Hydrophilic Matrices – A modern
Approach to a Classic Technology
QbD and Alternative Polymers
Kevin Hughes
Formulation Technology Manager, Colorcon Ltd
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Agenda
 Simple extended release matrices
— Introduction and basic rules of Hydrophilic matrices.
 Modern Approaches to hydrophilic matrices
— Branding
— Formulation Robustness
— QbD
— Alternative Polymers:
• Polymer Blends
• Polyethylene Oxide
 Summary and conclusions
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Sustained Action Dosage Forms
 First commercial oral extended-release dosage form was a pellet filled
capsule (Spansules). 1952 Smith, Kline and French.
 Different strategies have been developed since then to achieve
extended-release dosage forms:
— Simple matrix tablets, pellets, osmotic systems.
 Terminology has expanded but means the same thing:
— Extended Release
— Sustained Release
— Prolonged Release
— Long Acting
— Modified/Controlled Release (ER and DR)
— Abbr. ER, XR, XL, PR, SR, CR, LA etc.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Simple Extended Release Matrix Tablets
Hydrophilic matrices
• e.g. HPMC, PEO, Na CMC, Na alginate, MC,
HEC, gums, starches
• Polymer hydrates, forms gel & swells
• Drug release by erosion & diffusion
Release modifying polymer Inert matrices
Drug
Compression of a blend of
drug, retardant material and
other excipients, in which drug
is embedded in a matrix core of
the retardant material.
• e.g. ethylcellulose, cellulose acetate
• Does not break apart in the GI tract, egested
intact.
• Drug release by diffusion
Hydrophobic matrices
• e.g. waxes, oils, stearates, glycerol behenate
• Drug release by diffusion & erosion
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Hydrophilic Matrix Mode of Action
Ingestion of Tablet
Initial Wetting
Polymer at surface hydrates to
form protective gel layer.
Tablet Erosion
Outer polymer layer becomes fully
hydrated, eventually dissolving into
the gastric fluids. Water continues to
permeate toward the tablet core.
Insoluble drug
Soluble drug
is released primarily by gel erosion.
is released primarily by diffusion
through the gel layer.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Examples of Gel Layer
SEM across a Hydrated (10 mins) &
Freeze-fractured METHOCEL™ K4M Tablet
Methocel K4M Tablet partially
hydrated in water containing dye
Melia CD, Rajabi-Siahboomi AR, et al Int. J. Pharm. 1993
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Factors Influencing Drug Release
Formulation
 Polymer
— Substitution type
— Viscosity
— Concentration
— Particle size
Process
 Method of manufacture
 Tablet size and shape
 Film coating
 Drug
— Particle size
— Solubility
 Filler
— Solubility
— Concentration
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Chemical Structure of HPMC
CH3
CH3
H
O
H
HO
CH2
CH2CHCH3
OH
O
O
H
CH3CHCH2
O
OH
H
O
HO
H
O
H
HO
H
O
HO
O
H
H
H
H
CH2
O
HO
H
O
H
CH2
O
n-2
CH3
hydroxypropoxyl
substitution
CH3
methoxyl
substitution
 HPMC polymers are semi-synthetic materials derived from cellulose.
 Degree of substitution and polymerisation are very important.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
General Properties of Hypromellose
 Soluble in cold water, forming a viscous colloidal solution
 Nonionic
 Nontoxic
 Odourless and tasteless white powder
 Enzyme resistant
 pH stable (normal GI tract range)
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Typical Hydrophilic Matrix Formulation
Material
Relative concentration
Drug
Any
Polymer
≥ 30%
Filler
As required
Flow aid
~0.5%
Lubricant
~0.5%
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Effect of Polymer Substitution Type on Drug Release
The chemistry of HPMC
encourages a strong, tight gel
formation (compared to other
cellulose derivatives).
As a result, drug release rates
are sustained longer with
HPMC than with equivalent
levels of MC, HEC or
carboxymethylcellulose (CMC).
Methocel K chemistry is the
most common type of HPMC
to be used
Courtesy of Dow Chemical
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Effect of Polymer Viscosity on Drug Release
 The release rate decreases
as the molecular weight
(and hence viscosity)
increases.
Courtesy of The Dow Chemical Company
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Effect of Polymer Concentration on Drug Release
 Generally, the greater the
concentration of HPMC
within the matrix, the
slower the release rate of
the drug.
 It is recommended to use
at least 30% of polymer in
the ER formulation.
Courtesy of The Dow Chemical Company
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Effect of Polymer Particle Size on Drug Release
 Large fractions of HPMC
hydrate too slowly to allow
ER. Tablets may
disintegrate before gel layer
is formed.
 Small fractions of HPMC
allow uniform hydration into
the matrix.
 The more soluble the drug,
the more sensitive the
formulation is to polymer
particle size.
Courtesy of The Dow Chemical Company
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Drug Solubility
 Affects polymer and filler choice:
— Soluble drugs
• Are formulated with high viscosity polymer and insoluble filler
— Poorly soluble drugs
• Are formulated with low viscosity polymer and soluble filler
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Effect of Tablet Shape
100
% Drug Released
80
60
40
Caplet 450mg
20
Round 450mg
0
0
2
4
6
8
Time (hours)
Data copyright of The Dow Chemical Company
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
10
12
Simple to Manufacture
Most commonly
used concentrations
Courtesy of The Dow Chemical company
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Analysis of Technologies Used in Recent “ER”
Tablet Approvals
Approvals
Blends
HPMC
154
22
HPC
HEC
EC
6
4
13
4
1
9
PEO
5
3
Carbopol
Carbomers
MAC
7
6
5
6
Wax
2
0
197
50





Blends actively utilized in NA/EU
HPMC is backbone with 75% “share”
Other cellulosics in ~ 10% of approvals
PEO used in osmotic & blends with HPMC
Carbomers/MAC also in ~ 10% approvals
HPMC/EC/PEO ~ 90% of approvals
HPMC is dominant polymer but often “extended”
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
“MR” tablet v. MP dosage form development
629 approvals evaluated
Controlled Release
Tablets
MP
Delayed Release
Tablets
MP
United States
United Kingdom
85%
51%
15%
49%
50%
44%
50%
56%
Brazil
India
China
88%
73%
71%
12%
27%
29%
100%
50%
62%
0%
50%
38%
Summary
263
72%
101
28%
156
59%
109
41%
Tablets remain dominant but with MP playing significant role
Tablet formulations predominant in all markets
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Hypromellose Matrices - Summary
 Among the most widely used means for ER drug delivery.
 Simple concept
 Easy to manufacture
— Well established technology (DC, WG, RC)
 Robust system
— tolerant of variations in ingredients & production methods
 Suitable for a wide range of actives
— Soluble vs insoluble, high vs low dosage levels
 Requires careful formulation
— Colorcon technical support available
— HyperStart Formulation Service www.colorcon.com
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Modern Approaches
Branding
Formulation Robustness and QbD
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Matrix Brand Identity: Effect of Tablet Shape
on Drug Release
Colorcon Brand Enhancement Services : Effect of tablet shape on drug release from
METHOCEL™ matrices, when the surface area-to-volume ratio is kept constant.
Metformin (high dose, high solubility) & Indapamide (low dose/low solubility)
Round
Caplet
Bone
Metformine HCl Released (%)
120
100
80
60
Standard Concave
Caplet
40
Bone
20
0
0
2
4
6
8
10
Time (hours)
Constant surface area : volume ratio gives
consistent drug release
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
12
Matrix Brand Identity: Comparative release profiles of
coated vs. uncoated
% Metformin HCl Released
120
Material
100
80
60
Bone-Uncoated
Bone-Opadry II 32K10908
Bone-Opadry II 85F94544
Bone-Opadry AMB 80W90677
Bone-Opaglos 2 97W90646
40
20
0
0
2
4
6
8
10
12
Time (h)
%w/w
mg/tablet
Metformin HCl
(Wanbury)
50
500
HPMC
(METHOCEL K100M
PREM CR,Dow)
30
300
Microcrystalline
cellulose
(Emcocel 90M, JRS
Pharma)
19
190
Fumed silica
(Aerosil 200, Evonik)
0.5
5
Magnesium stearate
(Mallinckrodt)
0.5
5
Total
100
1000
f2 value (using uncoated profile as reference) > 70
Presence of film coating did not alter the drug release
profile for Metformin ER tablets
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Influence of Hydro-alcoholic Media on Release
from Matrix Formulations
 Effect of Alcohol (HPMC matrices):
— ER HPMC tablets retained their hydrated structural integrity when
exposed to 5% and 40% v/v ethanol solutions for up to 12 hours without
any failure of the matrices resulting in dose-dumping.
— Any differences in drug release profiles in water and ethanol solutions
were attributed to differences in drug solubility.
•
Levina et al. AAPS poster 2006 avail at www.colorcon.com
 Effect of Alcohol (PEO Matrices).
— No matrix failure was recorded for either formulation when exposed to
ethanol–water solutions.
— Pure PEO compacts made of three viscosity grades of polymer showed
consistent swelling upon exposure to hydro-alcoholic media.
•
“D. Palmer et al., “The Influence of Hydro-Alcoholic Media on Drug Release From Polyethylene Oxide Extended-Release
Matrix Tablets,” Pharmaceutical Technology, 35 (7) pages 50-58 (2011)”.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Quality by Design (QbD):
Means Design the Product And The Process
 Design the product to meet patient requirements
 Design the process to consistently meet product critical quality
attributes
 Understand the impact of starting materials and process
parameters on product quality
 Identify and control the source of process variation
 Continually monitor and update the process to allow consistent
quality over time
Know what we do not know
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Why is QbD important?
 High level of assurance of product quality
 Cost saving and efficiency for industry and regulators
— Increase manufacturing efficiency, reduce cost and product rejects
— Minimize potential compliance actions, costly penalties and recalls
— Enhance opportunities for first cycle approval
— Streamline post approval manufacturing changes and regulatory
processes
— Opportunities for continual improvement
 Reducing variability (or its effects) =  Quality &  Cost
Colorcon service model is built on improving quality and reducing cost
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Quality by Design Approach to Matrices
 QbD: design product & process to
ensure robust formulation
API
Variability
 Need to fully understand all
starting materials and influence of
batch variability on end product
 Functionally related
characteristics (for HPMC, as
mentioned in European
Pharmacopoeia )
• apparent viscosity
• degree of substitution
• particle size
• powder flow
Excipient
Variability
Process
Variability
σProduct = σAPI + σExcipients + σProcess + σInteractions
2
2
2
2
2
Ref: C. Moreton
Understanding variability & tolerating it = Robustness
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Typical Hydrophilic Matrix Formulation
Material
Drug
Polymer (METHOCEL™)
Filler
Critical Considerations
Low to high (dose/solubility)
Types/levels
Type/level/solubility
Glidant
Lubricant
Low (0.2 – 1%)
Low (0.5 – 1%)
Release modifiers/buffering agents/solubilizers/stabilizers
Film coating
Conventional IR/Functional MR
Decision on choice and level of polymer and filler depends on drug
properties and desired release profiles
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Case Study
Objective: Study influence of HP substitution, viscosity and particle size on
performance of a hydrophilic matrix using METHOCEL™ K15M premium CR
 Polymer concentrations
— 15% low level
— 30% recommended level
 Model APIs
— Propranolol HCl (50 mg/mL,160 mg dose)
— Theophylline anhydrous (8.3 mg/mL, 160 mg dose)
— Metformin HCl (100 mg/mL, 500 mg) – AAPS poster 2009 available on
Colorcon and DWC websites
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
METHOCEL™ K15M Premium CR Formulation
and Testing Methods
Composition of Propranolol HCl ER formulations
Ingredient
% Composition
Propranolol Hydrochloride
45.7
METHOCEL™ K15M Premium CR
15.0 or 30.0
Microcrystalline Cellulose
(Emcocel 90M)
38.8 or 23.8
Magnesium Stearate
0.5
Total
100.0
 Tablet weight 350 mg
 Direct compression method - 3/8" round, standard biconvex,
 Dissolution method: USP Apparatus II, 100 rpm, with sinkers,
1000 mL pH 6.8 phosphate buffer
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
METHOCEL™ K15M Premium CR Drug Release
Propranolol HCl release: effect of viscosity
100
f2 = 66.90
% PP dissolved
80
f2 = 74.21
60
40
20
0
0
120
240
High Viscosity/ Low Level
Low Viscosity/ Low Level
Center Point/ Low Level
360
Time (min)
480
600
720
High Viscosity/ High Level
Low Viscosity/ High Level
Center Point/ High Level
The similarity factor (f2) was calculated by comparing high vs. low end of the selected physicochemical property
• Higher polymer level  slower drug release
• Higher polymer level  lower variability
• Drug release is consistent across viscosity range
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
METHOCEL™ K15M Premium CR Drug Release
Propranolol HCl release: effect of % HP
content
100
f2 = 84.99
% PP dissolved
80
f2 = 94.83
60
40
20
0
0
120
240
High %HP/ Low Level
Low %HP/ Low Level
Center Point/ Low Level
360
Time (min)
480
600
High %HP/ High Level
Low %HP/ High Level
Center Point/ High Level
Drug release is consistent across HP range
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
720
METHOCEL™ K15M Premium CR Drug Release
Propranolol HCl release: effect of particle size
% PP dissolved
100
f2 = 48.23
80
f2 = 94.14
60
40
20
0
0
120
240
360
Time (min)
High % thru 230 mesh/ Low Level
Low % thru 230 mesh/ Low Level
Center Point/ Low Level
480
600
720
High % thru 230 mesh/ High Level
Low % thru 230 mesh/ High Level
Center Point/ High Level
Drug release is significantly affected by coarser P/S for lower polymer
level
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Physicochemical properties of METHOCEL™ K15M
Premium CR
2% Viscositya
(mPa.s)
% through 230
meshb
% HPc
% MeOd
High viscosity
24856
57.7
9.1
23.1
Low viscosity
13413
55.0
9.6
22.9
High % thru 230 mesh
17054
62.8
9.5
22.4
Low % thru 230 mesh
20156
52.6
9.4
23.1
High % HP
16698
56.2
10.5
22.5
Low % HP
16833
56.2
8.4
22.9
Center point
19036
57.5
9.4
22.6
Hypromellose Batch
a Max./nominal/min.
b Particle
c Typical
USP specification (mPa.s): 24780 / 17788 / 13275
size cut off is 95% through 100 mesh, here a second cut off % through 230 mesh has been used
max./nominal/min. production range (% HP): 10.5 / 9.5 / 8.5 (USP range 4-12% - DWC sales specification has
historically been 7-12%)
d Methoxyl
content not part of experimental design; supplied for information purposes only
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Conclusions
 At 30% w/w polymer level, drug release profiles were similar despite
variations in viscosity, %HP and particle size
 At 15% w/w polymer level, drug release profiles were generally more
variable.
 Colorcon generally recommends 30% polymer concentrations in
HPMC hydrophilic matrices
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Alternative Polymers
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Analysis of Technologies Used in Recent “ER” Tablet
Approvals
Approvals
Blends
HPMC
154
22
HPC
HEC
EC
6
4
13
4
1
9
PEO
5
3
Carbopol
Carbomers
MAC
7
6
5
6
Wax
2
0
197
50





Blends actively utilized in NA/EU
HPMC is backbone with 75% “share”
Other cellulosics in ~ 10% of approvals
PEO used in osmotic & blends with HPMC
Carbomers/MAC also in ~ 10% approvals
HPMC/EC/PEO ~ 90% of approvals
HPMC is dominant polymer but often “extended”
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Polymer Blends
 Polymer blends have been used in products
— Colorcon data shows synergistic interactions between HPMC, PVAP &
carbomer
 Still room for creativity in matrix applications using blends of polymers:
— pH control
— release profile control
— concentration/size of tablet control
— robust formulation  in vivo performance/food effects
Innovation in hydrophillic matrices will come from
polymers: blends of existing ones and new ones
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Polymer Blend Case Study: High Dose, High
Solubility API: Guaifenesin



Neutral (nonionic) API
High solubility/high dose API
Challenge to formulate 600 mg ER
~ High dose
~ High polymer requirement
~ Unacceptable tablet size
C10H14O4 :198.22 g/mol


Solubility ~ 50 mg/mL
Low melting point (~80 °C)
Polymer blends: 15 and 30 %
Tablet weight : 870 mg
Polymer blend evaluated for modulation capability with a
nonionic API with high water solubility
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
HPMC Matrix Formulation
Model drug: Guaifenasin (50 mg/ml in water), 600mg dose
Formulations: Polymer 30% or 15%, API 600 mg (DC)
Dissolution testing: Apparatus II, 100 rpm in 900 ml water at 37 ± 0.5°C
% Drug Released
100
80
60
40
15% METHOCEL
30% METHOCEL
15% Blend
30% Blend
20
0
0
2
4
6
Time [hr]
8
Micro pH: METHOCEL™ formulations:~ 7.4 - 8.2
Blend formulations:~ 3.8 - 4.4
10
12
Blend: HPMC:Carbomer:PVAP
Successful modulation of release profile, at lower
overall inclusion weight
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
HPMC: Methocel K4M CR
HPMC - Ionic Polymer Matrix Formulations
Model drug: Verapamil HCl (80 mg/mL in water)
METHOCEL™ E4M, verapamil HCl
Sodium alginate, METHOCELTM E4M, verapamil
HCl
US patent: 5132295
HPMC & sodium alginate resulted in pH independent release profile
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
HPMC - Ionic Polymer Matrix Formulations
Model drug: Diltiazem HCl (80 mg/m in water)
METHOCELTM K15M, Na CMC, Diltiazem HCl,
Na CMC
Blend
HPMC
HPMC
Blend
Na CMC
Conti, S et al, Int. J. Pharm., 333 (2007): 136-142
HPMC & Na carboxymethylcellulose resulted in pH
independent (zero order) drug release profile for diltiazem HCl
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Polyethylene Oxide (POLYOX™) in
Hydrophilic ER Matrices
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Physicochemical Properties of POLYOX™
H
H
PEG: n = 5 – 450
-C–C–O–
H
H
PEO: n = 2,000 – 180,000
n
Properties
Value
 Free flowing powder
True Density (g/cm3)
1.249
 Average particle size 150 µm
Aerated Bulk Density (g/cm3)
0.47
Packed Density (g/cm3)
0.51
Melting Point (ΟC)
~65

Linear, flexible molecular chains
 Nonionic, highly swelling
 Crystalline
 Thermoplastic
Glass Transition Temp. (ΟC)
Crystallinity (%)
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
-45 to -53*
95%
POLYOX™ Grades
Viscosity Range at 25°C, cP
Approximate*
Molecular Weight
5% Solution
WSR N-10 NF
100,000
30 - 50
WSR N-80 NF
200,000
55 - 90
WSR N- 750 NF
300,000
600 - 1,200
WSR 205 NF
600,000
4,500 - 8,800
WSR - 1105 NF
900,000
8,800 - 17,600
WSR N-12K NF
1,000,000
400 - 800
WSR N-60K NF
2,000,000
2,000 - 4,000
WSR - 301 NF
4,000,000
1,650 - 5,500
WSR Coagulant NF
5,000,000
5,500 - 7,500
WSR-303 NF
7,000,000
7,500 - 10,000
POLYOX NF Grades
2% solution
1% Solution
• Consistent physical properties for all grades
• Shaded area shows typical grades for ER matrix applications
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Hydrophilic Matrices Applications
Complimentary polymers
• Hydrophilic polymers
• Neutral polymers (pH independent)
8 hr
• Rapidly hydration and gel formation
15 hr
POLYOX™ faster than METHOCEL™
PEO swells more than METHOCEL™
• Wide range of viscosity grades
• Excellent compressibility
20 hr
PEO N60K
K4M
PEO 303
• PEO has excellent flow
The chemistries and properties of POLYOX™ and METHOCEL™
provide multiple formulation and processing options
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
K100M
Dissolution Methods
USP II Paddle
Quadrangular
Basket
a
b
c
d
e
USP I basket
Sinkers
a. W 5.0mm
b. W 7.0mm
c. W 6.0mm
d. W 8.0mm
e. W 11.0mm
L 15.5mm
L 19.3mm
L 18.0mm
L 23.0mm
L 31.0mm
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Reasons for Using Sinkers or QBs
Metformin & PEO 301
18 Hrs
To prevent PEO matrices from sticking to the bottom of the dissolution chamber or
floating onto the surface of the dissolution medium, resulting in a lack of reproducibility.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Dissolution Method Considerations for
POLYOX™ Matrices
Material
% w/w
mg/tablet
Metformin HCl (High Dose,)
50.0
500
POLYOX™ 1105 or METHOCEL™ K100M CR
30.0
300
MCC (Microcel® 102)
19.0
190
Fumed silica (Aerosil® 200)
0.5
5
Magnesium stearate (MS)
0.5
5
Material
% w/w
mg/tablet
Gliclazide (Medium Dose, <0.0001 mg/ml)
15.0
30
POLYOX™ 1105 or METHOCEL™ K100LV CR
35.0
70
MCC (Microcel® 102)
49.0
98
Fumed silica (Aerosil® 200)
0.5
1
Magnesium stearate (MS)
0.5
1
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Effect of POLYOX™ Viscosity Grades on Drug Release
Gliclazide
100
100
90
90
80
80
70
60
50
K100M CR
40
PEO 1105
30
PEO 301
20
PEO 303
10
Drug released (%)
Drug released (%)
Metformin HCl
K100LV CR
PEO 1105
PEO 301
70
PEO 303
60
50
40
30
20
10
0
0
0
1
2
3
4
5
6
7
8
9
10 0
1
2
3
Time (hours)
• 4cm QBs, 100 rpm
• 50% drug, 30% polymer
4
5
6
Time (hours)
• 4cm QBs, 100 rpm
• 15% drug, 35% polymer
 Increased MW  Slower drug release
 Very low standard deviations
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
7
8
9
10
Drug Release from POLYOX™ Matrices
Formulation Variables
 Polymer viscosity
— as viscosity ↑  rate of release ↓
 Polymer concentration (20-25% starting point)
— as concentration ↑  rate of release ↓
 Drug solubility
— as solubility ↑  rate of release ↑
— as solubility ↓  faster release with higher polymer content!
 IR coating applications
— No change on release profiles
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Summary and Conclusions

Hydrophilic matrices are a traditional and well understood dosage form,
simple formulations with a conventional manufacturing process mean this
dosage form will be here for many years to come

Hypromellose is the 1st choice polymer for ER hydrophilic matrix
formulations, but QbD principles need to be applied to ensure robust
formulations.

Polymer combinations, Polyethylene Oxide (POLYOX™) and others can be
effective alternatives
−
−
−
−
Advantages in flow
Increasing robustness
Unique option for insoluble APIs
Potential novelty / innovation
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.
Hydrophilic Matrices – A modern
Approach to a Classic Technology
QbD and Alternative Polymers
All trademarks, except where noted, are property of BPSI Holdings, LLC.
METHOCEL™, POLYOX™ are trademarks of The Dow Chemical Company.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.