A method of managing configuration changes in a data processing system, particularly a network wherein software products (250) must be distributed to client workstations. The method provides the definition of reference models (220e-220d) arranged in a tree (215); each reference model includes configuration elements (such as software products and/or hardware features and their desired target status) for the corresponding client workstations (subscribers). A target configuration (230) of the client workstations associated with each reference model is determined by inheriting the configuration elements of the parent reference models. A list of actions (245) to be carried out on each client workstation for reaching the corresponding target configuration is determined by comparing the target configuration with a current configuration of the client workstation stored in a corresponding inventory (245).

The present invention relates to a method and system for managing configuration changes in a data processing system.
Managing configuration changes in a data processing system is a time consuming activity, particularly when the system includes a great number of destination units on which new configurations must be enforced. A typical example is that of a large network with hundreds of workstations where software products and/or hardware features are periodically upgraded in order to be abreast of the information technology development.
Software distribution applications have been proposed in the last years to assist a system administrator in efficiently managing deployment of software products to (client) workstations. A software distribution application runs on a server workstation and controls building of packages including new software products (or new versions thereof) to be installed and instructions understandable by the client workstations. Each package is distributed to the respective client workstation through the network; the instructions embedded in the package cause the software products to be automatically installed or removed in order to reach the desired (software) configuration of the client workstation.
However, this solution is not completely satisfactory. Particularly, the administrator is faced with the burden of manually defining the packages to be distributed to the client workstations. Moreover, the administrator cannot rely on information provided by the software distribution application for deciding which software products must be installed and/or removed and on which client workstations the new configurations must be enforced. As a consequence, the process of managing the configuration changes is very complex and error-prone.
The drawbacks of the solutions known in the art are particularly acute in large systems, where different and frequent configuration changes are enforced on various destination units.
It is an object of the present invention to overcome the above-mentioned drawbacks. In order to achieve this object, a method as set out in the first claim is proposed.
Briefly, the present invention provides a method of managing configuration changes in a data processing system having a plurality of destination units, the method including the steps of providing a plurality of reference models arranged in a tree starting from a root reference model, associating each destination unit with a reference model including configuration information specific for the corresponding destination units, determining a target configuration for the destination units associated with a selected reference model according to the configuration information of the reference models in a path from the root reference model to the selected reference model, and causing each destination unit associated with the selected reference model to be updated according to the target configuration.
Moreover, the present invention also provides a computer program for performing the method, a product storing the program, and a corresponding data processing system.
With reference in particular to FIG. 1, there is shown a networking system 100, such as a WAN (Wide Area Network) used in a large company. The networking system 100 if formed by a plurality of workstations 105, typically consisting of PCs (Personal Computers). The workstations 105 are clustered around corresponding concentrators 110 (such as routers/hubs); the concentrators 110 are installed at distributed sites and are connectable by a telephone line 115. The networking system 100 has a client/server architecture, wherein one or more of the workstations 105 (generally consisting of powerful computers) manage network resources, such as shared files and devises; the other workstations 105 operate as clients on which end-users run applications relying on server resources.
Each workstation 105 includes several units, which are connected in parallel to a communication bus 120. In particular, a central processing unit (CPU) 125 controls operation of the workstation 105, a working memory 130 (typically a DRAM) is used directly by the CPU 125, and a read-only memory (ROM) 135 stores a basic program for starting the workstation 105. Various peripheral units are further connected to the bus 120 (by means of respective interfaces). Particularly, a bulk memory consists of a hard-disk 140 and of a driver unit (DRV) 145 for reading CD-ROMs 150; the workstation 105 further includes an input unit (IN) 155, which consists for example of a keyboard and a mouse, and an output unit (OUT) 160, which consists for example of a monitor. A network interface card (NIC) 165 is used to connect the workstation 105 to the concentrator 110.
Similar considerations apply if the networking system is associated with a department of the company (or with any other entity), if the networking system has a different topology, if the networking system consists of a LAN (Local Area Network), if the networking system includes different components (such as one or more switches), if each workstation has a different structure (for example with a multi-processor architecture), and the like.
Considering now FIG. 2, there is shown a partial content of the working memory 130 of a workstation operating as a software distribution server; the information (programs and data) is typically stored on the hard-disk and loaded (at least partially) into the working memory 130 when the programs are running, together with an operating system and other application programs (not shown in the figure). The programs are initially installed onto the hard disk of the server workstation from CD-ROM.
The working memory 130 includes an input/output interface (I/O) 205 for exchanging information with the peripheral units of the server workstation. The input/output interface 205 communicates with a change configuration management module (CONFIG) 210.
The configuration module 210 controls a repository (MODELS) 215 of reference models, each one defining a profile with configuration information specific for the corresponding client workstations. In the example at issue, the repository 215 includes an enterprise model 220e, a secretary model 220s, a manager model 220m and a developer model 220d. The configuration module 215 further accesses a company database 225.
A generic reference model includes one or more records defining respective configuration elements. Each record consists of a field ELE identifying the configuration element, such as a software product or a hardware feature. A field TGT denotes a desired target status of the configuration element; for example, the target status for a software product indicates that the software product is to be installed, removed, or installed/removed in an undoable manner, while the target status for a hardware feature indicates a hard-disk size, a CPU model, or a working memory capacity. A further field DPD includes dependency information indicating logic relations between the configuration elements; for example, the filed DPD contains the configuration elements required for running a software product (pre-requisites), the configuration elements in conflict with the software product (ex-requisites), or the configuration elements to be installed in a certain order together with the software product (co-requisites).
The reference model further includes a field SBS, which is used to associate the reference model with one or more client workstations (subscribers); the association is carried out statically and/or dynamically. When the subscribers are defined statically, the field SBS simply contains a list of the client workstations; conversely, when the subscribers are defined dynamically, the field SBS contains a query to be run on the company data base 225, whose result provides the list of the client workstations.
The reference models are hierarchically arranged in a tree. Particularly, the enterprise model 220e defines a root of the tree; the secretary model 220s and the manager model 220m depend on the enterprise model 220e, and in turn the developer model 230d depends on the manager model 220m. As described in detail in the following, each child reference model 220s, 220m and 220d (which depends on a corresponding parent reference model 220e, 220e and 220m, respectively) inherits the configuration information of all the reference models in a path from the root reference model 220e to the child reference model. It should be noted that the inheritance mechanism does not implement an "is-a" semantic; for example, a developer is not a manager, but all the configuration elements (not the subscribers) belonging to the manager model 220m are inherited by the developer model 220d.
The company database 225 defines an organisation chart of the company and consists of a relational table formed by a record for each employee. The record is composed of a field INFO containing information about the employee, such as his or her name, telephone and facsimile numbers, e-mail address, department, position, manager and subordinate persons (if any), and the like. A field WS identifies the client workstation assigned to the employee, for example its type, serial number, location, and IP address. A flag EX indicates that the client workstation assigned to the employee is to be excluded from the result of the query (when asserted).
The configuration module 210 generates a memory structure 230 indicating a target configuration for the client workstations associated with a selected reference model. The target configuration 230 includes one or more configuration elements, each one defined by the respective fields ELE and TGT (indicating the configuration element and its target status, respectively), and the list of the client workstations associated with the selected reference model, each one identified by the respective field WS.
The target configuration 230 is supplied to a synchronisation engine (SYNC) 235, which accesses an inventory 240 storing a current configuration of the client workstations. The configuration inventory 240 includes a record for each client workstation; the record consists of the respective field WS (identifying the client workstation) and a field CURR denoting the hardware features of the client workstation and the software products installed thereon. The synchronisation engine 235 further accesses a state transition table 243. The state transition table 243 consists of a lookup table, wherein each record has a key formed by a field STSs and a field STSe; the fields STSs and STSe indicate a starting status and an ending status, respectively, of a generic configuration element belonging to a corresponding category (such as hardware feature or software product). The key STSs,STSe is associated with an attribute consisting of a field ACT indicating an action to be performed for reaching the ending status STSe from the starting status STSs (for example installing a software product, removing a software product, upgrading the CPU, increasing the size of the hard-disk, and so on).
The synchronisation engine 235 generates a memory structure 245 defining a list of actions to be performed on each client workstation associated with the selected reference model for reaching the target configuration. Particularly, the action list 245 includes a series of records, each one consisting of the field WS identifying the client workstation, the field ELE identifying the configuration element involved, and the field ACT indicating the corresponding action to be carried out on the client workstation.
The action list 245 is provided to a deployment agent (DEPL) 250, which accesses a repository (SW) 255 of the software products. The deployment agent 250 builds a distribution package (PCK) 260 for each client workstation; the distribution package 260 consists of one or more files containing the software products to be installed on the client workstation and instructions for automatically executing the actions (relating to software products) indicated in the corresponding records of the action list 245 (such as installing the software products included in the package or removing other software products). The deployment agent 250 further controls the updating of information stored in the configuration inventory 240.
The distribution packages 260 are provided to a network interface (NET) 265, which sends the packages to the corresponding client workstations according to a plan scheduled by the deployment agent 250. The network interface 265 is also connected to the deployment agent 250 directly for supplying messages received from the client workstations. The synchronisation engine 235 and the deployment agent 250 further communicate with the configuration module 210 for receiving commands and providing return codes indicative of a result of the corresponding operations.
Similar considerations apply if the programs and data are structured in a different manner, if other modules or functions are provided, if the tree consists of a different number of reference models, if one or more of the reference models are dummy models without any subscriber associated therewith, if the company database has a different architecture and stores other information, if two or more client workstations are assigned to some employees, and the like. Alternatively, equivalent configuration information is included in the reference models, different configuration elements are managed (such as application parameters, databases, audio and video recordings, or any other digitally encoded product), different target status are supported (for example indicating that a software product must be simply disabled but not removed), or the subscribers consist of different destination units (such as software applications or profiles associated with respective users logging into the client workstations).
As shown in FIG. 3a-3b, a whole software distribution application consisting of the configuration module, the synchronisation engine and the deployment agent performs a method 300 when running on the server workstation. The method 300 starts at block 303 and then passes to block 306, wherein a menu with a series of possible choices is displayed to a system administrator on the monitor of the server workstation. The method executes the operations corresponding to the choice selected by the administrator. Particularly, if the administrator has selected the function of editing the reference model repository the blocks 309-318 are carried out, while if the administrator has selected the function of deploying a new configuration to the corresponding client workstations the blocks 320-375 are carried out; conversely, if the administrator has chosen to exit the software distribution application, the method ends at the final block 378.
Considering now block 309 (editing function), the administrator deletes a selected reference model (restructuring the tree accordingly), inserts a new reference model into the tree, or selects a reference model to be updated. The method continues to block 312, wherein if a reference model has been selected for updating the administrator deletes a configuration element, creates a new configuration element, or updates the target status of a selected configuration element. Passing to block 315, the administrator edits the dependency information for the selected configuration element (pre-requisites, ex-requisites or co-requisites), for example adding, updating or deleting items. With reference to block 318, the administrator modifies the subscribers assigned to the selected reference model; particularly, the identifier of a client workstation is deleted from the corresponding list, the identifier of a new client workstation is inserted, or the query dynamically defining the list of the client workstations is created or updated. The method then returns to block 306 waiting for a new command by the administrator.
Considering now block 320 (deployment function), the administrator selects one of the reference models to be enforced. The method descends into block 321, wherein all the configuration elements of the root reference model are added to the target configuration (empty at the beginning). The configuration module than checks at block 324 whether the selected reference model has been reached (and completely processed). If so, the method passes to block 325 (described in the following). On the contrary, the method proceeds to block 330, wherein a new configuration element of the reference models down the tree along a path from the root reference model to the selected reference model is considered (staring from the first configuration element in the child reference model depending from the root reference model directly). If the target configuration does not include the current configuration element, the method continues to block 333, wherein the current configuration element is added to the target configuration; conversely, the method continues to block 336, wherein the target status and the dependency information of the (previous) configuration element in the target configuration are replaced with the corresponding fields of the current configuration element. In both cases, the method returns to block 324 for processing a next configuration element of the same reference model or the first configuration element of a next reference model.
Considering now block 325, the target configuration is updated according to the corresponding dependency information, in order to resolve all the logic relations between the configuration elements. For example, configuration elements corresponding to the pre-requisite products and the co-requisite products to be installed are added, the configuration elements are rearranged for meeting the required order of installation, or configuration elements corresponding to the ex-requisite products to be removed are inserted.
The method then passes to block 338, wherein the configuration module verifies whether the subscribers are defined statically or dynamically in the selected reference model. In the first case, the list of the client workstations included in the selected reference model is added to the target configuration at block 339, and the method then descends into block 342 (described in the following). Conversely, if the subscribers are defined dynamically the corresponding query included in the selected reference model is run on the company database at block 345 in order to extract the list of the client workstations. The list is pruned at block 348 of the client workstations to be excluded from the deployment of the new configuration according to the corresponding flag. The method then passes to block 342.
Considering now block 342, the current configuration of the client workstations associated with the selected reference model is extracted from the configuration inventory. The synchronisation engine then generates at block 351 the action list for each client workstation by comparing the target configuration with the corresponding current configuration. Particularly, if the current status of each configuration element (software product or hardware feature) meets the desired target status, no action is performed; conversely, the action required to reach the target status of the configuration element from its current status is extracted from the state transition table and added to the list.
The method proceeds to block 354, wherein the deployment agent verifies whether a current hardware structure of the client workstations associated with the selected reference model meets the hardware pre-requisites of the target configuration. For all the client workstations that meet the hardware pre-requisites of the target configuration, the corresponding distribution package is built at block 357; more specifically, the deployment agent inserts each software product to be installed into the distribution package, and add instructions for performing the required actions. Conversely, for all the client workstations that do not meet the hardware pre-requisites of the target configuration, for example because the CPU model cannot run the software products to be installed or the hard-disk size is insufficient, an error condition is entered at block 366; particularly, a warning is provided to the administrator and the deployment of the target configuration to these client workstations is aborted.
In both cases, the method continues to block 372, wherein the packages (if any) are sent to the respective client workstations through the network. Each package is received on the client workstation; the instructions embedded in the package are executed in order to install or remove the corresponding software products. A return code message is sent back from each client workstation to the server workstation for reporting the result of the configuration change; the deployment agent updates the configuration inventory accordingly at block 375. The method then returns to block 306 waiting for a new command by the administrator.
The following tables define an example of configuration elements belonging to each reference model:
Field ELEField TGTEnterprise modelE-mail program (software program)InstalledAnti-virus (software program)InstalledWorking memory size (hardware feature)>=64 MBSecretary modelOffice automation (software program)InstalledGames (software program)Not installedManager modelOffice automation (software program)InstalledReporting (software program)InstalledDeveloper modelCompiler (software program)InstalledReporting (software program)Inst. undoableWorking memory size (hardware feature)>=128 MBLet us suppose now that we want to enforce the developer model. The target configuration for the client workstations associated with the developer model is defined as:
Field ELEField TGTE-mail program (software program)InstalledAnti-virus (software program)InstalledWorking memory size (hardware feature)>=128 MBOffice automation (software program)InstalledReporting (software program)Inst. undoableCompiler (software program)InstalledAs a consequence, if a client workstation associated with the developer model has only the anti-virus installed thereon and its working memory size is greater than 128 MB, the following list of actions is to be performed for reaching the target configuration:
Field ELEField ACTE-mail program (software program)InstallOffice automation (software program)InstallReporting (software program)Install, undoableCompiler (software program)Install
Likewise considerations apply if an equivalent method is performed, for example if report functions are provided, if the company inventory is stored elsewhere and the query is run by another workstation, and so on.
More generally, the present invention provides a method of managing configuration changes in a data processing system having a plurality of destination units. The method includes the steps of providing a plurality of reference models arranged in a tree starting from a root reference model, and associating each destination unit with a reference model including configuration information specific for the corresponding destination units; the method further includes the steps of determining a target configuration for the destination units associated with a selected reference model according to the configuration information of the reference models in a path from the root reference model to the selected reference model, and causing each destination unit associated with the selected reference model to be updated according to the target configuration.
The devised solution provides a scalable and flexible way of specifying the target configuration of each destination unit. Particularly, the reference models allow the destination units to be arranged into logical, functional groups according to the role that each destination unit plays in the system. Therefore, any profile or organisational change can be automatically reflected on the destination units involved simply modifying the corresponding reference models. In this way, a large system with a great number of destination units can be managed as a small system, by handling all the destination units associated with each reference model as a single entity.
The hierarchical structure of the reference models greatly simplifies the modelling of the destination units, by allowing a step-by-step definition of the target configuration of each destination unit; in fact, the configuration elements common to all the destination units are defined only in the root reference model, and the configuration elements specific for each functional group are defined moving down the tree. In this way, the number of reference models needed to describe the whole system is greatly reduced; moreover, each change to a reference model is automatically reflected into the target configuration of all the destination units associated with its child reference models.
The solution according to the present invention simplifies the deployment of new configurations in the system. As a consequence, the process of managing frequent configuration changes to different groups of destination units is made more reliable.
The preferred embodiment of the invention described above offers further advantages. For example, the algorithm proposed for determining the target configuration from the corresponding reference models along the path from the root reference model to the selected reference model is particular simple and effective. This solution allows any reference model to inherit all the configuration elements of the parent reference models; at the same time, each reference model can override the target status or block the installation/removal of any configuration element defined in the parent reference models.
Alternatively, the target configuration is determined in a different manner, for example without the possibility of overriding and/or blocking the configuration elements defined in the parent reference models.
The dependency information inserted in the reference models prevents definition and enforcement of incorrect configurations. In addition, the verification of the current hardware structure of each destination unit (in order to check whether it meets the hardware pre-requisites of the target configuration) ensures that each destination unit is at a level allowing all the software products to be installed to run correctly.
Likewise considerations apply if the dependency information is used in a different manner for determining the target configuration, if the method only verifies compliance of the target configuration with the corresponding dependency information (without modifying the target configuration but simply entering an error condition if the result of the verification is negative), if the dependency information is not defined in the reference models but in a distinct memory structure that is accessed by the configuration module each time a reference model must be enforced, if the package is sent to the client workstations in any case (even if an error condition has been entered), and so on. However, the solution according to the present invention leads itself to be carried out even without the possibility of defining any dependency information for the configuration elements or any hardware feature in the reference models.
The dynamic definition of the subscribers associated with each reference model makes it possible to evaluate the destination units to which the configuration changes must be enforced when the new configuration is actually deployed. Moreover, the possibility of excluding some destination unit from the result of the query allows these destination units to be left temporary unchanged without modifying the field defining the subscribers in the corresponding reference model.
Alternatively, the destination units are associated with each reference model in a different manner, for example defining groups of destination units (such as the client workstations attached to a specified router), the whole result of the query is always employed (without the possibility of excluding any destination unit), the subscribers are defined only statically or dynamically, and the like.
The inventory storing the current configuration of each destination unit allows a level of the configuration elements present on the client workstations to be efficiently tracked. For example, the administrator can easily decide where to distribute a new software product already installed on a subset of the client workstations and now to be installed on all the client workstations of the system, or where to distribute a new version of a software product already installed on a subset of the client workstations.
The method described above is particularly advantageous for a software distribution application used in a large network, wherein the new configurations are automatically deployed from the server workstation to a great number of client workstations.
Similar considerations apply if the state transition table is replaced by an equivalent memory structure, or if the list of actions is determined in a different manner according to a comparison between the target configuration and the current configuration of each destination unit (for example with an algorithm embedded in the synchronisation engine). However, the proposed solution leads itself to be implemented even without any configuration inventory (for example collecting the information indicative of the current configuration of each client workstation dynamically by the server workstation); moreover, the method of the invention is also suitable to be used in a different data processing system (even with the destination units not connected to each other in a network, for example copying the packages onto CD-ROMs that are manually distributed), or for controlling only hardware configurations.
Advantageously, the method proposed by the present invention is implemented with a computer program, which is provided on CD-ROM.
Alternatively, the program is provided on floppy-disk, is pre-loaded onto the hard-disk, or is stored on any other computer readable medium, is sent to the computer through the network, is broadcast, or more generally is provided in any other form directly loadable into a working memory of a computer. However, the method according to the present invention leads itself to be carried out even with a hardware structure installed on the server workstation, for example integrated in a chip of semiconductor material.
Naturally, in order to satisfy local and specific requirements, a person skilled in the art may apply to the solution described above many modifications and alterations all of which, however, are included within the scope of protection of the invention as defined by the following claims.

This patent is subject to a terminal disclaimer.

System for managing configuration changes in a data processing system

International Business Machines Corporation


The present invention relates to processes for converting clarithromycin Form I to clarithromycin Form II, which include slurrying clarithromycin the Form I in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter converting clarithromycin Form I to clarithromycin Form II by slurrying.

The invention relates to methods for making polymorphic Form II of clarithromycin via slurrying polymorphic Form I of clarithromycin in water.
By slurrying in water, clarithromycin Form I can be converted to clarithromycin Form II. The invention also relates to clarithromycin Form II prepared by slurrying polymorphic Form I in water and pharmaceutical compositions containing the same.
6-O-methyl erythromycin A (clarithromycin) is a semisynthetic macrolide antibiotic related to erythromycin A. Clarithromycin exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, Mycoplasma, and Chlamydia. It is stable under acidic conditions and is efficacious when administered orally. Clarithromycin is useful therapy for infections of the upper respiratory tract in children and adults. Clarithromycin is stable under acidic conditions and is efficacious when administered orally.
The chemical structure of clarithromycin is:
Several crystal forms of clarithromycin and/or solvates of clarithromycin, xe2x80x9cForm 0,xe2x80x9d xe2x80x9cForm Ixe2x80x9d, and xe2x80x9cForm IIxe2x80x9d have been identified as indicated in U.S. Pat. No. 5,945,405. The crystal form of clarithromycin is typically identified by the powder x-ray diffraction patterns. Different crystalline forms of clarithromycin may have different thermal stability, cost of preparation, dissolution characteristics and bioavailability.
Various methods of preparing clarithromycin described in the patent literature have been reported to result in different forms of clarithromycin. Purification of crude clarithromycin has been reported to convert one form of clarithromycin to another form. For example, methods in which the compound is purified by recrystallization from ethanol, have been reported to result in the initial formation of Form 0 solvate (see U.S. Pat. No. 5,945,405) or in the initial formation of Form I (See U.S. Pat. No. 5,858,986). The Form 0 solvate may be used as a therapeutic agent, as described in U.S. Pat. No. 5,945,405. The ""405 patent discloses that the Form 0 solvate may be converted to the non-solvated Form I by removing the solvent by drying at a temperature of from about 0xc2x0 C. to about 50xc2x0 C. Another form, Form II, is reported to be relatively thermodynamically stable compared to Form I. The clarithromycin currently marketed in the United States under the trademark Biaxin(copyright) is formulated using Form II.
Several methods of converting clarithromycin Form 0 or Form I to Form II have been described. One such method, as described in U.S. Pat. No. 4,945,405 and U.S. Pat. No. 5,858,986, is to heat Form 0 under vacuum at a temperature of between about 70xc2x0 C. and 110xc2x0 C. According to this patent, the Form 0 solvate first converts to Form I clarithromycin and then to Form II. This method is described in U.S. Pat. No. 4,945,405 and U.S. Pat. No. 5,858,986. However, this vacuum drying step of converting Form 0 to Form II is expensive in both energy and material handling. Clarithromycin Form II has been reported to be formed when Form I is crystallized from various solvents, including ethanol and water (U.S. Pat. No. 5,844,105).
The invention relates to methods for making polymorphic forms of clarithromycin via slurrying clarithromycin Form I in water. By slurrying in water, clarithromycin Form I can be converted to clarithromycin Form II. The invention also relates clarithromycin form II formed by this slurrying process and pharmaceutical compositions containing the same.
The present invention relates to a process for converting clarithromycin Form I to clarithromycin Form II, which includes slurrying clarithromycin Form I in water. The present invention also relates to processes for the preparation of clarithromycin Form II by converting erythromycin A to clarithromycin and thereafter, converting clarithromycin Form I to clarithromycin Form II by slurrying.
We have found that clarithromycin Form I undergoes transformation to Form II by simply slurrying the Form I clarithromycin with water. The present process for converting clarithromycin Form I to Form II is simpler and less expensive than previously described methods of converting Form I to Form II, which require for example, the use of organic solvents such as ethanol.
Form II prepared by this process can be formulated into pharmaceutical compositions that include a therapeutically effective amount of clarithromycin Form II and one or more pharmaceutically acceptable carriers. Those pharmaceutical compositions can be administered as a therapeutically effective antibiotic. Each of these aspects of the present invention is described in further detail below.
The terms xe2x80x9c6-O-methylerythromycin Axe2x80x9d and xe2x80x9cclarithromycinxe2x80x9d are used interchangeably herein and are meant to include clarithromycin in any crystalline form or mixtures thereof, as well as amorphous solids, syrups, or semisolids comprising 6-O-methylerythromycin A in any state of purity, unless specified otherwise, or as the context requires.
The term xe2x80x9cForm Ixe2x80x9d is used herein to mean the crystal Form I of clarithromycin. Form I has been characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 5.2xc2x10.2, 6.7xc2x10.2, 10.2xc2x0xc2x10.2, 12.3xc2x10.2, 14.2xc2x0xc2x10.2, 15.4xc2x0xc2x10.2, 15.7xc2x0xc2x10.2, and 16.4xc2x10.2. Form I has also been characterized by an exothermic transition at 132.2xc2x0 C. by differential scanning calorimetry, and by endothermic peaks at 223.4xc2x0 C., and 283.3xc2x0 C., followed by an exothermic peak at 306.9xc2x0 C.
The term xe2x80x9cForm IIxe2x80x9d is used herein to mean the crystal Form II of clarithromycin. Form II has been characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 8.5xc2x0xc2x10.2, 9.5xc2x10.2, 10.8xc2x0xc2x10.2, 11.5xc2x10.2, 11.9xc2x10.2, 12.4xc2x10.2, 13.7xc2x0xc2x10.2, 14.1xc2x0xc2x10.2, 15.2xc2x10.2, 16.5xc2x10.2, 16.9xc2x0xc2x10.2, 17.3xc2x0xc2x10.2, 18.1xc2x10.2, 18.4xc2x0xc2x10.2, 19.0xc2x0xc2x10.2, 19.9xc2x10.2, and 20.5xc2x10.2 Form II has also been characterized by melting at 223.4xc2x0 C., and by an endothermic peak at 283.3xc2x0 C. by differential scanning calorimetry.
The term xe2x80x9cForm 0xe2x80x9d is used herein to mean the crystal Form 0 or Form 0 solvate of 6-O-methylerythromycin A. Form 0 solvate is characterized by 2-theta angle positions in the powder x-ray diffraction pattern of 4.6xc2x0xc2x10.2, 6.5xc2x0xc2x10.2, 7.6xc2x0xc2x10.2, 9.2xc2x0xc2x10.2, 10.2xc2x0xc2x10.2, 11.0xc2x0xc2x10.2, 11.6xc2x0xc2x10.2, 12.5xc2x0xc2x10.2, 13.8xc2x0xc2x10.2, 14.8xc2x0xc2x10.2, 17.0xc2x0xc2x10.2, 18.2xc2x0xc2x10.2, 18.9xc2x0xc2x10.2 and 19.5xc2x0xc2x10.2. This pattern may be somewhat varied depending on the solvent. For example a Form 0 ethanolate may be characterized by 2-theta angle positions of 4.7xc2x0xc2x10.2, 6.60xc2x0xc2x10.2, 7.7xc2x0xc2x10.2, 9.3xc2x0xc2x10.2, 10.4xc2x0xc2x10.2, 11.1xc2x0xc2x10.2, 11.9xc2x0xc2x10.2, 12.7xc2x0xc2x10.2, 13.9xc2x0xc2x10.2, 15.0xc2x0xc2x10.2, 17.2xc2x0xc2x10.2, 18.5xc2x0xc2x10.2, 19.1xc2x0xc2x10.2, 19.7xc2x0xc2x10.2, 23.1xc2x0xc2x10.2 and 24.0xc2x0xc2x10.2.
Formation of Clarithromycin Form II
The present invention relates to processes for converting clarithromycin Form I to clarithromycin Form II, which include slurrying clarithromycin Form I with water. The present invention also relates to a process of preparing clarithromycin Form II from erythromycin A, which includes slurrying clarithromycin Form I in water. In one embodiment, this method includes first converting erythromycin A to clarithromycin and thereafter slurrying clarithromycin Form I with water to form clarithromycin Form II. There are several methods by which clarithromycin may be formed from erythromycin A, as described further below. In certain of these methods, the initial form of clarithromycin that is formed is Form I. In other methods, the initial form of clarithromycin that is formed is not Form I, but rather another form that is subsequently converted to Form I.
As used herein, the terms xe2x80x9cslurryingxe2x80x9d and xe2x80x9cslurriedxe2x80x9d are intended to include stirring particles in a liquid, preferably water.
In the present invention, a wet solid of clarithromycin is obtained, for example by treating clarithromycin with ethanol, filtering and washing the precipitate with ethanol. The wet solid is slurried with water, preferably at ambient temperature, for about 1 hour. The slurrying step may include stirring the clarithromycin and water.
After clarithromycin Form I is converted to clarithromycin Form II by slurrying, the resulting crystalline clarithromycin Form II may then isolated, preferably by filtration and dried in an oven, preferably a vacuum oven, at a temperature of between about ambient temperature and about 70xc2x0 C., preferably from about 40xc2x0 C. to about 60xc2x0 C., even more preferably, about 50xc2x0 C. Preferably, the drying takes place under vacuum.
In the slurrying step of any of the embodiments that involve converting Form I to Form II described herein, clarithromycin Form I is slurried in about 2 to about 25 ml of water per gram of clarithromycin Form I. More preferably clarithromycin Form I is slurried in about 3 to about 10 ml of water per gram of clarithromycin Form I. Most preferably clarithromycin Form I is slurried in about 5 ml of water per gram of clarithromycin Form I.
For purposes of this specification, ambient temperature is from about 20xc2x0 C. to about 25xc2x0 C.
The term xe2x80x9ctreatingxe2x80x9d as used herein refers to suspending, dissolving, washing, mixing, crystallizing or recrystallizing clarithromycin in any of the solvents described above.
As indicated above, processes for preparing clarithromycin Form II according to the present invention may include first converting erythromycin A to clarithromycin prior to slurrying the clarithromycin Form I with water to form clarithromycin Form II. This conversion of erythromycin A to clarithromycin may be performed by any method used by those in the art. In general, clarithromycin is prepared by methylation of the 6-hydroxy group of erythromycin A. However, in the conversion process it is necessary to protect various groups, especially hydroxy groups at positions of erythromycin A, which are potentially reactive with alkylating agents, prior to alkylation of the 6-hydroxy group. Examples of methods of preparing clarithromycin are described for example, in U.S. Pat. Nos. 4,331,803, 4,670,549, 4,672,109, 4,990,602, 5,858,986, 5,844,105 and 5,945,405, which are each herein incorporated by reference in there entirety. By way of example, U.S. Pat. Nos. 4,990,602 and 5,858,986 describe a method of preparing clarithromycin from erythromycin A by protecting the 9-oxo group with a substituted oxime group, protection of the C-2xe2x80x2 and C-4xe2x80x3 hydroxy groups, methylation of the C-6 hydroxy group, and deoximation and removal of the protecting groups. Removal of the protecting groups and deoximation of 6-O-methyl-2xe2x80x2,4xe2x80x3-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime (or other protected oxime) are then accomplished by treatment with acid and deoximating agent to give clarithromycin. Examples of suitable deoximating agents include inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium bisulfite, sodium dithionate, potassium hydrogen sulfite, potassium thiosulfate, potassium metabisulfite and the like. Particularly preferred deoximating agents are sodium metabisulfite and sodium bisulfite and the like. Deprotection may occur prior to deoximation or deprotection and deoximation may be accomplished in a single step (xe2x80x9cone-potxe2x80x9d synthesis) by treatment with acid, such as formic acid, and deoximating agent.
Various other methods of converting erythromycin A to clarithromycin that presently exist or methods that may be contemplated in the future may also be used.
Clarithromycin Form II Formed by Slurrying Form I
The present invention also relates to clarithromycin Form II prepared by slurrying clarithromycin Form I in water.
Pharmaceutical Compositions Including Clarithromycin Form II Formed by Slurrying Form I
Another aspect of the present invention provides pharmaceutical compositions including a therapeutically effective amount of clarithromycin Form II prepared by slurrying Form I in water or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
The pharmaceutical compositions of this invention are administered to humans and other animals by any acceptable route within sound medical judgment, such as orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. Preferably, the pharmaceutical compositions of this invention are formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The term xe2x80x9cparenteralxe2x80x9d administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection include for example pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
The pharmaceutical compositions of the present invention may also contain one or more adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include within the pharmaceutical composition one or more isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the clarithromycin Form II, it is desirable to slow the absorption of the clarithromycin Form II from subcutaneous or intramuscular injection. This may be accomplished for example by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the clarithromycin Form II then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered clarithromycin Form II form may be accomplished by dissolving or suspending the clarithromycin Form II in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the clarithromycin Form II in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of clarithromycin Form II release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the clarithromycin Form II in liposomes or microemulsions that are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the clarithromycin Form II is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such pharmaceutically acceptable excipients or carriers include sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agarxe2x80x94agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition such that they release the clarithromycin Form II only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more excipients, such as the above-mentioned excipients.
Liquid dosage form for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the clarithromycin Form II, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Oral compositions according to the present invention may also include one or more adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agarxe2x80x94agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the clarithromycin Form II.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods of forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The clarithromycin Form II is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants, which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of clarithromycin Form II in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the clarithromycin Form II that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend on various factors such as the activity of the particular compound, the route of administration, the severity of the condition being treated, the size of the patient and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the clarithromycin Form II at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. Thus, an appropriate therapeutically effective amount may be determined by a doctor, veterinarian or other healthcare professional having experience in determining appropriate dosages for treatment.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.

Processes for preparing clarithromycin polymorphs


The invention relates to a novel process for preparing functionalized PPE, the process comprising oxidative coupling in a reaction solution at least one monovalent phenol species using an oxygen containing gas and a complex metal catalyst to produce a PPE; and functionalizing the PPE prior to and/or during at least one isolation step for devolatilization of the reaction solvent. The invention also relates to the polyphenylene ether resin made by the process as well as blends and articles containing the polyphenylene ether resin made by the process.

Not Applicable.
Not Applicable.
1. Field of the Invention
The invention relates to a novel process for the manufacture of functionalized polyphenylene ether resin.
The invention also relates to the functionalized polyphenylene ether resins made by the process as well as blends and articles containing the functionalized polyphenylene ether resin made by the process.
2. Brief Description of the Related Art
Polyphenylene ether resins (hereinafter xe2x80x9cPPExe2x80x9d) are commercially attractive materials because of their unique combination of physical, chemical, and electrical properties. Furthermore, the combination of PPE with other resins provides blends which result in additional overall properties such as chemical resistance, high strength, and high flow.
One technical obstacle to the development of such blends is the lack of compatibility between PPE and many resins. This lack of compatibility manifests itself often through very poor physical properties as well as delamination in molded parts. Methods have been developed to improve the PPE compatibility with many resins such as, for example, with polyesters and polyamides. One of the more effective methods involves functionalizing PPE to make functionalized PPE containing moieties that are reactive with the other resin in the blend. It is believed that when the functionalized PPE is allowed to react with the other resin that relatively small amounts of copolymer between the resins are formed. The copolymer is believed to be in large part responsible for improved compatibility between the PPE and the other resin. Indications of improved compatibility include resistance to lamination, improved physical properties such as increased tensile and impact properties and a stabilized morphology between the blend component phases under static and/or low shear conditions.
Methods to prepare functionalized PPE have included solution functionalization with an acid halide containing compound, such as trimellitic anhydride acid chloride, to make an endcapped PPE containing the reactive moiety. This method is rather limited in the variety of functionalized PPE that can be made. Also, the by-products from the capping reaction tend to cause emulsion and/or isolation issues in the solvent precipitation stage of the process.
Another known method to prepare functionalized PPE related to melt functionalization of the PPE in an extruder. This method involved melting and mixing PPE with a functionalizing agent to result in a functionalized PPE. The additional polymers could be fed into the same extruder or alternatively, the functionalized PPE could be isolated and subsequently used to prepare other compositions. Melt functionalization has issues, such as difficulty in feeding PPE into the extruder due to low bulk density and wide particle size distribution. Moreover, PPE are often powders and require special handling to avoid potential dust explosion.
It is therefore apparent that a need continues to exist for improved methods to prepare functionalized PPE.
The needs discussed above have been generally satisfied by the discovery of a process for preparing functionalized PPE, the process comprising oxidative coupling in a reaction solution at least one monovalent phenol species using an oxygen containing gas and a complex metal catalyst to produce a PPE; and functionalizing the PPE prior to and/or during at least one isolation step for devolatilization of the reaction solvent.
The description that follows provides further details regarding various embodiments of the invention.
Not applicable.
One embodiment of this invention provides for a process for the preparation of functionalized PPE, preferably having an intrinsic viscosity between about 0.08 dl/g and 0.60 dl/g, by oxidative coupling at least one monovalent phenol species, preferably at least a portion of which have substitution in at least the two ortho positions and hydrogen or halogen in the para position, using an oxygen containing gas and a complex metal-amine catalyst, preferably a copper (I)-amine catalyst, as the oxidizing agent and, preferably extracting at least a portion of the metal catalyst as a metal-organic acid salt with an aqueous containing solution, and functionalizing the PPE prior to and/or during at least one isolation step for devolatilization of the reaction solvent. In one embodiment, the functionalization is at least partly done in a flash process to concentrate the PPE reaction solution. In another embodiment, the functionalization is at least partly done prior to a flash process to concentrate the PPE reaction solution. In yet another embodiment, the functionalization is at least partly done in a devolatilizing extruder. These and other embodiments will become apparent in the description that follows.
The PPE employed in the present invention are known polymers comprising a plurality of structural units of the formula
wherein each structural unit may be the same or different, and in each structural unit, each Q1 is independently halogen, primary or secondary lower alkyl (i.e., alkyl containing up to 7 carbon atoms), phenyl, haloalkyl, aminoalkyl, hydrocarbonoxy, or halohydrocarbonoxy wherein at least two carbon atoms separate the halogen and oxygen atoms; and each Q2 is independently hydrogen, halogen, primary or secondary lower alkyl, phenyl, haloalkyl, hydrocarbonoxy or halohydrocarbonoxy as defined for Q1. Most often, each Q1 is alkyl or phenyl, especially C1-4 alkyl, and each Q2 is hydrogen.
Both homopolymer and copolymer PPE are included. The preferred homopolymers are those containing 2,6-dimethyl-1,4-phenylene ether units. Suitable copolymers include random copolymers containing such units in combination with (for example) 2,3,6-trimethyl-1,4-phenylene ether units. Also included are PPE containing moieties prepared by grafting vinyl monomers or polymers such as polystyrenes and elastomers, as well as coupled PPE in which coupling agents such as low molecular weight polycarbonates, quinones, heterocycles and formals undergo reaction in known manner with the hydroxy groups of two poly(phenylene ether) chains to produce a higher molecular weight polymer, provided a substantial proportion of free OH groups remains. Also included are PPE""s containing a functional endgroup, obtained from reaction with a reactive compound having the functional endgroup.
The molecular weight and intrinsic viscosity of the PPE can vary widely, depending at least in part on the intended end-use for the PPE. The intrinsic viscosity (hereinafter xe2x80x9cI.V.xe2x80x9d) of the PPE is most often in the range of about 0.08-0.60 dl./g., preferably in the range of about 0.10-0.49 dl./g., as measured in chloroform at 25xc2x0 C. One unexpected aspect of the process is the ability to utilize a very wide range of I.V.
The PPE are typically prepared by the oxidative coupling of at least one monohydroxyaromatic compound such as 2,6-xylenol, 2,3,6-trimethylphenol, or mixtures of the foregoing. Catalyst systems are generally employed for such coupling and they typically contain at least one heavy metal compound such as a copper, manganese, or cobalt compound, usually in combination with various other materials.
It will be apparent to those skilled in the art from the foregoing that the PPE contemplated in the present invention include all those presently known, irrespective of variations in structural units or ancillary chemical features.
The polymerization of the phenolic monomer may be carried out by adding the phenolic monomer or monomers to a suitable reaction solvent and preferably, a copper-amine catalyst. It is preferred to carry out the polymerization in the presence of a cupric or cuprous salt-secondary amine catalyst such as, for example, cupric chloride and di-n-butylamine. The polymerizations are advantageously carried out in the presence of an inorganic alkali metal bromide or an alkaline earth metal bromide. The inorganic bromides may be used at a level of from about 0.1 mole to about 150 moles per 100 moles of phenolic monomer. These catalyst materials are described in U.S. Pat. No. 3,733,299 (Cooper et al.). Tetraalkylammonium salts may also be employed as promoters if desired. These promoters are disclosed in U.S. Pat. No. 3,988,297 (Bennett et al.).
The primary, secondary or tertiary amine component of the catalyst complex generally correspond to those disclosed in U.S. Pat. Nos. 3,306,874 and 3,306,875 (Hay). Illustrative members include aliphatic amines, including aliphatic mono- and di-amines, where the aliphatic group can be straight or branched chain hydrocarbon or cycloaliphatic. Preferred are aliphatic primary, secondary and tertiary monoamines and tertiary diamines. Especially preferred are mono-, di- and tri(lower)alkyl amines, the alkyl groups having from 1 to 6 carbon atoms. Typically, there can be used mono-, di- and tri-methyl, ethyl, n-propyl i-propyl, n-butyl substituted amines, mono- and di-cyclohexylamine, ethylmethyl amine, morpholine, N-(lower)alkyl cycloaliphatic amines, such as N-methylcyclohexylamine, N,Nxe2x80x2-dialkylethylenediamines, the N,Nxe2x80x2-dialkylpropanediamines, the N,N,Nxe2x80x2-trialkylpentanediamines, and the like. In addition, cyclic tertiary amines, such as pyridine, alpha-collidine, gamma picoline, and the like, can be used. Especially useful are N,N,Nxe2x80x2,Nxe2x80x2-tetraalkylethylenediamines, butane-diamines, and the like.
Mixtures of such primary, secondary and tertiary amines may be used. A preferred mono alkyl amine is n-butyl amine; a preferred dialkyl amine is di-n-butyl amine; and a preferred trialkyl amine is triethylamine. A preferred cyclic tertiary amine is pyridine. The concentration of primary and secondary amine in the reaction mixture may vary within wide limits, but is desirably added in low concentrations. A preferred range of non-tertiary amines comprises from about 2.0 to about 25.0 moles per 100 moles of monovalent phenol. In the case of a tertiary amine, the preferred range is considerably broader, and comprises from about 0.2 to about 1500 moles per 100 moles of monovalent phenol. With tertiary amines, if water is not removed from the reaction mixture, it is preferred to use from about 500 to about 1500 moles of amine per 100 moles of phenol. If water is removed from the reaction, then only about 10 moles of tertiary amine, e.g., triethylamine, per 100 moles of phenol need be used as a lower limit. Even smaller amounts of tertiary diamines, such as N,N,Nxe2x80x2Nxe2x80x2-tetramethylbutanediamine can be used, down to as low as about 0.2 mole per 100 moles of phenol.
Typical examples of cuprous salts and cupric salts suitable for the process are shown in the Hay patents. These salts include, for example, cuprous chloride, cuprous bromide, cuprous sulfate, cuprous azide, cuprous tetramine sulfate, cuprous acetate, cuprous butyrate, cuprous toluate, cupric chloride, cupric bromide, cupric sulfate, cupric azide, cupric tetramine sulfate, cupric acetate, cupric butyrate, cupric toluate, and the like. Preferred cuprous and cupric salts include the halides, alkanoates or sulfates, e.g., cuprous bromide and cuprous chloride, cupric bromide and cupric chloride, cupric sulfate, cupric fluoride, cuprous acetate and cupric acetate. With primary and secondary amines, the concentration of the copper salts is desirably maintained low and preferably varies from about 0.2 to 2.5 moles per 100 moles of monovalent phenol. With tertiary amines, the copper salt is preferably used in an amount providing from about 0.2 to about 15 moles per 100 moles of the monovalent phenol.
Cupric halides are generally preferred over cuprous halides for the preparation of the copper amine catalyst because of their lower cost. The use of the copper (I) species also greatly increases the rate of oxygen utilization in the early stages of the polymerization reaction and the lower oxygen concentration in the head space of the reactor helps in reducing the risk of fire or explosion in the reactor. A process for the preparation and use of suitable copper-amine catalysts is disclosed in U.S. Pat. No. 3,900,445 (Cooper et al.).
A faster initial reaction rate with the copper (I) based catalyst also results in less accumulation of unreacted monomer and a reduction in the amount of undesirable tetramethyldiphenylquinone produced. The tetramethyldiphenylquinone, a backward dimer, is believed to incorporate into the PPE through equilibration reactions. The equilibration reactions lead to a drop in the intrinsic viscosity of the PPE due to the decrease in molecular weight of the PPE from the incorporation of the dimer. Minimization of the tetramethyldiphenylquinone during the oxidation coupling is desirable so as to avoid the drop in molecular weight and the accompanying difficulties in having to build to a higher than desired molecular weight to offset the loss during equilibration of the backward dimer. It was unexpectedly found that the present invention affords a process in which the PPE in the reaction mixture shows less than a 10% drop, preferably less than a 5% drop, most preferably less than a 3% drop in I.V. during an equilibration step after the oxidative polymerization of the phenolic monomers.
The polymerization reaction is preferably performed in a solvent. Suitable solvents are disclosed in the above-noted Hay patents. Aromatic solvents such as benzene, toluene, ethylbezene, xylene, and o-dichlorobenzene are especially preferred, although tetrachloromethane, trichloromethane, dichloromethane, 1,2-dichloroethane and trichloroethylene may also be used. The weight ratio between solvent and monomer is normally in the range from 1:1 to 20:1, ie. up to a maximum 20-fold excess of solvent. The ratio between solvent and monomer is preferably in the range from 1:1 to 10:1 by weight.
One unexpected advantage of the present process when used to make low I.V. PPE is that a higher solids loading is possible as compared to processes that make higher (i.e.  greater than 0.28 I.V.) PPE. Without the increased solution viscosity build that concomitantly accompanies high molecular weight polymer, the final solids concentration can be increased by at least 20%, with increases of 30% or more possible. Thus, the present process affords a method for increased reactor utilization and productivity without increasing the size or number of the reactor vessels.
The process and reaction conditions for the polymerization, such as reaction time, temperature, oxygen flow rate and the like are modified based on the exact target molecular weight desired. The endpoint of the polymerization is conveniently determined with an in-line viscosity meter. Although other methods such as making molecular weight measurements, running to a predetermined reaction time, controlling to a specified endgroup concentration, or the oxygen concentration in solution may also be utilized.
The temperature to carry out the polymerization stage of the invention generally ranges from about 0xc2x0 C. to about 95xc2x0 C. More preferably, the temperature range is from about 35xc2x0 C. to about 45xc2x0 C. with the higher reaction temperature near the end of reaction. At substantially higher temperatures, side reactions can occur leading to reaction by-products and at temperatures substantially lower, ice crystals form in the solution.
Many diverse extractants or chelating agents may be used in the practice of the invention to complex with the catalyst after the end of the polymerization reaction. For example, sulfuric acid, acetic acid, ammonium salts, bisulfate salts and various chelating agents may be used. When these materials are added to a PPE reaction solution, the copper-amine catalyst becomes poisoned and further oxidation does not take place. Many different materials may be used but it is preferred to employ those chelating agents that are disclosed in U.S. Pat. No. 3,838,102 (Bennett et al.).
The useful chelating agents include polyfunctional carboxylic acid containing compounds such as, for example, sodium potassium tartrate, nitrilotriacetic acid (NTA), citric acid, glycine and especially preferably they will be selected from polyalkylenepolyamine polycarboxylic acids, aminopolycarboxylic acids, aminocarboxylic acids, aminopolycarboxylic acids, aminocarboxylic acids, polycarboxylic acids and their alkali metal, alkaline earth metal or mixed alkali metal-alkaline earth metal salts. The preferred agents include ethylenediaminetetraacetic acid (EDTA), hydroxyethylenediaminetriacetic acid, diethylenetriaminepentaacetic acid and their salts. Especially preferred are ethylenediaminotetraacetic acid or a mono-, di-, tri- and tetrasodium salt thereof and the resulting copper complex can be referred to as a copper carboxylate complex.
The chelated metallic catalyst component can be extracted with the water produced in the polymerization reaction through the use of a liquid/liquid centrifuge. The preferred extraction liquid for use in the process of the invention is an aqueous solution of lower alkanol, i.e., a mixture of water and an alkanol having from 1 to about 4 carbon atoms. Generally from about 1% to about 80% by volume of an alkanol or glycol may be employed. These ratios may vary from about 0.01:1 to about 10:1 parts by volume of aqueous liquid extractant to discrete organic phase.
The reaction media generally comprises an aqueous environment. Anti-solvents can also be utilized in combination with the aqueous media to help drive the precipitation of the copper (I) species. The selection of an appropriate anti-solvent is based partially on the solubility co-efficient of the copper (I) species that is being precipitated. The halides are highly insoluble in water, log K[sp]values at 25xc2x0 C. are xe2x88x924.49, xe2x88x928.23 and xe2x88x9211.96 for CuCl, CuBr and CuI, respectively. Solubility in water is increased by the presence of excess of halide ions due to the formation of, e.g., CuCl2, CUCl3, and CuCl4 and by other complexing species. Non-limiting examples of anti-solvents would comprise low molecular weight alkyl and aromatic hydrocarbons, ketones, alcohols and the like which in themselves would have some solubility in the aqueous solution. One skilled in the art would be able to select an appropriate type and amount of anti-solvent, if any was utilized.
After removal of the catalyst, the PPE containing solution is concentrated to a higher solids level as part of the isolation of the PPE. It was unexpectedly found that PPE can be readily functionalized prior to and/or during this solvent removal process by addition of at least one functionalizing agent, also known as compatibilizers or functionalizers. The location of the addition of the at least one functionalizing agent will depend on several factors such as the stability of the agent, the volatility of the agent to the isolation conditions, the flexibility of the equipment for addition points, and the like. For functionalizing agents that are volatile in the isolation process, addition of the functionalizing agent prior to solvent removal is often preferred so as not to remove the functionalizing agent before it has functionalized the PPE. For less volatile functionalizing agents, greater flexibility in the location of the addition is possible. It is also possible to add at least one functionalizing agent at several points during the process.
In one embodiment, the functionalizing agent includes compounds having both (i) a carbon-carbon double bond or a carbon-carbon triple bond and (ii) at least one species of the group consisting of carboxylic acids, acid anhydrides, acid amides, acid esters, imides, amines, ortho esters, hydroxyls and carboxylic acid ammonium salts. Illustrative compounds useful to accomplish the functionalization of the PPE include maleic anhydride, fumaric acid, maleimides such as N-phenylmaleimide and 1,4phenylene-bis-methylene-alpha, alphaxe2x80x2-bismaleimide, maleic hydrazide, methylnadic anhydride, fatty oils (e.g., soybean oil, tung oil, linseed oil, sesame oil), acrylate ortho esters and methacrylate ortho esters, unsaturated carboxylic acids such as acrylic, crotonic, methacrylic acid and oleic acid, unsaturated alcohols such as allyl alcohol and crotyl alcohol and unsaturated amines such as allylamine and trialkyl amine salts of unsaturated acids such as triethylammonium fumarate and tri-n-butylammonium fumarate. Examples of such typical reagents for preparing useful functionalized PPE are described in U.S. Pat. Nos. 4,315,086, 4,755,566, 4,888,397, and 5,247,006.
Non-polymeric aliphatic polycarboxylic acids are also useful for preparing functionalized PPE. Included in the group of species, are, for example, the aliphatic polycarboxylic acids, and acid esters represented by the formula:
(RIO)mR(COORII)n(CONRIIIRIV)s
wherein R is a linear or branched chain, saturated aliphatic hydrocarbon of from 2 to 20, preferably 2 to 10, carbon atoms; RI is selected from the group consisting of hydrogen or an alkyl, aryl, acyl, or carbonyl dioxy group of 1 to 10, preferably 1 to 6, most preferably 1 to 4, carbon atoms, with hydrogen being especially preferred; each RII is independently selected from the group consisting of hydrogen or an alkyl or aryl group of from 1 to 20 carbon atoms preferably from 1 to 10 carbon atoms; each RIII and RIV is independently selected from the group consisting essentially of hydrogen or an alkyl or aryl group of from 1 to 10, preferably from 1 to 6, most preferably 1 to 4, carbon atoms; m is equal to 1 and (n+s) is greater than or equal to 2, preferably equal to 2 or 3, and n and s are each greater than or equal to zero; and wherein (ORI) is alpha or beta to a carbonyl group and at least two carbonyl groups are separated by 2 to 6 carbon atoms. Obviously, RI, RII, RIII and RIV cannot be aryl when the respective substituent has less than 6 carbon atoms.
Illustrative of suitable polycarboxylic acids are citric acid, malic acid, and agaricic acid; including the various commercial forms thereof, such as, for example, the anhydrous and hydrated acids. Illustrative acid esters useful herein include, for example, acetyl citrate and mono- and/or di-stearyl citrates and the like. Suitable acid amides useful herein include, for example, N,Nxe2x80x2-diethyl citric acid amide; N,Nxe2x80x2-dipropyl citric acid amide; N-phenyl citric acid amide; N-dodecyl citric acid amide; N,Nxe2x80x2-didodecyl citric acid amide and N-dodecyl malic acid amide. Derivatives of the foregoing polycarboxylic acids are also suitable for use in the practice of the present invention. Examples of suitable functionalizing compounds can be found in U.S. Pat. Nos. 4,315,086, 4,755,566, 4,873,286 and 5,000,897.
Other useful functionalizing agents useful in the process of the invention for preparing functionalized PPE include compounds containing an acyl functional group and at least one species of the group consisting of carboxylic acids, acid anhydrides, acid esters, acid amides, imides, amines, ortho esters, hydroxyls and carboxylic acid ammonium salts. Non-limiting examples include chloroformyl succinic anhydride, chloroethanoyl succinic anhydride, trimellitic anhydride acid chloride, 1-acetoxy-acetyl-3,4-dibenzoic acid anhydride, terephthalic acid chloride, and reactive triazines including epoxyalkyl chlorocyanurates and chloroaryloxytriazines. Additional examples can be found in U.S. Pat. Nos. 4,600,741 and 4,642,358.
The amount of the above mentioned functionalizing agents that is required to appropriately functionalize the PPE is that which is sufficient to improve the compatibility between the various components in the final composition. As previously discussed, indications of improved compatibility include resistance to lamination, improved physical properties such as increased tensile and impact properties and a stabilized morphology between the blend component phases under static or low shear conditions.
An effective amount of the above mentioned functionalizers, based on the amount of the PPE, is generally up to about 8% by weight, and is preferably from about 0.05% to about 4% by weight. In the most preferred embodiments, the amount of functionalizing agent is in the range of about 0.1% to about 2.0% by weight based on the amount of the PPE. The actual amount utilized will also depend on the molecular weight of the functionalizing agent, the number and type of reactive species per molecule of functionalizing agent and the degree of compatibility that is desired in the final resin blend composition.
Concentration of the PPE containing solution is accomplished by reducing the pressure in a solvent flash vessel while preferably increasing the temperature of the PPE containing solution. Pressures of about to 35 to 50 bar are desirable with solution temperatures increased to at least 200xc2x0 C., preferably to at least 230xc2x0 C. A solids level of PPE of at least 55%, preferably of at least 65% or higher is desirable.
A total isolation process is preferred for isolating the PPE. As part of the total isolation, a portion of the solvent is preferably removed in order to reduce the solvent load on the total isolation equipment. Functionalizing agent can be effectively added to the PPE at several locations during the isolation process. For example, functionalizing agent may be added prior to removal of solvent, the functionalizing agent may be added during the concentration of the reaction mixture, or both. Likewise, functionalizing agent can be added with the concentrated reaction solution into the final devise for solvent removal. Functionalizing agent may alternatively be added simultaneously at several different locations. The selection of the addition location may be dictated by the actual equipment utilized and by the properties of functionalizing agent with a determination of an optimum location.
The final isolation of the PPE is preferably carried out in a devolatilizing extruder although other methods involving spray drying, wiped film evaporators, flake evaporators, and flash vessels with melt pumps, including various combinations involving these methods are also useful and in some instances preferred. As previously described, total isolation is preferable from the viewpoint that oligomeric species are not removed to the same degree as with precipitation. Likewise, isolation yields are extremely high and are near quantitative. These techniques require however that the catalyst removal be completed in the prior process steps as any catalyst remaining in solution will necessarily be isolated in the PPE.
Devolatilizing extruders and processes are known in the art and typically involve a twin-screw extruder equipped with multiple venting sections for solvent removal. The devolatilizing extruders most often contain screws with numerous types of elements adapted for such operations as simple feeding, devolatilization and liquid seal formation. These elements include forward-flighted screw elements designed for simple transport, and reverse-flighted screw and cylindrical elements to provide intensive mixing and/or create a seal. Particularly useful are counterrotating, non-intermeshing twin screw extruders, in which one screw is usually longer than the other to facilitate efficient flow through the die of the material being extruded. Such equipment is available from various manufacturers including the aforementioned Welding Engineers, Inc.
In the practice of the present invention, the preheated concentrated solution containing the PPE is fed into the devolatilizing extruder and maintained at a temperature less than about 300xc2x0 C., and preferably less than about 275xc2x0 C., with pressures in the vacuum vent of less than about 1 bar. The exact temperature will depend in large part on the I.V. of the PPE and the corresponding viscosity associated with that I.V. resin. The functionalizing agent can be added at various locations along the length of the extruder with good results. The resultant solvent level is preferably reduced to less than about 1200 ppm, preferably less than about 600 ppm, and most preferably less than about 400 ppm.
Another unexpected result obtained through the use of a devolatilizing extruder was the extremely high yield of PPE achieved in the process. For example, a PPE yield of over 99% was obtained even for PPE having a low I.V. (typically on the order of about 0.08 dl/g to about 0.25 dl/g) whereas in the precipitation process known in the art, the yield of similar low I.V. PPE was less than 90%. Thus, the present process comprising a devolatilizing extruder affords a method to prepare functionalized low molecular weight polyphenylene ether resin, typically within the intrinsic viscosity range of about 0.08 dl/g to about 0.25 dl/g, in a yield of over 90%, preferably over 95%, more preferably over 98% and most preferably over 99%, based upon the amount of monovalent phenol utilized in the oxidative coupling.
When using a devolatilization extruder for the total isolation of the low I.V. functionalized PPE as previous described, it was found that traditional underwater or water spray cooling of strands of extrudate followed by chopping the extrudate into pellets gave unacceptable results presumably due to the low melt strength and inherent brittle nature of low I.V. PPE. It was found that special pelletization techniques can overcome these difficulties. Useful techniques include die-face pelletization, including underwater pelletization and flaking, declining angle strand pelletization using water spraying, and vibration drop pelletization with underwater pelletization especially suitable.
The collected PPE pellets can be dried using techniques standard in the art including centrifugal dryers, batch or continuous oven dryers, fluid beds, and the like. Determination of an appropriate set of conditions can be readily determined by one of skill in the art without undue experimentation.
As an alternative to completely isolating the functionalized PPE, one or more resins may be added to the devolatilized functionalized PPE in the same process. The one or more resins may be fed into the devolatilizing extruder although additional extruders may also be used. Possible variations include melt feeding the one or more resins into the devolatilizing extruder or melt feeding the functionalized PPE from the devolatilizing extruder into a second compounding extruder as well as combinations of these. Accordingly, in one embodiment a compatibilized blend is afforded by the process without complete isolation of the functionalized PPE. The one or more resins can vary widely and can also include additives common to such compatibilized blends. Such additives include impact modifiers, lubricants, flame retardants, pigments, colorants, fillers, reinforcing agents, carbon fibers and fibrils, and the like. Preferred resins include polyamides, polyesters, polyarylene sulfides, polycarbonates, polyetherimides, functionalized polyolefins, polysulfones, polyethersulfones, and the like.
All patents cited by reference are incorporated herein by reference.
In order that those skilled in the art will be better able to practice the invention, the following examples are given by way of illustration and not by way of limitation.

Process for the manufacture of functionalized polyphenylene ether resins


An affordable Zero-Energy prefabricated modular building such as for housing, in which a Layered disposition of Envelope elements—including Structural Insulated Panels—in the wall, floor and roof sections of the building's thermal Envelope, provide a highly energy-efficient Building Envelope, which together with a modular building Support Structure including Aeriated Frames, and an adequately sized renewable energy power generator system, inexpensively achieves the energetic independence of the building. A method is disclosed for the adaptation of the building's design and construction to the bio-climatic conditions of its projected location, in which different possible configurations of the relevant elements of the Building Envelope, the building structure and the renewable power generator system are evaluated, discarding those configurations which don't meet the defined acceptable criteria for energy-efficiency, thermal isolation and water condensation risks. The building has a low environmental impact thanks to reduced greenhouse emissions during its construction and useful life.

Since the moment humanity became aware of the irreversible negative impact that the unrestricted consumption of fossil fuels and other nonrenewable energy sources in the construction industry was causing on our planet, the need for developing environmentally sensitive housing and commercial buildings was born.
At the global level, we are facing the so-called World Energy Trilemma, characterized by the increasing difficulty of balancing the concepts of Economy, Energy, and Environment for a given society. On one hand, we demand more and more electric power, to the point one could say that we have become "energyvorous", demand which in the near future is only expected to keep growing. On the other hand, the production, transportation, transformation and distribution of energy in its best form for human use (electrical power) is very expensive, and at the same time it usually produces a large impact on the environment to which it pertains (from the use of fossil energy—thermal power stations, combined cycle, etc., that prevail today, to the generation of major infrastructure projects for power generation, which impact is not negligible: hydroelectric dams, nuclear power plants and their waste, etc.).
In the United States, buildings are the biggest primary energy consumers, being responsible for more than 40% of the total fossil energy consumed by the nation. The residential and commercial sector is also responsible for almost 35% of the nation's total greenhouse gas emissions. In addition, the substantial amount of natural resources consumed, and the copious amounts of waste generated by the traditional processes of building and demolishing housing and other structures, evince the desirability of creating environmentally sensitive buildings, including for housing.
These facts highlight the relevance of reducing both building energy use and building greenhouse gas emissions as a key to balancing the Energy Trilemma. For this reason, the development of environmentally sensitive buildings has become a trend in the United States and in the world, with particular growth in the last decade.
The challenge of reducing the energy consumption of a building structure resides both in the sustainable generation of the energy it consumes and in the efficiency with which it utilizes such energy. Therefore, energetic independence is closely tied to the energy-efficiency of the Building Envelope, since the energy requirement for heating and/or cooling to keep the interior of the house at a comfortable temperature can be significant, globally accounting for over 35% of all energy consumed in buildings and rising to over 60% in cold climates.
As with every new challenge technology faces, the earlier attempts of developing energetically independent buildings either failed to achieve the desired degree of energy-efficiency or did it at a cost which made them absurdly unaffordable for a regular buyer. In 1996, the "Passivhous Institute" was founded in Germany to establish new standards for buildings pursuing a higher degree of energetic independence, but these houses still had a relatively inefficient performance and a very high cost, besides maintaining a substantial degree of greenhouse gas emissions during its construction and its useful-life. More recently, evolving from the Passivhous, the concept of "Zero-Energy homes" was born.
Zero-Energy homes combine advanced design and superior building systems with energy-efficiency and on-site solar panels to produce as much renewable energy as they consume over the course of a year, leaving the dwellers with a zero-dollar electricity bill, and a Zero-Emissions home. The main advantage of Zero-Energy homes for the home owner is the low cost of utilities, while at a national level it has the great advantage of a much lower environmental impact. Additionally, when implemented at the community level, Zero-Energy homes improve energy security and resilience against power outages and natural disasters.
However, nowadays, the initial investment required to build a Zero-Energy home is high. For the regular consumer, the desire of acquiring sustainable housing (and ideally, a Zero-Energy home) is countered by the much more pressing need of getting affordable housing. Today, the high costs of sustainable buildings make owning a house designed with an environmentally sustainable concept, and particularly one that meets the ambitious standards of being a Zero-Energy home, a luxury that only a few can afford.
Thus, the paramount importance of developing much more affordable Zero-Energy housing and other buildings such as commercial buildings becomes each day more pressing.
The goal of obtaining commercially viable Zero-Energy buildings is of such an importance that major regions of the world are developing policies to move toward them. The ASHRAE Vision 2020 report sets out requirements for enabling them by 2030. Numerous incentive policies, such as investment subsidies, feed-in tariff, net-metering schemes, etc., have been applied to promote the construction of Zero-Energy homes and buildings. Such programs have met with limited success so far for several reasons, one of them being the inherent difficulty of achieving a Building Envelope which is both energy-efficient and cost-efficient. As a result of this difficulty, only a handful of buildings that actually meet the Zero-Energy standard exist in the world, and none of them was built in a carbon-neutral, affordable manner.
Prefabricated homes are generally a good way of achieving affordable housing and reducing the use of natural resources and the greenhouse gas emissions during the construction. However, the current state of the art of prefabricated homes does not provide any options able of achieving the Zero-Energy goal.
For those reasons, we believe that the disclosed invention will provide substantial advancement to the field and become a valuable tool for housing developers, manufacturers and builders, in the quest for obtaining affordable Zero-Energy homes and buildings.

Bio-climatically adapted zero-energy prefabricated modular building and methods thereof