Direct compression and dry granulation processes for preparing carglumic acid tablets having less impurities than those produced by wet granulation process
Inventors
Kawale, Sanjay Rangnathrao • Patel, Mahendra R.
Assignees
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Publication Number
US-10064826-B2
Publication Date
2018-09-04
Expiration Date
Abstract
The invention provides a process for preparing stable, high API content, solid pharmaceutical dosage forms by direct compression or dry granulation, characterized in that the pharmaceutical tablets rapidly disintegrate in water or other aqueous solutions to produce a clear or almost clear solution. Also provided is a pharmaceutical carglumic acid tablet, which has improved manufacturing, dissolution, and stability properties, and is less expensive to produce, compared to the equivalent commercial product.
Core Innovation
The invention relates to stable, high-API-content carglumic acid dispersible tablets prepared by dry processes, including direct compression and dry granulation, instead of wet granulation. The tablets are produced by dry mixing a composition comprising carglumic acid with a cellulosic filler, then adding lubricant for blending and compressing to form a tablet.
The invention is directed to selecting cellulosic fillers such as microcrystalline cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, carboxymethylcellulose, methylcellulose, powdered cellulose, hydroxyethyl cellulose, and combinations thereof, for forming a blend with carglumic acid that is then dry mixed with a lubricant and compressed. Additional dry blending components such as anhydrous colloidal silicon dioxide and sodium lauryl sulfate may be included in the mixing sequence, and sodium stearyl fumarate may be included as a lubricant.
The invention addresses an impurity and stability problem arising from wet granulation and oven drying, which are stated to degrade hygroscopic carglumic acid and to cause higher impurities and poorer stability. In contrast, the dry processes are stated to maintain low levels of hydantoin-5-propionic acid (5-HPA) under accelerated and room-temperature storage when packaged with desiccant, and the tablets are characterized by rapid disintegration in water, producing clear or almost clear aqueous solutions.
Claims Coverage
The document provides two independent processes directed to preparing carglumic acid tablets with sealed, desiccant-containing storage and a stability requirement expressed as at least an order of magnitude less hydantoin-5-propionic acid versus a comparable wet-granulated tablet after specified storage. Across the two independent claims, the main inventive features include dry mixing with specified cellulosic filler selection, adding lubricant and optionally additional dry excipients, compressing to form a tablet, and sealing in a container with a dessicant unit to control hydantoin-5-propionic acid levels after storage at 50° C for 21 days.
Dry mixing with carglumic acid and a specified cellulosic filler blend
Dry mixing a composition comprising about 30 w/w % to about 50 w/w % of carglumic acid and about 40% w/w to about 60% w/w of a cellulosic filler to form a blend, wherein the cellulosic filler is selected from a group consisting of microcrystalline cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium, silicified microcrystalline cellulose, carboxymethylcellulose, methylcellulose, powdered cellulose, hydroxyethyl cellulose, and combinations thereof.
Dry mixing with lubricant and compressing to form a tablet
Dry mixing the blend with about 0.5% to about 2.5% by weight of a lubricant, and compressing the blend to form a tablet.
Sealing the tablet with a dessicant unit and achieving reduced hydantoin-5-propionic acid versus wet granulation
Sealing the tablet in a container with a dessicant unit, wherein the tablet contains at least an order of magnitude less hydantoin-5-propionic acid than a comparable tablet produced by wet granulation after each tablet is stored in a sealed container having desiccant at a temperature of 50° C. for 21 days.
Direct compression tablet composition with defined ranges of excipients
Dry mixing a composition consisting essentially of carglumic acid in an amount of from about 30.0% to about 70.0% by weight of the tablet, microcrystalline cellulose in an amount of from about 30.0% to about 75.0% by weight of the tablet, croscarmellose sodium in an amount of from about 2% w/w to about 8% by weight of the tablet, and hydroxypropylmethyl cellulose in an amount of from about 0.3% to about 2.0%, by weight of the tablet.
Dry mixing additional dry components and compressing to form a tablet
Dry mixing the blend with anhydrous colloidal silicon dioxide in an amount of from about 0.1% to about 1.0% by weight of the tablet and sodium lauryl sulfate in an amount of from about 0.05% w/w to about 0.5% w/w by weight of the tablet; dry mixing the blend with sodium stearyl fumarate in an amount of from about 0.5% to about 2.5% by weight of the tablet; and compressing the blend to form a tablet.
Sealing the direct compression tablet with a dessicant unit and reduced hydantoin-5-propionic acid versus wet granulation
Sealing the tablet in a container with a dessicant unit, wherein the tablet contains at least an order of magnitude less hydantoin-5-propionic acid than a comparable tablet produced by wet granulation after each tablet is stored in a sealed container having desiccant at a temperature of 50° C. for 21 days.
Across the independent claims, claim coverage centers on preparing carglumic acid tablets by dry mixing and compressing, using selected cellulosic fillers and, for the direct compression embodiment, defined excipient components and ranges, then sealing the tablets in containers with a dessicant unit to achieve at least an order of magnitude reduction in hydantoin-5-propionic acid versus a comparable wet-granulated tablet after sealed desiccant storage at 50° C. for 21 days.
Stated Advantages
Improved stability, with reduced hydantoin-5-propionic acid levels under accelerated and room-temperature storage when packaged with desiccant.
Improved manufacturing simplicity and reduced cost versus wet granulation.
Rapid disintegration in water, producing clear or almost clear aqueous solutions.
Improved stability up to 6 months at room temperature versus a commercial CARBAGLU that requires refrigeration and has limited room-temp stability after opening.
Documented Applications
Pharmaceutical carglumic acid tablet preparation, including carglumic acid dispersible tablets and pharmaceutically acceptable carglumic acid direct compression tablets, characterized by rapid disintegration to produce clear or almost clear aqueous solutions.
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