Protection of Core Tablets Using a Novel Undercoating ... · Core tablets intended for coating were required to have a maximum friability of 0.5%, mean hardness target range of 6-11

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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 well-recognized 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

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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.

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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

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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.

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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

5 mg Tablets (% label claim)

40 mg Tablets (% label claim)

Initial (Twin preparations) 94.1, 94.1 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

5 mg Tablets

Individual Values (% label claim dissolved)

40 mg Tablets Individual Values

(% label claim dissolved) Initial 0, 0, 0, 3, 0, 3 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

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CONCLUSIONS Based on the ongoing stability data, the novel subcoating system has helped protect the acid-labile API from the acidic enteric coat. Further studies will be necessary to examine the effect of alkalinizing agent levels and other formulation and processing considerations.

W4107 PROTECTION OF CORE TABLETS USING A NOVEL UNDERCOATING SYSTEM AND COMMON ENTERIC POLMER SYSTEM Joe Cobb, Brad Gold, PhD., Mike Schulz, Jennifer Alligood Metrics, Inc., 1240 Sugg Parkway, Greenville, NC 27834

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 well-recognized 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 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 !m 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.

Figure 1 – Side View of Sliced 5 mg Overcoated Tablet

Figure 2 – Side View of Sliced 40 mg Overcoated Tablet

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 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.

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.

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

5 mg Tablets (% label claim)

40 mg Tablets (% label claim)

Initial (Twin preparations) 94.1, 94.1 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

5 mg Tablets

Individual Values (% label claim dissolved)

40 mg Tablets Individual Values

(% label claim dissolved) Initial 0, 0, 0, 3, 0, 3 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

0

20

40

60

80

100

0 20 40 60 80

Time (minutes)

Per

cent

Dis

solv

ed

Initial2 Weeks6 Weeks

Figure 4 - Accelerated Stability Dissolution Data for 40 mg Overcoated Tablets in Neutral Buffer

0

20

40

60

80

100

0 20 40 60 80

Time (minutes)

Per

cent

Dis

solv

ed

Initial2 Weeks6 Weeks

CONCLUSIONS Based on the ongoing stability data, the novel subcoating system has helped protect the acid-labile API from the acidic enteric coat. Further studies will be necessary to examine the effect of alkalinizing agent levels and other formulation and processing considerations.