A process in which drug comes
out from drug product and exposed to ADME and finally become accessible for
pharmacological activity is known as drug release and mechanism involves the study
of its rate and factors influencing its rate. Factors influencing the rate of
drug release are drug related, polymer related and formulation variables. Drug
delivery systems are discriminated on the basis of way drug is delivered, which
are immediate release and modified release. Parenteral dosage forms are the
most prominent among different dosage forms. The mechanisms involved in drug
release are diffusion and dissolution-controlled processes. Nasal disposal
basically depends on the particle size, its geometry and rate of airflow. Nasal
sprays are commonly used than powders and gels. Buccal and sublingual systems
show more effective drug release mechanisms than oral and transdermal systems.
Main focus of paper is to elaborate different mechanisms performed by drug
delivery systems for drug release.
Mechanisms, Dosage Forms, Drugs, Parenteral, Diffusion
process via which a drug is left from a drug product and is exposed to ADME and
ultimately becomes accessible for pharmacological action is called drug
Release Mechanisms is the amount of drug release from a particular dosage form
after dissolution and the study of aspects affecting release rate of the drug.
Dissolution and release of drugs are essential terms for solid and semi-solid
dosage forms which are involved in delivering the drugs over the intended
period of time.
Involved in Drug Release Mechanism
They include diffusion, dissolution, swelling, precipitation and/or
it involves the transfer of mass from a solid to liquid phase.it
consists of 2 consecutive phases.
Noyes-Whitney-Nernst equation explains drug dissolution process of
solid dosages. (Hattori, Haruna& Otsuka 2013)
of dissolution= Ks (Cs-C)
Figure 1: Mathematical Model
for Drug Dissolution Noyes- Whitney Equation
is the wetting of surface and medium ingression into tablet, drug’s
dissolution, and diffusion of the soluble drug across hydrated matrix into the
affect Drug Release’s Mechanism
factors influenced the drug release’s mechanism.
release is shown by highly soluble drugs, while incomplete release is often
shown by poorly water-soluble drugs (<0.01 mg/mL) often show incomplete release.
The rate of release s
increased by increased
drug content at persistent polymer content and hence, higher chemical gradient
at the diffusion front.
MW and Size
When matrix is completely
drug’s diffusion coefficient slowly changes from near zero to maximum. The
diffusion coefficient is dependent on MW, solute molecule’s diameter, and
diffusion medium’s viscosity. Due to constrain imposed by the aqueous gel
structure, drugs with a MW of >500Da are poorly diffusible in hydrophilic
terms of effective surface area, drug release is determined by particle size
and shape of soluble drugs.
of Various Dosage forms
happens by two mechanisms, drug will either diffuse through polymer or polymer
erode. Diffusion of drug is increased as polymer content increases and the
interaction between the polymer and solute. The properties of polymers like
viscosity, etc must be measured. Viscosity of gel increases with an increase in
polymer content, leading to decrease in effective diffusion coefficient of the
drug and rate of drug release falls.
surface area is provided by an increased tablet size which leads to total
equilibrium in the release rate. drug release may be increased by adding
surfactant through improved wetting. Formulation components like binding
agents can hinder drug release, plasticizers may increase drug-release rates
and lubricants will delay drug release.
drug delivery systems according to their composition:
rate controlling step is dissolution in this system. The drug is implanted in erodible
matrix in this system.
It has 2 kinds:
limiting step is the diffusion of drug through membrane barrier that is water
insoluble. This system has 2 kinds:
and Diffusion-Controlled System
soluble membrane encloses a drug core. dissolution of the parts of membrane
creates pores that allow entrance of aqueous medium into core, therefore
dissolution of drug occurs and permit diffusion of dissolved drugs out of the
system. (Simon, Bolisetty&Erazo, 2011).
step is the penetration of water into the system is the rate controlling step.
It has 2 kinds:
Figure 3: Reservoir diffusion Swelling and b-matrix diffusion
are primarily dry and absorb water and other fluid when sited in body and
are devised by enclosing an osmotic drug core which contains an osmotically
active drug or combination of osmotically inactive drug with a salt (NaCl). A
slope of osmotic pressure has been formed, where the drug solutes have been
continually driven out over a prolonged period of time through delivery
orifice. (Gupta et al., 2010)
alter their chemical structure when visible to the biological fluid. The
polymer is degraded into biologically safe and smaller moieties as a result of
It has 2 kinds:
involves the occurrence of mechanism of drug release by erosion. Erosion may
have 2 kinds:
consists of linear or homo or copolymers attached to drug. The drug is release
from polymer by
or enzymatic degradation of the linkages.
are water swollen 3-D structure made up of chiefly hydrophilic polymers. They
are rendered insoluble because of chemical and physical cross links.
of Delivery Systems of Drugs Based on Drug Release Mechanisms
differentiated on the basis of drug release. Broadly, they are classified as:
administration there is immediate release of drug.
administration of drug its released time is
Modified release systems are classed as:
initial administration release of drug occurs just at some spot.
to reduce dosing frequency, it
dosage forms are released immediately or instantly after administration into
body. It is the required for some for some therapeutic causes. Example includes
IV injections and infusions which have fast onset of action and after
administration show pharmacological outcome in few seconds.
release dosage form is the formulation of such systems that release the active
ingredients after some time of administration instead of immediately. These
systems are very beneficial for those drugs which undergo degradation in the
acidic environment of stomach. So, in such circumstances there is delay in the
release of drug until it reaches the small intestine. For this purpose,
polymers are often used. The dosage form either tablet or capsule before
tableting undergoes coating of a polymer. When such dosage form moves from
acidic to basic pH environment i.e., from stomach to small intestine the
polymer dissolves so a polymer dissolves according to pH and the drug releases.
Once this process occurs the drug releases immediately and the curve obtained
between plasma concentration and time is exactly the same as for immediate
purpose of using the extended-release dosage
is to extend the time period for the release of drug. In this way there is
decrease in the dosing frequency of drug. Sustained – or controlled release
dosage forms play important role in achieving extended-release forms.
systems maintain rate of drug release over prolonged period. This can be
achieved by use of polymers which involve in the coating of tablets or granules
or for formation of matrix system in which there is usually dispersion of drug
matrix which is biodegradable is usually used for this system. Matrix consists
of therapeutic agent in the dispersed or enclosed form. So, this leads to the
formation of complex heterogeneous release pattern. First there is immediate
release of drug that means it’s not protected well by carrier. And then from
polymeric matrix there is controlled release of drug occurs. Mechanisms
involved in this system are combinations of diffusion and degradation.
is in the favor of some diseases having varied drug release rate depending on
requirements of patient or their body’s circadian rhythms. It can be explained
through an example regarding the concentration of insulin that is required in
greater amount after meal and B.P also varies as it is higher in morning and
afternoon while falls during night. This leads to analysis into thus known as
feedback regulated drug delivery system in which with help of sensor the
concentration of drug can be measured, and drug release is either enhanced or
decreased depending on the ideal drug concentration.
purpose of drug targeting is to manage disposition of drug within a body in a
way that majority of dose particularly binds to target tissue at cellular or
subcellular level. The purpose of this is to increase activity and selectivity
of drug and to decrease its side effects. Such systems are designed in which
targeting is done passively by altering natural conditions of target tissues to
achieve drug targeting. On the other hand, drug targeting can be achieved
directly by targeting groups so that they bind on cells at specific receptors.
Mechanisms from Different Dosage Forms
Delivery of Drug
Via Parenteral Route
dosage forms are the most prominent among different dosage forms and then
aerosols and nasal dosage forms stand. The mechanisms involved in drug release
are diffusion and dissolution-controlled processes. Mechanisms of drug release
mainly depends on the excipients, types of excipients, their amount,
manufacturing methods, dosage form’s geometry, routes of administration, drug’s
pharmacokinetic and physico-dynamics.
drug via respiratory route
of drugs respiratory tract is brought about by following mechanisms:
Impaction Due to Inertia
deposition is brought about by inertia of aerosol particles. Particles
possessing high mass or high velocity tend to show greater landing distances
and have greater probability of sticking on the interior periphery of
respiratory pathway. (Newman S. P., 2016)
tiny particles (0.5 to 3 μm) lands via sedimentation to
bronchioles and alveoli.
mechanism does not depend upon the density of a particle but increases when we
decrease the size of the particle and depends on time for which particle
resides and this deposition can me more significant if breath is held in for
exists for particles having unequal breadths and widths.
exists for particles possessing some charge. Increased landing of aerosol
particles in lung lining is brought about with greater percentage of particles
of size less than 5 μm. Factors responsible for
adhesion of particles as well as their dispersion include PK characteristics of
carrier and drug particle, for instance ratio between drug and its carrier. Drug
deposition of drug is mostly seen with carriers of small size and presence of
particles in greater percentage.
Delivery of Drug
Via Nasal Route
It is profoundly
dependent upon size of particle or droplet, rate of air flow, and topology of
nasal passage. Particles inhaled land majorly via impaction due to inertia.
Relocation via clearance through mucus and ciliary brings a further subsidiary
landing of drug.
bioavailability as well as absorption via nasal passage is influenced by PK
characteristics of drug. Nasal delivery via suspension dosage forms is not in
normal practice owing to finite volume of water present in nasal chamber for
case of dry powders or powders for suspension for nasal delivery, rate of
dissolution influence rate of absorption. Particles that are to land in nasal
space normally be in dissolved form before their absorption. Bioavailability
definitely reduces when drug particles leave the tract before they are
Delivery of Drug
Via Buccal and Sublingual Route
Movement of drug
to traverse mucosa oral passageway is brought about by para-cellular and
Absorption predominantly takes place via passive
diffusion. Absorption of drug is influenced by its lipophilicity, molecular
weight as well as dissolubility at the main absorption site. Greater potency is
a key for pronounced drug delivery via buccal and sublingual course, owing to
the confined surface area for drug absorption. (Senel et al., 2012)
Delivery of Drug
Via Oral Route
Drug absorption rate of oral dosage
form is governed by the PK characteristics of drug, features related to the
dosage form formulation, and state of body with respect to body’s physiology.
PK characteristics of drug influencing the absorption constitute (a)dissolution
rate, (b)extent to which the drug ionizes, and (c)molecular weight. Drugs that
do not ionize possess higher potential to permeate through the membrane.
Majority of the drugs get absorbed in colon from its small intestine portion,
despite the extent of ionization. Nevertheless, tiny particles accretion
sometimes may tend to expand the essential surface area, bringing about
constant or decreasing rate of dissolution and hence the resulting
Delivery of Drugs
Via Topical and Transdermal Course
delivery, the drugs must infiltrate skin barrier in quantities that are enough
to bring about systemic effect without being influenced by enzymes present in
the uppermost layer of skin i.e. epidermis. Potency to bring about therapeutic
effect must be achieved in doses lesser than 10mg.
Two fundamental constitutional layout of transdermal
patch system govern the release of drug from the system:
also Known as Monolithic System
this type of system, the drug binds to polymer considered for making matrix
should be inert in nature and should bind the drug and regulate the liberation
of drug from patch.
is also called depot system. The matrix is made up of polymer, but it does not
regulate the outflow of drug. Here is a membrane that exists between drug
matrix and an adhesive layer. This membrane serves to be rate limiting owing to
be a bottleneck step for the release of drug from the patch.
It is finally
concluded that the need for different release mechanism is significant to cater
the needs different patients, different diseases, different drugs, preference
in a specific case for the maximum benefit of patient and to provide the
patient with a drug which when given has such release mechanism that its
benefits outweigh its risks as far as the case of a patient is concerned and is
beneficial for improving the life of a patient. For the purpose stated above,
one should also consider the point that the treatment focused on a certain
release mechanism must not be financially unbearable to the patient. immediate
release drugs are given when we have to rehabilitate the patient as soon as
possible or when if the patient is not given immediate treatment, his or her
case would become detrimental e.g., angina pectoris, coma, anaphylaxis shock
etc. Among modified release dosage forms, delayed release dosage forms are
given when the drug needs to bypass certain length of its overall course so
that it can just work on its desired site of action and would not be degraded
before it reaches its actual site. Extended-release dosage forms are a choice
when there is a need for reduced frequency of dosing. Extended-release dosage
forms are employed when it calls for a drug to be released for a prolonged
duration of time. The main benefit of this release is reduced frequency.
Sustained release mechanism is employed to maintain a fixed concentration over
a particular period of time with least side effects. Controlled release dosage
forms are suitable when it calls for the therapeutic substances to be released
for longer duration of time with controlled rates and mostly for days to weeks
and even months and many a times year also. Its main benefit is minimal blood
plasma drug levels and low toxicity.
injection is an immediate release dosage form with bioavailability of 100
percent which seems an ideal case but exists in reality. IM preparations are
given in case of drugs when they are poorly hydrophilic and in situations where
systemic as well as local or anyone of these side effects occur due to
increased peak drug concentrations.
delivery by respiratory includes mechanisms such as impaction, sedimentation,
diffusion, interference, electrostatic effect. The nasal route follows mainly
the mechanism of impaction due to inertia. In buccal and sublingual routes,
absorption occurs significantly via passive diffusion and the bottleneck step
there is confined volume of fluid for effective absorption.
Drug delivery via transdermal route includes
absorption via the use of adhesive aka sticky devices that regulate the release
and absorption of a particular amount of drug over a period of time and the
basic infrastructure of these devices is different to serve the purpose
different on case-to-case basis. Some devices are disposable while others are
re-usable owing to their sterilization and economical affective conditions and
their frequent and easy availability.
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