Transport models : Permeability , solubility , charge state amd the ph partit...NishaN19p7504
this topic is all about influence of ph on drug solubilty and permeability , henderson hasselbalch equation , PH partition hypothesis and its deviations
Transport models : Permeability , solubility , charge state amd the ph partit...NishaN19p7504
this topic is all about influence of ph on drug solubilty and permeability , henderson hasselbalch equation , PH partition hypothesis and its deviations
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.
Solubility and dissolution enhancement strategies-Current understanding and r...ajaykumarpa
dentification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre- formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.
consolidation parameters, consolidation definition, consolidation parameters,
diffusion parameters,
dissolution parameters,
heckle plot, consolidation process, cold welding, fusion bonding, mechanical theory, inter molecular forces theory, liquid surface film theory, factors effecting consolidation, driving froces that facilitate diffusion, parameters related to diffusion in drug release, parameters in dissolution process, affect of agitation on dissolution, effect of dissolution fluid on dissolution, pH on dissolution fluid, viscosity effect on dissolution, effect of temperature on dissolution, pharmacokinetics parameters, C max, T max, AUC(area under curve), heckel plot, application and limitations of heckel plot, methods to compare dissolution profile, model independent method(F1 AND F2)difference factor, similarity factors, limits of difference factor and similarity factors, higuchi model(Diffusion matrix formulation), korsmeyer peppas model(the power law).
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.
Solubility and dissolution enhancement strategies-Current understanding and r...ajaykumarpa
dentification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre- formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.
consolidation parameters, consolidation definition, consolidation parameters,
diffusion parameters,
dissolution parameters,
heckle plot, consolidation process, cold welding, fusion bonding, mechanical theory, inter molecular forces theory, liquid surface film theory, factors effecting consolidation, driving froces that facilitate diffusion, parameters related to diffusion in drug release, parameters in dissolution process, affect of agitation on dissolution, effect of dissolution fluid on dissolution, pH on dissolution fluid, viscosity effect on dissolution, effect of temperature on dissolution, pharmacokinetics parameters, C max, T max, AUC(area under curve), heckel plot, application and limitations of heckel plot, methods to compare dissolution profile, model independent method(F1 AND F2)difference factor, similarity factors, limits of difference factor and similarity factors, higuchi model(Diffusion matrix formulation), korsmeyer peppas model(the power law).
Earliest Galaxies in the JADES Origins Field: Luminosity Function and Cosmic ...Sérgio Sacani
We characterize the earliest galaxy population in the JADES Origins Field (JOF), the deepest
imaging field observed with JWST. We make use of the ancillary Hubble optical images (5 filters
spanning 0.4−0.9µm) and novel JWST images with 14 filters spanning 0.8−5µm, including 7 mediumband filters, and reaching total exposure times of up to 46 hours per filter. We combine all our data
at > 2.3µm to construct an ultradeep image, reaching as deep as ≈ 31.4 AB mag in the stack and
30.3-31.0 AB mag (5σ, r = 0.1” circular aperture) in individual filters. We measure photometric
redshifts and use robust selection criteria to identify a sample of eight galaxy candidates at redshifts
z = 11.5 − 15. These objects show compact half-light radii of R1/2 ∼ 50 − 200pc, stellar masses of
M⋆ ∼ 107−108M⊙, and star-formation rates of SFR ∼ 0.1−1 M⊙ yr−1
. Our search finds no candidates
at 15 < z < 20, placing upper limits at these redshifts. We develop a forward modeling approach to
infer the properties of the evolving luminosity function without binning in redshift or luminosity that
marginalizes over the photometric redshift uncertainty of our candidate galaxies and incorporates the
impact of non-detections. We find a z = 12 luminosity function in good agreement with prior results,
and that the luminosity function normalization and UV luminosity density decline by a factor of ∼ 2.5
from z = 12 to z = 14. We discuss the possible implications of our results in the context of theoretical
models for evolution of the dark matter halo mass function.
(May 29th, 2024) Advancements in Intravital Microscopy- Insights for Preclini...Scintica Instrumentation
Intravital microscopy (IVM) is a powerful tool utilized to study cellular behavior over time and space in vivo. Much of our understanding of cell biology has been accomplished using various in vitro and ex vivo methods; however, these studies do not necessarily reflect the natural dynamics of biological processes. Unlike traditional cell culture or fixed tissue imaging, IVM allows for the ultra-fast high-resolution imaging of cellular processes over time and space and were studied in its natural environment. Real-time visualization of biological processes in the context of an intact organism helps maintain physiological relevance and provide insights into the progression of disease, response to treatments or developmental processes.
In this webinar we give an overview of advanced applications of the IVM system in preclinical research. IVIM technology is a provider of all-in-one intravital microscopy systems and solutions optimized for in vivo imaging of live animal models at sub-micron resolution. The system’s unique features and user-friendly software enables researchers to probe fast dynamic biological processes such as immune cell tracking, cell-cell interaction as well as vascularization and tumor metastasis with exceptional detail. This webinar will also give an overview of IVM being utilized in drug development, offering a view into the intricate interaction between drugs/nanoparticles and tissues in vivo and allows for the evaluation of therapeutic intervention in a variety of tissues and organs. This interdisciplinary collaboration continues to drive the advancements of novel therapeutic strategies.
Professional air quality monitoring systems provide immediate, on-site data for analysis, compliance, and decision-making.
Monitor common gases, weather parameters, particulates.
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 .
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
A brief information about the SCOP protein database used in bioinformatics.
The Structural Classification of Proteins (SCOP) database is a comprehensive and authoritative resource for the structural and evolutionary relationships of proteins. It provides a detailed and curated classification of protein structures, grouping them into families, superfamilies, and folds based on their structural and sequence similarities.
1. TRANSPORT MODELS : PERMEABILITY ,
SOLUBILITY – CHARGE STATE AND THE
PH PARTITION HYPOTHESIS
PRESENTED BY :
Nisha N .
M .Pharm 2nd Sem
Dept . Of Pharmaceutics
SUBMITTED TO :
Prof . H . S . Keerthy
Dept . Of Pharmaceutics
Mallige College of
Pharmacy
1/23
2. CONTENTS :
1) Permeability - solubility charge state
2) Ph partition theory
3) Influence of drug pka on drug absorption
4) Drug solubility and PH
5) Lipophilicity and drug absorption
6) Deviation from Ph partition theory
2/23
3. According to Ficks first law passive diffusion of a solute
is the product of diffusivity and concentration gradient of
the solute inside the membrane.
The membrane/water apparent partition coefficient
relates the latter internal gradient to the external bulk water
concentration difference between the two solutions
separated by the membrane
For an ionizable molecule to permeate by passive
diffusion most efficiently, the molecule needs to be in its
uncharged form at the membrane surface.
The amount of the uncharged form present at a given
pH, which directly contributes to the flux, depends on
several important factors, such as pH, binding to proteins
and bile acids, self-binding, and solubility
Permeability -Solubility charge state
3/23
5. Consider a vessel is divided into 2 chambers separated by
lipid membrane ,left side is the donor compartment and right
side is the acceptor compartment.
Fick’s first law applied to homogeneous membranes at steady
state is a transport equation,
J= Dm dCm/dx = Dm [ Cm0 - Cmh ] / h
J = flux
Cm0 – Cmh = are the concentrations in mol/cm3 units,
uncharged form of solute within the membrane at two water
membrane boundaries
h = thickness of the membrane
Dm = diffusivity of the solute within the membrane
At steady state, the concentration gradient, dCm/dx, within
the membrane is linear
5/23
6. The limitation of eq. 1 is that measurement of
concentrations of solute within different parts of the
membrane is very inconvenient.
So we can estimate the distribution coefficients between
bulk water and the membrane, log Kd (the pH dependent
apparent partition coefficient),
we can convert eq. 1 into a more accessible form,
J = Dm Kd (CD - CA)/h……... (2)
where the substitution of
Kd allows us to use bulk water concentrations in the donor
and acceptor compartments,
CD and CA, respectively. ( for ionizable molecules, CA
and CD refer to the concentrations of the solute summed
over all forms of charge state.)
6/23
7. Eq. 2 is still not sufficiently convenient, since we need to
estimate Dm and Kd.
It is a common practice to lump these parameters and the
thickness of the membrane into a composite parameter,
called “membrane permeability,” Pe,
Pe = Dm Kd / h……… (3)
The relevance of eq. 2 (which predicts how quickly
molecules pass through simple membranes) to solubility
comes in the concentration terms.
Consider “sink” conditions, where CA is essentially zero.
Eq. 2 reduces to the following flux equation
J = Pe C ………(4)
7/23
8. Flux depends on the product of membrane permeability
of the solute times the concentration of the solute (summed
over all charge state forms) at the water-side of the donor
surface of the membrane.
This concentration ideally may be equal to the dose of
the drug, unless the dose exceeds the solubility limit, in
which case it is equal to the solubility.
Since the uncharged molecular species is the permeant,
eq. 4 may be restated as
J = Po Co<Po So……… (5)
8/23
9. Where, Po = the intrinsic permeability
Co= concentration of the uncharged species,
respectively.
The intrinsic permeability does not
depend on pH, but its cofactor in the flux equation, Co,
does. The concentration of the uncharged species is always
equal to or less than the intrinsic solubility of the species,
So.
Note that for the uncharged species, eq. 3 takes on
the form
Po = Dm Kp/h………..(6)
where Kp = Cm(0) / CDo; also, Kp = Cm(h) / CAO;
CDo and CAo are the aqueous solution concentrations of
the uncharged species in the donor and acceptor sides,
respectively.
9/23
10. PH PARTITION THEORY
It explain drug absorption from GIT and its distribution
across bio-membranes.
Drug (>100 daltons) transported by passive diffusion
depend upon : dissociation constant, pka of the drug lipid
solubility, O/W pH at absorption site.
Most drugs are either weak acids or weak bases whose
degree of ionization is depend upon pH of biological fluid.
For a drug to be absorbed, it should be unionized and the
unionized portion should be lipid soluble.
10/23
11. The fraction of drug remaining unionised is a function of
both Dissociation constant (pka) and pH of solution.
The pH partition theory is based on following
assumption:
GIT acts as a lipoidal barrier to the transport of the drug .
The rate of absorption of drug is directly proportional to
its fraction of unionized drug
Higher the lipophilicity of the unionized degree, better
the absorption
11/23
12. For acid,
pKa -pH= log [Cu/Ci]
For base,
pKa-pH= log [Ci/Cu]
Ex: Weak acid aspirin (pKa=3.5) in stomach (pH=1) will
have > 99% of unionised form so gets absorbed in stomach.
Weak base quinine (pKa=8.5) will have very negligible
unionisation in gastric pH so negligible absorption.
Several pro-drugs have been developed which are lipid
soluble to overcome poor oral absorption of their parent
compounds.
HENDERSON HASSELBALCH EQUATION
12/23
13. EX: Pivampicilin, the pivaloyloxy-methyl ester of
ampicilin is more lipid soluble than ampicilin.
Lipid solubility is provided to a drug by its partition
coefficient between An organic solvent and water or an aq.
Buffer (same pH of ab. Site)
Ex: Barbital has a p.c. of 0.7 its absorption is 12 %
Phenobarbital (p.c = 4.8 absorption= 12 %)
Secobarbital (p.c =50.7 absorption= 40 %)
13/23
15. Drug Solubility:
The absorption of drug requires that molecule
be in solution at absorption site.
Dissolution, an important step, depends upon solubility of
drug substance.
pH solubility profile:
pH environment of GIT varies from Acidic
in stomach to slightly Alkaline in a small intestine.
1)Basic drug 1) Acidic medium( stomach)
2)Acidic drug 2) basic medium( intestine)
Drug Solubility and pH
15/23
16. Improvement of solubility:
Addition of acidic or basic excipient
Ex: Solubility of Aspirin (weak acid) increased by
addition of basic excipient.
For formulation of CRD , buffering agents may be added to
slow or modify the release rate of a fast dissolving drug.
16/23
17. Lipophilicity and Drug absorption
The gastrointestinal cell membrane are essentially
lipoidal. Highly lipid soluble drugs are generally absorbed
while lipid insoluble drugs are in general poorly absorbed.
Certain drugs are poorly absorbed after oral
administration even though they are largely unionised in
the small intestine, low lipid solubility of the uncharged
molecule may be the reason.
A guide to the lipophilic nature of a drug is its partition
coefficient between a fat like solvent and water or an
aqueous buffer.
The critical role of lipid solubility in drug absorption is a
guiding principle in drug development. Polar molecules
such as gentamicin, ceftriaxone, heparin and streptokinase
17/23
18. are poorly absorbed after oral administration and must be
given by injection.
Lipid soluble drugs with favorable partition coefficient are
usually well absorbed after oral administration. The
selection of a more lipid soluble compound from a series of
research compounds often result in improved pharmacologic
activity.
Occasionally the structure of an existing drug can be
modified to develop a similar compound with improved
absorption . Eg: The development of clindamycin, which
differs from lincomycin by the single substitution of chloride
for a hydroxyl group. Even slight molecular modification,
however runs the risk of also changing the efficacy and
18/23
19. safety profile of the drug. For this reason, medicinal chemists
prefer the development of lipid soluble prodrugs of a drug
with poor oral absorption characteristics. example:
cefuroxime (cefuroxime axetil - acetoxy ethyl ester)
The lipid solubility of a drug is determined from its
oil/water partition coefficient (ko/w) value.
This value is a measure of the degree of distribution of drug
between one of the several organic, water immiscible,
lipophilic solvents and an aqueous phase.
In general, the octonal/pH 7.4 buffer partition coefficient
value in the range of 1 to 2 of a drug is sufficient for passive
absorption across lipoidal membranes.
19/23
20. Deviations from pH-Partition Theory
The pH-partition theory provides a basic frame work for
understanding drug absorption, but it is an over
simplification of a more complex process.
The theory indicates that the relationship between pH and
permeation or absorption rate is described by an S-shaped
curve corresponding to the dissociation curve of the drug.
For a simple acid or base, the inflection point of the pH-
absorption curve should occur at a pH equal to the pka of the
drug. This is rarely observed experimentally
20/23
22. QUESTIONS :
1) Explain Ph partition hypothesis and its limitations ?
( Jan 2020 )
1) Discuss the Ph partition theory of drug absorption ?
( June 2019 )
22/23