pH - PARTITION THEORY, LIPID SOLUBILITY OF DRUGS, DRUG DISSOLUTION AND PH, SALTS, CRYSTAL FORM, DRUG STABILITY AND HYDROLYSIS IN GIT, COMPLEXATION, ADSORPTION
Biopharmaceutic considerations in drug product design and In Vitro Drug Produ...PRAJAKTASAWANT33
Introduction, biopharmaceutic factors affecting drug bioavailability, rate–limiting steps in drug absorption, physicochemical nature of the drug formulation factors affecting drug product performance
Myself Omkar Tipugade , M- Pharm ,Sem - II, Department of pharmaceutics , from Shree Santkrupa College Of Pharmacy , ghogaon . Today I upload presentation on Active Transport like P-gp , BCPR, Nucleoside transporters etc .
It includes Introductory part about what is Dissolution...then Mechanism of Dissolution is elaborated...Theories of Dissolution also given..It also includes Factors affecting Dissolution profile..Along with References given below for easily searching..
‘Targeted drug delivery system is a special form of drug delivery system where the medicament is selectively targeted or delivered only to its site of action or absorption and not to the non-target organs or tissues or cells.’
Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal epithelial surface, & mucin molecules & increase the residence time of the dosage form at the site of the absorption.
Mucoadhesive drug delivery system is a part of controlled delivery system.
Since the early 1980,the concept of Mucoadhesion has gained considerable interest in pharmaceutical technology.
combine mucoadhesive with enzyme inhibitory & penetration enhancer properties & improve the patient complaince.
MDDS have been devloped for buccal ,nasal,rectal &vaginal routes for both systemic & local effects.
Hydrophilic high mol. wt. such as peptides that cannot be administered & poor absorption ,then MDDS is best choice.
Mucoadhesiveinner layers called mucosa inner epithelial cell lining is covered with viscoelasticfluid
Composed of water and mucin.
Thickness varies from 40 μm to 300 μm
General composition of mucus
Water…………………………………..95%
Glycoproteinsand lipids……………..0.5-5%
Mineral salts……………………………1%
Free proteins…………………………..0.5-1%
The mechanism responsible in the formation of mucoadhesive bond
Step 1 : Wetting and swelling of the polymer(contact stage)
Step 2 : Interpenetration between the polymer chains and the mucosal membrane
Step 3 : Formation of bonds between the entangled chains (both known as consolidation stage)
Electronic theory
Wetting theory
Adsorption theory
Diffusion theory
Fracture theory
Advantages over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.
Targeting & localization of the dosage form at a specific site
-Painless administration.
-Low enzymatic activity & avoid of first pass metabolism
If MDDS are adhere too tightlgy because it is undesirable to exert too much force to remove the formulation after use,otherwise the mucosa could be injured.
-Some patient suffers unpleasent feeling.
-Unfortunately ,the lack of standardized techniques often leads to unclear results.
-costly drug delivery system
Gastrointestinal tract, Mechanism of drug absorption, Factors
affecting drug absorption, pH–partition theory of drug absorption. Formulation and physicochemical factors: Dissolution rate, Dissolution process, Noyes–Whitney equation and drug dissolution, Factors affecting the dissolution rate. Gastrointestinal absorption: Role of the dosage form: Solution (elixir, syrup and solution) as a dosage form ,Suspension as a dosage form, Capsule as a dosage form, Tablet as a dosage form ,Dissolution methods ,Formulation and processing factors, Correlation of in vivo data with in vitro dissolution data. Transport model: Permeability-Solubility-Charge State and the pH Partition Hypothesis, Properties of the Gastrointestinal Tract (GIT), pH Microclimate Intracellular pH Environment, Tight Junction Complex.
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
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".
Biopharmaceutic considerations in drug product design and In Vitro Drug Produ...PRAJAKTASAWANT33
Introduction, biopharmaceutic factors affecting drug bioavailability, rate–limiting steps in drug absorption, physicochemical nature of the drug formulation factors affecting drug product performance
Myself Omkar Tipugade , M- Pharm ,Sem - II, Department of pharmaceutics , from Shree Santkrupa College Of Pharmacy , ghogaon . Today I upload presentation on Active Transport like P-gp , BCPR, Nucleoside transporters etc .
It includes Introductory part about what is Dissolution...then Mechanism of Dissolution is elaborated...Theories of Dissolution also given..It also includes Factors affecting Dissolution profile..Along with References given below for easily searching..
‘Targeted drug delivery system is a special form of drug delivery system where the medicament is selectively targeted or delivered only to its site of action or absorption and not to the non-target organs or tissues or cells.’
Mucoadhesive drug delivery system interact with the mucus layer covering the mucosal epithelial surface, & mucin molecules & increase the residence time of the dosage form at the site of the absorption.
Mucoadhesive drug delivery system is a part of controlled delivery system.
Since the early 1980,the concept of Mucoadhesion has gained considerable interest in pharmaceutical technology.
combine mucoadhesive with enzyme inhibitory & penetration enhancer properties & improve the patient complaince.
MDDS have been devloped for buccal ,nasal,rectal &vaginal routes for both systemic & local effects.
Hydrophilic high mol. wt. such as peptides that cannot be administered & poor absorption ,then MDDS is best choice.
Mucoadhesiveinner layers called mucosa inner epithelial cell lining is covered with viscoelasticfluid
Composed of water and mucin.
Thickness varies from 40 μm to 300 μm
General composition of mucus
Water…………………………………..95%
Glycoproteinsand lipids……………..0.5-5%
Mineral salts……………………………1%
Free proteins…………………………..0.5-1%
The mechanism responsible in the formation of mucoadhesive bond
Step 1 : Wetting and swelling of the polymer(contact stage)
Step 2 : Interpenetration between the polymer chains and the mucosal membrane
Step 3 : Formation of bonds between the entangled chains (both known as consolidation stage)
Electronic theory
Wetting theory
Adsorption theory
Diffusion theory
Fracture theory
Advantages over other controlled oral controlled release systems by virtue of prolongation of residence of drug in GIT.
Targeting & localization of the dosage form at a specific site
-Painless administration.
-Low enzymatic activity & avoid of first pass metabolism
If MDDS are adhere too tightlgy because it is undesirable to exert too much force to remove the formulation after use,otherwise the mucosa could be injured.
-Some patient suffers unpleasent feeling.
-Unfortunately ,the lack of standardized techniques often leads to unclear results.
-costly drug delivery system
Gastrointestinal tract, Mechanism of drug absorption, Factors
affecting drug absorption, pH–partition theory of drug absorption. Formulation and physicochemical factors: Dissolution rate, Dissolution process, Noyes–Whitney equation and drug dissolution, Factors affecting the dissolution rate. Gastrointestinal absorption: Role of the dosage form: Solution (elixir, syrup and solution) as a dosage form ,Suspension as a dosage form, Capsule as a dosage form, Tablet as a dosage form ,Dissolution methods ,Formulation and processing factors, Correlation of in vivo data with in vitro dissolution data. Transport model: Permeability-Solubility-Charge State and the pH Partition Hypothesis, Properties of the Gastrointestinal Tract (GIT), pH Microclimate Intracellular pH Environment, Tight Junction Complex.
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
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".
The objective is to understand the buffer equation, factors influencing the pH of buffer solutions, Buffer capacity, Buffer in pharmaceutical systems and biologic system, Influence of buffer capacity and pH on tissue, pH and solubility
Ruchi rawat, romit vaishnav presentation on ph partitionRuchiRawat13
basic concept,digram showing drug transfer from membrane, ph partition throry, deviations,drug pka and GI ph, equations on weak acid and weak base, deviations from ph-partition theory.
includes different mechanism involved in the absorption of the drug s into the systemic circulation. different factors affecting absorption including characters of drugs and different dosage forms. bioavailability of different dosage forms
Pharmacology I- Pharmacokinetics (Absorption and Distribution)Subhash Yende
Transport of drug across cell membrane; Absorption- bioavailability, Bioequivalence; Distribution: Plasma protein binding, Physiological barrier, Apparent volume of distribution, redistribution
Dissolution and In Vitro In Vivo Correlation (IVIVC)Jaspreet Guraya
This presentation gives a bird's eye view on Dissolution in context with IVIVC. It discusses various levels of Correlations currently in practice. IVIVC are explained in light of biowaivers It also touches upon IVIVR, IVIVM etc.
BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGNN Anusha
BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
The brain is a delicate organ with many vital functions and many formidable mechanisms, isolate and protect it from the outside world. Unfortunately, the same mechanisms that prevent environmental chemicals accessing the brain also prevent the access of therapeutic chemicals. The brain is segregated from the circulating blood by a unique membranous barrier i.e the blood brain barrier.
DRUG INTERACTIONS (MECHANISMS OF DRUG-DRUG INTERACTIONS)N Anusha
A Drug interaction is an interaction between a drug and some other substance, such as another drug or a certain type of food, which leads to interaction that could manifest as an increase or decrease in the effectiveness or an adverse reaction or a totally new side effect that is not seen with either drug alone that can be severe enough to alter the clinical outcome.
Every time a drug is administered with any other prescription medicine, OTC products, herbs or even food we expose ourselves to the risk of a potentially dangerous interaction.
FORMULATION FACTORS EFFECTING BIOAVAILABILITY OF DRUGSN Anusha
Bioavailability means the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action.
When the drug is given orally, only part of the administered dose appears in the plasma.
By plotting plasma concentrations of the drug versus time, one can measure the area under the curve (AUC).
This curve reflects the extent of absorption of the drug.
PHYSIOLOGIC FACTORS RELATED TO DRUG ABSORPTIONN Anusha
ROUTES OF DRUG ADMINISTRATION
The route of administration (ROA) that is chosen has a large impact on how fast the drug is taken up and how much of it arrives at its destination in an active form.
MEMBRANE PHYSIOLOGY
The cell membrane also known as the plasma membrane or cytoplasmic membrane is a biological membrane that separates the interior of all cells from the outside environment.
GSTERO-INTESTINAL PHYSIOLOGY
AGE
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease causing microorganism and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body's immune system to recognize foreign agents, destroy it, and keep a record of it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.
TRANSDERMAL THERAPEUTIC DRUG DELIVERY SYSTEMS N Anusha
Transdermal drug delivery systems (TDDS) can be defined as self-contained discrete dosage forms which, when applied to the intact skin, delivers the drug(s) through the skin at a controlled rate to the systemic circulation.
For transdermal drug delivery, it is considered ideal if the drug penetrates through the skin to the underlying blood supply without drug buildup in the dermal layers.
They provide extended therapy with a single application, thereby improving patient compliance over other dosage forms requiring more frequent dose administration.
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses.
Monoclonal antibodies are important reagents used in biomedical research, in diagnosis of diseases, and in treatment of such diseases as infections and cancer.
These antibodies are produced by cell lines or clones obtained from animals that have been immunized with the substance that is the subject of study.
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.
IMPURITY PROFILING (SOURCES OF IMPURITIES)N Anusha
The description, characterization and quantitation of identified and unidentified impurities present in the drug substances is known as impurity profile.
IMPURITIES in pharmaceuticals are unwanted chemicals, that even in small amounts may influence the efficacy and safety of the pharmaceutical products.
2 Aspects of compatibility tests are:
Identification of compatible excipients for a formulation.
Identification of stable storage conditions
2 Types:
Solid state reactions: much slower and difficult to interpret.
Liquid state reactions: easier to detect
According to Stability Guidelines by FDA following conditions should be evaluated for solutions or suspensions
1. Acidic or alkaline pH.
2. Presence of added substances
3. High oxygen and nitrogen atmospheres.
4. Effect of stress testing conditions.
CHRONOPHARMACOKINETICS AND TIME DEPENDENT PHARMACOKINETICSN Anusha
Chronopharmacokinetic studies have been demonstrating that time of administration is a possible factor of variation in the kinetics of the drug.
It entails the study of temporal changes in drug absorption, distribution, metabolism and elimination.
It investigates the variation in drug plasma levels as a function of time of day and the mechanisms responsible for time dependant variations.
The term circadian coined by Franz Halberg, comes from Latin.
“Circa” means around &“diem” means day.
Asthma is a chronic inflammatory disorder of the airways that is characterized by increased responsiveness of the tracheobranchial tree to a variety of stimuli resulting in widespread spasmodic narrowing of the air passages which may be relieved spontaneously or by therapy.
Cough is a protective reflex, its purpose being expulsion of respiratory secretions or foreign particles from air passages.
It occurs due to stimulation of mechano or chemoreceptors in throat,
respiratory passages or stretch receptors in the lungs.
Act peripherally in the respiratory tract to reduce tussal impulses.
They aim to control rather than eliminate cough.
Many H-1 anti histamines have been conventionally added to antitussive /expectorant formulations.
Antihistamines afford relief in cough due to their sedative and Anticholinergic actions but lack selectivity for cough centre.
Analeptics stimulate respiration and can have resuscitative value in
Coma or fainting.
They stimulate respiration in sub convulsive doses,
but margin of safety is narrow.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Title: Sense of Smell
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 primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
2. CONTENTS
pH - PARTITION THEORY
LIPID SOLUBILITY OF DRUGS
DISSOLUTION AND PH
SALTS
CRYSTAL FORM
DRUG STABILITY AND HYDROLYSIS IN GIT
COMPLEXATION
ADSORPTION ANUSHA NADIKATLA
3. pH - PARTITION THEORY
For a drug to cross a membrane barrier it must normally be soluble in
the lipid material of the membrane to get into membrane and it has to
be soluble in the aqueous phase as well to get out of the membrane.
Many drugs have polar and non-polar characteristics or are weak acids
or bases.
For drugs which are weak acids or bases the pKa of the drug, the pH
of the GI tract fluid and the pH of the blood stream will control the
solubility of the drug and thereby the rate of absorption through the
membranes lining the GI tract.
Brodie et al. (Shore, et al. 1957) proposed the pH - partition theory to
explain the influence of GI pH and drug pKa on the extent of drug
transfer or drug absorption. Brodie reasoned that when a drug is
ionized it will not be able to get through the lipid membrane, but only
when it is non-ionized and therefore has a higher lipid solubility.
ANUSHA NADIKATLA
4. BRODIE'S D VALUE
Brodie tested this theory by perfusing the stomach or intestine of rat,
in situ, and injected the drug intravenously.
He varied the concentration of drug in the GI tract until there was no
net transfer of drug across the lining of the GI tract.
He could then determined the ratio, D as:
Brodie's D Value in Another Form
ANUSHA NADIKATLA
6. These values were determined experimentally, but we should be able
to calculate a theoretical value if we assume that only non-ionized
drug crosses the membrane and that net transfer stops when:
Brodie found an excellent correlation between the calculated D value
and the experimentally determined values.
[U]b = [U]g
ANUSHA NADIKATLA
7. REVIEW OF IONIC EQUILIBRIUM
The ratio [U]/[I] is a function of the pH of the solution and the pKa of
the drug, as described by the Henderson - Hasselbach equation
where HA is the weak acid and A- is the salt or conjugate base
WEAK ACIDS
ANUSHA NADIKATLA
8. Dissociation Constant equation - Weak Acids
Taking the negative log of both sides and rearranging gives the following
equation:
Where,pKa = -log Ka & pH = -log[H+]
Henderson - Hasselbach Equation - Weak Acids
ANUSHA NADIKATLA
9. WEAK BASES
where B is the weak base and HB+ is the salt or conjugate acid
Dissociation Constant equation - Weak Acids
Taking the negative log of both sides and rearranging gives the following equation:
where pKa = -log Ka and pH = -log[H+]
Henderson - Hasselbach Equation - Weak Bases
ANUSHA NADIKATLA
10. SOME TYPICAL PKA VALUES FOR WEAK ACIDS AT 25 °C
Weak Acid PKa
Acetic 4.76
Acetylsalicyclic 3.49
Ascorbic 4.3, 11.8
Boric 9.24
Penicillin V 2.73
Phenytoin 8.1
Salicyclic 2.97
Sulfathiazole 7.12
Tetracycline 3.3, 7.68, 9.69
ANUSHA NADIKATLA
11. SOME TYPICAL PKA VALUES FOR WEAK BASES AT 25 °C
WEAK BASE pKb
Ammonia 4.76
Atropine 4.35
Caffeine 10.4, 13.4
Codeine 5.8
Erythromycin 5.2
Morphine 6.13
Pilocarpine 7.2, 12.7
Quinine 6.0, 9.89
Tolbutamide 8.7
ANUSHA NADIKATLA
12. D VALUES AND DRUG ABSORPTION
Even though the D values refer to an equilibrium state a large D value
will mean that more drug will move from the GI tract to the blood side
of the membrane.
The larger the D value, the larger the effective concentration gradient,
and thus the faster the expected transfer or absorption rate.
Compare D for a weak acid (pKa = 5.4) from the stomach (pH 3.4) or
intestine (pH 6.4), with blood (pH = 7.4).
ANUSHA NADIKATLA
17. By comparison in the intestine, pH = 6.4 ,
The calculated D value is (100+1)/(10+1) = 9.2
From this example we could expect significant absorption of weak
acids from the stomach compared with from the intestine.
Remember however that the surface area of the intestine is much
larger than the stomach.
However, this approach can be used to compare a series of similar
compounds with different pKa values.
It has been applied for the pH - partition theory to drug absorption,
later this theory it will be used to describe drug re-absorption in the
kidney.
With this theory it should be possible to predict that by changing the
pH of the G-I tract that we would change the fraction non ionized (fu)
and therefore the rate of absorption.
ANUSHA NADIKATLA
18. Thus ka observed = ku • fu assuming that the ionized species is not
absorbed. ANUSHA NADIKATLA
19. PLOT OF KA (APPARENT) VERSUS FU FOR
SULFAETHIDOLE FROM RAT STOMACH
ANUSHA NADIKATLA
20. For some drugs it has been found that the intercept is not zero in the
above plot, suggesting that the ionic form is also absorbed.
For example, results for sulfaethidole.
Maybe the ions are transported by a carrier which blocks the charge, a
facilitated transport process, this is called the deviation from pH-
Partition theory .
ANUSHA NADIKATLA
21. LIPID SOLUBILITY OF DRUGS
Some drugs are poorly absorbed after oral administration even though
they are non-ionized in small intestine. Low lipid solubility of them
may be the reason. The best parameter to correlate between water and
lipid solubility is partition coefficient.
Partition coefficient (p) = [ L]conc / [W]conc , where
[ L]conc is the concentration of the drug in lipid phase,
[W]conc is the concentration of the drug in aqueous phase.
The higher p value, the more absorption is observed. Prodrug is one of
the option that can be used to enhance p value and absorption as
sequence.
It should be noted that extreme hydrophobicity has negative effect on
absorption, thus, sometimes enhanced water solubility also increase
bioavailability. This may be due to the unstirred layer (mucosa layer)
which is important in drug penetration. ANUSHA NADIKATLA
22. DRUG DISSOLUTION
So far we have looked at the transfer of drugs in solution in the G-I
tract, through a membrane, into solution in the blood.
However, many drugs are given in solid dosage forms and therefore
must dissolve before absorption can take place.
DISSOLUTION AND ABSORPTION
ANUSHA NADIKATLA
23. If absorption is slow relative to dissolution then all we are concerned
with is absorption.
However, if dissolution is the slow, rate determining step (the step
controlling the overall rate) then factors affecting dissolution will
control the overall process.
This is a more common problem with drugs which have a low
solubility (below 1 g/100 ml) or which are given at a high dose, e.g.
griseofulvin.
There are a number of factors which affect drug dissolution.
One model that is commonly used is to consider this process to be
diffusion controlled through a stagnant layer surrounding each solid
particle.
ANUSHA NADIKATLA
25. First we need to consider that each particle of drug formulation is
surrounded by a stagnant layer of solution.
After an initial period we will have a steady state where drug is
steadily dissolved at the solid-liquid interface and diffuses through the
stagnant layer.
If diffusion is the rate determining step we can use Fick's first law of
diffusion to describe the overall process.
ANUSHA NADIKATLA
26. PLOT OF CONCENTRATION GRADIENT
If we could measure drug concentration at various distances from the
surface of the solid we would see that a concentration gradient is
developed. If we assume steady state we can use Fick's first law to
describe drug dissolution. ANUSHA NADIKATLA
27. FICK'S FIRST LAW OF DIFFUSION APPLIED
TO DISSOLUTION
By Fick's first law of diffusion:
where D is the diffusion coefficient, A the surface area, Cs the solubility
of the drug, Cb is the concentration of drug in the bulk solution, and h
the thickness of the stagnant layer.
If Cb is much smaller than Cs then we have so-called "Sink Conditions"
FICK'S FIRST LAW - SINK CONDITIONS
ANUSHA NADIKATLA
28. SURFACE AREA, A
The surface area per gram (or per dose) of a solid drug can be changed
by altering the particle size.
For example, a cube 3 cm on each side has a surface area of 54 cm2.
If this cube is broken into cubes with sides of 1 cm, the total surface
area is 162 cm2.
Actually if we break up the particles by grinding we will have
irregular shapes and even larger surface areas.
Generally as A increases, the dissolution rate will also increase.
Improved bioavailability has been observed with griseofulvin,
digoxin, etc.
ANUSHA NADIKATLA
29. PARTICLE SIZE INCREASES SURFACE AREA
Methods of particle size reduction include mortar and pestle, mechanical
grinders, fluid energy mills, solid dispersions in readily soluble materials
(PEG's).
ANUSHA NADIKATLA
30. DIFFUSION LAYER THICKNESS, h
This thickness is determined by the agitation in the bulk solution.
In vivo we usually have very little control over this parameter.
It is important though, when we perform in vitro dissolution studies
because we have to control the agitation rate so that we get similar
results in vitro as we would in vivo.
ANUSHA NADIKATLA
31. PLOT OF CONCENTRATION VERSUS DISTANCE
FOR DISSOLUTION INTO A REACTIVE MEDIUM
ANUSHA NADIKATLA
32. The apparent thickness of the stagnant layer can be reduced when the
drug dissolves into a reactive medium.
For example, with a weakly basic drug in an acidic medium, the drug
will react (ionize) with the diffusing proton (H+) and this will result in
an effective decrease in the thickness of the stagnant layer.
The effective thickness is now h' not h.
Also the bulk concentration of the drug is effectively zero.
For this reason weak bases will dissolve more quickly in the stomach.
ANUSHA NADIKATLA
33. DIFFUSION COEFFICIENT, D
The value of D depends on the size of the molecule and the viscosity
of the dissolution medium.
Increasing the viscosity will decrease the diffusion coefficient and
thus the dissolution rate.
This could be used to produce a sustained release effect by including a
larger proportion of something like sucrose or acacia in a tablet
formulation.
ANUSHA NADIKATLA
34. DRUG SOLUBILITY, Cs
Solubility is another determinant of dissolution rate.
As Cs increases so does the dissolution rate.
We can look at ways of changing the solubility of a drug.
ANUSHA NADIKATLA
35. SALT FORM
If we look at the dissolution profile of various salts.
PLOT OF DISSOLVED DRUG CONCENTRATION VERSUS
TIME
ANUSHA NADIKATLA
36. Salts of weak acids and weak bases generally have
much higher aqueous solubility than the free acid or base,
therefore if the drug can be given as a salt the solubility can be
increased and we should have improved dissolution. One
example is Penicillin V.
ANUSHA NADIKATLA
38. This can lead to quite different Cp versus time results after oral
administration.
The tmax values are similar thus ka is probably the same.
Cmax might show a good correlation with solubility.
Maybe site limited (only drug in solution by the time the drug gets to
the 'window' is absorbed).
Use the potassium salt for better absorption orally.
These results might support the use of the benzathine or procaine
salts for IM depot use.
ANUSHA NADIKATLA
39. CRYSTAL FORM
Some drugs exist in a number of crystal forms or polymorphs.
These different forms may well have different solubility properties
and thus different dissolution characteristics.
Chloramphenicol palmitate is one example which exists in at least two
polymorphs.
The B form is apparently more bioavailable.
ANUSHA NADIKATLA
40. PLOT OF Cp VERSUS TIME FOR THREE FORMULATIONS OF
CHLORAMPHENICOL PALMITATE
ANUSHA NADIKATLA
41. The recommendation might be that manufacturers should use
polymorph B for maximum solubility and absorption.
However, a method of controlling and determining crystal form would
be necessary in the quality control process.
Shelf-life could be a problem as the more soluble (less stable) form
may transform into the less soluble form.
In time the suspension may be much less soluble with variable
absorption.
ANUSHA NADIKATLA
42. DRUG STABILITY AND HYDROLYSIS IN GIT
Acid and enzymatic hydrolysis of drugs in GIT is one of the reasons
for poor bioavailability.
Penicillin G (half life of degradation = 1 min at pH= 1)
Rapid dissolution leads to poor bioavailability (due to release large
portion of the drug in the stomach, pH = 1.2)
Prodrug (Conversion in the GIT to parent compound is rate limiting
step in bioavailability, either positively or negatively)
ANUSHA NADIKATLA
43. COMPLEXATION
Complexation of a drug in the GIT fluids may alter rate and extent of
drug absorption.
Intestinal mucosa + Streptomycin = poorly absorbed complex
Calcium + Tetracycline = poorly absorbed complex (Food-drug
interaction)
Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed
complex (tablet additive – drug interaction)
Polar drugs + complexing agent = well-absorbed lipid soluble
complex ( dialkylamides + prednisone)
Lipid soluble drug + water soluble complexing agent = well-
absorbed water soluble complex ( cyclodextrine)
ANUSHA NADIKATLA
44. ADSORPTION
Certain insoluble substance may adsorb co-administrated drugs
leading to poor absorption.
Charcoal (antidote in drug intoxication).
Cholestyramine ( insoluble anionic exchange resins)
ANUSHA NADIKATLA
45. 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.
2. Shargel L., Andrew B.C., Fourth edition “Physiologic factors
related to drug absorption” Applied Biopharmaceutics and
Pharmacokinetics, Prentice Hall International, INC., Stanford
1999. Page No. 99-128.
3. Pharmaceutics , the Science of Dosage form Design By M.E.
Aulton
4. Swarbrick J., Boylan J.C., “Absorption” Encyclopedia of
Pharmaceutical Technology, Marcel Dekker, INC., New York
1988:1:1-32.
ANUSHA NADIKATLA