Copyright CSC Publishing

Transcription

1 As appeared in March 2014 roller compaction Effect of roller compaction pressure on the blend and tablet properties of a formulation containing a poorly soluble drug E. E. Robles, P. M. Ved, N. Vora, T-Y. Kim, D. Cartwright, J. A. Williamson, N. Kanikkannan, and P. Skultety Xcelience This article describes a study of the effect of roll pressure on the blend characteristics and the tablet properties of an immediaterelease formulation comprising a poorly soluble active pharmaceutical ingredient (API). The results show that roll pressure has a significant effect on the dissolution of the tablets even when the tablet hardnesses are equal. These results suggest that roll pressure is a critical process parameter for poorly soluble APIs; that it needs to be optimized during the product development stage; and that it can be used as an in-process control during manufacture. Interest in using roller compaction to manufacture solid dosage forms has increased in recent years. It is a dry, continuous process that provides good control over final particle size and bulk density. The major advantage of roller compaction over wet granulation is that it requires no water or organic solvents. That is especially beneficial when working with APIs that are sensitive to heat and/or moisture. In operation, roller compaction densifies dry powders into a solid mass (compacted ribbon), which is then milled into granules of the desired size. The compaction process has several stages, including particle rearrange-

2 ment, particle deformation, particle fragmentation, and particle bonding [1]. While roller compaction seems simple, the fundamental mechanisms are complex because several material attributes and process parameters are involved. These include material flow properties, compactablity, compressibility, roll surface, roll pressure, roll speed, and feeding method. A review of the literature indicates that roll pressure is the most critical process parameter [2], and several researchers have studied its effect on tablet dissolution [3-6]. Sheskey and Dasbach [3] evaluated nine commonly used polymers as dry binders in the manufacture of an immediate-release tablet formulation using roller compaction and niacinamide, a water-soluble compound, as a model API. The authors investigated the impact of roll pressure (1, 3, and 6 tons) on the physical characteristics of the granule and tablet and on dissolution using three binder levels (6.25, 12.5, and 25 percent). Tablet compression force was kept at a constant kilonewtons for all the batches, and roll pressure did not have a significant effect on tablet dissolution. In most of the reported studies, granulations prepared at varying roll pressures were compressed at the same tablet compression force to investigate how roll pressure affected dissolution. The expectation is that this approach would yield tablets of different hardnesses according to the different roll pressures applied even though tablet compression force remained constant. Although many researchers have studied the effect of roll pressure on the dissolution of tablets, the effect of roll pressure on the dissolution of tablets that have been compressed to different hardness levels has not been explored. The objective of this study was to investigate the effect of roll pressure on the blend characteristics and on the properties of low-, medium- and high-hardness tablets of an immediate-release formulation, including the disintegration time (DT) and dissolution profile when indomethacin, a poorly soluble compound, was used as a model API. Experiment Materials. Indomethacin was obtained from Tokyo Chemical Industry (Tokyo, Japan). Excipients used in this study included anhydrous lactose (SuperTab 21AN, DFE Pharma, Princeton, NJ), co-processed microcrystalline cellulose (MCC) and anhydrous calcium phosphate (AvicelDG, FMC Biopolymer, Philadelphia, PA), sodium starch glycolate (Explotab, JRS Pharma, Patterson, NY), colloidal silicon dioxide (Cab-O-Sil M-5P, Cabot, Boston, MA), and magnesium stearate (Hyqual, Mallinckrodt, St. Louis, MO). Formulation and process. Table 1 shows the formulation used in this study. Both ductile (MCC) and brittle (anhydrous calcium phosphate and anhydrous lactose) diluents were used in order to have good compactability during roller compaction and good compressibility during the preparation of tablets. The process parameters (roll pressure range, roll speed, feeder speed, mill screen size, and mill speed) were defined based on results from preliminary studies. Each ingredient was sieved through a 20-mesh screen, except the magnesium stearate, which was sieved through a 40- mesh screen. Intragranular ingredients were placed in a V-type blender (Blend Master, Patterson-Kelley, East Stroudsburg, PA) and mixed for 10 minutes. The preblend was compacted into ribbons using a TFC-Lab Micro roll compactor (Freund-Vector, Marion, IA) fitted with serrated non-interlocking rolls. Three sets of ribbons were produced at roll pressures of 2 (low), 3.5 (target), and 5 megapascals (MPa) (high); a roll speed of 0.78 rpm; and a feeder speed of 9.30 rpm. Each set of ribbons was milled using a Comil 197 (Quadro Engineering, Waterloo, Ontario) fitted with a round arm impeller and a 991-micron screen (round holes). The milled granules were blended with the extragranular ingredients in a V-type blender for 3 minutes. Three final blends, from each set of ribbons, were generated for compression. Final blends were compressed into tablets of 7 (low), 10 (target) and 13 kiloponds (kp) (high) hardness using a B-10 Piccola tablet press (Riva, Buenos Aires, Argentina). Pre-blend, ribbon, and final blend characterization. Prior to roller compaction, the true density of the preblend was determined using an Accupyc II 1340 pycnometer (Micromeritics, Norcross, GA). During roller compaction, the apparent density (envelope density) of the compacted ribbons was determined using a GeoPyc 1360 pycnometer (Micromeritics). Next, the solid fraction an intrinsic attribute that can be used to monitor the characteristics and physical performance of the compacted ribbons [7] was determined. That required measuring the apparent densities of the ribbons at the beginning, middle, and end of roller compaction, as well as accounting for the apparent density of the compacted ribbons and the true density of the pre-blend. Monitoring the solid fraction of compacted ribbons provides insight into formulation strategy, enabling researchers to optimize the granules and control the roller compaction process. Table 1 Formulation composition Ingredients % w/w * Intragranular Indomethacin 10 Anhydrous lactose (SuperTab 21AN) Co-processed MCC-anhydrous calcium phosphate (Avicel DG) 30 Sodium starch glycolate (Explotab) 2 Colloidal silicon dioxide (Cab-O-Sil M-5P) 0.3 Magnesium stearate (Hyqual) 0.25 Extragranular Co-processed MCC-anhydrous calcium phosphate 10 Sodium starch glycolate 2 Colloidal silicon dioxide 0.2 Magnesium stearate 0.25 Total 100 * Tablet weight = 250 mg

3 Table 2 Physical evaluation of pre-blend and final blend the target and high roll pressures were equal. In general, the flow and compressibility of the final blend increased slightly as indicated by the flow index and CI values. The final blend particle size increased slightly as a function of roll pressure. Continuous and firm ribbons were obtained at all three roll pressures. Table 3 presents the solid fraction data of the compacted ribbons. As the roll pressure was increased from 2 MPa to 3.5 MPa, the solid fraction of the ribbons increased from to 0.4. No further increase in the solid fraction was observed as the roll pressure was increased to 5 MPa. DT and friability. Table 4 presents the tablet compression force used, DT, and friability results. The tablet compression forces needed to produce tablets of all hardnesses low of 7 kp, target of 10 kp, and high of 13 kp using the blend made at low roll pressure were less Bulk Tapped Flow Particle size distribution by sieve analysis (%) density density index Blend (g/ml) (g/ml) (mm) CI (%) 425 µm 180 µm 125 µm 106 µm µm µm < µm Pre-blend Blend, low roll pressure Blend, target roll pressure Blend, high roll pressure Bulk density, tapped density, flow, and particle size distribution. The bulk and tapped density of the preblend and final blend were determined per USP <616> using a VanKel Tapped Density Tester (Agilent Tech - nologies, Santa Clara, CA) and the Carr Index (CI) was calculated. The particle size distribution of the pre-blend and final blend were determined using a Sonic Sifter (ATM, Milwaukee, WI) in the sift-pulse mode with sift amplitude set at 9 and a shaking-sieving time of 5 minutes. The flows of the pre-blend and final blend were evaluated using a Flodex (Hanson Research, Chatsworth, CA). The diameter of the smallest orifice through which the blend passed freely under the influence of gravity three consecutive times was considered the Flodex index (denoted in millimeters) of the sample. Evaluation of tablets. The DT of the tablets was tested per USP <711> using a Dr. Schleuniger DTG 2000 IS disintegration apparatus (Sotax, Westborough, MA). Friability of the tablets was tested per USP <1216> using a Vankel friabilator (Agilent Technologies). The dissolution was performed in a 10-millimolar KH 2 PO 4 buffer of ph 7.2 using USP apparatus II at 50 and 250 rpm (infinity) for 5, 10, 20, 30,, 60, and minutes (infinity) pull times using an Evolution 6100 dissolution system (Distek, North Brunswick, NJ). The percentage of indomethacin dissolved was quantified at a 318-nanometer wavelength using a UV spectrophotometer (Agilent Technologies). Results and discussion Blend and ribbon physical test results. Table 2 presents the bulk density, tapped density, flow index, CI, and particle size distribution results. The bulk density of the final blend increased slightly as the roll pressure increased. However, the bulk densities of the blend from Table 3 Solid fraction of ribbons Time point Low roll Target roll High roll pressure pressure pressure (2 MPa) (3.5 MPa) (5 MPa) Beginning Middle End Average Standard deviation than what was required to make tablets from blends made at the target and high roll pressures. These results suggest that the blends made at the target and high roll pressure may have less compressibility from the granulation and require greater compression force to produce tablets of equal hardness. Indeed, many researchers have observed that a blend s compressibility diminishes after roller compaction at high pressure [1]. The DT of the tablets was hardness-dependent within each roll pressure group (Table 4). However, the DT increased linearly as the roll pressure of the blend used to Table 4 DT and friability of tablets Tablet Tablet compression DT Friability hardness force (kn) (min:sec) (%) Low roll pressure (2 MPa) Low (7 kp) 4. 1: Target (10 kp) : High (13 kp) 7. 5: Target roll pressure (3.5 MPa) Low (7 kp) : Target (10 kp) : High (13 kp) : High roll pressure (5 MPa) Low (7 kp) : Target (10 kp) : High (13 kp) :26 0.1

4 make the target- and high-hardness tablets increased. The DTs of target-hardness tablets compressed using the blend from low, target, and high roll pressures were 4:00, 4:57, and 6:13 (minutes:seconds), respectively. Also, the DTs of the high-hardness tablets compressed using the blend from low, target and high roll pressures were 5:33, 7:59, and 8:26, respectively. Overall, the roll pressure had a significant effect on the DT of the target- and highhardness tablets, even though the hardness values were equal. These results suggest that it is important to optimize the roll pressure during product development and to control the roll pressure during product manufacture. The friability of the tablets from all groups was acceptable (0.2 percent or less). Dissolution profiles. Figures 1 to 3 illustrate the ef fect of roll pressure on the dissolution of indomethacin tablets compressed at low, target, and high hardness. The dissolution profile of tablets compressed with a blend made using low roll pressure was faster at all three hardness levels. At the target hardness, the dissolution profile of tablets compressed with a blend made using low roll pressure was significantly higher than those made at the target roll pressure (similarity factor, or f2, of 48) and the high roll pressure (f2 of ). This may be due to the fact that the target- and high-hardness tablets required more force when compressed from blends made at the target and high roll pressures, possibly because of work hardening. At the target and high roll pressures, the solid fraction of the ribbons was found to be higher (Table 3). Fur ther - more, the higher tablet compression force used on the blend made at the target and high roll pressures might have decreased the porosity of the tablets; tablets containing poorly soluble APIs such as indomethacin have slower dissolution profiles when tablet porosity is low. In general, the dissolution profiles of the tablets compressed with blends made at the target and high roll pressures were similar for all three hardness levels. This might be because the final blends had equal bulk densities when the target and high roll pressures were used. The dissolution at 5 minutes was significantly greater for tablets compressed from the blend made at low roll pressure. These results demonstrate that roll pressure has a significant effect on the dissolution of indomethacin tablets, even though the tablet hardnesses are equal. It should be noted that the force required to produce a particular tablet hardness was less for the blend made at low roll pressure than it was for blends made with the target and high roll pressure. The differences in the dissolution values at the earlier time points might indicate significant differences in the bioavailability of tablets containing poorly soluble APIs, such as indomethacin. These results suggest that roll pressure is a critical process parameter for tablets containing poorly soluble APIs and it needs to be optimized during product development and used as an in-process control during product manufacture. Figures 4 to 6 illustrate the effect of tablet hardness on the dissolution profile of tablets made from blends at the low, target, and high roll pressure. The dissolution of the high-hardness tablets showed the least dissolution at 5 minutes compared to the target- and low-hardness tablets. In general, the standard deviations of dissolution results for the tablets made from blends using high roll pressure were higher than those made with blends using low and Figure 1 compressed at low hardness (7 kp) Low pressure (2 MPa), low hardness (7 kp) Target pressure (3.5 MPa), low hardness (7 kp) High pressure ( 5 MPa), low hardness (7 kp) Figure 2 compressed at target hardness (10 kp) 105 Low pressure (2 MPa), target hardness (10 kp) Target pressure (3.5 MPa), target hardness (10 kp) High pressure ( 5 MPa), target hardness (10 kp) Figure 3 compressed at high hardness (13 kp) Low pressure (2 MPa), high hardness (13 kp) Target pressure (3.5 MPa), high hardness (13 kp) High pressure ( 5 MPa), high hardness (13 kp)

5 target roll pressures. Overall, roll pressure had a significant effect on the dissolution of tablets, even though the hardness of the tablets remained the same, and the roll pressure range needs to be optimized and controlled. Figure 4 blend is prepared at low roll pressure (2 MPa) Figure 5 blend is prepared at target roll pressure (3.5 MPa) Figure 6 blend is prepared at high roll pressure (5 MPa) Conclusion In this study, the DT of the tablets increased linearly as the roll pressure increased for the target- and highhardness tablets. The dissolution profile of the tablets compressed with a blend made with low roll pressure was faster at all three hardness levels. At the target hardness, the dissolution profile of tablets compressed with a blend made at low roll pressure was significantly faster compared to tablets compressed from blends made at the target and high roll pressures. These results suggest that roll pressure is a critical process parameter for poorly soluble APIs and needs to be optimized during product development. Furthermore, roll pressure should be used as an inprocess control parameter during product manufacture. T&C References 1. Miller, R.W. Roller compaction technology. In: Parikh, D.M., (Ed), Handbook of pharmaceutical granulation technology, Marcel Dekker, New York, pp , Li, F., Meyer, R.F., and Chem, R. Understanding critical parameters in roller compaction process and development of a novel scaling method. Abstract #203, Milling and Blending, Fifth World Congress on Particle Technology, Sheskey, P.J. and Dasbach, T. Evaluation of various polymers as dry binders in the preparation of an immediate-release tablet formulation by roller compaction. Pharm Technol., 19, , Dave, V.S., Fahmy, R.M., Bensley, D., and Hoag, S.W. Eudragit RS PO/RL PO as rate-controlling matrixformers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets. Drug Dev Ind Pharm, 38, , Sheskey, P.J., Cabelka, T., Robb, R., and Boyce, B., Use of roller compaction in preparation of controlledrelease hydrophilic tablets containing methylcellulose and hydroxypropylmethyl cellulose polymers. Pharm Technol, 18, , Inghelbrecht, S. and Remon, J.P., Reducing dust and improving granule and tablet quality in the roller compaction process. Int J Pharm., 171, 1-206, Hancock, B.C., Colvin, J.T., Mullarney, M.P., and Zinchuk, A.V. The relative densities of pharmaceutical powders, blends, dry granulations and immediate release tablets. Pharm Technol, 64-80, April E. E. Robles is a scientist; P. M. Ved is a formulator III; N. Vora is a formulator II; T-Y. Kim is a team leader; D. Cartwright is a formulator III; J. A. Williamson is a team leader; N. Kanikkannan is a manager; and P. Skultety is vice president of pharmaceutical development services at Xcelience, 5415 West Laurel St, Tampa, FL Tel Website: