MODULE - 4

Syllabus

• Process Research
– Formulation dosage form
– synthesis methods
– delivery methods
– scale up and manufacturing plans
 Formulation dosage form
• Dosage Form (DF) is defined as the physical form of a dose of a chemical compound used as a drug
or medication intended for administration or consumption.
• Common dosage forms include pill, tablet, or capsule, drink or syrup, aerosol or inhaler, liquid
injection, pure powder or solid crystal (e.g., via oral ingestion or freebase smoking), and natural or
herbal form such as plant or food of sorts, among many others.
• The route of administration (ROA) for drug delivery is dependent on the dosage form of the
substance
• Direct clinical use of the active drug substances is rare: Why??
– API handling and Accurate dosing can be difficult or impossible (e.g., potent drugs: low mg
and micro g doses)
– API administration can be impractical/unfeasible because of size, shape, smell/odour, taste
and low activity.
– Some API are chemically unstable in light, moisture, O2
– API can be degraded at the site of administration (e.g., low pH in stomach).
– API may cause local irritations or injury when they are present at high concentrations at the
site of administration.
– Administration of active substance would mean to have no chance for modification
(improvement) of its PK profile
 Need for dosage forms
• providing the mechanism for the safe and convenient delivery of accurate dosage
• To protect the drug substance from the destructive influences of atmospheric oxygen or humidity
(coated tablets, sealed ampuls)
• To protect the drug substance from the destructive influence of gastric acid after oral
administration (enteric-coated tablets)
• To conceal the bitter, salty, or offensive taste or odor of a drug substance (capsules, coated tablets,
flavored syrups)
• To provide liquid preparations of drug substances, either as dispersions (suspensions) or as clear
preparations (solutions)
• To provide rate-controlled drug action (various controlled-release tablets, capsules, and
suspensions)
• To provide optimal drug action through different routes of administration
 GENERAL CONSIDERATIONS IN DOSAGE FORM DESIGN
• Before a medicinal agent is formulated into one or more dosage forms, among the factors
considered are such therapeutic matters as the nature of the illness, the manner in which it is
treated (locally or through systemic action), and the age and anticipated condition of the patient.
• If the medication is intended for systemic use and oral administration is desired, tablets and/or
capsules are usually prepared because they are easily handled by the patient and are most
convenient in the self-administration of medication.
• If a drug substance has application in an emergency in which the patient may be comatose or
unable to take oral medication, an injectable form of the medication may also be prepared.
• The age of the intended patient also plays a role in dosage form design. For infants and children
younger than 5 years of age, pharmaceutical liquids rather than solid forms are preferred for oral
administration
• Before formulating a drug substance into a dosage form, the desired product type must be
determined as far as possible to establish the framework for product development.
• Then, various initial formulations of the product are developed and examined for desired features
(e.g., drug release profile, bioavailability, clinical effectiveness) and for pilot plant studies and
production scale-up.
• The formulation that best meets the goals for the product is selected to be its master formula.
• Each batch of product subsequently prepared must meet the specifications established in the
master formula.
• There are many different forms into which a medicinal agent may be placed for the convenient and
efficacious treatment of disease. Most commonly, a manufacturer prepares a drug substance in
several dosage forms and strengths for the efficacious and convenient treatment of disease
 Additives/Excipients in dosage form
• An excipient is a substance formulated alongside the active ingredient of a medication, included for
the purpose of long-term stabilization, bulking up solid formulations that contain potent active
ingredients in small amounts (thus often referred to as "bulking agents", "fillers", or "diluents"), or
to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as
facilitating drug absorption, reducing viscosity, or enhancing solubility
• Generally, an excipient has no medicinal properties. Its standard purpose is to streamline the
manufacture of the drug product and ultimately facilitate physiological absorption of the drug.
• The selection of appropriate excipients also depends upon the route of administration and the
dosage form, as well as the active ingredient
• Pharmaceutical regulations and standards require that all ingredients in drugs, as well as their
chemical decomposition products, be identified and shown to be safe.
• Fillers: Adds to the volume and/or mass, thereby helping in precise dosing and handling. Eg: Plant
cellulose, lactose, manitoll, dibasic calcium phosphate
• Binders: Hold the ingredients together, gives mechanical strength. Adds cohesion to the powder. Eg:
cellulose, polyethylene glycol
• Disintegrants: facilitates dispersion or breakup for quicker dissolution when it comes into contact
with water in the gastrointestinal tract. Eg: Sodium starch glycolate, carboxy methyl cellulose
• Coating agent: protect and mask the API, ease of swallowing etc. eg: hydroxypropyl methylcellulose
• Antiadherents: Antiadherents reduce the adhesion between the powder (granules) and the punch
faces and thus prevent sticking to tablet punches by offering a non-stick surface. They are also used
to help protect tablets from sticking. The most commonly used is magnesium stearate.
 Additives/Excipients in dosage form
• Colours: Colours are added to improve the appearance of a formulation. Colour consistency is
important as it allows easy identification of a medication. Eg: titanium oxide
• Flavors can be used to mask unpleasant tasting active ingredients and improve the acceptance that
the patient will complete a course of medication. Flavorings may be natural (e.g. fruit extract) or
artificial. Eg: Vanilla
• Glidants are used to promote powder flow by reducing interparticle friction and cohesion. Eg:
magnesium carbonate
• Lubricants prevent ingredients from clumping together and from sticking to the tablet punches or
capsule filling machine. Lubricants also ensure that tablet formation and ejection can occur with low
friction between the solid and die wall e.g. vegetable stearin, magnesium stearate or stearic acid
• Preservatives—Preservatives are substances that prevent or minimize the growth of bacteria or
other microorganisms in the dosage form, typically used in multi-dose vials. Single-dose vials are
discarded immediately after use, while multi-dose vials, once opened, may be stored for a period.
After a vial has been opened, however, the risk of bacterial overgrowth increases. To prevent or
minimize the risk of bacterial overgrowth, preservatives are added to the medication
• Sweeteners are added to make the ingredients more palatable, especially in chewable tablets such
as antacid or liquids like cough syrup. Sugar can be used to mask unpleasant tastes or smells
• Vehicle: In liquid and gel formulations, the bulk excipient that serves as a medium for conveying the
active ingredient is usually called the vehicle. Petrolatum, dimethyl sulfoxide and mineral oil are
common vehicles.
 Solid Dosage Forms
Solid dosage forms include tablets, capsules, caplets,
lozenges/troches, pastilles, powders, and granules. Solid dosage
forms offer several advantages:
– Increased stability
– Ease of packaging, storage, and dispensing
– Convenience
– Little or no taste or smell
• Solid dosage forms also allow for accurate dosing.
• The entire dose is contained within the contents of the solid
dosage form, which minimizes measuring errors.
• Solid dosage forms may, however, be difficult to swallow, have a
slow onset of action, and may be degraded by the acidic contents
in the stomach.
 Solid Dosage Forms
• Tablets/Caplets
• Tablets are available in variety of sizes, shapes, colors, and thicknesses. They are formed in molds
or produced by compression, and are composed of one or more active ingredients and one or
more inert substances.
• Some pharmaceutical manufacturers manufacture a hybrid of the capsule and tablet, called a
caplet. A caplet is a tablet that is shaped like a capsule, but smooth-sided like a tablet. It is often
easier to swallow than large tablets, and is more stable than capsules (Oblong tablets are known as
caplets)
• Most tablets and caplets are designed to be swallowed whole and dissolve in the gastrointestinal
tract, but some are also made to be administered sublingually (under the tongue), buccally, or
vaginally. Some tablets are available in a scored form so they may be easily broken in halves or
quarters. Tablets can be formulated with delayed-release characteristics to allow for less-frequent
dosing and/or side effects.
 Solid Dosage Forms
• A chewable tablet is designed to be chewed. Chewable tablets contain a base that is flavored or
colored. They are convenient for patients who have difficulty swallowing tablets or for children
who are unable to swallow large tablets.
• An oral disintegrating tablet (ODT) is designed to dissolve in the mouth without water. These
tablets are useful for pediatric and geriatric patients who have difficulty swallowing medication and
in patients who are experiencing nausea and vomiting.
• Enteric-Coated Tablets: tablets are coated with a substance that prevents dissolution of the drug in
the stomach. They are meant to dissolve in the intestine to protect the drug from being broken
down in the stomach or to protect the stomach lining from the drug. Enteric-coated dosage forms
should not be chewed, broken, or crushed. Examples of drugs that are available in enteric-coated
formulations include aspirin.
• Film-coated tablets are coated with a thin outer layer of water-soluble material that dissolves
rapidly in the stomach. The coating is designed to cover the unpleasant taste or smell of the
medication or protect sensitive drugs from deterioration due to air and light. Erythromycin is an
example of a medication available as a film-coated tablet.
• Sugar-coated tablets are coated with an outside layer of sugar that protects the medication and
improves the taste and the appearance of the medication.
 Solid Dosage Forms
• Capsules
• Capsules are a solid dosage form in which the drug is enclosed within a hard or soft gelatin shell.
The gelatin shell dissolves in the stomach, releasing the drug. The gelatin shell may be transparent,
semitransparent, or opaque. A capsule may contain powders, granules, crushed tablets, or liquids
with one or more active ingredients and one or more inert ingredients. Capsules can be formulated
with delayed-release characteristics to allow for less-frequent dosing and/or side effects.
• Spansules are capsules that are filled with granules that dissolve at different rates, in effect causing
a sustained release of the active ingredients.
• Sprinkles or sprinkle capsules are similar to spansules but unique in that they are designed to be
pulled apart and the contents sprinkled onto food, making it easier to administer the medication.
The medication inside a sprinkle capsule is specially coated to allow the medication to be delivered
after the contents have been ingested. They are convenient for patients who have difficulty
swallowing large capsules or for children who are unable to swallow capsules.

Sprinkles: Encapsulated drug multiparticulates or

sprinkles, containing a defined dose of medicine
that can be sprinkled on food or beverages, is a
known alternative for people with challenges
swallowing
 Solid Dosage Forms
• Dosage Formulations Designed to Alter the Rate of Release
• Tablets and capsules can be designed in immediate-release formulations, in which the medication
is released within a short period of time after the drug is taken. They can also be designed in
delayed-release formulations, which administer the drug over an extended period of time. A
delayed-release formulation may be enteric coated, thus delaying the release of the medication
until the formulation has passed through the stomach.
• Dosage forms designed to vary the rate or extent of release include the following:
– Controlled release—Controlled-release dosage forms regulate the rate of release of the active
ingredient. They are designed to vary the dissolution rate or release of the active drug. These
dosage forms are also referred to as long-acting and timed-release formulations. controlled
forms follow zero order kinetics. controlled release formulation when ever release the drug
the concentration of drug candidate is same every time. in controlled forms, drug release is
very definite per unit time.
– Sustained release—Sustained-release dosage forms allow the frequency of dosing of a
medication to be reduced compared to that of immediate-release dosage forms. sustained
release dosage forms follow first order kinetics. sustain release formulation when ever release
the drug the time interval of release is same every time. In sustained forms the dosage is
sustained for prolonged period of time and drug release is not definite per unit time
 Solid Dosage Forms
• Lozenges: also known as troches or pastilles, are hard, oval, or discoid solid dosage forms with a
drug contained in a flavored sugar base. They are dissolved in the mouth and generally have local
therapeutic effects. Over-the-counter lozenges for relief of sore throat are a common example of
this dosage form. Antibiotics, analgesics, cough suppressants, and antiseptics are also available as
lozenges.
• Powders: are finely ground mixtures of dry drugs and inactive ingredients that can be used
topically or internally. When used internally, they should be dissolved in water prior to ingestion.
• Granules: are larger than powders and are wetted, allowed to dry, and ground into coarse,
irregularly shaped pieces. Granules are generally more stable than powders and are more suitable
for use in solutions because they are not as likely to float on the surface of a liquid.
 Solid Dosage Forms
– Extended release—Extended-release dosage forms are formulated so that the active
ingredient is released at a constant rate for a prolonged period so that the frequency of dosing
is less than that of immediate-release dosage forms. They usually allow for once-daily dosing,
as the contained medication is available over an extended period of time following ingestion
of the formulation.
• Compared to immediate-release preparations, advantages of extended-release dosage forms
include the following:
– Constant drug levels following long-term administration
– Reduction in adverse side effects
– Reduction in the frequency of administration
– Increased patient
 Semi-Solid Dosage Forms
• Semisolid agents are different in their composition from liquids or solids. They are
usually intended for topical application.
• They may be applied to the skin, placed on mucous membranes, or used in the nasal,
rectal, or vaginal cavity.
• These dosage forms are too thick to be considered a liquid dosage form and not solid
enough to be considered a solid dosage form.
• Examples include ointments, creams, lotions, gels, pastes, and suppositories.
• An emulsion is a type of semi-solid dosage form. It is a mixture of two substances that
are unblendable. One substance is dispersed in the other.
• An oil-in-water (O/W) emulsion contains a small amount of oil dispersed in water. A
water-in-oil (W/O) emulsion contains a small amount of water dispersed in oil.
• Ointment: is applied externally to the skin or mucous membranes. An ointment is an
example of a W/O emulsion because it contains a small amount of water dispersed
throughout oil. Ointments can also be formulated and sterilized for use in the eye.
Ointments contain medication in a glycol or oil base and can effectively cover the
surface of the skin. Examples of ointments include erythromycin ophthalmic ointment
and Neosporin. Ointments are generally greasier than creams or gels, and can leave an
oily residue at the site of application.
 Semi-Solid Dosage Forms
• Cream: contains suspensions or solutions of drugs intended for external use. A cream is an example
of an O/W emulsion because it contains a small amount of oil dispersed in water. Creams can be
easily massaged into the skin, without leaving an oily residue. They usually have medications in a
base that is part oil and part water. Creams can also be formulated for vaginal or rectal use.
Examples of creams include hydrocortisone cream, benzoyl peroxide cream, and betamethasone
valerate cream.
• Lotion: is an O/W emulsion that is thinner than a cream because its base contains more water.
Lotions penetrate into the skin and can cover large areas without leaving an oily residue. Examples
of lotions include calamine lotion and hydrocortisone lotion.
• Gel: contains solid medication particles, like a suspension, in a thick liquid. It can be used internally
and externally. The particles in a gel are ultrafine and are linked to form a semisolid. Gels penetrate
the skin without leaving a residue. Examples of gels include aluminum hydroxide gel and
benzocaine gel.
• Paste: contains more solid material and less liquid base than a solid. Pastes are like ointments, but
are stiffer, less greasy, and applied more thickly. One example of a paste is zinc oxide.
• Suppository: is designed to be inserted rectally, vaginally, or urethrally. The suppository base is an
inactive ingredient, which melts or dissolves in the body cavity, releasing the medication. Some
suppositories are designed for local action, while others are used as vehicles for systemic drugs. A
hydrocortisone rectal suppository is used for local relief. Suppositories are often used in children
and in adults who are unable to take oral medications. Rectal suppositories bypass the stomach,
which is helpful if the patient has nausea or vomiting. They are also used to treat inflammatory
bowel disease or pain. Vaginal suppositories are used to treat yeast infections and vaginal atrophy.
Examples of suppositories include miconazole vaginal suppositories and bisacodyl rectal
suppositories.
 Liquid Dosage Forms
• Liquid dosage forms contain one or more active ingredients in a liquid vehicle such as a solution,
suspension, or emulsion. The drug may be dissolved in the vehicle or suspended as very fine
particles. They can be administered by many routes, but are often less stable than medications in
solid dosage forms.
• In aqueous formulations, there is a need for preservatives or antimicrobial devices to ensure the
microbiological stability over storage and in-use conditions. Another major issue with liquid
formulations is taste
• Liquid dosage forms offer several advantages:
– They allow for easier dosage adjustments, particularly for pediatric patients.
– They are easier to swallow, particularly for pediatric and geriatric patients.
– The onset of action is faster than that of solid dosage forms.
– They are easier to place down a feeding tube.
• Liquid dosage forms have several disadvantages:
– Loss of potency occurs faster than with solid dosage forms.
– There is difficulty in masking bitter taste or odor.
– There is a need for preservatives because liquid doses provide an excellent medium for the
growth of microorganisms.
– There is a potential for dosing inaccuracy.
– They are inconvenient
 Liquid Dosage Forms
• Solutions
• A solution is an evenly distributed (homogenous) mixture of one or more dissolved medications (solutes) in a liquid
vehicle (solvent). Solutions can be classified by vehicle as an aqueous solution (water-based), an alcoholic solution
(alcohol-based), or a hydroalcoholic solution (water- and alcohol-based). Solutions can be for internal and external
use.
• Solutions can also be classified by their contents:
– Aromatic water—Aromatic water is a solution of water that contains oil or other substances that are volatile.
They usually have a pleasant smell.
– Elixir—An elixir is a clear, sweet solution that contains dissolved medication in a base of water and ethanol
(hydroalcoholic).
– Syrup—Syrup is a sugar-based solution that may be medicated or non-medicated. Syrups mask the taste of the
drug.
– Extract—An extract is a powder or liquid derived from animal or plant sources in which all or most of the solvent
has been evaporated.
– Tincture—A tincture is an alcoholic or hydroalcoholic solution that contains plant extracts.
– Spirit—A spirit is an alcoholic or hydroalcoholic solution that contains volatile, aromatic ingredients.
– Irrigating solution—An irrigating solution is a solution that is used for cleansing an area of the body.
• Solutions can also be classified by their method of administration as topical, systemic, epicutaneous, percutaneous,
oral, otic, ophthalmic, parenteral, vaginal, or urethral.
• A parenteral solution is a sterile solution that is administered by a needle or catheter via injection or infusion. It can be
administered in an intravenous (IV), intramuscular (IM), subcutaneous (SC), or intradermal (ID) manner.
• Injectable dosage forms are marketed in ampules, vials, pre-filled syringes, and pre-filled infusion bags. A vial will
contain either a single dose, which is meant for withdrawal of one dose before the vial is discarded, or multi-dose,
which means the vial can be pierced multiple times to retrieve multiple doses. Some vials come in powder form and
will need to have diluents added before administration. The addition of a diluent to a powder vial is called
reconstitution. The vial will give information as to how much and which diluent is needed to obtain a specific
concentration. Pre-filled syringes or infusion bags have the medication in ready-to-administer form.
 Liquid Dosage Forms
• Dispersions
• Some drugs do not dissolve in the solvents that are used to prepare liquid dosage forms. In a
dispersion, the medication is not dissolved, but distributed throughout the vehicle. A suspension is
a mixture of undissolved, very fine, solid particles distributed through a gas, liquid, or solid. Most
suspensions contain medications distributed in water; this type of suspension is called an aqueous
suspension. Suspensions are used for drugs that are not able to dissolve readily into a solution.
Suspensions need to be shaken prior to use and should contain a “shake well” auxiliary label.
• Injectable suspensions allow for insoluble drugs to be administered intramuscularly or
subcutaneously. They are often used for depot therapy, where the drug is released over a long
period of time.
• Suspensions have the following characteristics:
– The suspended material should be evenly distributed when the container is shaken.
– It should pour freely from the bottle or pass easily through a syringe or needle.
– When used externally, it should dry quickly and spread easily over the affected area
 Liquid Dosage Forms
• An emulsion is a mixture of two liquids that are immiscible (do not blend). It is a dispersion, with
one liquid being dispersed in the other. They vary in their viscosity from liquids such as lotions to
semisolid dosage forms such as ointments and creams. In an emulsion, one liquid is broken into
small particles and evenly scattered throughout the other liquid. The liquid that is in small particles
is called the internal phase, and the other liquid is called the external phase. The two liquids will
separate into two phases unless an emulsifying agent, an ingredient used to bind together
substances that normally do not mix, is used. An emulsifying agent is a chemical that has water-
loving and lipid-loving properties that can keep oil and water together.
• Enemas: are used to deliver medication, rectally, a way that bypasses the stomach. Enemas are
manufactured in a water base and can also be used to evacuate the lower intestine to prepare for
surgeries or examinations involving the intestine.
 Inhalation Dosage Forms
• Some patient populations, such as asthmatic patients, need to have their medications delivered to
a specific site in the body, such as the bronchial tree.
• Gases, vapors, aerosols, powders, sprays, solutions, and suspensions intended to be inhaled via the
nose or mouth are known as inhalations, after the term inhalation, or the acts of inhaling or
breathing in.
• The medication particles must be extremely fine to reach these areas effectively. Devices that
enable the medication to reach the lungs easily include vaporizers, humidifiers, and nebulizers.
• An aerosol is a spray that contains very fine liquid or solid drug particles in a gas propellant that is
packaged under pressure. An aerosol dosage form consists of the medication, the container, and
the propellant. Pressurized aerosol containers should be stored away from heat. The medication
may be released as a spray, foam, or solid, depending on the formulation of the product and on the
design of the valve. Aerosols have a rapid onset of action because the drug bypasses the
gastrointestinal tract.
• A spray consists of a container that has a valve assembly unit that contains various bases, such as
alcohol or water, in a pump-type dispenser. When activated, it emits a fine dispersion of liquid,
solid, or gaseous material.
 Transdermal Dosage Forms
• A transdermal patch dosage form is designed to hold a specific amount of medication to be
released into the skin and absorbed into the bloodstream over time via a patch or disk. The patch
consists of a backing, drug reservoir, control membrane, and adhesive layer. The backing is
removed and the adhesive layer is applied to the skin. The drug is slowly absorbed across the
membranes of the skin and into the skin where optimal absorption into the bloodstream will occur.
• Patches are convenient because they can be applied easily and minimize stomach upset. They can
also improve compliance because they eliminate the need for more frequent dosing that is often
associated with oral dosage forms. Drugs such as nitroglycerin, fentanyl, scopolamine, and nicotine
are administered in this manner for their systemic effects.
• Not all medications designed to be administered transdermally are in the form of patches. Some
gels are also formulated to be administered transdermally. These gels are also designed to hold a
specific amount of medication to be absorbed into the skin and bloodstream over time. The drug is
slowly absorbed across the membranes of the skin and into the skin, where optimal absorption in
the bloodstream will occur
 Drug Delivery and formulations
• Read different routes of drug
delivery/administration from previous semester.
Very important
 Drug Delivery and formulations
• Drug delivery refers to approaches, formulations, technologies, and systems for transporting a
pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effect.
• Drug delivery technologies modify drug release profile, absorption, distribution and elimination for
the benefit of improving product efficacy and safety, as well as patient convenience and
compliance
• Oral Route
• Oral drug administration is the preferred route of administration both in the paediatric and the
adult population. In general, peroral dosage forms can be distinguished in solid or liquid forms
• Oromucosal Drug Delivery
• Solid preparations which spontaneously disperse in the oral cavity (e.g. orodispersible tablets, thin
film strips, oral lyophilisates) stand also on the periphery of solids and liquids.
• Rectal route
• The rectal administration route can be used for local (e.g. laxative or antiinflammatory) or systemic
(e.g. antipyretic or anticonvulsive) treatment. The administration of drugs by rectal formulations
(e.g. suppositories, solution, soft capsules or ointments) can result in a wide variability in the rate
and extent of absorption in children. The rectal administration of suppositories or enemas for
systemic effects may nevertheless be chosen because the patient cannot take medication orally,
because the oral dosage form is rejected as a result of palatability issues or because immediate
absorption is required in emergency cases
Conventional Drug delivery
Conventional Drug delivery

Disadvantages include
• Cause uneven therapeutic effect
• Increases the potential adverse events
• Frequent dosing
Controlled Drug delivery
 Controlled Drug delivery

Advantages Of Controlled Drug Therapy

• This delivery system improved the patient compliance especially with long-term treatments for
chronic diseases.
• Conventional dosages form produce fluctuation in plasma drug concentration.
• These fluctuations depend on the drug kinetics within the body like absorption, distribution,
metabolism and excretion.
• Controlled release eliminates this type of fluctuation in plasma drug concentration.  Reduction
in dose and dosing frequencies
• Maintenance of required drug concentration in plasma thus eliminates the failure of drug
therapy and improved the efficiency of treatments.
• A suitable delivery system for drugs which having a short biological half-life (3-4 hrs) and drug
rapidly eliminate from the body.

Disadvantages
• Dumping is a major disadvantage of CRDDS (Controlled Release Drug Delivery System), which
refers to the rapid release of a relatively large quantity of drug from a controlled release
formulation. This phenomenon becomes hazardous with potent drugs
• Poor in-vivo & in-vitro correlations
• Difficult to optimize the accurate dose and dosing interval
• Patient variability affects the release rate like GI emptying rate, residential time, fasting or non-
fasting condition, etc.
 Targeted Drug delivery
• Targeted drug delivery, also known as smart drug delivery, is a method of treatment that involves
the increase in medicament in one or few body parts in comparison to others.
• There are four principle requirements for a successful targeted drug delivery system: retain,
evade, target and release, i.e., there should be proper loading of the drug into an appropriate
drug delivery vehicle, it must possess an ability to escape the body's secretions that may degrade
it, leading to a long residence time in circulation and thereby reaching the site of interest and,
should release the drug at the specific site within the time that calls for effective drug functioning
• Different sites of interest within the body necessitate the use of different drug delivery systems,
depending upon the route to be followed
 Targeted Drug delivery

• Strategies of Drug Targeting

• Drug targeting to an area of interest within the body increases the therapeutic effectiveness as
well as it reduces the toxicity that may arise otherwise. Two strategies are widely used for drug
targeting to the desired organ/tissue
• Passive targeting
• This is based on the accumulation of drug at areas around the site of interest, such as in case of
tumor tissues. This is called Enhanced Permeability Retention (EPR) effect. Such a types of
targeting occurs with almost all types of drug delivery carriers.
• Passive targeting is actually a misnomer because it cannot really be described as a form of
selective targeting.
• Although the EPR effect applies for nanoparticle administered, the majority (>95%) of these
nanoparticles tend to accumulate in organs other than those of interest such as liver, lungs and
spleen.
• Thus, it is the distribution of drug by blood circulation. Examples include the use of antimalarial
drugs being targeted for the treatment of microbial infections such as leishmaniasis, candidiasis
and brucellosis
 Targeted Drug delivery

• Active targeting
• Through the use of ligand-receptor interactions, active targeting describes the drug targeting
interactions.
• However, interactions between a ligand and a receptor are possible only when the two are in
close propinquity, (i.e. less than about 0.5mm).
• The currently available drug delivery systems are able to reach the target by the virtue of blood
circulation and extravasation. Therefore, we can conclude that active receptor targeting actually
means ligand-receptor interaction but that takes place only after blood circulation and
extravasation. Active targeting can further be divided into three different targeting levels.
• First order targeting
• This is the distribution of drug to capillary beds of target sites- organ or tissue, for example,
in case of lymphatic tissue, peritoneal cavity, pleural cavity, cerebral ventricles, eyes, joints,
etc.
• Second order targeting
• This is the targeting of drugs to specific sites such as the tumor cells, for example, to kupffer
cells in liver
• Third order targeting
• It is the type of drug targeting wherein the drug is intracellularly localized at the target site
via endocytosis or through receptor-based ligand mediated entry.
Targeted Drug delivery
 Targeted Drug delivery

• Components of Drug Targeting

• Target: Target means an organ or a tissue or a cell, which is in need of treatment
• Drug Carrier or Marker
• Drug delivery is possible only by means of a carrier system. Carriers are molecules or any other
systems responsible for the successful transportation of a drug to the site of interest. Carriers are
vectors specifically engineered for the purpose of holding a drug inside them. This is possible by
means of encapsulation
• Drug delivery Vehicles
• These transport the drug either within or in the vicinity of target. An ideal drug delivery vehicle is
supposed to cross even stubborn sites such as a blood brain barrier. It should be easily
recognized by the target cells and the drug-ligand complex hence formed should be stable. These
need to be non-toxic, biodegradable as well. The biodegradable nature of drug carrier enables
them to be easily cleared away by the body and physiological mechanism, and thus avoids any
chance of their accumulation within cells that may lead to cytotoxicity
 Targeted Drug delivery

• Nanotechnology-based delivery systems

• Nanomaterials were initially studied for their properties and then they came into use in different
applications. However, the recent observations have been diverted towards the field of drug
delivery.
• This came into being due to complications involved in the use of large-sized materials for drug
delivery, such as poor solubility, poor bioavailability, therapeutic inefficacy, side effects and need
for targeted delivery of drugs.
• These nanostructures are assumed to possess the potential of protecting drugs from their
disintegration by the various enzymes of the gastrointestinal tract. Since nanoparticles are very
small in size, nanodrug delivery can allow for the delivery of drugs with poor solubility in water
and also aid in avoiding the first pass metabolism of liver.
• Nanotechnology derived drug delivery can cause the drug to remain in blood circulation for a
long time, thereby leading to lesser fluctuations in plasma levels and therefore, minimal side
effects.
• These particles or structures can easily penetrate tissues and are readily taken up by cells. This
allows for effective targeted delivery.
• The uptake of nano-sized particles is reported to be about 15-250 times higher in comparison to
microparticles
 Targeted Drug delivery

• Polymer-drug conjugates
• Polymer-drug conjugates, arising from polymer therapeutics, comprise of water soluble polymer
being conjugated to a drug chemically with the help of a biodegradable coupler
• Owing to their colloidal nature, these conjugates are stable to sustain in the circulation for
extended periods of time. The major difference between these conjugates and drug delivery
vehicles with the drug entrapped by physical means in them (e.g. liposomes), is that the polymer-
drug conjugates are conjugated chemically and this makes them new chemical entities (NCE).
• A multitude of drug conjugates, employing linear polymers, have been manufactured. The most
widely explored ones are those made using polyethylene glycol (PEG) and N-(2-hydroxypropyl)
methacrylamide (HPMA) copolymers.
• PEG-protein conjugates are of significant interest, since PEG can provide protection against
enzymatic degradation of proteins
• PEGylation of proteins has resulted in the manufacture of various therapeutic products that
include many FDA-approved drugs as well, such as- PEG- asparaginase (Oncaspar®), PEG-
adenosine deaminase (Adagen®), PEG-interferon α-2a (Pegasys®), PEGinterferon α-2b (PEG-
Intron®), PEG-granulocyte colony-stimulating factor (Neulasta®) among others
Targeted Drug delivery
 Targeted Drug delivery

• Liposomes
• Liposomes are the first to be explored as drug delivery vehicles.
• These are vesicles composed of an aqueous core bounded by a hydrophobic lipid bilayer.
• Solutes in the core, such as drugs, cannot overcome the hydrophobic barrier.
• However, the bilayer allows for the absorption of hydrophobic molecules and therefore,
liposomes are known to be ampiphilic carriers.
• Liposomes differ in composition, size, number of layers, etc.
• These can either have a single bilayer, known as "unilamellar" or multiple bilayers, termed as
"multilamellar".
• Unilamellar vesicles are further grouped into small unilamellar vesicles (SUVs) and large
unilamellar vesicles (LUVs) according to their size.
• Drugs held and delivered by liposomes have significantly improved pharmacokinetic properties
such as the therapeutic index.
• Also, these have a quick metabolism action, lower toxicity apart from in vitro and in vivo anti-
cancerous activity.
 Targeted Drug delivery

• The encapsulation of drugs by liposomes leads to the prevention of their untimely degradation.
Liposomes can be coated with polyethylene glycol, besides other polymers, resulting in an
increased half-life.
• These can amplify target-specificity once they are associated with ligands or antibodies.
• Liposomal drugs are among the first nanotechnology products used as therapeutic agents to get
the approval of FDA for the clinical use. DOXIL® (doxorubicin liposomes) was approved in 1995 as
a medicament for Kaposi‟s sarcoma -related AIDS.
• Therapeutic potency of drugs is elevated by their targeted delivery through ligand-conjugated
liposomes.
• Pervasive preclinical studies further emphasize the importance of targeted liposomes. For
example, entire nucleosome, attached to the surface of tumor cells is identified by the
monoclonal antibody 2C5 (mAb 2C5).
• Enhanced cell targeting is obtained by the mAb 2C5- DOXIL liposome conjugation.
• This also results in an improved drug potency.
• However, it has been found that liposomes are not suitable for sustained release of drugs, which
is a limitation on their part
 Targeted Drug delivery

A schematic representation of the accumulation of liposomes, through passive or active targeting, in

breast cancer tumors via the EPR effect. (A) Liposomes, containing an anti-cancer drug, extravasate from
blood and accumulate in tumor cells. The dark green cells represent the tumor tissue while the light
green portion represents the normal tissue. (B) Liposomes release the anti-cancer drug in the proximity
of tumor cells that take them up. (C) Ligand-targeted liposomes bind to cell-surface receptors and finally,
the drug reaches its site of action
 Targeted Drug delivery

• Lipid-polymer hybrid nanoparticles

• Lipid polymer hybrid nanoparticles act as a platform to unite the merits of liposomes and
polymer nanoparticles.
• Several of them have been developed so far.
• Recently, characterization of polymeric nanoparticles with a lipid coating and comprising a core
of PLGA (poly(lactic-co-glycolic acid)) , a shell of PEG and a monolayer of lipid, was done.
• The core can carry sparsely water soluble drugs, the shell increases circulation half-life and the
lipid monolayer at the interface of core and shell serves to boost drug retention and its sustained
release from the core.
• In comparison to polymer-drug conjugate, the lipid polymer conjugates enable a stable
encapsulation of drug, its flexible and sustained release and a longer circulation half-life.
• The PLGA-conjugated drug doxorubicin, effective against cancer, is encased in the nanocell.
• The multilayered shell of lipids aids in combating tumor angiogenesis as it contains
combretastatin, an anti angiogenic promoter.
 Targeted Drug delivery

• Quantum Dots
• Quantum dots are nanocrystalline semiconductors that range in size from 2 to 10 nm in diameter.
• Their size increases approximately two-fold after encapsulation by a polymer.
• These nanocrystals possess distinctive optical properties and are therefore, widely used in the
fields of imaging and detection.
• Hydrophobic drug molecules can be implanted between the core and the layer of polymer
cladding.
• Quantum dots are now found to be efficient enough to carry out targeted drug delivery and
imaging of this process concurrently.
• This is particularly useful in the case of cancer diagnosis and treatment.
• Quantum dots, made up of ZnO: Mn2+, loaded with drugs and enclosed in chitosan, possess the
potential for delivering drugs specifically targeted to tumors and also to report the process of
drug delivery at the same time.
• Apoptosis of tumor cells is expected to improve by the use of ZnO: Mn2+ quantum dots
Targeted Drug delivery
 Targeted Drug delivery

• Hydrogels
• Hydrogels are three-dimensional, polymeric cross linked networks capable of imbibing large
amounts of water.
• Hydrogel nanoparticles, known as “nanogels” are fast emerging as a favourable method of
nanoparticulate drug delivery systems.
• Drug loading into the gel matrix is possible due to the highly porous structure.
• Drug loading and the efficacy of entrapping drug are largely dependent on the drug solubility in
the matrix .
• Rapid release of drug from the polymeric gel matrix takes place owing to the high content of
water in hydrogels.
• This is specifically useful for delivery of hydrophilic drugs.
• Hydrophobic drugs can also be delivered using hydrogels by the application of certain strategies
such as the copolymerisation of hydrogels with hydrophilic monomers or the introduction of
cyclodextrins in the structure of hydrogel
Targeted Drug delivery
Scale up and manufacturing plans
 Scale up and manufacturing plans

• The traditional process of pharmaceutical product development until it reaches the global market
involves a long journey of many experiments, observations, challenges, and resolutions.
• During the initial formulation stage, certain physicochemical parameters are considered to
convert the raw materials into a drug formulation with an aim to maintain the required quality
attributes such as potency, release time, etc.
• However, at the initial level, these investigations are performed at a small scale by using small-
output equipment, where the methods and results observed from these investigations are
pertinent to that scale only
• Transformation of these small-scale observations into the large-scale development mostly
requires entirely varied design strategies and equipment which may result in differences in
quality
• As the development of a new drug product progresses, the batch sizes manufactured generally
increase. The early First Time in Man (FTIM) clinical trials commonly involve dosing to a small
number of subjects, with the majority of the manufactured product often being required for
stability studies and analytical testing. As one proceeds from formulation design to Phase I
clinical trials and subsequently through to Phase II & III, batch sizes generally increase. Following
a successful clinical trial outcome, resulting in the granting of a marketing authorization, the
batch sizes manufactured may be further increased to cover the market demands.
 Scale up and manufacturing plans

• Laboratory-scale batches. 
• These are produced at the research and early development laboratory stage. They may be of very
small size (e.g., 100–1000 times less than production scale).
• Laboratory-scale batches may be used to support formulation and packaging development, early
clinical and/or preclinical stages.
• Laboratory-scale batches can also be analyzed to assist in the evaluation and definition of critical
quality attributes (CQAs).
• A CQA is a physical, chemical, biological, or microbiological property or characteristic that should
be within an appropriate limit, range, or distribution to ensure the desired product quality.
• CQAs are generally associated with the drug substance, excipients, intermediates, and drug
product.
 Scale up and manufacturing plans

• Pilot-scale batches. 
• These may be used in the process-development or optimization stage.
• They may be used to support preclinical and mid- to later-stage clinical evaluation and also to
support formal stability studies.
• If supporting formal registration, a pilot-batch size should correspond to at least 10% of the
production-scale batch.
• For oral solid-dosage forms, this size should generally be 10% of production scale or 100,000
units, whichever is greater.
• The choice of pilot scale is often difficult for the project team as members must balance
parameters such as anticipated product volumes, anticipated site of production, equipment
constraints at that site, and regulatory expectations.
• With the increasing trend toward developing orphan drugs, the authors believe that the
regulatory expectation of pilot-scale batches of 100,000 units is not always valid and should be
discussed with the relevant regulatory authority
 Scale up and manufacturing plans

• Production-scale batches.
• These batches are of the size that will be produced during the routine manufacturing and
marketing of the product. Data on production-scale batches may not always be available prior to
granting marketing authorization.
• Approaches to process optimization and scale-up
• Pharmaceutical development activities around the scaling-up and optimizing for pilot- or
commercial-scale manufacture should include, at a minimum, the following elements:
• Defining the target product profile as it relates to quality, safety and efficacy, considering,
for example, the route of administration, dosage form, bioavailability, dosage, and stability
• Identifying CQAs of the drug product, so that those product characteristics having an
impact on product quality can be studied and controlled
• Determining the quality attributes of the drug substance and excipients, and selecting the
type and amount of excipients to deliver drug product of the desired quality and efficacy
• Selecting an appropriate manufacturing process
• Where possible, identifying a control strategy.