BASF Aktiengesellschaft

New Crospovidone Grades with Surprising Disintegration Activity

K. Kolter (karl.kolter@basf.com), B. Fussnegger and K. Meyer-Boehm, BASF Aktiengesellschaft, Development Pharma Ingredients, 67056 Ludwigshafen, Germany

Abstract Summary
Various disintegrants including the new crospovidone grades Kollidon CL-SF and CL-F were investigated regarding their disintegration activity and physico-chemical properties. The short disintegration times of the new grades result from swelling behavior, hydration capacity, particle size and viscosity in solution.

Manufacturing of formulation 1 All ingredients were sieved (0.8 mm), blended for 10 min. in a Turbula mixer and compressed into 12 mm tablets on a single punch press Korsch EKO at 18 kN. Manufacturing of formulation 2 9.0 kg Aspirin powder, 9.0 kg acetaminophen cryst. and 1.8 kg caffeine were granulated in a Diosna mixer at stage 2 (with choppers) for 2 min. using a solution of 0.99 kg Kollidon 30 in 1.21 kg water and sieved in an Alexanderwerk sieve granulator through 1000 m. The granules were dried on a tray for 2 days at ambient conditions and sieved through 1000 m. The disintegrant and magnesium stearate were admixed in a Turbula blender for 10 min and the mixture was compressed on a Korsch EKO at 18 kN.

Formulations
Formulation 1 Ludipress LCE Disintegrant Magnesium stearate 467.50 mg 30.00 mg 2.50 mg Formulation 2 Aspirin powder Acetaminophen cryst. Caffeine gran. 0.20.5 Kollidon 30 Disintegrant Magnesium stearate Tablet weight Table 1 500.00 mg Tablet weight 250.00 mg 250.00 mg 50.00 mg 27.50 mg 16.00 mg 5.00 mg 598.50 mg

Disintegration of various disintegrants in formulation 1 (mean values of 3 resp. 2 batches disintegrant)

Without disintegrant Kollidon CL Kollidon CL-M Kollidon CL-F Kollidon CL-SF Polyplasdone XL Polyplasdone XL-10 Ac-di-sol Primojel Figure 1 0 1 01:33 01:21 01:13 01:56 02:09 02:00 2 3 4 5 Disintegration [min : s] 6 7 8 01:09 04:10 07:13

Introduction
In various dosage forms disintegrants are very important since disintegration of a tablet is a prerequisite for a quick dissolution. Generally, disintegrants are considered to be strongly swellable materials, which disrupt the integrity of a tablet according to their increase in volume. To date, there has been a general perception that besides swelling volume and swelling pressure, particle size would strongly determine the disintegration efficacy [1], [2]. Therefore, various crospovidone grades differing in particle size as well as other polymer structures (croscarmellose sodium, sodium starch glycolate) have been included in this study. The overall goal was to correlate the disintegration activity determined in 2 standard tablet formulations with physicochemical properties of the disintegrants.

Powder properties of disintegrants

Bulk density [g/ml] Kollidon CL Kollidon CL-M Kollidon CL-F Kollidon CL-SF Polyplasdone XL Polyplasdone XL-10 Ac-di-sol Primojel Table 2 0.33 0.20 0.21 0.14 0.28 0.33 0.46 0.76 Tapped density [g/ml] 0.43 0.27 0.28 0.21 0.36 0.48 0.72 0.92 Particle size D [4.3] [m] 124 5 29 17 140 27 49 41

Experimental Methods
Materials Crospovidone (Kollidon CL, CL-F, CL-SF and CL-M; BASF Aktiengesellschaft), Crospovidone (Polyplasdone XL, XL-10; ISP), Croscarmellose sodium (Ac-di-sol; FMC), Sodium starch glycolate (Primojel; DMV). Methods Particle size: [4,3], Malvern Mastersizer X, 2 bar, 300 mm lens. Hydration capacity: 2 g of polymer were swollen for 15 min in 40 ml of water. Thereafter, the suspension was centrifuged at 2000 revolutions (equivalent RCF 640 g) for 15 min, the supernatant poured off and the residual weight determined; ratio of weight after swelling / weight before swelling was calculated. Viscosity: 5 % solution using a Brookfield DV-II Viscosimeter. Disintegration time: Erweka ZT 74 using water.

All the materials tested showed a significant reduction of the disintegration time of tablets. In formulation 1 with lactose as a water-soluble ingredient Kollidon CL performed best, followed by Polyplasdone XL and Kollidon CL-SF. The ranking of the top 3 disintegrants in formulation 2 with less soluble, interacting actives, which is a real challenge for disintegrants, was Kollidon CL, Kollidon CL-SF and Kollidon CL-F. The disintegration performance of the fine cross-linked PVP grades is surprising since to date it has been considered that a coarse particle size is generally required to achieve a rapid disintegration. However, other physico-chemical parameters such as the capability of absorbing water, called hydration capacity, and swelling behaviour seem to have a strong influence. Within the crospovidone grades Kollidon CL-SF exhibited by far the highest hydration capacity. Bulk density values provide an indication that Kollidon CL-SF has a very porous structure. Despite extremely high hydration capacities Ac-di-sol and Primojel were less effective in disintegrating tablets. The resulting swelling is almost unlimited leading to a gel which blocks tablets pores and prevents further penetration of water into deeper zones. In contrast swelling of crospovidones is limited still maintaining a particle structure with a defined surface. In the case of fine crospovidones, the increased number of particles in a tablet covers a larger surface area of the other ingredients. This results in a wicking effect leading water quickly into the tablet.

Results and Discussion

Disintegration time of various disintegrants in formulation 2 (mean values of 3 resp. 2 batches disintegrant)
Without disintegrant Kollidon CL Kollidon CL-M Kollidon CL-F Kollidon CL-SF Polyplasdone XL Polyplasdone XL-10 Ac-di-sol Primojel 0 Figure 2 10 20 08:45 12:46 11:08 09:06 12:30 22:37 23:28 33:56 30 40 50 Disintegration time [min : s] 60 70 80 70:40

Behavior of disintegrants in water

Products Kollidon CL Kollidon CL-M Kollidon CL-F Kollidon CL-SF Polyplasdone XL Polyplasdone XL-10 Ac-di-sol Primojel Table 3 Hydration capaity g water/g polymer 4.4 3.9 5.9 8.1 5.8 4.6 12.1 18.3 Viscosity 5 % dispersion [mPas] 12 12 15 19 15 15 65 1770

Conclusion
Particle size of crospovidones is no longer considered to be the most important parameter for disintegration activity. Swelling behaviour (limited or unlimited), viscosity and hydration capacity are also relevant to disintegration. Kollidon CL-SF shows excellent disintegration characteristics.

References

[1] Polyvinylpyrrolidone Excipients for Pharmaceuticals, V. Bhler, Springer Verlag 2005, 125 -178. [2] The mechanism of disintegrant action, J. L. Kanig and E. M. Rudnic, Pharmaceutical Technology 1984 (4), 50-63. CRS 2006 Vienna, Austria; G-MEP/ML 0174