Abot Bpolymers in Pharmacy

Polymers in Oral Controlled
Release Drug Delivery Systems
Y.RAMESH
M.PHARMACY, (DEPARTMENT OF PHARMACEUTICS)
RAO’S COLLEGE OF PHARMACY, NELLORE.
Pharmaceutical Polymers
Definition
 Compounds formed by the joining of
smaller, usually repeating, units linked by
covalent bonds.
 These compounds form large

macromolecules called as polymers.
Pharmaceutical Polymers
 Oral dosage forms are broadly divided

into Liquid and Solid forms
 Suspensions and Tablets are commonly
formulated with various polymers
– some times in combination to achieve

the desired product profile.
Polymers in Tablets
 Conventional (IR) Tablets – where

Polymers are employed as Binders –
Polymers in Tablets
 Controlled/Modified/Extended/Delayed
Release Tablets –
where Polymers are employed as

Controlled Release agents -
 Hydrophilic Cellulose Derivatives
 Eudragit Matrix Formulations

Commonly used Polymers in Tablets
Hydrophilic Cellulose Derivatives
 Hydrophilic matrices are most popular

Modified release oral dosage forms
 Swellable polymers used to prolong drug

release
HPMCs are of high interest due to their:

 Good compression characteristics,
including Direct Compression
 Adequate swelling property, that allows
rapid external gel formation allowing CR
of Drug
 Available in several substitution and

viscosity grades
 Well characterized in compendia and

most of them have US GRAS status
Compressed Cellulose ether systems as Swelling Controlled
Systems - ROLE OF POLYMERS
POLYMERS RELATED FACTOR IN CR

 Volume change of the swellable matrix
and countercurrent diffusion of the solvent
PHOTO OF SWELLEN TABLET also FIG 1

Erodible, swellable systems, where zero-order

release is achieved -
 when the movements of the diffusing front (solid
drug-drug solution interface) and
 the eroding front (rubbery polymer-solvent
interface) are SYNCHRONIZED
 Solute release is governed by the penetration

velocity of the solvent (swelling front).
 Constant release is observed when the solvent
penetration is much slower than drug diffusion
in the swollen gel (case 2, transport)
 Thickness of the gel layer as a function of time,
rate of swelling, and velocity of the eroding front
 Gel thickness is proportional to the square

root of time as long as the swelling front
moves more rapidly than the eroding
front,
– (but synchronization of both fronts may occur
leading to constant drug release)
 Third front i.e., diffusion front which is an

interface between still un-dissolved (solid) drug
and the dissolved drug in the gel layer.
 Drug release is a function of the dissolved drug
gel layer that separates the diffusion front from
the erosion front.
 shows the relative positions of the three moving fronts in swellable matrix.
 The diffusion front is present as long as

the concentration of the undissolved drug
exceeds its solubility in the swollen
polymer matrix.
Systems - POLYMER CHARACTERISTICS
 Release mechanism from compressed HPMC

are discussed earlier
 However other cellulose derivatives such as
- Methyl Cellulose (MC)
- Hydroxyl ethyl cellulose (HEC) &
- Hydroxy propyl cellulose (HPC)
have different drug release behavior.

 Physicochemical properties of six non-ionic

cellulose ethers are compared
– varying by their substitution type (HPMC, MC, HEC,
and HPC) or
– Degree of substitution (USP HPMC 2208, 2906, and
2910)
 Polymers of similar viscosity grades(4000-5000 mPas)

– although not identical molecular masses – they are
characterized by their hydrophilicity.
 Phenylpropanolamine (PPA) HCL as water

soluble model drug
– Used at various loadings.
 Compressed matrices made of pure

polymers and drugs were assessed for
their
– swelling,
– erosion, and
– release properties.
Materials
– HPMC 2208, 2906, 2910 (Methocel K4M,
F4M, E4MCR)
– HEC (Natrosol 250 M)
– HPC (Klucel 99MF)

Materials
– All materials had moisture less than 5 %
– Size fractions of less than 63 µm were used

to minimize the lag time observed during drug
release with coarse fractions
 POLYMER MOLECULAR WEIGHT

 DS Degree of Substitution
 MS: Molar Substitution (HEC & HPC)
 Nominal Viscosity
 Grade Weight-Average Molecular Weight MW
 Molecular Weight of the Repeating Unit MO
 Weight-Average Degree of Polymerization DPW
Systems – POLYMER CHARACTERISTICS
 POLYMER HYDROPHILICITY
– Using hygroscopicity
 COMPACT PREPARATION
– Polymer and Drug ration 80:20 weight ratio, 500mg

directly compressed 10kN in 15-mm die using
hydraulic press equipped with flat-faced punches
 SWELLING AND FRONT MOVEMENTS

– The position of the fronts upon water
penetration inside the tablets
– The drug release behavior
– Polymer dissolution
SWELLING AND FRONT MOVEMENTS

– Circular device (Bettini 33) allowing water to
enter only from the lateral side.
– The cylindrical matrix is locked between two
transparent poly(methyl methacrylate) disks
and
– the assembly is placed in USP 23 dissolution
apparatus 2.
SWELLING AND FRONT MOVEMENTS
– Paddle RPM 75 and 400ml Dissolution medium.

– Methylene blue (0.004%) to improve visualization of the three
concentric circles corresponding to
– Swelling
– Diffusion and
– Erosion
 POLYMER DISENTANGLEMENT CONCENTRATION
– Water as medium, polymer dissolved is

estimated calorimetricaly
– Mass balance is estimated by adding tablet’s
initial weight, released drug and dissolved
polymer. (dry weight of swollen tablets after
4hours of drying)
POLYMER DISENTANGLEMENT CONCENTRATION
– Matrix erosion is described as the

dissolution of the disentangled
macromolecules from the rubbery
polymer.
– Polymer disentanglement occurs beyond a

critical concentration Cd,
– depending on the molecular weight of the

chains, and
– on their conformation in a given solvent and

at a given temperature.
– Cd is difficult to estimate accurately, hence

the coil overlap concentration C*p beyond
which polymer chain disentanglement
commences.
– Overlap concentrations were obtained by low

shear viscometry
Systems – POLYMER CHARACTERISTICS - RESULTS
POLYMER HYDROPHILICITY
– Ability to absorb water vapor
– In increasing order
– HPC ≈ MC < HPMC 2910 ≈ HPMC 2906 <
HPMC 2208 < HEC
 EFFECT OF SUBSTITUTION TYPE ON MATRIX

CHARACTERISTICS
SWELLING CHARACTERISTICS
 When tablet containing PPA and the cellulose
derivatives were in contact with water (containing
Methylene blue)
 the swelling, the diffusion, and the erosion fronts could
be seen and their position evaluated
 Position 0 at the beginning of the experiment
corresponds to the interface between the matrix and
water.
Compressed Cellulose ether systems as Swelling Controlled Systems – POLYMER
CHARACTERISTICS - RESULTS
 b’ Vs e’ HPMC 2208 and HEC – rapid inward

movement of swelling front in hydrophilic e’, whereas b’
inward movement of swelling front is at a constant rate
 The diffusion front was rather steady relative to the initial

position.
 Though diffusion front moves inwards, it is compensated

by the expansion of swelling matrix.
 The erosion front exhibited a rapid initial movement for

all polymers, (spectacular movement for HEC) followed
by an almost linear change.
 No recession of the erosion front, which if existed could

have indicated predominant erosion.
 Figure 3
Polymer Erosion and Overlap/Disentanglement Concentration
 Hydrophilic matrices of cellulose ethers undergo erosion

upon contact with dissolution media.
 Polymer dissolution was the highest for HEC and MC
and then for other polymers.
 Among the three HPMC grades type 2906 was having
slowest erosion.
 Fig 5
Drug Release
 Release profiles of PPA increases in the order of
HPMC 2208 < HPMC 2906 = HPMC 2910 = HPC < HEC = MC.
 Release differed markedly during the early time points.

 Ability of the polymer to rapidly form a continuous gel
layer at the matrix surface and thus preventing initial
dissolution of the surface drug. Example HEC
 Fig 6
EFFECT OF DRUG LOADING ON MATRIX CHARACTERISTICS
 Data so far discussed have 20% PPA loaded in the

matrix
 In this two polymers with extreme release characteristics
namely HPMC 2208 and HEC and by incorporating 20,
40, 60 % of PPA.
 Fig 8
 Drug loading had very little influence on front

movements of HPMC 2208 matrices
 At most the swelling front moved more quickly
due to osmotic effect
 The effect was more pronounced for HEC

matrices especially with regard to diffusion and
erosion fronts.
 The diffusion front moved faster as the
proportion of drug increased,
 whereas the observed erosion front movements
were small as the proportion of PPA increased,
due to more marked polymer dissolution
RECONSTITUTABLE ORAL SUSPENSIONS
- Polymers commonly used
 Carboxymethylcellulose sodium
 Microcrystalline cellulose & Carboxymethylcellulose

sodium
 Povidone
 Propylene glycol alginate
 Silicon dioxide, colloidal
 Sodium starch glycolate

 Chemical analysis for drug and preservative

 Preservative challenge test
 Appearance compared to that of sample stored at 2º to 5 º C
 Viscosity
 Homogeneity
 pH
 Sedimentation volume
 Ease of redispersion
IJPS, 2008 Volume : 70 Issue : 4 Page : 531-534
- Typical example
AMPICILLIN TRIHYDRATE R O S
 Ampicillin trihydrate 5.77%
 Sucrose 60.00%
 Sodium alginate 1.50%
 Sodium benzoate 0.20 %
 Sodium citrate 0.125%
 Citric acid 0.051%
 Tween 80 0.08%
 Max. stability at pH4.85
 Sedimentation value 0.97 (10days at 30 C)
Pharmaceutical dosage forms: disperse systems, Herbert A.
Lieberman
Oral controlled release suspension
 Development and evaluation of oral controlled

release chlorpheniramine-ion exchange resinate
suspension
 using ion-exchange resin technology.
 A strong cation exchange resin Indion 244 was

utilized for the sorption of the drug and the drug
resinates was evaluated for various physical and
chemical parameters.
 The drug-resinate complex was micro-

encapsulated with a polymer Eudragit RS 100 to
further retard the release characteristics.
 Both the drug-resinate complex and
microencapsulated drug resinate were
suspended in a palatable aqueous suspension
base and
 were evaluated for controlled release
characteristics.
 Stability study indicated that elevated

temperature did not alter the sustained release
nature of the dosage form
 indicating that polymer membrane surrounding

the core material remained intact throughout the
storage period.
Eudragit Matrix Formulations
Drug release mechanisms and functionality advantages

 In contrast to hydrocolloids, poly(meth)acrylates form inert
matrices.
 The insoluble types EUDRAGIT RL/RS and NE/NM provide
time controlled systems which release the drug by
diffusion and pore diffusion in a manner that is pH-
independent.
 The matrix structure stays intact and may even be found as
an “empty sponge” in the feces.
Drug release mechanisms and functionality advantages
 Anionic polymers EUDRAGIT S and FS 30 D

which dissolve pH-dependently beyond pH 7.
 However, under physiological conditions matrix
systems built from these polymers maintain
intact.
 Anionic poly(meth)acrylate EUDRAGIT L-Types, the matrix

structure begins to dissolve by salt formation in the small
intestine.
 From this point onwards drug release is enhanced by

erosion of the matrix structure.
 At lower pH values, representing stomach and upper small

intestine, low dissolution rates are observed;
 whereas in media with a pH above that which the polymer

is soluble, the drug release is increased.
Flexible processing
 EUDRAGIT polymers are available as granules,

powders, aqueous dispersions and organic
solutions.
 Every common processing technology from
direct compression to high-shear granulation, as
well as innovative technologies like melt
extrusion possible.
 In wet granulation processes the polymers can be
used as granulating binders in both organic and
aqueous processing.
Flexible processing
 EUDRAGIT NE 40 D, an aqueous dispersion with

40% polymer content, is useful where a reduced
amount of granulating fluid is desired.
 The powder grades can be utilized in granulation
processes to increase polymer content and a
shortened process time.
 The higher the distribution of the matrix former,
the stronger will be the SR effect in the tablet.
EUDRAGIT features
 EUDRAGIT matrix tablets exhibit superior
hardness values due to their excellent binding
properties.
 The addition of only 7.5% EUDRAGIT NE 30 D
yields tablets with high crushing strengths.
 When the concentration of EUDRAGIT NE 30 D is
increased to 20%, the elastic properties of this
highly flexible polymer become more dominant.
 The insoluble, but swellable, EUDRAGIT NE 30 D
gives systems where the drug release rate is time
controlled.
Gastroresistance and GI Targeting
 To protect the drug from the gastric fluid and would like to
improve drug effectiveness - EUDRAGIT L and S polymers
are preferred choice of coating polymers.
 They enable targeting specific areas of the intestine.
 Anionic EUDRAGIT grades which dissolve at rising PH

values.
 In addition, the different grades can be combined with each

other, making it possible to adjust the dissolution pH, and
thus to achieve the required GI targeting for the drug.
Advantages of EUDRAGIT enteric coatings:

 PH-dependent drug release
 Protection of actives sensitive to gastric fluid
 Protection of gastric mucosa from aggressive
actives
Advantages of EUDRAGIT enteric coatings:

 Increase in drug effectiveness
 Good storage stability
 GI and colon targeting
Polymer Availability Dissolution Properties
EUDRAGIT L 30 D-55 30% Aqueous Dispersion

Dissolution above pH 5.5
EUDRAGIT L 100-55 Powder
EUDRAGIT L 100 Powder

Dissolution above pH 6.0
EUDRAGIT L 12,5 12,5% Organic Solution
Powder
EUDRAGIT S 100
EUDRAGIT S 12,5
12,5% Organic Solution Dissolution above pH 7.0
EUDRAGIT FS 30 D 30% Aqueous

Dispersion
Moisture Protection and Odor/Taste Masking
 EUDRAGIT E polymers helps to seal

sensitive actives and increase patient
compliance by taste and odor masking.
 Even thin layers of EUDRAGIT E provide
the desired effect, making it an extremely
economical application.
Advantages of protective EUDRAGIT coatings:

 pH-dependent drug release
 Protection of sensitive actives
 Taste and odor masking
 Moisture protection
Advantages of protective EUDRAGIT coatings:

 Economical application
 Improved transit of the dosage form
 Smooth and glossy surfaces, excellent color
coating
Dissolution
Polymer Availability
Properties
EUDRAGIT E 100 Granules

Soluble in gastric
Organic Solution fluid up to pH 5.5
EUDRAGIT E 12,5 12,5%
Swellable and
Powder permeable above
EUDRAGIT E PO pH 5.0
Time-Controlled Drug Release
 EUDRAGIT polymers are useful, if the drug to

release over a specific period of time or
– to achieve the advantages of multi-particulate or matrix

formulations
– to achieve your desired release profile.
 Drug delivery can be controlled throughout the

entire gastrointestinal tract to increase
therapeutic effect and patient compliance.
 Different polymer combinations of

EUDRAGIT RL and RS grades allow
 custom-tailored release profiles to achieve
the desired drug delivery performance.
 EUDRAGIT NE an NM grades are neutral
ester dispersions which do not require
additional plasticizers.
Benefit from EUDRAGIT coatings with sustained

release:
 Time-controlled release of active ingredients
 Therapeutically customized release profiles
 Higher patient compliance due to reduced
number of doses to be taken
 Cost-effective processing
Granules
EUDRAGIT RL 100
Powder Insoluble
EUDRAGIT RL PO
30% Aqueous High permeability

EUDRAGIT RL 30 D Dispersion
pH-independent
swelling
12.5% Organic
EUDRAGIT RL 12.5 Solution
EUDRAGIT RS 100 Granules Insoluble

Low permeability
EUDRAGIT NM 30 D Powder
pH-independent swelling
EUDRAGIT RS PO 30% Aqueous

Dispersion
EUDRAGIT RS 30 D 12,5% Organic
Solution
EUDRAGIT RS 12,5 30% Aqueous
Insoluble, low
Dispersion
permeability,
EUDRAGIT NE 30 D 40% Aqueous
Dispersion pH-independent swelling
No plasticizer required
EUDRAGIT NE 40 D 30% Aqueous
Dispersion Highly flexible
Polymers used as Tablet Binders
Typical Use
Suggested Compendial Level
Application Advantages
Products Name
( % w/w)
Wet Granulation Plasdone® Povidone 1-5% Highlyefficient binding capacity at

K-25 low use levels
Reduces binder solution
Plasdone preparation time
K-29/32
Low solution viscosity simplifies
Plasdone binder solution handling
K-90/K-90D No impact on tablet dissolution
Dry Granulation Plasdone 1 to 10% Excellent binding properties owing to high

Copovidone degree of plasticity
S-630 Spherical spray-dried particles for
excellent flow properties
Direct Compression Plasdone 1 to 15% Increases tablet strength and reduces
Copovidone friability
S-630

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Polymers in Oral Controlled

Release Drug Delivery Systems

 These compounds form large

 Oral dosage forms are broadly divided

– some times in combination to achieve

 Conventional (IR) Tablets – where

where Polymers are employed as

 Eudragit Matrix Formulations

 Hydrophilic matrices are most popular

 Swellable polymers used to prolong drug

HPMCs are of high interest due to their:

 Available in several substitution and

 Well characterized in compendia and

POLYMERS RELATED FACTOR IN CR

PHOTO OF SWELLEN TABLET also FIG 1

Erodible, swellable systems, where zero-order

 Solute release is governed by the penetration

 Gel thickness is proportional to the square

 Third front i.e., diffusion front which is an

 The diffusion front is present as long as

 Release mechanism from compressed HPMC

have different drug release behavior.

 Physicochemical properties of six non-ionic

 Polymers of similar viscosity grades(4000-5000 mPas)

 Phenylpropanolamine (PPA) HCL as water

 Compressed matrices made of pure

– HEC (Natrosol 250 M)

– HPC (Klucel 99MF)

– Size fractions of less than 63 µm were used

 POLYMER MOLECULAR WEIGHT

– Polymer and Drug ration 80:20 weight ratio, 500mg

 SWELLING AND FRONT MOVEMENTS

– The drug release behavior

SWELLING AND FRONT MOVEMENTS

SWELLING AND FRONT MOVEMENTS

– Paddle RPM 75 and 400ml Dissolution medium.

 POLYMER DISENTANGLEMENT CONCENTRATION

– Water as medium, polymer dissolved is

POLYMER DISENTANGLEMENT CONCENTRATION

– Matrix erosion is described as the

 POLYMER DISENTANGLEMENT CONCENTRATION

– Polymer disentanglement occurs beyond a

– depending on the molecular weight of the

– on their conformation in a given solvent and

 POLYMER DISENTANGLEMENT CONCENTRATION

– Cd is difficult to estimate accurately, hence

– Overlap concentrations were obtained by low

 EFFECT OF SUBSTITUTION TYPE ON MATRIX

 b’ Vs e’ HPMC 2208 and HEC – rapid inward

 The diffusion front was rather steady relative to the initial

 Though diffusion front moves inwards, it is compensated

 The erosion front exhibited a rapid initial movement for

 No recession of the erosion front, which if existed could

Polymer Erosion and Overlap/Disentanglement Concentration

 Hydrophilic matrices of cellulose ethers undergo erosion

 Release differed markedly during the early time points.

EFFECT OF DRUG LOADING ON MATRIX CHARACTERISTICS

 Data so far discussed have 20% PPA loaded in the

 Drug loading had very little influence on front

 The effect was more pronounced for HEC

 Microcrystalline cellulose & Carboxymethylcellulose

 Propylene glycol alginate

 Silicon dioxide, colloidal