Plinio Sandoval

Regional Technical Manager, Colorcon.

Latin America North & Puerto Rico.
psandoval@colorcon.com

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Controlled Release Alliance – Unique Together

 Global supply and customer support network

 Leading polymer expertise
 Dedicated technical support around the world
 Quality excellence
 Unmatched application knowledge for
 Manufacturing reliability and consistency
formulation simplification
 Solution innovation
 Extensive training and education programs

Manufacturing Efficiency and Productivity Improvement

DOW and Colorcon CONFIDENTIAL - Do not share without permission

 HPMC Matrix Tablets for
Modified Release Oral Drug Delivery
Matrix tablets are: 5% theophylline, 20% HPMC
74.5% lactose, 0.5% mag stearate
• Robust to improve patient compliance 100

Percent Drug Released

• Reduce dosing frequency 80

• Reduce adverse effects from API 60

Methocel K3 Premium LV

• Relatively simple & easy to develop, 40

Methocel K100 Premium LV
Methocel K4M Premium
and inexpensive to manufacture 20
Methocel K15M Premium
Methocel K100M Premium
0
0 2 4 6 8 10 12

HPMC 2208 is the predominant matrix tablet excipient Time (hours)

OCH3 OH OCH3 Time lapse images of tablets swelling over 24 hours

OH OCH3
O HO O O
O O HO O
HO O HO O O
OCH3 O
O O CH3O
OH OCH3 OCH3
R = CH3 OH

Chemical Structure of HPMC 2208

DOW and Colorcon CONFIDENTIAL - Do not share without permission
Matrix Tablet Manufacture

Granulation or
Powder Blend

Tableting
Matrix Tablets

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Balancing Performance Attributes

Particle size Particle size

Sphericity Surface area

Modified
Permeability Flowability Hydrophilicity
Release Tunable by substitution

Density
Erodability
Tunable by molecular weight

Particle size Compactibility

Sphericity

Density

Surface area

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Evolution of METHOCEL™ Premium

Innovating to Address Industry Needs:

METHOCEL™ DC2

Engineered morphology
METHOCEL™ CR
Enhanced flow

Particle size Direct compression

METHOCEL™ guarantee
Tighter specifications
Lower-cost, more consistent
manufacturing processes
Established over 50 years
Robust, optimized
Premium quality product line MR performance
Proven track record

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Morphology and Flow Performance

METHOCEL™ DC2 Competitor HPMC DC

Red indicates presence of

additional ingredient

METHOCEL™ DC2 is a chemically pure hypromellose,

meeting all compendial requirements

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Proof Points – Tablet Weight Variation
Direct Compression Minitablet Production: Wet Granulation  DC
Collaboration with GEA
Competitor HPMC DC METHOCEL DC2 HPMC

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Matrix Tablet Manufacture

Improved More Efficient

Engineered Modified
Flow & Tablet Production
Morphology Release
Attributes

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Wet Granulation Considerations for
Hydrophilic Matrices

New Product Development & Applications

Department - Colorcon

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Drivers to Use a Direct Compression Process

• Cost savings through elimination of multiple processing steps

• What other reasons should be considered?
• Wet granulating a matrix formulation can be very challenging

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Why Granulate?

• Improve flow
• reduce weight variation Disadvantages:
• improve content uniformity
• Improve tableting properties
• Multi- step process
• compactibility • Additional equipment
• Prevent segregation • Heat and moisture
• Increase density of product • Potential stability problems
• Granulation endpoint control
• Minimize dust strategy
• increasing particle size
• reduce exposure
• improve yield

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Process Complexity

ICH Q8, 2009, Pharmaceutical Development

Q8(R2), http://www.ich.org

Nagar M, Singhai SK, Chopra VS, Bala I,

Trivdei P (2010). Der Pharmacia Lettre
2(2), 370-392.

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Granulation Rate Processes
Three simultaneous processes

Nucleation

Consolidation
and Growth

Breakage
Hapgood et al., J.Coll.Int.Sci., 253, 353-366, 2002

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Controlling Granule Nucleation
Dimensionless Spray Flux - a

.
V = Volumetric Spray Rate
.
A = Powder Flux (m2/sec)
dd = Drop Diameter

High a Low a
• High spray rate or low • Low spray rate or
powder velocity high powder velocity
• High spray density • Low spray density
• Significant drop overlap • Minimal drop overlap

Hapgood et al., J.Coll.Int.Sci., 253, 353-366, 2002

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Problems – Liquid Addition

• Poor liquid addition = Poor granule nucleation

• lack of spray nozzle/ atomization of liquid
• results in large agglomerates/ non-uniform particle size
• difficulty in drying and milling

• High moisture quantity

• results in large agglomerates/ large particle size
• difficulty in drying and milling

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Trial Runs: With and Without Spray Gun

Trial Set Up
• 70:30 ratio of powdered lactose/ METHOCEL™ K100M CR
• Glatt VG 25M with 5 L bowl, 800 g batch size
• 120 g of water: sprayed with nozzle at 10 psi, or without nozzle and air
• Water added over 3 minutes, with pump
• Wet mass for 1 min
• 100 g of granulation sifted through 12 mesh screen, by hand

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Example of Granules Without Spraying

Bulk Powder 33 g Retains

<3g

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Example of Granules With Spraying

Bulk Powder 3 g Retains

33g

DOW and Colorcon CONFIDENTIAL - Do not share without permission

 Use of Organic Solvent (Alcohol)

The picture can't be display ed.

• To avoid poor granule formation, use of liquid that will
not swell the HPMC
• Ethanol/ Isopropanol
• By reducing the hydration of the polymer, the granulation
formation process can be more uniform
• Use of organic solvents pose serious issues
The picture can't be display ed.

• Explosivity/ and explosion rated equipment and facilities

• Cost, as most do not recover the solvent
• No granule formation unless some water, or an alcohol soluble
binder is used
• Impurity generation for some API salt forms
• Residual solvents after drying

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Problems – Process/ Equipment
Improper processing parameters
• High water levels
• High impeller speeds
• Long wet massing times
• Slow spray rates

http://glatt.com

 Results in over densified granulations causing poor compaction

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Impact of Granulation Parameters on Tablet
Compaction Properties
Granulation Bulk Density Bulk Density Impact on Hardness

DOW and Colorcon CONFIDENTIAL - Do not share without permission

 Poor Formulation Practices

• Lack of low viscosity binder resulting in poor

incorporation of API crystals into the granules
• more prevalent with larger particle size APIs
• results in segregation and content uniformity issues

http://jenike.com

http://www.zi-online.info

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Wet Granulation Overview

• Wet granulation is not a simple process

• High viscosity HPMC can present many challenges

• Utilizing a direct compression process can provide advantages

and significantly reduce the complexity of the manufacturing
process

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Comparison of a Low-dose Formulation in
Wet Granulation and Direct Compression

Technical Service & Development, DowDuPont

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Case Study 1:
Transition from Wet Granulation to Direct Compression

Performance comparison in low dose formulation

• Direct compression using METHOCEL™ K100LV DC2
• Wet granulation with METHOCEL™ K100LV CR
Model formulation

Component Weight %
Indapamide 0.75
METHOCEL K100 LV 30.00
(CR or DC2) (HPMC)
Lactose 34.13
Avicel PH 102 (MCC) 34.12
Silica 0.50
Magnesium stearate 0.50 200 mg tablets

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Processing Steps

Wet Granulation = 7 steps

Weigh/ Wet Blend/

Wet Mill Dry Mill Compress
Sieve Granulate Lubricate

Direct Compression = 3 steps

Weigh/ V-blend/
Compress
Sieve lubricate

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Tablet Weight

• METHOCEL™ DC2 in direct compression shows improved tablet

weight reproducibility over the course of the tableting run, when
compared to wet granulation
Direct Compression Wet Granulation

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Tablet Strength

• The DC formulation exhibited higher tablet tensile strength values

than with wet granulation

Direct Compression Wet Granulation

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Modified Release Performance

• No significant difference between processing techniques

• Acceptable content uniformity for all samples
• Tablets produced via direct compression have lower %RSD

Unit-Dose Content Uniformity Values

Average Std Dev % RSD

DC 95.2 1.8 1.9

WG 105.6 2.3 2.2

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Case Study 1: Summary

Low-dose formulation, direct compression using METHOCEL™ DC2

 Tablet weight, hardness and release performance comparable to, or

better than, METHOCEL™ CR in wet granulation

 Acceptable content uniformity achieved, without specialized blending

techniques

 METHOCEL™ DC2 eliminates costly wet granulation processing

steps for matrix tablets, particularly for low-dose APIs, without
compromising tablet physicals or modified release performance

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Case Study 2
METHOCEL™ DC2 in Mini-tab Processing

Tablet compression optimization and excipient polymer

design for high-productivity mini-tab production

7.5 mg tablets

Method: Component Weight %

• GEA MODUL-P™ rotary tablet press with double feeder Chlorpheniramine maleate
(CPM)
12.0
paddles using the Dual-Control Method
METHOCEL™ K100M DC2 30.0
• multi-tip tooling with nineteen 2 mm tips
• the process stability, weight uniformity, and tablet
Avicel PH 102 (MCC) 56.5
Magnesium stearate 1.0
hardness were assessed for a range of tableting speeds
Silica 0.5

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Mini-Tab Production

• Initial analysis focused on optimizing

tableting parameters in manual mode
• Formulation tableted at all speeds
• Tablet weight robust at lower tableting
speeds, as rate increased the RSD
5 increased
4
Tablet Weight RSD

3 • RSD was below 5% at all tableting

2 speeds
1

0
20 40 60 80
Tableting Speed (rpm)

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Process Control
• Process control in automatic Dual-Control mode at 80 rpm analyzed
• Target Sigma values achieved, indicating good process control
• Low rejection rate: <171 out of 152,000 matrix mini-tabs produced
• Production rate of 16 kg/hour, using fully-tooled press

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Case Study 2: Summary

• Tablet compression process can have a significant impact on

mini-tab production efficiency and product quality

• METHOCEL™ DC2 showed acceptable weight uniformity and

process control, even at high tableting speeds

• By controlling weight via displacement at pre-compression and

tablet hardness at main compression, more uniform tablet
properties can be obtained

DOW and Colorcon CONFIDENTIAL - Do not share without permission

Direct Compression for Matrix Tablets

 Utilizing direct compression streamlines the manufacturing

process, saving time and cost

 Simplified process, results in better control throughout

 Balance of performance attributes is needed for the ideal
excipient

 METHOCEL™ DC2 is designed for improved dry powder flow,

enabling a shift to direct compression without a compromise in
tablet quality

DOW and Colorcon CONFIDENTIAL - Do not share without permission

 METHOCEL™ DC2

Streamlined Manufacture of Modified Release

Matrix Tablets via Direct Compression

DOW and Colorcon CONFIDENTIAL - Do not share without permission