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Alternative method of Dissolution
Meeting dissolution requirements
Performance of drug product
Dissolution profile comparison
by-
Sahil Suleman
M. Pharm (2st Sem)
CONTENTS
Introduction
Dissolution Methods
Alternative Methods Of Dissolution Testing
Meeting Dissolution Requirements
Problems Of Variable Control In Dissolution Testing
Performance Of Drug Products: In Vitro–in Vivo Correlation
Dissolution Profile Comparisons
DISSOLUTION
• Dissolution is a dynamic process by which solid solutes dissolve in a solvent to yield a
solution. Mass transfer of drug from solid into solvent.
• Dissolution rate may be defined as the amount of substances that goes into solution per
unit time under standard conditions of temperature, pressure and solvent composition.
• A drug is expected to be released from the solid dosage forms (granules, tablets, capsules
etc.) and immediately go into molecular solution.
• Dissolution is the rate determining step for hydrophobic, poorly aqueous soluble drugs.
For instance : Griseofulvin, Spironolactone.
DISSOLUTION METHODS
COMPENDIAL METHODS OF
DISSOLUTION
1. Apparatus 1: Rotating Basket
2. Apparatus 2: Paddle Method
3. Apparatus 3: Reciprocating Cylinder
4. Apparatus 4: Flow-through-Cell
5. Apparatus 5: Paddle-over-Disk
6. Apparatus 6: Cylinder
7. Apparatus 7: Reciprocating Disk
ALTERNATIVE METHODS OF
DISSOLUTION TESTING
1. Rotating Bottle Method
2. Intrinsic Dissolution Method
3. Peristalsis Method
4. Diffusion Cells
Rotating Bottle Method
• Used mainly for controlled-release beads.
• For this purpose the dissolution medium may be easily changed, such as from simulated
gastric juice to simulated intestinal juice.
• The equipment consists of a rotating rack that holds the sample drug products in bottles.
• The bottles are capped tightly and rotated in a 37±0.5°C temperature bath. At various
times, the samples are removed from the bottle, decanted through a 40-mesh screen, and
the residues are assayed.
• An equal volume of fresh medium is added to the remaining drug residues within the
bottles and the dissolution test is continued.
• A dissolution test with pH 1.2 medium
for 1 hour, pH 2.5 medium for the next
1 hour, followed by pH 4.5 medium for
1.5 hours, pH 7.0 medium for 1.5 hours,
and pH 7.5 medium for 2 hours was
recommended to simulate the condition
of the gastrointestinal tract.
• Used between 10 and 60 rpm.
• The main disadvantage is that this
procedure is manual and tedious.
Simulated gastric fluid is a solution that simulates the composition and pH of
gastric juice. The reagent is sterilized by 0.2 µm filtration.
Simulated gastric juice is prepared by dissolving pepsin (1 g), gastric mucin (1.5
g), and NaCl (8.775 g) in 1 L distilled water with pH of 1.3 adjusted using 6 N
HCI.
Simulated Intestinal fluid composition –
1.725mL of KCl, 0.025mL of KH2PO4, 3.125mL of NaHCO3, 7.375mL of NaCl,
0.1mL of MgCl2.6H2O and 0.125mL of (NH4)2CO3
Intrinsic Dissolution Method
• Most methods for dissolution deal with a finished drug product.
• Sometimes a new drug or substance may be tested for
dissolution without the effect of excipients or the fabrication
effect of processing.
• The dissolution of a drug powder by maintaining a constant
surface area is called intrinsic dissolution.
• Intrinsic dissolution is usually expressed as mg/cm2/min. In one
method, the basket method is adapted to test dissolution of
powder by placing the powder in a disk attached with a clipper
to the bottom of the basket.
Peristalsis Method
• The peristalsis method attempts to simulate the hydrodynamic conditions of the
gastrointestinal tract in an in vitro dissolution device.
• The apparatus consists of a rigid plastic cylindrical tubing fitted with a septum and
rubber stoppers at both ends.
• The dissolution chamber consists of a space between the septum and the lower stopper.
• The apparatus is placed in a beaker containing the dissolution medium.
• The dissolution medium is pumped with peristaltic action through the dosage form.
Schematics of the peristaltic
dissolution assembly. Plastic
tubing is used to connect the
combined Y-shaped connectors to
the two hypodermic needles at the
top of the disintegrating chamber
and the outlet-inlet connectors of a
Brewer pipetting pump assembly
equipped with a 50 mL syringe
Diffusion Cells
• Static and flow-through diffusion cells are used to characterize in vitro drug release and drug
permeation kinetics from topically applied dosage form or transdermal drug product.
• The Franz diffusion cell is a static diffusion system that is used for characterizing drug
permeation through a skin model.
• The source of skin may be human cadaver skin or animal skin (e.g.., hairless mouse skin).
Anatomically, each skin site (e.g., abdomen, arm) has different drug permeation qualities.
• The skin is mounted on the Franz diffusion cell system.
• The drug product (e.g.., ointment) is placed on the skin surface and the drug permeates across
the skin into a receptor fluid compartment that may be sampled at various times.
• The Franz diffusion cell system is useful for comparing in vitro drug release profiles
and skin permeation characteristics to aid in selecting an appropriate formulation that
has optimum drug delivery
FRANZ DIFFUSION CELL
MEETING DISSOLUTION REQUIREMENTS
According to CFR (21CFR 343.90), a drug product application should include the
specifications necessary to ensure the identity, strength, quality, purity, potency, and
bioavailability of the drug product, including, and acceptance criteria relating to, dissolution
rate in the case of solid dosage forms.
For dissolution acceptance criteria, the following points should be considered:
1. The dissolution profile data from the pivotal clinical batches and primary (registration)
stability batches should be used for the setting of the dissolution acceptance criteria of
the product (i.e., specification-sampling time point and specification value).
• A significant trend in the change in dissolution profile during stability should be
justified with dissolution profile comparisons and in vivo data in those instances where
the similarity testing fails.
2. Specifications should be established based on average in vitro dissolution data for each
lot under study, equivalent to USP Stage 2 testing (n = 12).
3. For immediate-release formulations, the last time point should be the time point where
at least 80% of drug has been released.
• If the maximum amount released is less than 80%, the last time point should be the
time when the plateau of the release profile has been reached. Percent release of less
than 80% should be justified with data (e.g.., sink conditions information).
4. For extended-release formulations, a minimum of three time points is recommended to
set the specifications.
• These time points should cover the early, middle, and late stages of the release profile.
The last time point should be the time point where at least 80% of drug has been
released.
• If the maximum amount released is less than 80%, the last time point should be the time
when the plateau of the release profile has been reached.
5. The dissolution acceptance criterion should be set in a way to ensure consistent
performance from lot to lot, and this criterion should not allow the release of any lots
with dissolution profiles outside those that were studied clinically
PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION
TESTING
• Dissolution testing involves various steps such as solid–liquid mass transfer, particle erosion,
possible particle disintegration, particle suspension, and particle–liquid interactions.
• It is complicated by other factors such as shear stress distribution as a function of tablet
location within the apparatus, and the location of the tablet upon its release inside the apparatus.
• Depending on the particular dosage form involved, the variables may or may not exert a
pronounced effect on the rate of dissolution of the drug or drug product.
• Variations may occur with the same type of equipment and procedure.
• The centering and alignment of the paddle is critical in the paddle method.
• Turbulence can create increased agitation, resulting in a higher dissolution rate.
• Wobbling and tilting due to worn equipment should be avoided. The basket
method is less sensitive to the tilting effect.
• However, the basket method is more sensitive to clogging due to gummy materials.
• Pieces of small particles can also clog up the basket screen and create a local non-
sink condition for dissolution.
• Dissolved gas in the medium may form air bubbles on the surface of the dosage
form unit and can affect dissolution in both the basket and paddle methods.
• Small variations in the location of the tablet on the vessel bottom caused by the
randomness of the tablet descent through the liquid are likely to result in
significantly different velocities and velocity gradients near the tablet
The Reynolds number is calculated with this equation:
Where,
Re is the Reynolds number,
is the density of the fluid,
v is the velocity of the fluid flow,
d is the diameter of the pipe, and
µ is the viscosity of the fluid.µ
PERFORMANCE OF DRUG PRODUCTS: IN VITRO–IN
VIVO CORRELATION
• For CR or ER formulation - dissolution is the rate-limiting step, hence it is possible to
establish a relationship between the release of the drug in vitro and its release in vivo or its
absorption into the systemic circulation.
• If such correlation exists, then one is able to predict the plasma concentration time profile of a
drug from its in vitro dissolution.
• Usually such a correlation is developed with two or more formulations with different release
characteristics. (Recommended- 3 or more formulations)
• If the dissolution of the drug is independent of the dissolution conditions (such as apparatus
agitation rate, pH, etc), then it is possible to establish such a correlation with only one
formulation
• The establishment of a predictive IVIVC also enables us to decrease the number of in
vivo studies needed to approve and maintain a drug product on the market resulting in an
economic benefit as well as a decreased regulatory burden.
• It also enables to set clinically meaningful dissolution specifications based on the
predicted plasma concentration time profile.
• There are two ways in evaluating the predictability of the correlation:
1. Internal predictability refers to the ability to predict the pharmacokinetic profile
of the formulations that were used to develop the correlation;
2. External predictability refers to the ability to detect the profile of a lot or
formulation that was not used to develop the IVIVC.
Categories of In Vitro–In Vivo Correlations
1. Level A Correlation
2. Level B Correlation
3. Level C Correlation
a) Dissolution rate versus absorption rate.
b) Percent of drug dissolved versus percent of drug absorbed.
c) Maximum plasma concentrations versus percent of drug dissolved in vitro.
d) Serum drug concentration versus percent of drug dissolved.
e) Biopharmaceutic Drug Classification System
4. Multiple level C correlation
LEVEL A CORRELATION
• Highest level of correlation and represents
a point-to-point (1:1) relationship between
an in vitro dissolution and the in vivo
input rate of the drug from the dosage
form.
• Level A correlation compares the percent
(%) drug released versus percent (%) drug
absorbed.
• The percentage of drug absorbed can be
calculated by the Wagner– Nelson or Loo–
Riegelman procedures or by direct
mathematical deconvolution.
Advantages-
• A point-to-point correlation is developed.
• In vitro dissolution profile can serve as a
surrogate for in vivo performance.
• A change in manufacturing site, method of
manufacture, raw material supplies, minor
formulation modification, and product
strength using the same formulation can be
justified without the need for additional
human studies.
• Enables the in vitro dissolution test to become
meaningful and clinically relevant quality
control test that can predict in vivo drug
product performance
% drug dissolved in-vitro
% drug
Absorbed
in-vivo
LEVEL A CORRELATION
WAGNER NELSON METHOD
• The Wagner Nelson method can be used to calculate the absorption rate
constant when the absorption process follows zero-order or first-order.
• The model also generates AUCs (Areas Under the Curve) and rate of
absorption values.
• This method estimates the loss of drug from the GI over time, whose slope
is inversely proportional to ka.
• After a single oral dose of a drug, the total dose should be completely
accounted for the amount present in the body, the amount present in the
urine, and the amount present in the GI tract.
• Dose (D0) is expressed as follows:
LOO–RIEGELMAN
• Used to calculate the relative amount absorbed as a function of time from
plasma concentration data which follow a two-compartment open model.
• After oral administration of a dose of a drug that exhibits two-compartment
model kinetics, the amount of drug absorbed is calculated as the sum of the
amounts of drug in the central compartment (Dp), in the tissue compartment
(Dt), and the amount of drug eliminated by all routes (Du).
Ab = Dp + Dt + Du
DECONVOLUTION
LEVEL B CORRELATION
• Level B correlation utilizes the principle of statistical moment in which the mean
in-vitro dissolution time is compared to either the mean residence time (MRT) or
the mean in-vivo dissolution time (MDT).
• Level B correlation uses all of the in vitro and in vivo data, but is not a point-to-
point correlation.
• Different profiles can give the same parameter values.
• The Level B correlation alone cannot justify formulation modification,
manufacturing site change, excipient source change, batch-to-batch quality, etc.
MRT(Mean residence time) represents the average time a molecule stays in the body.
The MRT is calculated by summing the total time in the body and dividing by the number of
molecules.
AUMC is obtained from a plot of product of plasma drug concentration and time (i.e. C.t) versus time
t from zero to infinity. Mathematically, it is expressed by equation:
AUC is obtained from a plot of plasma drug concentration versus time from zero to infinity.
Mathematically, it is expressed by equation:
MDT (The mean dissolution time ) can be calculated arithmetically the following equation:
where W(t) is the cumulative amount of drug dissolved at time t.
This equation is very useful, especially in cases where a correlation of in vitro and in vivo MDT
values is attempted.
In actual practice, an equivalent form of this equation is used to derive an estimate of MDT from
experimental dissolution data
where W∞ is the asymptote of the dissolved amount of drug and ABC is the area between the
cumulative dissolution curve and W∞
• Not a point-to-point correlation.
• Establishes a single-point relationship between
a dissolution parameter (such as drug released
at a certain time ) and a pharmacokinetic
parameter of interest (such as AUC and Cmax).
• Useful for formulation selection and
development but has limited application.
• Multiple Level C correlation relates one or
several pharmacokinetic parameters of interest
to the amount of drug dissolved at several time
points of the dissolution profile.
• In general, if one is able to develop a multiple
Level C correlation, then it may be feasible to
develop a Level A correlation.
LEVEL C CORRELATION
Fig- Level C correlation showing the
relationship between the amount of drug
dissolved at a certain time and the peak plasma
concentration
Examples of Level C correlation:-
• Dissolution rate versus absorption rate.
• Percent of drug dissolved versus percent of drug
absorbed.
• Biopharmaceutic Drug Classification System
Dissolution Rate Versus Absorption Rate
• If dissolution is rate limiting,
faster dissolution - faster rate of appearance of the drug in the plasma.
correlation between rate of dissolution and rate of absorption may be established .
• The absorption rate is usually more difficult to determine than peak absorption time.
Therefore, the absorption time may be used in correlating dissolution data to
absorption data.
• In the analysis of in vitro–in vivo drug correlation, rapid drug dissolution may be
distinguished from the slower drug absorption by observation of the absorption time
for the preparation.
• The absorption time refers to the time for a constant amount of drug to be absorbed.
Fig- An example of correlation between time required for a given amount of drug to
be absorbed and time required for the same amount of drug to be dissolved in vitro
for three sustained-release aspirin products
Percent of drug dissolved versus percent of drug absorbed
• If a drug is absorbed completely after dissolution, a linear correlation may be obtained
by comparing the percentage of drug absorbed to the percentage of drug dissolved.
• In choosing the dissolution method, appropriate dissolution medium and slow
dissolution stirring rate is considered so that in vivo dissolution is approximated.
• Aspirin is absorbed rapidly, and a slight change in formulation may be reflected in a
change in the amount and rate of drug absorption during the period of observation.
• If the drug is absorbed slowly, which occurs when absorption is the rate-limiting step, a
difference in dissolution rate of the product may not be observed. In this case, the drug
would be absorbed very slowly independent of the dissolution rate.
Fig- An example of correlation between time
required for a given amount of drug to be absorbed
and time required for the same amount of drug to
be dissolved in vitro for three sustained-release
aspirin products
Fig- An example of continuous in
vivo–in vitro correlation of aspirin.
Biopharmaceutic Drug Classification System
• BCS is a predictive approach to relate certain physicochemical characteristics of a
drug substance and drug product to in vivo bioavailability.
• The BCS is not a direct in vitro– in vivo correlation.
• For example, BCS Class I drugs- rapidly and mostly absorbed. (oral and IR)
• A BCS Class I drug (highly soluble & permeable) rapidly dissolves from the drug
product over the physiologic pH range of 1–7.4.
• Highly permeable drugs are drugs whose absolute bioavailability is greater than 90%.
• BCS only applies to oral immediate-release formulations and cannot be applied to
modified-release formulations or for buccally absorbed drug products.
MULTIPLE LEVEL C CORRELATION
• This level refers to the relationship between one or more pharmacokinetic parameters of
interest (Cmax,,AUC, or any other suitable parameters) and amount of drug dissolved at several
time points of dissolution profile.
• Multiple point level C correlation may be used to justify a biowaver provided that the
correlation has been established over the entire dissolution profile with one or more
pharmacokinetic parameter of interest.
• A multiple level C correlation should be based on atleast three dissolution time points
covering the early, middle, and last stages of the dissolution profile.
• The development of a level A correlation is also likely, when multiple level C correlation is
achieved at each time point at same parameter such that the effect on the in vivo performance
of any change in dissolution can be assessed.
DISSOLUTION PROFILE COMPARISONS
• Dissolution profile comparisons are used to assess the similarity of the dissolution
characteristics of two formulation or different strengths of the same formulation to decide
whether in vivo bioavailability/ bioequivalence studies are needed.
• The SUPAC-IR and SUPAC-MR provide recommendations to firms who intend, during
the post-approval period, to change
a) The components or compositions
b) The site of manufacture
c) The scale-up/scale-down of manufacture; and/or
d) The manufacturing (process and equipment) of the drug product.
For each type of change, these guidance list documentation (e.g., dissolution testing,
bioequivalence, etc) should be normally provided to support the change depending on the
level of complexity of the proposed change
• For minor changes and some major changes for which in vivo bioequivalence is not
warranted, dissolution profile comparisons either in the proposed media or in multimedia
can be submitted to support the change.
• Dissolution profiles may be considered similar by virtue of overall profile similarity
and/or similarity at every dissolution sample time point.
• According to the FDA - three statistical methods for the evaluation of similarity:
1. Model-independent approach using a similarity factor;
2. Model-independent multivariate confidence region procedure; and
3. Model dependent approach
Model-independent approach
Difference factor (f1)
• The difference factor (f1) calculates
the percent (%) difference between the
two curves at each time point and is a
measurement of the relative error
between the two curves.
Similarity factor (f2)
• It is logarithmic reciprocal square root
transformation of the sum of squared
error and is a measurement of the
similarity in the percent (%) dissolution
between the two curves.
n - number of time points,
R - dissolution value of the reference batch at time t,
T - dissolution value of the test batch at time t
A specific procedure to determine difference and similarity :
1. Determine the dissolution profile of two products (12 units each) of the test and reference
products.
2. Using the mean dissolution values from both curves at each time interval, calculate the
difference factor (f1 ) and similarity factor (f2 ) using the given equations.
3. For curves to be considered similar, f 1 values should be close to 0, and f2 values should be
close to 100.
• Generally, f1 values up to 15 (0-15) and f2 values greater than 50 (50-100) ensure sameness
or equivalence of the two curves and, thus, of the performance of the test and reference
products.
• This model independent method is most suitable for dissolution profile comparison when
three to four or more dissolution time points are available.
Recommendations to be considered:
• The dissolution measurements of the test and reference batches should be made under
exactly the same conditions. The dissolution time points for both the profiles should be
the same (e.g.., 15, 30, 45, 60 minutes). The reference batch used should be the most
recently manufactured prechange product.
• Only one measurement should be considered after 85% dissolution of both the products.
• To allow use of mean data, the percent coefficient of variation at the earlier time points
(e.g.., 15 minutes) should not be more than 20%, and at other time points should not be
more than 10%.
• The mean dissolution values for R can be derived either from (1) last batch or (2) last two
or more consecutively manufactured reference batches.
Model Independent Multivariate Confidence Region Procedure
In instances where within batch variation is more than 15% CV, a multivariate model
independent procedure is more suitable for dissolution profile comparison.
Steps:
1. Determine the similarity limits in terms of multivariate statistical distance (MSD) based
on inter batch differences in dissolution from reference (standard approved) batches.
2. Estimate the MSD between the test and reference mean dissolutions.
3. Estimate 90% confidence interval of true MSD between test and reference batches.
4. Compare the upper limit of the confidence interval with the similarity limit. The test batch
is considered similar to the reference batch if the upper limit of the confidence interval is
less than or equal to the similarity limit.
Model Dependent Approaches
Several mathematical models are described to fit dissolution profiles. To allow
application of models to comparison of dissolution profiles, the following procedures
are suggested:
1. Select the most appropriate model for the dissolution profiles from the standard,
prechange, approved batches. A model with no more than three parameters (such as
linear, quadratic, logistic, probit, and Weibull models) is recommended.
2. Using data for the profile generated for each unit, fit the data to the most
appropriate model.
3. A similarity region is set based on variation of parameters of the fitted model for
test units (e.g.., capsules or tablets) from the standard approved batches.
4. Calculate the MSD in model parameters between test and reference
batches.
5. Estimate the 90% confidence region of the true difference between the
two batches.
6. Compare the limits of the confidence region with the similarity region. If
the confidence region is within the limits of the similarity region, the test
batch is considered to have a similar dissolution profile to the reference
batch.
DRUG PRODUCT STABILITY
• Product stability is usually determined by testing a variety of stability indicating attributes
such as drug potency, impurities, dissolution, and other relevant physicochemical
measures of performance as necessary.
• Stability studies are performed under well-controlled testing conditions and provide
evidence on how the quality of a drug product varies with time under the influence of a
variety of environmental factors such as temperature, humidity, oxygen, and light.
• The time period during which a drug product is expected to remain within the established
product quality specification under the labelled storage conditions is generally termed
“shelf-life”(expiration period, expiry date, or expiration date).
ICH Q1A(R2)
CONSIDERATIONS IN THE DESIGN OFA DRUG PRODUCT
Biopharmaceutic Considerations
The essential elements include-
1. The physicochemical nature of the drug to be used, for example, salt and particle size;
2. The timing of these studies in relation to the preclinical studies with the drug;
3. The determination of the solubility and dissolution characteristics;
4. The evaluation of drug absorption and physiological disposition studies; and
5. The design and evaluation of the final drug formulation.
• The finished dosage form should not produce any additional side effects or discomfort
due to the drug and/or excipients.
• Ideally, all excipients - pharmacologically inactive ingredients in the final dosage form
Pharmacodynamic Considerations
• The therapeutic objective influences the design of the drug product, route of drug administration,
dose, dosage regimen, and manufacturing process.
• An oral drug used to treat an acute illness is generally formulated to release the drug rapidly,
allowing for quick absorption and rapid onset.
• If more rapid drug absorption is desired , then an injectable drug is formulated.
• Nitro-glycerine, is highly metabolized if swallowed, hence, a sublingual tablet formulation.
• To reduce unwanted systemic side effects - locally acting drugs (such as inhaled drugs)
• Advantage – drug can be delivered directly into the lungs.
• For the treatment of certain diseases, such as hypertension, chronic pain, etc, an extended or
controlled-release dosage form is preferred
Drug Substance Considerations
• The physicochemical properties of the drug substance are major factors.
• It include solubility, stability, chirality, polymorphs, solvate, hydrate, salt form, ionizable
behaviour, and impurity profile.
• They influence the type of dosage form, the formulation, and the manufacturing process.
• Physical properties of the drug such as intrinsic dissolution rate, particle size, and crystalline
form are influenced by methods of processing and manufacturing.
• If the drug has low aqueous solubility and an intravenous injection is desired, a soluble salt of the
drug may be prepared.
• Chemical instability or chemical interactions with certain excipients also affect the type of drug
product and its method of fabrication.
Pharmacokinetics of the Drug • Clinical failures of about 50% of the
Investigational New Drug (IND) filings are
attributed to their inadequate ADME attributes.
• the integration of PK and PD allows for the
characterization of the onset, intensity, and
duration of the pharmacological effect of a drug
and its interaction to the mechanism of action.
• The degree of polymorphism can significantly
affect the drug metabolism and, therefore, the
pharmacokinetics and the clinical outcome of
the drug.
• Pharmacokinetic properties(ADME), of
the molecules being investigated as
potential drug candidates is a major factor.
• The data obtained from ADME studies
allow the development of a dose and
dosage regimen that are age appropriate
including avoidance of drug–drug
interactions, food effect interactions, and
achieving an appropriate drug release rate.
Bioavailability of the Drug
• Dissolve > disintegrate > Absorb
• The stability of the drug in the gastrointestinal tract, is one consideration.
• Some drugs, (e.g.. penicillin G) are unstable in the acidic medium of the stomach > the
addition of buffer or the use of an enteric coating.
• Some drugs have poor bioavailability because of first-pass effects.
• If oral drug bioavailability is poor due to metabolism by enzymes in the GIT or in the liver,
then a higher dose may be needed (e.g.., Propranolol), or an alternative route of drug
administration, (e.g.., Nitro-glycerine).
• Incompletely absorbed drugs and drugs with highly variable bioavailability, under
unusual conditions (e.g.., change in diet or disease condition, drug–drug interaction),
excessive drug bioavailability can occur leading to more intense pharmacodynamic
activity and possible adverse events.
• If the drug is not absorbed after the oral route or a higher dose causes toxicity > drug is
given by alternative route, and a different dosage form.
Dose Considerations
• Because of differences in pharmacokinetic parameters several patients, require individualized
dosing, therefore, the drug product must usually be available in several dose strengths.
• Some tablets are also scored for breaking, to allow the administration of fractional tablet doses.
• When pediatric studies are necessary, they must be conducted with the same drug and for the
same use for which they were approved in adults.
• Thus, specific dosing guidelines and useful dosage forms for pediatric patients are being
developed to optimize therapeutic efficacy and limit, or prevent serious adverse side effects.
• Renal or liver impairment > the drug metabolism or excretion process may be altered > requiring
smaller dose.
• For example, in case of renal insufficiency, phenobarbitone, which is mainly excreted by
the kidneys, should be given in smaller dose, and in case of patients with liver impairment,
morphine should be given in smaller dose.
• The size and the shape of a solid oral drug product are designed for easy swallowing.
• For example, many patients may find a capsule-shaped tablet (caplet) easier to swallow than
a large round tablet.
Dosing Frequency
• The dose is the amount of drug taken at any one time.
• This can be expressed as the wt. of drug, volume of drug solution, or some other quantity
(2 puffs).
• The dosage regimen is the frequency at which the drug doses are given. Examples - two
puffs twice a day, one capsule two times a day, etc.
• The total daily dose is calculated from the dose and the number of times per day the dose
is taken.
• If the drug has a short elimination half-life or rapid clearance > the drug is given more
frequently or in an extended release drug product.
• Simplifying the medication dosing frequency improves compliance.
• To minimize fluctuating plasma drug concentrations and improve patient compliance >
extended-release drug product may be preferred.
Patient Considerations
• The drug product and therapeutic regimen must be acceptable to the patient.
• Poor patient compliance may result from poor product attributes, such as difficulty
in swallowing, disagreeable odor, bitter medicine taste, or too frequent and/or
unusual dosage requirements.
• Orally disintegrating tablets and chewable tablets allow the patient to typically
take the medication without water.
• These innovations improve compliance, pharmacodynamic factors, such as side
effects of the drug or an allergic reaction, also influence patient compliance.
• Transmucosal (nasal) administration of antiepileptic drugs may be more
convenient, easier to use, just as safe, and is more socially acceptable than rectal
administration.
Route of Drug Administration
• The route of drug administration affects the bioavailability, thereby affecting the
onset, duration, and intensity of the pharmacologic effect.
• For IV delivery, the total dose of drug reaches the systemic circulation. However,
drug delivery by other routes result in only partial absorption, resulting in lower
bioavailability.
• In the design of a drug dosage form, the manufacturer must consider:-
1. the intended route of administration;
2. the size of the dose;
3. the anatomic and physiologic characteristics of the administration site, such
as membrane permeability and blood flow;
4. the physicochemical properties of the site, such as pH, osmotic pressure, and
presence of physiologic fluids; and
5. the interaction of the drug and dosage form at the administration site,
including alteration of the administration site due to the drug and/or dosage
form.
• Pharmacodynamic activity of the drug at
the receptor site is similar with different
routes of administration, severe
differences in the intensity of the
pharmacodynamic response and the
occurrence of adverse events may be
observed.
• For example, isoproterenol has a
thousandfold difference in activity when
given orally or by IV injection.
• The use of novel drug delivery methods
could enhance the efficacy and reduce the
toxicity of antiepileptic drugs.
• Slow-release oral forms of medication or
depot drugs such as skin patches might
improve compliance and, therefore,
seizure control.
Dose–response curve to isoproterenol by
various routes in dogs
Alternative method of dissolution in-vitro in-vivo correlation and dissolution profile comparison

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Alternative method of dissolution in-vitro in-vivo correlation and dissolution profile comparison

  • 1. Alternative method of Dissolution Meeting dissolution requirements Performance of drug product Dissolution profile comparison by- Sahil Suleman M. Pharm (2st Sem)
  • 2. CONTENTS Introduction Dissolution Methods Alternative Methods Of Dissolution Testing Meeting Dissolution Requirements Problems Of Variable Control In Dissolution Testing Performance Of Drug Products: In Vitro–in Vivo Correlation Dissolution Profile Comparisons
  • 3. DISSOLUTION • Dissolution is a dynamic process by which solid solutes dissolve in a solvent to yield a solution. Mass transfer of drug from solid into solvent. • Dissolution rate may be defined as the amount of substances that goes into solution per unit time under standard conditions of temperature, pressure and solvent composition. • A drug is expected to be released from the solid dosage forms (granules, tablets, capsules etc.) and immediately go into molecular solution. • Dissolution is the rate determining step for hydrophobic, poorly aqueous soluble drugs. For instance : Griseofulvin, Spironolactone.
  • 4. DISSOLUTION METHODS COMPENDIAL METHODS OF DISSOLUTION 1. Apparatus 1: Rotating Basket 2. Apparatus 2: Paddle Method 3. Apparatus 3: Reciprocating Cylinder 4. Apparatus 4: Flow-through-Cell 5. Apparatus 5: Paddle-over-Disk 6. Apparatus 6: Cylinder 7. Apparatus 7: Reciprocating Disk ALTERNATIVE METHODS OF DISSOLUTION TESTING 1. Rotating Bottle Method 2. Intrinsic Dissolution Method 3. Peristalsis Method 4. Diffusion Cells
  • 5. Rotating Bottle Method • Used mainly for controlled-release beads. • For this purpose the dissolution medium may be easily changed, such as from simulated gastric juice to simulated intestinal juice. • The equipment consists of a rotating rack that holds the sample drug products in bottles. • The bottles are capped tightly and rotated in a 37±0.5°C temperature bath. At various times, the samples are removed from the bottle, decanted through a 40-mesh screen, and the residues are assayed. • An equal volume of fresh medium is added to the remaining drug residues within the bottles and the dissolution test is continued.
  • 6. • A dissolution test with pH 1.2 medium for 1 hour, pH 2.5 medium for the next 1 hour, followed by pH 4.5 medium for 1.5 hours, pH 7.0 medium for 1.5 hours, and pH 7.5 medium for 2 hours was recommended to simulate the condition of the gastrointestinal tract. • Used between 10 and 60 rpm. • The main disadvantage is that this procedure is manual and tedious.
  • 7. Simulated gastric fluid is a solution that simulates the composition and pH of gastric juice. The reagent is sterilized by 0.2 µm filtration. Simulated gastric juice is prepared by dissolving pepsin (1 g), gastric mucin (1.5 g), and NaCl (8.775 g) in 1 L distilled water with pH of 1.3 adjusted using 6 N HCI. Simulated Intestinal fluid composition – 1.725mL of KCl, 0.025mL of KH2PO4, 3.125mL of NaHCO3, 7.375mL of NaCl, 0.1mL of MgCl2.6H2O and 0.125mL of (NH4)2CO3
  • 8. Intrinsic Dissolution Method • Most methods for dissolution deal with a finished drug product. • Sometimes a new drug or substance may be tested for dissolution without the effect of excipients or the fabrication effect of processing. • The dissolution of a drug powder by maintaining a constant surface area is called intrinsic dissolution. • Intrinsic dissolution is usually expressed as mg/cm2/min. In one method, the basket method is adapted to test dissolution of powder by placing the powder in a disk attached with a clipper to the bottom of the basket.
  • 9. Peristalsis Method • The peristalsis method attempts to simulate the hydrodynamic conditions of the gastrointestinal tract in an in vitro dissolution device. • The apparatus consists of a rigid plastic cylindrical tubing fitted with a septum and rubber stoppers at both ends. • The dissolution chamber consists of a space between the septum and the lower stopper. • The apparatus is placed in a beaker containing the dissolution medium. • The dissolution medium is pumped with peristaltic action through the dosage form.
  • 10. Schematics of the peristaltic dissolution assembly. Plastic tubing is used to connect the combined Y-shaped connectors to the two hypodermic needles at the top of the disintegrating chamber and the outlet-inlet connectors of a Brewer pipetting pump assembly equipped with a 50 mL syringe
  • 11. Diffusion Cells • Static and flow-through diffusion cells are used to characterize in vitro drug release and drug permeation kinetics from topically applied dosage form or transdermal drug product. • The Franz diffusion cell is a static diffusion system that is used for characterizing drug permeation through a skin model. • The source of skin may be human cadaver skin or animal skin (e.g.., hairless mouse skin). Anatomically, each skin site (e.g., abdomen, arm) has different drug permeation qualities. • The skin is mounted on the Franz diffusion cell system. • The drug product (e.g.., ointment) is placed on the skin surface and the drug permeates across the skin into a receptor fluid compartment that may be sampled at various times.
  • 12. • The Franz diffusion cell system is useful for comparing in vitro drug release profiles and skin permeation characteristics to aid in selecting an appropriate formulation that has optimum drug delivery FRANZ DIFFUSION CELL
  • 13. MEETING DISSOLUTION REQUIREMENTS According to CFR (21CFR 343.90), a drug product application should include the specifications necessary to ensure the identity, strength, quality, purity, potency, and bioavailability of the drug product, including, and acceptance criteria relating to, dissolution rate in the case of solid dosage forms. For dissolution acceptance criteria, the following points should be considered:
  • 14. 1. The dissolution profile data from the pivotal clinical batches and primary (registration) stability batches should be used for the setting of the dissolution acceptance criteria of the product (i.e., specification-sampling time point and specification value). • A significant trend in the change in dissolution profile during stability should be justified with dissolution profile comparisons and in vivo data in those instances where the similarity testing fails. 2. Specifications should be established based on average in vitro dissolution data for each lot under study, equivalent to USP Stage 2 testing (n = 12). 3. For immediate-release formulations, the last time point should be the time point where at least 80% of drug has been released. • If the maximum amount released is less than 80%, the last time point should be the time when the plateau of the release profile has been reached. Percent release of less than 80% should be justified with data (e.g.., sink conditions information).
  • 15. 4. For extended-release formulations, a minimum of three time points is recommended to set the specifications. • These time points should cover the early, middle, and late stages of the release profile. The last time point should be the time point where at least 80% of drug has been released. • If the maximum amount released is less than 80%, the last time point should be the time when the plateau of the release profile has been reached. 5. The dissolution acceptance criterion should be set in a way to ensure consistent performance from lot to lot, and this criterion should not allow the release of any lots with dissolution profiles outside those that were studied clinically
  • 16. PROBLEMS OF VARIABLE CONTROL IN DISSOLUTION TESTING • Dissolution testing involves various steps such as solid–liquid mass transfer, particle erosion, possible particle disintegration, particle suspension, and particle–liquid interactions. • It is complicated by other factors such as shear stress distribution as a function of tablet location within the apparatus, and the location of the tablet upon its release inside the apparatus. • Depending on the particular dosage form involved, the variables may or may not exert a pronounced effect on the rate of dissolution of the drug or drug product. • Variations may occur with the same type of equipment and procedure.
  • 17. • The centering and alignment of the paddle is critical in the paddle method. • Turbulence can create increased agitation, resulting in a higher dissolution rate. • Wobbling and tilting due to worn equipment should be avoided. The basket method is less sensitive to the tilting effect. • However, the basket method is more sensitive to clogging due to gummy materials. • Pieces of small particles can also clog up the basket screen and create a local non- sink condition for dissolution. • Dissolved gas in the medium may form air bubbles on the surface of the dosage form unit and can affect dissolution in both the basket and paddle methods. • Small variations in the location of the tablet on the vessel bottom caused by the randomness of the tablet descent through the liquid are likely to result in significantly different velocities and velocity gradients near the tablet
  • 18. The Reynolds number is calculated with this equation: Where, Re is the Reynolds number, is the density of the fluid, v is the velocity of the fluid flow, d is the diameter of the pipe, and µ is the viscosity of the fluid.µ
  • 19. PERFORMANCE OF DRUG PRODUCTS: IN VITRO–IN VIVO CORRELATION • For CR or ER formulation - dissolution is the rate-limiting step, hence it is possible to establish a relationship between the release of the drug in vitro and its release in vivo or its absorption into the systemic circulation. • If such correlation exists, then one is able to predict the plasma concentration time profile of a drug from its in vitro dissolution. • Usually such a correlation is developed with two or more formulations with different release characteristics. (Recommended- 3 or more formulations) • If the dissolution of the drug is independent of the dissolution conditions (such as apparatus agitation rate, pH, etc), then it is possible to establish such a correlation with only one formulation
  • 20. • The establishment of a predictive IVIVC also enables us to decrease the number of in vivo studies needed to approve and maintain a drug product on the market resulting in an economic benefit as well as a decreased regulatory burden. • It also enables to set clinically meaningful dissolution specifications based on the predicted plasma concentration time profile. • There are two ways in evaluating the predictability of the correlation: 1. Internal predictability refers to the ability to predict the pharmacokinetic profile of the formulations that were used to develop the correlation; 2. External predictability refers to the ability to detect the profile of a lot or formulation that was not used to develop the IVIVC.
  • 21. Categories of In Vitro–In Vivo Correlations 1. Level A Correlation 2. Level B Correlation 3. Level C Correlation a) Dissolution rate versus absorption rate. b) Percent of drug dissolved versus percent of drug absorbed. c) Maximum plasma concentrations versus percent of drug dissolved in vitro. d) Serum drug concentration versus percent of drug dissolved. e) Biopharmaceutic Drug Classification System 4. Multiple level C correlation
  • 22. LEVEL A CORRELATION • Highest level of correlation and represents a point-to-point (1:1) relationship between an in vitro dissolution and the in vivo input rate of the drug from the dosage form. • Level A correlation compares the percent (%) drug released versus percent (%) drug absorbed. • The percentage of drug absorbed can be calculated by the Wagner– Nelson or Loo– Riegelman procedures or by direct mathematical deconvolution. Advantages- • A point-to-point correlation is developed. • In vitro dissolution profile can serve as a surrogate for in vivo performance. • A change in manufacturing site, method of manufacture, raw material supplies, minor formulation modification, and product strength using the same formulation can be justified without the need for additional human studies. • Enables the in vitro dissolution test to become meaningful and clinically relevant quality control test that can predict in vivo drug product performance
  • 23. % drug dissolved in-vitro % drug Absorbed in-vivo LEVEL A CORRELATION
  • 24. WAGNER NELSON METHOD • The Wagner Nelson method can be used to calculate the absorption rate constant when the absorption process follows zero-order or first-order. • The model also generates AUCs (Areas Under the Curve) and rate of absorption values. • This method estimates the loss of drug from the GI over time, whose slope is inversely proportional to ka. • After a single oral dose of a drug, the total dose should be completely accounted for the amount present in the body, the amount present in the urine, and the amount present in the GI tract. • Dose (D0) is expressed as follows:
  • 25. LOO–RIEGELMAN • Used to calculate the relative amount absorbed as a function of time from plasma concentration data which follow a two-compartment open model. • After oral administration of a dose of a drug that exhibits two-compartment model kinetics, the amount of drug absorbed is calculated as the sum of the amounts of drug in the central compartment (Dp), in the tissue compartment (Dt), and the amount of drug eliminated by all routes (Du). Ab = Dp + Dt + Du
  • 27. LEVEL B CORRELATION • Level B correlation utilizes the principle of statistical moment in which the mean in-vitro dissolution time is compared to either the mean residence time (MRT) or the mean in-vivo dissolution time (MDT). • Level B correlation uses all of the in vitro and in vivo data, but is not a point-to- point correlation. • Different profiles can give the same parameter values. • The Level B correlation alone cannot justify formulation modification, manufacturing site change, excipient source change, batch-to-batch quality, etc.
  • 28. MRT(Mean residence time) represents the average time a molecule stays in the body. The MRT is calculated by summing the total time in the body and dividing by the number of molecules. AUMC is obtained from a plot of product of plasma drug concentration and time (i.e. C.t) versus time t from zero to infinity. Mathematically, it is expressed by equation: AUC is obtained from a plot of plasma drug concentration versus time from zero to infinity. Mathematically, it is expressed by equation:
  • 29. MDT (The mean dissolution time ) can be calculated arithmetically the following equation: where W(t) is the cumulative amount of drug dissolved at time t. This equation is very useful, especially in cases where a correlation of in vitro and in vivo MDT values is attempted. In actual practice, an equivalent form of this equation is used to derive an estimate of MDT from experimental dissolution data where W∞ is the asymptote of the dissolved amount of drug and ABC is the area between the cumulative dissolution curve and W∞
  • 30.
  • 31. • Not a point-to-point correlation. • Establishes a single-point relationship between a dissolution parameter (such as drug released at a certain time ) and a pharmacokinetic parameter of interest (such as AUC and Cmax). • Useful for formulation selection and development but has limited application. • Multiple Level C correlation relates one or several pharmacokinetic parameters of interest to the amount of drug dissolved at several time points of the dissolution profile. • In general, if one is able to develop a multiple Level C correlation, then it may be feasible to develop a Level A correlation. LEVEL C CORRELATION Fig- Level C correlation showing the relationship between the amount of drug dissolved at a certain time and the peak plasma concentration
  • 32. Examples of Level C correlation:- • Dissolution rate versus absorption rate. • Percent of drug dissolved versus percent of drug absorbed. • Biopharmaceutic Drug Classification System
  • 33. Dissolution Rate Versus Absorption Rate • If dissolution is rate limiting, faster dissolution - faster rate of appearance of the drug in the plasma. correlation between rate of dissolution and rate of absorption may be established . • The absorption rate is usually more difficult to determine than peak absorption time. Therefore, the absorption time may be used in correlating dissolution data to absorption data. • In the analysis of in vitro–in vivo drug correlation, rapid drug dissolution may be distinguished from the slower drug absorption by observation of the absorption time for the preparation. • The absorption time refers to the time for a constant amount of drug to be absorbed.
  • 34. Fig- An example of correlation between time required for a given amount of drug to be absorbed and time required for the same amount of drug to be dissolved in vitro for three sustained-release aspirin products
  • 35. Percent of drug dissolved versus percent of drug absorbed • If a drug is absorbed completely after dissolution, a linear correlation may be obtained by comparing the percentage of drug absorbed to the percentage of drug dissolved. • In choosing the dissolution method, appropriate dissolution medium and slow dissolution stirring rate is considered so that in vivo dissolution is approximated. • Aspirin is absorbed rapidly, and a slight change in formulation may be reflected in a change in the amount and rate of drug absorption during the period of observation. • If the drug is absorbed slowly, which occurs when absorption is the rate-limiting step, a difference in dissolution rate of the product may not be observed. In this case, the drug would be absorbed very slowly independent of the dissolution rate.
  • 36. Fig- An example of correlation between time required for a given amount of drug to be absorbed and time required for the same amount of drug to be dissolved in vitro for three sustained-release aspirin products Fig- An example of continuous in vivo–in vitro correlation of aspirin.
  • 37. Biopharmaceutic Drug Classification System • BCS is a predictive approach to relate certain physicochemical characteristics of a drug substance and drug product to in vivo bioavailability. • The BCS is not a direct in vitro– in vivo correlation. • For example, BCS Class I drugs- rapidly and mostly absorbed. (oral and IR) • A BCS Class I drug (highly soluble & permeable) rapidly dissolves from the drug product over the physiologic pH range of 1–7.4. • Highly permeable drugs are drugs whose absolute bioavailability is greater than 90%. • BCS only applies to oral immediate-release formulations and cannot be applied to modified-release formulations or for buccally absorbed drug products.
  • 38. MULTIPLE LEVEL C CORRELATION • This level refers to the relationship between one or more pharmacokinetic parameters of interest (Cmax,,AUC, or any other suitable parameters) and amount of drug dissolved at several time points of dissolution profile. • Multiple point level C correlation may be used to justify a biowaver provided that the correlation has been established over the entire dissolution profile with one or more pharmacokinetic parameter of interest. • A multiple level C correlation should be based on atleast three dissolution time points covering the early, middle, and last stages of the dissolution profile. • The development of a level A correlation is also likely, when multiple level C correlation is achieved at each time point at same parameter such that the effect on the in vivo performance of any change in dissolution can be assessed.
  • 39. DISSOLUTION PROFILE COMPARISONS • Dissolution profile comparisons are used to assess the similarity of the dissolution characteristics of two formulation or different strengths of the same formulation to decide whether in vivo bioavailability/ bioequivalence studies are needed. • The SUPAC-IR and SUPAC-MR provide recommendations to firms who intend, during the post-approval period, to change a) The components or compositions b) The site of manufacture c) The scale-up/scale-down of manufacture; and/or d) The manufacturing (process and equipment) of the drug product. For each type of change, these guidance list documentation (e.g., dissolution testing, bioequivalence, etc) should be normally provided to support the change depending on the level of complexity of the proposed change
  • 40. • For minor changes and some major changes for which in vivo bioequivalence is not warranted, dissolution profile comparisons either in the proposed media or in multimedia can be submitted to support the change. • Dissolution profiles may be considered similar by virtue of overall profile similarity and/or similarity at every dissolution sample time point. • According to the FDA - three statistical methods for the evaluation of similarity: 1. Model-independent approach using a similarity factor; 2. Model-independent multivariate confidence region procedure; and 3. Model dependent approach
  • 41. Model-independent approach Difference factor (f1) • The difference factor (f1) calculates the percent (%) difference between the two curves at each time point and is a measurement of the relative error between the two curves. Similarity factor (f2) • It is logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) dissolution between the two curves. n - number of time points, R - dissolution value of the reference batch at time t, T - dissolution value of the test batch at time t
  • 42. A specific procedure to determine difference and similarity : 1. Determine the dissolution profile of two products (12 units each) of the test and reference products. 2. Using the mean dissolution values from both curves at each time interval, calculate the difference factor (f1 ) and similarity factor (f2 ) using the given equations. 3. For curves to be considered similar, f 1 values should be close to 0, and f2 values should be close to 100. • Generally, f1 values up to 15 (0-15) and f2 values greater than 50 (50-100) ensure sameness or equivalence of the two curves and, thus, of the performance of the test and reference products. • This model independent method is most suitable for dissolution profile comparison when three to four or more dissolution time points are available.
  • 43. Recommendations to be considered: • The dissolution measurements of the test and reference batches should be made under exactly the same conditions. The dissolution time points for both the profiles should be the same (e.g.., 15, 30, 45, 60 minutes). The reference batch used should be the most recently manufactured prechange product. • Only one measurement should be considered after 85% dissolution of both the products. • To allow use of mean data, the percent coefficient of variation at the earlier time points (e.g.., 15 minutes) should not be more than 20%, and at other time points should not be more than 10%. • The mean dissolution values for R can be derived either from (1) last batch or (2) last two or more consecutively manufactured reference batches.
  • 44. Model Independent Multivariate Confidence Region Procedure In instances where within batch variation is more than 15% CV, a multivariate model independent procedure is more suitable for dissolution profile comparison. Steps: 1. Determine the similarity limits in terms of multivariate statistical distance (MSD) based on inter batch differences in dissolution from reference (standard approved) batches. 2. Estimate the MSD between the test and reference mean dissolutions. 3. Estimate 90% confidence interval of true MSD between test and reference batches. 4. Compare the upper limit of the confidence interval with the similarity limit. The test batch is considered similar to the reference batch if the upper limit of the confidence interval is less than or equal to the similarity limit.
  • 45.
  • 46. Model Dependent Approaches Several mathematical models are described to fit dissolution profiles. To allow application of models to comparison of dissolution profiles, the following procedures are suggested: 1. Select the most appropriate model for the dissolution profiles from the standard, prechange, approved batches. A model with no more than three parameters (such as linear, quadratic, logistic, probit, and Weibull models) is recommended. 2. Using data for the profile generated for each unit, fit the data to the most appropriate model. 3. A similarity region is set based on variation of parameters of the fitted model for test units (e.g.., capsules or tablets) from the standard approved batches.
  • 47. 4. Calculate the MSD in model parameters between test and reference batches. 5. Estimate the 90% confidence region of the true difference between the two batches. 6. Compare the limits of the confidence region with the similarity region. If the confidence region is within the limits of the similarity region, the test batch is considered to have a similar dissolution profile to the reference batch.
  • 48. DRUG PRODUCT STABILITY • Product stability is usually determined by testing a variety of stability indicating attributes such as drug potency, impurities, dissolution, and other relevant physicochemical measures of performance as necessary. • Stability studies are performed under well-controlled testing conditions and provide evidence on how the quality of a drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, oxygen, and light. • The time period during which a drug product is expected to remain within the established product quality specification under the labelled storage conditions is generally termed “shelf-life”(expiration period, expiry date, or expiration date). ICH Q1A(R2)
  • 49. CONSIDERATIONS IN THE DESIGN OFA DRUG PRODUCT Biopharmaceutic Considerations The essential elements include- 1. The physicochemical nature of the drug to be used, for example, salt and particle size; 2. The timing of these studies in relation to the preclinical studies with the drug; 3. The determination of the solubility and dissolution characteristics; 4. The evaluation of drug absorption and physiological disposition studies; and 5. The design and evaluation of the final drug formulation. • The finished dosage form should not produce any additional side effects or discomfort due to the drug and/or excipients. • Ideally, all excipients - pharmacologically inactive ingredients in the final dosage form
  • 50. Pharmacodynamic Considerations • The therapeutic objective influences the design of the drug product, route of drug administration, dose, dosage regimen, and manufacturing process. • An oral drug used to treat an acute illness is generally formulated to release the drug rapidly, allowing for quick absorption and rapid onset. • If more rapid drug absorption is desired , then an injectable drug is formulated. • Nitro-glycerine, is highly metabolized if swallowed, hence, a sublingual tablet formulation. • To reduce unwanted systemic side effects - locally acting drugs (such as inhaled drugs) • Advantage – drug can be delivered directly into the lungs. • For the treatment of certain diseases, such as hypertension, chronic pain, etc, an extended or controlled-release dosage form is preferred
  • 51. Drug Substance Considerations • The physicochemical properties of the drug substance are major factors. • It include solubility, stability, chirality, polymorphs, solvate, hydrate, salt form, ionizable behaviour, and impurity profile. • They influence the type of dosage form, the formulation, and the manufacturing process. • Physical properties of the drug such as intrinsic dissolution rate, particle size, and crystalline form are influenced by methods of processing and manufacturing. • If the drug has low aqueous solubility and an intravenous injection is desired, a soluble salt of the drug may be prepared. • Chemical instability or chemical interactions with certain excipients also affect the type of drug product and its method of fabrication.
  • 52. Pharmacokinetics of the Drug • Clinical failures of about 50% of the Investigational New Drug (IND) filings are attributed to their inadequate ADME attributes. • the integration of PK and PD allows for the characterization of the onset, intensity, and duration of the pharmacological effect of a drug and its interaction to the mechanism of action. • The degree of polymorphism can significantly affect the drug metabolism and, therefore, the pharmacokinetics and the clinical outcome of the drug. • Pharmacokinetic properties(ADME), of the molecules being investigated as potential drug candidates is a major factor. • The data obtained from ADME studies allow the development of a dose and dosage regimen that are age appropriate including avoidance of drug–drug interactions, food effect interactions, and achieving an appropriate drug release rate.
  • 53. Bioavailability of the Drug • Dissolve > disintegrate > Absorb • The stability of the drug in the gastrointestinal tract, is one consideration. • Some drugs, (e.g.. penicillin G) are unstable in the acidic medium of the stomach > the addition of buffer or the use of an enteric coating. • Some drugs have poor bioavailability because of first-pass effects. • If oral drug bioavailability is poor due to metabolism by enzymes in the GIT or in the liver, then a higher dose may be needed (e.g.., Propranolol), or an alternative route of drug administration, (e.g.., Nitro-glycerine). • Incompletely absorbed drugs and drugs with highly variable bioavailability, under unusual conditions (e.g.., change in diet or disease condition, drug–drug interaction), excessive drug bioavailability can occur leading to more intense pharmacodynamic activity and possible adverse events. • If the drug is not absorbed after the oral route or a higher dose causes toxicity > drug is given by alternative route, and a different dosage form.
  • 54. Dose Considerations • Because of differences in pharmacokinetic parameters several patients, require individualized dosing, therefore, the drug product must usually be available in several dose strengths. • Some tablets are also scored for breaking, to allow the administration of fractional tablet doses. • When pediatric studies are necessary, they must be conducted with the same drug and for the same use for which they were approved in adults. • Thus, specific dosing guidelines and useful dosage forms for pediatric patients are being developed to optimize therapeutic efficacy and limit, or prevent serious adverse side effects. • Renal or liver impairment > the drug metabolism or excretion process may be altered > requiring smaller dose. • For example, in case of renal insufficiency, phenobarbitone, which is mainly excreted by the kidneys, should be given in smaller dose, and in case of patients with liver impairment, morphine should be given in smaller dose. • The size and the shape of a solid oral drug product are designed for easy swallowing. • For example, many patients may find a capsule-shaped tablet (caplet) easier to swallow than a large round tablet.
  • 55. Dosing Frequency • The dose is the amount of drug taken at any one time. • This can be expressed as the wt. of drug, volume of drug solution, or some other quantity (2 puffs). • The dosage regimen is the frequency at which the drug doses are given. Examples - two puffs twice a day, one capsule two times a day, etc. • The total daily dose is calculated from the dose and the number of times per day the dose is taken. • If the drug has a short elimination half-life or rapid clearance > the drug is given more frequently or in an extended release drug product. • Simplifying the medication dosing frequency improves compliance. • To minimize fluctuating plasma drug concentrations and improve patient compliance > extended-release drug product may be preferred.
  • 56. Patient Considerations • The drug product and therapeutic regimen must be acceptable to the patient. • Poor patient compliance may result from poor product attributes, such as difficulty in swallowing, disagreeable odor, bitter medicine taste, or too frequent and/or unusual dosage requirements. • Orally disintegrating tablets and chewable tablets allow the patient to typically take the medication without water. • These innovations improve compliance, pharmacodynamic factors, such as side effects of the drug or an allergic reaction, also influence patient compliance. • Transmucosal (nasal) administration of antiepileptic drugs may be more convenient, easier to use, just as safe, and is more socially acceptable than rectal administration.
  • 57. Route of Drug Administration • The route of drug administration affects the bioavailability, thereby affecting the onset, duration, and intensity of the pharmacologic effect. • For IV delivery, the total dose of drug reaches the systemic circulation. However, drug delivery by other routes result in only partial absorption, resulting in lower bioavailability. • In the design of a drug dosage form, the manufacturer must consider:- 1. the intended route of administration; 2. the size of the dose; 3. the anatomic and physiologic characteristics of the administration site, such as membrane permeability and blood flow; 4. the physicochemical properties of the site, such as pH, osmotic pressure, and presence of physiologic fluids; and 5. the interaction of the drug and dosage form at the administration site, including alteration of the administration site due to the drug and/or dosage form.
  • 58. • Pharmacodynamic activity of the drug at the receptor site is similar with different routes of administration, severe differences in the intensity of the pharmacodynamic response and the occurrence of adverse events may be observed. • For example, isoproterenol has a thousandfold difference in activity when given orally or by IV injection. • The use of novel drug delivery methods could enhance the efficacy and reduce the toxicity of antiepileptic drugs. • Slow-release oral forms of medication or depot drugs such as skin patches might improve compliance and, therefore, seizure control. Dose–response curve to isoproterenol by various routes in dogs