This document discusses biopharmaceutical factors that can affect the bioavailability of drugs. It focuses on pharmaceutical factors including physicochemical properties of drug molecules and dosage form characteristics. Physicochemical properties like solubility, dissolution rate, particle size, polymorphism, salt form, and ionization state can impact drug absorption. The pH-partition hypothesis explains how a drug's pKa and lipid solubility relate to absorption based on gastrointestinal pH. Dosage form properties such as disintegration time, manufacturing methods, and ingredients are also discussed as formulation factors influencing bioavailability.
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
drug execipent compatibilty studies is of prime importance for the better formulation of the new drug and also for reducing cost by verfication of the data at the earlier atage.
this presentation will give the brief explanation of the goal, importance, dteps involve to studi the drug execient compatibility studies with different examples suitable accordiingly.
Dissolution : Official and Non official methods, Alternative methods of dissolution testing and transport models, Drug release testing, Invitro drug release testing
drug execipent compatibilty studies is of prime importance for the better formulation of the new drug and also for reducing cost by verfication of the data at the earlier atage.
this presentation will give the brief explanation of the goal, importance, dteps involve to studi the drug execient compatibility studies with different examples suitable accordiingly.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
introduction
mechanisms of protein drug binding
binding of drugs
binding of drugs to blood components
determination of protein drug binding
factors affecting
significance
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
Pilot plant Techniques and Product consideration for liquid dosage forms.D.R. Chandravanshi
CONTENTS:-
DEFINITION
INTRODUCTION
OBJECTIVES
LIQUID DOSAGE FORM
STEPS INVOLVED IN PILOT PLANT FOR ORAL LIQUID
GENERAL CONSIDERATION
Reporting responsibility
Personal requirements
Space requirements
Review of formula
Raw materials
Relevant processing equipments
Process evaluation
GMP consideration
Assurance
PILOT PLANT SCALE UP FOR SUSPENSION
PILOT PLANT SCALE UP FOR EMULSION
REFERENCES
The release of the drug substance from the drug product leading to the bioavailability of the drug substance. The assessment of drug product performance is imp. Since bioavailability is related both to the pharmacodynamic responses and the adverse events. The performance tests relate the quality of a drug product to clinical safety and efficacy.
Bioavailability studies are drug product performance studies used to define
the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug, and the manufacturing process of the drug product.
CLINICAL SIGNIFICANCE OF BIOEQUIVALENCE STUDIES, BIOEQUIVALENCE, REASONS TO PERFORM BIOEQUIVALENCE STUDIES , NEED FOR BIOEQUIVALENCE STUDIES, IMPORTANCE OF BIOEQUIVALANCE STUDIES, DETERMINATION OF BIOEQUIVALENCE OF A DRUG PRODUCT, CLINICAL SIGNIFICANCE.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
introduction
mechanisms of protein drug binding
binding of drugs
binding of drugs to blood components
determination of protein drug binding
factors affecting
significance
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
Pilot plant Techniques and Product consideration for liquid dosage forms.D.R. Chandravanshi
CONTENTS:-
DEFINITION
INTRODUCTION
OBJECTIVES
LIQUID DOSAGE FORM
STEPS INVOLVED IN PILOT PLANT FOR ORAL LIQUID
GENERAL CONSIDERATION
Reporting responsibility
Personal requirements
Space requirements
Review of formula
Raw materials
Relevant processing equipments
Process evaluation
GMP consideration
Assurance
PILOT PLANT SCALE UP FOR SUSPENSION
PILOT PLANT SCALE UP FOR EMULSION
REFERENCES
The release of the drug substance from the drug product leading to the bioavailability of the drug substance. The assessment of drug product performance is imp. Since bioavailability is related both to the pharmacodynamic responses and the adverse events. The performance tests relate the quality of a drug product to clinical safety and efficacy.
Bioavailability studies are drug product performance studies used to define
the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug, and the manufacturing process of the drug product.
CLINICAL SIGNIFICANCE OF BIOEQUIVALENCE STUDIES, BIOEQUIVALENCE, REASONS TO PERFORM BIOEQUIVALENCE STUDIES , NEED FOR BIOEQUIVALENCE STUDIES, IMPORTANCE OF BIOEQUIVALANCE STUDIES, DETERMINATION OF BIOEQUIVALENCE OF A DRUG PRODUCT, CLINICAL SIGNIFICANCE.
By Monika (LECTURER) physicochem. prop. of drugMonika Dahiya
Physico-chemical properties of drug (like dissolution, salt form, particles size, polymorphism, etc.) which affect the absorption and therapeutic efficacy of drug are described in very easy and short way.
Biopharmaceutic considerations in Drug Product DesignRiaz Islam
Drug product Design remain one of the most challenging aspects in formulation development. But nowadays formulation strategies have been far more successful in improving the bioavailability of the compounds with poor solubility, poor dissolution rate, and poor chemical stability in acidic environment. This article begins with a brief discussion on Physical and Chemical Properties of the Drug Impacting Oral Absorption. This article also reviews the Factors Contributing to Poor Aqueous Solubility. and a brief relationship between Physicochemical Properties and Drug Delivery System.
A drug injected intravascularly directly enters the systemic circulation and exerts its pharmacological effects.
Majority of drugs administered extravascularly, generally orally.
If intended to act systemically, such drugs can exert their pharmacological actions only when they come into blood circulation from their site of application. So, absorption is an important step.
Nutraceutical market, scope and growth: Herbal drug technologyLokesh Patil
As consumer awareness of health and wellness rises, the nutraceutical market—which includes goods like functional meals, drinks, and dietary supplements that provide health advantages beyond basic nutrition—is growing significantly. As healthcare expenses rise, the population ages, and people want natural and preventative health solutions more and more, this industry is increasing quickly. Further driving market expansion are product formulation innovations and the use of cutting-edge technology for customized nutrition. With its worldwide reach, the nutraceutical industry is expected to keep growing and provide significant chances for research and investment in a number of categories, including vitamins, minerals, probiotics, and herbal supplements.
The increased availability of biomedical data, particularly in the public domain, offers the opportunity to better understand human health and to develop effective therapeutics for a wide range of unmet medical needs. However, data scientists remain stymied by the fact that data remain hard to find and to productively reuse because data and their metadata i) are wholly inaccessible, ii) are in non-standard or incompatible representations, iii) do not conform to community standards, and iv) have unclear or highly restricted terms and conditions that preclude legitimate reuse. These limitations require a rethink on data can be made machine and AI-ready - the key motivation behind the FAIR Guiding Principles. Concurrently, while recent efforts have explored the use of deep learning to fuse disparate data into predictive models for a wide range of biomedical applications, these models often fail even when the correct answer is already known, and fail to explain individual predictions in terms that data scientists can appreciate. These limitations suggest that new methods to produce practical artificial intelligence are still needed.
In this talk, I will discuss our work in (1) building an integrative knowledge infrastructure to prepare FAIR and "AI-ready" data and services along with (2) neurosymbolic AI methods to improve the quality of predictions and to generate plausible explanations. Attention is given to standards, platforms, and methods to wrangle knowledge into simple, but effective semantic and latent representations, and to make these available into standards-compliant and discoverable interfaces that can be used in model building, validation, and explanation. Our work, and those of others in the field, creates a baseline for building trustworthy and easy to deploy AI models in biomedicine.
Bio
Dr. Michel Dumontier is the Distinguished Professor of Data Science at Maastricht University, founder and executive director of the Institute of Data Science, and co-founder of the FAIR (Findable, Accessible, Interoperable and Reusable) data principles. His research explores socio-technological approaches for responsible discovery science, which includes collaborative multi-modal knowledge graphs, privacy-preserving distributed data mining, and AI methods for drug discovery and personalized medicine. His work is supported through the Dutch National Research Agenda, the Netherlands Organisation for Scientific Research, Horizon Europe, the European Open Science Cloud, the US National Institutes of Health, and a Marie-Curie Innovative Training Network. He is the editor-in-chief for the journal Data Science and is internationally recognized for his contributions in bioinformatics, biomedical informatics, and semantic technologies including ontologies and linked data.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
Introduction:
RNA interference (RNAi) or Post-Transcriptional Gene Silencing (PTGS) is an important biological process for modulating eukaryotic gene expression.
It is highly conserved process of posttranscriptional gene silencing by which double stranded RNA (dsRNA) causes sequence-specific degradation of mRNA sequences.
dsRNA-induced gene silencing (RNAi) is reported in a wide range of eukaryotes ranging from worms, insects, mammals and plants.
This process mediates resistance to both endogenous parasitic and exogenous pathogenic nucleic acids, and regulates the expression of protein-coding genes.
What are small ncRNAs?
micro RNA (miRNA)
short interfering RNA (siRNA)
Properties of small non-coding RNA:
Involved in silencing mRNA transcripts.
Called “small” because they are usually only about 21-24 nucleotides long.
Synthesized by first cutting up longer precursor sequences (like the 61nt one that Lee discovered).
Silence an mRNA by base pairing with some sequence on the mRNA.
Discovery of siRNA?
The first small RNA:
In 1993 Rosalind Lee (Victor Ambros lab) was studying a non- coding gene in C. elegans, lin-4, that was involved in silencing of another gene, lin-14, at the appropriate time in the
development of the worm C. elegans.
Two small transcripts of lin-4 (22nt and 61nt) were found to be complementary to a sequence in the 3' UTR of lin-14.
Because lin-4 encoded no protein, she deduced that it must be these transcripts that are causing the silencing by RNA-RNA interactions.
Types of RNAi ( non coding RNA)
MiRNA
Length (23-25 nt)
Trans acting
Binds with target MRNA in mismatch
Translation inhibition
Si RNA
Length 21 nt.
Cis acting
Bind with target Mrna in perfect complementary sequence
Piwi-RNA
Length ; 25 to 36 nt.
Expressed in Germ Cells
Regulates trnasposomes activity
MECHANISM OF RNAI:
First the double-stranded RNA teams up with a protein complex named Dicer, which cuts the long RNA into short pieces.
Then another protein complex called RISC (RNA-induced silencing complex) discards one of the two RNA strands.
The RISC-docked, single-stranded RNA then pairs with the homologous mRNA and destroys it.
THE RISC COMPLEX:
RISC is large(>500kD) RNA multi- protein Binding complex which triggers MRNA degradation in response to MRNA
Unwinding of double stranded Si RNA by ATP independent Helicase
Active component of RISC is Ago proteins( ENDONUCLEASE) which cleave target MRNA.
DICER: endonuclease (RNase Family III)
Argonaute: Central Component of the RNA-Induced Silencing Complex (RISC)
One strand of the dsRNA produced by Dicer is retained in the RISC complex in association with Argonaute
ARGONAUTE PROTEIN :
1.PAZ(PIWI/Argonaute/ Zwille)- Recognition of target MRNA
2.PIWI (p-element induced wimpy Testis)- breaks Phosphodiester bond of mRNA.)RNAse H activity.
MiRNA:
The Double-stranded RNAs are naturally produced in eukaryotic cells during development, and they have a key role in regulating gene expression .
Seminar of U.V. Spectroscopy by SAMIR PANDASAMIR PANDA
Spectroscopy is a branch of science dealing the study of interaction of electromagnetic radiation with matter.
Ultraviolet-visible spectroscopy refers to absorption spectroscopy or reflect spectroscopy in the UV-VIS spectral region.
Ultraviolet-visible spectroscopy is an analytical method that can measure the amount of light received by the analyte.
This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
Thanks...!
Observation of Io’s Resurfacing via Plume Deposition Using Ground-based Adapt...Sérgio Sacani
Since volcanic activity was first discovered on Io from Voyager images in 1979, changes
on Io’s surface have been monitored from both spacecraft and ground-based telescopes.
Here, we present the highest spatial resolution images of Io ever obtained from a groundbased telescope. These images, acquired by the SHARK-VIS instrument on the Large
Binocular Telescope, show evidence of a major resurfacing event on Io’s trailing hemisphere. When compared to the most recent spacecraft images, the SHARK-VIS images
show that a plume deposit from a powerful eruption at Pillan Patera has covered part
of the long-lived Pele plume deposit. Although this type of resurfacing event may be common on Io, few have been detected due to the rarity of spacecraft visits and the previously low spatial resolution available from Earth-based telescopes. The SHARK-VIS instrument ushers in a new era of high resolution imaging of Io’s surface using adaptive
optics at visible wavelengths.
1. 1
Biopharmaceutical Factors Effecting Bioavailability
Prepared By:
Syed Rashed Faizan Mehdi
170717885012
M. Pharm, Pharmaceutical Analysis
Dept. of Pharmaceutical Analysis
DECCAN SCHOOL OF PHARMACY
Guided by :
DR. Mohammed Younus
M. Pharm, Pharmaceutical Analysis.
Ph D
Dept. of Pharmaceutical Analysis
DECCAN SCHOOL OF
PHARMACY
2. 2
TABLE OF CONTENTS
CONTENTS
• Introduction
• Bioavailability
• Factors Influencing Absorption
a) Pharmaceutical Factors.
1. Physicochemical properties of drug molecules
2. Dosage Form Characteristics And Pharmaceutical ingredients
b) Patient related factors.
3. 3
Bioavailability can be defined as the fraction of administered drug that
reaches the systemic circulation
Pharmacokinetics
• Evaluate the way in which a drug interacts with various barriers
within a biological system
Pharmacodynamics
• Study of the relationship between systemic exposure of a drug and it’s
biological effects on tissue
Absorption can be defined as the movement of active drug (or prodrug)
from the site of administration across biologic barriers into a site where
it is measured in the blood. This site of measurement is not specified.
Note the difference in endpoint measurement sites
Introduction
5. 5
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
1.Drug dissolution & solubility rate.
2. Particles size & effective surface area.
3. Polymorphism & amorphism.
4. Solvates & hydrates.
5.salt form of drug.
6. Ionization state.
7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis.
Physicochemical properties of drug substances:
A detailed study of physicochemical properties of drug molecules may help to
enhance the rate as well as the extent of drug absorption.
It also serve to formulate the drug in most suitable dosage form.
Biopharmaceutical factors effecting drug absorption:
6. 6
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
1.Drug dissolution & solubility rate:
• Dissolution is the process of solubilization of a substance in a
given solvent.
• Drug dissolution rate is the amount of drug that goes into solution
per unit time under the standard conditions of temperature, pH,
solvent composition and constant solid surface area.
• Dissolution plays a significant role as it is regarded as the rate
determining step in the process of absorption.
• Solutions > Suspensions > Capsules > Tablets > Coated tablets.
Drug in particle
form
Drug in solution
form
Drug in blood
stream
Dissolution is rate limiting
step for lipophilic drugs
e.g. Griseofulvin
Permeation is rate limiting
step for hydrophilic drugs.
e.g., Neomycin
7. 7
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
1.Drug dissolution & solubility rate:
• Solubility: The quantity of drug that dissolves in the gastrointestinal
fluid is indicative of vivo drug absorption.
• A drug is said to be undergo appreciable bioabsorption if it exhibits
aqueous solubility greater than 10mg/ml at 37℃ and pH ranging
between 1-7.
• When the solubility is less than 1mg/ml, it undergoes undesirable GI
absorption.
• Thus with the aid of solubility and dissolution data, potential
problems related to bioavailability and therapeutic activity of the
drug can be recognized.
• Both solubilty and absorption can be correlated by the concept of
maximum absorbable dose (MAD).
8. 8
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
1.Drug dissolution & solubility rate:
• maximum absorbable dose
(MAD).
• Biopharmaceutics Classification
Systems (BCS).
9. 9
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
2. Particles size & effective surface area:
Smaller the particle size (by micronization i.e reduction in particle size)
Greater is the effective surface area
More intimate contact b/w solid surface and aqueous solvent
Higher is the dissolution
Rate increase in absorption efficiency
Types of surface area:
1) Absolute surface area: it is
the total solid surface area
2) Effective surface area: it is the
solid surface area of particle exposed
to the dissolution medium.
• In order to convert the absolute surface area to effective surface area,
surfactants like polysorbate 80 or diluents like PEG, dextrose.
• Griseofulvin, chloramphenicol on micronization show increased
absorption and decrease in therapeutic dose.
10. 10
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
3. Amorphism and Polymorphism :
Amorphous forms generally dissolve faster than crystalline forms
because no energy is needed to break up the crystal lattice.
For this reason, the amorphous form is often preferred over the
crystalline form and several drugs, including hydrocortisone and
prednisolone, are marketed in the amorphic form.
Amorphous form
More soluble
Rapidly dissolving
Readily absorbed
Crystalline form
Less soluble
Slower dissolving
Not absorbed to significant extent
The crystalline form of drugs may exist as polymorphs or molecular
adducts or both.
11. 11
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
3. Amorphism and Polymorphism :
Polymorphism is the ability of compound to exist in more than one
crystalline form. These polymorphs may have different physical
properties, such as dissolution rate and solubility.
Ex:
Chloramphenicol palmitate exists in three crystalline forms, form A, B,
C. form B is the most soluble and therefore exhibits more bioavailability
than the other forms
Stable form
- Lowest energy state
- Highest m.pt.
- Least aq solubility
- Dissolution rate limited
Metastable form
- Less stable form
- Highest energy state
- Lowest m.pt.
- Higher aq solubility
- Better absorption and Bioavailability
12. 12
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
4. Solvates & hydrates:
During their preparation, drug crystals may incorporate one or more
solvent molecules to form solvates.
The solvent trapped is known as solvent of crystallization.
The solvates may exists in varying crystalline forms known as
pseudopolymorphs and the phenomenon is known as pseudo
polymorphism.
The molecular complex is referred as hydrates if water molecules has been
reported as solvent.
Anhydrous – Drug is not associated with water,
monohydrate and Dihydrated – drug is associated with one and more
water molecules respectively.
The anhydrous form have higher energy states, higher aq solubilities,
dissolves at faster rate and hence exhibit higher bioavailability.
Ex: anhydrous ampicillin more soluble than their hydrous form
13. 13
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
5. Salt form of drug:
At given pH, the solubility of drug, whether acidic/basic or its salt, is a
constant.
While considering the salt form of drug, pH of the diffusion layer is
important not the pH of the bulk of the solution.
E.g. of salt of weak acid. ---Which increases the pH of the diffusion layer,
which promotes the solubility and dissolution of a weak acid and
absorption is bound to be rapid.
14. 14
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
6. Ionization state:
Unionized state is important for passive diffusion through membrane so
important for absorption.
Ionized state is important for solubility.
7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis.
pH – Partition theory states that drug compounds of molecular weight
more than 100 daltons , which are primarily transported across the
biological membrane by passive diffusion, the process of absorption is
governed by
- Pka of drug (Dissociation constant)
- The lipid solubility of unionized drug
- pH at the absorption site.
15. 15
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis.
Pka of drug (Dissociation constant)
Amount of drug that exist in unionized form and in ionized form is a
function of pKa of drug & pH of the fluid at the absorption site and it can
be determined by Henderson- hesselbach equation: -
pH = pKa + log [ionized form] For, Acidic drugs
[Unionized form]
pH = pKa + log [unionized form] For, Basic drugs
[ionized form]
16. 16
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis.
Drugs PKa PH/site of
absorption
Very weak acids e.g.
pentobarbital
Hexobarbital
>8
Unionized at all pH
values; Absorbed along
the entire length of GIT
Moderately weak acids
e.g. aspirin Ibuprofen
2.5 – 7.5
Unionized in gastric pH&
ionized in intestinal pH;
better absorption from
stomach
Stronger acids
E.g. disodium cromogylate < 2.0
Ionized at all pH values;
Poorly absorbed from
GIT
Very weak bases
e.g. theophylline
Caffeine
< 5.0
Unionized at all pH
values; Absorbed along
entire GIT
Moderately weak bases
e.g. codeine 5 – 11
Ionized at gastric pH,
unionized at intestinal pH;
better absorption from
intestine.
Stronger bases e.g.
guanethidine > 11
Ionized at all pH values;
Poorly absorbed from
GIT
17. 17
A. Pharmaceutical Factors
1. Physicochemical properties of drug substances
7.Drug pKa & lipophilicity & GI pH - pH partition hypothesis.
b) Lipophilicity and drug absorption:
Ideally for optimum absorption, a drug should have sufficient aq.
solubility to dissolve in fluids at absorption site and lipid solubility
(Ko/w) high enough to facilitate the partitioning of the drug in the
lipoidal membrane i.e. drug should have perfect HLB for optimum
Bioavailability.
Ko/w = Distribution of drug in organic phase (octanol)
Distribution of drug in aq phase
As Ko/w or lipid solubility i.e. partition coefficient increases percentage
drug absorbed increases.
18. 18
2] Formulation Factors
1. Disintegration time
2. Manufacturing variables
a. Method of granulation
b. Compression force
3. Nature & type of dosage form
4. Pharmaceutical ingredients
5. Product age & storage conditions
1. Disintegration time (DT):
It is defined as the time taken by the solid dosage form to breakdown
into smaller particles in the body after their ingestion.
Order of disintegration of the solid dosage forms:
Capsules > Tablets > Coated tablets > Enteric coated tablets >
sustained release tablets
A. Pharmaceutical Factors
2. Formulation Factors.
19. 19
1. Disintegration time (DT):
a)Method of granulation:
Wet granulation: By selecting a suitable granulating liquid , the
dissolution rate of insoluble drugs can be enhanced.
Direct compression: dissolution rate of tablets prepared by this method
are higher than the wet granulation method.
b) Compression force:
Higher compression force yields a tablet with greater hardness and
reduced wettability & hence have a long D.T. but on other hand higher
compression force cause crushing of drug particles into smaller ones with
higher effective surface area which in decrease in D.T. So effect of
compression force should be thoroughly studied on each formulation.
2. Manufacturing variables:
• It Harder the tablet, greater is its disintegration time.
• Disintegration of solid dosage forms can be enhanced by incorporating
appropriate amounts of disintegrants in the formulation.
A. Pharmaceutical Factors
2. Formulation Factors.
20. 20
3. Nature and type of dosage form
• Depending upon the nature and type of dosage form, the absorption
pattern of a drug decreases in the following order
• Solutions > Emulsions > Suspensions > Capsules > Tablets Coated
tablets > Enteric coated tablets > Sustained release tablets
A. Pharmaceutical Factors
2. Formulation Factors.
21. 21
4. Pharmaceutical ingredients
• More the no. of excepients in dosage form, more complex it is & greater
the potential for absorption and Bioavailability problems.
a) Vehicle:
vehicles are used in parenteral and oral liquids preparations.
Rate of absorption – depends on its miscibility with biological fluid.
Miscible solvents-rapid absorption of drug.
Immiscible solvent-slow absorption of drug.
Non-Aqueous water immiscible
E.g.: Vegetable oil,
Sesame oil,
Peanut oil.
Aqueous
E.g.: Water,
Syrup
Non-Aqueous water miscible
E.g.: Propylene glycol,
Glycerol,
Sorbital.
Vehicles
A. Pharmaceutical Factors
2. Formulation Factors.
22. 22
4. Pharmaceutical ingredients
b) Diluents
Diluents are added to increase the bulk of the dosage form, especially
in tablets and capsules.
Hydrophilic diluents-form the hydrophilic coat around hydrophobic
drug particles –thus promotes dissolution and absorption of poorly
soluble hydrophobic drug.
Inorganic diluents
E.g.: Dibasic calcium phosphate,
Calcium carbonate.
Organic diluents
E.g.: Dextrose,
Sorbitol,
Mannitol.
Diluents
A. Pharmaceutical Factors
2. Formulation Factors.
23. 23
4. Pharmaceutical ingredients
c) Binding Agents
Although binders are incorporated to produce cohesive bonding
between granules during the process of compaction of tablets.
Hydrophilic binders are for enhancing the dissolution rate of poorly
soluble drug. e.g. starch, gelatin, PVP.
More amount of binder increases hardness of tablet and decrease
dissolution & disintegration rate.
d) Disintegrating Agents
They are added to the tablet to disrupts the cohesive forces between
the granules, thereby causing the breakdown of the tablet to attain
faster dissolution.
Mostly hydrophilic in nature, increase in disintegration increase the
bioavailability.
e.g.: Guar gum, Starch, Microcrystalline cellulose
A. Pharmaceutical Factors
2. Formulation Factors.
24. 24
4. Pharmaceutical ingredients
e) Lubricating Agents
These agents when added to a tablet formulation decrease the
friction between the granules and die wall of the tablet press.
Commonly hydrophobic in nature – therefore inhibits penetration of
water into tablet and thus dissolution and disintegration.
Insoluble Lubricants
E.g.: Mineral oil,
Talc
Soluble Lubricants
E.g.: PEG 4000,
PEG 6000.
Lubricant
A. Pharmaceutical Factors
2. Formulation Factors.
25. 25
4. Pharmaceutical ingredients
f) Surfactants
They are commonly used in the formulations as solubilizers, emulsifiers,
wetting agents etc.
At lower concentrations, they increase the rate of absorption of poorly
water soluble drugs.
Physiologic surfactants like bile salts they promotes absorption
e.g.: Griseofulvin, steroids
g) Complexing Agents
They increase the absorption rate of other drugs due to
• Formation of soluble complexes which enhances the dissolution.
• Increased the lipophilicity which enhances membrane permeability.
h) Colorants
Water-soluble dyes even inleast concentrations get adsorbed on the
crystal faces and delay their dissolution rate.
e.g.: Brilliant blue retards dissolution of sulfathiazole.
A. Pharmaceutical Factors
2. Formulation Factors.
26. 26
5. Product age and storage Conditions:
Alterations in storage conditions and prolonged duration of storage of
drug products may modify their physicochemical properties resulting in
altered drug absorption patterns.
B. Patient related factors:
A. Pharmaceutical Factors
2. Formulation Factors.
1) Age
2) Gastric Emptying
3) Intestinal Transit
4) Diseases
5) Effect of Food
6) Blood Flow to GIT
7) First pass metabolism
27. 27
B. Patient related factors:
1) Age:
Absorption pattern of drugs may vary among different age groups.
Infant have less acidic G.I fluids, smaller intestinal surface area and
comparatively less blood flow than adults.
Intestinal surface area and blood flow, bacterial overgrowth in small
intestine, altered gastric emptying, retard the drug absorption
2) Gastric Emptying:
Gastric emptying is the entry of gastric content into the small intestine.
Gastric emptying rate: It is the rate at which gastric contents empty into
the small intestine.
Gastric emptying time: It is the time required for gastric content to empty
into the small intestine.
Rapid Gastric Emptying is required when the consumed drugs
• Are unstable in gastric pH (Penicillin G)
• Are better absorbed from the small intestine (Vit B12)
Delayed Gastric Emptying is required when
• The drug (Griseofulvin) dissolves slowly.
• Food enhances the dissolution and absorption of drugs.
28. 28
B. Patient related factors:
3) Intestinal Transit:
The residence time of foodor drug substance in intestine is known as
intestinal transit time.
As small intestine is major site of absorption longer or delayed transit
time is required for the complete absorption of drugs
Delayed intestinal transit is recommended for those drugs which
• Exhibits sustained release action.(Diclofenac sodium)
• Are enteric coated and hence dissolves only in the intestine.
4) Diseases:
(A) GI Diseases and Infections
Drug absorption may be influenced by several pathophysiological
conditions of GIT.
Malabsorption syndrome like celiac disease and Chrons disease.
(B) Gastrointestinal Surgery.
Gastrointestinal surgery especially gastrectomy may cause drug dumping
in the intestine.
29. 29
B. Patient related factors:
5) Effect of Food:
The presence of food in the GI tract can affect the bioavailability of the
drug from an oral drug product.
Food contain amino acids, fatty acids, and many nutrients that may affect
intestinal pH and solubility of drugs.
The effects of food are not always predictable and can have consequences.
Some effects are:
• Delay in gastric emptying
• Stimulation of bile flow
• A change in the pH of the GI tract
• A change luminal metabolism of the drug substance
• Physical or chemical interaction of the meal with the drug product or
drug substance
The absorption of some antibiotics, such as penicillin and tetracycline, is
decreased with food; whereas other drugs, particularly lipid-soluble
drugs such as griseofulvin and metazalone, are better absorbed when
given with food containing a high fat content.
30. 30
B. Patient related factors:
7) First pass metabolism:
A drug administered orally, passes through the GIT and liver where it
undergoes extensive metabolism before reaching the systemic circulation,
thereby leading to decreased bioavailability, this phenomenon is called as
first pass metabolism.
6) Blood Flow to GIT:
Increase in the blood flow to the site of absorption (GIT), increases the
drug absorption as rapid removal of drug from its absorption site helps
to maintain sink conditions.
Drug (Administered Orally)
Destroyed in the gut
Unabsorbed drug
Destroyed in the gut wall
Reaches the systemic circulation
Destroyed by the liver
31. 31
References:
1) Brahmankar D.M., Jaiswal S.B., First edition, “Absorption of Drugs”
Biopharmaceutics and Pharmacokinetics – A treatise, Vallabh Prakashan,
Delhi 1995, Page No. 5-75.