in order to meet sensitivity issues for analysis, the total media volume had to be decreased The USP Apparatus 4 was modified to run in the range of 5–50 ml total volume In 2007, a new USP Apparatus 4 was developed using a microvolume autosampler that can take accurate samples as low as 100 ul into capped vials. Evolution to Small Volume Dissolution and Elution Testing

130. 130 The SOTAX CE 7smart is capable of employing the Flow-Through Method for many different dosage forms. As the method evolved, new cells have been developed and optimized according to the dosage form The position of the sample can be addressed by the choice of the cell and its internal arrangement Possibilities include solutions for suspension and injectable introduction, powder and granule dissolution, drug eluting stents and implant positioning, and oils and fats associated with soft gelatin capsules and suppository testing Eight main cell types are available to accommodate most dosage forms Flow-Through Cells for a Variety of Dosage Forms

131. 131 Flow-Through Cells for a Variety of Dosage Forms

132. 132 Flow-Through Cells for a Variety of Dosage Forms

133. 133 Tablet Cell 12 mm (1) This cell is described in the EP, USP and JP as a small cell for tablets and capsules. A tablet holder is also described. It is also used for suspensions, injectables, small medical devices and stents Tablet Cell 22.6 mm (2) This cell is described in the EP, USP and JP as a large cell for tablets and capsules A tablet holder is also described. It can be used for larger doses of a suspensions and microspheres. There are a variety of holding devices developed for this cell This is the most widely used of all Flow-Through Cell Cell for powders and granulates (3) This cell is described in the EP chapter 2.9.43 Apparent Dissolution and is used to determine the apparent dissolution rate of pure solid substances (API characterization) and of active substances in preparations presented as powders It is also used for granule and bead formulations Cell for Drug Eluting Stents (4) This cell is manufactured in teflon and is used for Medical Devices like Drug Eluting Stents It eliminates potential adsorption problems encountered with Polycarbonate cells The inner diameter can be custom manufacture to fit the medical device accordingly Flow-Through Cells for a Variety of Dosage Forms

134. 134 Cell for Large Medical Devices (5) This cell can be used for longer Medical Devices and has a maximum length of 80 mm Cell for implants (6) This cell is used for small implants and has a small chamber to house the dosage Cell for suppositories and soft gelatin capsules (7) This cell is described in the EP Chapter 2.9.42 „ Dissolution test for lipophilic dosage forms“ and has a special two chambers design which blocks the lipidic excipients and allows the dissolution media to pass up to the filter Cell for Diffusion/Convection study (8) This cell has been designed for parenteral forms to simulate a first phase of diffusion and a second phase of convection without using a membrane It can also be used for the evaluation of topical formulations Holding Devices for creams and gels (9) This cell is based on a 22.6 mm cell An insert cup allows testing on gels, creams and ointments with a permeation membrane Holding Device for ophtalmic lens (10) This cell is based on a 22.6 mm cell An insert holder allows testing on drug coated ophthalmic lenses Flow-Through Cells for a Variety of Dosage Forms

135. 135 History of USP Apparatus 4 and Flow-Through Cell 1.1976 – 1978 2. CE 6 1978 – 1992 3. CE 70 1992 – 2001 4. CE 7smart 2001 – today

136. 136 The first documented concept of the Flow-Through Cell technique came as early as 1957 from an FDA laboratory Vliet,E,B .; Letter sent to the USP Subcommittee on tablets, August 23, 1957 proposing an assembly for testing Timed-Release Preparations In 1968, a continuous flow dissolution apparatus by Pernarowski was described However, it was not until the early 1970’s that the first conceptual drawings for a true apparatus received from the now creator of the Flow-Through Method, Chemist Dr Langenbucher at Ciba-Geigy was manufactured Dr Langenbucher, in his visionary article “In Vitro Assesment of Dissolution Kinetics: Description and Evaluation of a Column-type Method” was already predicting what would soon change the testing of modified and extended release dosage forms. SOTAX, a small engineering firm at the time, now considered a global leader in Pharmaceutical Testing Solutions, has been the pioneer ever since in FlowThrough Cell technology designing the first prototype for Dr Langenbucher in 1973 Today, SOTAX is considered 1st in Class and known throughout the world with thousands of companies using USP Apparatus 4. History of USP Apparatus 4 and Flow-Through Cell

137. 137 It was not until 1981 when the FIP proposed the “Flow-Through” Method as an alternative to basket and paddle methods for poorly soluble and extended-release dosage forms that the method started gaining acceptance The method became an official compendial apparatus when it was accepted by the US and European Pharmacopoeia in 1990 followed by the JP in 1996 Today, USP Apparatus 4 can be found in USP <711> Dissolution for Immediate Release Dosages and USP <724> Drug Release for Extended Release testing It describes the specifications for the instrument, flow cells and methodology Today, several monographs and NDAs have been approved by health authorities. Acceptance by Regulatory Authorities Worldwide

138. 138 Flow-Through Cell is widely recommended for poorly soluble, modified release and extended release tablets, and medical devices With the evolution of new drug delivery platforms, USP Apparatus 4 has also been used for IVIVC studies, suspensions, injectables, drug coated medical devices, parenteral formulations, implants, gels, ointments, creams, liquids, ophthalmic solutions and lenses, suppositories, soft gelatin capsules, beads, granules, APIs, microspheres and more The Flow-Through Cell can now be recommended for most novel dosage forms and was used for the first accepted submission for a drug-eluting stent on the market Because of the methods highly flexible configurations, ability to work in a variety of solubility conditions, Flow-Through Cell types and positioning of the dosage form, hydrodynamics and flow rates, USP Apparatus 4 will continue to evolve to meet the changing needs of today’s dissolution and elution testing The Flow-Through Cell Today

139. 139 Introduction of the USP Apparatus IV The flow-through cell apparatus which is described as Apparatus IV in the USP has gained recent acceptance into the dissolution world for its versatility in the testing of novel dosage forms where traditional dissolution apparatus and methods have failed Dosage forms including poorly soluble and extended release tablets, drug eluting stents, microspheres, suspension and injectable formulations, implants, soft gelatin capsules, and powders, all have provided exciting results and a solution to the troubles associated with the traditional dissolution methods.

140. 140 Introduction of the USP Apparatus IV

141. 141 Introduction of the USP Apparatus IV

142. 142 Open Loop Setup

143. 143 Open Loop Setup Originally designed for poorly soluble compounds where more than the compendial USP 1, 2 and 3 media volumes are required, the flow-through cell system has always been linked to “optimal sink conditions” allowing for flexibility in terms of media volume required. In the “open loop” configuration, fresh media crosses the dosage form. Samples are collected as fractions within a defined time interval, analyzed online by a UV-Vis spectrophotometer, or collected offline. The total amount of media is determined by the flow rate. This means that the influence of poor sink conditions on the test can be avoided altogether by using larger volumes of media without the need for solubilizing agents

144. 144 Dissolution profile of an open loop setup

145. 145 Open loop setup with offline sample collection

146. 146 In the open loop setup, it is possible to change the type of media that passes through the flow cell after predefined time intervals. Using the media selector, media is automatically switched to draw from a different source. Up to 3 different media can be programmed. Bio-relevant dissolution media can be used depending on filter performance. This feature is useful for performing IVIVC studies where the dosage form is exposed to the different pH’s of the digestive tract. Studies have shown improved correlations due in part to maintaining sink conditions as well as differing hydrodynamics in the flow-through cell. It is also useful for enteric coated products, modified release and extended release products Unlike the USP apparatus 1, 2 and 3 methods, where changing to a new media can be tedious, USP 4 simplifies this workflow allowing for a straightforward and documented media change. Automated media change

147. 147 Close Loop Setup

148. 148 In a closed system, the flow-through method is conducted much like a USP apparatus 1 and 2 experiment where a fixed volume of media circulates across the dosage form Samples can be taken at predetermined times by an autosampler or read by an online UV-Vis spectrophotometer. Results are expressed as a cumulative dissolution curve Closed systems are ideal for dosage forms where solubility and sink conditions are optimal in a volume range from 25 mL to 5 L USP 4 offers another possible way to compare results with traditional 250 mL, 500 mL,90 mL, 1 L, 2 L paddle, baskets, and USP 3 methods This method also provides advantages over other USP methods such as different hydrodynamic and mixing effects eliminating the coning or dead zones as well as sampling issues or sample introduction effects sometimes seen in USP apparatus 1 and 2. Close Loop Setup

149. 149 Dissolution profile of a closed loop setup

150. 150 Dissolution profile of an open loop setup

151. 151 As a direct result of low dose formulations such as drug eluting stents, implants, coated medical devices, injectables, and microspheres, the USP 4 method has evolved to fulfill even lower media volume testing. Within the medical device field, the term “dissolution” has been replaced by “elution” where the amount of drug released from a polymer coating or drug depot is measured These drug amounts are often so low that in order to meet LOQ issues for analysis, the total media volume had needs to be decreased Note that (when compared with USP 1, 2) the dosage form remains in equivalent hydrodynamic conditions – whatever volume is used. Small volume dissolution and elution testing

152. 152 Composition of USP Apparatus IV The assembly consists of a reservoir containing the release medium, a pump that forces the release medium upwards through the vertically positioned flow-through cell, and a water bath. The pump usually has a flow rate delivery capacity between 4 and 16 ml min-1, with typical flow rates of 4, 8 and 16 ml min-1. Usually the bottom cone of the cell is filled with small glass beads of about 1 mm diameter and with one bead of about 5 mm diameter positioned at the apex to protect the fluid entry tube, whereas a filter (most frequently, a glass fiber filter) is positioned at the inner top of the cell. For orally administered solid dosage forms, two different cells are described: the large cell (22.6 mm i.d. ) and the small cell (12 mm i.d. ) USP Apparatus IV can be operated under different conditions such as open or closed system mode, different flow rates and temperatures. The diversity of available cell types allows the application of this apparatus for testing of a wide range of dosage forms including tablets, powders, suppositories or hard and soft gelatin capsules.

153. 153 It is the method of choice for extended release and poorly soluble products USP Apparatus IV requires the sampling pump to be on continuously throughout the analysis, as the dissolution rate is directly proportional to the flow rate of the medium that is pumped into the flow-through cell. Sampling for this technique therefore requires that continuous collection or measurement of the eluted sample be maintained. As the dissolution time increases, large sample storage may be required, which may not be practical. Fraction collectors have a finite number of positions that are reduced as the volume of samples to be collected increases, which can limit the number of time points that can be collected. Sample splitters can also be used to divert the eluent sequentially between collection and waste, thus reducing the volume of sample to be collected. More recently a dual sampling rack has been designed to Singh & Aboul-Enein 221 allow samples to be collected while simultaneously diluting, if required, and injecting into either an HPLC system or a UV spectrophotometer Composition of USP Apparatus IV

154. 154 The flow-through cell apparatus can also be operated as a closed system by recycling a fixed volume of the medium. The medium passes the sample and is returned by the pump to the flow-through cell and the sample. A reservoir is placed in the line allowing the medium to be stirred, heated and sampled. By determining the concentration of analyte and the volume in the system, the cumulative release can be directly calculated Closed Configuration of USP Apparatus IV

155. 155 One distinct advantage of the open flow-through apparatus over the traditional closed apparatus (rotating paddle and/or rotating basket type) is that media and/or flow rate changes can be performed easily within the same run. This application is helpful in testing the robustness of the formulation with respect to the variations in the intralumenal environment. Intralumenal hydrodynamics are more efficiently simulated in this system than in other in vitro systems. It is possible to sustain sink conditions in the open flow-through apparatus for longer periods. This application is especially important for poorly soluble drugs, making the development of in vitro-in vivo correlations easier for such drugs Advantage of USP Apparatus IV

156. 156 Furthermore, the floating and other special dosage forms can be more easily studied with USP Apparatus IV The flow-through cell apparatus can also be operated as a closed system by recycling a fixed volume of the medium. The medium passes the sample and is returned by the pump to the flow-through cell and the sample. A reservoir is placed in the line allowing the medium to be stirred, heated and sampled. By determining the concentration of analyte and the volume in the system, the cumulative release can be directly calculated Advantage of USP Apparatus IV

157. 157 Jack et al. have compared USP Apparatus II and IV for the dissolution of soft gelatin capsule formulations of a poorly water-soluble amine drug. Using an acidic medium with added surfactant, both apparatuses gave similar dissolution profiles. Apparatus II tended to give faster rates of dissolution but Apparatus IV was better able to distinguish between different formulations. Sunesen et al. developed in vitro-in vivo correlations for danazol hard gelatin capsules using the flow-through cell apparatus, media simulating the intraintestinal composition, and higher than physiological flow rates (at least 8 ml min-1). With this methodology, point-to-point in vitro-in vivo correlations were developed under both fasted and fed conditions. Correlations in the fed state were better when lipid digestion products had been included in the relevant release media. However, it has been shown that the improved in vivo dissolution of spironolactone particles and troglitazone tablets in the fed small intestine can be correctly predicted with the flow-through cell apparatus when physiologically relevant media and flow rates are used Example of application

158. 158 The flow-through cell apparatus has been successfully used for assessing the disintegration of cross-linked gelatin capsules containing amoxicillin Emara et al. showed that for ER formulations of vincamine (a compound with pH-dependent dissolution characteristics) the in vitro release data with the flow-through cell apparatus could be correlated point-to-point with in vivo data only if used as an open system Fotaki et al. were able to develop a point-to-point correlation of in vitro release data using the flow-through cell apparatus with in vivo absorption data of two monolithic extended-release formulations of a highly soluble-highly permeable compound (isosorbide-5-mononitrate) in the fasted state by using physiologically relevant media and physiologically relevant flow rates. Closed Configuration of USP Apparatus IV

159. 159 The flow-through dissolution method offers complete flexibility on media volumes and allows repeatable positioning of virtually all dosage forms such as powders, APIs, lipophilic forms, suppositories, suspensions, liposomes, microspheres, semi-solids, implants, and medical devices including drug eluting stents. Described in the United States Pharmacopeia (USP) as Apparatus 4, in the European Pharmacopeia (EP) as Flow-through cell, in the Japanese Pharmacopeia (JP) as Apparatus 3, in the Chinese Pharmacopeia ( ChP ) as Method 6, and other Pharmacopeia, dissolution and drug release testing using a flow-through cell is proven to characterize the active drug release in terms of bioequivalence and in-vitro / in-vivo correlation (IVIVC) in clinical studies and daily QC routines alike. Flow-Through Cell Method(USP IV)

160. 160 Flow-Through Cell Method(USP IV) Sometimes referred to as the "Swiss Army Knife", flow-through cells allow dissolution testing of virtually all dosage forms. SOTAX was the first manufacturer to develop a standardized flow-through dissolution tester and has ever since helped pharmaceutical companies all over the world in designing robust flow-through methods - and new flow-through cells for novel dosage forms.

161. 161 Flow-Through Cell Method(USP IV)

162. 162 Flow-Through Cell Method(USP IV)

163. 163 Flow-Through Cell Method(USP IV)

164. 164 CE7smart ONLINE Configuration - YouTube Flow-Through Cell Method(USP IV)

165. 165 LOGAN Instruments USP4 SYSTEM 4000 USP apparatus 4 Flow through cell Flow-Through Cell Method(USP IV)

166. 166 Flow-Through Cell Method(USP IV) Large cell for tablets (22.6mm) Dissolution Testing USP4

167. USP V Paddle-Over Disk Method 167

168. 168 Paddle-Over Disk Method(USP V)

169. 169 Paddle over disk (screen and watch glass) Clip to hold screen and watch glass Paddle-Over Disk Method(USP V)

170. 170 Paddle-Over Disk Method(USP V)

171. 171 Paddle-Over Disk Vs Rotating Cylinder Paddle over Disk is the more popular performance test method for TDPs (images left and center) but the Rotating Cylinder (image on the right) method also enjoys significant use

172. 172 Paddle-Over Disk Method(USP V)

173. 173 첨부자료

174. 174 Classification of Dissolution Test Method

175. 175

176. Diffusion Layer Model/Film Theory This is the simplest and the most common theory for dissolution. Here, the process of dissolution of solid particles in a liquid, in the absence of reactive or chemical forces, consists of two consecutive steps: Solution of the solid to form a thin film or layer at the solid/liquid interface called as the stagnant film or diffusion layer which is saturated with the drug; this step is usually rapid Diffusion of the soluble solute from the stagnant layer to the bulk of the solution; this step is slower and is therefore the rate-determining step in drug dissolution. 1. Drug Solubility and Dissolution Rate 176

177. Diffusion Layer Model/Film Theory 1. Drug Solubility and Dissolution Rate 177 h

178. The earliest equation to explain the rate of dissolution when the process is diffusion controlled and involves no chemical reaction was given by Noyes and Whitney: dc/dt = dissolution rate of the drug k = dissolution rate constant (first order) Cs = concentration of drug in the stagnant layer (also called as the saturation or maximum drug solubility ) C b = concentration of drug in the bulk of the solution at time t. Equation was based on Fick's second law of diffusion. Noyes & Whitney Equation 1. Drug Solubility and Dissolution Rate 178 d c /dt = k (C s - C b )

179. Nernst and Brunner incorporated Fick‘s first law of diffusion and modified the Noyes-Whitney’s equation to: D = diffusion coefficient (diffusivity) of the drug A= surface area of the dissolving solid K w/o = water/oil partition coefficient of the drug considering the fact that dissolution body fluids are aqueous. ※ Since the rapidity with which a drug dissolves depends on the Kw/o, it is also called as the intrinsic dissolution rate constant [It is a characteristic of drugs] V = volume of dissolution medium. h = thickness of the stagnant layer. (Cs – Cb) = concentration gradient for diffusion of drug. Nernst and Brunner Equation (Modified Noyes-Whitney Equation) 1. Drug Solubility and Dissolution Rate 179 d c /dt = ADK(C s - C b ) / V h

180. 180 Factors affecting in vitro dissolution rates of solids in liquids 1. Drug Solubility and Dissolution Rate

181. Influence of Some Parameters on Dissolution Rate of Drug 1. Drug Solubility and Dissolution Rate 181

182. Equation represents first-order dissolution rate process, the driving force for which is the concentration gradient (Cs – Cb). Under such a situation, dissolution is said to be under non-sink conditions. This is true in case of  in vitro  dissolution in a limited dissolution medium. Dissolution in such a situation slows down after sometime due to build-up in the concentration of drug in the bulk of the solution. The  in vivo  dissolution is always rapid than  in vitro  dissolution because the moment the drug dissolves; it is absorbed into the systemic circulation. ☞ C b  = 0, and dissolution is at its maximum. ☞ Under  in vivo  conditions, there is no concentration build-up in the bulk of solution and hence no retarding effect on the dissolution rate of the drug ☞ Cs >> Cb and  sink conditions  are maintained. ☞ Under sink conditions, if the volume and surface area of solid are kept constant, then equation reduces to: where K incorporates all the constants in equation Equation 2.5 represents that the dissolution rate is constant under sink conditions and follows zero-order kinetics i.e. yields a linear plot 1. Drug Solubility and Dissolution Rate 182 d C /dt = K

183. 183 Intrinsic D issolution Rate(IDR) ?

184. 184 The intrinsic dissolution rate is defined as the rate of dissolution of a pure pharmaceutical active ingredient when the surface area, stirring speed, pH and ionic strength of the dissolution medium is kept constant. The surface area of the compound is well defined in contrast to in a dissolution rate measurement. Intrinsic Dissolution Rate

185. 185 Accordingly, the intrinsic dissolution rate (IDR) is defined as the dissolution rate of a pure active substance, where the conditions of surface area, temperature, agitation, and medium pH and ionic strength are all constant. Thus, it is possible to obtain data on the chemical purity and equivalence of drugs from different sources. This information is related to the variability of raw material available on the market, which results from distinctive synthesis processes, especially in the final stages of crystallization, and may lead to different particle sizes, degrees of hydration, habits, and crystalline forms for a single drug Intrinsic Dissolution Rate Skinner and Kanfer suggested that the main physicochemical aspects pertaining to drug absorption are the intrinsic dissolution rate and solubility. Because these two parameters are highly dependent on pH, their influence on absorption could easily be determined by the entire pH range of the gastrointestinal tract. Intrinsic dissolution is the dissolution of a pure active substance, and the determination of the dissolution rate can be important during the development of new molecules, because with small quantities of material, it is possible to execute the test and predict potential problems

186. 186 The IDR can be obtained by employing a specific device for this purpose, where the compressed drug is exposed in a dissolution medium over a constant surface area, and its value is expressed in mg cm -2 s -1 Intrinsic Dissolution Rate Applications for intrinsic dissolution tests are related to their use as a tool in the characterization of solid-state drugs, such as the determination of thermodynamic parameters associated with transition from crystalline phases, degrees of hydration, the investigation of the phenomenon of mass transfer in the dissolution process, the evaluation of the dissolution rate of a drug in different media (variation of pH or use of surfactants), and the IDR can be obtained by employing a specific device for this purpose, where the compressed drug is exposed in a dissolution medium over a constant surface area, and its value is expressed in mg cm -2 s -1 relationship between the dissolution rate of an active substance and that of its crystalline form (15, 37)

187. 187 Recent studies have proved the usefulness of the IDR in determining solubility in the sphere of the Biopharmaceutics Classification System. Because this test is not related to equilibrium but rather to the rate, there is expected to be a greater correlation in the in vivo dissolution dynamic than in the solubility test. In a conventional solubility test, where a quantity of a drug is kept under constant agitation and temperature until the solution is saturated, any determination of the actual solubility of the material may be compromised because of possible occurrences of recrystallization, which may result in alteration of the crystalline form, and hydrate and solvate formation Intrinsic Dissolution Rate Changes on the material surface of the compressed drug during the intrinsic dissolution test may also occur, such as the conversion of amorphous atorvastatin into crystalline atorvastatin, the transformation of diclofenac salt into its acid form, the hydration of anhydrous forms of carbamazepine and theophylline, and the conversion of rifampicin into a more stable polymorph

188. Intrinsic dissolution rate (mg/cm 2 /min) is characteristics of each solid compound in a given solvent under fixed hydrodynamic conditions Intrinsic dissolution rate helps in predicting if absorption would be dissolution rate-limited > 1 mg/cm 2 /min ☞ not likely to present dissolution rate-limited absorption problems < 0.1 mg/cm 2 /min ☞ usually exhibit dissolution rate-limited absorption 0.1 - 1.0 mg/cm 2 /min ☞ more information is needed before making any prediction Intrinsic Dissolution Rate

189. 189 Intrinsic Dissolution Rate

190. 190 IDR Values (mg min -1 cm -2 ) Vs BCS Solubility

191. 191 Solubility Test Vs IDR Test Because intrinsic dissolution is a feasible alternative for determining the solubility class, it can be noted that this test has several advantages over the phase solubility method, especially with respect to time, quantity of material, and handling of samples.

192. Apparatus Used to Determine IDR Pharmacopeias list two types of apparatus for the intrinsic dissolution test A fixed-disk system , described only in the USP, and a rotating-disk system , known as “Wood’s apparatus,” described in the USP and the European and British pharmacopeias. The rotating-disk system is used most commonly. A good correlation of results is observed compared with the fixed-disk system and even other systems not detailed in pharmacopeias but tested in several studies to determine the intrinsic dissolution rate. The latter include the flowcell system and a miniature apparatus (Mini-IDR) similar to the rotating disk

193. Apparatus Used to Determine IDR Pharmacopeias list two types of apparatus for the intrinsic dissolution test A fixed-disk system , described only in the USP, and a rotating-disk system , known as “Wood’s apparatus,” described in the USP and the European and British pharmacopeias. The rotating-disk system is used most commonly. A good correlation of results is observed compared with the fixed-disk system and even other systems not detailed in pharmacopeias but tested in several studies to determine the intrinsic dissolution rate. The latter include the flowcell system and a miniature apparatus (Mini-IDR) similar to the rotating disk

194. Apparatus Used to Determine IDR The characteristics of these apparatus include their use in conventional dissolution equipment. They have a cavity for placing the drug, where a press is required for the formation of the compressed drug. The geometry and size of the exposure, surface of the drug are known. When placed in the dissolution equipment, the apparatus enable the compressed drug to be exposed in a place of lower hydrodynamic variability. The IDR is influenced by various internal and external factors. The internal factors are related to the properties of the solid state of the drug, and the external factors are related to the surface area, the hydrodynamic condition, and the composition of the dissolution medium (viscosity, pH, and ionic strength).

195. Apparatus Used to Determine IDR Rotating-disk system Fixed disk method

196. Fixed Disk Method

197. Rotating-Disk System

198. 198 Common ion effect and buffer solution

199. 199 건강한 사람의 혈액은 pH 가 7.3~7.4 정도로 일정하게 유지된다 . 음식물을 섭취하거나 운동을 할 때에도 혈액의 pH 는 잘 변하지 않으며 , 만약 일정 범위를 넘는다면 생명이 위험할 수도 있다 . 이렇게 우리 몸속 혈액은 완충 작용을 하며 생명을 지켜준다 . 완충 용액 & 산 , 염기 개념 산과 염기는 아레니우스와 브뢴스테드 - 로우리 , 루이스에 의해 정의 산 (Acid) 루이스의 정리 : 산은 다른 물질의 비공유 전자쌍을 받아들이는 물질 ( 예 : HCl, CH3COOH) 산은 수소보다 반응성이 큰 금속과 반응하면 수소 기체를 발생시키는데 , 이는 금속이 산의 수용액에서 이온으로 녹으며 내놓은 전자를 산이 이온화된 수소 이온이 받아 만들어진다 . 염기 (Basic) 다른 물질에게 비공유 전자쌍을 내놓는 물질 염기의 묽은 수용액은 쓴 맛 단백질을 녹이는 성질 비누도 물에 녹아 염기성을 띠는 물질 비누를 오랫동안 방치하면 Na2CO3 가 생기는데 , 이는 비누 중의 NaOH 가 산성물질인 CO2 와 반응하여 생성된 것이다 .

200. 200 산과 염기

201. 201 정의 : ＂ 화학 평형 상태에서 농도 , 온도 , 부피 , 압력 등이 변화할때 , 화학 평형은 변화를 가능한 상쇄시키는 방향으로 움직인다 → 농도의 경우 어떤 이온을 함유하는 용액에 그것과 동일한 이온을 방출하는 물질을 하면 상대 이온의 농도가 감소하는 방향으로 화학 평형이 일어나게 됩니다 . Example I : 농도 증가 CO + 2H 2 ⇌ CH 3 OH CO 의 농도를 증가시키면 , 화학 물질의 농도 변화는 그 농도의 변화를 감소시키는 방향으로 평형을 이동 → 화학평형은 오른쪽인 정반응으로써 CH3OH( 메탄올 ) 의 생성량이 증가 르 샤틀리에 원리

202. 202 Example II : 압력 증가 N 2 + 3H 2 ⇌ 2NH 3 암모니아의 합성을 증가시키기 위해 온도를 일정하게 하고 압력을 증가 → 압력을 감소시키는 방향으로 화학 평형 발생 질소 1 몰과 수소 3 몰을 혼합하여 2 몰의 암모니아가 합성되는 과정이므로 , 몰수는 암모니아쪽이 작습니다 → 화학반응에서 압력을 가하게 되면 , 압력을 감소시키는 방향으로 일어나므로 정반응인 암모니아의 생성이 촉진됩니다 . [Example I 의 경우와 마찬가지로 압력의 증가는 농도의 증가와 유사 ] 르 샤틀리에 원리

203. 203 염 (Salt) 산과 염기를 반응시키면 산의 음이온과 염기의 양이온이 결합해 염을 만들고 , 수소 이온과 수산화 이온이 결합하여 물을 만든다 . 염은 주로 중성을 띄는 경우가 대부분이며 , 염화 나트륨이 주성분인 소금 결정도 염이다 . 화합물의 pH 가 7 보다 큰지 작은지에 따라서 염을 산성염 , 염기성염 , 정염으로 구분할 수 있으나 , 산성염이라 해서 꼭 염의 수용액에 산성이라는 뜻은 아니다 .

204. 204 염은 중화 반응뿐만 아니라 금속과 산의 반응 , 산과 금속 산화물의 반응 , 염기와 비금속 산화물의 반응 등에서도 생성된다 . 염은 대부분 녹는점이 높은 이온 결정이며 , 전하가 작은 이온으로 구성된 염은 물에 잘 녹는 경향을 보인다 . 산이나 염기와 반응할 때는 약산이나 약염기 또는 휘발성 산이 생성되는 방향으로 반응이 진행된다 . 염 (Salt)

205. 205 공통 이온 효과 & 완충용액 공통 이온 효과 같은 이온을 가지고 있는 두 이온성 화합물을 녹이면 용해도가 낮아지는 현상 전해질 수용액에 존재하는 이온과 같은 이온을 포함하는 물질을 수용액에 첨가하면 공통 이온이 감소하는 쪽으로 반응이 진행 ☞ 외부 조건이 변화하면 변화를 없애려는 방향으로 평형이 이동한다는 르샤틀리에 원리로 설명 완충 용액 산이나 염기를 가해도 pH 가 거의 변하지 않는 용액 약산에 그 짝염기를 넣었을 때나 약염기에 그 짝산을 넣은 용액 완충 용액의 pH 가 변하지 않는 이유는 공통 이온 효과 때문이다 .

206. 206 공통 이온 효과 & 완충용액 예시 : 아세트산과 아세트산 나트륨을 1:1 의 몰수 비로 혼합 산 (H+) 을 넣으면 용액의 H+ 증가 →평형이 역반응 쪽으로 이동 , H+ 가 CH3COO- 과 반응해 CH3COOH 생성 → 용액의 pH 는 거의 변하지 않음 염기 (OH-) 를 넣으면 용액의 OH- 증가 → 평형이 정반응 쪽으로 이동 , OH- 가 CH£COOH 과 중화 반응을 하여 소모됨 → 용액의 pH 는 거의 변하지 않음

207. 207 완충용액 혈액 속에는 탄산과 탄산수소 이온이 있어 완충 작용을 가능하게 한다 . 사람의 혈액은 탄산 , 인산과 단백질로 이루어져 있으며 , 혈액의 pH 가 6.8 이하거나 7.8 이상이면 죽을 수도 있다 . 혈액에 산성 물질이 들어오면 탄산수소 이온과 중화 반응을 일으키고 , 염기성 물질이 들어오면 탄산과 중화 반응을 일으킨다 . 정상적인 산 - 염기 균형을 이루기 위한 탄산과 탄산수소 이온의 비율은 탄산 : 탄산수소 이온 = 1 : 20 이라 한다 . 혈액에 H+ 가 증가하면 → ( 나 ) 의 역반응이 일어나 pH 일정하게 유지 → ( 가 ) 의 역반응이 일어나 CO2 가 생성되고 , 몸 밖으로 배출된다 . 혈액에 OH- 가 증가하면→ OH- 와 탄산이 반응하여 물과 탄산수소 이온을 만든다 . 이 외에도 인산수소 이온과 단백질에 의한 완충 작용으로 혈액의 pH 는 거의 항상 일정하게 유지될 수 있다 . 또한 , 혈액 속의 혈장도 pH 를 조절하는 데 중요한 역할을 한다 .

208. 208 완충용액 & Henderson-Hasselbalch equation 완충 용액에서 가장 중요한 식은 Henderson-Hasselbalch 방정식 ! 방정식으로부터 약산과 그 짝염기가 동시에 존재하는 용액의 pH 는 약산의 pKa 를 중심으로 약산과 짝염기의 농도 비에 의존함을 알 수 있다 . 만약 약산과 약염기의 농도가 같으면 ([HA] = [A-]), 용액의 pH 는 약산의 pKa 와 같다 . 약산의 농도가 약염기의 농도보다 더 클 때는 ([HA] > [A-]) 용액의 pH 가 약산의 pKa 보다 더 작게 되며 , 약산의 농도가 약염기의 농도보다 작은 경우 반대가 된다 . 완충용액에 강산이나 강염기가 첨가된 경우에도 이 식으로부터 변화된 pH 를 계산할 수 있다 . Lawrence Joseph Henderson Karl Albert Hasselbalch

209. 209 완충용액 & Henderson-Hasselbalch equation

210. 210 Definition of Buffering Capacity Buffer capacity quantifies the ability of a solution to resist changes in pH by either absorbing or desorbing H + and OH - ions. When an acid or base is added to a buffer system, the effect on pH change can be large or small, depending on both the initial pH and the capacity of the buffer to resist change in pH. Buffer capacity (β) is defined as the moles of an acid or base necessary to change the pH of a solution by 1, divided by the pH change and the volume of buffer in liters A buffer resists changes in pH due to the addition of an acid or base though consumption of the buffer. As long as the buffer has not been completely reacted, the pH will not change drastically. The pH change will increase (or decrease) more drastically as the buffer is depleted: it becomes less resistant to change.

211. 211 Donald Van Slyke

212. 212 Buffer Capacity & Van Slyke Equation Koppel and Spiro and Van Slyke introduced the concept of buffer capacity and defined it as the ratio of the increment of strong base (or acid) to the small change in pH brought about by this addition.

213. 213 Buffer Capacity & Van Slyke Equation

214. 214 Buffer Capacity & Van Slyke Equation

215. 215 BUFFER CAPACITY: influence of C on β

216. 216 BUFFER CAPACITY: influence of C on β

217. 217 Maximum BUFFER CAPACITY

218. 218 Food Effect of Dissolution Test

219. 219 When dissolution testing is used to forecast the in vivo performance of a drug, it is critical that the in vitro test mimic the conditions in vivo as closely as possible. A team of researchers, led by Dr. Jennifer Dressman has developed biorelevant gastrointestinal media that simulate the fasted and fed states. These media have been used to examine the solubility and dissolution characteristics of several classes of drugs including poorly soluble weak bases and lipophilic drugs to assist in predicting in vivo absorption behavior Biorelevant in vitro dissolution testing is useful for qualitative forecasting of formulation and food effects on the dissolution and availability of orally administered drugs. It has been observed that biorelevant media can provide a more accurate simulation of pharmacokinetic profiles than simulated gastric fluid or simulated intestinal fluid. The use of biorelevant media can have a great impact on the pharmacokinetic studies performed to optimize dosing conditions and product formulation. In addition, biorelevant dissolution testing could be used to assess bioequivalence of post-approval formulation changes in certain kinds of drugs Dissolution Media Simulating Fasted and Fed States

220. 220 Dissolution Media Simulating Fasted and Fed States

221. 221 Fasted State Simulated Gastric Fluid ( FaSSGF )

222. 222 Fasted State Simulated Intestinal Fluid (FaSSIF) Preparation of blank FaSSIF Dissolve 1.74 g of NaOH (pellets), 19.77 g of NaH2PO4.H2O or 17.19 g of anhydrous NaH2PO4, and 30.93 g of NaCl in 5 L of purified water. Adjust the pH to exactly 6.5 using 1 N NaOH or 1 N HCl Preparation of FaSSIF Dissolve 3.3 g of sodium taurocholate in 500 mL blank FaSSIF. Add 11.8 mL of a solution containing 100 mg /mL lecithin in methylene chloride, forming an emulsion. The methylene chloride is eliminated under vacuum at about 40°C. Draw a vacuum for fifteen minutes at 250 mbar, followed by 15 minutes at 100 mbar. This results in a clear, micellar solution, having no perceptible odor of methylene chloride. After cooling to room temperature, adjust the volume to 2 L with blank FaSSIF For dissolution tests a volume of 500 mL is recommended.

223. 223 Preparation of blank FeSSIF Dissolve 20.2 g of NaOH (pellets), 43.25 g of glacial acetic acid, and 59.37 g of NaCl in 5 L of purified water. Adjust the pH to exactly 5.0 using 1 N NaOH or 1 N HCl Preparation of FeSSIF Dissolve 16.5 g of sodium taurocholate in 500 mL of blank FeSSIF. Add 59.08 mL of a solution containing 100 mg/mL lecithin in methylene chloride, forming an emulsion. The methylene chloride is eliminated under vacuum at about 40°C. Draw a vacuum for fifteen minutes at 250 mbar, followed by 15 minutes at 100 mbar. This results in a clear to slightly hazy, micellar solution having no perceptible odor of methylene chloride. After cooling to room temperature, adjust the volume to 2 L with blank FeSSIF. The recommended volume for simulating conditions in the upper small intestine after a meal is one liter. Fed State Simulated Intestinal Fluid (FeSSIF)

224. 224 Dissolution profiles of Danatrol ® tablets obtained in media simulating the intralumenal composition of the small intestine before and after a meal Example I

225. 225 Dissolution profiles of Phenhydan ® tablets obtained in compendial and biorelevant media simulating the intralumenal composition of stomach and small intestine before and after a meal Example II

226. 226 Solubility data of itraconazole formulated with HB en BCD in compendial and biorelevant medium Example III

227. 227 Dissolution profiles of a itraconazole– HBenBCD complex obtained in compendial and biorelevant media simulating the intralumenal composition of stomach and small intestine before and after a meal Example III

228. 228

229. 229

230. 230 FEDGAS High-Fat Meal Dissolution Kit

231. 231 Product Description

232. 232 Product Description

233. 233 Use FaSSIF buffer concentrate for best results (biorelevant.com) How to prepared for FaSSIF

234. 234 CI (Confidence Interval)

235. 235 정규분포

236. 236 정규분포

237. 237 정규분포

238. 238 표준정규분포

239. 239 통계적 추정 (statistical inferences)

240. 240 통계적 추정 (statistical inferences) 모수 : 모집단에는 모평균 , 모분산 , 모비율 , 모상관계수 등과 같이 모집단의 특성을 나타내는 수치값 통계적 추론 : 모집단의 미지인 모수 값을 표본 정보를 이용하여 알아내는 과정 추정 (estimation) 1. 점추정 (point estimation) : 모수의 대한 추정값으로 표본자료를 이용하여 하나의 값으로 추정 2. 구간추정 (interval estimation) : 모수가 포함되리라고 기대하는 범위 ( 구간 ) 을 추정 가설검정 (hypothesis test) : 모집단 분포 또는 모수에 대한 가설을 세우고 , 표본자료를 이용하여 옳고 그름을 판단

241. 241 모평균의 구간추정 신뢰구간 (confidence interval) : 모수가 포함되도록 추정치를 이용하여 구성한 구간 중에서 간격이 가장 작은 구간 신뢰수준 (confidence level) : 신뢰구간을 구할 때 , 먼저 신뢰구간에 모수가 포함될 확률을 지정하는데 이 확률을 신뢰수준 이라고 함

242. 242 모평균의 구간추정 : 모집단 표준편차 ( σ ) 을 아는 경우

243. 243 모평균의 구간추정 : 모집단 표준편차 ( σ ) 을 아는 경우

244. 244 모평균의 구간추정 : 모집단 표준편차 ( σ ) 을 아는 경우 154.10 195.9

245. 245 CI ( Confidence Interval ) ? What does a 95% confidence interval mean? The 95% confidence interval is a range of values that you can be 95% confident contains the true mean of the population. Due to natural sampling variability, the sample mean (center of the CI) will vary from sample to sample. If we repeated the sampling method many times, approximately 95% of the intervals constructed would capture the true population mean. ☞As the sample size increases, the range of interval values will narrow, meaning that you know that mean with much more accuracy compared with a smaller sample.

246. 246 CI ( Confidence Interval ) ? For example, the probability of the population mean value being between -1.96 and +1.96 standard deviations (z-scores) from the sample mean is 95%. Accordingly, there is a 5% chance that the population mean lies outside of the upper and lower confidence interval (as illustrated by the 2.5% of outliers on either side of the 1.96 z-scores).

247. 247 CI ( Confidence Interval ) ?

248. 248 CI ( Confidence Interval ) ?

249. 249 Why do researchers use confidence intervals? It is more or less impossible to study every single person in a population so researchers select a sample or sub-group of the population. This means that the researcher can only estimate the parameters (i.e. characteristics) of a population, the estimated range being calculated from a given set of sample data. Therefore, a confidence interval is simply a way to measure how well your sample represents the population you are studying. The probability that the confidence interval includes the true mean value within a population is called the confidence level of the CI. You can calculate a CI for any confidence level you like, but the most commonly used value is 95%. A 95% confidence interval is a range of values (upper and lower) that you can be 95% certain contains the true mean of the population.

250. 250 Why do researchers use confidence intervals?

251. 251 How do I calculate a confidence interval? To calculate the confidence interval, start by computing the mean and standard error of the sample. Remember, you must calculate an upper and low score for the confidence interval using the z-score for the chosen confidence level

252. 252 How do I calculate a confidence interval? Confidence Interval Formula For the lower interval score divide the standard error by the square root on n, and then multiply the sum of this calculation by the z-score (1.96 for 95%) Finally, subtract the value of this calculation from the sample mean. 표본수가 많을수록 모평균에 근접 편차가 적을수록 모평균에 근접

253. 253 C.I Calculation

254. 254 Example I X (mean) = 86 Z = 1.960 (from the table above for 95%) s (standard error) = 6.2 n (sample size) = 46 Lower Value: 86 - 1.960 × 6.2/√46 = 86 - 1.79 = 84.21 Upper Value: 86 + 1.960 × 6.2 /√46 = 86 + 1.79 = 87.79 So the population mean is likely to be between 84.21 and 87.79

255. 255 상용로그 Vs 자연로그

256. 256 자연상수 e( 오일러 상수 )

257. 257 자연상수 e( 오일러 상수 )

258. 258 1/x 적분

259. 259 1/x 적분

260. 260 1/x 적분

261. 261 1/x 적분

262. 262 자연상수 e( 오일러 상수 ) 자연 로그 (natural logarithm) : ln 자연로그 : 자연 상수 e 를 밑으로 하는 로그 (log)  = 2.7182818284 → log x = ln x / 2.303  

263. 263 Log( 상용로그 )vs Ln( 자연로그 )

264. 264 Log( 상용로그 )vs Ln( 자연로그 )

265. 265 자연상수 e( 오일러 상수 ) 자연 로그 (natural logarithm) : ln 자연로그 : 자연 상수 e 를 밑으로 하는 로그 (log)  = 2.7182818284 → log x = ln x / 2.303  

266. 266 First-Order Release Kinetics

267. 267 The Ideal Dissolution Media?

268. 268 The Ideal Dissolution Media

269. 269 Media Selection Solubility screen in multiple media should be done to determine optimal solubility – pH 1.1 / pH 2-3 / pH 4-5 / pH 6.8 / pH 7.5 If needed, use as little surfactant as necessary Evaluate multiple surfactants (pay attention to grades and vendors) Rules of Thumb for Media Limits Surfactants below 1% tend to be accepted >1% require greater scrutiny, other surfactants usually >1.5% tends to be very difficult to handle with automation Alcohol is generally a last resort – unless doing a dose dumping study specifically Stay within pH 1.1 – pH 7.5 if at all possible

270. 270 Sink Condition Vs Non-Sink Condition?

271. 271 Sink Condition Vs Non-Sink Condition

272. 272 Sink condition is mentioned a lot when it comes to dissolution testing, but the importance of it to dissolution testing is left out. Sink condition is the ability of the dissolution media to dissolve at least 3 times the amount of drug that is in your dosage form. Having sink conditions helps your dissolution have more robustness as well as being more biologically relevant. Why is 3 times the magic number when it comes to sink condition? This value comes out of the Noyes-Whitney equation. What is sink condition in dissolution test ? R = Dissolution Rate K 2 = Intrinsic Dissolution Rate D = Diffusion Coefficient / S = Surface Area V = Volume / H = Thickness of Stagnant Layer Cs = Saturation Constant of API / Ct = API Concentration at Time t

273. 273 Looking at this equation, we see that the Dissolution Rate is proportional to the term (Cs - Ct). This is the difference of the concentration at saturation compared to the concentration at a given time. ☞ The closer our concentration gets to saturation, the slower the dissolution rate becomes. ※ You can see this same thing happen when you make sugar water - The first scoop may need no mixing and goes readily in solution, but the 10th scoop requires mixing and heating and quite a bit of time. The dosage form is moving through the body and we are eating and drinking throughout the day (and often too much around the holidays). ☞ When we are testing in vitro, we must minimize this artificial issue and this is where sink condition comes in. What is sink condition in dissolution test ?

274. 274 If you are meeting sink conditions, then at the beginning of the dissolution the (Cs-Ct) would be 3-0. At the end of the dissolution, you would be at 3-1 or 2. Over the course of the dissolution, your dissolution rate would be slowed by only 1/3 due to the drug already dissolved in solution. If you fail to meet sink conditions, then you're more likely to not match in vivo performance (since in vivo doesn't experience saturation). If you aren't meeting sink conditions, then there are a few ways to improve the solubility of your product: What is sink condition in dissolution test ?

275. 275 1) Change the API If this is early on in formulation development, you may be able to find an API with better solubility, such as one complexed with a salt. 2) Change the pH of the dissolution media (pH-Solubility Profile) 3) Add surfactants, make sure to try multiple types of surfactants. SLS is most popular, but has a lot of challenges associated with it. CTAB, Tween , Triton X, and others are all commonly used and effective. 4) Use a greater volume of media. Larger vessel systems are available from some dissolution vendors for 2L vessels and even higher. What is sink condition in dissolution test ?

276. 276 What is sink condition in dissolution test ?

277. 277 0.5L / 2L Vessel Dissolution Tester

278. 278 2L Vessel Dissolution Tester 708-DS Dissolution Apparatus equipped with DDM, Sampling and AutoTemp options

279. 279 Similarity Factor in Dissolution Test

280. 280 After a drug is approved for commercial marketing, there may be some changes with respect to chemistry, manufacturing, and controls. Before the postchange formulation can be approved for commercial use, its quality and performance need to be demonstrated to show similarity to the prechange formulation. Because drug absorption depends on the dissolved state of drug products, in vitro dissolution testing is believed to provide a rapid assessment of the rate and extent of drug release. As a result, Leeson (1995) suggested that in vitro dissolution testing be used as a substitute for in vivo bioequivalence studies to assess equivalence between the postchange and prechange formulations Histories of Introducing Fit Factors

281. 281 These postmarketing changes include scale-up, manufacturing site, component and composition and equipment and process changes . In 1995, the U.S. FDA published ‘‘Immediate Release Solid Oral Dosage Forms: Scale-Up and Postapproval Changes : Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation’’ (SUPAC–IR). Moore JW, Flanner HH (1996) proposed difference factor 𝑓 1 and similarity factor 𝑓 2 for the comparison of dissolution profiles. In 1996, Shah, Tsong and Sathe formed a working group to develop and evaluate methods for the comparison of dissolution profiles Histories of Introducing Fit Factors

282. 282 Fit factors in Dissolution Test

283. 283 Similarity Factor in Dissolution Test The fit factors can be expressed by two approaches: f1 (the difference factor) and f2 (the similarity factor). Two dissolution profiles to be considered similar and bioequivalent, f1 should be between 0 and 15 whereas f2 should be between 50 and 100

284. 284 식약처 가이드라인