Minimizing agglomeration, aeration, and preserving the coating of pharmaceutical compositions comprising ibuprofen
11077067 · 2021-08-03
Assignee
Inventors
- Rosaleen MCLAUGHLIN (Swindon, GB)
- Simon Andrew Martyn HOWES (Swindon, GB)
- Craig WHEADON (Swindon, GB)
- Jonathon WHITEHOUSE (Herne Bay, GB)
- Adam PARKER (Swindon, GB)
Cpc classification
A61K9/5063
HUMAN NECESSITIES
A61K31/192
HUMAN NECESSITIES
A61K9/5073
HUMAN NECESSITIES
A61K47/26
HUMAN NECESSITIES
A61K47/44
HUMAN NECESSITIES
A61K9/19
HUMAN NECESSITIES
A61K47/42
HUMAN NECESSITIES
A61K9/2081
HUMAN NECESSITIES
A61K9/0056
HUMAN NECESSITIES
International classification
A61K9/50
HUMAN NECESSITIES
A61K9/19
HUMAN NECESSITIES
A61K47/36
HUMAN NECESSITIES
A61K47/42
HUMAN NECESSITIES
A61K47/44
HUMAN NECESSITIES
A61K47/26
HUMAN NECESSITIES
Abstract
Provided are pharmaceutical compositions and methods for preparing pharmaceutical compositions comprising Ibuprofen using solventless mixing methods. Excess coating material that is not bound to coated Ibuprofen may be removed by a sieving process. Coating and dosing ratios can also be optimized to minimize the amount of excess unbound coating material. Additionally, the compositions can be formulated to preserve the functional coating of coated Ibuprofen and to minimize aeration of Ibuprofen when mixed into suspension.
Claims
1. A pharmaceutical composition comprising: more than 75% w/w coated API, wherein the API coating comprises a first coating material and 0.5-5% w/w silica surrounding, partially embedded in, and/or embedded in the first coating material; 3-7% w/w matrix former; 2-6% w/w structure former; 0.1-2% w/w anti-aerating agent; and 0.01-0.2% w/w viscosity modifier.
2. The pharmaceutical composition of claim 1, wherein the first coating material comprises 10-30% w/w of the coated API.
3. The pharmaceutical composition of claim 1, wherein the first coating material comprises a wax.
4. The pharmaceutical composition of claim 3, wherein the first coating material comprises one or more of carnauba wax, synthetic wax, or candelilla wax.
5. The pharmaceutical composition of claim 1, wherein the matrix former comprises one or more of a water soluble material, a water dispersible material, a polypeptide, a polysaccharide, a polyvinyl alcohol, a polyvinylpyrrolidone, and an acacia.
6. The pharmaceutical composition of claim 5, wherein the matrix former comprises a polypeptide.
7. The pharmaceutical composition of claim 6, wherein the polypeptide comprises gelatin.
8. The pharmaceutical composition of claim 1, wherein the structure former comprises one or more of mannitol, dextrose, lactose, galactose, and cyclodextrin.
9. The pharmaceutical composition of claim 8, wherein the structure former comprises mannitol.
10. The pharmaceutical composition of claim 1, wherein the viscosity modifier comprises xanthan gum.
11. The pharmaceutical composition of claim 1, wherein the anti-aerating agent comprises one or more of a terpene or a terpinol.
12. The pharmaceutical composition of claim 11, wherein the anti-aerating agent comprises limonene.
13. The pharmaceutical composition of claim 1, wherein the anti-aerating agent comprises one or more of orange flavor, lemon flavor, grapefruit flavor, lime flavor, strawberry flavor, or peppermint flavor.
14. The pharmaceutical composition of claim 1, further comprising a sweetener.
15. The pharmaceutical composition of claim 1, wherein the API comprises Ibuprofen.
16. A method of preparing a pharmaceutical composition comprising: forming a pharmaceutical suspension comprising: 30-50% w/w a coated API, wherein the API coating comprises a first coating material and 0.5-5% w/w silica surrounding, partially embedded in, and/or embedded in the first coating material; 50-70% w/w a matrix solution or suspension comprising: 1-5% w/w a matrix former; 0.5-4% w/w a structure former; 0.01-0.1% w/w a viscosity modifier; 0.1-1% w/w an anti-aerating agent; and a solvent; dosing the pharmaceutical suspension into a mold; freezing the pharmaceutical suspension in the mold; and freeze drying the dosed pharmaceutical suspension in the mold to form the pharmaceutical composition.
17. The method of claim 16, wherein the first coating material comprises 10-30% w/w of the coated API.
18. The method of claim 16, wherein the first coating material comprises one or more of carnauba wax, synthetic wax, or candelilla wax.
19. The method of claim 16, wherein the matrix former comprises gelatin.
20. The method of claim 16, wherein the structure former comprises mannitol.
21. The method of claim 16, wherein the viscosity modifier comprises xanthan gum.
22. The method of claim 16, wherein the anti-aerating agent comprises one or more of a terpene or a terpinol.
23. The method of claim 22, wherein the anti-aerating agent comprises limonene.
24. The method of claim 16, wherein the matrix solution or suspension comprises a sweetener.
25. The method of claim 16, wherein the API comprises Ibuprofen.
26. The method of claim 16, wherein the solvent comprises water.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) The invention will now be described, by way of example only, with reference to the accompanying drawings, in which:
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DETAILED DESCRIPTION
(20) Described herein are exemplary embodiments of methods for minimizing and/or preventing the agglomeration of the coating material of coated Ibuprofen, methods for preserving the coating of coated Ibuprofen, and methods of minimizing aeration of Ibuprofen in a pharmaceutical suspension. Also described are pharmaceutical compositions comprising Ibuprofen prepared by any one or more of the disclosed methods. Each of these methods and pharmaceutical compositions are described in detail below. Pharmaceutical compositions comprising Ibuprofen may be prepared using any combination of features from the preparation methods described below.
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(22) For example,
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(24) In some embodiments, one or more of the coating materials may not be deformable but may be embedded in the deformable coating layer. Thus, the continuous film may comprise solid particles of the non-deformable material embedded within the deformed coating material.
(25) As used herein, the terms “deformable”, “deformable components”, “deformable components of the coating material” and other related terms refer to one or more components of the water soluble, water swellable, and/or water insoluble materials that can be broken down when subjected to mechanical stress and/or elevated temperature.
(26) In some embodiments, the coated API particles may comprise Ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise from 30.0 to 90.0% w/w Ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise from 40.0 to 85.0% w/w, from 50.0 to 80.0% w/w, or from 70.0 to 80.0% w/w Ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise more than 40.0% w/w, more than 50.0% w/w, more than 60.0% w/w, more than 65% w/w, more than 70.0% w/w, more than 75.0% w/w, more than 80.0% w/w, or more than 85.0% w/w Ibuprofen. In some embodiments, the coated API particles or pharmaceutical composition may comprise less than 90.0% w/w, less than 85.0% w/w, less than 80.0% w/w, less than 75.0% w/w, less than 70.0% w/w, less than 60.0% w/w, less than 50.0% w/w, or less than 40.0% w/w Ibuprofen.
(27) Coating 104 surrounding the API particle 102 may comprise materials including a water soluble and/or water swellable material and a water insoluble material. In some embodiments, this coating may coat an API particle (e.g., Ibuprofen) directly, or it may coat an API particle already comprising one or more coatings. In some embodiments, the ratio of coating material to API may be optimized to minimize excess coating material. For example, the coating material may comprise 5-85% w/w, 10-50%, 15-30% of the API and coating material mixture or pharmaceutical composition. In some embodiments, the coating material may comprise less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, or less than 10% of the API and coating material mixture or pharmaceutical composition. In some embodiments, the coating material may include more than 5%, more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, or more than 75% of the API and coating material mixture or pharmaceutical composition. In some embodiments, the coating material percentage may include two or more layers of coating material.
(28) The water swellable material of the coating material may be a particle comprising a median particle size of about 0.5 μm to about 20 μm or about 1 μm to about 10 μm. In some embodiments, the water swellable material may be approximately ten times smaller than that of the Ibuprofen to enable ordered mixing and coating. The water swellable material can swell upon absorption of water such that a diameter of the water swellable particle increases at least by about 120-600%. The coating material or pharmaceutical composition may comprise from 0 to 8% w/w or from 0.1 to 0.9% w/w water swellable materials. In some embodiments, the coating material or pharmaceutical composition may comprise from 0.5 to 6.0% w/w, from 1.0 to 4.0% w/w, from 1.5 to 3.5% w/w, or from 2.0 to 3.0% w/w water swellable materials. In some embodiments, the coating material or pharmaceutical composition may comprise less than 8.0% w/w, less than 6.0% w/w, less than 4.0% w/w, less than 2.0% w/w, less than 1.0% w/w, or less than 0.5% w/w water swellable materials. In some embodiments, the coating material or pharmaceutical composition may comprise greater than 0.1% w/w, greater than 0.5% w/w, greater than 1.0% w/w, greater than 2.0% w/w, greater than 3.0 w/w %, greater than 5.0% w/w, or greater than 6.0% w/w water swellable materials. The water swellable material of the coating material may be deformable under mechanical stress and/or elevated temperature (described in detail below). The water swellable material may be any one or more of crospovidone, croscarmellose, sodium starch glycolate, or any other suitable disintegrant used in the pharmaceutical industry as an additive or blend made for tableting.
(29) The water soluble material of the coating material may also be a particle comprising a median particle size of about 0.5 μm to about 20 μm or about 1 μm to about 10 μm. In some embodiments, the water soluble material may be approximately ten times smaller than that of the Ibuprofen to enable ordered mixing and coating. The water soluble material may have a water solubility of at least about 50 mg/ml in water at a neutral pH and at 20° C. Further, the water soluble material can have an intrinsic dissolution rate of about 3-60 μg/m.sup.2s. The water soluble material of the coating material may be deformable under mechanical energy and/or thermal energy. The coating material or pharmaceutical composition may comprise from 0 to 35% w/w water soluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise from 0.5 to 25% w/w, from 1.0 to 15% w/w, from 1.5 to 10% w/w, or from 2.0 to 3.0% w/w water soluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise less than 35% w/w, less than 30% w/w, less than 25% w/w, less than 20% w/w, less than 15% w/w, less than 10% w/w, less than 5.0% w/w, less than 4.5% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, less than 1.0% w/w, or less than 0.5% w/w water soluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than 2.5% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 8.0% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25% w/w, or more than 30% w/w water soluble materials. The water soluble material may be one or more of sucrose, mannitol, sorbitol, polyvinylpyrrolidone, hydroxypropylcellulose, lactose, poly-(ethylene oxide), and any other suitable micronizable materials or polyols.
(30) In addition to an intrinsic dissolution rate of 3-60 μg/m.sup.2s discussed above, processes provided can permit the use of water soluble and/or water swellable materials having a higher intrinsic dissolution rate of about 60-300 μg/m.sup.2s as well. However, Ibuprofen with coating materials having a higher intrinsic dissolution rate should be dry coated with hydrophobic silica. Dry coating Ibuprofen wherein the coating comprises water soluble and/or water swellable materials having higher intrinsic dissolution rates can increase the disintegration time of the ibuprofen, such that they are incapable of masking the Ibuprofen's taste effectively. Accordingly, dry coating the Ibuprofen with silica as a second coating material to slow the dissolution rate can improve the in-vivo taste-masking performance of the coating. The coated Ibuprofen may comprise from 0.5 to 35% w/w silica. In some embodiments, the coated Ibuprofen or pharmaceutical composition can comprise from 0.5 to 20% w/w, from 0.5 to 10% w/w, or from 0.5 to 5% w/w hydrophobic fumed silica. In some embodiments, the coated Ibuprofen or pharmaceutical composition can comprise more than 0.5% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than 2.5% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25% w/w, or more than 30% w/w hydrophobic fumed silica. In some embodiments, the coated Ibuprofen or pharmaceutical composition can comprise less than 35% w/w, less than 25% w/w, less than 15% w/w, less than 10% w/w, less than 5.0% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w hydrophobic fumed silica. Examples of silica that may be used include, but are not limited to, Aerosil R972 silica (Degussa), CAB-O-SIL EH-5 silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan)), P-500 hydrophilic silica (Catalyst & Chemical Ind. Co. Ltd (Japan)), and TS5 silica (Cabot). Further, suitable devices that may be used to dry coat with silica include, but are not limited to, Comil (U3 Quadro Comil of Quadro Pa., U.S.), LabRAM (Resodyne Minn., U.S.), Magnetically Assisted Impact Coater (MAIC, Aveka Minn., U.S.), and Fluid Energy Mill (FEM, Qualification Micronizer of Sturtevant Mass. U.S.).
(31) A pharmaceutical composition may be prepared by dosing the pharmaceutical suspension into preformed blister packs. In some embodiments, a freeze-dried orally disintegrating tablet may be prepared by dosing the suspension into blister packs. In some embodiments, dosing pumps pump by volume, but the process is controlled by weight. Thus, to ensure content uniformity from one dosage form to the next, the dosing process may be controlled such that the volume-to-weight percentage of dosed suspension is consistent. For example, a volume-to-weight percentage may be consistent within 10 percent, within 8 percent, within 6 percent, within 5 percent, within 4 percent, within 3 percent, within 2 percent, within 1.5 percent, within 1 percent, within 0.5 percent, or within 0.25 percent. In some embodiments, the weight of the dosed pharmaceutical suspension is within 10 percent, within 8 percent, within 6 percent, within 5 percent, within 4 percent, within 2.5 percent, within 2 percent, within 1.5 percent, within 1 percent, within 0.5 percent, or within 0.25 percent of a target weight. Additionally, the viscosity of the pharmaceutical suspension should be kept low enough for ease of dosing. As described above, a high viscosity of the pharmaceutical suspension can case pump seizures during dosing.
(32) The water insoluble material of the coating materials may also be a particle comprising an average particle size less than that of the Ibuprofen. For example, the water insoluble material(s) may comprise an average particle size from about 1-20 μm, about 1-12 μm, about 2-10 μm, about 5-12 μm, or about 5-6 μm. In some embodiments, the water insoluble material may be approximately ten times smaller than that of the Ibuprofen to enable ordered mixing and coating. The water insoluble material of the coating material may be deformable under mechanical stress and/or elevated temperature. The coating material or pharmaceutical composition may comprise from 5 to 70% w/w, from 10 to 60% w/w, from 10 to 50% w/w, from 10 to 40% w/w, from 10 to 35% w/w, or from 15 to 30% w/w water insoluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise more than 5% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25% w/w, more than 30% w/w, more than 35% w/w, or more than 40% w/w water insoluble materials. In some embodiments, the coating material or pharmaceutical composition may comprise less than 70% w/w, less than 60% w/w, less than 50% w/w, less than 45% w/w, less than 40% w/w, less than 35% w/w, or less than 30% w/w water insoluble materials. Examples of suitable water insoluble materials include, but are not limited to ethylcellulose, polyethylene, polypropylene, polytetrafluoroethylene, carnauba wax, candelilla wax, castor wax, polyamide wax and/or synthetic wax.
(33) In some embodiments, mechanical and/or thermal energy may be used to deform the one or more water insoluble materials, water swellable materials, and/or water insoluble materials. For example, mechanical stress can be applied to the functionally-coated Ibuprofen using a PharmaRAM II acoustic mixer, a RAM 5 Pharma mixer, or a RAM 55 Pharma mixer (Resodyn Mixers). The coated Ibuprofen may be exposed to up to 100 times the force of gravity (100G acceleration) during this acoustic mixing process. These high forces cause particle-particle collisions that generate energy in the form of heat, which may be used to deform the one or more water insoluble materials, water swellable materials, and/or water insoluble materials onto the API.
(34) However, the coating process described above can also generate “loose”, or “free” coating material particles.
(35) Once sieved, the coated Ibuprofen can be mixed into a matrix solution/suspension to form a pharmaceutical suspension (e.g., coated Ibuprofen plus matrix solution/suspension) and dosed by weight into pockets of preformed blister packs to form aliquots of pharmaceutical suspension. Once dosed, the blister packs with aliquots pharmaceutical suspension are frozen under sub-zero conditions. The frozen aliquots of dosed pharmaceutical suspension is held frozen until it is ready for freeze drying during which the solvent of the pharmaceutical suspension is removed to form the pharmaceutical composition.
(36) The matrix solution/suspension may include a matrix former, a structure former, and a solvent. For example, the matrix former may include any water soluble or water dispersable material that is pharmacologically acceptable or inert to the functionally-coated Ibuprofen. In some embodiments, the matrix former may be a polypeptide such as gelatin. The gelatin may be at least partially hydrolyzed (by heating in water). Other suitable matrix former materials include, but are not limited to, polysaccharides such as hydrolyzed dextran, dextrin, and alginates, polyvinyl alcohol, polyvinylpyrrolidone, and/or acacia. In some embodiments, the amount of matrix in a pharmaceutical composition (e.g., an orally disintegrating tablet) may be 1-30% w/w. In some embodiments, the amount of matrix may be less than 30% w/w, less than 25% w/w, less than 20% w/w, less than 15% w/w, less than 10% w/w, less than 5% w/w, or less than 3% w/w. In some embodiments, the amount of matrix may be more than 1% w/w, more than 3% w/w, more than 5% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, or more than 25% w/w.
(37) In some embodiments, the amount of matrix former in a matrix solution/suspension or pharmaceutical suspension can be from about 0.1 to 10% w/w. In some embodiments, the amount of matrix former in the matrix solution/suspension or pharmaceutical suspension may include from 1.0 to 8.0% w/w or from 2.0 to 5.0% w/w. In some embodiments, the amount of matrix former in the matrix solution/suspension or pharmaceutical suspension may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 4.5% w/w, more than 5.0% w/w, or more than 8.0% w/w. In some embodiments, the amount of matrix former in the matrix solution/suspension or pharmaceutical suspension may include less than 10% w/w, less than 8.0% w/w, less than 6.0% w/w, less than 5.0% w/w, less than 4.0% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w. In some embodiments, the amount of matrix former in a pharmaceutical composition can be about 3-15% w/w, about 4-10% w/w, or about 4-7% w/w. In some embodiments, the amount of matrix former in the pharmaceutical composition may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 6.0% w/w, more than 7.0% w/w, more than 8.0% w/w, more than 9.0% w/w, more than 10.0% w/w, more than 11.0% w/w, more than 12.0% w/w, more than 13.0% w/w, or more than 14.0% w/w. In some embodiments, the amount of matrix former in the pharmaceutical composition may include less than 15% w/w, less than 14.0% w/w, less than 13.0% w/w, less than 12.0% w/w, less than 10.0% w/w, less than 9.0% w/w, less than 8% w/w, less than 7% w/w, less than 6% w/w, less than 5% w/w, or less than 4.0% w/w.
(38) A structure former, or bulking agent, of the matrix may include a sugar. For example, suitable structure formers include, but are not limited to, mannitol, dextrose, lactose, galactose, glycine, cyclodextrin, or combinations thereof. The structure former can be used in freeze drying as a bulking agent as it crystallizes to provide structural robustness to the freeze-dried dosage form. In some embodiments, the amount of structure former in the matrix solution/suspension can be from about 0.1 to 10% w/w. In some embodiments, the amount of structure former in the matrix solution/suspension or pharmaceutical suspension may include from 1.0 to 8.0% w/w or from 1.5 to 5.0% w/w. In some embodiments, the amount of structure former in the matrix solution/suspension or pharmaceutical suspension may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 4.0% w/w, more than 5.0% w/w, or more than 8.0% w/w. In some embodiments, the amount of structure former in the matrix solution/suspension or pharmaceutical suspension may include less than 10% w/w, less than 8.0% w/w, less than 6.0% w/w, less than 5.0% w/w, less than 4.0% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w. In some embodiments, the amount of structure former in a pharmaceutical composition can be about 3-15% w/w, about 4-10% w/w, or about 4-7% w/w. In some embodiments, the amount of structure former in the pharmaceutical composition may include more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 6.0% w/w, more than 7.0% w/w, more than 8.0% w/w, more than 9.0% w/w, more than 10.0% w/w, more than 11.0% w/w, more than 12.0% w/w, more than 13.0% w/w, or more than 14.0% w/w. In some embodiments, the amount of structure former in the pharmaceutical composition may include less than 15% w/w, less than 14.0% w/w, less than 13.0% w/w, less than 12.0% w/w, less than 10.0% w/w, less than 9.0% w/w, less than 8% w/w, less than 7% w/w, less than 6% w/w, less than 5% w/w, or less than 4.0% w/w.
(39) In some embodiments, a matrix solution/suspension and pharmaceutical suspension may include a viscosity modifier. For example, a viscosity modifier according to embodiments provided herein may include vegetable gums such as xanthan gum, alginin, guar gum, or locust bean gum, proteins such as collagen or gelatin, sugars such as agar, carboxymethyl cellulose, pectin, or carrageenan, starches such as arrowroot, cornstarch, katakuri starch, potato starch, sago, or tapioca, and/or other suitable viscosity modifiers. In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension, or the pharmaceutical composition may be from 0 to 0.2% w/w or from 0.01 to 0.1% w/w. In some embodiments, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension, or the pharmaceutical composition may be greater than 0.01% w/w, greater than 0.03% w/w, greater than 0.05% w/w, greater than 0.07% w/w, greater than 0.1% w/w, greater than 0.12% w/w, greater than 0.15% w/w, or greater than 0.17% w/w. In some embodiment, the amount of viscosity modifier in the matrix solution/suspension, pharmaceutical suspension, or the pharmaceutical composition may be less than 0.2% w/w, less than 0.18% w/w, less than 0.15% w/w, less than 0.12% w/w, less than 0.1% w/w, less than 0.08% w/w, less than 0.06% w/w, or less than 0.03% w/w.
(40) The solvent of the matrix solution/suspension and pharmaceutical suspension may be water, but the suspension solution may include a cosolvent as well. In some embodiments, the solvent can be ethanol, alcohol, isopropanol, other lower alkanols, water (e.g., purified water), or combinations thereof. For example, a suitable solvent and/or cosolvent may be an alcohol, such as tert-butyl alcohol. In some embodiments, the balance remaining of the pharmaceutical suspension is the solvent (i.e., Q.S. 100%).
(41) The matrix solution/suspension and pharmaceutical suspension may also contain additional pharmaceutically acceptable agents or excipients. Such additional pharmaceutically acceptable agents or excipients include, without limitation, sugars, inorganic salts, such as sodium chloride and aluminum silicates, modified starches, preservatives, antioxidants, viscosity enhancers, coloring agents, flavoring agents, pH modifiers, sweeteners, taste-masking agents, and combinations thereof. Suitable coloring agents can include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue No. 2 and FD & C Red No. 40, and combinations thereof. Suitable flavoring agents can include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these. Suitable pH modifiers can include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide (e.g., 3% w/w sodium hydroxide solution), and combinations thereof. Suitable sweeteners can include aspartame, acesulfame K and thaumatin, and combinations thereof. Suitable taste-masking agents can include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives, and combinations thereof. One of ordinary skill in the art can readily determine suitable amounts of these various additional excipients if desired.
(42) Minimizing and/or Preventing the Agglomeration of the Coating Material of Coated Ibuprofen
(43) Described below are methods for preparing pharmaceutical compositions comprising Ibuprofen that minimize the amount of excess coating material and/or the amount of agglomeration of excess coating material on storage.
(44) Methods according to some embodiments include removing excess coating material particles to minimize and/or to prevent agglomeration of coating material in a pharmaceutical product. In some embodiments, methods may include sieving the raw Ibuprofen and/or the coated Ibuprofen. Specifically, methods provided may include sieving the Ibuprofen and/or the coated Ibuprofen to remove any undesired particles, such as excess coating material particles. Sieving processes according to embodiments disclosed may help prevent and/or minimize the potential of coating material agglomeration that can adversely affect a disintegration time and/or a dissolution rate of the final product. Methods may also include optimizing the coating and/or dosing ratios of the process.
(45) Methods for minimizing and or preventing agglomeration of coating material particles according to embodiments described herein may be applied to dry, solventless mixing processes for coating Ibuprofen. Accordingly, methods provided are described below in context of one or more dry, solventless mixing processes for coating Ibuprofen. However, other variations of coating/encapsulating processes may be used as well. For example, sugar coating, film coating, other variations of microencapsulation, compression coating, other variations of dry coating, melting coating, dip coating, rotary die coating, electrostatic coating, and/or other suitable types of coating may be used.
(46) Generally, a solventless mixing process for coating Ibuprofen includes mixing coating materials with Ibuprofen to produce coated Ibuprofen. The coated Ibuprofen are then stressed mechanically and/or thermally to deform the deformable coating material, creating a continuous film surrounding the Ibuprofen. The coated Ibuprofen are then mixed with a matrix solution/suspension to form the pharmaceutical suspension. The pharmaceutical suspension comprising the coated Ibuprofen can be dosed into preformed molds, such as blister packs, and further treated to produce a dispensable pharmaceutical composition (e.g., a lyophilizate, a wafer, a tablet, etc.).
(47) However, when the final product (i.e., pharmaceutical composition) is stored, any excess coating material particles not bound to coated Ibuprofen can agglomerate. The amount and/or severity of agglomeration may increase over time. Agglomeration of excess coating material can increase the disintegration times and/or decrease the dissolution rate of the pharmaceutical product and adversely affect any functional properties of the coating material. An increased disintegration time may also cause unacceptable dispersion and mouthfeel characteristics in vivo.
(48) Accordingly, it has been discovered that by sieving the coated Ibuprofen, excess coating material can be removed, thus minimizing the amount of agglomeration of excess coating material upon storage. Further, some embodiments include optimizing the coating ratio (amount of coating materials to the amount of uncoated Ibuprofen) and optimizing the dosing ratio (amount of coated Ibuprofen to the aqueous solution matrix comprising all the other inactive ingredients) can also minimize the agglomeration of excess coating material particles.
(49) Embodiments provided herein can be applied to coated Ibuprofen produced using dry, solventless processes. Some mixing processes according to embodiments described herein include coating Ibuprofen with a taste-masking coating. Such coatings can control the disintegration time and/or the dissolution rate of an orodispersible pharmaceutical composition such that the release of the Ibuprofen upon oral administration is delayed or significantly reduced during the first few minutes when it is in the mouth, yet a satisfactory amount of the Ibuprofen is released within 30 minutes from oral administration post swallowing. (For example, a satisfactory amount of Ibuprofen may be 90% of the Ibuprofen amount which would be released without the coating). U.S. Pat. No. 9,107,851 (the '851 patent) is directed to an example dry, solventless process for coating pharmaceutical ingredients, the entirety of which is incorporated herein.
(50) However, other variations of coating/encapsulating processes may be used as well. For example, sugar coating, film coating, other variations of microencapsulation, compression coating, other variations of dry coating, melting coating, dip coating, rotary die coating, electrostatic coating, and/or other suitable types of coating may be used.
(51) Additionally, specific data as provided herein is related to disintegration times. However, disintegration time is inversely related to dissolution rates. Thus, the data inherently provides information on dissolution rates as well. Disintegration time may be measured according to methods set forth by the United States Pharmacopeia (Disintegration 701). In some embodiments, the disintegration time may be from 2-30 seconds or 5-20 seconds. In some embodiments, the disintegration time may be less than 30 seconds, less than 25 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, or less than 5 seconds. In some embodiments, the disintegration time may be greater than 2 seconds, greater than 5 seconds, greater than 10 seconds, greater than 15 seconds, greater than 20 seconds, or greater than 25 seconds. Similarly, dissolution rate may also be tested according to methods set forth by the United States Pharmacopeia (Dissolution 711).
(52) In some embodiments, raw Ibuprofen may be sieved prior to the coating process to achieve a narrower particle size range. For example, the raw Ibuprofen may be sieved to remove oversized particles and/or to remove undersized particles. In some embodiments, more than one mesh can be used to remove certain particles. For example, a sieving device may comprise a series of two or more meshes to remove particles of a certain size according to the size of the mesh(s). The sieve can incorporate a vacuum transfer system to transport the particles through the series of meshes of the device. Additionally, ultrasonic probes may be incorporated into the sieving device to improve material flow and minimize blinding of the mesh during processing.
(53) In some embodiments, the raw Ibuprofen can be sieved using a mesh size from 30 μm to 500 μm, from 50 μm to 450 μm, from 100 μm to 400 μm, from 150 μm to 350 μm, or from 200 μm to 300 μm. In some embodiments, the raw Ibuprofen can be sieved using a mesh size less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, less than 200 μm, less than 150, or less than 100 μm. In some embodiments, the raw Ibuprofen can be sieved using a mesh size greater than 30 μm, greater than 50 μm, greater than 100 μm, greater than 150 μm, greater than 200 μm, greater than 250 μm, greater than 300 μm, greater than 350 μm, or greater than 400 μm.
(54) Once the Ibuprofen have been coated by the coating material to produce coated Ibuprofen, the coated Ibuprofen may be sieved to remove excess coating material and residual fine Ibuprofen, either uncoated, partially coated or coated. Excess coating material may include any coating material particles not bound to a coated Ibuprofen. Upon storage of the final pharmaceutical product, any excess coating material can agglomerate. For example, fusion may occur between excess coating particles and coating particles that are already bound to an Ibuprofen, preventing ingress of media that would otherwise aid in disintegration of the unit or tablet or dissolution of the coated Ibuprofen. Accordingly, agglomeration of excess coating material can cause increased disintegration times and/or decreased dissolution rates upon administration.
(55) However, it has been determined that methods of sieving excess coating material from the coated Ibuprofen can minimize agglomeration of the coating material and maintain the initial disintegration time and/or dissolution rate of the final product. The sieving process can be either batch or continuous. Additionally, this sieving process may be performed in addition to or in lieu of the sieving process performed on raw Ibuprofen, described above. In some embodiments, the sieving process parameters may be different between the uncoated, raw Ibuprofen and the coated Ibuprofen.
(56) In some embodiments, coated Ibuprofen may be sieved to remove coating material particles having an average particle size less than a desired average coated Ibuprofen particle size. In some embodiments, more than one mesh can be used to remove certain particles. For example, a sieving device may comprise a series of two or more meshes to remove particles of a certain size according to the size of the mesh(s). The sieve can incorporate a vacuum transfer system to deliver the particles to the series of meshes of the device. Additionally, ultrasonic probes may be incorporated into the sieving device to improve material flow and minimize blinding of the mesh during processing. A flow aid (e.g., silica) may be included to promote movement through the sieve. For example, the coating material used to coat the Ibuprofen may comprise a flow aid. Conversely, raw Ibuprofen may not be cohesive and not require the assistance of a flow aid during sieving. The sieving process may be a batch process or a continuous process.
(57) In some embodiments, the raw Ibuprofen can be sieved using a mesh size from 30 μm to 500 μm, from 50 μm to 450 μm, from 100 μm to 400 μm, from 150 μm to 350 μm, or from 200 μm to 300 μm. In some embodiments, the raw Ibuprofen can be sieved using a mesh size less than 500 μm, less than 450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than 250 μm, less than 200 μm, less than 150, or less than 100 μm. In some embodiments, the raw Ibuprofen can be sieved using a mesh size greater than 30 μm, greater than 50 μm, greater than 100 μm, greater than 150 μm, greater than 200 μm, greater than 250 μm, greater than 300 μm, greater than 350 μm, or greater than 400 μm.
(58) The coating ratio (i.e., the amount of coating materials to the amount of uncoated Ibuprofen) may be optimized to minimize and/or prevent the agglomeration of the excess coating materials. For example, in some embodiments, the coating ratio can ranges from 5-85% or 10-50% w/w coating materials to 15-95% or 50-90% w/w uncoated Ibuprofen. In some embodiments, the amount of coating materials may be less than 80% w/w, less than 70% w/w, less than 60% w/w, less than 50% w/w, less than 40% w/w, less than 30% w/w, less than 20% w/w, or less than 10% w/w. In some embodiments, the amount of coating materials may be more than 5% w/w, more than 10% w/w, more than 20% w/w, more than 30% w/w, more than 40% w/w, more than 50% w/w, more than 60% w/w, or more than 70% w/w. In some embodiments, the amount of uncoated Ibuprofen may be less than 95% w/w, less than 85% w/w, less than 75% w/w, less than 65% w/w, less than 55% w/w, less than 45% w/w, less than 35% w/w, or less than 25% w/w. In some embodiments, the amount of uncoated API may be more than 20% w/w, more than 30% w/w, more than 40% w/w, more than 50% w/w, more than 60% w/w, more than 70% w/w, more than 80% w/w, or more than 90% w/w.
(59) The dosing ratio (i.e., the amount of coated Ibuprofen to the amount of matrix solution/suspension comprising all the inactive ingredients) may be optimized to minimize and/or prevent the agglomeration of the excess coating materials. For example, in some embodiments, the dosing ratio can range from 5-60% w/w coated Ibuprofen to 40-95% w/w matrix solution/suspension. In some embodiments, the dosing ratio may include less than 60% w/w, less than 50% w/w, less than 40% w/w, less than 30% w/w, less than 20% w/w, or less than 10% w/w coated Ibuprofen. In some embodiments, the dosing ratio may include more than 5% w/w, more than 10% w/w, more than 20% w/w, more than 30% w/w, more than 40% w/w, or more than 50% w/w coated Ibuprofen. In some embodiments, the dosing ratio may include less than 95% w/w, less than 90% w/w, less than 80% w/w, less than 70% w/w, less than 60% w/w, or less than 50% w/w matrix solution/suspension. In some embodiments, the dosing ration may include more than 40% w/w, more than 50% w/w, more than 60% w/w, more than 70% w/w, more than 80% w/w, or more than 90% w/w matrix solution/suspension.
(60) Preserving Functionally-Coated Ibuprofen Produced by a Dry, Solventless Mixing Process and Mixed in a Suspension
(61) Pharmaceutical compositions and methods for preparing pharmaceutical compositions provided herein may include adding hydrophobic fumed silica during the coating process to provide a protective layer surrounding and/or partially or fully embedded into a functional (or “first coating”) of the functionally-coated Ibuprofen. The addition of this hydrophobic fumed silica layer (or “second layer”) can provide a protective layer to a first coating layer of functionally-coated Ibuprofen and can minimize erosion of the first coating layer from shear forces necessary to mix the functionally-coated Ibuprofen into pharmaceutical suspension.
(62) Generally, a solventless mixing process for coating Ibuprofen includes mixing coating materials with Ibuprofen to produce functionally-coated Ibuprofen. The functionally-coated Ibuprofen are then stressed mechanically and/or thermally to deform the deformable coating material, creating a continuous film surrounding the Ibuprofen. The functionally-coated Ibuprofen are then mixed with a matrix solution or suspension to form the pharmaceutical suspension. The pharmaceutical suspension comprising the functionally-coated Ibuprofen can be dosed into preformed molds, such as blister packs, and further treated to produce a dispensable pharmaceutical composition (e.g., a lyophilizate, a wafer, a tablet, etc.). In some embodiments, the dispensable pharmaceutical composition may be an orodispersible product. Ideally, a minimal amount, if any, of the Ibuprofen of the final dispensable pharmaceutical composition dissolves within the first few minutes of oral administration. This delay, or substantial reduction of Ibuprofen release, allows for the taste of the Ibuprofen to be masked when the orodispersible product is in a patient's mouth. Instead, the Ibuprofen can release once the pharmaceutical composition has passed to the gastrointestinal tract.
(63) However, when the functionally-coated Ibuprofen are mixed into a matrix solution/suspension, the shear forces required to mix the particles into the matrix solution/suspension can erode the functional coating of the Ibuprofen. Erosion of the coating can destroy or damage the properties of the functional coating. For example, erosion of the functional coating can destroy or damage any taste-masking properties of the functional coating and allow the Ibuprofen to undergo dissolution in the oral cavity.
(64) Accordingly, it has been discovered that hydrophobic fumed silica, as well as being used as a flow aid for the functionally-coated Ibuprofen to aid downstream processing, may also be used to provide a hydrophobic barrier layer surrounding and/or partially or fully embedded into the functionally-coated Ibuprofen. Specifically, the hydrophobic barrier layer formed by the hydrophobic fumed silica can protect one or more underlying coatings of the functionally-coated Ibuprofen during preparation of the pharmaceutical suspension and other downstream processing of the functionally-coated Ibuprofen. Thus, Ibuprofen according to some embodiments described herein may have a first, functional coating and a second, protective coating
(65) However, some pharmaceutical compositions and methods of preparing pharmaceutical compositions provided herein may include more than a first coating and a second coating. For example, some pharmaceutical compositions and methods of preparing the same may include three, four, five, six, or more coatings. Thus, the terms “first coating” and “second coating” as used herein should not be construed narrowly. As used herein, the term “first coating” refers to a functional coating of Ibuprofen, and “second coating” refers to a protective coating comprising silica. In some embodiments, functionally-coated Ibuprofen may have one or more coating layers between a “first coating” and a “second coating”. In some embodiments, functionally-coated Ibuprofen may have one or more coating layers between the Ibuprofen and the “first coating”. In some embodiments, a functionally-coated Ibuprofen may have one or more coating layers on top of a “second coating”.
(66) Once the functionally-coated Ibuprofen are prepared, they can be mixed into the matrix/suspension solution to form a pharmaceutical suspension for dosing. Mixing functionally-coated Ibuprofen into a matrix solution/suspension can erode the functional coating of the functionally-coated Ibuprofen. In some embodiments, to minimize this erosion, hydrophobic fumed silica can be used to form a second coating layer surrounding and/or partially embedded and/or embedded into the functionally-coated Ibuprofen.
(67) However, coating functionally-coated Ibuprofen (i.e., Ibuprofen comprising at least a first coating, as described above) that will later be mixed into a matrix solution/suspension with hydrophobic fumed silica is not naturally intuitive. As described above, to create an orodispersible pharmaceutical composition according to embodiments described herein, the functionally-coated Ibuprofen are mixed into a matrix solution/suspension comprising a matrix former, a structure former, and a solvent (often water) to form a pharmaceutical suspension. However, a hydrophobic material is naturally resistant to mixing into a matrix solution/suspension. Accordingly, one might assume that hydrophobic fumed silica would increase the interfacial tension between the functionally-coated Ibuprofen and the matrix solution/suspension, increasing the difficulty of incorporating the functionally-coated Ibuprofen into the matrix solution/suspension and potentially causing phase separation of the pharmaceutical suspension.
(68) Interestingly, it has been determined that hydrophobic fumed silica can be used to coat functionally-coated Ibuprofen comprising to preserve the first, functional coating without substantially interfering with the incorporation of the functionally-coated Ibuprofen into the matrix solution/suspension. As described above, a hydrophobic material in a matrix solution/suspension, such as the functionally-coated Ibuprofen covered with the hydrophobic fumed silica in the matrix solution/suspension described above, characteristically exhibits a relatively high surface tension between the hydrophobic material and the matrix solution/suspension. Accordingly, the surface tension between the hydrophobic functionally-coated Ibuprofen and the matrix solution/suspension is likely relatively high as well.
(69) However, as discussed below, the matrix solution/suspension may comprise a matrix former such as gelatin. Some matrix formers, including gelatin, are mild surfactants, meaning that they can lower the surface tension between two materials. Accordingly, it is believed that matrix formers exhibiting surfactant-like behaviors can reduce the surface tension between the functionally-coated Ibuprofen and the matrix solution/suspension, which in turn allows for incorporation of the functionally-coated Ibuprofen into the matrix solution/suspension, while at the same time maintaining the protective properties of the hydrophobic fumed silica coating layer with respect to the first, functional coating of the functionally-coated Ibuprofen. This second coating layer comprising hydrophobic fumed silica can provide a hydrophobic barrier to the underlying first coating of the functionally-coated Ibuprofen, to protect the underlying first coating from the shear forces required to mix the functionally-coated Ibuprofen into a pharmaceutical suspension. By coating the functionally-coated Ibuprofen with a hydrophobic barrier comprising hydrophobic fumed silica, the underlying (first) coating may be protected from erosion. Further, using hydrophobic fumed silica according to described methods can prevent the matrix solution/suspension from penetrating through the coating to the Ibuprofen.
(70) Under normal processing conditions, without a hydrophobic fumed silica coating layer, the coating of the functionally-coated Ibuprofen can erode over time under the shear forces required to mix the functionally-coated Ibuprofen into the matrix solution/suspension. However, there can be a “processing window” of two or more hours from the time the functionally-coated Ibuprofen are first mixed into the matrix solution/suspension wherein the coating can remain intact and its functionality can remain uncompromised. The exact time of this “processing window” varies and can depend upon the composition of the various components of the functionally-coated Ibuprofen, the composition of the matrix solution/suspension, the amount of material used to prepare the coating of the functionally-coated Ibuprofen, and/or the physicochemical properties of the Ibuprofen. However, with functionally-coated Ibuprofen having a second coating comprising fumed silica, this “processing window” can be extended.
(71) In some embodiments, the pharmaceutical composition or the coated Ibuprofen can comprise from 0.5 to 35% w/w hydrophobic fumed silica. In some embodiments, the pharmaceutical composition or the coated Ibuprofen can comprise from 0.5 to 20% w/w, from 0.5 to 10% w/w, or from 0.5 to 5% w/w hydrophobic fumed silica. In some embodiments, the pharmaceutical composition or the coated Ibuprofen can comprise more than 0.5% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than 2.5% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25% w/w, or more than 30% w/w hydrophobic fumed silica. In some embodiments, the pharmaceutical composition or the coated Ibuprofen can comprise less than 35% w/w, less than 25% w/w, less than 15% w/w, less than 10% w/w, less than 5.0% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w hydrophobic fumed silica. The hydrophobic fumed silica may be any of Aerosil R972 silica (Degussa), CAB-O-SIL EH-5 silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & Chemical Ind. Co. Ltd (Japan)), TS5 silica (Cabot), and/or other suitable types of silica.
(72) The effectiveness of the hydrophobic fumed silica-comprising protective layer can be determined by measuring the particle size of the functionally-coated Ibuprofen in the pharmaceutical suspension over time. If the hydrophobic fumed silica is effective at preserving the coating, the particle size of the functionally-coated Ibuprofen can remain constant or decrease very little over time. If ineffective, the particle size of the functionally-coated Ibuprofen can decrease more substantially over time. The particle size of the functionally-coated particles can be measured using laser diffraction, a particle analyzer such as a Malvern Mastersizer, or any other suitable means for analyzing fine particles.
(73) The effectiveness of the hydrophobic fumed silica-comprising protective layer can also be determined by conducting dissolution testing on the functionally-coated Ibuprofen. If the hydrophobic fumed silica is effective at preserving the coating, the release amount (e.g., percent of release) of the functionally-coated Ibuprofen over time will be slower in dissolution testing. If ineffective, the release amount of the functionally-coated Ibuprofen over time will be greater. The release amount of the functionally-coated particles can be measured using dissolution testing, a spectrophotometric analyzer such as a Pion MicroDISS Profiler, or any other suitable means for conducting dissolution testing.
(74) Minimizing the Aeration of Suspensions Comprising Ibuprofen
(75) Embodiments provided herein may include adding a chemical compound comprising terpene and/or terpinol to the matrix solution/suspension. Specifically, embodiments of the pharmaceutical suspensions provided herein may include liquid flavors comprising terpene and/or terpinols. In some embodiments, the liquid flavor(s) may include the terpene limonene. Particular chemical compounds, and specifically the addition of liquid flavors comprising limonene, can minimize the aeration of the suspension, increase the homogeneity of the suspension, and improve the dose weight accuracy when the suspension is injected into molds. As used herein, “dose weight accuracy” and related terms refer to the ability to accurately dispense a pharmaceutical suspension into a pre-formed mold. The dose weight accuracy of the dosed pharmaceutical suspension may depend on a number of variables, including, but not limited to, homogeneity, viscosity, chemical components, dosing instrument, etc.
(76) As described above, traditional mechanical means of anti-aeration and/or minimizing aeration have not been found to be successful due to the high viscosity of the pharmaceutical suspension. For example, applying a vacuum to the pharmaceutical suspension can cause a height of the suspension to rise because the viscous suspension “holds onto” the entrained air. Volatile formulation components may also be lost during vacuum processing. Further, traditional anti-aerating agents, such as ethanol or simethicone emulsion are similarly ineffective at anti-aerating the suspension.
(77) Accordingly, it has been discovered that some chemical compounds, and in particular, liquid flavors comprising terpenes and/or terpinols such as limonene, can minimize the aeration of the pharmaceutical suspension when hydrophobic coated Ibuprofen are mixed in to the matrix solution/suspension. By minimizing aeration, the hydrophobic coated Ibuprofen are more efficiently and effectively dispersed throughout the pharmaceutical suspension. This increased dispersion can increase the homogeneity of the pharmaceutical suspension, the dose weight accuracy, as well as the content uniformity of the finished product.
(78) As described above, mixing hydrophobic coated Ibuprofen into a matrix solution/suspension can generate entrained air, or air bubbles in the liquid. Because the coated Ibuprofen are hydrophobic, they have a generally low affinity for the matrix solution/suspension. Thus, instead of readily associating with and dispersing into the matrix solution/suspension, the hydrophobic coated Ibuprofen preferably associate with the entrained air. In many fluids, air bubbles typically travel to the surface of the fluid and disappear into the air above. However, because the hydrophobic coated Ibuprofen have an affinity for the entrained air, the hydrophobic coated Ibuprofen “hold onto” the air bubbles, preventing them from traveling to the surface and releasing into the air above the fluid. This causes the pharmaceutical suspension to become aerated. Aeration of the pharmaceutical suspension can cause phase separation, and thus, a non-homogeneous suspension. The phase separation can also become exaggerated upon exposure to shear forces introduced by dosing pumps. Non-homogenous pharmaceutical suspensions can cause pump seizures when passed through dosing pumps, leading to inaccurate dose weights and a lack of uniformity throughout the finished product as well as poor production efficiency through stoppages.
(79) Additionally, pharmaceutical suspensions comprising hydrophobic coated Ibuprofen can have high viscosities due to a high loading of hydrophobic coated Ibuprofen (i.e., as much as 50 wt. % hydrophobic coated Ibuprofen). Entraining air into the pharmaceutical suspension during in-line mixing of the hydrophobic coated Ibuprofen into suspension, as described above, can increase the viscosity of the pharmaceutical suspension even further. Accordingly, not only does the phase separation and non-homogeneity of the suspension adversely impact the dose weight accuracy and uniformity of the final product, but so too does the increased viscosity.
(80) Interestingly, it has been found that certain chemical compounds, when added to the matrix solution/suspension, can minimize the aeration of pharmaceutical suspensions comprising hydrophobic coated Ibuprofen. Particularly, chemical compounds comprising terpene and/or terpinol, according to some embodiments provided herein, may minimize the amount of the entrained air in pharmaceutical suspensions caused by in-line mixing of hydrophobic coated Ibuprofen into matrix solutions/suspensions. For example, suspensions comprising liquid flavors comprising terpenes and/or terpinols, even in relatively low concentrations, can minimize aeration of pharmaceutical suspensions. Specifically, it has been discovered that matrix solutions/suspensions comprising one or more liquid flavor comprising limonene can minimize aeration in pharmaceutical suspensions during in-line mixing of hydrophobic coated Ibuprofen. Other chemical compounds including terpenes and terpinols have been shown to be successful at minimizing aeration of pharmaceutical suspensions as well. For example, chemical compounds including terpenes such as limonene, carvone, humulene, taxadiene, and squalene may be suitable for minimizing the aeration of the pharmaceutical suspension. Terpinol may also be a suitable anti-aerating agent. In some embodiments, pure terpenes and/or pure terpinols may be used as an anti-aerating agent. In some embodiments, a liquid flavor comprising terpene and/or terpinol may be used as an anti-aerating agent. In some embodiments, other suitable chemical compounds comprising terpene and/or terpinol may be used as an anti-aerating agent.
(81) One challenge posed with some chemical compounds comprising terpene and/or terpinol, such as some liquid flavors, is that they tend to be relatively oily. As with conventional oil and water, these oily chemical compounds may not readily disperse into a matrix solution/suspension. However, as discussed below, matrix solutions/suspensions according to embodiments here may include gelatin as a matrix former. Gelatin is inherently a mild surfactant. Surfactants can lower the surface tension between two materials. Accordingly, in some embodiments, the gelatin of the matrix solution/suspension can reduce the surface tension between the oily chemical compounds and the matrix solution/suspension. This can allow adequate incorporation of the oily chemical compounds, such as liquid flavors, into the matrix solution/suspension.
(82) Under normal processing conditions, without use of chemical compounds comprising terpene and/or terpinol, the coating of the hydrophobic coated Ibuprofen erodes with time due to shear forces required to mix the hydrophobic coated Ibuprofen into the matrix solution/suspension to form the pharmaceutical suspension. However, there is a “processing window” of two or more hours wherein the coating retains significant functionality. The exact time of this “processing window” varies for each product, and can depend upon the composition of the components of the hydrophobic coated Ibuprofen, the composition of the matrix solution/suspension, the amount of material used to prepare the hydrophobic coated Ibuprofen, the physicochemical properties of Ibuprofen, and/or the conditions of mixing. Unfortunately, in the presence of chemical compounds comprising terpenes and/or terpinols this “processing window” can be significantly reduced due to interactions between these chemical compounds and the coating of the hydrophobic coated Ibuprofen. These interactions may damage the functional properties of the coating. For example, interactions between liquid flavors and the coating of the hydrophobic coated Ibuprofen may damage any taste-masking functionality of the coating. That said, it has been discovered that there is a threshold chemical compounds (i.e., liquid flavor) concentration below which the chemical compound does not significantly compromise the coating, yet the “processing window” is not reduced so much that the coating of the hydrophobic coated Ibuprofen significantly erodes. Accordingly, this optimal amount of chemical compound comprising terpene and/or terpinol adequately minimizes the aeration of the pharmaceutical suspension, resulting in a homogenous pharmaceutical suspension that can be accurately dosed into molds to yield a uniform final product.
(83) Additionally, chemical compounds comprising terpene and/or terpinol, and specifically liquid flavors comprising limonene, have the potential to lower the freezing point of the pharmaceutical suspension, which could lead to melting defects for products further processed by freeze-drying. In particular, limonene has a freezing point of −74° C. However, no melting defects have been observed during the preparation of the disclosed product, and thus at least some chemical compounds comprising terpene and/or terpinol do not impact the pharmaceutical suspension such that the freezing and freeze-drying process steps downstream are adversely affected. The absence of melting defects under the present circumstances is believed to be due to the high solids content of the suspension, which helps to maintain the structure of the product, even in the presence of a freezing point depressing agent (i.e., limonene).
(84) Matrix solution/suspension compositions according to embodiments described herein may include a matrix former, a structure former, an anti-aerating agent, a viscosity modifier, and/or a solvent.
(85) In some embodiments, an amount of a chemical compounds comprising terpene and/or terpinol (i.e., an anti-aerating agent) in the matrix solution/suspension, the pharmaceutical suspension, or the pharmaceutical composition may be from 0.001 to 5.0% w/w. In some embodiments, an amount of chemical compounds comprising terpene and/or terpinol (i.e., an anti-aerating agent) in the matrix solution/suspension, the pharmaceutical suspension, or the pharmaceutical composition can be 1-5% w/w, 1-4% w/w, 1-3% w/w, 1-2% w/w, 0.05 to 3.0% w/w, 0.1 to 2.0% w/w, or 0.5 to 1.0% w/w. In some embodiments, more than 0.001% w/w, more than 0.01% w/w, more than 0.05% w/w, more than 0.1% w/w, more than 0.3% w/w, more than 0.5% w/w, more than 0.8% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than 2.5% w/w, more than 3.0% w/w, more than 3.5% w/w, more than 4.0% w/w, or more than 4.5% w/w of chemical compounds comprising terpene and/or terpinol (i.e., an anti-aerating agent) are in the matrix solution/suspension, the pharmaceutical suspension, or the pharmaceutical composition. In some embodiments, less than 5.0% w/w, less than 4.5% w/w, less than 4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, less than 1.0% w/w, less than 0.8% w/w, less than 0.6% w/w, less than 0.3% w/w, or less than 0.1% w/w of chemical compounds comprising terpene and/or terpinol (i.e., an anti-aerating agent) are in the matrix solution/suspension, the pharmaceutical suspension, or the pharmaceutical composition. In some embodiments, a suitable anti-aerating agent may include orange flavor, strawberry flavor, mint flavor, raspberry flavor, licorice flavor, orange flavor, lemon flavor, lime flavor, grapefruit flavor, caramel flavor, vanilla flavor, cherry flavor, grape flavor, mixed fruit flavor, tutti-frutti flavor or any combination thereof.
(86) Minimizing Agglomeration Examples
(87) Several trials were performed to evaluate the effectiveness of removing excess coating material from coated Ibuprofen by sieving and to optimize the coating ratios and dosing ratios. Disintegration times of pharmaceutical compositions containing various coated Ibuprofen were measured under various conditions to study the effect of sieving excess coating material. It may be reasonably assumed that removing excess coating material can minimize agglomeration of the coating material. Optimizing the coating and dosing ratios can also aid in minimizing coating material agglomeration. In turn, minimizing the amount of agglomeration can help maintain desired disintegration times and/or dissolution rates of the pharmaceutical composition and coated Ibuprofen. Accordingly, disintegration time is used as a metric to evaluate the amount of agglomeration in the following Examples. In some embodiments, the 50° C. accelerated disintegration data can be indicative of the presence of unsieved, excess coating material.
(88) Additionally, coating ratio and dosing ratio information is provided for the Examples below. Coating ratio refers to the amount of coating materials to the amount of uncoated Ibuprofen. Dosing ratio refers to the amount of coated Ibuprofen to the matrix solution/suspension comprising of all the inactive ingredients.
(89) Example 1: Ibuprofen was coated with carnauba wax with a coating ratio of 26:74. A dosing ratio of 40:60 was used to produce freeze dried tablets. Four separate batches of tablets were tested—Batch 1-3 over a period of 2 months, and Batch 4 over a period of 6 months. These batches of tablets were each tested at ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) stability conditions of 25° C./60% RH, 30° C./65% RH, and 40° C./75% RH and sampled at one month and two months for Batches 1, 2, and 3. Additionally, each batch was exposed to a 50° C. stress condition to provide accelerated data at both two weeks and at four weeks for each study. Table 1 below provides the disintegration time data for Batches 1-3 of the two-month study of coated ibuprofen.
(90) TABLE-US-00001 TABLE 1 Carnauba Wax (Dosing Ratio 40:60) (2-Month Study) 1 Month 1 Month 1 Month 2 Month 2 Month 2 Month Initial 2 Week 4 Week 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Batch Batch Nos Strength DT 50° C. 50° C. 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 1 Z3876/128 400 MG <2 s <4 s <10 s <4 s <4 s <4 s <3 s <4 s <7 s 2 Z4630/97 50 MG <2 s <4 s <7 s <2 s <2 s <2 s <2 s <2 s <15 s 3 Z4630/101 50 MG <3 s <3 s <4 s <1 s <2 s <3 s <2 s <2 s <2 s
(91) Coated Ibuprofen for Batch 2 was poorly sieved post Ibuprofen coating. Microscopic examination (
(92) Conversely, coated Ibuprofen for Batch 3 was sieved well post Ibuprofen coating. Microscopic examination (
(93) The coated Ibuprofen for Batch 1 was sieved post Ibuprofen coating. Batch 1 exhibited similar disintegration time of less than 2 seconds compared to Batch 2 and 3 for the initial time data points. However, at the 40 C/75% RH stability testing conditions after two-months, the disintegration time increased to approximately 7 seconds or less. When stored for 4 weeks at 50° C., the disintegration time increased to approximately 10 seconds or less. This suggests that the sieving process for this batch did not sufficiently remove the excess coating material, hence the presence of residual unbound coating material. Batch 2 experienced even more unbound coating material and agglomeration on storage to a greater extent than that of Batch 1. Microscopic examination (
(94) Table 2 below shows the disintegration time data for the six-month study of coated Ibuprofen (i.e., Batch 4).
(95) TABLE-US-00002 TABLE 2 Carnauba Wax (Dosing Ratio 40:60) (6-Month Study) 1 1 1 3 3 3 6 6 6 Month Month Month Month Month Month Month Month Month 2 4 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Week Week 60% 65% 75% 60% 65% 75% 60% 65% 75% Batch Batch Nos Strength Initial 50° C. 50° C. RH RH RH RH RH RH RH RH RH 4 Z3876/131 200 MG <5 s <20 s <13 s <5 s <4 s <5 s <4 s <3 s <4 s <2 s <2 s <2 s
(96) The coated Ibuprofen for Batch 4 was sieved post Ibuprofen coating. Batch 4 of Table 2 did not show much change in disintegration time throughout the duration of the six-month study. The initial disintegration time of Batch 4 was approximately five seconds, and the final disintegration time of the 25° C./60% RH samples was approximately two seconds; the 30° C./65% RH samples approximately two seconds, and the 40° C./75% RH samples approximately two seconds. However, an increase was seen when stored at 50° C. Since no increase was seen in the tablets stored at temperatures of 40° C. and below, this suggests that sieving has removed most of the unbound excess coating material but with sufficient residue amount that agglomerate when the tablets were placed at 50° C. Microscopic examination (
(97) Example 2: Ibuprofen was coated with Sasol (synthetic) wax with a theoretical coating ratio of 26:74. The coated Ibuprofen was sieved after coating. A dosing ratio of 40:60 was used to produce freeze dried tablets and tested over two months. The Ibuprofen strength was 200 mg. Each batch was tested at ICH stability conditions of 25° C./60% RH, 30° C./65% RH, and 40° C./75% RH. Additionally, the samples were exposed to a 50° C. stress condition to provide accelerated data at two weeks and at four weeks during the study. Table 3 below provides the disintegration time data for the 40:60 dosing ratio two month study of coated Ibuprofen. Microscopic examination (
(98) TABLE-US-00003 TABLE 3 Sasol Wax (Dosing Ratio 40:60) Ibuprofen Strength: 200 mg 1 Month 1 Month 1 Month 2 Month 2 Month 2 Month Initial 2 Week 4 Week 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Batch Batch Nps DT 50° C. 50° C. 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 5 Z3876/138 <3 s <3 s <4 s <2 s <2 s <5 s <4 s <4 s <4 s
(99) Batch 5 of Table 3 shows no substantial change in the disintegration time during the two months of the study, nor at the 50° C. accelerated conditions. Specifically, the initial disintegration time of Batch 5 was approximately three seconds, and the disintegration time at two months for all three ICH stability conditions (25° C./60% RH, 30° C./65% RH, and 40° C./75% RH) was approximately four seconds. The disintegration time for the 50° C. accelerated condition at two weeks was approximately three seconds and at 4 weeks was approximately four seconds. Based on the 50° C. data, a small residue amount of unbound excess coating material may be present. If so, this small amount of unbound excess coating material does not cause a significant amount of agglomeration on storage, since the disintegration time does not increase much, if at all. This compares well with Batch 3 in Example 1 where a different wax was used. These 2 examples demonstrate that if the unbound excess coating material is efficiency removed by sieving, agglomeration of the coating material in the pharmaceutical product on storage can be minimized or prevented, in particular at higher temperatures and upon prolonged storage period.
(100) Example 3: Ibuprofen was coated with Sasol (synthetic) wax with a theoretical coating ratio of 26:74. The coated ibuprofen was then sieved after coating. A dosing ratio of 50:50 was used to produce freeze dried tablets and tested over three months. The Ibuprofen strength was 200 mg. As above in Examples 1 and 2, each batch was tested at ICH stability conditions of 25° C./60% RH, 30° C./65% RH, and 40° C./75% RH. The samples were also exposed to a 50° C. stress condition to provide accelerated data at two weeks and at four weeks during each study. Table 4, below, provides data for the three-month study of 50:50 Sasol wax-coated Ibuprofen. Microscopic examination (
(101) TABLE-US-00004 TABLE 4 Sasol Wax (Dosing Ratio 50:50) Ibuprofen Strength: 200 mg 1 1 2 2 2 3 3 3 1 Month Month Month Month Month Month Month Month 2 4 Month 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Initial Week Week 25° C./ 65% 75% 60% 65% 75% 60% 65% 75% Batch Batch Nos DT 50° C. 50° C. 60% RH RH RH RH RH RH RH RH 6 Z3876/142 <1 s <2 s <2 s <2 s <2 s <2 s <2 s <1 s <2 s <2 s <2 s <2 s 7 Z3876/141/1 <2 s <5 s <5 s <2 s <3 s <3 s <2 s <2 s <3 s <2 s <2 s <3 s
(102) Neither Batch 6 nor Batch 7 showed significant change in disintegration time over the course of the three month study. Specifically, the initial disintegration time of the samples of Batch 6 was approximately one second, and the final three-month disintegration time for each of the three ICH stability conditions (25° C./60% RH, 30° C./65% RH, and 40° C./75% RH) was approximately two seconds. The disintegration time for both the two-week and the four-week accelerated 50° C. condition for Batch 6 was approximately two seconds.
(103) The initial disintegration time for the samples of Batch 7 was approximately two seconds, and the final three-month disintegration time for the 25° C./60% RH and 30° C./65% RH ICH stability conditions was approximately two seconds. The final three-month disintegration time for the 40° C./75% RH ICH stability condition was approximately three seconds. The disintegration time for both the two-week and the four-week accelerated 50° C. condition was approximately five seconds. A high coating ratio of 50:50 can increase the amount of excess unbound coating material when left unsieved. Although both batches used a higher dosing ratio of 50:50, which means a high loading of the coated Ibuprofen and any unbound excess coating material, these data inferred that the sieving process of the coated Ibuprofen has been effective in removing the unbound excess coating materials to minimize agglomeration.
(104) Example 4: Ibuprofen was coated with Carnuba Wax at a theoretical coating ratio of 22.5:77.5 and 30:70. A dosing ratio of 30:70 was used to produce freeze dried tablets and study over a period of 2 months. The Ibuprofen strength was 200 mg. The batches were stored in an oven at 40° C. Tablets were tested for disintegration time at the initial, Day 25, and 2 month time points. Table 5 below provides the disintegration times for the study. Microscopic examination of the unsieved coated Ibuprofen (
(105) TABLE-US-00005 TABLE 5 Carnuba Wax (Dosing Ratio 30:70) Ibuprofen Strength: 200 mg Day 24 2 Month Coated Coating At At Batch Bach Nps API Ratio Initial 40° C. 40° C. 8 Z4750/ Unsieved 22.5:77.5 5 s 2 s 2 s 186/2a 9 Z4750/ Sieved 22.5:77.5 4 s 3 s 3 s 186/4a 10 Z4750/ Unsieved 30:70 1 s 2 s 2 s 186/6a 11 Z4750/ Sieved 30:70 2 s 3 s 3 s 186/8a
(106) Batch 8-11 show that using a dosing ratio of 30:70 for coated Ibuprofen, either unsieved (Batches 8 and 10) or sieved (Batches 9 and 11), the disintegration times of the tablets stored at 40° C. has not increased over time. This supports the hypothesis that by reducing the dosing ratio; such as to 30:70, the amount of excess unbound wax is sufficiently reduced to a level that can minimize agglomeration of the excess unbound material when stored at higher temperatures over time.
(107) The overall summary of results from the above examples are tabulated the Table 6.
(108) TABLE-US-00006 TABLE 6 Overall Summary of Results for Batches 1-11. Disintegration Sieving Time at of Coating Unbounded 40° C./75% Disintegration Strength Coating Dosing Coated Assessment Excess Wax RH at time at 50° C. Batch Batch Nos Drug (mg) Ratio Ratio API (Microscopy) (Microscopy) 1/2/3/6 mths at 2/4 wk 1 Z3876/128 Ibuprofen 400 26:74 40:60 Sieved Moderate Present <4-7 s <4-10 s 2 Z4630/97 Ibuprofen 50 26:74 40:60 Sieved Poor Present <2-15 s <4-7 s (poor) 3 Z4630/101 Ibuprofen 50 26:74 40:60 Sieved Good Absent <2-3 s <3-4 s (well) 4 Z3876/131 Ibuprofen 200 26:74 40:60 Sieved Moderate Present <2-5 s <13-20 s 5 Z3876/138 Ibuprofen 200 26:74 40:60 Sieved Good Present <4-5 s <3-4 s 6 Z3876/142 Ibuprofen 200 26:74 50:50 Sieved Good Present <2 s <2 s 7 Z3876/141/ Ibuprofen 200 25:75 50:50 Sieved No Photo No Photo <3 s <5 s 1 8 Z4750/186/ Ibuprofen 200 22.5: 30:70 Unsieved Good Present <2 s No data 2a 77.5 9 Z4750/186/ Ibuprofen 200 22.5: 30:70 Sieved Good Absent <3 s No data 4a 77.5 (well) 10 Z4750/186/ Ibuprofen 200 30:70 30:70 Unsieved Good Present <2 s No data 6a 11 Z4750/186/ Ibuprofen 200 30:70 30:70 Sieved Good Absent <3 s No data 8a
Preserving Functionally-Coated Ibuprofen Examples
(109) Example 5: Hydrophobic fumed silica was used to coat functionally-coated Ibuprofen according to embodiments described herein. Specifically, the hydrophobic fumed silica that was used was Aerosil R972 (“Aerosil”). Two different concentrations of Aerosil R972 were tested-1.5% w/w and 1.0% % w/w. The size of the functionally-coated Ibuprofen were evaluated over a 6-hour holding period, during which they were subjected to low shear mixing.
(110)
(111) As shown in
(112)
(113)
(114) Additionally, as the particle size of the functionally-coated Ibuprofen decreased, a separate population of particles comprising a particle size of 5 μm to 20 μm appeared and increased with time. These particles are believed to be non-deformable coating material particles embedded within the deformed, continuous coating material prior to erosion of the coating due to shear forces. Accordingly, as the coating erodes, and the particle size of the functionally-coated Ibuprofen decreases, the population size of these smaller particles increases as the deformed coating material surrounding them erodes, causing these non-deformable particles to release from the functionally-coated Ibuprofen.
(115) Overall, these trials suggest that 1.5% w/w Aerosil coating the functionally-coated Ibuprofen may increase the “processing window” to approximately 4 hours, instead of the 2 hour “processing window” that exists without the silica. Within the first four hours of processing in suspension and comprising a second, outer coating comprising 1.5% w/w Aerosil, the functionally-coated Ibuprofen exhibit little, if any, erosion of the coating.
(116) Example 6: Hydrophobic fumed silica was used to coat functionally-coated Ibuprofen according to embodiments described herein. Specifically, the hydrophobic fumed silica that was used was Aerosil R972 (“Aerosil”). Five different concentrations of Aerosil R972 were tested-0.0% w/w, 1.5% w/w, 2.5% w/w, 5.0% w/w and 10.0% w/w. The release amount of the functionally coated Ibuprofen was evaluated using dissolution testing (i.e., dissolution media of 0.01% SDS in pH 7.2 phosphate buffer, media temperature of 37° C., and media volume of 10 ml (Ibuprofen)).
(117)
(118)
(119)
(120) Minimizing Aeration Examples
(121) The effectiveness of chemical compounds comprising terpene and/or terpinol at minimizing aeration can be determined in part by measuring the particle size of the hydrophobic coated Ibuprofen in pharmaceutical suspension over time. If the chemical compound is effective, the aeration of the suspension will be adequately low and the particle size of the hydrophobic coated Ibuprofen will remain constant or decrease very little over time. If ineffective, the aeration of the suspension will be higher than desired and the particle size of the hydrophobic coated Ibuprofen can decrease more substantially over time. The extent of aeration of the suspension is assessed by measurement of height of the foam in the mixing vessel. The particle size of the functionally-coated particles can be measured using laser diffraction, a particle analyzer such as a Malvern Mastersizer, or any other suitable means for analyzing fine particles.
(122) Example 7: A series of suspension mixes were manufactured by mixing the coated Ibuprofen in the matrix solution/suspension containing various levels of limonene, orange flavor, and strawberry flavor. The height of the foam from these suspension is summarized in Table 7, 8, and 9 respectively.
(123) TABLE-US-00007 TABLE 7 Height of foam from mixes containing various levels of limonene. Concentration of Foam limonene (% w/w) Height (mm) 0 5 0.15 2 0.30 1 0.6 1
(124) TABLE-US-00008 TABLE 8 Height of foam from mixes containing various levels of orange flavor. Concentration of orange Foam flavor (% w/w) Height (mm) 0 5 0.15 1 0.30 0 0.6 0
(125) TABLE-US-00009 TABLE 9 Height of foam from mixes containing various levels of strawberry flavor. Concentration of Foam strawberry flavor (% w/w) Height (mm) 0 5 0.15 3 0.30 3 0.6 3
(126) The results in Tables 7 and 8 show that the addition of limonene and orange flavor at level 0.15% w/w and above minimize the aeration. For strawberry (Table 9), it also reduced aeration but not to the same extent.
(127) Example 8:
(128) At concentrations of up to 0.45% w/w of orange flavor (including 0.15% w/w), the decrease in d10, d50, and d90 particle size within the first 2 hour “processing window” is largely similar to that of a pharmaceutical suspension comprising hydrophobic coated Ibuprofen without any liquid flavor (0% liquid flavor). However, at a concentration of 0.6% w/w liquid orange flavor, the coating of the hydrophobic coated Ibuprofen is readily removed and a rapid decrease in particle size is observed. Further, at a liquid orange flavor concentration of 0.3% w/w, the aeration of the suspension was sufficiently low with only little, if any damage to the coating of the coated ibuprofen, and only minimal decrease in particle size of the hydrophobic coated Ibuprofen.
(129) Example 9:
(130) Example 10:
(131) Additionally, it was observed in all trials that as the particle size of the hydrophobic coated API (Ibuprofen) particles decreased, a separate population of particles comprising a particle size of 5 μm to 20 μm appeared and increased with time. These particles are believed to be non-deformable coating material particles embedded within the deformed, continuous coating material prior to erosion of the coating due to shear forces. Accordingly, as the coating erodes, and the particle size of the hydrophobic coated Ibuprofen decreases, the population size of these smaller particles increases as the deformed coating material surrounding them erodes, causing these non-deformable particles to release from the hydrophobic coated Ibuprofen.
(132) Overall, these trials show that by optimizing the amount of the terpene limonene to add to the pharmaceutical suspension comprising hydrophobic coated Ibuprofen, the amount of aeration in the suspension can be minimized to permit downstream processing while at the same time not having an adverse effect on the coating of the hydrophobic coated Ibuprofen (as determined by the particle size of the hydrophobic coated Ibuprofen.)
(133) The foregoing description, for the purpose of explanation, has been described with reference to specific embodiments. However, the illustrative discussions above are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the techniques and their practical applications. Others skilled in the art are thereby enabled to best utilize the techniques and various embodiments with various modifications as are suited to the particular use contemplated.
(134) Although the disclosure and examples have been fully described with reference to the accompanying figures, it is to be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications are to be understood as being included within the scope of the disclosure and examples as defined by the claims.