Pharmaceutical Polymers for Tablets and Capsules Edition: March 23, 2010
Wet Granulation Direct compression is not feasible for matrix formulations containing high levels of powder Carbopol polymers (>5% wt). Wet granulation can be used for powder grades of Carbopol polymers (971P NF, 97P NF) or Noveon AA-1 polycarbophil. Typical usage levels are 5-10% wt polymer. Wet granulation is generally more efficient (lower polymer levels are necessary) than direct compression due to different surface area of the polymers used (powder vs. granular). 2
Wet Granulation Processing Considerations The polymer should be incorporated in the powder blend (versus adding it as aqueous dispersion) due to the high viscosity of the polymer. Screening or combining the polymer with other ingredients is beneficial to improve dry polymer handling (compensates for static charge and fine particle size). No additional binder is required because Carbopol polymers have good binding properties. In order to avoid fast and extensive swelling of the polymer, use a low amount of granulation liquid added at a slow rate in fine droplets sprayed (uniform distribution of the water in the wet mass). Granulation should be controlled in order to prevent overwetting (sticky, rubbery mass). Incorporation of low levels of microcrystalline cellulose improves the processability of the formulation. It is very important to control the drying process and residual moisture in the granules (typical values 1-3%). Selection of container/closure system is essential for product stability (moisture permeation). 3
High Shear Granulation Guaifenesin 600 mg Tablets Objective: determine effect of granulation conditions on properties of Guaifenesin 600 mg extended release tablets with 10% Carbopol 971P NF polymer. Ingredient Guaifenesin Carbopol 971P NF Polymer Avicel PH 101 Microcrystalline Cellulose Magnesium stearate Total Tablet weight (mg) % w/w 8.5 10.0 5.0 0.5 100 710 High shear granulation with deionized water in TMG Glatt machine at various impeller and chopper speeds, spraying rates.
Granulation Parameters Guaifenesin 600 mg Tablets #1 #2 #3 # #5 #6 #7 Dry mixing Speed (impeller / chopper) rpm Mixing time (min.) Spraying Speed (impeller / chopper) rpm 00/750 00/750 00/750 Spray rate (%w/w /min.) 0.68 1.59 2.2 2.2 1.59 0.68 0.68 Wet massing Speed (impeller / chopper) rpm - Time (min) 2.0* Total water added (%w/w) 6.9 7.1 7.1 3.5 7.1 6.8 6.9 *#1 - wet massing: 1 min at rpm and 1 min at 00/750 rpm 5
Guaifenesin Granule Properties % retained 60 50 0 30 20 #1 #2 #3 # #5 #6 #7 10 0 20 0 60 80 100 200 >200 Particle size (mesh) 6 More fines: # - granulated with lower amount of water; lower flow rate, higher compressibility index, higher friability. #7 - processed under high agitation speed and low spray rate
Guaifenesin Release in ph=6.8 Phosphate Buffer 110 100 90 80 % released 70 60 50 0 30 20 10 0 #1 - ph=6.8 buffer #2 - ph=6.8 buffer #3 - ph=6.8 buffer # - ph=6.8 buffer #5 - ph=6.8 buffer #6 - ph=6.8 buffer #7 - ph=6.8 buffer 0 2 6 8 10 12 time (h) 7 Slower release for run # - granulated with lower amount of water and having different granule properties. No effect of mixing speed: 00/750 rpm vs. rpm: #1 vs. #7; #2 vs. #5. No influence of spraying rate #2, #3, #7 (processed at rpm)
Guaifenesin Release in 0.1N HCl 110 100 90 80 % released 70 60 50 0 30 20 10 0 #1-0.1N HCl #2-0.1N HCl #3-0.1N HCl # - 0.1N HCl #5-0.1N HCl #6-0.1N HCl #7-0.1N HCl 0 2 6 8 10 12 time (h) Slower release for run #. Robustness for formulations granulated with ~7% water in different processing conditions. 8
Guaifenesin Release 110 100 90 80 % released 70 60 50 0 30 20 10 0 #1 - ph=6.8 buffer #1-0.1N HCl #1-R - ph=6.8 buffer #1-R - 0.1N HCl #2 - ph=6.8 buffer #2-0.1N HCl #2-R - ph=6.8 buffer #2-R - 0.1N HCl 0 2 6 8 10 12 time (h) Good reproducibility and low intra-batch variability. No significant effect of the dissolution medium observed. 9
High Shear Granulation - Guaifenesin 600 mg Carbopol 971P NF polymer (10% w/w) could be efficiently used for Guaifenesin 600 mg extended release tablets. The polymer imparted binding properties, no additional binder was necessary. Low amount of water (<10% w/w) required - prevent overwetting and reduce drying time. A sufficient amount of granulation liquid should be used to assure good granule formation (less fines) and consistent drug release. High agitation speed not recommended - powder segregation, more difficult control of the granule formation. Reproducibility and robustness were demonstrated. 10
The information contained herein is believed to be reliable, but no representations, guarantees or warranties of any kind are made as to its accuracy, suitability for particular applications or the results to be obtained. The information often is based on laboratory work with small-scale equipment and does not necessarily indicate end product performance or reproducibility. Formulations presented may not have been tested for stability and should be used only as a suggested starting point. Because of the variations in methods, conditions and equipment used commercially in processing these materials, no warranties or guarantees are made as to the suitability of the products for the applications disclosed. Full-scale testing and end product performance are the responsibility of the user. Lubrizol Advanced Materials, Inc. shall not be liable for and the customer assumes all risk and liability for any use or handling of any material beyond Lubrizol Advanced Materials, Inc. s direct control. The SELLER MAKES NO WARRANTIES, EXPRESS OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE. Nothing contained herein is to be considered as permission, recommendation, nor as an inducement to practice any patented invention without permission of the patent owner. Copyright 2010 Lubrizol Advanced Materials, Inc. 11