The document discusses comparison of dissolution profiles through different methods and establishing an IVIVC (in vitro-in vivo correlation). It provides definitions of dissolution profile and objectives of comparing profiles. Various methods for comparing profiles are described, including graphical, statistical, and model-dependent/independent methods. Key factors for determining similarity between dissolution profiles using statistical methods like difference factor and similarity factor are outlined. The importance of developing an IVIVC to reduce costs and the need for bioavailability studies is also mentioned. A research article comparing different brands of metformin tablets using tests like dissolution rate, drug content and disintegration is briefly summarized.
Physics of Tablet compression is very useful during study of the tablet. It contains the mechanism of tablet compression. It also contains the process of tablet compression.
Physics of Tablet compression is very useful during study of the tablet. It contains the mechanism of tablet compression. It also contains the process of tablet compression.
it provide a brief note on the drug excipient interaction and various technique to find it which is a part of preformulation studies. it gives help to mpharm(pharmaceutics) students. i.
This slide share includes the introduction about smedds, difference between emulsion and smedd and sedds and smedds, composition and its formulation aspects.
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
it provide a brief note on the drug excipient interaction and various technique to find it which is a part of preformulation studies. it gives help to mpharm(pharmaceutics) students. i.
This slide share includes the introduction about smedds, difference between emulsion and smedd and sedds and smedds, composition and its formulation aspects.
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
For More Medicine Free PPT - http://playnever.blogspot.com/
For Health benefits and medicine videos Subscribe youtube channel - https://www.youtube.com/playlist?list=PLKg-H-sMh9G01zEg4YpndngXODW2bq92w
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
IN-VITRO-IN VIVO CORRELATION (IVIVC).pptxRAHUL PAL
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
Modeling and comparison of dissolution profiles - Review by Paulo Costa*, Jos...MAHENDRA PRATAP SWAIN
Over recent years, drug release / dissolution from solid pharmaceutical dosage forms has been the subject of intense and profitable scientific developments. Whenever a new solid dosage form is developed or produced, it is necessary to ensure that drug dissolution occurs in an appropriate manner. The pharmaceutical industry and the registration authorities do focus, nowadays, on drug dissolution studies. The quantitative analysis of the values obtained in dissolution / release tests is easier when mathematical formulas that express the dissolution results as a function of some of the dosage forms characteristics are used. In some cases, these mathematics models are derived from the theoretical analysis of the occurring process. In most of the cases the theoretical concept does not exist and some empirical equations have proved to be more appropriate. Drug dissolution from solid dosage forms has been described by kinetic models in which the dissolved amount of drug is a function of the test time. Some analytical definitions of function are commonly used, such as zero order, first order, Hixson–Crowell,Weibull, Higuchi, Baker–Lonsdale, Korsmeyer–Peppas and Hopfenberg models. Other release parameters, such as dissolution time, assay time, dissolution efficacy, difference factor (f1), similarity factor (f2) and Rescigno index can be used to characterize drug dissolution / release profiles.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
1. COMPARISON OF DISSOLUTION PROFILE BY
DIFFERENT METHODS
&
IVIVC
Presented By
Mr.Akash Gujarathi
M.Pharm 1st sem
Dept. of Pharmaceutics
1
Poona College Of Pharmacy,
Centre of Advanced Research In Pharmaceutical
Sciences
Guided By
Dr. Mrs. V.B. Pokharkar,
Vice Principal and
Head Of Department of
Pharmaceutics
2. CONTENTS….
Definition
Objectives
Importance
Different methods used for dissolution comparison
Comparison of different methods
IVIVC
References
2
3. DEFINITION:
It is graphical representation [in terms of
concentration vs. time] of complete release of A.P.I. from a
dosage form in an appropriate selected dissolution medium.
i.e. in short it is the measure of the release of A.P.I from a
dosage form with respect to time.
3
4. OBJECTIVE:
To Develop invitro-invivo correlation which can help to
reduced costs, speed-up product development and
reduced the need of perform costly bioavailability human
volunteer studies.
Demonstrating equivalence after change in formulation of
drug product
Establish the similarity of pharmaceutical dosage forms,
for which composition, manufacture site, scale of
manufacture, manufacture process and/or equipment
may have changed within defined limits.
4
5. IMPORTANCE OF DISSOLUTION
PROFILE
Dissolution profile of an A.P.I. reflects its release pattern
under the selected condition sets. i.e. either sustained
release or immediate release of the formulated formulas.
For optimizing the dosage formula by comparing the
dissolution profiles of various formulas of the same A.P.I
The most important application of the dissolution profile is
that by knowing the dissolution profile of particular product
of the BRAND LEADER, we can make appropriate necessary
change in our formulation to achieve the same profile of the
BRAND LEADER.
5
6. METHODS TO COMPARE DISSOLUTION PROFILE
6
Grafical
Method
Statistical
Analysis
Model
Dependent
Method
Model
Independent
Method
Zero
order
First
order
Hixson-
crowell
Higuchi
model
Korsemeyar
and peppas
model
Baker-
Lonsdale
model
Ratio Test
Procedure
Pair Wise
Procedure-
(f1andf2)
Multivariate
Confidence
regionProcedure
t Test ANOVA
7. GRAPHICAL METHOD
In this method we plot graph of Time V/S concentration of
solute (drug) in the dissolution medium or biological fluid.
The shape of two curves is compared for comparison of
dissolution pattern and the concentration of drug at each
point is compared for extent of dissolution.
If two or more curves are overlapping then the dissolution
profile is comparable.
If difference is small then it is acceptable but higher
differences indicate that the dissolution profile is not
comparable.
7
9. MODEL DEPENDENT METHODS
1) Zero order kinetics (osmotic system
,transdermal system)
Zero order A.P.I.release contributes drug release from
dosage form that is independent of amount of drug in
delivery system. ( i.e., constant drug release)i.e.,
A0-At = kt
Where ,A0 = initial amount of drug in the dosage form;
At = amount of drug in the dosage form at time‘t’
k = proportionality constant
Application: Transdermal systems as well as matrix
tablets with low solubility drugs in coated forms,
osmotic systems.etc 9
10. 2) FIRST ORDER KINETICS (WATER SOLUBLE DRUGS IN
POROUS MATRIX)
Using Noyes Whitney’s equation, the rate of loss of drug
from dosage form (dA/dt) is expressed as;
-dA/dt = k (Xs – X)
Assuming that,
sink conditions = dissolution rate limiting step for in-vitro
study
absorption = dissolution rate limiting step for in-vivo study.
Then (1) turns to be:
-dA/dt = k (Xs ) = constant
So it becomes,
A = Ao × e-k
Applications: This relationship can be used to described the
drug dissolution in phaarmaceutical dossage forms
containing water soluble drugs in porous matrices
10
11. 3)HIGUCHI MODEL (DIFFUSION MATRIX
FORMULATION)
Higuchi in 1961 developed models to study the release of water
soluble and low soluble drugs incorporated in semisolid and solid
matrices.
To study the dissolution from a planer system having a
homogeneous matrix the relation obtained was;
A = [D (2C – Cs)Cs × t]1/2
Where A is the amount of drug released in time‘t’ per unit
area,
C is the initial drug concentration,
Cs is the drug solubility in the matrix media
D is the diffusivity of drug molecules in the matrix
substance.
Applications: Modified release dossage forms, transdermal systems
and matrix tablets with water soluble drugs
11
12. 4) BAKER-LONSDALE MODEL(MICROSPHERES ,
MICROCAPSULES)
In 1974 Baker-Lonsdale (Baker and Lonsdale, 1974)
developed the model from the Higuchi model and
describes the controlled release of drug from a spherical
matrix that can be represented as:
3/2 [1-(1-At/A∞)2/3]-At/A∞ = (3DmCms) / (r02C0) X t
Where At is the amount of drug released at time’t’
A∞ is the amount of drug released at an infinite time,
Dm is the diffusion coefficient,
Cms is the drug solubility in the matrix,
ro is the radius of the spherical matrix
Co is the initial concentration of the drug in the matrix. 12
13. 5) HIXON – CROWELL MODEL (ERODIBLE MATRIX
FORMULATION)
To evaluate the drug release with changes in the surface
area and the diameter of the particles /tablets
The rate of dissolution depends on the surface of
solvent - the larger is area the faster is dissolution.
Hixon-Crowell in 1931 ( Hixon and Crowell, 1931)
recognized that the particle regular area is proportional
to the cubic root of its volume, desired an equation as
Wo
1/3-W1/3 = K × t
where, Wo= original mass of A.P.I.particles
K = cube-root dissolution rate constant
W = mass of the A.P.I at the time ‘t’
This model is called as “Root law”. 13
14. GUIDANCE FOR INDUSTRY
To allow application of these models to comparison of
dissolution profiles, the following procedures are suggested:
1. Select the most appropriate model for the dissolution profiles from the standard,
prechange, approved batches. A model with no more than three parameters
(such as linear, quadratic, logistic, probit, and Weibull models) is recommended.
2. Using data for the profile generated for each unit, fit the data to the most
appropriate model.
3. A similarity region is set based on variation of parameters of the fitted model for
test units (e.g., capsules or tablets) from the standard approved batches.
4. Calculate the MSD (Multivariate Statistical Distance) in model parameters
between test and reference batches.
5. Estimate the 90% confidence region of the true difference between the two
batches.
6. Compare the limits of the confidence region with the similarity region. If the
confidence region is within the limits of the similarity region, the test batch is
considered to have a similar dissolution profile to the reference batch. 14
15. MODEL INDEPENDENT METHODS
PAIRED WISE PROCEDURE
DIFFERENCE FACTOR (f1) & SIMILARITY FACTOR (f2)
The difference factor (f1) as defined by FDA calculates the %
difference between 2 curves at each time point and is a
measurement of the relative error between 2 curves.
f1 = × 100
where, n = number of time points
Rt = % dissolved at time t of reference product (pre change)
Tt = % dissolved at time t of test product (post change) 15
n
t
n
t
Rt
TtRt
1
1
16. The similarity factor (f2) as defined by FDA is logarithmic
reciprocal square root transformation of sum of squared error
and is a measurement of the similarity in the percentage (%)
dissolution between the two curves
f2 = 50 ×
Limits for similarity and Difference factors
16
100
1
log )(
1
1
5.0
n
r
TtRtwt
n
Difference
Factor
Similarity Factor Inference
0 100 Dissolutions
profile are similar
≤15 ≥50 Similarity or
equivalence of
two profiles
17. Advantages:
1. They are easy to produce
They provide single number to describe the comparison of
dissolution profile data
Disadvantages:
1. The values of f1 and f2 are sensitive to the number of
dissolution time point used
2. If the test and reference formulation are interchanged, f2
is unchanged but f1 is not, yet difference between two
mean profiles remains same
3. The basis of criteria for deciding the difference or
similarity between dissolution profile is unclear
17
18. The evaluation of similarity between dissolution profile is based
on following conditions
Minimum of three dissolution time points are measured
Number of drug products tested for dissolution is 12 for both
test and reference
Not more than one mean value of >85% dissolved for each
product
Standard deviation of mean of any product should not be
more than 10% from 2nd to last dissolution time point
18
19. RESEARCH ARTICLE:
A Comparative Study for Evaluation of
Different Brands of Metformin
Hydrochloride 500 Mg Tablets
Marketed in Saudi Arabia
Corresponding author
Samar A. Afifi1&2
1 Department of Pharmaceutics, College of Pharmacy,
King Saud University, Riyadh, Saudi Arabia
Life Science Journal 2012;9(4)
http://www.lifesciencesite.com 19
20. Abstract:
The physicochemical equivalence of six brands of
Metformin hydrochloride tablets were determined through the
evaluation of both official and non-official standards according to
the USP pharmacopoeia including uniformity of weight, friability,
hardness,disintegration, dissolution rate and drug content.
All the six brands evaluated in this study could be
considered biopharmaceutically and chemically equivalent and
therefore they can be substituted with the innovator product in
clinical practice except Glucare®. Therefore, patients can safely
switch from one brand to another.
20
21. MATERIALS
Metformin hydrochloride brands having label
strength of 500 mg (Table 1) were purchased from a retail
pharmacy in Riyadh city, Saudi Arabia. All tests were
performed within product expiration dates.
The reagents used were potassium dihydrogen
orthophosphate (WINLAB chemicals, UK) and sodium
hydroxide pellets (Poole BH15, UK).
All reagents used were of analytical grade. Distilled
water was used throughout the work.
21
23. EXPERIMENTAL CONDITUIONS:
stimulated intestinal fluid pH 6.8
Apparatus-ERWEKA DT600 dissolution apparatus
(Heusenstamm,Germany)
Volume-1000ml
Temperature-37 ± 0.5 °C
Speed-100 rpm
Sample Withdrawing Intervals-10 min
Each of the withdrawn sample was filtered with syringe filter
0.45μm, the filtrate diluted.
The absorbance was measured at λ max 233nm using Uv-
visible spectrophotometer.
The concentration was determined against standard solution
having a known concentration of Metformin hydrochloride RS
in the same medium.
23
24. The difference factor (f1) and similarity
factor (f2) was calculated for each local brand
respect to the reference brand (Glucophage®)
equation (1) and (2), respectively.
The percentage of drug released from
Glucophage® as an innovative was compared
with the percentage of drug released from each
brand individually using the f1 and f2 formula
24
25. Five generic brands of Metformin hydrochloride tablets,
namely Formit® , Glucare®, Dialon®,Metaphage® and Metfor®
together with the innovative (Glucophage®) have been
subjected to analysis according to the monograph of USP 32
Pharmacopoeia.
The results have shown that all the tested brands satisfied the
USP requirements in terms of identification, assay and
dissolution.
Dissolution profiles revealed differences between the different
generics. Four generic products could be said to be equivalent
to the originator (Glucophage®) while the Glucare® was
nonequivalent.
According to the present study patients can safely switch from
one brand to another but with consulting them of the
possibility of some minor GIT complications that may occur
after the treatment with new alternative brand.
25
Conclusion
26. IN VITRO IN VIVO CORRELATION (IVIVC)
In IVIVC, "C" denotes "Correlation", which means
"the degree of relationship between two variables".
IVIVC is defined as the predictive mathematical
model that describes the relationship between an
in-vitro property(such as rate and extent of
dissolution) of dossage form and an in-vivo
response (such as plasma drug concentration)
26
27. DEFINATION
The Food and Drug Administration (FDA) defines
“A predictive mathematical model describing the
relationship between an in-vitro property of a dosage
form and an in-vivo response”.
The United States Pharmacopoeia (USP) also defines
“The establishment of a relationship between a
biological property, or a parameter derived from a
biological property produced from a dosage form,
and a physicochemical property of the same dosage
form”.
27
28. IMPORTANCE OF IVIVC
To serve as a surrogate(alternate) for in vivo bioavailability.
To support biowaivers for bioequivalence testing.
To validate the use of dissolution methods and set the
dissolution specifications.
IVIVC proves an important research tool in the development
of drug delivery systems.
The IVIVC model facilitates the rational development &
evaluation of immediate or extended release dosage forms.
Hence it acts as a tool for formulation screening.
To assist quality control for certain scale-up and post-
approval changes (SUPAC).
28
29. 1. CORRELATIONS BASED ON THE PLASMA LEVEL
DATA:
Parameters used for correlating In Vitro Dissolution
with Plasma Data
29
In vitro dissolution parameters In vivo plasma data parameters
Time for specific amount of drug to dissolve
(e.g. 50% of the dose)
Amount dissolved at a specific time point
Mean dissolution time
Parameter estimated after modeling the
dissolution process
AUC, Cmax
Fraction absorbed, absorption rate constant Ka
Mean residence time, mean dissolution time,
mean absorption time
Concentration at time t, amount absorbed at time
t
30. 2. CORRELATION BASED ON THE
URINARY EXCRETION DATA
Dissolution parameters are correlated to the amount of
drug excreted unchanged in the urine, cumulative
amount of drug excreted as a function of time, etc.
30
An acute pharmacological effect such as LD50 in
animals is related to any of the dissolution parameters.
3. CORRELATION BASED ON THE
PHARMACOLOGICAL ACTION
31. FACTORS AFFECTING IVIVC
Complexity of the
delivery system.
Composition of
formulation.
Physicochemical
properties of
drug.
Dissolution
method
Method of
manufacture 31
32. BASIC DEFINATIONS ABOUT IVIVC
•The mean time for which the drug resides in the body. Also known as mean transit time.
•MRT = AUMC / AUC
•where, AUMC = Area under first moment Curve (Concentration*time Vs time)
•AUC = Area under curve (Concentration Vs time)
•Both AUMC & AUC can be obtained by using Trapezoidal rule.
Mean Residence Time:
•The mean time required for drug to reach systemic circulation from the time of drug
administration.
•MAT = MRT oral – MRT i.v.
Mean Absorption Time:
•It reflects the mean time for drug to dissolve in-vivo. For solid dosage form:
•MDT solid = MRT solid – MRT solution
Mean In-vivo Dissolution Time:
•% PE = [(Observed value – Predicted value) / Observed value] x 100
Percent Prediction Error: 32
33. LEVELS OF IVIVC
Level A
• Most
informative &
recommended
Level B
• Least useful in
regulatory
purpose
Level C
• Useful for
early stages
of formulation
development
Multiple
Level C
• Useful as
Level A
33
34. 34
It is defined as a hypothetical model describing the
relationship between a fraction of drug absorbed and
fraction of drug dissolved.
In order to develop a correlation between two parameters
one variable should be common between them.
The data available is in vitro dissolution profile and in vivo
plasma drug concentration profile whose direct comparison is
not possible.
To have a comparison between these two data, data
transformation is required.
It is considered as a predictive model for relationship
between the entire in vitro release time courses.
Level A Level B Level C Multiple C
35. 35
Advantages:
1. A point to point correlation is developed. The in vitro dissolution curve serves as
a surrogate for in vivo performance. Any change in manufacturing procedure or
modification in formula can be justified without the need for additional human
studies.
2. The in vivo dissolution serves an in vivo indicating quality control procedure for
predicting dosage form’s performance.
Level A Level B Level C Multiple C
36. 36
Level B IVIVC uses the principles of
statistical moment analysis. The mean in
vitro dissolution time(MDTvitro) is compared
either to the mean residence time (MRT) or
to the mean in vivo dissolution time
(MDTvivo).
Level B correlation, like a Level A, uses all of
the in vitro and in vivo data, but is not
considered to be a point-to-point
correlation.
Level B correlation does not uniquely
reflect the actual in vivo plasma level curve,
because a number of different in vivo curves
will produce similar mean residence time
values.
MATHS TOOL : MDTvitro VS MDTvivo or
MRTvivo
Level A Level B Level C Multiple C
37. 37
In this level of correlation, one dissolution
time point (t50%, t90%, etc.) is compared to
on mean pharmacokinetic parameter such
as AUC, t max or C max.
It represents a single point correlation and
doses not reflect the entire shape of the
plasma drug concentration curve.
Level C correlations can be useful in the early
stages of formulation development when
pilot formulations are being selected.
While the information may be useful in
formulation development, biowaiver is
generally not possible.
Level A Level B Level C Multiple C
38. A multiple level C correlation relates one or several
pharmacokinetic parameters of interest (Cmax, AUC,
or any other suitable parameters) to the amount of
drug dissolved at several time points of the dissolution
profile.
A multiple point level C correlation may be used to
justify a bio waiver, provided that the correlation has
been established over the entire dissolution profile with
one or more pharmacokinetic parameters of interest.
38
Level A Level B Level C Multiple C
39. VARIOUS PARAMETERS USED IN IVIVC
DEPENDING ON THE LEVEL
Level In vitro In vivo
A Dissolution curve
Input (absorption)
curves
B
Statistical Moments:
MDT
Statistical Moments:
MRT, MAT
C
Disintegration time,
Time to have 10, 50,
90% Dissolved,
Dissolution rate,
Dissolution efficiency
Cmax,
Tmax,
Ka,
Time to have 10, 50,
90% absorbed,
AUC (total or
cumulative)
39
40. APPLICATIONS OF IVIVC IN DRUG
DELIVERY
1. Early Stages of Drug Delivery & Development:
• Proof of Concept
2. Formulation Assessment:
• In Vitro Dissolution
3. Dissolution Specifications
4. Future Biowaivers
5 . IVIVC – Parenteral Drug Delivery
• Potent Drugs & Chronic Therapy
• Limited volume of tissue fluids and Area of absorption
40
41. SOFTWARES USED IN IVIVC
41
IVIVC
Software
WinNonlin-
IVIVC
Toolkit
GastroPlus
v. 6.1
IVIVCPlus
PDx-
IVIVC
DDDPlu
s v. 3.0
IVIVC
for R
Kinetica
42. REFERENCES
Biopharmaceutics and Pharmacokinetics by D. M.
Brahmankar, 2nd edition 2009, page no. 432 to 434
By Madhusmruti Khandai Research article of
International Journal of Pharmaceutical Sciences
Review and Research Volume 1, Issue 2, March – April
2010; Article 001
Guidance for Industry Dissolution Testing of Immediate
Release Solid Oral Dosage Forms U.S. Department of
Health and Human Services Food and Drug
Administration Center for Drug Evaluation and Research
(CDER), August-2011
International Journal of Pharmaceutical Science Vol-1,
Issue-1, page no.57-64, 2010 42
43. Research Article on:A Comparative Study for Evaluation of
Different Brands of Metformin Hydrochloride 500 Mg Tablets
Marketed in Saudi Arabia;by-Samar A. Afifi1&2
Life Science Journal 2012;9(4) http://www.lifesciencesite.com
Guidance for Industry; Extended Release Oral Dosage Forms:
Development, Evaluation, and Application of In Vitro/In Vivo
Correlations. www.fda.gov/cder/guidance/index.htm
Dissolution, Bioavailability and Bioequivalence by Hamed M.
Abdou, Mack Publishing House.
IVIVC: Methods and Applications in Modified-Release Product
Development; Harald Rettig and Jana Mysicka. Dissolution
Technologies | FEBRUARY 2008
IVIVC: An Important Tool in the Development of Drug Delivery
Systems; Gangadhar Sunkara, PhD, and Dakshina M. Chilukuri,
PhD. http://www.drugdeliverytech.com/cgi-
bin/articles.cgi?idArticle=144 43