Poster Reprint AAPS Annual Meeting and Exposition November 2005

Investigation of a Directly Compressible Hypromellose Matrix Formulation for a Low Dose, Practically Insoluble Drug
Marina Levina, Fiona Palmer, Ali. R. Rajabi-Siahboomi; Colorcon, Dartfird, Kent, UK ([email protected])

Introduction The objective of this study was to investigate a direct compression (DC) extended release (ER) tablet formulation of a low dose, practically insoluble drug using hypromellose (HPMC, Methocel*). HPMC is extensively used in the formulation of extended release matrix systems. The rate of drug release is mediated by a hydrated gel layer on the surface of the matrix. Critical factors impacting drug release from these matrices include HPMC polymer type & concentration, drug solubility, choice of fillers, tablet size and polymer/drug ratio1. Indapamide, a low dose thiazide type diuretic which is practically insoluble in water, was chosen as the model drug. The primary benefit of an ER preparation of Indapamide is that a lower dosage is needed to maintain a uniform blood plasma concentration and therefore provides uniform clinical effect2. An initial formulation was generated using the HyperStart formulation service3, and compared to a reference product, Natrilix SR table. The effects of filler types was investigated.

Methodology The particle size of the Indapamide (Calao Srl, Italy) was measured using laser scattering technique (Malvern Mastersizer). The mean particle size was 13.54 microns. 500g formulations containing 0.75% w/w drug, 38.68% w/w HPMC (Methocel K15MCR), 0.50% fumed silica (Aerosil 200)) and 0.5%w/w magnesium stearate (Peter Greven) were prepared. Two different fillers were used at 59.75%w/w i.e. spray-dried lactose (FastFlo) or microcrystalline cellulose (Avicel PH102).

Table 1. Formulations Used in this Study

Concentration (% w/w) A* B 0.75 0.75 Indapamide 38.68 38.68 HPMC K15M CR 59.57 Lactose 59.57 Microcrystalline cellulose 0.50 0.50 Fumed silica 0.50 0.50 Magnesium stearate *Formulation generated using HyperStart Materials

Mixing procedure for low dose active drug: 1. Drug and a portion of the filler were pre-blended in a Diosna high shear granulator for 5 minutes (impeller speed = 200 rpm and chopper speed = 500 rpm). 2. The rest of the filler (pre-screened with fumed silica through a 500 m mesh) was added to the Diosna bowl and mixed for 5 minutes at the above conditions. 3. The HPMC was then added and blended for an additional 5 minutes at the above conditions. 4. Finally, magnesium stearate was added and the formulation was mixed for a further 1 minute at an impeller speed of 400 rpm. A tap density tester (Sotax, UK) was used to measure the bulk and tapped densities of the blends. 200 mg tablets containing 1.5 mg drug were manufactured using direct compression on an instrumented 10 station rotary tablet press (Piccola, Riva, Argentina) fitted with 7mm standard concave tooling, at 20 rpm. Tablet ejection force was measured. Dissolution testing was performed according to the USP monograph <711> for indapamide tablets4. A USP compliant Vankel dissolution bath fitted with Apparatus I (basket method) at 100 rpm was used. The dissolution medium was 900ml of 0.05M phosphate buffer (pH 6.8). Samples were taken over a 24 hour time period and analysed by HPLC. Tablet content uniformity tests were carried out according to the USP monograph <905> for indapamide tablets4. Tablet mechanical strength was determined using an automated tablet tester (Schleuniger, Germany) and friability tester (Copley, UK).

Results and Discussion Table 2. Physical Properties of the Tablets Formulations Bulk density Tapped density Carrs Index (%) Ejection force (N) Compression force (kN) Diameter (mm) Thickness (mm) Weight (mg) Breaking force (kN) Friability (%) Content uniformity (%) A 0.52 0.69 25.0 136.6 3.6 12.9 0.3 7.0 0.0 4.8 0.0 204.0 0.0 11.4 0.3 0.1 95.0 0.9 B 0.43 0.58 26.0 50.3 2.3 4.7 0.2 7.0 0.0 5.1 0.0 204.5 1.5 12.2 0.5 0.3 96.9 1.0

All mixtures showed acceptable flow characteristics. Formulation A containing lactose required a higher compression force (12.9 kN) to obtain tablets with the required breaking force. Low tablet ejection values were seen for both formulations (A: 136.6 and B: 50.3N). Robust physical properties were attained for all matrix tablets and content uniformity values were within the USP limits (Table 2). Figure 1. Drug Dissolution Profiles
100 90 80 70 60 50 40 30 20 10 0 0 2

Drug Released (%)

Natrilix SR tablets Formulation A Formulation B

10 12 14 Time (hours)

16

18

20

22

24

Drug release profiles were compared using F2 metric test5,6. An F2 value between 50 and 100 indicates similarity between two dissolution profiles. The HyperStart formulation A was compared to the reference product and an F2 value of 70 was obtained indicating similarity. Formulations A and B were compared to assess the effect of filler type on the release profiles; an F2 result of 83.5 indicates that changing the filler type did not affect drug release behaviour from these matrices. The release profiles were analysed using the power law model to determine drug release mechanism7. Mt/Minf = ktn An n value of 0.5 indicates diffusion and a value of 1.0 indicates erosion control. Values of 1.014, 0.834 and 0.771 were obtained for Natrilix SR, formulations A and B, respectively. These values indicated that erosion was the primary mechanism of drug release from all these formulations.

Conclusions Extended release matrices containing the low dose, practically insoluble drug, indapamide were successfully manufactured by direct compression. Tablets with good physical characteristics, weight and content uniformities, reproducible and desired drug release profiles were successfully produced in both formulations A and B. The choice of filler did not significantly affect the drug release profile in this study.

References 1. Slow release HPMC matrix systems ; Rajabi-Siahboomi, A. R., and Jordan, M.P. (2000) European Pharmaceutical Review 5: 21-23. 2. Martindale Pharmaceutical Press, London, UK 3. Colorcon technical literature 2004 4. The United States Pharmacopeia, The United States Pharmacopeial Convention, Inc., Rockville, MD, 2004 5. Dissolution testing of immediate release oral solid dosage forms, FDA Guidance for Industry (1997) 6. Extended release oral dosage forms, scale up and post approval changes (SUPAC-MR), FDA Guidance for Industry (1997) 7. Spiepmann J, Peppas NA (2001). Modelling of Drug Release from Delivery Systems Based on Hydroxypropyl Methylcellulose (HPMC). Adv. Drug Deliv. Rev. 48: 139-157

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The information contained herein, to the best of our knowledge is true and accurate. Any recommendations or suggestions are made without warranty or guarantee, since the conditions of use are beyond our control. Any information contained herein is intended as a recommendation for use of our products so as not to infringe on any patent. Colorcon, 2005. The information contained in this document is proprietary to Colorcon and may not be used or disseminated inappropriately. HyperStart is a registered trademark of Colorcon Inc. Methocel* is a registered trademark of The Dow Chemical Company. Natrilix is a registered trademark of Servier. Aerosil is a registered trademark of Degussa AG. Fast Flo is a registered trademark of Foremost Farms. Avicel is a registered trademark of FMC. mr/aaps2005/gliclazide_fp.mle/11.2005