a case study of using common low moisture fillers in the ... · a case study of using common low...
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A Case Study of Using Common Low Moisture Fi l lers in the Rol ler Compacted Tablets
Anshul Gupte, Charles Reynolds, Jerry Mizell, Russell Branch, Brian Warren, Wayne Jefferson, Brad Gold OBJECTIVE The aim of this study was to compare the benefit of using common low moisture grade pharmaceutical excipients: Mannitol, NF (Grades: Pearlitol® 300 DC, Pearlitol® 160c) (Roquette) and/or Microcrystalline Cellulose, NF (Grades: Avicel® PH-‐200 LM, Avicel ® PH 112) (FMC Corp.) as fillers in a tablet formulation to limit the moisture uptake by a model hygroscopic drug manufactured with a roller compaction process. INTRODUCTION The model compound (X) is highly compressible with poor flow properties. Moreover, it is not suited for a direct blend process, without increasing the tablet size to one larger than deemed acceptable. Amongst the means used to affect densification of a blended formulation are various forms of granulation: notably low-‐shear or high-‐shear wet granulation or roller compaction. In the cases where the Active Pharmaceutical Ingredient (API) has exhibited chemical or polymorphic instability in water or other common wet granulation solvents, the process of roller compaction is preferred. METHODOLOGY The study focuses on the use of two commonly used pharmaceutical fillers/diluents: Pearlitol ® (Mannitol) or Avicel ® (Microcrystalline Cellulose). In order to illustrate the differences between Avicel and Mannitol as fillers with respect to moisture uptake by the drug in the tablet dosage form, various tablet formulations were manufactured, most notably containing either Avicel (100%), or Avicel/Mannitol (75/25%) or Avicel/Mannitol (25/75%) as fillers/diluents. It should be noted that Mannitol was always used as an intra-‐granular filler, while Avicel was used either as intra-‐granular or as extra-‐granular filler. The tablets were stored for long term under two stability conditions: 25°C/60% RH or 40°C/75% RH in calibrated and under ICH storage conditions stability chambers. The tablets were analyzed at initial, 3 and 7 months of storage for Assay and Impurity levels (by HPLC), Moisture (by Karl Fisher), Dissolution (by USP Apparatus and HPLC detection). Additionally any thermal changes in the drug were tracked with Differential Scanning Calorimetry (DSC) at initial, 3 and 7 months of stability storage.
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Manufacturing Equipment 30-‐mesh Hand Screen or VortiSiv 15� sifter with 20 mesh screen Twin shell or Tote Blenders Roller Compactor (Powtec or Fitzpatrick L-‐83) Quadro Comil Globe Pharma Mini Press Analytical Equipment Vankel Tap Density Tester Hanson Flodex Flowability Tester USP Apparatus 2 Dissolution Bath
Figure 1: Roller Compaction/Granulation Process Flow Diagram
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Figure 2: List of Ingredients for Roller Compaction Process
Functionality
Amounts per Tablet
Amounts per Tablet (%)
Amounts per Tablet (mg)
Intra-‐granular Ingredients
Compound X Active Pharmaceutical ingredient
33.3 100.0
Mannitol NF (Pearlitol® 160c) and/or Avicel PH 112 Diluent
Varied Varied
Colloidal Silicon Dioxide, NF Glidant 0.25 0.750
Magnesium Stearate, NF (Non-‐bovine Hyqual®) Lubricant
0.5 1.500
Extra-‐granular Ingredients
Mannitol NF (Pearlitol® 300DC) and/or Avicel PH 200 LM Diluent
Varied Varied
Colloidal Silicon Dioxide, NF Glidant 0.25 0.750
Magnesium Stearate, NF (Non-‐bovine Hyqual®) Lubricant
0.5 1.500
Total 100.0 300.0
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RESULTS Figure 3: Comparison of Physical Attributes of Various Blends Manufactured with Combinations of
Diluents
Formulation 100% Avicel®
75/25% (Avicel®/ Pearlitol®)
50/50% (Avicel®/ Pearlitol®)
25/75% (Avicel®/ Pearlitol®)
100% Pearlitol®
Flow Dex 8 (Very Good)
4 (Excellent)
5 (Excellent)
16 (Poor)
8 (Very Good)
Bulk Density (g/mL) 0.5 0.5 0.54 0.57 0.4
Tap Density (g/mL) 0.6 0.65 0.7 0.76 0.56
Carr’s Index 22.9 21.5 22.9 25.0 21.4
% Fines 29.0 30.4 20.7 30.4 14.0
Loss on Drying (%) 3.2 2.5 2.1 1.0 0.6
• Avicel (100%): Intra-‐granular: Avicel PH 112. Extra-‐granular: Avicel PH 200 LM • Avicel/Mannitol (75/25%): Intra-‐granular: Avicel PH 112 + Pearlitol 160 c. Extra-‐
granular: Avicel PH 200 LM • Avicel/Mannitol (50/50%): Intra-‐granular: Pearlitol 160 c. Extra-‐granular: Avicel PH 200
LM • Avicel/Mannitol (25/75%):Intra-‐granular: Pearlitol 160 c. Extra-‐granular: Avicel PH 200
LM + Pearlitol 300 DC • Pearlitol (100%): Intra-‐granular: Pearlitol 160 c. Extra-‐granular: Pearlitol 300 DC
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Figure 4: Comparison of Tablet Formulation Before and After 7-‐month Accelerated Stability Study
Figure 5: Thermogram of Tablet formulations after 7-‐month Accelerated Stability Study
19 ± 1.440 ± 0.462 ± 2.840°C/75% RH
58 ± 2.071 ± 2.4
70 ± 0.765 ± 8.6
78 ± 2.777 ± 2.9
25°C/60% RHDissolution (%)
(@ 15minutes)
94.895.191.1 40°C/75% RH97.2
99.690.3
98.991.0
99.525°C/60% RH
Assay (%)
1.4 ± 0.23.2 ± 0.24.1 ± 0.140°C/75% RH
1.3 ± 0.12.5
3.1 ± 0.24.0
3.8 ± 0.24.0
25°C/60% RHMoisture (%w/w)
7 monthsInitial7monthsInitial7 monthsInitial
Avicel/Mannitol(25/75%)
Avicel/Mannitol(75/25%)
Avicel(100%)
19 ± 1.440 ± 0.462 ± 2.840°C/75% RH
58 ± 2.071 ± 2.4
70 ± 0.765 ± 8.6
78 ± 2.777 ± 2.9
25°C/60% RHDissolution (%)
(@ 15minutes)
94.895.191.1 40°C/75% RH97.2
99.690.3
98.991.0
99.525°C/60% RH
Assay (%)
1.4 ± 0.23.2 ± 0.24.1 ± 0.140°C/75% RH
1.3 ± 0.12.5
3.1 ± 0.24.0
3.8 ± 0.24.0
25°C/60% RHMoisture (%w/w)
7 monthsInitial7monthsInitial7 monthsInitial
Avicel/Mannitol(25/75%)
Avicel/Mannitol(75/25%)
Avicel(100%)
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CONCLUSIONS
• The assay of drug after 7 months storage at both 25°C/60% RH and 40°C/75% RH was Avicel/Mannitol (25/75%) > Avicel/Mannitol (75/25%) > Avicel (100%), which indicated that Mannitol as a diluent in comparison to Avicel better protected the drug against degradation over long term stability storage.
• The above result was further supported by the amount of moisture present in the tablets at 7 months storage: Avicel/Mannitol (25/75%) < Avicel/Mannitol (75/25%) < Avicel (100%).
• The lowest initial dissolution rate after 7 month storage was observed for the Avicel/Mannitol (25/75%) formulation.
• The above results suggest that Mannitol as a diluent offers moisture barrier and protect the drug from degradation.