Sustained Drug Delivery:
It is the dosage form that modifies the drug release by prolongs therapeutics action of drug.
The concentration of drug in body releases slowly once it reach maximum level so it will take
prolonged time to fall under the therapeutic range. The major goal of sustained release dosage
form is to keep the therapeutic blood or tissue level of the drug for a prolonged period and
generally it can be achieved by obtaining ‘zero order’ release from the drug or dosage form as
shown in figure 1.1
It can be formulated when a polymer either natural or synthetic, is prudently joined with a
drug in such manner that drug is released from the dosage form over a prolonged time 1, 2. So it is
required continuous release of drug in order to retain the constant plasma levels as per figure 1.1
and 1.2.
Figure 1.1: Drug levels in the blood with Conventional drug delivery systems
Figure 1.2: Drug levels in the blood with Controlled drug delivery systems
The hypothetical drug blood level and hypothetical plasma concentration patterns of drug
from both formulations traditional and controlled are given in Figure 1.3 and 1.4.
Figure 1.3: Hypothetical drug blood level – time curves for a conventional solid
dosage form and a multiple action product.
Figure
1.4: Hypothetical plasma concentration- time profiles from conventional multiple dosing
and single doses of sustained controlled release formulation.
1.1.1. Merits of Sustained release product: 3, 4
� Enhanced Patient compliance.
• By minimizing number of daily doses.
• Minimizing dosing at night time.
• Minimizing patient carefulness time.
• Affordable to patients as number of tablets required for patients can be minimized by
formulating with sustain dosage form.
• Minimizing systemic as well as local side effects and gastrointestinal irritation.
� Enhanced treatment efficiency.
• Optimized therapy.
• Maintain constant blood concentration.
• Minimizing drug level fluctuation so constant pharmacological response.
• Reduced accumulation of drug.
1.1.2. Demerits of Sustained release product:
� Dose dumping: It may chances release of excess quantity of active substance or drug at
the initially and may lead to toxicity due to excess quantity (toxic quantity) of the active
substance or drug in the body.4,5
� Development Costs: The inert materials and equipment required for this formulation is
expensive.
� Release rate: Food and GIT transit time effect the release pattern of drug so fluctuation
between the releases rate of doses.
� Cannot crush or chew products: Sustain release formulation can’t be chewed or
crushed as drug product loses its release characteristics.
� Minimize potential for accurate dose adjustment.
� Require patient education for sustain release product.
� More likely to first pass metabolism.
� Minimizing systemic availability.
� Irregular or poor correlation between in vitro and in vivo.
� Stability problems: It may chances to get either slower or faster release rate than
estimated after time interval of stability
1.1.3. Drug properties relevant to Sustained release formulation:
Table 1.1: Properties of drug to be considered for Sustained Release
Drug Suitable Drug not Suitable
Physicochemical 4,6
1. Low molecular size compounds
2. Compounds which are highly water
soluble and pH independent
3. Compounds which are non-aqueous
soluble.
4. Unionized (at least 0.1 to 5%) in GIT
5. Compounds with very weak acid and
moderately weak acid.
6. Compounds with very weak base and
moderately weak bases.
Pharmacokinetic/Pharmacodynamic
1. Compounds having short half-
to5 h.
2. Compounds having good absorption
all areas of Gastrointestinal tract
1.1.4. Principle of sustained release drug delivery:
As shown in below pattern
into body.
Low molecular size compounds
Compounds which are highly water
aqueous
Unionized (at least 0.1 to 5%) in GIT
Compounds with very weak acid and
Compounds with very weak base and
1. Compounds having large molecular
weight
2. low aqueous soluble compounds
3. Largely in ionized form in the GIT
4. Strong bases having pKa more than
11.0
5. Strong acids having pKa less than
2.5
/Pharmacodynamic7
-life from 2
Compounds having good absorption from
tract
Compounds that show
1. Slow absorption
2. Carrier mediated transport
3. Site definite absorption
4. Irritation in GIT
5. First pass metabolism
6. Those inhibit metabolism
7. Large dose
8. Drug’s metabolites are actives too
Principle of sustained release drug delivery:
As shown in below pattern conventional drug delivery release drug substance immediately
Compounds having large molecular
low aqueous soluble compounds
Largely in ionized form in the GIT
more than
having pKa less than
. Drug’s metabolites are actives too
conventional drug delivery release drug substance immediately
The absorption pool characterizes that drug solution present at the site of absorption, and the
term Kr, Ka and Ke represents first order release constant, absorption and elimination respectively.
For conventional dosage form immediate drug release indicates that Kr>>>>Ka. In another word
drug absorption through biological membrane is the rate limiting step. And drug
release represents Kr<<< Ka, means drug release from the conventional dosage form is the rate
limiting step. And this kinetics can be represented as following.
For formulating sustained drug delivery the major objectives is to deliver the rate at a
predetermined rate and maintain a persistent drug blood level. The constant drug level can be
achieved by constant intravenous infusion as supplying continuous drug
It refers that for providing constant drug release the dosage form should refers
described in formula 1.1,
Kr° = Rate In = Rate Out = K
Where,
Kr° : Zero-order rate constant for drug release
Ke : First-order rate constant for overall drug elimination
Cd : Desired drug level in the body
Vd : Volume space in which the drug is distributed
Zero order release rate consta
Vd are attained from appropriately designed single dose pharmacokinetic study. For m
The absorption pool characterizes that drug solution present at the site of absorption, and the
represents first order release constant, absorption and elimination respectively.
For conventional dosage form immediate drug release indicates that Kr>>>>Ka. In another word
drug absorption through biological membrane is the rate limiting step. And drug with no immediate
release represents Kr<<< Ka, means drug release from the conventional dosage form is the rate
limiting step. And this kinetics can be represented as following.
For formulating sustained drug delivery the major objectives is to deliver the rate at a
predetermined rate and maintain a persistent drug blood level. The constant drug level can be
intravenous infusion as supplying continuous drug to the patient a
It refers that for providing constant drug release the dosage form should refers zero
° = Rate In = Rate Out = Ke C
d V
d-------------------------- (1.1)
e constant for drug release-Amount/time
order rate constant for overall drug elimination-time-1
Cd : Desired drug level in the body – Amount/volume, and
Vd : Volume space in which the drug is distributed-Liters
ero order release rate constant can be calculated by this equation. The value
Vd are attained from appropriately designed single dose pharmacokinetic study. For m
The absorption pool characterizes that drug solution present at the site of absorption, and the
represents first order release constant, absorption and elimination respectively.
For conventional dosage form immediate drug release indicates that Kr>>>>Ka. In another word
with no immediate
release represents Kr<<< Ka, means drug release from the conventional dosage form is the rate
For formulating sustained drug delivery the major objectives is to deliver the rate at a
predetermined rate and maintain a persistent drug blood level. The constant drug level can be
the patient at a fixed rate.
zero-order kinetics as
The values of Ke, Cd and
Vd are attained from appropriately designed single dose pharmacokinetic study. For majority of
drugs, there is more complex elimination kinetics and also other factors that affect the drug
disposition and due to this it affects the nature of the release kinetics which is essentially for preserve
constant drug blood level.
1.1.5. Mechanism of Sustained drug delivery
Sustained drug delivery classified in different categories depending upon their drug
release mechanism:
� Dissolution controlled release
o Encapsulation dissolution control
o Matrix dissolution control
� Diffusion controlled release
o Reservoir devices
o Matrix devices
� Diffusion and dissolution systems
� Ion-exchange resins
� Osmotically controlled release
� Gastroretentive systems
Altered density formulation
o High density approach
o Low density approach (Floating system)
Swelling and expanding systems
Bioadhesive systems
1.1.5.1. Dissolution controlled release
Release of drug based on dissolution controlled mechanism can be accomplished by
encapsulating drug with polymers which are relatively insoluble. One of the regular methods
used to prepare sustained formulation is to add a drug in hydrophobic polymers such
polyethylene, polypropylene, wax
propyl methylcellulose, methylcellulose,
methylcellulose. The availability of drug is controlled by the penetration of dissolution fluid into
matrices through polymer membrane and depends on porosity of matrices. The mechanism for
the dissolution controlled release can be understand by the following figure.
Figure 1.5: Dissolution controlled mechanism
1.1.5.2. Diffusion controlled release:
Like dissolution controlled drug release by diffusion controlled release through the
polymer membrane can be achieved by encapsulating drug in polymer matrices or by dispersing
the drug in polymer matrix. The availability of drug through diffusion controlled by
through the polymer, and this represents mainly
used to prepare sustained formulation is to add a drug in hydrophobic polymers such
wax and ethyl cellulose; or hydrophilic matrices such as,
propyl methylcellulose, methylcellulose, hydroxyl propyl cellulose and sodium carboxy
The availability of drug is controlled by the penetration of dissolution fluid into
matrices through polymer membrane and depends on porosity of matrices. The mechanism for
the dissolution controlled release can be understand by the following figure.
gure 1.5: Dissolution controlled mechanism
Diffusion controlled release:
Like dissolution controlled drug release by diffusion controlled release through the
polymer membrane can be achieved by encapsulating drug in polymer matrices or by dispersing
drug in polymer matrix. The availability of drug through diffusion controlled by
, and this represents mainly non-zero-order rate as increase in
used to prepare sustained formulation is to add a drug in hydrophobic polymers such as
such as, hydroxyl
and sodium carboxy
The availability of drug is controlled by the penetration of dissolution fluid into
matrices through polymer membrane and depends on porosity of matrices. The mechanism for
Like dissolution controlled drug release by diffusion controlled release through the
polymer membrane can be achieved by encapsulating drug in polymer matrices or by dispersing
drug in polymer matrix. The availability of drug through diffusion controlled by partitioning
as increase in diffusional
resistance as well as decrease in diffusion area. The diffusion con
understand by following figure.
Figure 1.6: Diffusion controlled release mechanism
1.1.6. Polymers in sustained drug delivery:
For formulating sustained drug delivery polymers play a vital role and they are classified
as below:
Classification of polymers:
A. Non-biodegradable hydrophobic polymers:
Non-biodegradable hydrophobic polymers
eliminated or extracted intact from the site of administration and serve essentially
as rate limiting barriers to the transport and release of drug form the device.
E.g. Polyethylene vinyl acetate, ethyl cellulose. cellulose acetate.
B. Hydrogels:
as well as decrease in diffusion area. The diffusion controlled mechanism can also be
Figure 1.6: Diffusion controlled release mechanism
Polymers in sustained drug delivery:
For formulating sustained drug delivery polymers play a vital role and they are classified
Classification of polymers:
biodegradable hydrophobic polymers:
biodegradable hydrophobic polymers are inert in the environment of use are
eliminated or extracted intact from the site of administration and serve essentially
rate limiting barriers to the transport and release of drug form the device.
E.g. Polyethylene vinyl acetate, ethyl cellulose. cellulose acetate.
trolled mechanism can also be
For formulating sustained drug delivery polymers play a vital role and they are classified
are inert in the environment of use are
eliminated or extracted intact from the site of administration and serve essentially
Hydrogels are swells when coming in contact with water but will not dissolve in water.
They are inert removed intact from the site of administration and function by forming a rate
limiting barrier to the transport and release of drugs.
E.g. Poly hydroxyethyl methacrylate (p-HEMA), cross-linked polyvinyl alcohol
(PVA), cross-linked polyvinyl pyrrolidone, polyacrylamide and dextran etc.
C. Soluble polymers:
These are the polymers that soluble in water and will not cross link. Soluble polymers can
be used as alone or in combination with other hydrophobic polymers to provide devices that
slowly erode over time.
E.g. Polyethylene glycol, uncross-linked polyvinyl alcohol, polyvinyl pyrrolidone (PVP),
Hydroxy propylmethyl cellulose (HPMC),
D. Biodegradable polymers:
Biodegradable polymers slowly remove from the site of administration; and be achieved
by chemical reaction occurs in body such as hydrolysis and lead to disappear the biodegradable
polymer at the site of administration.
E.g. Polylactic acid, polyglycolic acid (PGA), polycaprolactone (PCL),
E. Mucoadhesive polymers:
Mucoadhesive polymers develop adhesive on hydration and show the property of
bioadhesion, i.e. adhesion to a biological membrane or tissue by interfacial forces.
The terms mucoadhesion means polymer attached to the mucin layer of mucosal tissue.
E.g. Methylcellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose,
1.1.7. Drug release mechanisms for polymeric drug delivery:
For preparing sustained drug release two major polymer categories have been studied i.e.
reservoir type and matrix type. The reservoir type represents encapsulation of drug in a polymer
shell while matrix type represent that drug is entrapped within the polymer. The release of drug
through this polymer may be diffusion controlled or dissolution controlled. Different polymers
used for the development of sustained release are summarized in table 1.2.
Table 1.2:Polymer used in oral controlled release technologies
Method of achieving
controlled release
Polymer used Examples of
dosage forms
Matrix or Embedding
Hydrophilic Carriers Methyl Cellulose, Sodium CMC,
Carboxymethyl cellulose,
Polyacrylic acid, HPMC,
Hydroxyethyl cellulose,
Methacrylate Hydrogels,
Polyethylene Glycols, Galactose
Mannate, Sodium Alginate
Multilayer tablets
with slow
releasing cores
Compressed-coated
tablets
Hydrophobi
c Carriers
Soluble
carrier
Glycerides, waxes, fatty
alcohols, fatty Acids
Matrix tablets Insoluble
carrier
Polyethylene, polyvinyl chloride,
polyvinyl acetate, waxes23,
calcium sulfate
Reservoir Type
Coating with insoluble
Membrane
Ethyl cellulose Granules, pellets,
Tablets
Osmotic Systems Vapor permeable walls
- Tenite 808A polyethylene
- Kynar 460 polyvinylidene
• Vapor permeable
capsules
• Vapor permeable
Fluoride
HPMC , HPC, Sodium CMC
Ethyl cellulose
tablets
• Single and
bilayer tablets
Ion-exchange Resins Dowex® 50, Amberlite® IRC
50 With polystyrene-based
polymeric backbone
Controlled
release capsules
Chewable tablets
Chewable gums
Liquid suspension
Gastric retention
Systems
HPMC, Agar, Carrageenans,
Alginic acid, Oils, Porous
calcium silicate, Superporous
hydrogels, Ion-exchange resin
beads coated with bicarbonate,
Ethyl cellulose for coatings
Compressed
tablets
Gelatin capsules
1.2. MICROSPHERES: 8, 9
Microspheres are solid spherical particle having dispersed drug either in solution or
microcrystalline form and size of the microspheres ranging from 1 to 1000 micrometer.
Microencapsulation is a fast growing technology for the development of sustained formulation.
In this process relatively thin layer of coating is applied to small drug particles of solid or liquid
droplets. By formulating microspheres sustainedrelease characteristics of drug can be
accomplished by coating the drug with release retardant polymer.
Microcapsule Microsphere
Figure 1.3: Difference between microcapsule and microsphere
1.2.1. Polymer used in microsphere:
II. Synthetic Polymer:
III. Non-biodegradablePolymers: e.g. Poly methyl methacrylate (PMMA), Acrolein,
Glycidyl methacrylate
IV. Biodegradable polymers: e.g. Glycolides,Lactides & their copolymers, Poly
alkylcyano acrylates, PolyAnhydrides.
1. Natural Polymer: Natural polymers foundfrom different sourceslike proteins,
carbohydrates andchemically modified carbohydrates.
Proteins: Albumin,Gelatin, and Collagen
Carbohydrates: Agarose, Carrageenan,Chitosan, Starch
Chemically modifiedCarbohydrates: PolyDextran, PolyStarch.
1.2.2. Methods of Preparation of microspheres: 9, 10
1. Solvent removed technique:-
• Emulsion – solvent evaporation technique.
i) Oil inWater (o/w)
ii) Water inOil (w/o)
iii) Water in oil inWater Oil Water (W/O/W)
• Emulsion solvent extraction.
• Emulsion solvent diffusion.
2. Coacervation and phase separation technique.
a) With temperature modification.
b) Using incompatible polymer.
c) With addition of non solvent.
d) With addition of salt.
e) Interaction of polymer with polymer.
f) Using evaporation of solvent.
3. Cross – linking technique.
a) Chemical cross linking.
b) Thermal cross linking.
c) Ionic cross linking method
4. Polymerization Technique.
a) Normal polymerization.
b) Vinyl polymerization.
c) Interfacial polymerization.
5. Spray congealing & spraydrying.
6. Freeze drying technique.
7. Precipitationtechnique.
8. Multi orificecentrifugal process
9. PanCoating.
10. Air suspensioncoating.
11. Melt dispersiontechnique
1.2.2.1. Ionotropic gelationmethod: 11-13
Ionotropic gelation can be established by capacity of polyelectrolytes that cross link to
form hydrogel beads with presence of counter ion and is referred as gelispheres. Gelispheres
have tendency to swell in stimulated fluid and capacity to release drug for prolonged time due to
relaxation of polymer also due to hydrophilic nature of gelispheres. Gelispheres can be
formulated by placing the drug and polymer solution to counter ion solution with continue
stirring.
Figure
1.8: Basic technique of Gelispheres preparation
Figure 1.9: Formulation of Gelispheres by polyelectrolytecomplexation technique
Natural polymer has more interest for the development of ionotropic gelation technique.
There are so many semisynthetic polymers like chitosan,gum can be used for the preparation of
microspheres using encapsulation technique. In the chemical structure natural polyelectrolytes
comprises certain anions/cations those have capacity to form meshworkstructure with merging
counter ions.
1.2.3. Factors affectingIonotropic gelation method:
I. Polymer and crosslinking electrolyte concentration
Polymer andelectrolyte concentration have key result on preparation of beads developed
by ionotropicgelation method and also depends on concentrationof both calculated fromnumber
of crosslinking units.
II. Temperature
The bead size also sometimes depends on temperature as well as total time consumed for
crosslinking.
III. pH of crosslinking solution
pH of crosslinkingsolution also significant factor considering for the formulation because
pH having influence on reactionrate, size andshape of beads.
IV. Drug concentration
The ratio of drug with polymer can be considered as important factors for the parameters
like drug entrapment efficiency. When the drug with polymer ratio is more than one than it may
be chances for bursting effect. The ratio also effect on morphology of gelispheres.
V. Gas forming agent concentration
Porous gelispheres can be prepared by using gas inducing agent that also effect on
morphology of microspheres. There are widely available agent that produces gases like calcium
and sodium bicarbonate.
1.3. BIODEGRADABLE POLYMER: 14,15
Biodegradable polymers are in vivo degradable, that can be degraded by enzymatically or
non-enzymatically, and produce biocompatible or nontoxic by-products. These polymers have
the capacity to metabolize using enzymes and also eliminated through normal
physiologicalpathways. They are separated into three collections on the basis of their availability
source i.e. natural, semi synthetic and synthetic. Most generally available natural biodegradable
polymers likegelatin, alginate, andchitosan and so widely used for microspheres. Biodegradation
is the process in which compounds can be redistributed in environment cycle as carbon, sulphur,
nitrogen etc. The release of drug from the biodegradablepolymer can be maintained by so many
factors like kinetics of biodegradation, drug characteristics and compatibility of drug to polymer
and also morphology of devices.
1.3.1. Mechanism of drug release from Biodegradable polymer: 16, 17
The drugrelease mechanism form the erodible polymers can be happen by one of the
mechanism as shown in Figure 1.10 and 1.11.
As per mechanism1, the drug is ready to available for connect with polymeric backbone
with alabile bond; this bond hadgreater action toward hydrolysis than thepolymer reactivity to
breakdown. As per mechanism 2, the drug available in the core and is coated with biodegradable
ratecontrolling membrane. This isreservoir type mechanism and it erodes to eliminate the drug.
Mechanism 3 represents a uniformly dispersion of drug in the biodegradablepolymer and
dissolution of drug for as per mechanism III is by erosion,diffusion, or combination ofboth.
Figure 1.10: Possible drug release mechanism for polymeric drug delivery.
Figure 1.11: Diagram for the drugrelease mechanism from the biodegradable polymer
1.4. MELT GRANULATION TECHNIQUE: 19
Melt granulation is technique through which fine solid particle are agglomerates by
kneading, agitation and layering using molten binding liquid. After solidifying dry agglomerates
are formed at room temperature. Melt granulation is most widely used techniques for the
development of meltagglomeration. There are no proper justifications for distinguish between
pelletization and melt granulation. So granulation may be considered as pelletizationprocess
when agglomerates of extremely spherical and narrowsize are produced.
In this techniques the polymer melted at their meltable temperature and drug is added to
the molten solution. The drug meltable solution was cooled at room temperature for
solidification. From the solidification granules can be formed by sizing of different granules
using different sieves. The meltable solution also prepared by using hot air or heatingjacket.
Most widely used meltable binders melts at 50 to 80°C.
1.4.1. Mechanism of melt granulation: 19
The melt granulation process comprises of three combined phases:
I. Wetting andnucleation,
II. Coalescencestep,
III. Attrition andbreakage.
I. Wetting and nucleation step:
During the this step the liquid bridges are formed when meltable binders come into contact
with the powder bed and it may lead to the formation of small agglomerates.
a) Immersion
Immersion of the melt granulation occurs when the meltable granules size is more than
that of fine solid particle. Immersion can be accomplished by the depositionof solid fine
particlesonto the droplet surfaces ofmolten binder. (Figure 1.8)
b) Distribution
In this case a molten bindingliquid is dispersed over the surfaces of solid fine particles.
So nuclei are producedby the collision betweenthe wetted particles. Normally, smaller droplet
size as well as reduced viscosity of binder along with high shearingforces are suitable conditions
for the development of nucleation bythe distributionmethod. (Figure 1.8)
II. Coalescence step:
It exhibits nuclei that haveresidual liquid surface to increase success fulfusion ofnuclei.
The surface liquid have ability to increase plasticity tothe nuclei and is important for supporting
the deformation ofnuclei surface for coalescence as well as enhancing granulation efficiency.
III. Attrition-breakage step:
Attrition andbreakage is nothing but one type of granulation fragmentation technology in
which materials are dried by tray cooling to room temperature withoutthe use of tumblingprocess
for the drying. Furthermore, breakage is identical that have characteristics role for influencing
the final properties of granules that performed by meltgranulation.
Figure 1.12: Modes ofagglomeration(a)Distribution (b)Immersion
1.4.2. Requirements of melt granulation:
Usually, 10–30% w/w meltable binder can be used for the development of product.
� Polymer used for melt granulation have melting point in range of 50–100ºC.
� Hydrophilic meltable binders are considered for the development of fast release product
whereas the hydrophobicmeltable binders are utilized for development of prolonged-
release product.
� Solid particles should have melting points at least 20°C greater thanfrom the
maximumprocessing temperature.
1.4.3. Meltable binders:
• It must be solid at normal room temperature and melt within range of 40 and 80°C,
• Physical and chemical stable
There are two type of Meltable binder
1) Hydrophilic Meltable binders [Table 1.3]
2) Hydrophobic Meltable binder [Table 1.4]
Table 1.3 Hydrophilic meltablebinders in the meltgranulation technique.
Hydrophilicmeltable binder Typicalmelting range (°C)
Gelucire 44-50
Poloxamer 50.9
PolyethyleneGlycol
2000 42-53
3000 48–63
6000 49-63
8000 54-63
10000 57-64
20000 53-66
Stearate 6000 WL1644 46-58
Table 1.4 Hydrophobic meltablebinders in the meltgranulation technique.
Hydrophobicmeltable binder Typicalmelting range (°C)
Beeswax 56-60
Carnauba wax 75-83
Glyceryl behenate 67-75
Glyceryl monostearate 47-63
Glyceryl palmitostearate 48-57
Glyceryl stearate 54-63
HydrogenatedCastor oil 62-86
MicrocrystallineWax 58-72
ParaffinWax 47-65
StearicAcid 46-69
StearicAlcohol 56-60
1.5.1. Tramadol Hydrochloride (TM): 20
ChemicalName: (±) cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)
CyclohexanolHydrochloride.
ChemicalStructure:
MolecularFormula: C16H25O2N . HCl
Molecular weight: 299.8
Melting point: 180 to 184°C
Description: white, bitter, crystalline and odorless powder.
Solubility: Readily soluble in water and ethanol
PKa: 9.41
PartitionCoefficient 1.35 atpH 7.
1.5.2. Mechanism ofAction:
TM has the action against opioid analgesic. Two possible mechanism can considered as
binding of parent as well as M1metabolite to µ-opioidreceptors and weak inhibition ofreuptake
of nor epinephrine andserotonin. Opioid management of TM is because of less binding attraction
of the parentmolecule and more attraction binding of theO-demethylated metaboliteM1 to µ-
opioidreceptors. As per model developed from animal, M1 having the great potency upto 6 times
greater than that of TM ingenerating analgesia As well as 200 times extra potency in µ-
opioidbinding. In humans the effect of analgesia starts probably form 1 h afteradministration and
reaches peakin approximately 2 to3 h.
1.5.3. Pharmacokinetics:
The TM effect ofanalgesia is because ofboth M1metabolite as well as parent drug. TM is
taken as aracemate and both the [-]and [+] formsof both TM andM1 are detectedin the
circulation. The TM pharmacokinetics can be understand by following figure 1.13.
� Absorption:
TM is capable of fast and nearly completelyabsorbed after oral administration. The oral
bioavailability for TM is approximately 75% for 100 mg dose. The mean peakplasma
concentration ofTM and M1 found at 2 and 3 h, respectively, after administration of TM product
in healthy adults. The plasma steady-state concentrations is observed for bothTM as well as M1
within two dayswith q.i.d. dosing. There is noevidence ofself-induction.
� Distribution
The volume ofdistribution in the body for the female as well as males ofTM was 2.9
and2.6 lit/kg respectively, when the 100 mg of TM is taken as intravenously. The plasmaprotein
binding for theTM is approximately 20% inbody and also observed that binding isindependent of
concentration upto 10µg/ml.
Figure 1.13: Mechanism action for Tramadol Hydrochloride
: Mechanism action for Tramadol Hydrochloride
� Metabolism
After the drug administration nearly 60% of TM is eliminated asmetabolites. Nearly 30%
of the TM is removed through urine as unchangeddrug, whereas 60% of theTM is separated for
metabolism. There are number of enzymes available in body capable for metabolism in body like
CYP2D6, CYP3A4, as well as by N - and O - demethylationand glucuronidation orsulfation in
liver.
� Elimination
The Major elimination for TM through liver and kidneys also play role for elimination of
TM.
1.5.4. Side effects of TM:
The major side effect of TM is swelling of eyes, face, throat, mouth, hands, feet, ankles or
lower legs. It was also found that sometimes difficult in breathing. Other side effects like
diarrhea, constipation, nausea, heartburn, vomiting. TM having the effect on skin like hives, rash,
itching, sweating and chills. It also effect on central neuron like headache, drowsiness, insomnia,
nervousness and agitation.
Figure 1.14: Adverse effects of TM. Red color indicates more adverse, necessary for
1.5.5. Indications and usage:
The major indication for TM is thesevere pain management.
Figure 1.14: Adverse effects of TM. Red color indicates more adverse, necessary for
immediate contact.
The major indication for TM is thesevere pain management.
Figure 1.14: Adverse effects of TM. Red color indicates more adverse, necessary for
1.5.6. Dosage andAdministration:
For the ages above 17 years dosing of TM should be started initially as 25 mg/day and
increase dose of TM to 25 mg every 3 days toreach 100 mg/day. After reaching 100 mg dose
further dosing of TM can be raised by 50 mg for every 3 days to reach200 mg/day (50 mg q.i.d.).
After reaching 200 mg doseof TM further can be increased upto 100 mg as needed.TM does
should not be exceed from 400 mg/day.
1.6. Chitosan: 21, 22
Chitosan, a natural linear biopolyaminosaccharide, polymer derived from chitin using
alkaline deacetylation. Chitin is found to be major element available in protective cuticlesof
crustaceans suchas shrimps, crabs,lobsters, prawns also cellwalls of certainfungi such as
aspergillus andmucor. To prepare chitin, demineralised the crab and shrimp hells in
diluteHydrochloric acid (HCl), then deproteinated using dilute NaOH, followed by decolourised
with potassium permangate KMnO4) as shown in figure 1.12. The chitin is then deacetylated by
boiling in a concentrated NaOH solution to become chitosan. Pharmaceutical grade chitosan is
deacetylated within 90 and 95% where as food grade between 75 and 80%. Chitosan is
structurally represented as Figure 1.11.
Figure 1.15: Chitosan Chemical Structure Molecular formula: (C6H11NO4)n
CAS registry no: 9012-76-4
Synonyms; 2-Amino-2-deoxy-(1,4)-β-D-glucopyranam
Chemical name: Poly-β-(1-4)-2-Amino-2-deoxy--D-Glucose
Appearance: White to light yellow flake
pKa: 6.2- 7.0
Solubility:
Chitosan is soluble at pH less than 7.0 in dilute acids. Chitosan dissolve rapidly in dilute
solution of most organic acid. Chitosan is insoluble in pH more than 6.5 in alkaline solution.
Chitosan can precipitated in + 3 alkaline and have capacity to form gel at reduced pH
Figure 1.1
Because of readily available free amine groups inch
also have capacity to interact with
1.6.1. Important characteristics of Chitosan to be considered in the pharmaceutical
formulations.
� Molecular weight
• Low molecular weight
• High molecular weight
Figure 1.16: Synthesis of Chitosan from chitin
Because of readily available free amine groups inchitosan, it carry a +ve charged ion
also have capacity to interact with –ve charged surfaces or polymers andundergoes chelation
Important characteristics of Chitosan to be considered in the pharmaceutical
molecular weight – 10,000
High molecular weight – 1000,000
carry a +ve charged ion and
undergoes chelation.
Important characteristics of Chitosan to be considered in the pharmaceutical
� Viscosity
At conc. of 1.25% in dilute acetic acid has a viscosity of
• 1200 cps – good quality
• 160 cps – medium quality
• 161 cps – low quality
� Degree of deacetylation:
Commercial deacetylated chitin is approximately 80 – 85% deacetylated. Degree
ofdeacetylation is important and it should be 80 – 85% (or) higher for the development of soluble
product.
� Density: between 1.35 and 1.40 g/cc3
� pH: 4.0 – 6.0
� Glass transition temperature: 203ºC
� Viscosity: There are different types of viscosity grades available for Chitosan. Chitosan
was observed to be good viscosity promoting agent when product developed in acidic
condition. It also behave as apseudo-plasticmaterial, that mean to say that with
increasingshear rate viscosity of Chitosandecreased.
� Deacetylation: The degree ofdeacetylation is important characteristics and it should be
more than 80-85% for development more soluble product.
� Particle size distribution: <30 µm
� pKa: ~6.5
� Storage condition: Chitosan should be placed in a tightly closedcontainer in a cool as
well as dry place. The PhEur 2005 specifies that chitosan should be stored at room
temperature of 2ºC-8ºC.
� Incompatibility: Chitosan is incompatible with strong oxidizing agent.
1.6.2. Application: 23
• Chitosan can be used in biomedical and pharmaceutical formulations because Chitosan
have properties like lowtoxicity, biodegradability ans well as good biocompatibility.
• In case of pharmaceutical applications chitosan can be utilizes as a vehiclefor directly
compressedtablets24, asDisintegrant25,binder26, granulatingaaAgent27, in
groundmixtures28. Chitosan also having properties as a drug carrierfor sustained release
development29 and co-grindingdiluent for the improvement of dissolutionrate and
bioavailabilityof water insolubledrugs.
• As chitosan has interaction between negatively charged mucosal surface so can be used
in mucoadhesive formulation.
• Because of properties like film forming can be used for preparation of contact lenses.
• Chitosan membranes can be usedartificial kidney.
• Chitosan possess carrier for microsphere drug delivery so used for sustained and
controlled drug delivery.
• Reaction of chitosan withmultivalent anion so crosslinking between chitosan molecules.
This effect mostly in developemt of chitosanmicrosphere as shown in figure 1.13.
• Chitosan also have characteristics for filmforming and has been utilized for
developmentof contact lenses.
• Chitosan membrane also used in artificial kidney membranes.
• Chitosan have suitable properties for the preparation of microspheres as a carrier.
Microspheres prepared using chitosan can used for formulation of sustained and
controlled
release
product.
Chitosan
microspheres
having
characteristic
s to improve
bioavailabilit
y of
degradable
substances.
Figure 1.17:
Method of
preparation of chitosan microspheres
Formation of crosslinking between polymer functional groups reduces hydrophlilicity
and due to decreasing permeation rate for biologicalfluids through the hydratedmatrix. Physical
bonds formation between polymer molecules can be attained by ionotropic gelation that involves
interaction of polymer with opposite charged ions. Cross-linking can also been achieved by
adding agents for the formation of chemical bonds but has the main disadvantage is chemicals
having more toxicity like formaldehyde. BY crosslinking with ionization has an advantage that
can avoid toxicity. Chitosan has now growing interest in ionization technology because their
network forming capacity as shown in figure below.
Figure 1.18: Formation of cross
1.7. Sodium Tripolyphosphate (Na
Tripolyphosphate (TPP) has different synonyms like Sodium triphosphate,
triphosphoric acid, pentasodium salt, sodium tripolyphosphate (Na
triphosphate, pentasodium Tripolyphosphate.
TPP is free from toxic and carrying anion which having capacity to crosslinks with
positively chargedamine groups by ionic
Figure 1.19: Chemical structure of sodium tripolyphosphat
TPP is an broadly researched cross
When Chitosan interact with TPP it will form good spherical complex and have excellent
properties like pH-responsive drug
characteristics that they can improve product stability and can be utilized for development of
controlleddrug delivery.
1.8. Glyceryl Palmitostearate:
• Chemical Name: Glycerin
oxohexadecyl)-oxy]-1,3-propanediyl dioctadecanoate and 1,2,3
• Empirical Formula:
andtriglycerides of C16 and C18 fatty
• Description: Glyceryl palmitostearate available
: Formation of cross-linked gels by use of polyelectrolyte complexion
Sodium Tripolyphosphate (Na-TPP)
Tripolyphosphate (TPP) has different synonyms like Sodium triphosphate,
pentasodium salt, sodium tripolyphosphate (Na-TPP), pentasodium
triphosphate, pentasodium Tripolyphosphate.
TPP is free from toxic and carrying anion which having capacity to crosslinks with
by ionicinteraction.
: Chemical structure of sodium tripolyphosphate:
TPP is an broadly researched cross-linking agent with five bonding sites on the molecule.
When Chitosan interact with TPP it will form good spherical complex and have excellent
e drugrelease properties. The TPP and Chitosan complexes have
they can improve product stability and can be utilized for development of
: 30-32
Glycerin palmitostearate; glycerol palmitostearate; 2
propanediyl dioctadecanoate and 1,2,3-propane triol.
Glyceryl palmitostearate is a combination
triglycerides of C16 and C18 fattyacids.
palmitostearate available as a fine whitepowder with a
linked gels by use of polyelectrolyte complexion
Tripolyphosphate (TPP) has different synonyms like Sodium triphosphate,
TPP), pentasodium
TPP is free from toxic and carrying anion which having capacity to crosslinks with
e:.
linking agent with five bonding sites on the molecule.
When Chitosan interact with TPP it will form good spherical complex and have excellent
The TPP and Chitosan complexes have
they can improve product stability and can be utilized for development of
; glycerol palmitostearate; 2-[(1-
propane triol.
palmitostearate is a combination of mono-,di-,
powder with a faint odor.
• BoilingPoint: 200°C
• Melting Point:52-55° C
• Solubility: Easily soluble in chloroform as well as dichloromethane; whereas practically
insoluble inethanol (95%), mineraloil, and water.
• Storage condition: Glyceryl palmitostearate should be stored at a temperature of 5–
158C in an airtight container, protected from light and moisture.
• Functional category: Biodegradable material; coating agent; gelling agent; release
modifying agent; sustained-release agent; diluents in tablet capsule formulation;
lubricant; taste-masking agent.
• Application in pharmaceutical formulation or technology:
Glyceryl palmitostearate is widely used in oralsolid-dosage pharmaceutical formulations
aslubricant. Tablet disintegration and strengths depends on mixing time of glyceryl
palmitostearate, as increase the blending time, increases disintegration time of tablets and also
decreases strength of tablet. It is used as a lipophilicmatrix for preparation of sustained-release
product. Tablet formulations maybe developed by granulation or any hot-melttechnique, the
former producing tablets that have the faster release profile. Release rate decreases with
increased glyceryl palmitostearate content. Glyceryl palmitostearate is used to form
microspheres, which may be used in capsules or compressed to form tablets,) pellets, coated
beads and biodegradablegels. It is also used for taste-masking. See Table 1.5
Table 1.5: Uses of glyceryl palmitostearate
Sr. No. Use Concentration
1 Matrix for sustained release 10.0-25.0
2 Tablet masking 2.0-6.0
3 Tablet lubricant 1.0-3.0
1.9. Glyceryl Behenate : 33-35
• Synonyms: Compritol 888 ATO; 2,3-dihydroxypropyldocosanoate; docosnoic acid, 2,3-
dihydroxypropylester; E471; glycerol behenate; glyceryl monobehenate.
• Chemical Name: Docosanoic acid, monoester with glycerin
• Functional Category: Coating agent; tablet binder; tablet and capsule lubricant.
• Melting point: 65-77°C
• Solubility: soluble in chloroform & dichloromethan when heated, practically glyceryl
behanate is not soluble in 95% ethanol, hexane, mineraloil, and alo in water.
• Applications in Pharmaceutical Formulation or Technology:
Glyceryl behenate have its effect in foods, cosmeteics, as well as oral pharmaceutical
development. In cosmetics, glyceryl behanate widely used for viscosity enhancing polymer for
the manufacturing of emulsions; see Table 1.6. In pharmaceutical preparations, it is can be
widely utilized as lubricant and also observed have characteristics like lipidic coating. It also is
having properties for encapsulation of different drugs like retinoids. It also observed that can be
used as matrixagent for sustained products; mainly have the more effect with watersoluble drugs
for their sustained effect. Like glyceryl palmitostearate, behanate also having properties like
lubricant for oral soliddosage formulations. Because of its low melting point glyceryl behnate
can be utilized for ho-melt coating agent.
Table 1.6: Uses of Glyceryl Behenate
Lipophilic matrix/coating for sustained released tablets and capsules
>10.0
Tablet and capsule lubricant 1.0-3.0
Viscosity increasing agent in silicone gels (Cosmetics) 1.0-15.0
Viscosity increasing agentin w/o or o/w emulsion (cosmetics) 1.0-5.0
Storage Condition: Glyceryl behenate should be stored in a tight container, at a temperature less
than 35ºC.
K.S.Y Hemant et al36 studied microspheres for the drugs amoxicillin trihydrate and
Metronidazole with chitosan used as mucoadhesive polymer. Here microspheres were developed
by cross linking using sodium tripolyphosphate. The influence of formulation parameters were
evaluated on particle size, swelling studies, content uniformity, and mucoadhesive studies.
Release of drug from chitosan microspheres were evaluated in 0.1N HCl at 370±0.50C. The
chitosan microspheres indicated good mucoadhesive property and showing sustained effect. The
spherical shape of microspheres confirmed with SEM. Further concluded that prepared
microspheres can be used in the treatment of gastric ulcer.
Maryam Amidi et al 37 studied chitosan containing drug delivery systems that improve drug
absorption of the formulation from the mucosal sites. Chitosan is a mucoadhesivepolysaccharide
and have capacity that can open the tight junctions among epithelial cells for chemical alteration,
resulted in a development of great range of chitosan derivatives used for improve the drug
absorption rate. This review offers the physicochemical properties of chitosan and their uses for
the preparation of product like protein and antigen that can be delivered through mucosal and
parenteral administrations discussed.
Preeti K. Suresh et al38 prepared metronidazole loaded chitosan microspheres prepared with
external gelation technique using tripolyphosphate as the cross-linker. The drug and polymer
ratios were studied at three levels: 1:4, 1:5 and 1:6 (by weight) and also studied concentration of
tripolyphosphate at three levels: 6, 12 and 18 (%). The prepared microspheres were evaluated
size of particle, morphology of microspheres, entrapmentefficiency, swelling, erosion,
bioadhesion and drug release profile. Microspheres with size ranging from ~ 800 µm with
spherical in nature produced. Drug entrapment efficiency, percentage swelling, erosion and
biosdhesion was found to be in the range of 60-75%, 10-25%, 5-15% and 43-59% respectively.
Devika R. Bhumkar et al39 evaluated pH effect on cross-linking belongings of chitosan with Na
tripolyphosphate. She prepared microspheres with ionotropic gelation method using chitosan and
concluded that cross-linked particles having capacity to modify with adjusting the pH of chitosan
solution. At lower pH chitosan was cross-linked ionically whereas at higher pH chitosan cross-
linked by deprotonation mechanism. The swelling behavior of chitosan microspheres depends on
pH of TPP, and concluded that chitosan cross-linked showed higher swelling ability at lower pH.
S. Senthil kumar et al40 prepared clobazam loaded chitosan microspheres with ionic gelation
method using Natripolyphosphate as the crosslinking agent. Microspheres were evaluated for
size of microspheres, particle size distribution, drug content, encapsulationefficiency and in-vitro
drugrelease. The surface characteristics of the developed microspheres were confirmed by SEM.
From drug release data concluded that as increasing the crosslinking density the drug release rate
decreased. The physical form of microspheres also confirmed by DSC and XRD and confirmed
that clobazam existed as a molecular dispersion in the polymeric microsphere matrix in an
amorphous state.
Magdalena Gierszewska et al41 studied the crosslinking efficiency condition when the
formulation prepared with chitosan. He studied the influence of molecular structure of chitosan.
Various crosslinking conditions like pH and crosslinking time were studied. The drug form and
surface morphology of microsphere were conformed using X-ray device and SEM. The effect of
crosslinking was confirmed by atomic force microscopy (AFM). Finally he concluded that pH of
crosslinking TPP solution are playing more important role on surface smoothness and roughness
of of the microspheres.
Emmanuel Chinedum Ibezim et alc42 formulated chitosan with tripolyphosphate microparticles
for the controlled drug delivery of pyrimethamine. Chitosan was ionically cross-linked along
with tripolyphosphate at controlled temperatures i.e. 25oC, 40oC, and 50oC and also with varying
cross-linking times i.e. 30 min, 2 h and 4 h respectively was taken to form microparticles. The
yield of microparticles found 0.3515 to 0.7749 g per 100 ml of crosslinking solution. The
entrapmentefficiency of microspheres was found 25.55 to 99 %. And concluded that
microspheres prepared at ambient temperature and 30 min cross linking time having the highest
efficiency.
Aliasgar J. Kundawala et al43 formulated isoniazid microspheres for pulmonary delivery using
chitosan as polymer. Tripolyphospate was used for crosslinking of chitosan based microspheres
to attain sustained drug release. Chitosan microspheres were developed by spray drying method.
The developed microspheres were confirmed for their microspheres size, droplet shape, drug
release characteristics and in vitro drug deposition at pulmonary. The developed cross linked
microspheres was having entrapment efficiency of 72 to 88 % and microspheres particle size was
found from 3.6 to 5.2 µm and fine particle fraction of 67 %.
Obaidat AA et al44 prepared controlled drug release formulation contains tramadol using
glyceryl behenate. This investigation revealed that glyceryl behenate having tendency to
formulate sustain release product and is a suitable waxy material that can be utilized for the
development of sustained the drug release product. He investigated this development with the
use ofwater soluble drug like tramadol.
Tiwari S et al45 studied impact of concentration of hydrophobic and hydrophilic polymer the
drug release rate. He taken tramadol as model drug and hydrophilic and hydrophobic polymers
are hydrogenated castor oil; ethyl cellulose on were studied. Wet granulation was used for the
development of hydrophilic matrix tablets whereas melt granulation technique was used for the
development of hydrophobic (wax). He concluded that hydrophobic materials having more
sustained effect when compared with hydrophilic polymer. Tables prepared with hydrogenated
castor oil were observed to be mist and formulation was more suitable for drugs which are
greatly water soluble in order to achieve sustained effect.
Shu XZ et al 46 prepared complex beads of tripolyphosphate with chitosan for controlled release
drug delivery. A innovative method was used to improve the mechanical strength of bead of
tripolyphosphate(TPP)/ chitosan formulated under cooled condition at 4˚C in the existence of
gelatin. The pH effects of TPP cross-linking have capacity to modify the drug release behavior of
beads. And concluded that beads prepared with chitosan and tripolyphosphate was having
significant effect in the terms of development of prolonged release formulation.
D. Singh et al47 formulated gentamicin sulphate microspheres for controlled release using
chitosan as rate controlling polymer. The independent variables was designated for formulation
of microspheres were drug concentration (X1), cross linking agent (X2) and polymer (chitosan)
concentration (X3) whereas dependent variables designated were entrapment efficiency (Y1) and
average diameter (Y2) of microspheres. It was concluded that formulation containing 10 mg
gentamicin, 2% (w/v) tripolyphosphate and 3% (w/v) chitosan, was recognized for maximizing
drug entrapment (80.04±2.24%) and minimizing average particle size to optimum level
(18.64±0.61µm). Surface smoothness of droplets was confirmed by SEM and confirmed that
microspheres with smooth spherical surface with size from 11.42±0.56µm to 26.34±0.72µm.
R. Jayakumar et al48 prepared microspheres of phosphorus for controlled release using chitosan
as drug retardant polymer. Tripolyphosphate was used for the complexion with chitosan at lower
pH as 4.0 and confirmed by SEM. The effect of pH solution was studied by taking into
consideration of drug release profile using indomethasin as model drug and was taken into two
different concentrations i.e. 0.3% as lower and 0.6% as higher w/w. From the data of in vitro
profile concluded that with increasing buffer solution pH the drug release increased. In another
word in vitro release was observed more at pH 7.4 and in vitro release observed lower at pH 1.4,
the reason for these characteristics was phosphorous ionization groups and solubility of IM was
greater at basic medium.
Akanksha Garud et al49 prepared metronidazole mucoadhesive microcapsules using chitosan as
drug retardant polymer. Tripolyphosphate was used as cross-linking agent with linkage of
chitosan. The prepared microcapsules characterized for different parameters like size, shape,
particle size, entrapment efficiency. They concluded that swelling of chitosan microcapsules
depends on cross-linking characteristics with tripolyphosphate. The developed microcapsules
showed greater mucoadhesive tendency at intestinal pH 7.4 whereas lower tendency at pH 1.2.
The in vitro release was observed to be slow and also for prolonged time.
Hui Liu et al 50 investigated characteristics of ionically cross-linked chitosan nanoparticles. They
concluded that nanoparticles can be developed only inside suitable zone of TPP and chitosan
concentrations. The surface zetapotential and droplet size have the significant impact of ratio as
well as concentration of chitosan with TPP. The droplets characteristics also can be modified by
factors like addition of salt form and solution of pH. From the data inferred that developed
formulation was stable.
J. Berger et al51 reviewed interactions in covalently and ionically crosslinked chitosan hydrogels
for biomedical applications. The formulated linkages have characteristics to permit water as well
as other compounds absorption and maintain the diffusion release characteristics without
dissolution. This type of formulation pH induced can be developed by placing another polymer.
Ionically prepared crosslinked hydrogels have more swelling tendency in the terms of pH
change.
Mahaparale PR et al 52 prepared sustained release metronidazole succinate matrices with using
two different meltable binders for the formulation one is Compritol888 ATO and another is
PrecirolATO 05. Matrices were formulated by melt granulation technique. From the drug release
study it was concluded that matrices formulated from mixture of two waxes showed more
sustained release effect than the formulation prepared using compritol and precirol alone.
J.K patel et al53 reviewed chitosan based nanoparticle in drug delivery. Several polymeric
nanoparticlulate systems have been developed and evaluated in recent year, using both natural as
well as systemic polymers. The formulation developed using different polymers having their
own benefits and disadvantages. From the natural polymers, the nanoparticles formulation were
developed with chitosan and evaluated. Somasundaram Ramachandran et al 54 formulated
famotidine microspheres using biodegradable polymer as chitosan for increase bioavailability
and decrease dose frequency of the famotidine. Chitosan containing microspheres were
developed by simpleemulsification technique with glutaraldehyde ascrosslinking. Several
process parameters such as emulsification speed and stirringtime and formulation variables like
drug/polymer ratio, volume of glutaraldehyde and surfactant volume were evaluated. The
developed microspheres studied for different parameters and the surface morphology of
microspheres were confirmed by SEM. From data it was concluded that droplets having smooth
surface. The in vitro release data showed that famotidine release was upto 24 h.
Lian-Yan Wang et al 55 prepared chitosan microspheres holding insulin for enhancement of
release behavior. In this study Lian-Yan developed suitable method for the development of even
sized microspheres using emulsion technique. Lian-Yan also optimized process variables for the
uniform sized droplets. Lian-Yan also evaluated parameters like protein’s chemicalstability, in
vitro release characteristics and encapsulationefficiency was matched with different alternative
method of microspheres containing chitosan. From these data equally parallel chitosan droplets
were developed.
M.D.Dhanaraju et al 56 prepared Lamivudin microspheres using chitosan as release controlling
polymer. They developed microspheres using crosslinking technique with glutaraldehyde. The
developed microspheres were examined for physicalcharacterization. From the data,
encapsulationefficiency was observed to be 54.83-63.70 %w/w, size of droplets was measured
from of 5 to 40 µm and said that approximately 68% of the droplets was lying between 27 to 37
µm sizes. From the investigation M.D. Dhanaraju concluded that in vitro release of lamivudine
was managed by crosslinking density.
Rajesh Pandey et al 57 prepared alginate–chitosan microspheres for check the integrity on anti-
tubercular drug activity. Three an anti-tubercular drugs (ATDs), rifampicin, isoniazid and
pyrazinamide, were studied the efficacy of anti-tubercular activity by preparing microspheres.
Microspheres were evaluated for their physical characterization. Form the result drug
encapsulation efficiency was found from 65% to 85% and drug loadingefficiency was 220–280
mg in microspheres. The developed microspheres were administrated to guinea pigs for evaluate
sustain effect in plasma and organ for seven days and nine days respectively. From the result
concluded that drug encapsulated as microspheres increase the bioavailabilty up to 13- to 15
fold.
Sanju Dhawan et al 58 developed microspheres to study the impact on mucoadhesive
characteristics by using chitosan. Microspheres developed with different techniques with
different crosslinking agent like glutaraldehyde and tripolyphosphate. The strength of the
interface among chitosan and mucin microspheres was reliant on microspheres preparation and
the addition of mucin quantity. Adsorption of mucus level was directly related to the entire +ve
zeta potential values presented in microspheres. Finally concluded that microspheres formulated
with thermal crosslinking and glutaraldehyde exposed more stable in acid HCl when
microspheres developed with emulsificationionotropic gelation using tripolyphosphate as
crosslinking agent.
Rajesh R. Dubey et al 59 studied two-stage optimization process for development of
microspheres containing chitosan. Chitosan containing microspheres were developed with
chemicaldenaturation technique. The developed microspheres droplets were confirmed for their
physical representation like surface characteristics, particle size of droplets, particle
sizedistribution, drug entrapmentefficiency, drug content, and in vitro release. From the result
concluded that morphology of the microspheres was dependent on process constraints. Rahesh
also concluded that average microspheres size was depends on polymer solution, the stirring rate.
Kiran S. Bhise et al 60 studied effect of two major characteristics like dissolution medium and
oppositely charged polymer in microspheres formulated with chitosan. For this naproxen was
selected as model drug. They studied effect on erosion, swelling and drug release. Also studied
effect of buffer pH and drug : polymer ratio on water uptake, drug release and matrix erosion
were studied. The rapid drug release of naproxen was found on matrices that comprising 100%
polymer so it may lead to reduce the matrix cohesiveness of matrix; whereas, in vitro release
observed to be minimum for matrices developed by using optimum κ-carrageenan. The reason
for getting slower in vitro release for naproxen was confirmed by its poor solubility at different
pH.
Sanat Kumar Basu et al 61 prepared tramadol microspheres containing chitosan and gelatin B
the microspheres was prepared by ionotropic gelation method. Ionotropicgelation was developed
using Na-tripolyphosphate. The prepared microspheres were studied for their physical
characterization. All the microspheres exhibited initial burst release then maintaining the
sustained effect. The release of drug followed as fickian diffusion mechanism. The physical
properties of drug from the microspheres were confirmed by DSC and XRD analysis and
confirmed that drug present in matrix.
Soheila Honary et al 62 studied effect of mucoadhesive characteristics on molecular weight of
chitosan. The microspheres were developed with use of combination of alginate and chitosan.
Three different chitosan molecular concentrations were selected for optimization of investigation
like minimum, medium and maximum and studied the effect on particle size and drug release.
The microparticle was prepared by directly spraying alginate solution onto the chitosan and
calcium chloride solution at desired conditions. From the results indicated that formulation
prepared with high molecular weight of chitosan having smaller and uniform particle size. And
the formulation containing high molecular weight having stronger electrostatic and hydrogen
bonding confirmed by FTIR and DSC study.
Hailong Peng et al 63 prepared resveratrol microspheres with chitosan as drug coating materials
for controlled release. Vanillin was selected for cross-linking with chitosan. The microspheres
were formulated by emulsion chemical cross-linking method. The prepared microspheres exhibit
smaller particles with smoother surface and the size distribution between 53 and 311 lm. The
encapsulation efficiency of Res within microspheres was up to 93.68%.
Kesari Asha et al 64 formulated zidovudine microspheres for controlled release using chitosan as
rate controlling agent. Gluteraldehyde was used as a crosslinking agent. Microspheres were
developed by emulsification method. The developed microspheres were confirmed for their
physical characterization like shape and size of microspheres droplets, drug
entrapmentefficiency, drug content and in vitro release. Form the data microspheres was
spherical and uniform small particle size with free flowing. The percent entrapment efficiency of
the microspheres were found to be 72-94 % and drug release was spread over 12 hrs. The
physical state of the Zidovudin in microspheres were confirmed by X-ray and indicated that drug
is present as crystalline form.
Lourdes O et al 65 studied effect on sustain release on the formulation prepared with melt
granulation method using hydrophilic matrices. Theophylline was selected as model drug to
investigate the impact of hydrophilic polymers on formulation. From the result of dissolution
profile concluded that formulation having HPMC K4 M, Gelucire or PEG showed similar
dissolution profile with marketed approved products. Drug release found to be relatively lower
when microspheres formulated with lipophilic binders.
Paradkar et al 66 studied the effect of formulation developed by two different methods like
direct compression and melt granulation method to study the impact on in vitro release
characteristics. The formulation prepared with metformin and glyceryl behenate (Compritol)
were selected as meltable binders. The effect of diluents like lactose andMCC on in vitro release
characteristics also studied. From the data it was confirmed that glyceryl behanate showed good
sustained effect when the formulation prepared with melt granulation. And concluded that
glyceryl behanate was good waxy materials utilized for controlling the drug release behavior.
Amaral et al 67 prepared naproxen matrix tablet with hydrophilic and hydrophobic hydrogenated
castor oil. They investigated impact of hydrophilic concentration as well as hydrophobic
concentration on in vitro release characteristics. Lactose and dicalcium phosphate was used as
filler. Matrices formulated with HPMC and hydrogenated castor oil exhibit that concentration of
polymer was inversely depended on in vitro release characteristics. Drug release was moderated
by adding proper diluents. And finally concluded that lipid matrices were suitable for attaining
sustained release for highly water soluble drug.
Jiping L et al 68 studied the effect of different process like holt melt extrusion with melt
granulation. Jiping also studied granules properties with the formulation prepared by two
techniques. The tablets prepared by different methods were studied for their drug release
characteristics. From the result of drug release characteristics it was found as slower tablet
prepared with melt extrusion having slow frug release whe tanlet prepared with melt granulation
method.
Shimpi et al 69 investigated the impact of Gelucire for developing of multiunitfloating system of
highlywater soluble drug like Diltiazem hydrochloride. The diltiazem granules were prepared by
using melt granulation technique with the use of Gelucire. From the granules tables was
developed using tablet press machine. Afetr developing the tablet studied for tablets parameters
and also confirm the floating ability of tablets. Prepared matrices were studied for DSC, HSPM,
SEM and in-vitro release. Aged samples presented phase transformation of Gelucire 43/01 that
causes increase in release of drug.
Kamble et al 70 prepared ibuprofen matrix tablet using wax. Matrices were formulated by melt
solidification techniques. With adding more amount of wax to the matrices increase integrity and
increase prolongation of drug release. Cetyl alcohol and Palmitic acid mixures was used to
improve matrix integrity and release of drug form the DSC concluded that various solidification
and erosion characteristics of waxes are responsible on drug retardant properties.
Paradkar et al 71 prepared flurbiprofen matrix tablet with cetyl alcohol. Melt solidification
technique was used to develop matrices of flurbiprofen. The process involved for formulation of
matrices was emulsification technique. The mixture of flurbiprofen cetylalcohol melted at
significant temp (50ºC) and solidified. Impact of cetylalcohol amount and agitation speed was
also optimized observed. Form the drug release behavior it was summarized that invitro release
from the cetyl alcohol followed zero order.
Chauhan et al 72 prepared floating risedronate sodium matrices using Gelucire 39/01 as meltable
binders. The matrices were formulated by melt solidification and prepared tablets were studied
for their invitro floating characteristics and invitro release. Ageing of matrices evaluated for
DSC, HSPM, SEM and invitro release. The Ageing is responsible for alterations in physical
properties of Gelucire that is impact on drug release characteristics.
Mahaparale PR et al 74 prepared metoprolol succinate matrices for sustained release. Matrices
prepared by melt granulation technique Compritol and PrecirolATO were utilized as
meltablebinders for the development of matrices. The developed tablets were evaluated for
different characteristics. From the drug release data it was conformed that matrices prepared with
combination of both meltable binders having more drug retardant efficiency when compared
with the formulation prepared with alone meltable binders.
Feng QL et al 74 prepared sodium ferualte matrix tablet prepared by solid method. Compritol
888 ATO was utilized by means of meltable binders for the development of melt granulation.
From the tablet properties it was exposed that tablet developed with dispersion based observed to
be have significant effective than from the direct compressionmethod. Invitro release behavior
was studied for the tablets prepared with both process and concluded that tablets prepared with
direct compression completed full drug release within 12 hour while tablet prepared from solid
dispersion sustained the drug release upto 24 h.
Jannin V et al 75 prepared theophylline matrix tablet by melt granulation method. precirol ATO
05 was used as meltable binders for the development of melt granulation. They also studied the
effect of poloxomers on dissoluition behavior and also developed stable formulation that have
capacity to release drug in controlled manner with precirol. From the drug release data concluded
that drug release can be improved with hydrophilicpolymers with the generation of a
porousnetwork into inert lipidmatrix.
M.C. Gohel et al 76 prepared diclofenac sodium microspheres using chitosan as drug retardant
polymer. Microspheres were formulated by coacervation phase separation method.
Glutaraldehyde was used as cross-linking agent with chitosan. They evaluated conditions for
preparations, factors affecting the in-vitro drug release from hard gelatin capsules in phosphate
buffer (pH 6.5) and drug release mechanism were identified. From the results concluded that
prepared microspheres showed good spherical morphology and release mechanism from the drug
followed to the Higuchi mechanism.
J.K.Patel et al 77 developed Metoclopramide mucoadhesive microspheres. Chitosan was used to
develop mucoadhesion in the formulation and also as coating materials. The microspheres were
developed by emulsification phaseseparation technology and glutaraldehyde was selected as
crosslinking polymer. Microspheres were evaluated for both formulation and process
optimization, like volume of crosslinking agent, time for crosslinking and speed of rotation.
Mucoadhesive properties of microspheres were depended on polymer ratio. From the drug
release it was exposed that invitro of drug was diffusioncontrolled and followed non-Fickian
diffusion.
B. Arul et al 78 formulated chitosan microspheres containing isoniazid. The microspheres were
formulated by glutaraldehyde cross-linking method using various concentrations of chitosan. The
prepared microspheres investigated for drug content, PSD studies and compared with marketed
tablets. The percentage of entrapment obtained was 60%. Stability studies were carried out at
different temperatures and found that all the formulation was more stable at 4o and room
temperature.
Dong Yanga et al 79 studied impact of the meltgranulation on the dissolution features of
griseofulvin. Granules were developed in small scale process at the temperature range at 60 °C
and the RPM range for impeller was designed approximately 20,000. Dong also investigated
formulation characterization for robust composition like impact of drug loading, concentration of
binder, selection of filler, and also impact of HPMC on release of griseofulvin. Dong developed
composition with factorialdesign. From the factorial data exposed that availability of more
HPMC decrease dissolution of griseofulvin, and also availability of starch promote the
dissolution of griseofulvin.
M.U. Uhumwangho et al 80,developed acetaminophen granules using meltgranulation. The
waxes used were goat wax, carnuba wax and glyceryl monostearate. The acetaminophen release
data were analyzed for their in vitro mechanism with mathematicalmodels (release kinetics)
namely, – zero order, firstorder, and third one was Higuchisquare root. The developed granules
was showed zero order acetaminophen release for first 55% and after this acetaminophen release
depends on firstorder for last 45%.
Nirav V Patel et al 81 developed instant release tablets of oxcarbazepine by meltgranulation
technology. The oxcarbazepine granules were developed with PEG4000 as a melting polymer.
Nirav also used filler for the instant release oxcarbazepine tablets like lactose monohydrate
having the hydrophilic tendency. From the investigation nirav investigated impact of disintegrant
on dissolution and also studied the impact of starch for the promotion of dissolution rate.
Kapil Kalra et al 82 investigated effect on dissolution characteristics and solubility behavior for
the tablet developed by meltgranulation using rifapentine as drug. Rifapentine granules were
developed using different variables of polyethyleneglycol and different variables of poloxomers.
From the drug release data it was conformed that matrices developed with polyethyleneglycol
and different variables of poloxomers having more drug retardant efficiency when compared
with the other marketed formulation.
Dhruvita Patel et al 83 developed two layered tablet for metformin along with pioglitazone with
meltgranulation technology. The matrices consist of two layers, form this one layer having the
fast release effect and this layer contains pioglitazone whereas other layer having retardant effect
the release and this layer contains metformin. Dhrivita has developed matrices for use in
diabetes mellitus. She investigated impact of hydrophilic as well as hydrophobic compounds on
invitro release of metformin.