Protection of Core Tablets Using a Novel Undercoating System and

Protection of Core Tablets Using a Novel
Undercoating System and Common Enteric
Polmer System
Joe Cobb, Brad Gold, PhD., Mike Schulz, Jennifer Alligood
OBJECTIVE
To demonstrate the effectiveness of a novel subcoat to protect core tablets containing
an acid-labile active pharmaceutical ingredient (API “X”) from a methacrylic acid
copolymer enteric coat.
BACKGROUND
Protection of certain API’s from the acidic environment of the stomach is a wellrecognized practice with solid oral drug delivery systems for many different reasons.
Typical drug delivery systems include hard gelatin capsules filled with coated particles
and monolithic tablets, each containing API’s. For some drug products such as aspirin,
the protection is required due to irritation of the stomach lining by the API itself. For other
drug products, protection is required because of a degradation pathway catalyzed by the
presence of excess hydrogen ions. Enteric polymers such as methacrylic acid
copolymer, type C, donate limited quantities of hydrogen ions when exposed to aqueous
media during dissolution testing or during storage under elevated controlled humidity
conditions. It is believed that migration of the excess hydrogen ions from the enteric
coating into the dosage form during storage causes undesirable degradation of the drug
substance. Mitigation of the degradation pathway can be accomplished by inclusion of
an alkalinizing agent and the inclusion of a barrier coat between the core tablet and the
acidic enteric coating.
METHODOLOGY
Materials
Active Pharmaceutical Ingredient (API) X, supplied by client
Avicel ® Microcrystalline Cellulose, NF, various PH grades donated and supplied by
FMC
Lactose Monohydrate, NF, various grades supplied by Foremost
Magnesium Hydroxide DC (Starch), supplied by SPI Pharma
Explotab ® (Sodium Starch Glycolate, NF), supplied by JRS Pharma
Cab-o-Sil® M5P (Colloidal Silicon Dioxide, NF), supplied by Cabot
Magnesium Stearate, NF, (non-bovine), supplied by Mallinckrodt
Opadry® II Y-30-18037 White, supplied by Colorcon
Acryleze® 93F19255 Clear, supplied by Colorcon
HDPE bottles, 60 cc
Polypropylene Caps, 33 mm, Child Resistant, Induction Seal
Silica Gel Desiccant Packs, 1.5 g
Page 1 Equipment (Manufacturing and Analytical)
Key KG-5 Vertical Shaft High-Shear Mixer
20-mesh Hand Screen
8 quart Twinshell Blender
Powtec Roller Compactor with Inline Scraper Mill and Separator
Manesty Betapress with Variable Speed Feed Frame
O’Hara Coating Pan with 15” side vented insert
Hitachi 7000 Series Gradient HPLC System with Shisheido Capcell Pak SG C18
Column, 4.6 mm x 250 mm, 5 µm
Cary 300 Bio UV-Visible Spectrophotometer
Olympus Model C2020Z Digital Camera
Formulation Rationale
Choices for excipients for core tablets centered on compatibility studies conducted by
client prior to formulation development at Metrics. Excipients that are considered acidic
were avoided in favor of those that are neutral/alkaline or insoluble in aqueous media.
For the 40 mg core tablet formulation, impalpable grades of intragranular excipients
were preferred because of the inherent design characteristics of the roller compaction
equipment. Extragranular excipients for the 40 mg tablets were chosen based on the
need for enhanced flowability. For the 5 mg core tablet formulation, all excipients were
chosen based on the same need for enhanced flowability. The alkalinizing agent used
for both core tablet formulations is a non-compendial grade of magnesium
hydroxide/starch that was specified by the client.
Numerous patents (US Patent 4853230, Lovgren, et al., etc.) cite the inclusion of a
barrier layer between a substrate particle or dosage form and a functional coating that
may actually serve to degrade the drug being delivered. The novelty of these
formulations lie in the choice of the subcoating material, Opadry II Y-30-18037, not
previously considered a suitable candidate for such an application. Acryleze 93F19255
was recommended based on its relative lack of acidity in applications where acidity
causes degradation.
Manufacturing Procedures for 5 mg Core Tablets
API (X), Avicel PH 102, Magnesium Hydroxide/Starch, and Explotab were pre-blended in
a high-shear granulator. The pre-blend was then screened and combined with screened
Lactose 316, Cab-o-Sil, and Magnesium Stearate in a low shear tumble blender.
The blend was compressed into tablets on a rotary tablet press equipped with the
following tooling:
4 sets of 7.0 mm round standard concave tooling (bisected upper punch), size ‘B’, and
12 blanks
Core tablets intended for coating were required to have a maximum friability of 0.5%,
mean hardness target range of 6-11 kp, and a disintegration time using standard USP
apparatus of less than 2 minutes.
Page 2 Manufacturing Procedures for 40 mg Core Tablets
API (X), Avicel PH 101, and Explotab were pre-blended in a high-shear granulator. The
pre-blend was then screened and combined with screened Lactose 312 and 1/3 of the
total level of Magnesium Stearate in a low shear tumble blender. This blend was then
put through the roller compactor with the following settings:
Roller RPM: Target 4 RPM
Roller Pressure: Target 200 bar
Mill Screen Size (opening): Target 1.25 mm
Mill Speed: Target 150 RPM
Separator Screen: Target 80 mesh
Material designated as fines was recycled until a minimal amount remained. All
acceptable granulated material was collected and reconciled for yield calculation.
Recalculation of extragranular excipient amounts to be dispensed was necessary if the
acceptable product yield from roller compaction was <97%. All acceptable granulated
material was then combined with screened extragranular Lactose 316 and Avicel PH
102, Magnesium Hydroxide/Starch, Cab-o-Sil, and the remaining Magnesium Stearate in
a low shear tumble blender.
The blend was compressed into tablets on a rotary tablet press equipped with the
following tooling:
4 sets of 3/8” round standard concave tooling, size ‘B’, and 12 blanks
Core tablets intended for coating were required to have a maximum friability of 0.5%,
mean hardness target range of 6-11 kp, and a disintegration time using standard USP
apparatus of less than 2 minutes.
Manufacturing Procedures for Subcoating and Enteric Coating of 5 mg and 40mg
Core Tablets
Core tablets were placed in an O’Hara standard side-vented 15” coating pan and
undercoated with Opadry II Y-30-18037 White using the following setup and operating
parameters:
Inlet Air Volume: Target 160-250 cfm
Inlet Air Temperature: Target 60-65°C
Suspension Spray Rate: Target 15-20 mL/min
Pan Speed: Target 16-20 RPM
Target Exhaust Temp: Target 46-50°C
Atomization Air Pressure: Target 20 psi
Pattern Air Pressure: Target 25 psi
Undercoated tablets were placed in the same coating pan and overcoated with Acryleze
93F19255 Clear using the following setup and operating parameters:
Inlet Air Volume: Target 160-250 cfm
Inlet Air Temperature: Target 60-65°C
Suspension Spray Rate: Target 15-20 mL/min
Pan Speed: Target 16-20 RPM
Page 3 Target Exhaust Temp: Target 46-50°C
Atomization Air Pressure: Target 20 psi
Pattern Air Pressure: Target 25 psi
See Figures 1 and 2 for over coated tablet photomicrographs. Overcoated tablets of both
5 mg and 40 mg strengths were packaged for stability. Packaging consisted of 50 tablets
per bottle with two 1.5 g silica gel desiccant packs per bottle, induction-sealed with a
child resistant cap.
Figure 1 – Side View of Sliced 5 mg Overcoated Tablet
Figure 2 – Side View of Sliced 40 mg Overcoated Tablet
RESULTS
Characterization of the core tablet manufacturing process consisted of physical testing in
process during compression. Results for in process testing for both 5 mg core tablets
and 40 mg core tablets are given in Table 1.
Page 4 Table 1 – Summary of In-Process Testing for Core Tablets
5 mg Core Tablets
40 mg Core Tablets
Hardness (kp)
Target 6 – 11 kp
Beginning = 6.5
Middle = 8.0
End = 8.1
Beginning = 7.2
Middle = 8.5
End = 8.7
Friability (% loss)
Target < 0.5%
Beginning = 0.014
Composite = 0.153
Beginning = 0.103
Composite = 0.089
USP
Disintegration
(Mean Time)
Target < 10
minutes
Beginning = 36 seconds
Composite = 32 seconds
Beginning = 30 seconds
Composite = 27 seconds
Individual Weight
Checks (mg)
Low Weight = 180.6
High Weight = 188.3
Low Weight = 344.1
High Weight = 368.2
Overcoated tablets of both 5 mg and 40 mg strengths were tested initially and at 2
weeks and 6 weeks under accelerated (40°C / 75% RH) conditions. The results for
assay values are presented in Table 2, the results for acid resistance in USP Apparatus
II using 0.1N HCl are presented in Table 3. The results for neutral media dissolution in
USP Apparatus II, using pH 6.8 Phosphate buffer with 0.22% w/w Sodium Lauryl Sulfate
are presented in Figures 3 and 4.
Table 2 – Assay Values for 5 mg and 40 mg Overcoated Tablets on Stability
Specifications = 90.0 - 110.0% of label claim
Initial (Twin preparations)
5 mg Tablets
(% label claim)
94.1, 94.1
40 mg Tablets
(% label claim)
97.2, 100.3
2 week
92.2
96.5
6 week
92.1
98.0
Table 3 – Acid Resistance Values for 5 mg and 40 mg Overcoated Tablets on Stability
Specifications = NMT 10% label claim dissolved after 2 hrs
Initial
5 mg Tablets
Individual Values
(% label claim dissolved)
0, 0, 0, 3, 0, 3
40 mg Tablets
Individual Values
(% label claim dissolved)
1, 1, 2, 2, 1, 1
2 week
0, 0, 1, 0, 0, 0
1, 0, 0, 0, 0, 0
6 week
4, 5, 3, 3, 3, 3
0, 0, 0, 0, 0, 0
Page 5 Initial
5 mg Tablets
Individual Values
(% label claim dissolved)
0, 0, 0, 3, 0, 3
40 mg Tablets
Individual Values
(% label claim dissolved)
1, 1, 2, 2, 1, 1
2 week
0, 0, 1, 0, 0, 0
1, 0, 0, 0, 0, 0
6 week
4, 5, 3, 3, 3, 3
0, 0, 0, 0, 0, 0
Figure 3 - Accelerated Stability Dissolution Data for 5
mg Overcoated Tablets in Neutral Buffer
Percent Dissolved
100
80
Initial
60
2 Weeks
40
6 Weeks
20
0
0
20
40
60
80
Time (minutes)
Figure 4 - Accelerated Stability Dissolution Data for 40
mg Overcoated Tablets in Neutral Buffer
Percent Dissolved
100
80
Initial
60
2 Weeks
40
6 Weeks
20
0
0
20
40
60
80
Time (minutes)
CONCLUSIONS
BasedCONCLUSIONS
on the ongoing stability data, the novel subcoating system has helped protect the
acid-labile
API
the acidic
enteric
Further
studiessystem
will behas
necessary
to examine
Based
on from
the ongoing
stability
data,coat.
the novel
subcoating
helped protect
the
the effect
of alkalinizing
levels
andcoat.
other
formulation
processing
acid-labile
API from agent
the acidic
enteric
Further
studiesand
will be
necessary to examine
the effect of alkalinizing agent levels and other formulation and processing
considerations.
considerations.
Page 6