Dissolution Test(Ver26.0).pptx

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

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

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Definition of Dissolution test

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dissolution Steps of Solid Dosage Forms

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dissolution Steps of Solid Dosage Forms

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Roles of in vitro dissolution testing
in pharmaceutical drug development

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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.

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.
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h
Cs

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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)

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What is diffusion
 분산계수(D)
 membrane의 종류에 따라 결정되는 고유 값
 해당 재질에 대해 단위 면적(1㎠), 단위 시간(1초), 단위 두께(1cm) 조건에서 얼마나 많은 양이
이동했는지 측정된 것이기 때문에 단위는 ㎠/s
 얇든 두껍든 단위 두께에 대한 값이니 같은 재질의 membrane이라면 항상 같은 값
 투과상수(P)
 물질이 membrane을 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 제3의 물질(C)를
가해줬을 때 C의 농도가 A와 B 각각에서 어떤 값을 갖는지 구해서 그 비를 구한 것
 K = CA/CB

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확산의 속도 및 양은 어떻게 정량화 할 수 있을까?

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확산의 속도 및 양은 어떻게 정량화 할 수 있을까?

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Noyes & Whitney Equation & 1st Ficks Law

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)
 Cb = 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
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dc/dt = k(Cs- Cb)

 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
 Kw/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)
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dc/dt = ADKo/w(Cs- Cb) / Vh

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 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.
☞ Cb = 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
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dC/dt = K

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 For example, a preparation of drug particles weighing 550 mg and having a total
surface area of 0.28 × 104 cm2 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

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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 cm2 / min
Calculation Example

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Factors influencing
dissolution rate

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Factors influencing dissolution rate
1. 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.

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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.

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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.

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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.

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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.
a. 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.

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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.

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Factors affecting in vitro dissolution
rates of solids in liquids

Influence of Some Parameters on
Dissolution Rate of Drug
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Schema of the current strategy in a dissolution data
comparison by the EMA and FDA guidelines

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Frequently used mathematical models
to describe the drug dissolution profiles

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Frequently used mathematical models
to describe the drug dissolution profiles
 Zero-order Model
 Mt : Amount of drug released in the time t
 K0 : zero-order release rate constant
 First-order Model
 M∞ : Maximum amount of drug which can be released from a dosage form in infinite time
 K1 : First-order release rate constant
 Weibull model
 kw : Constant of Weibull model
 β : Parameter characterizes the shape of the exponential curve
 Korsmeyer–Peppas model
 KKP : Constant of Korsmeyer–Peppas model
 Higuchi model
 KH : Constant of Higuchi model
 Hixson–Crowell model
 M’t : Drug amount in a dosage form in the time t
 KHC : Constant of Hixson–Crowell model
 Hopfenberg model
 KHP : Constant of Hopfenberg model.

Classification of
Dissolution Test
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List of the Official Dissolution Apparatus
and their uses

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 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:

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Classification of of dissolution test apparatus

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Classification of of dissolution test(USP)

Summary of
Dissolution Test Method
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 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 (USPApparatus 1)

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 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 37oC.
Paddle type (USPApparatus 2)

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 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 (USPApparatus 3)

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 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 (USPApparatus 4)

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 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 (USPApparatus 5)

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 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 (USPApparatus 6)

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 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 (USPApparatus 7)

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TYPICAL DISSOLUTION PARAMETER
OVERVIEW USPAPPARATUS 1 AND 2

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

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Summarization
 USPApparatus 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.

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 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 )

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 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 )

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 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 )

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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

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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

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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

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

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Schematic representation of fluid-flow past a tablet
in the inner cylinder of USPApparatus III
Schematic representation of the free-stream velocity
past a tablet when agitated using USPApparatus III

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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

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APPLICATIONS FOR MODIFIED-RELEASE
SOLID ORAL DOSAGE FORMS

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 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
SOLID ORAL DOSAGE FORMS ( I )

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 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
SOLID ORAL DOSAGE FORMS ( II )

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 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
SOLID ORAL DOSAGE FORMS ( III )

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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)
SOLID ORAL DOSAGE FORMS ( IV )

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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)
SOLID ORAL DOSAGE FORMS ( V )

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USP Dissolution Test III ;
SIMULATION OF FASTED AND FED STATES

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 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 )

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 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 )

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 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 )

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

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

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

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

95
History of the USPApparatus 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
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 USPApparatus 3

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
Factors for USPApparatus 3
 Type of product
 Volume of medium
 Number of rows
 Mesh size
 Medium in each row
 Dip speed per row
 Residence time per row

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
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
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
Typical Conditions for Extended-Release Testing

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

USP IV
Flow-Through Cell Method
122

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
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
 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 USPApparatus 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.

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

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
 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 USPApparatus 4 was modified to run in the range of 5–50 ml total volume
 In 2007, a new USPApparatus 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
 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

132

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

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

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

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 USPApparatus 4.
History of USPApparatus 4 and
Flow-Through Cell

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, USPApparatus 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
 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, USPApparatus 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, USPApparatus 4 will continue to evolve to meet the
changing needs of today’s dissolution and elution testing
The Flow-Through Cell Today

139
Introduction of the USPApparatus 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

141

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
Dissolution profile of an open loop setup

145
Open loop setup with offline sample collection

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

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
Dissolution profile of a closed loop setup

150
Dissolution profile of an open loop setup

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
Composition of USPApparatus 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.)
 USPApparatus 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
 It is the method of choice for extended release and poorly soluble products
 USPApparatus 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 USPApparatus IV

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 USPApparatus IV

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 USPApparatus IV

156
Furthermore, the floating and other special dosage forms can be more
easily studied with USPApparatus 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 USPApparatus IV

157
 Jack et al. have compared USPApparatus 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
 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 USPApparatus IV

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
 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

162

163

164
CE7smart ONLINE Configuration - YouTube

165
LOGAN Instruments USP4 SYSTEM 4000 USP apparatus 4 Flow through cell

166
Large cell for tablets (22.6mm) Dissolution Testing USP4

USP V
Paddle-Over Disk Method
167

168
Paddle-Over Disk Method(USP V)

169
Paddle over disk (screen and watch glass)
Clip to hold screen and watch glass

170

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

174
Classification of Dissolution Test Method

 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
h

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)
 Cb = 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
178
dc/dt = k(Cs- Cb)

 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
 Kw/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.
179
dc/dt = ADK(Cs- Cb) / Vh

180
Factors affecting in vitro dissolution rates of solids in liquids

Influence of Some Parameters on Dissolution Rate of Drug
181

 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.
☞ Cb = 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
182
dC/dt = K

183
Intrinsic Dissolution Rate(IDR) ?

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
 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
 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
 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
 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
 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
 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

 Intrinsic dissolution rate (mg/cm2/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/cm2/min
☞ not likely to present dissolution rate-limited absorption problems
 < 0.1 mg/cm2/min
☞ usually exhibit dissolution rate-limited absorption
 0.1 - 1.0 mg/cm2/min
☞ more information is needed before making any prediction

189

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

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.

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

 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).

Rotating-disk system Fixed disk method

198
Common ion effect and buffer solution

199
 건강한 사람의 혈액은 pH가 7.3~7.4 정도로 일정하게 유지된다.
 음식물을 섭취하거나 운동을 할 때에도 혈액의 pH는 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 Na2CO3가 생기는데, 이는 비누 중의 NaOH가 산성물질인 CO2와
반응하여 생성된 것이다.

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 + 2H2 ⇌ CH3OH
 CO의 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
 Example II : 압력 증가
N2 + 3H2 ⇌ 2NH3
 암모니아의 합성을 증가시키기 위해 온도를 일정하게 하고 압력을 증가
→ 압력을 감소시키는 방향으로 화학 평형 발생
 질소 1몰과 수소 3몰을 혼합하여 2몰의 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
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 pH가 7보다 큰지 작은지에 따라서 염을 산성염, 염기성염, 정염으로
구분할 수 있으나, 산성염이라 해서 꼭 염의 수용액에 산성이라는 뜻은 아니다.

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
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 pH가 거의 변하지 않는 용액
 약산에 그 짝염기를 넣었을 때나 약염기에 그 짝산을 넣은 용액
 완충 용액의 pH가 변하지 않는 이유는 공통 이온 효과 때문이다.

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

207
완충용액
 혈액 속에는 탄산과 탄산수소 이온이 있어 완충 작용을 가능하게 한다.
 사람의 혈액은 탄산, 인산과 단백질로 이루어져 있으며, 혈액의 pH가 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 : 20이라 한다.
 혈액에 H+가 증가하면 → (나)의 역반응이 일어나 pH 일정하게 유지 → (가)의
역반응이 일어나 CO2가 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 pH는 거의 항상
일정하게 유지될 수 있다.
 또한, 혈액 속의 혈장도 pH를 조절하는 데 중요한 역할을 한다.

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

209
완충용액 & Henderson-Hasselbalch equation

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.

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

214

215
BUFFER CAPACITY: influence of C on β

216
BUFFER CAPACITY: influence of C on β

218
Food Effect of Dissolution Test

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
Dissolution Media Simulating
Fasted and Fed States

221
Fasted State Simulated Gastric Fluid (FaSSGF)

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

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

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

230
FEDGAS High-Fat Meal Dissolution Kit

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

239
통계적 추정(statistical inferences)

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
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
: 모집단 표준편차( σ )을 아는 경우

243

244
154.10 195.9

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
 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

248

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
Why do researchers use confidence intervals?

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
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

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
상용로그 Vs 자연로그

256
자연상수 e(오일러 상수)

257

262
 자연 로그(natural logarithm) : ln
 자연로그 : 자연 상수 e를 밑으로 하는 로그(log)
= 2.7182818284
𝐥𝐧 𝒙 = 𝒍𝒐𝒈𝒆𝒙 =
𝒍𝒐𝒈𝒙
𝒍𝒐𝒈𝒆
=
𝒍𝒐𝒈𝒙
𝒍𝒐𝒈𝟐. 𝟕𝟏𝟖
=
𝒍𝒐𝒈𝒙
𝟎. 𝟒𝟑𝟒𝟐𝟗
= 𝟐. 𝟑𝟎𝟑𝒍𝒐𝒈𝒙
→ log x = ln x / 2.303

263
Log(상용로그)vs Ln(자연로그)

264
Log(상용로그)vs Ln(자연로그)

265
 자연 로그(natural logarithm) : ln
 자연로그 : 자연 상수 e를 밑으로 하는 로그(log)
= 2.7182818284
𝐥𝐧 𝒙 = 𝒍𝒐𝒈𝒆𝒙 =
𝒍𝒐𝒈𝒙
𝒍𝒐𝒈𝒆
=
𝒍𝒐𝒈𝒙
𝒍𝒐𝒈𝟐. 𝟕𝟏𝟖
=
𝒍𝒐𝒈𝒙
𝟎. 𝟒𝟑𝟒𝟐𝟗
= 𝟐. 𝟑𝟎𝟑𝒍𝒐𝒈𝒙
→ log x = ln x / 2.303

266
First-Order Release Kinetics

267
The Ideal Dissolution Media?

268
The Ideal Dissolution Media

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
Sink Condition Vs Non-Sink Condition?

271
Sink Condition Vs Non-Sink Condition

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
 K2 = 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
 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.

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:

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.

276

277
0.5L / 2L Vessel Dissolution Tester

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

279
Similarity Factor in Dissolution Test

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
 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 𝑓1 and similarity
factor 𝑓2 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
Fit factors in Dissolution Test

283
 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

286
Comparison of dissolution profile similarity
between reference and various test batches

287

288

290
(Example I)

291
Amoxicillin 500 mg Capsule
Dissolution test conditions for
amoxicillin capsule as per USP

292
Fit Factor
 The factor, f1, is the average % difference over all time points in the
amount of test brand dissolved as compared to the reference brand.
 The f1 value is 0 when the test and the reference profiles are identical and
increases proportionally with the dissimilarity between the two profiles.
 The f2 value is between 0 and 100.
 The value is 100 when the test and the reference profiles are identical and
approaches zero as the dissimilarity increases
 Rt : % of dissolved product for a reference batch at time point t
 Tt : % of dissolved product for the test batch
 N : the number of time points.
 For each brand, the calculations were made on the mean values for the six vessels
f1 : Difference Factor f2: Similarity Factor

293
Dissolution profiles of nine brands of amoxicillin capsule

294
Dissolution data for the calculation of f1 and f2

295
(Example II)
Bilayer tablets with sustained-release metformin and immediate-release
sitagliptin: preparation and in vitro/in vivo evaluation
Journal of Pharmaceutical Investigation (2021) 51:579–586

296
Wet Granulation Method
Direct Compression Method
Compositions of the optimal bilayer tablets
containing immediate-release sitagliptin layer and
sustained-release metformin

297
Bilayer tablets containing immediate-release sitagliptin
layer and sustained-release metformin layer (in-house name
SiMet XR, left) and Janumet XR® 50/500 mg (MSD, right

298
In vitro drug release of sitagliptin and metformin hydrochloride in
media pH 1.2, 4.5, and 6.8, at various time points, of the bilayer
tablet, in comparison with the reference Janumet XR® 50/500 mg

299
In vitro release profiles of metformin hydrochloride of
the bilayer tablet (test sample)and the reference Janumet XR®
50/500 mg, in media pH 1.2 (a),4.5 (b), and 6.8 (c)

300
Drug plasma concentration–time profiles of 50-mg-sitagliptin and
500-mg-metformin bilayer tablet(test sample) and Janumet XR
50/500 mg (reference) following oral administration
(mean±SD, n=14)

301
Pharmacokinetic parameters in in vivo bioequivalence study
between the oral administration of 50mg sitagliptin and
500mg metformin bilayer tablets(test sample, T), and
Janumet XR® 50/500 mg (reference sample, R)
 Cmax : maximum concentration / Tmax time to reach Cmax
 t1/2 elimination half-life
 AUC0-t , AUC0−inf area under the curve from 0 (initial) to 48 h and to infinity, respectively

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