LOW-DUSTING, FLOWABLE AMINOPYRIDINE PRODUCTS

Abstract: Described are preferred processes for producing extrusion-granulated aminopyridine products, and granular products obtainable therefrom. Preferred products are prilled aminopyridines providing a low-dusting, flowable product form, especially prilled 2-aminopyridine.

Description: LOW-DUSTING, FLOWABLE AMINOPYRIDINE PRODUCTS BACKGROUND OF THE INVENTION The present invention resides generally in the field of the preparation and use of aminopyridine compounds, and in one particular embodiment to novel prilled forms of aminopyridine compounds. As further background, aminopyridines are well known intermediates to a broad range of useful compounds including for example pharmaceuticals, for instance antihistamines, dyestuffs, and other compounds. 2-aminopyridine in particular is used on a large scale worldwide as an intermediate to pharmaceutical compounds. Aminopyridines such as 2-aminopyridine have heretofore been available in crystalline or flaked forms. However, such product forms have exhibited tendencies to agglomerate and dust, thus complicating storage and transfer operations. As a consequence, new product forms of aminopyridines are needed that avoid or reduce these difficulties which have been encountered in the handling of crystalline or flaked aminopyridine forms. The present invention addresses this need. SUMMARY OF THE INVENTION It has been discovered that aminopyridines in molten form exhibit properties whereby advantageous granular aminopyridine product forms can be provided by a melt extrusion processes, especially a prilling process. Accordingly, one embodiment of the present invention provides a process for manufacturing an aminopyridine product in a unique form which has reduced tendency to dust and improved free-flowing properties as compared, for example, to known flaked forms. The preferred process for preparing an aminopyridine product, especially 2-aminopyridine, includes a step of providing the aminopyridine as a molten flowable mass. This flowable mass is then extruded through an orifice into discrete liquid portions each corresponding to a granule to be formed. These liquid portions, in turn, are cooled to form a granular aminopyridine product. The granular aminopyridine product, most preferably 2-aminopyridine, desirably has an average particular diameter of about 1 to about 10 mm. Suitable melt temperatures range from the melting point for the aminopyridine up to just below the decomposition temperature for the aminopyridine, with preferred melt temperatures ranging from about the melting point of the aminopyridine up to about 90° above that point, more preferably from the melting point up to about 20°C above the melting point. In still more preferred processes, the extruding step is conducted using equipment optimally designed for forming the discreet portions. For example, such may involve an extrusion apparatus equipped to deliver the flowable mass through an orifice for a predetermined period of time to provide drops of the appropriate size. This control can be achieved, for example, by providing first and second wall members movable relative to one another to periodically align one or more orifices in the first member with one or multiple orifices in the second member for the predetermined period of time. The flowable mass is pressurized against the first wall member such that when orifice (s) in the first wall member are each aligned with one or multiple orifice (s) in the second wall member, an amount of the flowable mass is extruded through the orifices in the second wall member, for example downwardly onto a conveyor belt. Most preferred devices for these purposes include as the first member, a first container filled and pressurized with the flowable mass, and as the second member a second container, e.g. a drum, encasing the first container. The containers are movable (e.g. rotatable) with respect to one another, preferably provided by a static inner container and a movable (rotating) outer container. Movement of the second container results in periodic alignment of the orifice (s) in the first container with orifice (s) of the second container for the predetermined time, during which the drops of aminopyridine product material are extruded through the aligned orifices and downwardly onto a passing conveyer belt. Such processes provide preferred, smooth- surfaced aminopyridine product granules of uniform size and shape, for example generally hemispherical in shape . Another preferred embodiment of the invention provides a composition comprising a granulated aminopyridine, especially a granulated 2-aminopyridine product. Preferred such products have an average particle diameter of about 1 mm to about 10 mm, with most preferred product forms having smooth granules of substantially uniform size and/or shape. The invention provides improved aminopyridine products that overcome handling and processing difficulties previously encountered with aminopyridine products. Additional objects, features and advantages of the invention will be apparent from the description that follows. DESCRIPTION OF THE PREFERRED EMBODIMENTS For the purposes of promoting an understanding of the principles of the invention, reference will now be made to certain preferred embodiments thereof and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations, further modifications and applications of the principles of the invention as described herein being contemplated as would normally occur to one skilled in the art to which the invention relates. As disclosed above, one preferred embodiment of the present invention provides novel forms of aminopyridine products. The novel forms in accordance with the invention are granular, and are preparable by melt extrusion processes which yield discreet liquid portions which upon solidification form smooth granules or prills. In this regard, it has been discovered that 2-aminopyridine exhibits properties under melt which render it advantageous in such melt extrusion processes. For example, these properties include relatively rapid crystallization upon cooling, and the absence of substantial supercooling that would frustrate the ability to yield a three-dimensional particle in a melt extrusion process such as prilling. It is expected that the structurally similar compounds, 3-aminopyridine and 4-aminopyridine, will similarly exhibit such properties. Preferred melt extrusion processes of the invention involve the extrusion of molten 2-, 3- or 4- aminopyridine products. Preferred products for use in the invention thus include those of the formula: The most preferred aminopyridine for melt extrusion processing in accordance with the invention is 2-aminopyridine: As disclosed above, the aminopyridine is extruded, while molten, through an orifice in a fashion which provides granules of the desired size. Processes of the invention can, for example, be conducted in an extrusion apparatus as described in U.S. Patent No. 4,279,579, which is hereby incorporated herein by reference in its entirety. Such an apparatus includes a first container having a plurality of orifices and a second container disposed within the first container. Means are provided for admitting the flowable molten mass of product into the second container, and means are also provided for producing relative rotation between the containers to periodically align the orifices of the first container with a fluid passage (s) of the second container, so as to deposit drops of the flowable mass through the orifices of the first container downwardly onto a conveyor belt also provided in the apparatus. Such processes in which discreet drops or portions are caused to solidify to form flowable granules are generally referred to as prilling processes, and the resulting granules are referred to as prills. In the preferred process, the conveyor belt is a cooled stainless steel belt, which hastens the solidification of the flowable mass drops as they exit the passage provided by the aligned orifices. Suitable devices for the conduct of such processes are commercially available from Sandvic Process Systems, Inc. of Totowa, New Jersey, U.S.A. Further information regarding such devices is available from Sandvic 's trade literature, including that entitled Sandvik Rotoform® Process, Premium Pastilles at high production rates, low production costs (1993); A World of Chemical Experience in Chemical Processing: Sandvik Process Systems. As indicated, the aminopyridine compound is provided in a molten state for extrusion processing. Preferred melt processing temperatures will range from about the melting point of the product up to the decomposition temperature of the compound. More preferred temperatures will be at about the melting point up to about 90°C above the melting point of the compound in hand. For the most preferred compound, 2- aminopyridine, a generally suitable temperature range is about 56°C to about 150°C, and a more preferred temperature range is about 60°C to about 80°C. For 3- aminopyridne, a suitable temperature range is about 64°C to about 150°C, more preferably about 64°C to 90°C; and, for 4-aminopyridine, a suitable temperature range is about 158°C to about 250°C, more preferably about 158°C to about 180°C. In any event, the temperature utilized will be selected in light of the conditions at hand, and will be optimized to provide the desired viscosity of the flowable product mass for extrusion processing in accordance with the invention. Granulated products in accordance with the invention will preferably have smooth granules with an average particle diameter of about 1 to about 10 mm, more preferably about 1 to about 5 mm. In addition, preferred products will have granules of substantially uniform shape and size. When produced by preferred extrusion processes as described above, granulated products of the invention will have a substantially 3- dimensional shape (i.e. the deposited drops will solidify prior to their spreading to form a substantially 2-dimensional flake) , which provides improved flow properties for the solid product in accordance with the invention. Preferred granules so prepared will generally also have a non-uniform thickness, with a relatively flat or planar surface on a first side (from contact with the conveyor belt) , and a generally arcuate surface on a second side opposite the first side. Preferred granulated products of the invention also exhibit desirable dissolution properties in aqueous medium, meaning that while provided in a readily handled and manipulated granulated form in the dry state, once placed in aqueous media, the product granules break up and dissolve into solution with relative ease and quickness, generally within about a few minutes with agitation. In addition, preferred granulated products of the invention will have a low level of fines having a particle diameter of less than 600 microns, more preferably less than 5% by weight fines. Particle integrity of preferred products will also minimize the generation of fines under conditions of abrasion and impact. The preferred granulated products of the invention are free-flowing, and exhibit a reduced tendency to aggregate as compared to corresponding flaked product forms. These products thus overcome difficulties which have been encountered with prior flaked aminopyridine forms, and are advantageously handled in manufacturing, storage and use operations. As illustrations, products of the invention demonstrate advantages making them well suited for transport operations including gravity flow or vacuum, (e.g. as in gravity flow addition or vacuum addition to reactors) , and can optionally be packaged in containers adapted to facilitate such operations. For instance, in the case of gravity flow addition, granulated products of the invention can be packaged in containers that are adapted for connection to reactor ports and that incorporate product release mechanisms that are activatable upon or after such connection. Such containers may also be adapted for efficient gravity flow of the granular product out of an opening of the container, and in this regard may have a shape adapted to release all of the granular product upon activation of the product release mechanism. To this end, the container may include one or more wall members inclined downwardly toward the opening of the container adapted for connection to the reactor port. In this manner, safe, efficient and convenient use of granular products of the invention is facilitated. For purposes of promoting a further understanding of the present invention and its advantages, the following specific Examples are provided. It will be understood that these Examples are illustrative, and not limiting, of the present invention. Example 1 Preparation of 2-Aminopyridine Prills In this example a Rotoformer available from Sandvik Process Systems, Inc., Totowa, New Jersey, USA, was used to prepare 2-aminopyridine prills. This machine generally has the features described U.S. Patent No. 4,279,579, and is also described in Sandvik Rotoform® Process, Premium Pastilles at high production rates, low production costs (1993); A World of Chemical Experience in Chemical Processing: Sandvik Process Systems. The bore size on the rotating shell of the rotoformer was 1.5 mil. 2-aminopyridine was maintained as a melt at about 60°C-70°C for feed to the rotoformer. During operation of the machine, molten 2- aminopyridine was extruded through the bores onto the cooled belt of the rotoformer, providing 2- aminopyridine prills having diameters of about 2-3 mm. The prills were removed at the end of the belt by a micarta laminated plastic blade, at which point the prills exhibited a temperature of about 27-28°C. Upon inspection, the prills were found to be substantially uniform in shape and to exhibit excellent hardness and integrity. The prills also exhibited little or no tendency to cake. Example 2 Preparation of 3-Aminopyridine Prills The procedure of Example 1 is repeated, except using 3- aminopyridine to make a prilled 3-aminopyridine product. In addition, the 3-aminopyridine is maintained as a melt at 65°C to 75°C for feed to the rotoformer. Example 3 Preparation of 4-Aminopyridine Prills The procedure of Example 1 is repeated, except using 4-aminopyridine to make a prilled 4-aminopyridine product. In addition, the 4-aminopyridine is maintained as a melt at 160°C to 170°C for feed to the rotoformer. The invention has been described above in detail, with specific reference to its preferred embodiments. It will be understood, however, that a variety of modifications and additions can be made to the procedures disclosed without departing from the spirit and scope of the invention. Such modifications and additions are desired to be protected. In addition, all publications cited herein are indicative of the level of skill in the relevant art, and are each hereby incorporated by reference each in their entirety as if individually incorporated by reference and fully set forth .

Claims: WHAT IS CLAIMED IS: 1. A process for preparing a low-dusting, free- flowing aminopyridine product, comprising: providing an aminopyridine as a molten flowable mass; extruding said molten flowable mass through an orifice into discrete liquid portions each corresponding to a granule to be formed; and cooling said discrete liquid portions to form a granular aminopyridine product. 2. The process of claim 1, wherein said aminopyridine is 2-aminopyridine. 3. The process of claim 1, wherein said granules have an average particle diameter of about 1 to about 10 mm. 4. The process of claim 3, wherein said granules have an average particle diameter of about 2 to about 5 mm. 5. The process of claim 2, wherein said molten flowable mass has a temperature of about 58°C to about 150°C. 6. The process of claim 1, wherein said extruding includes: providing first and second wall members each having orifices, wherein the wall members are movable relative to one another to periodically align orifices in the first member with those in the second member for the predetermined period of time; providing the molten flowable mass under pressure against the first wall member such that when the orifices in the first and second wall members are aligned, said discrete portions are extruded through the aligned orifices; and receiving and cooling said discreet portions on a conveyor belt to form said granular aminopyridine product. 7. The process of claim 2, wherein said extruding includes: providing first and second wall members each having orifices, wherein the wall members are movable relative to one another to periodically align orifices in the first member with those in the second member for the predetermined period of time; providing the molten flowable mass under pressure against the first wall member such that when the orifices in the first and second wall members are aligned, said discrete portions are extruded through the aligned orifices; and receiving and cooling said discreet portions on a conveyor belt to form a granular 2-aminopyridine product. 8. The process of claim 7, wherein said granules have an average particle diameter of about 1 to about 10 mm. 9. The process of claim 8, wherein said granules have an average particle diameter of about 1 to about 5 mm. 10. The process of claim 9, wherein said molten flowable mass has a temperature of about 58°C to about 150°C. 11. A composition, comprising a granulated aminopyridine. 12. The composition of claim 11, wherein said aminopyridine is 2-aminopyridine. 13. The composition of claim 11, wherein said aminopyridine is 3-aminopyridine. 14. The composition of claim 11, wherein said aminopyridine is 4-aminopyridine. 15. The composition of any of claims 11-14, which is a prilled aminopyridine having prills with an average diameter of about 1 to about 10 mm. 16. The composition of claim 15, wherein said aminopyridine is 2-aminopyridine.

Inventors: CURTIS JOE W, DUFFY KEVIN HARRISON, HOPPER CHARLES R, HUCKSTEP L MARK, CURTIS, JOE, W., DUFFY, KEVIN, HARRISON, HOPPER, CHARLES, R., HUCKSTEP, L., MARK
Applicants: CURTIS JOE W, DUFFY KEVIN HARRISON, HOPPER CHARLES R, HUCKSTEP L MARK, REILLY IND INC, CURTIS, JOE, W., DUFFY, KEVIN, HARRISON, HOPPER, CHARLES, R., HUCKSTEP, L., MARK, REILLY INDUSTRIES, INC.
Application year: 2000
Main classification: C07D213
IPC codes: C07D213