Streamlined Manufacture of Modified Release Matrix Tablets via Direct Compression. Katie Hewlett, Dow Gus LaBella, Colorcon

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1 Streamlined Manufacture of Modified Release Matrix Tablets via Direct Compression Katie Hewlett, Dow Gus LaBella, Colorcon

2 Controlled Release Alliance Unique Together Leading polymer expertise Quality excellence Manufacturing reliability and consistency Solution innovation Global supply and customer support network Dedicated technical support around the world Unmatched application knowledge for formulation simplification Extensive training and education programs Manufacturing Efficiency and Productivity Improvement

3 Percent Drug Released HPMC Matrix Tablets for Modified Release Oral Drug Delivery Matrix tablets are: Robust to improve patient compliance Reduce dosing frequency Reduce adverse effects from API Relatively simple & easy to develop, and inexpensive to manufacture Time lapse images of tablets swelling over 24 hours Video and data from internal studies carried out in Midland, MI Increasing 2% Viscosity 5% theophylline, 20% HPMC 74.5% lactose, 0.5% mag stearate 100 HPMC 2208 is the predominant matrix tablet excipient OCH 3 O O HO HO O OCH 3 OH OH OCH OCH 3 O 3 O HO O HO O O O O OH O O CH 3 O OCH OCH 3 3 R = CH 3 OH Chemical Structure of HPMC 2208 R Methocel K3 Premium LV Methocel K100 Premium LV Methocel K4M Premium Methocel K15M Premium Methocel K100M Premium Time (hours)

4 Matrix Tablet Manufacture Granulation or Powder Blend Tableting Matrix Tablets

5 Balancing Performance Attributes Particle size Particle size Sphericity Permeability Density Flowability Modified Release Surface area Hydrophilicity Tunable by substitution Erodability Tunable by molecular weight Particle size Compactibility Sphericity Density Surface area

6 Evolution of METHOCEL Premium Innovating to Address Industry Needs: METHOCEL DC2 METHOCEL CR Engineered morphology Enhanced flow METHOCEL Established over 50 years Premium quality product line Proven track record Particle size guarantee Tighter specifications Robust, optimized MR performance Direct compression Lower-cost, more consistent manufacturing processes

7 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

8 Matrix Tablet Manufacture Engineered Morphology Improved Flow & Tablet Attributes Modified Release More Efficient Production

9 Wet Granulation Considerations for Hydrophilic Matrices Gus LaBella Formulation Technologies Manager, Colorcon

10 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

11 Why Granulate? Improve flow Reduce weight variation Improve content uniformity Improve tableting properties Compactibility Prevent segregation Increase density of product Minimize dust Increasing particle size Reduce exposure Improve yield Disadvantages: Multi-step process Additional equipment Heat and moisture Potential stability problems Granulation endpoint control strategy

12 Process Complexity ICH Q8, 2009, Pharmaceutical Development Q8(R2), Nagar M, Singhai SK, Chopra VS, Bala I, Trivdei P (2010). Der Pharmacia Lettre 2(2),

13 Granulation Rate Processes Three simultaneous processes Nucleation Consolidation and Growth Breakage Hapgood et al., J.Coll.Int.Sci., 253, , 2002

14 Controlling Granule Nucleation Dimensionless Spray Flux - a High a High spray rate or low powder velocity High spray density Significant drop overlap Ψ a =. V = Volumetric Spray Rate. 3 ሶ V 2 ሶ Ad d A = Powder Flux (m 2 /sec) d d = Drop Diameter Low a Low spray rate or high powder velocity Low spray density Minimal drop overlap Hapgood et al., J.Coll.Int.Sci., 253, , 2002

15 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

16 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 and 10 psi or without nozzle and air Water added over 3 minutes with a pump Wet massed for 1 min after water addition was complete 100 g of granulation sifted through 12 mesh screen by hand

17 Example of Granules Without Spraying Bulk Powder 33 g Retains <3g

18 Example of Granules With Spraying Bulk Powder 3 g Retains 33g

19 Use of Organic Solvent (Alcohol) 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 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

20 Problems Process/ Equipment Improper processing parameters High water levels High impeller speeds Long wet massing times Slow spray rates Results in over densified granulations causing poor compaction

21 Increasing Wet Massing Time Impact of Granulation Parameters on Tablet Compaction Properties Granulation Bulk Density Decreasing Spray Rate Bulk Density Impact on Hardness

22 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

23 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

24 Comparison of a Low-dose Formulation in Wet Granulation and Direct Compression: Case Study Kathryn Hewlett Technical Service & Development, Dow

25 Transition from Wet Granulation to Direct Compression Purpose: To compare the performance of METHOCEL K100LV DC2 in direct compression with METHOCEL K100LV CR in wet granulation for a low-dose formulation Model formulation Component Weight % Indapamide 0.75 METHOCEL K100 LV (CR or DC2) (HPMC) Lactose Avicel PH 102 (MCC) Silica 0.50 Magnesium stearate mg tablets

26 Wet Granulation = 8 steps Processing Steps Weigh/ Sieve Pre-mix Wet Granulate Wet Mill Dry Mill Blend/ Lubricate Compress Direct Compression = 4 steps Weigh/ Sieve V-blend Lubricate Compress

27 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

28 Tablet Strength The DC formulation exhibited higher tablet tensile strength values than with wet granulation Direct Compression Wet Granulation

29 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 WG

30 Case Study: Summary Low-dose indapamide formulation produced via DC using METHOCEL DC2 Tablet weight, hardness and release performance of a directly compressed formulation with METHOCEL DC2 were comparable to, or better than METHOCEL CR in wet granulation Acceptable content uniformity was achieved with METHOCEL DC2 in direct compression 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

31 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 Excipients, such as METHOCEL DC2, which are designed for improved dry powder flow, can enable a shift to direct compression without a compromise in tablet quality

32 METHOCEL DC2 Streamlined Manufacture of Modified Release Matrix Tablets via Direct Compression