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Formulation/Processing Considerations
Table 1: Formulation/Processing Considerations
Method of Tablet Manufacture Recommended Polymers Typical Polymer Levels 10 - 30% 3 - 5% 3 - 5% 3 - 5%
n n
Formulation/Processing Considerations
Direct Compression
Carbopol 71G NF Polymer Carbopol 974P NF Polymer Carbopol 971P NF Polymer Noveon AA-1 Polycarbophil
Carbopol polymers have good binding properties (compressibility). Powder grades have very fine particle size and static charge (thus not free flowing) maximum 5% can be included in direct compressible formulations. Carbopol 71G NF polymer is in granular form and has good flowability. Therefore, it can be processed easier than the powder Carbopol polymers. Powder grades of Carbopol polymer are more efficient in extending drug release than the granular grade due to the larger surface area, thus lower levels of polymer are generally needed. Carbopol polymers can be used alone or in combination with other extended release excipients such as hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polyethylene oxide, sodium alginate and methacrylic polymers. The combination allows for flexibility in achieving various release profiles. Additionally, lower total polymer levels may be needed compared to using a single polymer, thus enabling overall cost savings and smaller tablet sizes. Carbopol 71G NF polymer can be combined with other extended release excipients to improve the flow properties of the formulation. Compression forces which result in acceptable hardness are not expected to significantly affect the drug release characteristics. An important consideration is that segregation may occur in the powder blend. Segregation might be prevented by pre-blending of the active pharmaceutical ingredient (API) and polymer; use of ingredients with similar particle size distribution and density or by achieving ordered mixing. Processing conditions should be controlled (low relative humidity) to address the hygroscopicity of the polymer. Selection of container/closure system is critical for product stability (moisture permeation). APIs with poor flowability or compressibility can be granulated and the granules blended with Carbopol polymers. In some cases using the same polymer grade, direct compression leads to slower release than aqueous or non aqueous granulation. The advantage of using Carbopol polymers in non aqueous solvents is to avoid rapid swelling of the polymer in order to facilitate processing. Non aqueous granulation is possible at Carbopol polymer levels greater than 10% of the blend, when aqueous granulation is difficult. Ethanol and isopropyl alcohol can be used as granulating solvents. The gelling of Carbopol polymers is faster in ethanol than in isopropyl alcohol. It is important to avoid contact with water and moisture (control relative humidity, use dry equipment).
5 - 25% 5 - 25%
5 - 25%
n
Important Notice: In mid 2007, Noveon, Inc., a subsidiary of The Lubrizol Corporation, changed its name to Lubrizol Advanced Materials, Inc.
Formulation/Processing Considerations
Controlled release can be efficiently achieved at low levels (5 - 10%) due the large surface area of the powder grade polymer. High polymer levels (>10 - 15%) might be difficult to process. Generally, it is recommended to incorporate the polymer in the powder blend (versus adding it as a dispersion in water) 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 (uniform distribution of the water in the wet mass). Incorporation of microcrystalline cellulose improves the processability of the formulation. Generally less than 10% of microcrystalline cellulose should be used to prevent disintegration of the tablets. Granulation should be controlled in order to prevent overwetting (sticky, rubbery mass). It is very important to control the drying process and residual moisture in the granules (typical values 1 - 3%), however these parameters are formulation specific. If overdried, Carbopol polymers form hard granules. High residual moisture might lead to tablets sticking to the punches and stability problems. Selection of container/closure system is essential for product stability (moisture permeation). Compression forces which result in acceptable hardness are not expected to significantly affect the drug release characteristics. Carbopol polymers have small particle size, static charge and low density. Therefore, precautions need to be taken during granulation. The fluidization should be kept low at the beginning of the process to prevent adherence of Carbopol polymer to the filter bag. The spray rate should be controlled to prevent formation of large, over wet agglomerates. Roller compaction avoids rapid polymer swelling in water. It is recommended to blend all of the ingredients, except the lubricant prior to compaction to achieve slower release rates. The formulation does not need an additional binder when Carbopol polymer is included. For example, Carbopol 71G NF polymer is currently manufactured by roller compaction of Carbopol 971P NF polymer with no additional additives. The polymer properties are not affected by multiple compaction steps. Processing conditions should be controlled (low relative humidity) to address the hygroscopicity of the polymer.
5 - 10%
n
5 - 10% 5 - 10%
5 - 10%
n
Formulation/Processing Considerations
Table 1 (continued): Formulation/Processing Considerations
Method of Tablet Manufacture Recommended Polymers Typical Polymer Levels 5 - 20% 5 - 20%
n
Formulation/Processing Considerations
Extrusion Spheronization
Carbopol polymer must be used with microcrystalline cellulose in order to reduce the tackiness of the wet mass and facilitate processing. Extrusion spheronization using water is possible and recommended vs. a solution of electrolytes. The amount of water, extrusion speed, spheronization speed and time need to be optimized in order to obtain the highest yields and sphericities. In the presence of electrolytes (e.g. calcium chloride), the processing is easier, but the electrolyte has a negative consequence on the bioadhesion and drug release. Processing temperature should be maintained below the polymer glass transition temperature (~105C). Carbopol polymers can be used in the presence or absence of hot melt binders. The method is also suitable to obtain solid dispersions of low solubility APIs.
5 - 20%
5 - 50% 5 - 50%
5 - 50%
n
Low polymer levels (1 - 3%) can be used in conventional formulations (immediate release) to provide binding properties. The polymers can be incorporated by direct compression or wet granulation (preferably added to the dry powder blend or as a dispersion in water or solvents). Powder grades of Carbopol polymer are more efficient in extending drug release than the granular grade, however the powder grades are not free flowing. As a general rule, the methods which are most efficient for the powder grades in extending drug release are: Aqueous granulation Non aqueous granulation Increasing Efficiency Dry granulation
Carbopol polymers enable processing versatility in order to achieve targeted drug release profiles. 1. Availability of powder and granular grades allows manufacturing by different types of technology (e.g. direct compression and granulation) 2. Powder and granular Carbopol polymer grades can be combined in a formulation 3. Carbopol polymers can be used part intragranularly and part extragranularly in a formulation
Technical References
Direct Compression
Thapa, P ., Ghimire, M., Alex B. Mullen, A.B., Stevens, H., Controlled Release Oral Drug Delivery Systems containing Water Insoluble drugs, Kathmandu University Journal of Science, Engineering and Technology, No.1, Sept. 2005. Method for administering a phosphodiesterase 4 inhibitor, United States Patent 20030212112. Dosage form of N-acetyl cysteine, United States Patent 6623754.
Aqueous Granulation
Sandile, K.M., Walker, R.B., Evaluation of Rate of Swelling and Erosion of Verapamil (VRP) Sustained-Release Matrix Tablets, Drug Dev. Ind. Pharm. 32(10), 11391148, 2006. Controlled release solid dosage carbamazepine formulations, United States Patent 6572889. Controlled release solid dosage nifedipine formulations, United States Patent 20040219210.
Extrusion Spheronization
Bommareddy, G.S., Paker-Leggs, S., Saripella, K.K., Neau, S.H., Extruded and spheronized beads containing Carbopol 974P to deliver nonelectrolytes and salts of weakly basic drugs, Int. J. Pharm. 321(1-2), 62-71, 2006. Mezreb, N., Charrueau, C., Boy, P ., Allain, P ., Chaumeil, J.C., Production of Carbopol 974P and Carbopol 971P Pellets by ExtrusionSpheronization: Optimization of the Processing Parameters and Water Content, Drug Dev. Ind. Pharm. 30(5), 481-490, 2004. Gomez-Carracedo, A., Alvarez-Lorenzo, C., Gomez-Amoza, J. L., Martinez-Pacheco, R., Souto, C., Concheiro, A., Extrusion-spheronization of blends of Carbopol 934 and microcrystalline cellulose, Drug Dev. Ind. Pharm. 27(5), 381-391, 2001.
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PH-004
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. Lubrizol Advanced Materials, Inc. is a wholly owned subsidiary of The Lubrizol Corporation