Co-processed additive composition

Abstract

In the present disclosure, a co-processed additive composition is provided that includes (i) a vinyl lactam derived polymer, (ii) silica, and (iii) at least one lubricant. The co-processed additive has a Brookfield Flow Factor of 5 to 9. Also provided is a process for preparing the same. The co-processed additive is further used in continuous or direct compression batch manufacturing with excellent flow properties and self-lubrication.

Description

[Technical field]

[0001] The disclosed process(es), procedure(s), method(s), product(s), result(s), and / or concepts (collectively hereinafter referred to as "the disclosure") generally relate to co-processed additive compositions derived from vinyl lactam polymers and methods for preparing same. The disclosure further relates to composition(s) derived from the co-processed additive compositions and process(es) for preparing same. [Background technology]

[0002] Tablets and capsules represent the most preferred and most commonly dispensed drug dosage form for administering active pharmaceutical ingredients (APIs). Tablets can be manufactured by direct compression or via dry, wet or melt granulation of the drug(s) / excipient(s) mixture. Direct compression is the most preferred manufacturing process for producing tablets due to several benefits, such as time savings, ease of production, absence of heat and moisture in the process, and the like. The selection of the tableting process is highly influenced by the flow and compressibility of the tableting mixture, e.g., the active pharmaceutical ingredient (API)-excipient mixture. Two major factors that adversely affect the direct compression process are: compressibility and flow of the tableting mixture. The direct compression method requires excellent flow and compression of the tableting mixture. Most of the commercially available excipients cannot meet the desired functional set, as this is not an easy task to achieve, as the more highly compressible the material is, the less flowable it is.

[0003] One of the techniques to enhance the specific functionality of existing additives is to use spray drying or granulation methods. International Publication WO2012 / 116402A1, assigned to University of Monash, teaches binder powders for use in powder material processing. These binder powders are prepared by using techniques such as spray drying and mechanofusion. However, these processes lead to a reduction in the particle size of the polymer. Furthermore, these processes are costly, time-consuming, and require specialized equipment that is not commonly available in manufacturing units.

[0004] Another important technology is co-processing, which is referred to as the science of particle engineering, in which two or more additives are synergistically combined into a single multifunctional additive with superior inherent performance.

[0005] U.S. Patent No. 4,74,285, assigned to Dow Chemical Company, teaches delayed release solid tablets of therapeutically active compositions and a process for preparing such compositions. Fine particles of hydroxypropyl methylcellulose ether capable of passing through a 100 mesh screen (149 micrometer mesh size), and preferably a 140 mesh screen (105 micrometer mesh size), are present as an additive in the tablet composition. These fine particles are very small in size and exhibit poor flowability. Insufficient particle flow can lead to caking of the powder bed in processing equipment such as storage bins and tablet press feed hoppers. Problems can include increased inconsistencies in tablet weight or tablet crush strength from tablet to tablet, as well as inconsistencies in the amount of active ingredient incorporated into each dosage form.

[0006] WO2004 / 022601, assigned to JRS Pharma LP, and U.S. Patent No. 5,585,115, assigned to Edward H. Mendell Co, Inc., teach agglomerated microcrystalline cellulose blends containing silicon dioxide, which are intended to have improved compressibility. These disclosures state that silicon dioxide is a critical ingredient to improve compressibility. The two-step process described involves spray granulation followed by wet granulation. The prepared granules are further dried using heat, which is not advantageous. Furthermore, granulation is time consuming and adds cost to the process due to lost time, additional labor, energy consumption, and additional equipment required.

[0007] Several processes for dry grinding wet cellulose derivatives are known in the art, such as those described in patent applications GB 2262527A; European Publication EP 0824107A2; European Patent EP-B 0370447 (corresponding to U.S. Patent No. 4,979,681); EP 1127895A1 (corresponding to U.S. Patent No. 6,509,461); EP 0954536A1 (corresponding to U.S. Patent No. 6,320,043); WO96 / 00748A1; WO2011 / 046679 (corresponding to U.S. Publication US 2012 / 187225) and WO2012 / 138532.

[0008] Additionally, US 2012 / 160944 A1 assigned to ICEUTICA PTY LTD teaches a method for producing nanoparticle and microparticle powders of biologically active materials with improved powder handling characteristics using a dry milling process.

[0009] US2012 / 01788A assigned to ISP INVESTMENTS INC teaches co-processing of PVP and calcium silicate by using ball milling, spray drying or freeze drying.

[0010] Increase in the flow of cellulose polymers by co-milling microcrystalline cellulose with nanosilica is described in J. Pharm. Sci. 2011 November;100(11):4943-52, Chattoraj S, Shi L, Sun CC.

[0011] Additionally, U.S. Patent No. 10,596,261, assigned to Hercules LLC, teaches a co-processed excipient having a vinyl lactam derived polymer and deaggregated silica as co-processing agents. The vinyl lactam derived polymer and deaggregated silica are co-processed together sequentially to obtain the co-processed excipient. The co-processed excipient has a Brookfield flocculation factor of less than 0.2 kPa and a bulk density of at least 0.249 g / ml.

[0012] Similarly, U.S. Patent No. 10,172,944, assigned to Hercules LLC, teaches a co-processed additive composition having a cellulose-derived polymer and deagglomerated silica as a co-processed agent. The co-processed additive is prepared in a continuous process and has a Brookfield flocculation factor of less than 0.2 kPa and a bulk density of at least 0.249 g / ml.

[0013] Cross-linked polyvinylpyrrolidone (crospovidone type B) is a commonly used additive in oral solid dosage (OSD) forms that promotes rapid disintegration. Additionally, agglomerated silica is a glidant commonly used to enhance the flow of OSD blends. Another additive commonly used in OSD forms is a lubricant. Lubricants are known to extend the life of production equipment used during OSD manufacturing. Nevertheless, these lubricants are notoriously difficult to supply due to their low bulk density and adhesion, making their implementation in continuous manufacturing schemes problematic; these challenges will be exacerbated as the pharmaceutical industry increasingly adopts continuous manufacturing processes.

[0014] Thus, there is a long felt need in the art to develop co-processed excipient compositions that have good or superior flow properties and compression behavior, and where the excipient further provides an OSD with superior hardness when used in a drug formulation, particularly an OSD form. Summary of the Invention [Means for solving the problem]

[0015] In one aspect, the present disclosure provides a method for the preparation of a tertiary amine comprising the steps of: (i) N-vinyl-2-pyrrolidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl The co-processed additive includes: (i) 90.0% to 99.9% by weight of a vinyllactam-derived polymer comprising a monomer selected from the group consisting of N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, and combinations thereof; (ii) 0.1% to 5.0% by weight of silica; and (iii) 0.1% to 5.0% by weight of at least one lubricant. In one non-limiting embodiment of the present disclosure, the vinyllactam-derived polymer is selected from the group consisting of poly(vinylpyrrolidone), crosslinked poly(vinylpyrrolidone), and combinations thereof.

[0016] In one non-limiting embodiment of the disclosure, the vinyl lactam derived polymer is present in an amount of from 98.0 to 99.0 wt %, based on the total weight of the additive composition. In another non-limiting embodiment of the disclosure, the silica is present in an amount of from 0.5 to 2.0 wt %, based on the total weight of the additive composition. In yet another non-limiting embodiment of the disclosure, the lubricant is present in an amount of from 0.1 to 3.0 wt %, based on the total weight of the additive composition.

[0017] In one non-limiting embodiment of the present disclosure, the silica is selected from the group consisting of colloidal silica, fumed silica, silicon dioxide, calcium silicate, and any combination thereof. In yet another non-limiting embodiment of the present disclosure, the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl dibehenate, and any combination thereof.

[0018] In one non-limiting embodiment of the present disclosure, the co-processed additive has a Brookfield Flow Factor of from 5 to 9.

[0019] Another aspect of the present disclosure provides a process for preparing the co-processed additive of the present disclosure, the process comprising the steps of: (i) blending a vinyl lactam derived polymer, silica and a lubricant to obtain a blend, and (ii) grinding the resulting blend to obtain a co-processed additive. In a non-limiting embodiment of the present disclosure, the process is a single-step process or a two-step process. In another non-limiting embodiment of the present disclosure, the process is a two-step process comprising the steps of: (i) blending a vinyl lactam derived polymer with silica; (ii) adding a lubricant to the blend of step (i) to obtain a blend; and (iii) grinding the resulting blend of step (ii) to obtain a co-processed additive.

[0020] In yet another aspect, the present disclosure provides a composition comprising the co-processed additive of the present disclosure for use in industrial applications selected from paints and coatings, personal care, detergents, medicines, dietary supplements, ceramics, insulation, pet food, animal and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic converters, and electronics. In one non-limiting embodiment of the present disclosure, the composition is used in medicine.

[0021] In yet another aspect, the present disclosure provides a directly compressible pharmaceutical composition comprising: (i) an active pharmaceutical ingredient; (ii) a co-processed additive of the present disclosure; and (iii) optionally one or more pharma- ceutically acceptable additives.

[0022] In another aspect, the present disclosure provides a method for preparing a directly compressible pharmaceutical composition of the present disclosure, comprising the following steps: (i) compressing an active pharmaceutical ingredient, a co-processed additive of the present disclosure, and optionally one or more additives; and (ii) compressing the resulting mixture of step (i). [Brief description of the drawings]

[0023] The objects, features and advantages of the present disclosure will become apparent from reading the following description in conjunction with the drawings / figures.

[0024] [Figure 1] FIG. 1 shows the Brookfield flow function coefficient (fcc) of the co-processed additive of Example 1 prepared using cross-linked polyvinylpyrrolidone (PVPP) and 0.7 wt%, 1.0 wt%, and 1.4 wt% silica (without the addition of any lubricant). [Diagram 2] FIG. 2 shows the feed factor (loss-in-weight feeder (LWF)) throughput analysis of the co-processed additive composition of Example 2 (Ex.2) and its comparison with the LWF throughput analysis of PVPP alone. [Diagram 3] The Brookfield flow function coefficient of the co-processed additive composition (Ex.2) and its comparison with PVPP alone are shown. [Figure 4] FIG. 1 shows the feed factor (Loss-in-Weight Feeder (LWF) throughput analysis) of the co-processed additive composition of Example 3 prepared using different lubricants. [Diagram 5] 1 shows the crush strength or hardness of the co-processed additive composition of Example 3 and its comparison with the co-processed additive composition of Example 1 (Ex.1A). [Figure 6]1 shows the hardness (kp) of directly compressed tablet samples of Ex.3B and Ex.3E. [Figure 7] FIG. 2 shows the feed factor (Loss-in-Weight Feeder (LWF) throughput analysis of the co-processed additive compositions of Example 4 and Example 3 (Ex. 3B) prepared by using 3.0 wt.% and 1.0 wt.% sodium stearyl fumarate. [Figure 8] 1 shows the release force data of acetaminophen tablet sample prepared by using the present co-processed excipient of Example 5A and its comparison with the control tablet sample CE 5A. [Figure 9] 1 shows the hardness (kp) of acetaminophen tablet samples prepared by using the co-processed excipient of Example 5A and its comparison with the control tablet sample CE 5A. [Figure 10] FIG. 1 shows the disintegration time (seconds) of acetaminophen tablet samples prepared by using the present co-processed excipient of Example 5A and its comparison with the control tablet sample CE 5A. [Figure 11] The crushing strength (kP) of the present tablet compositions, namely EX.5A, EX.5B and EX.5C, and its comparison with control tablet samples CE.5A and CE.5B are shown. [Figure 12] 1 shows the hardness (kp) of ibuprofen tablet samples prepared from direct compression of co-processed additive compositions Ex.3B (having 1 wt. % SSF) and Ex.4 (having 3.0 wt. % SSF). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Before describing in detail at least one embodiment of the inventive concept(s) as exemplary figures, experiments, results, and laboratory procedures, it is understood that the inventive concept(s) is not limited in its application to the details of the configuration and arrangement of components described in the following description or illustrated in the figures, experiments, and / or results. The inventive concept(s) is capable of other embodiments or of being practiced or performed in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning, and the embodiments are meant to be exemplary - not exhaustive. It is also understood that the phraseology and terminology employed herein is for the purpose of description and should not be considered as limiting.

[0026] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by one of ordinary skill in the art.

[0027] All patents, published patent applications, and non-patent publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All patents, published patent applications, and non-patent publications referenced in any part of this application are expressly incorporated by reference in their entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0028] All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that variations may be made to the compositions and / or methods, and in the steps or sequence of steps of the methods described herein, without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the inventive concept(s) as defined by the appended claims.

[0029] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0030] When used in conjunction with the term "comprising" in the claims and / or specification, the use of the word "a" or "an" can mean "one," but it is also consistent with the meanings of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and / or," unless the disclosure supports a definition that refers to only alternatives and "and / or," and the only alternatives or alternatives are explicitly indicated to be mutually exclusive. Throughout this application, the term "about" is used to indicate that values ​​include inherent variations of error for design, and methods are employed to determine values ​​and / or variations that exist among study subjects. Use of the term "at least one" will be understood to include 1 as well as any quantity greater than 1, including, but not limited to, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. This term may extend to 100 or 1000 or more depending on the term to which it is appended, and in addition, the 100 / 1000 amount should not be considered limiting, as higher limits may also produce satisfactory results. Additionally, use of the term "at least one of X, Y, and Z" will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z.

[0031] As used in this specification and claim(s), the words "comprising" (and any form of comprising, such as, for example, "comprise" and "comprises"), "having" (and any form of having, such as, for example, "have" and "has"), "including" (and any form of including, such as, for example, "includes" and "include") or "containing" (and any form of containing, such as, for example, "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0032] As used herein, the term "or combinations thereof" refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of the following: A, B, C, AB, AC, BC, or ABC, and also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB, where order is important in a particular context. Continuing with this example, expressly included are combinations that include one or more repeats of an item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. A skilled artisan will understand that there is typically no limit to the number of items or terms in any combination, unless otherwise clear from the context.

[0033] As used herein, the term "bulk density" refers to bulk density (BD), which is defined as the ratio of the apparent volume of a sampled material to its mass, referred to as the untapped bulk density, and also as the ratio of the tapped volume of a sampled material to its mass, referred to as the tapped bulk density. Useful procedures for measuring these bulk densities are described in United States Pharmacopeia 24, Test 616, "Bulk Density and Tapped Density", United States Pharmacopeia Convention, Inc, Rockville, Md, 1999.

[0034] As used herein, the term "deagglomeration" refers to the process of breaking down or dispersing aggregates, agglomerations, or clusters together.

[0035] As used herein, the term "co-processed excipient composition" refers to a co-processed excipient that is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing and without significant chemical changes.

[0036] As used herein, the term "mill" refers to a high-speed hammer mill for dry grinding or deagglomerating a variety of products. In particular, the mill is utilized as a hammer mill, which is characterized by an impact process between the blades and the input material. The material and air enter the mill and are impacted by the blades, after which gravity and material momentum force the material through a screen.

[0037] As used herein, the term "blender" refers to a continuous single or double helical ribbon blender having at least one second residence time; or a blender for batch processing, including, but not limited to, a "V" blender or a cone blender.

[0038] As used herein, the term "compaction" refers to the simultaneous process of compression and solidification of a two-phase system (solid air) by an applied force.

[0039] As used herein, the term "direct compression" or "DC" refers to obtaining a dosage form by directly compressing and molding raw powders. This process is described in publications such as The Theory and Practice of Industrial Pharmacy (3rd Edition) (Leon Lachman et al.: LEA & FEBIGER 1986) and Pharmaceutical Dosage Forms: Tablets Volume 1 (2nd Edition) (Herbert A. Lieberman et al.: MARCEL DEKKER INC. 1989).

[0040] As used herein, the term "continuous process" refers to steady production, such as manufacturing on a continuous blend, rather than being performed batchwise. In non-continuous processes, i.e., batch production processes, the insertion of raw materials into a machine / mill and the subsequent removal of the freshly manufactured composition from the machine / mill takes too long to permit low-cost production. The significance of the term "continuous production" here is the potential importance of the benefits gained by an assembly line with each step characterized by an average residence time.

[0041] In one aspect, the present disclosure provides a co-processed additive composition comprising: (i) a vinyl lactam-derived polymer; (ii) at least one silica; and (iii) at least one lubricant.

[0042] In one non-limiting embodiment of the present disclosure, the vinyl lactam derived polymer is N-vinyl-2-pyrrolidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5 -trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, and any combination thereof; in one non-limiting embodiment of the present disclosure, the vinyl lactam derived polymer can be polyvinylpyrrolidone or crosslinked polyvinylpyrrolidone, or a combination thereof.

[0043] Polyvinylpyrrolidone (PVP) useful for purposes of this disclosure refers to a polymer available in different pharmaceutical grades. A particularly preferred source of polyvinylpyrrolidone is Plastidone, available commercially from Ashland LLC. TM (Plastidon, TM (trademark in the United States, etc.) povidone.

[0044] Additionally, polyvinylpyrrolidone useful for the purposes of the present disclosure can be cross-linked polyvinylpyrrolidone (also referred to as cross-linked PVP or PVPP). Such polymers are also commercially available in different pharmaceutical grades and can be used for the purposes of the present disclosure. A suitable and non-limiting example of such a commercially available cross-linked PVP is Polyplasdone XL. (R) (Polyplasdone XL, (R)is a registered trademark in the United States, etc.), Polyplasdone XL-10 (R) , Polyplasdone INF-10 (R) and Polyplasdone ultra, marketed by Ashland LLC. Cross-linked PVP is a commonly used excipient in oral solid dosage forms that promotes rapid disintegration.

[0045] Further, the vinyl lactam derived polymer can be present in an amount of from 90.0% to 99.9% by weight based on the total weight of the co-processed additive composition. In one non-limiting embodiment of the present disclosure, the amount of vinyl lactam derived polymer can range from about 90.0% to about 95.0% by weight, or from about 95.0% to about 99.0% by weight, or from about 98.0% to about 99.0% by weight based on the total weight of the co-processed additive composition.

[0046] The silica used in the co-processed additive composition of the present disclosure may be selected from the group consisting of colloidal silica, fumed silica, silicon dioxide, calcium silicate, and any combination thereof.

[0047] In a non-limiting embodiment of the present disclosure, the silica can be fumed silica. Moreover, the silica can be present in an amount of about 0.1% to about 5.0% by weight based on the total weight of the co-processed additive. In a non-limiting embodiment of the present disclosure, the amount of silica can vary in the range of about 0.1% to about 4.0% by weight, or about 0.1% to about 3.0% by weight, or about 0.1% to about 2.0% by weight, or about 0.5% to about 4.0% by weight, or about 0.5% to about 3.0% by weight, or about 0.5% to about 2.0% by weight, or about 0.5% to about 1.0% by weight based on the total weight of the co-processed additive composition.

[0048] Silicon dioxide, particularly colloidal silicon dioxide, has a particle size, particularly less than 500 nm, more particularly less than 400 nm. Those skilled in the art will recognize that the name and / or preparation method of the silicon dioxide utilized in the present invention is not determinative of the usefulness of the product. Rather, it has been surprisingly discovered that it is the physical properties of the silicon dioxide that are important. In particular, silicon dioxide having a relatively large particle size (and correspondingly small surface area), such as silica gel, has been found not to be useful in the present disclosure. Silica itself is commercially available from Cabot Corporation (under the trade name Cab-O-Sil); Degussa, Inc. (under the trade name Aerosil (R) Colloidal silicon dioxide is a submicron, fluffy, light, loose, bluish-white, odorless, and tasteless amorphous powder that is commercially available from several sources, including Aerosil; EI DuPont & Co.; and WR Grace & Co. Colloidal silicon dioxide is, among others, colloidal silica, fumed silica, amorphous fumed silica, silicon dioxide, amorphous silica, light silicic acid anhydride, silicic acid anhydride, and fumed silicon dioxide. However, the amount of silicon dioxide included in pharmaceutical applications is limited, and it ranges from 0.01-1% by weight. Handbook of Pharmaceutical Excipients, COPYRGT. 1986 American Pharmaceutical Association, p. 255.

[0049] The co-processing excision point of the present disclosure may further comprise at least one lubricant. Lubricants are typically added to reduce tablet ejection force. Suitable and non-limiting examples of such lubricants for the purposes of the present disclosure may include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, glyceryl dibehenate, talc, sucrose fatty acid esters and the like. In one non-limiting embodiment of the present disclosure, the lubricant may be sodium stearyl fumarate. Furthermore, the lubricant may be added in an amount ranging from about 0.1% to about 5.0% by weight, or from about 0.1% to about 3.0% by weight, based on the total weight of the additive composition.

[0050] The co-processed additive composition of the present disclosure can be prepared by co-processing various components as described herein. In another aspect, the present disclosure provides a process for preparing the co-processed additive of the present disclosure. The process according to the present disclosure typically involves blending and grinding various components. Furthermore, the process can be a single step process or a two-step process. In one non-limiting embodiment of the present disclosure, the process can be a two-step process including the following steps: (i) blending the vinyl lactam derived polymer and silica for 1 to 30 minutes; (ii) adding a lubricant to the blend of step (i) and blending for an additional 1 to 30 minutes to obtain a blend; and (iii) grinding the resulting blend of step (ii) for 1 to 30 passes to obtain a co-processed additive.

[0051] The method according to the present disclosure provides a co-processed additive having a Brookfield Flow Factor of from 5 to 9. Additionally, the method according to the present disclosure is advantageous because it avoids two additional time consuming manufacturing steps, namely, the separate addition of silica and lubricant.

[0052] Another aspect of the present disclosure provides a composition comprising the co-processed additive composition of the present disclosure, where the composition can be useful in industrial applications. Suitable and non-limiting examples of such industrial applications include, but are not limited to, paints and coatings, personal care, detergents, medicines, nutraceuticals, ceramics, insulation, pet food, animal and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic converters, and electronics. In one non-limiting embodiment of the present disclosure, the composition can be used in pharmaceutical applications.

[0053] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising the co-processed additive of the present disclosure. The pharmaceutical composition according to the present disclosure can comprise: (i) an active pharmaceutical ingredient; and (ii) a co-processed additive of the present disclosure.

[0054] Any active pharmaceutical ingredient (API) well known to those skilled in the relevant art can be suitably used for the purpose of the present disclosure, for example, as a drug or biofunctional ingredient(s).Suitable examples of bioactive ingredients useful for the purpose of the present disclosure include, but are not limited to, dietary supplements, including vitamins, such as vitamin C, vitamin Bl, B2, B3, B6 and B12; minerals, such as zinc, magnesium, iron, and melatonin; herbal dietary supplements, such as curcumin, ashwagandha, and fenugreek extract; amino acids, such as isoleucine, glycine, L-tryptophan, glucosamine, chondroitin, and the like.

[0055] In another non-limiting embodiment of the present disclosure, the active pharmaceutical ingredient can be a drug. Any drug with a wide range of water solubility can be suitably used in the pharmaceutical composition of the present invention. In one non-limiting embodiment of the present disclosure, the drug can be selected from a group of drugs belonging to different therapeutic classes, such as, for example, antipyretics, analgesics and anti-inflammatory drugs, anthelmintics, cardiovascular drugs, antibacterial drugs, bronchodilators, antiasthmatic drugs, gastrointestinal drugs, antidiabetic drugs, antiprotozoal drugs, antiviral drugs, antiepileptic drugs, antidiuretics, or their pharma-ceutically acceptable salts and esters.

[0056] Further, the active pharmaceutical ingredient can be present in a pharmaceutical effective amount. The amount of the active pharmaceutical ingredient can vary depending on various factors, including, but not limited to, the type of drug or drugs used, the nature and severity of the disease to be treated / cured, the type and content of the active ingredient or other ingredients contained in the pharmaceutical composition, the dosage form, the age, weight, health condition and feeding behavior of the patient, the time of administration of the drug, and the like. In one non-limiting embodiment of the present disclosure, the amount of the active pharmaceutical ingredient can vary from about 10.0% to about 70.0% by weight, or from about 20.0% to about 70.0% by weight of the total weight of the pharmaceutical composition.

[0057] The composition for pharmaceutical use according to the present disclosure can further comprise at least one pharmaceutical acceptable excipient.The pharmaceutical acceptable excipients generally used in pharmaceutical compositions are also suitable for use in the present composition, for example, the excipients described in Handbook of Pharmaceutical Excipients, Row et al., Eds., 4th Edition, Pharmaceutical Press (2003) or Remington; The Science and Practice of Pharmacy (previously called Remington's Pharmaceutical Sciences), Alfonso R. Gennaro, ed., Lippincott Williams & Wilkins; 20th Edition (December 15, 2000). Examples of such additives can include, but are not limited to, fillers, pigments, binders, lubricants, flow aids, flavors, sweeteners, preservatives, stabilizers, antioxidants, and the like.

[0058] Furthermore, the pharmaceutical ingredient can be present in an amount that does not affect the therapeutic properties of the composition for medicinal use. The pharma-ceutically acceptable ingredient can be present in an amount of about 1.0% to about 85.0% by weight of the total weight of the composition. In one non-limiting embodiment of the present disclosure, the amount of the pharma-ceutically acceptable ingredient can vary in the range of about 5.0% to about 75.0% by weight, or about 5.0% to about 60.0% by weight of the total weight of the medicinal composition.

[0059] Further, in one non-limiting embodiment of the present disclosure, the co-processed additive of the present disclosure can be present in an amount from about 2.0% to about 20.0% by weight, based on the total weight of the pharmaceutical composition.

[0060] The composition for medicinal use according to the present disclosure can be in a dry solid dosage form. Dry solid dosage forms are useful for delivering precise doses to a specific site, usually orally, but can also be administered via other routes known to those skilled in the relevant art, such as sublingual / buccal, rectal, vaginal, and ocular. In a non-limiting embodiment of the present disclosure, the composition for medicinal use can be in a solid dosage form suitable for oral administration. Such dosage forms can include, but are not limited to, tablets, capsules, powders, granules, sachets, or lozenges. In a non-limiting embodiment of the present disclosure, the composition for medicinal use can be a tablet formulation.

[0061] Tablet formulations according to the present disclosure can be prepared, for example, by tableting methods well known to those skilled in the pharmaceutical art, such as wet granulation tableting or dry granulation tableting or dry direct tableting, etc. In one non-limiting embodiment of the present disclosure, the tablet formulation can be prepared by dry direct tableting or direct compression (DC) methods.

[0062] In another aspect, the present disclosure provides a directly compressible tablet formulation. A directly compressible tablet formulation typically includes: (i) a co-processed excipient of the present disclosure; (ii) at least one active pharmaceutical ingredient (API); and (iii) at least one active pharmaceutical excipient.

[0063] In yet another aspect, the present disclosure provides a process for preparing a directly compressible tablet formulation. The directly compressible tablet formulation can be prepared continuously or batchwise. The method can include the steps of: (i) pre-grinding or sieving various components of the composition, such as the co-processed additives of the present disclosure; active pharmaceutical ingredients, such as drug(s) and the like; and pharma-ceutically acceptable additive(s) to obtain finely powdered components; (ii) blending or mixing the finely powdered components uniformly to obtain a homogenous blend; and (iii) compressing the homogenous blend to obtain a directly compressible tablet formulation.

[0064] The co-processed additive composition according to the present disclosure is a multifunctional disintegrant suitable for use in oral solid dosage form manufacturing. The co-processed additive demonstrates excellent flow properties and self-lubrication. The co-processed additive of the present invention provides tablets with improved hardness, improved process throughput and enhanced quality performance when used in direct compression tablet manufacturing.

[0065] Further, certain aspects of the present application are illustrated in detail by the following examples, which are provided herein to illustrate the present application and are not intended to be limiting thereof. EXAMPLES

[0066] How we tested Unless otherwise indicated, the following test methods were utilized in the examples below. Bulk density

[0067] Bulk density testing was performed via standard USP method: material was dispensed into a 100 ml graduated cylinder and the mass was recorded. particle size

[0068] A Malvern Mastersizer 2000 was used for particle size analysis. The experimental method is called dynamic light scattering (dls). Flow characteristics

[0069] Flow characteristics were measured using a loss-in-weight feeder (LWF). In a typical experiment, ~1.5 kg (~ is used before numbers to indicate "approximately" or "about") of material was introduced into a concave-thread fed K-TRON KSU-II LWF. The material was then studied as it flowed at the nominal mass flow rate set point of ~2 kg / hr.

[0070] Mass flow rate and CMD% (motor speed) were then recorded over a period of time. The experiment was determined to be over when a value of 5 or greater of 110% CMD was recorded, indicating that the feeder was no longer able to reliably maintain the mass flow rate set point.

[0071] The mass flow rate was then divided by the CMD% to produce a number called the feed factor, which represents the inherent flowability of the powder when it is used on the LWF. As an example, a higher feed factor indicates higher inherent flowability (i.e. the feeder needs less CMD% (energy) to maintain the mass flow set point).

[0072] For benchtop flow studies, perform a Brookfield Flow Function test to generate a flow function coefficient (ffc), which is the reported simple 1 / slope of the test. Example 1: Co-processing of cross-linked polyvinylpyrrolidone (PVPP) with silica

[0073] In this example, cross-linked polyvinylpyrrolidone (PVPP) (available as Polyplasdone XL-10 from Ashland LLC.) was co-processed with fumed silica (available as Cab-O-Sil from Cabot Corporation) and lubricated. Three different samples were prepared using PVPP and fumed silica in the weight ratios shown in Table 1. In a typical expeiment, PVPP and silica were blended in a ribbon blender (200 Ft3) at 1.5 rpm for ∼10 minutes. The Brookfield Flow Function Coefficients (ffc) of all samples were measured and are provided in Table 1 and further illustrated in Figure 1. [Table 1] Example 2: The present co-processed additive composition (Ex.2)

[0074] The co-processed additive composition of this example was prepared on a pilot scale. 0.35 lb (0.7 wt%) silica and 49.15 lb (98.3 wt%) cross-linked polyvinylpyrrolidone (PVPP: Polyplasdone XL-10) were blended together for 10 minutes on a 5Ft3 Ross Ribbon blender at 49.3 m / s. The resulting blend was then mixed with 0.5 lb (1.0 wt%) sodium stearyl fumarate (SSF) for an additional 2 minutes. The resulting blend thus obtained was then milled using a Fitz Mill (Model JT, SN 1408) on a 0.033'' screen to obtain the resulting co-processed additive (Ex.2) (Polyplasdone XL-10 DC). The loss-in-weight feeder (LWF) throughput analysis, Brookfield flow function coefficient (ffc) and particle size distribution (PSD) of the co-processed additive composition (Ex.2) were measured and compared to crosslinked PVP alone. [Table 2]

[0075] From Table 2, it is clear that co-processing of Example 2 does not change the PSD of the co-processed excipient (Ex.2). Also illustrated in Figures 2 and 3 are the feed factor (loss-in-weight feeder (LWF)) throughput analysis and Brookfield flow function coefficient (Ex.2) of the co-processed excipient composition (Ex.2) and its comparison with PVPP. The figures provided show that the feed factor of the co-processed excipient composition (Ex.2) increased by ~9%, the % relative standard deviation (RSD) of the feed factor decreased by 32%, and the flow function increased by 29% compared to PVPP alone. Example 3: Co-processed additive composition with different lubricants

[0076] Three different samples (Ex.3A, Ex.3B and Ex.3C) of the present co-processed additive composition using different lubricants were prepared in this example. The various components including their weight ratios used to prepare the co-processed additive composition are shown in Table 3. These additives were prepared on a laboratory scale. In a typical experiment, 14.0 gm (0.7 wt%) of silica and 1966.0 gm (98.3 wt%) of cross-linked polyvinylpyrrolidone (PVPP) were blended together in a ribbon blender (200Ft3) at 1.5 rpm for ∼10 minutes. The resulting blend was then mixed with 20.0 gm (1.0 wt%) of sodium stearyl fumarate (SSF) and blended for ∼5 minutes. The resultant blend thus obtained was then milled for ∼1 minute using a Fitz Mill (Model DAS06) at a tip speed of 59.2 m / s, a hammer advancing through a 0.033″ screen to obtain the resultant co-processed additive (Ex.3A). The feed factor analysis of all samples in this example is illustrated in FIG. [Table 3]

[0077] The co-processed excipient compositions (Ex.3A, Ex. 3B, Ex.3C and Ex. 3D) were further directly compressed into tablets, as was cross-linked PVP (Polyplasdone) alone (Ex.3E). In a typical process, each co-processed excipient composition was blended on a Turbula mixer for ∼10 minutes. The resulting homogenous blend was then compressed into tablets with individual tablet weights of 400 mg on a StylCam, a compaction simulator simulating a Manesty Betapress operating at ∼37 RPM. 11.28 mm flat faced tooling (TSM B) was used at the reported compression force. These tablets were characterized for crushing strength or hardness (kp). Their crushing strength or hardness was further compared to tablets prepared using the co-processed excipient composition of Example 1 (Ex.1A). Their comparative analysis is further illustrated in Figure 5. Additional comparative analysis was performed comparing the tablet hardness of Ex. 3B with Ex 3E (Figure 6). This demonstrated that the novel excipient composed of co-processed cross-linked PVP, silica, and sodium stearyl fumarate (Ex. 3B) was more compressible than the original polymer (cross-linked PVP) alone (Ex. 3E). Example 4: Co-processed additive with different weight percentages of sodium stearyl fumarate

[0078] The co-processed additive composition of this example (Ex. 4) was prepared in the same manner as described in Example 3, except that 3 wt. % sodium stearyl fumarate was used. The feed factor analysis of this additive composition and a comparison with the additive composition of Example 3 (Ex. 3B with 1 wt. % SSF) is illustrated in FIG. Example 5: Directly compressed (DC) acetaminophen (APAP) tablets (Ex. 5A, Ex. 5B and Ex. 5C)

[0079] Acetaminophen (APAP) was used as a model drug to prepare directly compressible tablets. A typical tablet formula is shown in Table 4. In a typical process, the ingredients in the weight ratios as listed in Table 4 were blended on a Turbula mixer for .about.10 minutes. The resulting homogenous blend was then compressed into tablets with individual tablet weights of 400 mg on a StylCam, a compaction simulator simulating a Manesty Betapress operating at .about.37 RPM. Production equipment (TSM-B) with 11.28 mm flat faces was used at the reported compression forces. Control directly compressed acetaminophen (APAP) tablets (CE. 5A and CE.5B)

[0080] A comparative or control directly compressed tablet formulation (CE.5A) was prepared in the same manner as described in Example 5, using the ingredients in the weight ratios listed in Table 4. In this example, crosslinked PVP, fumed silica and sodium stearyl fumarate were blended together without co-processing them. The physical blend thus obtained was mixed with APAP and compressed into tablets in the same manner as described in Example 5. Another comparative or control directly compressed APAP tablet formulation (CE.5B) was also prepared using only crosslinked PVP. [Table 4]

[0081] The ejection force data of tablet samples, Ex.5A and CE.5A, were recorded by the instrument and are illustrated in FIG. 8. The tablets were held and subsequently characterized for hardness and disintegration time. FIG. 9 and FIG. 10 further illustrate the hardness (kp) and disintegration time (sec) of tablet samples Ex.5A and CE.5A. From the figures provided, it is clear that the directly compressed tablets of Ex.5A achieve a lower ejection force compared to the control tablet sample of CE.5A. Furthermore, the directly compressed tablets of Ex.5A achieve a higher tablet hardness and comparative tablet disintegration time compared to the control tablet sample of CE.5A. FIG. 11 depicts the crushing strength (kP) of the present tablet samples, i.e., EX.5A, EX.5B and EX.5C, in comparison with the control tablet samples CE.5A and CE.5B. Example 6: Directly compressed (DC) ibuprofen tablets:

[0082] In this example, another direct compression (DC) tablet formulation was prepared using ibuprofen as the active pharmaceutical ingredient. The tablet formulation (500 mg individual tablet weight) was prepared in the same manner as described in Example 5 using the ingredients in the weight ratios listed in Table 5. The tablet samples in this example were characterized for hardness and disintegration time similar to the tablet samples in Example 5. The hardness and disintegration time are further illustrated in Figure 12. [Table 5]

Claims

1. (i) N-vinyl-2-pyrrolidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl from about 90.0% to about 99.9% by weight of a vinyl lactam-derived polymer comprising a monomer selected from the group consisting of N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2-caprolactam, and combinations thereof; (ii) from about 0.1% to about 5.0% by weight of silica; and (iii) from about 0.1 wt. % to about 5.0 wt. % of at least one lubricant; and A co-processed excipient comprising:

2. 2. The co-processed additive of claim 1, wherein the vinyl lactam derived polymer is selected from the group consisting of polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and combinations thereof.

3. 2. The co-processed additive of claim 1, wherein the vinyl lactam derived polymer is present in an amount of from about 98% to about 99% by weight based on the total weight of the additive composition.

4. 2. The co-processed additive of claim 1, wherein the silica is present in an amount of from about 0.5% to about 2.0% by weight based on the total weight of the additive composition.

5. 2. The co-processed additive of claim 1, wherein the silica is selected from the group consisting of colloidal silica, fumed silica, silicon dioxide, calcium silicate, and any combination thereof.

6. 10. The co-processed additive of claim 1, wherein the lubricant is present in an amount of from about 0.1% to about 3.0% by weight based on the total weight of the additive composition.

7. 2. The co-processed additive of claim 1, wherein the lubricant is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, stearic acid, glyceryl dibehenate, and any combination thereof.

8. 2. The co-processed excipient of claim 1, wherein the co-processed excipient has a Brookfield flow factor of 5 to 9.

9. 10. The co-processed additive of claim 1, wherein the co-processed additive is further combined with an active or functional ingredient selected from the group consisting of paints, coatings, personal care ingredients, detergents, drugs, dietary supplements, ceramics, insulators, pet food animal foods, human foods, agricultural products, adhesives, electroplating ingredients, inks, dyes, paper ingredients, catalytic converters, electronics, and combinations thereof.

10. 2. A process for preparing the co-processed additive of claim 1, comprising: (i) combining a vinyl lactam derived polymer, a silica and a lubricant to obtain a blend; (ii) grinding the resulting blend of step (i) to obtain a co-processed excipient; The process includes:

11. 11. The process of claim 10 which is a single step process or a two step process.

12. The process is (i) combining a vinyl lactam derived polymer and silica; (ii) adding a lubricant to the blend of step (i) to obtain a blend; (iii) grinding the resulting blend of step (ii) to obtain the co-processed excipient; 11. The process of claim 10, which is a two-step process comprising:

13. 11. The process of claim 10, wherein the co-processed additive has a Brookfield flow factor of 5 to 9.

14. 13. A composition comprising the co-processed additive of claim 1 for use in an industrial application selected from paints and coatings, personal care, detergents, pharmaceuticals, dietary supplements, ceramics, insulation, pet food, animal and human food, agricultural products, adhesives, electroplating, inks, dyes, paper, catalytic converters, and electronics.

15. 15. The composition of claim 14, wherein the composition is for use in medicine.

16. 15. The composition of claim 14, wherein the composition is formulated into an oral dosage form by dry granulation, wet granulation, roller compaction, direct or hot melt extrusion processing, and said oral dosage form is prepared by a batch process or by a continuous process.

17. (i) at least one active pharmaceutical ingredient; (ii) a co-processed excipient according to claim 1; (iii) optionally one or more pharma- ceutically acceptable excipients; 1. A directly compressible pharmaceutical composition comprising:

18. The composition may be formulated into a modified release, controlled release, sustained release, extended release, immediate release or soluble dosage form; 20. The directly compressible pharmaceutical composition of claim 17, wherein the composition is prepared by a batch process or by a continuous process.

19. (i) combining said active pharmaceutical ingredient, the co-processed excipient of claim 1, and optionally one or more additives; (ii) compressing the resulting mixture of step (i); and 20. A process for preparing the directly compressible pharmaceutical composition of claim 17, comprising:

20. 20. The process of claim 19 which is a batch process or a continuous process.

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