CN109663524B

CN109663524B - Direct injection probe temperature sensing method for speed change of heat sensitive portion of thermodynamic melt blending batch

Info

Publication number: CN109663524B
Application number: CN201710952394.4A
Authority: CN
Inventors: 克里斯·布鲁格
Original assignee: DISPERSOL TECHNOLOGIES LLC
Current assignee: Austin Pharmaceutical Co ltd
Priority date: 2017-10-13
Filing date: 2017-10-13
Publication date: 2022-07-15
Anticipated expiration: 2037-10-13
Also published as: CN109663524A

Abstract

The present disclosure provides a method for thermokinetic mixing of a component composition comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, in which method the thermokinetic mixing of the component composition is performed in a thermokinetic mixer at a lower first shaft speed, wherein monitoring of a batch by a temperature rate increase determination achieves a determination that a substantial portion of the required thermokinetic mixing has occurred, after which different shaft speeds are used to accomplish the required thermokinetic mixing of the component composition.

Description

Direct injection probe temperature sensing method for speed change of heat sensitive portion of thermodynamic melt blending batch

Technical Field

The present disclosure relates generally to the field of pharmaceutical manufacturing, and more particularly to the thermodynamic admixing of Active Pharmaceutical Ingredients (APIs) to produce new dosage forms.

Background

Current high throughput molecular screening methods used in the pharmaceutical industry have resulted in a large increase in the proportion of newly discovered poorly water soluble molecular entities. The therapeutic potential of many of these molecules is often not fully realized due to poor pharmacokinetic profiles that allow the molecules to be abandoned during development, or due to non-optimal product performance. In addition, in recent years, the pharmaceutical industry has begun to rely more and more on formulation methods to improve drug solubility due to practical limitations of salt forms and chemical modification of neutral or weakly acidic/basic drugs. Therefore, advanced formulation techniques aimed at enhancing the dissolution characteristics of poorly water-soluble drugs are becoming increasingly important for modern drug delivery.

U.S. patent application No.8,486,423, filed by the same inventor as the present application and by another co-inventor, relates to the application of thermodynamic compounding in the field of pharmaceutical manufacturing. Thermodynamic compounding or "TKC" is a process of thermodynamic mixing until melt blending. Pharmaceutical compositions or composites prepared by thermodynamic compounding may be further processed according to methods well known to those skilled in the art, including, but not limited to, hot melt extrusion (hot melt extrusion), melt granulation (melt granulation), compression molding (compression molding), tablet compression (tablet compression), capsule filling (capsule filling), film-coating (film-coating), or injection molding (injection molding) into the final product.

While the use of thermodynamic compounding in the pharmaceutical manufacturing field provides significant advantages over other methods known in the pharmaceutical field, the process of continuously melt mixing certain heat-sensitive or thermolabile components using a thermodynamic mixer may be improved in some cases. Blending such combinations of components may require the use of increased or decreased shaft speeds to extend the processing time sufficient to impart complete amorphicity (amorphosity) to the fully processed batch. It has been found that in some cases such treatment may result in exceeding the ultimate temperature or heat input which may result in degradation of the thermolabile components. It appears that the large amount of heat absorbed by the entire batch may cause thermal degradation of the thermolabile components rather than increasing the overall batch temperature. Substantially completely amorphous is a well-known measure in the art of pharmaceutical preparation and handling, and in compositions lacking substantially complete amorphous, bioavailability may be compromised.

Disclosure of Invention

The present disclosure continues to strive for research and development applications related to the application of thermodynamic compounding to the production of pharmaceutical composites and compositions. A brief description of the basic physical processing of pharmaceutical components introduced as batches into the thermodynamic mixing chambers of a thermodynamic mixer will aid in understanding such processing.

The thermodynamic mixer is completely unique in the field of processing equipment. The heating during the mixing process is generated by the process material itself (without the need for chemical reactions itself, but the structure of the crystalline drug may change) without external heat exchange such as indirect heat transfer by radiation or convection, or even without direct heating such as by direct flame contact. The thermodynamic mixer has a proprietary extension extending from the drive shaft, where the drive shaft extends through the axis of the cylindrical mixing chamber. These proprietary extensions are formed to provide angled contact surfaces oriented in the direction of the angular drive direction, wherein the angled contact surfaces are adapted to reduce or eliminate fracturing, tearing, or breaking of the treatment component molecules. The process steps that occur within the thermodynamic mixer during processing are typically:

1. controlled sliding, frictional heating contact occurs between the treatment component particles and the extension contact surface, thereby creating a high transient temperature at the contact side of the treatment component particles (heated side due to the particles can roll and can slide across the contact surface);

2. Before local high transient temperatures can adversely affect the chemical composition of the process component particles heated by the extension, these process component particles are angularly ejected away from the contact surface of the extension, thereby resulting (due to the extremely turbulent conditions within the mixing chamber) in immediate cooling contact with the mixing chamber air and other process component particles, thereby causing the heat generated by the prior sliding and frictional heating contact to be immediately distributed to substantially the entire batch of process component particles;

3. the angularly deflected particles rub against each other, producing heating that is instantaneously diffused, and in the event that the fusible particles reach the melting temperature, the fused particles engage with the captured non-fused particles and are pulled apart, so that the very finely divided or molecularly dispersed non-fused particles are uniformly distributed within the fused particles;

4. the angularly deflected particles are also directed axially and angularly outward from the drive shaft, causing sliding, frictional heating and some tangential contact with the inner surface of the cylindrical mixing chamber, thereby creating high transient temperatures at the contacting sides of the process component particles, such that as the particles lose kinetic energy due to their contact (directly or indirectly) with the extension, the particles quickly leave the inner surface of the mixing chamber and/or are pushed away or deflected from the inner surface by other more energetic process component particles;

5. Repeating the instant cooling contacting and mixing of step 2 above for releasing the sliding and frictionally heated particles from contact with the mixing chamber surface; and

6. the intense and extreme turbulence of the particles of the process components is substantially instantaneous and substantially continuous (but not constant with variations in the speed of the motor shaft) from the start of the thermodynamic mixer switch-on until the thermodynamic mixer is switched off at the end of the thermodynamic mixing step, so that the temperature of the entire batch is substantially uniform throughout the mixing chamber, where the temperature is measured at a distance of 1 cm to 2 cm from the frictional heating surface of the extension and the inner surface of the mixing chamber.

The thermodynamic mixer is used primarily for mixing before it is used to heat the treatment component particles to an elevated temperature where they will fuse together, heat generation being an unwanted side effect, and thus reduced by the use of a cooling jacket external to the mixing chamber. The present inventors have made a partial and isolated effort to find the use of thermodynamic compounding in pharmaceutical processing, wherein the present disclosure relates not only to the field of chemical composition-retention-blending, but also to the structural changes that cause thermally unstable pharmaceutical components.

The present disclosure relates to at least one active pharmaceutical ingredient "API", preferably at least a part of the active pharmaceutical ingredient in crystalline form (hereinafter referred to as component composition) in combination with at least one excipient, polymeric carrier or similar less active or inactive ingredient. The present disclosure provides a method of mixing component compositions in a single batch for only a few seconds using the following improved apparatus and/or method: the improved apparatus and/or method reduces batch processing time as compared to thermodynamic mixing that uses only batch temperature measurements to determine when thermodynamic mixing should be terminated and the batch removed from the mixing chamber.

In a first embodiment of the present disclosure, component composition mixing is performed at a lower first shaft speed, wherein monitoring of the batch by a temperature rate increase determination effects a determination that a substantial portion of the desired thermodynamic mixing has occurred, after which a higher second shaft speed is used to complete the desired thermodynamic mixing of the component compositions.

In a second embodiment of the invention, component composition mixing is performed at a lower first axis speed, wherein the batch is monitored by either an absolute determination of the crystallinity of the batch or a determination of the rate of decrease of the crystallinity of the batch. Thermodynamic mixing is terminated at a predetermined value of crystallinity or rate of crystallinity decay, or a higher second axis speed is used to achieve the desired thermodynamic mixing of the component compositions at a second predetermined value of crystallinity or rate of crystallinity decay.

An inherent finding in both embodiments is that after extensive testing and error in the thermodynamic mixing of the component compositions, prolonged exposure to the elevated temperatures required to achieve the desired mixing can result in degradation of the expensive and thermolabile drug molecules. A method for shortening the required mixing time must be found. Both embodiments meet these requirements.

The first embodiment has the following findings: lower first axis speed mixing of the component compositions provides the desired mixing of a substantial portion of the component compositions within just a few seconds of the start of the process, but a prolonged mixing time that can lead to degradation of the drug is clearly desirable, so a higher second axis speed is used later in the process. The first embodiment includes the discovery that: the lower first shaft speed step need only be relatively short and its end (and the start of the higher second shaft speed) is triggered by a considerable drop in the temperature rise rate of the batch. The higher second axis velocity will begin when the rate of temperature rise is about 10% to 100% less than the maximum temperature rate of temperature rise of the batch calculated in the first few seconds, or when the rate of temperature rise has a rate of increase (temperature (° F or ℃)/time (seconds)) of 1.5 degrees/second to 0 degrees/second. Surprisingly, the desired level of mixing (determined experimentally and incorrectly, i.e. testing the mixed component compositions after mixing) can be achieved in a shorter time and typically at a lower final batch temperature than in the first embodiment, which uses a single shaft speed throughout the mixing process or a single temperature measurement for the batch only. The shorter processing time and lower final temperature of the first embodiment results in a drug that is not substantially degraded and may be nearly as valuable as the final product and substantially eliminates the initial crystallinity of the drug or drug product component. The reasons for reducing the crystallinity and increasing the amorphous nature of the mixed component composition will now be discussed.

The structural change required in the mixed drug components is often referred to as amorphous or amorphous state. It is well known that the complex handling of producing solid particulate drugs prior to final mixing or processing results almost exclusively in crystalline compounds. These pure compounds are preferably amorphous prior to mixing with the other components to produce the final desired pharmaceutical composition. It is well known that amorphous drugs have a significantly increased predicted solubility compared to their crystalline phase (Hancock et al, Pharm Res.2000, 4 months; 17 (4): 397. The increased solubility is only one of the bioavailability advantages of converting a pharmaceutical compound to an amorphous state prior to administration-the importance of an "amorphous pharmaceutical solid is its useful properties, prevalence and physicochemical instability relative to the corresponding crystals. "(Yu, L., 5/16/2001 of Adv Drug Deliv Rev.48 (1): 27-42 published as" Amorphous pharmaceutical solids: preparation, characterization and stabilization "; www.ncbi.nlm.nih.gov/pubmed/11325475). Yu further illustrates the state of the art in restoring crystalline and thermolabile pharmaceutical compounds (e.g., proteins and peptides) to an effectively amorphous state-melt quenching, freeze spray drying, milling, wet granulation, and drying of solvated crystals. These processes are time consuming and labor intensive and must be done separately from the other components to mix with the final amorphous drug solid and subject the processed crystalline drug solid to degradation and recrystallization. There is a need for a process that can achieve mixing of single or multiple crystalline drug solids to produce a desired final drug dosage composition, and at the same time achieve a desired amorphous state of the drug solids as part of the desired final drug dosage composition.

A second embodiment includes a novel method of monitoring the thermodynamic mixing of component compositions. The present inventors have discovered a method by which the crystallinity of a mixed batch in a thermodynamic mixer can be measured. The environment within the mixing chamber during thermodynamic mixing is preferably dark and turbulent and lasts no more than about 30 seconds. Although it is desirable to be able to directly measure the crystallinity of a mixed batch so that mixing can be terminated when the crystallinity is sufficiently reduced or effectively eliminated, methods that have been achievable in the past are not known in the art of turbulent batch mixing of dry particles. The present inventors have first found that the crystallinity of a mixed static amount of a solid material is measured using a raman spectrometer, and thus the crystallinity of a mixed component composition can be measured using a raman spectrometer. In analyzing static samples of unmixed and mixed component compositions, commercial raman spectrometers allow a user to filter out all detected wavelengths associated with other components of the component compositions and to detect and measure the percent crystallinity of a drug or pharmaceutical of the component composition. The present inventors have discovered a raman spectroscopy probe comprising a relatively narrow tube with the necessary lenses oriented axially within the tube, the end of the tube being open for receiving and transmitting light waves suitable for detection by a raman spectrometer. Without being limited thereto, a suitable Raman spectrometer for an example of the second embodiment may be Princeton instruments, in particular Trivista CRS (http:// www.princetoninstruments.com/products/specsys/trivistacr /), the laser and detection device of which has been adapted to such a narrower tube (in the case of Trivista CRS, the tube is a standard microscope lens tube). The probe in the second embodiment uses the lens extension tube of the raman spectrometer such that the distal end portion of the lens extension tube is guided into the mixing chamber, preferably so that the probe can detect the crystallinity of the particles moving between the rotational axis extensions. The proximal end of the raman spectroscopy probe is connected to the raman spectrometer and to a device microprocessor having a device user interface that allows for viewing and/or transmitting the crystallinity-determining data of the raman spectrometer to the mixer control microprocessor. When the raman spectrometer determines the mix batch crystallinity and transmits this data to the mixer control microprocessor, the mixer control microprocessor can terminate the mixing of the component composition batches or increase the shaft speed and terminate the mixing thereafter. In a second embodiment, upon conversion of the drug or drug from the crystalline amorphous form, raman scattering from the drug or drug crystal ceases or is not detectable, i.e., energy is now absorbed by a different energy state than the drug or drug crystal. The raman probe detects when the drug or drug crystals are substantially lost, thereby eliminating the need for temperature measurement for process control of the thermodynamic mixing of the component compositions.

Brief summary of the invention

In contrast, neither the treatment of the thermolabile drug component in admixture with other components nor the treatment of the thermolabile drug component itself in powder form is intended to bring the thermolabile drug component to its melting temperature. Rather, the desired result is a substantially complete mix or powder form. A separate processing step would be avoided if substantially complete amorphicity could be achieved in the same mixing step. The present inventors believe that due to his many years of experience in processing commercial polymers using a thermodynamic mixer, the thermodynamic mixer can avoid decomposition of thermolabile pharmaceutical ingredients in the desired mixing process. However, the inventors also contemplate that even a short period of heating may result in decomposition of components that often require several prior processing steps for costly application of specialized techniques. The inventors considered how the processing time of the mixed batch in the thermodynamic mixer could be further reduced, but still achieve substantially complete amorphicity of the batch.

Additional overview of the first and second embodiments of the present invention

The present inventors have observed, when experimenting with thermolabile pharmaceutical components of test batches in a thermodynamic mixer, the phenomenon that he appears when using a thermodynamic mixer. After an initial mixing period at a lower shaft rotation speed, the temperature of the batch will rise and stabilize (plateau). Further processing at a slower rate will not result in substantially complete amorphicity in the processing batch. The inventors have found that increasing the shaft rotation speed to a higher level for a rather short period of time can produce substantially complete amorphicity in the resulting batch, and that the components are hardly decomposed by the heat of treatment.

However, the present inventors have found that the above-described methods of achieving the desired results may unnecessarily extend the processing time. In the present invention, the processing time for processing a batch and the time exposed to high temperatures are reduced compared to waiting to observe that the temperature at a lower shaft rotation speed is stable and then increasing the shaft rotation speed to a higher shaft rotation speed. In the present invention, a high speed temperature sensor accurately and substantially instantaneously measures the average batch temperature, which is stored in a mixer or batch microprocessor (including CPU, memory, clock and input/output units) operating under a batch control program. The sensed temperature is compared to one or more previously stored temperatures and their recorded times to calculate a rate of temperature change. When it is detected that the rate of temperature change has decreased or increased to the desired temperature increase trigger rate, the shaft rotational speed is increased from a lower shaft rotational speed to a higher shaft rotational speed.

The raman spectroscopy probe is preferably positioned to detect crystallinity of particles in motion located in a smaller sample space near the distal end of the probe which is illuminated by the laser beam. Light from the illuminated area is collected by a lens and sent through a monochromator of a raman spectrometer. Wavelengths close to the laser and the drug or pharmaceutical are filtered out due to elastic rayleigh scattering, while the rest of the collected light is dispersed onto the detector. Laser light interacting with molecular vibrations, phonons, or other excitations in the system causes the energy of the laser photons to shift up or down. The transfer of energy gives information on the vibration modes in the system. In the case of the second embodiment, these vibration patterns are processed by the temperature sensor manufacturer's algorithm to determine the average crystallinity of the mixed batch. Since the detection time for the crystallinity of the mixed batch can be extended to about 3 seconds, the equipment microprocessor or mixer control microprocessor optionally runs a crystallinity set point program that determines the rate of decrease of the crystallinity of the batch and stores it for predictive use. Since over-mixing for 3 seconds or more (batch crystallinity detection by raman probe) may result in degradation of the drug or drug, it is preferred to test the test batch for the desired component composition to obtain a stop-mixing or rate-increasing trigger set point. These trigger set points are used with the absolute value of the crystallinity currently measured or the rate of crystallinity decay such that mixing (or shaft speed increase) is stopped to achieve the desired thermodynamic mixing before the desired level of crystallinity is currently detected.

Referring now to the first embodiment, the inventors have also found that the rate of change of temperature at a point on the first temperature plateau corresponds to a change in viscosity indicative of an optimal time to increase the rotational speed of the shaft. The present invention measures the rate of temperature change of a mixed batch and increases the shaft rotation speed from a lower level to a higher level according to the following process: (1) the rate of change of the average batch temperature is calculated as having reached a trigger rate of temperature change indicating that the batch has achieved the desired viscosity change indicating a significant increase in amorphousness, or (2) the rate of change of the average batch temperature has reached an expected trigger rate of temperature change indicating that the batch will achieve the desired viscosity change indicating a significant increase in amorphousness during a short processing period after taking into account the processing speed of temperature detection and calculation. In the case of the processing method (2), the shaft rotation speed is increased to a higher level before the desired temperature change rate is actually detected and calculated, in order to avoid unnecessary mixing time after the desired temperature change rate is detected and calculated.

In the present invention, the resulting pharmaceutical composition preferably has increased bioavailability and stability due to being substantially completely mixed and having amorphous properties.

As described above, a thermodynamic mixer provides a method of blending and dispersing a self-heating mixture in a mixing chamber of a high-speed mixer, where a first speed is changed to a second speed in a process after a first desired process parameter is reached. In another embodiment, the second speed may be maintained until the final processing parameters are reached, at which time the shaft rotation is stopped and the melt-blended batch is withdrawn or discharged from the mixing chamber for further processing. In another embodiment, one or more intermediate speed changes may be made to the shaft rotational speed between the second speed and stopping the shaft rotation. The process parameters that determine the change in shaft speed are predetermined and can be sensed and displayed, calculated, inferred or otherwise established with reasonable certainty such that the speed change is made during a single rotation of the batch in the mixing chamber of the high speed mixer. Another embodiment is to use the changes in shape, width and angle of the face portion of the shaft extension or protrusion protruding into the main processing volume to control the conversion of the rotational shaft energy delivered to the extension or protrusion into thermal energy within the particles impacting the portion of the extension or protrusion.

The inventors have investigated melt blending of various mixtures containing thermolabile components in a thermodynamic mixing chamber. The present inventors have unexpectedly discovered that the use of multiple speeds in a single rotary continuous operation of certain batches containing thermolabile components solves the problem of exceeding the limit temperature or excessive heat input of the batch. The inventors have also unexpectedly discovered that varying the shape, width, and angle of the shaft extension or protrusion from the axial plane of the shaft provides a method of controlling the shear delivered to the particles, which in turn provides control of the shaft energy converted into thermal energy that can be used to soften or melt the polymer portion of the particles in the thermokinetic mixing chamber.

One embodiment of the present disclosure is a method of blending a composition of two or more ingredients, wherein the ingredients include one or more heat sensitive or thermolabile components, wherein the resulting composition is amorphous, homogeneous (heterogenous), heterogeneous (heterogenous), or heterogeneously homogeneous (heterogenous) comprising mixing the ingredients in a thermodynamic mixing chamber, wherein a thermodynamic mixer shaft is operated at a first speed until a predetermined parameter is reached, at which time the shaft speed is adjusted to a second speed and for a second period of time, wherein the mixing process is substantially uninterrupted between the first and second periods of time. In another embodiment of the present disclosure, the thermodynamic mixer shaft is run at one or more speeds until a predetermined parameter is reached, at which time the shaft speed is adjusted to a different speed for a different time period, wherein the mixing process is substantially uninterrupted between the two or more time periods. One example of such an embodiment is a method of blending a composition of two or more ingredients, wherein the thermodynamic mixer shaft is operated at a first speed until a first predetermined parameter is reached, at which time the shaft speed is adjusted to a second speed for a second time period, wherein the mixing process is substantially uninterrupted between the first time period and the second time period, and wherein, at the end of the second time period, the rotational speed of the shaft is changed from the second speed to a third speed after the predetermined parameter is reached and for a third time period. In one embodiment, the mixing process is substantially uninterrupted between the second time period and the third time period.

In certain embodiments, the thermosensitive or thermolabile component may comprise one or more active pharmaceutical ingredients, one or more pharmaceutically acceptable excipients, or one or more pharmaceutically acceptable thermosensitive polymers. In other embodiments, the heat-or thermolabile component may comprise one or more active pharmaceutical ingredients and one or more pharmaceutically acceptable excipients or heat-sensitive polymers. In other embodiments, the active pharmaceutical ingredient and one or more pharmaceutically acceptable excipients are added in a ratio of about 1:2 to 1:9, respectively. In yet other embodiments, the active pharmaceutical ingredient and the one or more pharmaceutically acceptable thermosensitive polymers are added in a ratio of about 1:2 to 1:9, respectively. In certain embodiments, the second time period may be at least about 5%, 10%, 15%, 20%, 25% or more of the first time period. In other embodiments, the speed during the second time period is increased by about 100 Revolutions Per Minute (RPM), 200RPM, 300RPM, 400RPM, 500RPM, 600RPM, 700RPM, 800RPM, 900RPM, 1000RPM, 1100RPM, 1200RPM, 1300RPM, 1400RPM, 1500RPM, 1600RPM, 1700RPM, 1800RPM, 1900RPM, 2000RPM, RPM 2100, 2200RPM, 2300RPM, 2400RPM, 2500RPM, or more compared to the speed during the first time period. For example, in one embodiment, the first speed is greater than 1000RPM and the second speed is 200 to 400RPM greater than the first speed. In another embodiment, the first speed is greater than 1000RPM and the second speed is 200 to 1000RPM greater than the first speed. In other embodiments, the first speed is greater than 1000RPM and the second speed is 200 to 2500RPM greater than the first speed.

In one embodiment, the end of the first time period is substantially before the mixing chamber temperature reaches the shear transition temperature (shear transition temperature) or melting point of any substantial component (substential component) in the composition. In another embodiment, the end of the first period of time is a predetermined period of time and is automatically changed to the second speed by the thermodynamic mixer at the end of the first period of time. In another embodiment, the end of the first period of time is substantially before the mixing chamber temperature reaches the shear transition temperature of the active pharmaceutical ingredient in the composition. In another embodiment, the end of the first period of time is substantially before the mixing chamber temperature reaches the shear transition temperature of the excipients in the composition. In another embodiment, the end of the first period of time is substantially before the mixing chamber temperature reaches the shear transition temperature of the thermosensitive polymer in the composition.

In one embodiment, the end of the second time period or any subsequent time period is substantially before the active pharmaceutical ingredient undergoes significant thermal degradation. In another embodiment, the end of the second time period or any subsequent time period is substantially before the excipient ingredient undergoes significant thermal degradation. In another embodiment, the end of the second time period or any subsequent time period is substantially before the heat-sensitive polymer composition undergoes substantial thermal degradation. In one embodiment, at the end of the second time period or any subsequent time period, the active pharmaceutical ingredient and excipients of the composition are substantially amorphous. In another embodiment, at the end of the second time period or any subsequent time period, the active pharmaceutical ingredient and the thermosensitive polymer of the composition are substantially amorphous. In other embodiments, after the final processing parameters are reached, the shaft rotation is stopped and the batch or composite material is withdrawn or discharged from the mixing chamber for further processing. In certain embodiments, the batch or composite is withdrawn or discharged at or below the glass transition temperature (glass transition temperature) of at least one component of the batch or composite. In other embodiments, the batch or composite is further processed by hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film coating, or injection molding. In other embodiments, the batch or composite material is withdrawn or discharged at the beginning of the RPM plateau, e.g., before degradation of the batch or composite material occurs. In other embodiments, the RPM deceleration is adjusted prior to drawing or discharging the batch or composite material to produce a more uniform batch or composite material.

Another embodiment of the present disclosure is directed to a method of compounding one or more active pharmaceutical ingredients and at least one polymeric pharmaceutically acceptable excipient to produce an amorphous, homogeneous, heterogeneous, or heterogeneously homogeneous composition, the method comprising thermodynamically mixing the active pharmaceutical ingredients and the at least one polymeric pharmaceutically acceptable excipient in a chamber at a first speed effective to increase the temperature of the mixture, and increasing the rotation of the mixer to a second speed to produce the amorphous, homogeneous, heterogeneous, or heterogeneously homogeneous composition at a point in time at which the temperature is below the shear transition temperature of any active pharmaceutical ingredient or polymeric pharmaceutically acceptable excipient in the mixture, wherein the increase is achieved without requiring neither stopping the mixing nor opening the chamber. In another embodiment of the disclosure, the method comprises thermodynamically mixing in the chamber at one or more speeds effective to increase the temperature of the mixture, at which time the shaft speed is adjusted to a different speed for a different period of time, and increasing the rotation of the mixer to the one or more different speeds at a point in time at a temperature below the shear transition temperature of any active pharmaceutical ingredient or polymeric pharmaceutically acceptable excipient in the mixture, wherein the increase is achieved without requiring neither stopping the mixing nor opening the chamber.

Certain embodiments of the present disclosure relate to a thermodynamic mixer for producing a pharmaceutical composition comprising one or more heat-sensitive or thermolabile components. Embodiments of the mixer may include one or more of the following and any combination of the following: (1) a mixing chamber, such as a generally cylindrical mixing chamber; (2) a shaft disposed through a central axis of the mixing chamber; (3) a motor connected to the shaft, the motor being effective to impart rotational motion to the shaft, for example; (4) one or more projections or extensions from the shaft and perpendicular to the long axis of the shaft; (5) one or more thermal sensors, for example attached to a wall of the mixing chamber and operative to detect heat or temperature of at least a portion of the interior of the mixing chamber; (6) a frequency conversion device, which is connected to the motor, for example; (7) a door disposed in a wall of the mixing chamber, the door being effective to allow contents of the mixing chamber to exit the mixing chamber, for example when opened during a program run; and (8) an electronic controller. In certain embodiments, hygroscopic conditions are maintained in the thermodynamic mixer. In other embodiments, the thermodynamic mixer is designed to maximize shear during batch processing.

In certain embodiments, the electronic controller is in communication with the temperature sensor, the door, and the variable frequency device. In some embodiments, the electronic controller comprises a user input device, a timer, an electronic storage device, and a display, wherein the electronic storage device is configured to receive user input of process parameters or predetermined parameters for two or more stages of a thermodynamic mixing process. In one embodiment, the process parameters or predetermined parameters are stored in a storage device and displayed on a monitor for one or more stages of a process run. In some embodiments, one is satisfied during a phase of a process runThe electronic controller automatically moves the process run to a subsequent stage at a predetermined parameter. In other embodiments, the interior of the mixing chamber is lined with an internal liner piece. The lining may be made of a material that minimizes any stickiness of the batch during processing, for example, stainless steel and other such steel alloys, titanium alloys (such as nitrided or nitride-containing peptides), and wear and heat resistant polymers (such as

) And (4) preparing.

In one embodiment of the present disclosure, at least one of the temperature sensors detects infrared radiation, for example, where the radiation level is output as a temperature on the display. In other embodiments, the predetermined parameter may be any one or combination of the following: temperature, rate of change of temperature, shaft rotation speed (e.g., rate of acceleration and deceleration), current amperage of the motor (amplitude draw), time of phase, or rate of batch or composite draw or exit. One skilled in the art will be able to vary each of the following parameters by routine experimentation to obtain a batch or composite material having the desired properties. In another embodiment, the output display may be any one or combination of the following: chamber temperature, motor rpm, motor amperage, or cycle elapsed time.

In certain embodiments of the present disclosure, the one or more projections or extensions from the shaft comprise a base and an end, and for example, the end may be removable from the base and the base may be removable from the shaft. In other embodiments, the projections or extensions in the thermodynamic mixer are replaceable, for example based on wear and tear or different batch parameters. In one embodiment, the one or more projections or extensions from the shaft comprise one or more major face portions having a width of at least about 0.75 inches and an angle to the axial plane of the shaft of 15 to 80 degrees. In other embodiments, the one or more protrusions or extensions from the shaft comprise one or more of the following major face portions: the one or more major face portions have a width of at least about 0.80 inch, 0.85 inch, 0.90 inch, 0.95 inch, 1.0 inch, 1.1 inch, 1.2 inch, 1.3 inch, 1.4 inch, 1.5 inch, 1.6 inch, 1.7 inch, 1.8 inch, 1.9 inch, 2.0 inch, 2.1 inch, 2.2 inch, 2.3 inch, 2.4 inch, 2.5 inch, 2.6 inch, 2.7 inch, 2.8 inch, 2.9 inch, 3.0 inch, 3.1 inch, 3.2 inch, 3.3 inch, 3.4 inch, 3.5 inch, 3.6 inch, 3.7 inch, 3.8 inch, 3.9 inch, 4.0 inch, 4.1 inch, 4.2 inch, 4.3 inch, 4.4 inch, 4.5 inch, 4.6 inch, 4.7 inch, 4.8 inch, 4 inch, 4.5 inch, 4 inch, 8 inch, 4.5 inch, 4 inch, 9 inch, or more, the angle to the axial plane of the shaft is about 15 degrees, 20 degrees, 25 degrees, 30 degrees, 35 degrees, 40 degrees, 45 degrees, 50 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees, or 80 degrees. In certain embodiments, the one or more projections or extensions from the shaft control the conversion of the rotational shaft energy delivered to the projections or extensions into thermal energy within the particles impacting the projections.

In other embodiments, these dimensions of the one or more projections or extensions from the shaft are designed to improve the shear properties of the shear resistant population of particles in the batch, e.g., to produce a substantially amorphous composite. In certain embodiments, the one or more protrusions or extensions from the shaft are sized to produce at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% amorphous composite material.

Drawings

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of some specific embodiments presented herein.

FIG. 1 is a view of a thermodynamic mixer assembly.

FIG. 2 is an exploded view of the thermodynamic mixer.

FIG. 3 is an axial radial cross-sectional view of a thermodynamic mixing chamber.

FIG. 4 is an exploded view of a thermodynamic mixing chamber.

FIG. 5. analysis of batch sensed temperature, shaft rotation speed in RMP, and motor current amperage as a measure of the direct proportion of energy input into a batch with one rotating shaft speed at any one time.

FIG. 6 analysis of batch sensed temperature, shaft rotational speed in RMP, and motor current amperage as a measure proportional to the energy input into the batch with both rotational shaft speeds at any one time.

FIG. 7 is a block diagram of a thermodynamic mixer process for two or more rotating shaft speeds.

Fig. 8. cross section of a prior art shaft extension main face portion.

FIG. 9 is a cross section of a major face portion of the shaft extension at an angle of about 15 degrees from the axial plane of the shaft.

Figure 10. cross section of the main face portion of the shaft extension at an angle of about 30 degrees to the axial plane of the shaft.

FIG. 11. cross section of a main face portion of the shaft extension at an angle of about 45 degrees to the axial plane of the shaft.

Figure 12. cross-section of the main face portion of the shaft extension at an angle of about 60 degrees to the axial plane of the shaft.

FIG. 13. alternative design of the cross section of the shaft extension main face portion.

FIG. 14 is an alternative design of a cross section of a main face portion of the shaft extension.

FIG. 15 is an alternative design of a cross section of a shaft extension main face portion.

FIG. 16 is an alternative design of a cross section of a main face portion of the shaft extension.

FIG. 17 is an alternative design of a cross section of a shaft extension main face portion.

FIG. 18 is an alternative design of a cross section of a shaft extension main face portion.

FIG. 19 is an exploded view of the thermodynamic mixer showing the inner liner.

FIG. 20 is a schematic side view of the top face of the shaft extension interacting with the inner surface of the mixing chamber.

FIG. 21 is a perspective view of a shaft extension with a variable top face path length.

FIG. 22. alternative design of the front face of the shaft extension.

Fig. 23 is a flow chart depicting an alternative embodiment of the present invention.

FIG. 24 is a high level process flow diagram of an alternative embodiment of the present invention using a trigger set point to increase shaft rotational speed and/or stop thermodynamic mixing.

FIG. 25 is an analytical graph of a single axis speed batch showing sensed temperature in F and axis rotation speed in RPM as a function of process time with the process stopped at the detected temperature plateau.

FIG. 26 is an analytical graph of a single axis speed batch showing sensed temperature in ° F and axis rotation speed in RPM as a function of treatment time, wherein treatment is stopped after detecting a temperature plateau for a second period of time or detecting a decrease in crystallinity.

FIG. 27 analysis graph of a dual spindle speed batch showing sensed temperature in F and spindle rotational speed in RPM as a function of processing time, where spindle speed is increased at a detected temperature plateau and processing is stopped when a temperature of a second speed time or a decrease in crystallinity is detected.

Detailed Description

While various embodiments of making and using the present disclosure are discussed in detail below, it should be appreciated that the present disclosure provides many inventive concepts that can be embodied in a wide variety of different contexts. The specific aspects and embodiments discussed herein are merely illustrative of ways to make and use the disclosure, and do not limit the scope of the disclosure.

To facilitate an understanding of the present disclosure, a number of terms are defined below. Terms defined herein have meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Terms without numerical modification are not intended to refer to only a single entity, but include the general class of specific examples that may be used for illustration. For values and ranges recited herein, the term "about" is intended to include variations above and below the indicated number that may achieve substantially the same result as the indicated number. In the present disclosure, each of the various indicated ranges is intended to be continuous, such that each numerical parameter between the minimum and maximum values indicated for each range is included. For example, a range of about 1 to about 4 includes about 1, about 2, about 3, about 4, and 4. The terminology herein is used to describe some specific embodiments of the disclosure, but its use is not limiting of the disclosure.

The term "thermokinetic compounding" or "TKC" as used herein refers to a process of thermokinetic mixing until melt blending. TKC can also be described as a thermodynamic mixing process, where the process is sometimes terminated at a point prior to agglomeration.

The term "major face portion" as used herein refers to the "top face" of the shaft extension. The top face of the shaft extension is the face facing the inner wall of the mixing chamber of the thermodynamic mixer.

The term "shear transition temperature" as used herein refers to the point at which further energy input does not result in an immediate temperature rise.

The term "homogeneous, heterogeneous or heterogeneously homogeneous composite or amorphous composite" as used herein refers to a variety of compositions that can be prepared using TKC methods.

The term "heterogeneous homogeneous composition" as used herein refers to a material composition having at least two different materials that are uniformly and consistently distributed throughout a volume.

The term "bioavailability" as used herein means the degree to which a drug is available to a target tissue after administration to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing non-highly soluble active ingredients. In certain embodiments (e.g., protein formulations), the protein may be water soluble, poorly soluble, non-highly soluble, or insoluble. The skilled artisan will recognize that a variety of methods can be used to increase the solubility of a protein, such as the use of different solvents, excipients, carriers, formation of fusion proteins, targeted control of amino acid sequences, glycosylation, lipidation, degradation, combination with one or more salts, and addition of multiple salts.

The phrase "pharmaceutically acceptable" as used herein refers to molecular entities, compositions, materials, excipients, carriers, and the like that do not typically produce allergic or similar untoward reactions when administered to a human.

The term "active pharmaceutical ingredient" or "API" as used herein is interchangeable with the terms "drug product", "pharmaceutical product", "medicament", "liquid", "biological" (biological) "or" active ingredient ". An "API" as used herein is any component intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or any function of the human or other animal body. In certain embodiments, the water solubility of the API may be poor solubility.

Examples of APIs that may be used in the present disclosure include, but are not limited to, antibiotics, analgesics, vaccines, anticonvulsants, antidiabetic agents, antifungal agents, antineoplastic agents, antiparkinson agents, antirheumatic agents, appetite suppressants, biological response modifiers, cardiovascular agents, central nervous system stimulants, contraceptives, dietary supplements, vitamins, minerals, lipids, sugars, metals, amino acids (and precursors), nucleic acids and precursors, contrast agents, diagnostic agents, dopamine receptor agonists, erectile dysfunction agents, fertility agents, gastrointestinal agents, hormones, immunomodulators, antihypercalcemic agents, mast cell tranquilizers, muscle relaxants, nutritional agents, ophthalmic agents, osteoporosis agents, psychotherapeutic agents, parasympathomimetic agents, parasympathetic blockers, respiratory agents, sedative-hypnotics, skin and mucosae, smoking cessation agents, steroids, film forming agents, anti-inflammatory agents, anti, Sympathetic blocking agent, urinary tract agent, uterine relaxant, vaginal agent, vasodilator, antihypertensive agent, hyperthyroidism agent, antithyroidism agent, antiasthmatic agent, and vertigo agent. In certain embodiments, the API is a poorly water soluble drug or a drug with a high melting point.

The API may exist in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs and solvates thereof. As used herein, "pharmaceutically acceptable salt" should be understood to mean a compound formed by the interaction of an acid and a base, the hydrogen atom of the acid being replaced by the cation of the base. Non-limiting examples of pharmaceutically acceptable salts include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. Another method for defining ionic salts may be acid functionalities, such as carboxylic acid functionalities, and pharmaceutically acceptable inorganic or organic bases. Non-limiting examples of bases include, but are not limited to: hydroxides of alkali metals (such as sodium, potassium, and lithium); hydroxides of calcium and magnesium; hydroxides of other metals (e.g., aluminum and zinc); ammonia; and organic amines such as unsubstituted or hydroxy-substituted monoalkylamines, dialkylamines, or trialkylamines; dicyclohexylamine; tributylamine; pyridine; N-methyl-N-ethylamine; diethylamine; triethylamine; mono (2-hydroxy-lower alkylamine), di (2-hydroxy-lower alkylamine), or tri (2-hydroxy-lower alkylamine), such as mono (2-hydroxyethyl) amine, di (2-hydroxyethyl) amine, or tri (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine, or tri- (hydroxymethyl) methylamine, N-di-lower alkyl-N- (hydroxy-lower alkyl) -amine (such as N, N-dimethyl-N- (2-hydroxyethyl) amine), or tri- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and amino acids (e.g., arginine, lysine), and the like.

A variety of routes of administration can be used to deliver the API to a patient in need thereof. The particular route chosen will depend on the particular drug chosen, the weight and age of the patient, and the dosage required for therapeutic effect. The pharmaceutical compositions may conveniently be presented in unit dosage form. APIs and pharmaceutically acceptable salts, derivatives, analogs, prodrugs and solvates thereof suitable for use according to the present disclosure can be administered alone, but are generally administered in admixture with suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.

The API may be used in a variety of application forms, including oral delivery as a tablet, capsule, or suspension; pulmonary and nasal delivery; topical delivery as a cream, ointment or cream; transdermal delivery; and parenteral delivery as suspensions, microemulsions or depots. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, or infusion routes of administration.

Excipients and adjuvants that may be used in the compositions and composites disclosed herein while potentially having some activity per se, such as antioxidants, are generally defined herein as compounds that enhance the efficiency and/or effectiveness of the active ingredient. It is also possible to have more than one active ingredient in a given solution so that the particles formed contain more than one active ingredient.

As noted, excipients and adjuvants may be used to enhance the efficacy and efficiency of the API. Non-limiting examples of compounds that may be included are binders, cryoprotectants, lyophilization protecting groups, surfactants, bulking agents, stabilizers, polymers, protease inhibitors, antioxidants, and absorption enhancers. Excipients may be selected to modify the intended use of the active ingredient by enhancing flow or bioavailability, or to control or delay the release of the API. Specific non-limiting examples include: sucrose, trehalose, Span 80, Tween 80, polyoxyethylene fatty alcohol ether (Brij)35, Brij 98, Pluronic, sucrose ester 7, sucrose ester 11, sucrose ester 15, sodium lauryl sulfate, oleic acid, laureth-9, laureth-8, lauric acid, vitamin E TPGS, Gelucire 50/13, Gelucire 53/10, Labrafil, dipalmitoylphosphatidylcholine, glycolic acid and salts, deoxycholic acid and salts, sodium fusidate, cyclodextrin, polyethylene glycol, labrasol, polyvinyl alcohol, polyvinylpyrrolidone and tyloxapol. Using the methods of the present disclosure, the morphology of the active ingredient can be altered, resulting in highly porous microparticles and nanoparticles.

Exemplary thermal adhesives that may be used in the compositions and composites disclosed herein include, but are not limited to: polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinyl acetate; acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polyethylene-co-polypropylene; alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose; starch, pectin; polysaccharides, such as tragacanth, acacia, guar gum and xanthan gum. One embodiment of the binder is POLY (ethylene oxide) (PEO), which is commercially available from, for example, the Dow Chemical Company, which sells PEO under the trademark POLY ox. tm. an exemplary grade of which can include WSR N80 having weight average molecular weights of about 200,000, 1,000,000, and 2,000,000.

Suitable PEO grades may also be characterized by the viscosity of a solution containing a fixed concentration of PEO, such as, for example:

suitable thermal adhesives that may or may not require a plasticizer include, for example, Eudragit. TM. RS PO, Eudragit. TM. S100, Kollidon SR (poly (vinyl acetate) -co-poly (vinylpyrrolidone) copolymer), Ethocel. TM. (ethylcellulose), HPC (hydroxypropylcellulose), cellulose acetate butyrate, poly (vinylpyrrolidone) (PVP), poly (ethylene glycol) (PEG), poly (ethylene oxide) (PEO), poly (vinyl alcohol) (PVA), Hydroxypropylmethylcellulose (HPMC), Ethylcellulose (EC), Hydroxyethylcellulose (HEC), carboxymethylcellulose sodium (CMC), dimethylaminoethylmethacrylate-methacrylate copolymer, ethyl acrylate-methyl methacrylate copolymer (GAM-MA), C-5 or 60SH-50(Shin-Etsu Chemical Corp.), Cellulose Acetate Phthalate (CAP); and, Cellulose Acetate Trimellitate (CAT), poly (vinyl acetate) phthalate (PVAP), hydroxypropylmethylcellulose phthalate (HPMCP), poly (ethyl methacrylate) (1:1) copolymer (MA-EA), poly (methyl methacrylate) (1:1) copolymer (MA-MMA), poly (methyl methacrylate) (1:2) copolymer, Eudragit L-30-D.TM. (MA-EA, 1:1), Eudragit L-100-55.TM. (MA-EA, 1:1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric. TM. (PVAP), Aquateric. TM. (CAP), and AQUACOAT. TM. (HPMCAS), polycaprolactone, starch, pectin; polysaccharides such as gum tragacanth, gum acacia, guar gum and xanthan gum.

The stable and non-solubilizing carrier can also comprise a variety of functional excipients, for example: hydrophilic polymers, antioxidants, super disintegrants, surfactants including amphiphilic molecules, wetting agents, stabilizers, retardants, similarly functioning excipients, or combinations thereof, and plasticizers (including citrate esters, polyethylene glycol, PG, triacetin, diethyl phthalate, castor oil), as well as other excipients known to those skilled in the art. The extruded material may further comprise: acidulants, adsorbents, alkalizing agents, buffers, colorants, flavorants, sweeteners, diluents, opacifiers, complexing agents, fragrances, preservatives, or combinations thereof.

Exemplary hydrophilic polymers that may be primary or secondary polymeric carriers that may be included in the composites or compositions disclosed herein include poly (ethylene glycol) (PVA), polyethylene-polypropylene glycol (e.g., poloxamer. tm.), carbomer, polycarbophil, or chitosan. Hydrophilic polymers for use in the present disclosure may also include: one or more of hydroxypropyl methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, natural gums (e.g., guar gum, gum arabic, tragacanth gum, or xanthan gum), and povidone. The hydrophilic polymer further comprises: polyethylene oxide, sodium carboxymethylcellulose, hydroxyethyl methylcellulose, hydroxymethyl cellulose, carboxypolymethylene, polyethylene glycol, alginic acid, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polymethacrylamide, polyphosphazine, polyphospholine

Oxazolidines, poly (hydroxyalkylcarboxylic acids), carrageenan alginate, carbomers, ammonium alginate, sodium alginate, or mixtures thereof.

By "immediate release" is meant that once release begins, the active agent is released into the environment over a period of several seconds to no more than about 30 minutes, and release begins no more than about 2 minutes after administration. Immediate release does not exhibit a significant delay in drug release.

By "rapid release" is meant that once release begins, the active agent is released into the environment over a period of from 1 minute to 59 minutes, or from 0.1 minute to three hours, and release may begin a few minutes after administration, or after a delay time (lag time) has elapsed after administration.

The "extended release" profile as used herein adopts a widely recognized definition in the field of pharmaceutical science. Sustained release dosage forms will release drug (i.e., active agent or API) at a substantially constant rate over an extended period of time, or a substantially constant amount of drug will be released incrementally over an extended period of time. Sustained release tablets generally result in at least a 2-fold reduction in dosing frequency as compared to the drug present in conventional pharmaceutical dosage forms (e.g., solutions or rapid release conventional solid dosage forms).

By "controlled release" is meant that the active agent is released into the environment over a period of about 8 hours to about 12 hours, 16 hours, 18 hours, 20 hours, 1 day, or more than 1 day. By "sustained release" is meant a sustained release of the active agent to maintain a constant drug level in the blood or target tissue of the subject to which the device is administered.

"controlled release" with respect to drug release includes the terms "sustained release", "extended release", "sustained release" or "slow release", as these terms are used in pharmaceutical science. The controlled release may begin a few minutes after administration or after a delay time (lag time) has elapsed after administration.

A slow release dosage form is a dosage form that provides a slow rate of drug release such that the drug is released slowly and substantially continuously, for example, over a period of 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 or more days, 1 week, 2 weeks, or more.

The term "mixed release" as used herein refers to an agent comprising two or more release profiles of one or more active pharmaceutical ingredients. For example, the mixed release may include an immediate-release portion and a sustained-release portion, each of which may have the same API or may have different APIs.

A timed release (timed release) dosage form is a dosage form that begins to release drug after a predetermined period of time as measured from the time of initial exposure to the use environment.

Targeted release dosage forms generally refer to oral dosage forms designed to deliver a drug to a specific portion of the gastrointestinal tract of a subject. An exemplary targeted dosage form is an enteric dosage form that delivers the drug to the mid-to-lower intestinal tract but not into the stomach or mouth of the subject. Other targeted dosage forms may be delivered to other parts of the gastrointestinal tract, such as the stomach, jejunum, ileum, duodenum, caecum, large intestine, small intestine, colon or rectum.

By "delayed release" is meant that the initial release of the drug occurs after about the end of the delay. For example, if the release of drug from a sustained release composition is delayed by two hours, the release of drug begins about 2 hours after administration of the composition or dosage form to a subject. In general, delayed release is in contrast to immediate release, wherein release of the drug begins no more than a few minutes after administration. Thus, the drug release profile from a particular composition may be a delayed sustained release or a delayed rapid release. A "delayed-extended" release profile is one in which the sustained release of the drug begins after the end of the initial delay time. The "delayed-rapid" release profile is where rapid release of the drug begins after the end of the initial delay time.

A pulsatile release dosage form is a dosage form that provides a pulse of high active ingredient concentration interspersed with low concentration valleys (trough). A pulse profile including two peaks can be described as a "bimodal". A pulse profile with more than two peaks can be described as multimodal.

A pseudo-first order release curve is a curve that approximates a first order release curve. The first order release profile characterizes a dosage form release profile that releases a constant percentage of the initial drug load (drug charge) per unit time.

The pseudo zero order release profile is a profile that approximates a zero order release profile. The zero order release profile characterizes the release profile of a dosage form that releases a constant amount of drug per unit time.

The resulting composites or compositions disclosed herein may also be formulated such that the formulated poorly water soluble drug exhibits enhanced dissolution rates.

The following are examples of compositions or formulations having a stable release profile. Two tablets with the same formulation were prepared. The first tablet was stored for one day under the first set of conditions and the second tablet was stored for 4 months under the same first set of conditions. The release profile of the first tablet was determined after a storage period of 1 day and the release profile of the second tablet was determined after a storage period of 4 months. A tablet/film formulation is considered to have a stable release profile if the release profile of the first tablet is about the same as the release profile of the second tablet.

The following is another example of a composition or formulation having a stable release profile. Tablets a and B, each comprising a composition according to the disclosure, and tablets C and D, each comprising a composition not according to the disclosure, were prepared. Tablets a and C were each stored under the first set of conditions for one day, and tablets B and D were each stored under the same first set of conditions for three months. The release profiles of each of tablets a and C were determined after a 1 day storage period and are referred to as release profiles a and C, respectively. The release profiles of each of tablets B and D were determined after a three month storage period and are referred to as release profiles B and D, respectively. The difference between release profiles a and B is quantified as the difference between release profiles C and D. Tablets a and B are considered to provide a stable or more stable release profile if the difference between release profiles a and B is less than the difference between release profiles C and D.

In particular, TKC treatment may be used for one or more of the following pharmaceutical applications.

Dispersions of one or more APIs wherein the API is a small organic molecule, protein, peptide or polynucleotide in a polymeric and/or non-polymeric pharmaceutically acceptable material are useful for delivering the API to a patient by oral, pulmonary, parenteral, vaginal, rectal, transurethral, transdermal or topical delivery routes.

Dispersions of one or more APIs in polymeric and/or non-polymeric pharmaceutically acceptable materials are used to improve oral delivery of the APIs by increasing the bioavailability of the APIs, prolonging the release of the APIs, targeting the release of the APIs to specific sites in the gastrointestinal tract, delaying the release of the APIs, or creating a pulsatile release system of the APIs.

Dispersions of one or more APIs in polymeric and/or non-polymeric pharmaceutically acceptable materials are used to produce bioerodible, biodegradable, or controlled release implantable delivery devices, wherein the APIs are small organic molecules, proteins, peptides, or polynucleotides.

Solid dispersions of thermolabile APIs are produced by treating at low temperatures for very short durations.

Solid dispersions of API in thermolabile polymers and excipients are produced by treatment at low temperatures for very short durations.

The small organic API is rendered amorphous while dispersed in a polymeric, non-polymeric or combination excipient carrier system.

The crystalline API is dry milled to reduce the particle size of the bulk material (bulk material).

The crystalline API is wet milled using a pharmaceutically acceptable solvent to reduce the particle size of the bulk material.

The crystalline API is melt milled using one or more molten pharmaceutical excipients having limited miscibility with the crystalline API to reduce the particle size of the bulk material.

The crystalline API is milled in the presence of a polymeric or non-polymeric excipient to produce an ordered mixture in which the fine drug particles are adhered to the surface of the excipient particles and/or the excipient particles are adhered to the surface of the fine drug particles.

Heterogeneous homogeneous or amorphous composites of two or more pharmaceutical excipients for post-processing such as grinding and sieving are produced which are subsequently used in secondary pharmaceutical operations well known to those skilled in the art, such as film coating, tableting, wet and dry granulation, roller compaction, hot melt extrusion, melt granulation, compression molding, capsule filling and injection molding.

Single phase miscible composites that produce two or more drug materials that were previously considered immiscible are used in secondary processing steps such as melt extrusion, film coating, tableting, and granulation.

The polymeric material is preplasticized for subsequent use in film coating or melt extrusion operations.

A crystalline or semi-crystalline drug polymer that can be used as a carrier for an API is made amorphous, where the amorphous character increases the dissolution rate of the API-polymer composite, the stability of the API-polymer composite, and/or the miscibility of the API with the polymer.

The engineered particles are deagglomerated and dispersed in the polymer carrier without altering the characteristics of the engineered particles.

The API in powder form is simply blended with one or more pharmaceutical excipients.

Composite materials comprising one or more high melting point APIs and one or more thermolabile polymers are produced without the use of processing aids.

The colorant or opacifying agent is uniformly dispersed in the polymer carrier or excipient blend.

In the following detailed description of the preferred embodiments of the disclosure, reference is made to the accompanying drawings in which like numerals in the various figures refer to the same or similar parts.

The present disclosure relates to novel thermodynamic mixers and mixing methods that can blend heat-sensitive or thermolabile components without substantial thermal degradation. In particular, the present disclosure can be used to treat mixtures containing thermolabile components that are exposed to melting temperatures or cumulative heat inputs for defined periods of time to cause degradation. One embodiment of the present disclosure is directed to a method for continuous melt blending a self-heating mixture in a mixing chamber of a high-speed thermodynamic mixer, wherein a first speed is changed to a second speed in a process after a first desired or predetermined process parameter is reached. In other embodiments, the second speed is changed to a third speed in the process after a second desired or predetermined process parameter is reached. Additional speed changes are also within the scope of the present disclosure, as indicated by several desired or predetermined processing parameters required to produce the desired composition or composite.

The method is particularly suitable for: producing a solid dispersion of thermolabile API by treating at low temperatures for very short durations at multiple speeds; producing a solid dispersion of API in thermolabile polymer and excipient by treating at low temperature for a very short duration at multi-stage speeds; producing a solid dispersion of API in a thermolabile excipient by treating at low temperatures for very short durations at multiple speeds; and producing a solid dispersion of the thermosensitive polymer by treating at low temperature at multi-stage speed for a very short duration.

One embodiment is to use two or more different speeds in the thermodynamic processing of a batch to reduce the processing time required after reaching the shear transition temperature of a portion of the batch. Another embodiment is to use two or more different speeds in the thermodynamic processing of a batch to reduce the processing time required after the batch reaches a temperature after which the substantial heat generated by frictional contact with the shaft extension and/or the inner surface of the mixing chamber causes thermal degradation of one or more components of the batch and reduces the speed. Another embodiment is to use two or more different speeds in the thermodynamic processing of a batch to reduce the processing time required after the batch has reached a temperature after which the bulk temperature change of the batch is not caused by the large amount of heat generated by frictional contact with the shaft extension and/or the inner surface of the mixing chamber. Another embodiment provides a thermodynamic processing method using two speeds to reduce thermal degradation of thermolabile or heat sensitive polymers or components of the batch so processed.

In one embodiment, at least a portion of the batch in the high-speed mixer mixing chamber contains a heat-sensitive or thermolabile component, which exposure to extreme temperatures or extreme heat build-up over a defined period of time must be substantially prevented or limited to obtain a melt-blended batch with acceptable degradation of the heat-sensitive or thermolabile component. In this embodiment, at least one speed change is made between the beginning and the end of the treatment so that the limit temperature or limit heat input is not exceeded, thereby preserving the heat-sensitive or thermolabile components in the composition or composite.

Thermolabile components include, but are not limited to, APIs, excipients, or polymers that are thermolabile. Heat-sensitive polymers include, but are not limited to, nylons, polytrimethylene terephthalate, polybutylene-1, polybutylene terephthalate, polyethylene terephthalate, polyolefins (e.g., polypropylene and high or low density polyethylene), and mixtures or copolymers thereof, which can be subject to surface and bulk polymer defects and extrusion limitations. Other thermosensitive polymers include poly (methyl methacrylate), polyacetals, polyionomers, EVA copolymers, cellulose acetate, rigid polyvinyl chloride, and polystyrene or copolymers thereof. The limiting temperature used in the disclosed method of such thermosensitive polymers may be selected by keeping the sensed temperature of the batch within an acceptable range, according to the known degradation temperature of the polymer, such as about 5 ℃, 10 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃, or 100 ℃ from which the desired processing parameters of the thermosensitive polymer begin to degrade, as known in the art.

One embodiment of the present disclosure is a method for continuously blending and melting a self-heated mixture in a mixing chamber of a high-speed mixer, wherein after a first desired or predetermined process parameter is reached, the first speed is changed in the process to a second speed. In one embodiment, the second speed is maintained until a final desired or predetermined process parameter is reached, at which time the shaft rotation is stopped and the melt-blended batch is withdrawn or discharged from the mixing chamber for further processing. The shaft operates at one or more intermediate rotational speeds between the changing to the second speed and the stopping of the shaft rotation. The process parameters that determine the change in shaft speed are predetermined and may be sensed and displayed, calculated, inferred or otherwise determined with reasonable certainty such that the speed change is made during a single rotational continuous process of a batch in the mixing chamber of the high speed mixer. Process parameters include, but are not limited to, temperature, motor RPM, current amperage, and time.

The present disclosure also relates to a thermodynamic mixer that can blend heat-sensitive or thermolabile components without substantial thermal degradation. One embodiment of the thermodynamic mixer has a high horsepower motor driving rotation of a horizontal shaft having toothed projections extending outwardly normal to the axis of rotation of the shaft. The shaft is connected to a drive motor. The portion of the shaft comprising the projection is included in the closed container in which the compounding operation takes place, i.e. in the thermodynamic mixing chamber. The high rotational speed of the shaft plus the design of the shaft projections imparts kinetic energy to the process material. A temperature sensor senses a temperature in the thermodynamic mixing chamber. Once the set temperature is sensed, the first speed is changed to the second speed.

FIG. 1 illustrates a view of one embodiment of the disclosed thermodynamic mixer assembly. The temperature sensor 20 is connected to the thermodynamic mixing chamber MC. The temperature sensor 20 provides information to the programmable logic controller 20a that is displayed on the programmable logic controller display 20 b. The drive motor 15 controls the speed of the shaft rotating through the mixing chamber MC. The drive motor 15 is controlled by a variable frequency drive 20 c. Variable frequency drive 20c also provides information to programmable logic controller 20a, which is displayed on programmable logic controller display 20 b. When the desired process parameters are met, the programmable logic controller 20a signals the variable frequency drive 20c to change the frequency of the electrical power supplied to the drive motor 15. The drive motor 15 changes the shaft speed of the shaft. The temperature sensor 20 may be a sensor of the radiation emitted by the batch component.

FIG. 2 illustrates an exploded view of one embodiment of a thermodynamic mixer. The frame 1 supports the relative components so that the shaft assembly 2 is inserted in the axis of the shaft hole through the end plate 3 and the feed screw hole through the end plate 4, which define the closed end of the mixing chamber cylinder, the bottom of which is defined by the inner surface of the lower casing 5. The lower case 5 includes a discharge opening that is closed during operation of a discharge door 6. The upper housing 7 includes an upper portion of a cylinder of the inner surface of the mixing chamber. The feed housing 8 is adapted to allow the materials to be fed to the feed screw of the shaft assembly such that these materials are forcibly compressed from the external feed device into the mixing chamber in conjunction with the rotation of the feed screw. The door 6 can be closed in a rotating manner about the discharge door pivot pin 9. The end plate 3 has a rack-and-pinion wheel cylinder 18 attached thereto, and a spacer 10 is interposed between the end plate 3 and the rack-and-pinion wheel cylinder 18. At the top of the housing 7 a bracket 11 is mounted, the bracket 11 supporting an infrared temperature sensor 20 for the mixing chamber. The door guard 12 protects the door 6, which is sometimes hot, from accidental contact of a person with the release material. The rotation guard 13 and the drive coupling guard 14 prevent a human operator from coming into contact with the rotating parts during operation. The drive motor 15 is preferably a motor with sufficient power to accomplish the disclosed operation. Pillow blocks 16 and 17 support the shaft assembly 2.

In an example of a system in which process parameters that determine shaft speed changes are measured in a mixing chamber and/or drive motor, fig. 7 shows a block diagram flow diagram of the disclosed process, in which the mixing chamber MC is connected by a shaft to a drive motor 42, with a variable frequency drive 41 controlling the rotational speed of the drive motor 42. In some embodiments, the shaft speed may be from 0RPM to 5000 RPM. Further, according to the disclosed process, programmable logic controller 40 determines the rotational axis speed and varies the rotational axis speed using variable frequency drive 41. Programmable logic controller 40 includes a user-entered set point for determining the need to change the speed of the rotating shaft of drive motor 42 and sending instructions to variable frequency drive 41 to change the speed after the rotational processing of the batch load is added to the mixing chamber. The programmable logic controller may comprise a microprocessor including a memory including a control program adapted to act upon reaching a set point entered by a user in dependence upon sensor data delivered by the drive motor 42 and/or the mixing chamber MC, and a user interface such as a programmable logic controller display for the user to view the run time and sensor data delivered by the drive motor 42 and/or the mixing chamber MC. The programmable logic controller optionally includes the following method: the method provides for the user to directly vary the motor shaft speed after taking into account predetermined process parameters (such as run time) or after comparing the predetermined process parameters with sensor data delivered by the sensor data (such as batch temperature, current amperage, and shaft speed) delivered by the drive motor 42 and/or the mixing chamber MC. The programmable logic controller optionally includes an automatic control method that varies the motor shaft speed after the microprocessor is run at a predetermined, stored process parameter (such as run time) or after comparing the predetermined, stored process parameter with sensor data delivered by the drive motor 42 and/or the mixing chamber MC (such as batch temperature, current amperage, and shaft speed).

A description of the components of one embodiment of a thermodynamic mixer for use in the disclosed process is shown in fig. 3 and 4. FIG. 3 shows an axial radial cross-section of a mixing chamber MC for the thermodynamic mixer of the present disclosure with

halves

5 and 7 joined to form a cylindrical mixing chamber, with shaft 23 rotating in direction of rotation 24 over the axial length of the chamber. The shaft extension 30 extends from its detachable connection on the shaft 23 to a position proximate the inner surface 19. The shaft extension 30 includes a top face 22 and a front face 21. Particles 26a to 26e illustrate the impact of these particles on the shaft protrusions 30 and inner surface 27, such impact causing the particles to shatter and/or frictionally heat by the shear created by such impact. Further, fig. 4 is an exploded view of the extensions and mixing chamber shown in fig. 3, wherein

shaft extensions

30a, 30b, and 30c, each having top and front faces 22 and 21, are defined on replaceable teeth adapted to be secured to foot portion 31 by bolts 33. The portion 31 is adapted to be fixed to the shaft 23 (continuing from the motor shaft 34) in an exchangeable manner at a slot 35 via the bottom 32 of the portion 31. Fig. 4 shows that the particles move generally in direction 37 as they encounter the shaft extensions 30 a-30 c. The shaft extension 30a is shown as having a front face 21 that is effectively aligned with respect to the front faces of the

shaft extensions

30b and 30 c.

For a typical batch process, the user first selects two components, which may comprise, for example, a thermolabile API and a polymeric excipient. The user then empirically determines the shear transition temperature of the two components. The user will set the process parameters (temperature, RPM, current amperage, and time) in the programmable logic controller to change the first speed to the second speed when the process parameters are appropriate for the shear transition temperature of the composition. Any set point input by the user may be used as a stopping point after the second speed period.

FIG. 5 illustrates certain potential differences between the presently disclosed method and a thermodynamic hybrid method using substantially single-axis speeds. FIG. 5 shows a plot of batch sensed temperature, shaft rotation speed in RPM, and current amperage measured directly in energy input into the batch at any time of the process. As a specific example, the following composition was thermodynamically processed to form a batch of griseofulvin PVP (1:2 ratio) having a batch size of 60 grams. Griseofulvin represents a thermolabile API. PVP represents the excipient. A series of three tests are shown in fig. 5 and were conducted in a thermodynamic mixer similar in construction to that shown in fig. 3 and 4, with the front face 21 protruding in the forward rotational direction with a transverse width of about 1.0 inch, and remaining about 30 degrees from a plane extending from the axis of the shaft 23 through the leading edge of the front face 21 and having a height of about 2.5 inches. The batch in fig. 5 was processed under thermodynamic self-heating conditions, wherein a substantially single axis velocity was used. The y-axis applies to temperature (value multiplied by 10) and shaft speed in RPM (value multiplied by 30). Time on the x-axis is in 0.1 second increments. If the batch of composition is thermodynamically mixed at a rotating shaft speed significantly higher than that shown in FIG. 5, i.e., 2500RPM or higher, inspection of the final product indicates unacceptable crystallization and inadequate amorphization. This result is unexpected to those skilled in the art. The art of thermodynamic mixing teaches higher shaft speeds to ensure better mixing, but it does not occur at the higher shaft speeds of these materials. When the example batch composition was processed as shown in fig. 5 at a lower rotational shaft speed, inspection of the final product indicated that it was sufficiently amorphous and had sufficient bioavailability. However, unacceptable thermal degradation of the thermolabile API occurred, which resulted in unacceptable batches.

In fig. 5, at time zero, the current amperage immediately increases to 35 amps (1050 in the figure). The discharge of the batch was about 17.6 seconds, or when the RPM was significantly reduced. The rotating shaft speed was set to 1800RPM and reached within the first approximately 2 seconds. Within about 7 seconds, the batch temperature reached 260 ° F, the shear transition temperature of the excipients. Above the shear transition temperature, the shear resistance of the excipient is significantly reduced, and the energy delivered into the batch by the impact of the particles and molten material against the surface of the protrusions and the inner surface of the mixing chamber is subsequently also significantly reduced (the current amperage is reduced to about half when the batch temperature reaches the shear transition temperature). From about 7 seconds to about 16 seconds, the batch temperature of the composition does not rise while the batch continues to absorb a large amount of energy. This energy, which does not lead to a temperature increase, is converted into thermolabile or heat-sensitive components. This test generally confirms that once a significant amount of the components in a thermodynamic melt blend batch, i.e., greater than 5 weight percent, 10 weight percent, 20 weight percent, or 30 weight percent, reaches their shear transition temperature or melting point, the bulk heat absorbed by the entire batch results in thermal degradation of thermolabile or heat sensitive components, rather than raising the temperature of the entire batch. This is evident in the time range of 7 to 16 seconds in fig. 5, when the batch temperature is actually reduced and there is a continuous energy input into the batch.

The same batch and thermodynamic mixer as in fig. 5 is used in fig. 6, but two speeds are used in the continuous rotary batch process. In FIG. 6, a programmable logic controller connected to an infrared sensor and variable frequency drive is used to detect the batch temperature, compare the batch temperature to a predetermined set point, and automatically change the rotational shaft speed of the thermodynamic mixer to another speed, continuing the process until the batch is released by opening the bottom release door. The first speed is set to 1800RPM and the second speed is set to 2600 RPM. The predetermined set point for the batch temperature is selected to be substantially 200 ° F below the level of the shear transition temperature of the excipient. In a preferred embodiment, the speed change can be made before the shear transition temperature of the substantial component is reached, and the system requires that the sensed batch temperature be communicated to the programmable logic controller for the response time between the actual change in shaft speed. As shown in fig. 6, substantially no energy input to the batch is used to raise the overall batch temperature. The treated batch exhibited essentially complete amorphicity and no detectable thermal degradation of the API over the entire treatment time of about 6.5 seconds. This time is in sharp contrast to the 17.6 second process time in fig. 5.

Fig. 6 shows that the shaft rotation speed of certain thermolabile components should be significantly increased at or before the substantial component or portion of the thermodynamic batch reaches the shear transition temperature or melting point, and the processing time thereafter should be minimized. In certain embodiments, the first speed should be increased to the second speed by about 100RPM, 200RPM, 300RPM, 400RPM, 500RPM, 600RPM, 700RPM, 800RPM, 900RPM, 1000RPM, or more. In other embodiments, the processing time after the second speed begins until the batch is released from the mixing chamber should be about 5%, 10%, 15%, 20%, 25% or more of the total time the batch is processed at the first speed.

It is well known in the art that the impact of particles on a surface imparts energy to the particles. One feature of a thermokinetic self-heating mixer is to provide impact on polymer-containing particles, thereby converting imparted energy in part into thermal energy to soften and/or melt the polymers. However, the art of thermodynamic mixing generally directs those skilled in the art to provide for the impact of particles in a thermodynamic mixer in a manner that does not allow for fine control of the conversion of impact energy into heat energy. The present disclosure provides and describes methods for such control. Highly crosslinked polymers and thermosetting compounds are very difficult to soften and melt, and for this reason they are preferred, i.e. highly crosslinked polymers and thermosetting compounds are resistant to fracture. However, in some combinations of components using thermodynamic mixing processes, highly crosslinked polymers and thermoset compounds represent value. In fact, thermodynamic mixing is essentially the only way to handle highly crosslinked polymers and thermosets due to resistance to melting and blending in any other way. In the field of thermodynamic mixing, increasing the speed of the rotating shaft and/or the processing time is understood to be a process that can be used to induce the melt-resistant polymer to convert sufficient impact energy into thermal energy to cause a softened or molten state for further processing. The embodiment discloses a device and a method capable of effectively controlling the conversion of impact energy into heat energy.

Two major impingement surfaces, the front and top faces of the shaft, control the conversion of impingement into heat energy in a thermodynamic mixer. These two surfaces are the facial portion of the shaft extension that protrudes outward by 30% or less of the volume of the mixing chamber (this volume is also referred to hereinafter as the "main process volume" which includes the majority of the restricted area about 1 inch radially inward from the inner cylindrical wall of the mixing chamber) and the facial portion of the inner cylindrical surface of the mixing chamber itself. Changing the internal cylindrical surface of the mixing chamber is not a practical option since the surface is fixed and must remain smooth and uniformly cylindrical to resist the accumulation of molten material and allow sliding and sliding self-heating contact with the particles moving through the mixing chamber.

The present disclosure uses the variation of the top face of the shaft extension protruding into the main processing volume to control the conversion of the rotary shaft energy delivered to the extension into thermal energy within the particles impacting the portion. It has been found that varying the width of the major face portion and the angle from the axial plane of the shaft provides a controlled change in shear delivered to the particles impinging on the portion, which in turn controls the shaft energy converted into thermal energy that can be used to soften or melt the polymer portion of the particles in the thermokinetic mixing chamber.

Referring again to fig. 3 and 4, it was found that the shear experienced cumulatively as long as the particles are in the mixing chamber, determined by the shape and size of the face portion surface in the direction of rotation from the extension of the shaft and the inner surface of the mixing chamber, leads to a self-heating phenomenon of thermodynamic mixing. Substantially all of the particles in the mixing chamber during rotation of the shaft are in the outer 30% volume of the interior space, i.e., the centrifugal force of rotation of the extension keeps the particles and molten material from exiting the central volume of the mixing chamber. Therefore, an efficient thermodynamic mixing chamber must be designed such that the distal portion of the shaft extension is formed to perform the three functions of direct high shear (on the extension end front face), indirect high shear (on the mixing chamber inner surface), and centrifugal retention of the material in the mixing chamber outer volume. The top faces of the shaft extension portions 30a to 30c form a substantially vertical rectangular portion that is disposed at an angle to a plane passing through the axis of the shaft 23. It has been found that varying the width, angle or shape of the simple rectangular portion or arcuate blade of the shaft unexpectedly improves and controls the cumulative shear of the particles delivered into the mixing chamber of the thermodynamic mixer, which in turn provides control over the imparted thermal energy and desired heat input of the heat-sensitive or thermolabile components in the processing batch.

For these particular comparisons of operation of a thermodynamic mixer having several major face portion configurations, it is assumed that the energy input through the shaft and the shaft rotational speed are substantially the same, and the number of shaft extensions and their spacing along the shaft length in the mixing chamber are substantially the same. Thus, the comparison will show the effect of changing the shape of the main face portion.

In general, reducing the width relative to the length of the major face portion increases the shaft energy that is converted into thermal energy that can be used to soften or melt the polymer portion of the particles in the thermokinetic mixing chamber. The width must be greater than the minimum contact width so that the particles undergo a sliding impact along the width, are induced to "slide" or are in energetic frictional contact, roll and slide for the period of time that the part is impacted. Only normal grazing impingement of particles on the surface is relatively ineffective in imparting thermodynamic self-heating energy for softening or melting. However, in some cases, only such glancing impact (glancing impact) is sometimes provided with the use of a polymer that is readily melted and not heat resistant or heat sensitive by treatment at the major face portions to provide more control over the heat applied to the components. Consistent with the present teachings, polymers that are difficult or resistant to softening or melting by application of heat are typically treated with a major face portion of minimum width (at least 0.25 inches) aligned with an axial plane minimum angle of the shaft (e.g., at least 10 degrees or at least 15 degrees), providing contact times with substantially the same energy input, so that distributing this energy into sliding and rotating motion improves self-heating of the particulate polymer content.

Currently in Draiswerke

The design of the shaft extension found in the thermodynamic mixer has a cross-section 50 shown in fig. 8, the cross-section 50 having a circular main face portion 51 and an overall generally helical shape with a width of about 2 inches. The relative shear 52 of the design, shown with a few short arrows pointing towards the main face portion 51, is not significant. Thus, such devices are relatively expensive in increasing processing time and shaft power to produce sufficient thermodynamic heating to melt a melt blended polymer that is substantially resistant to softening or melting. Therefore, thermolabile or thermosensitive polymers having such resistance to handling are relatively insufficient. The field of thermodynamic mixing does not suggest that varying the width or angle of the main face portion relative to the axial plane of the shaft has any effect on the thermodynamic processing of the polymer. The present disclosure discloses some such embodiments in fig. 9 to 12.

Fig. 9 to 12 show main face portion cross sections 53 to 56, respectively, the cross sections 53 to 56 having main face portions 57 to 60 of the same width and angled at 15, 30, 45 and 60 degrees to the axial plane of the extension represented thereby. The projected widths of the main face portions 57 to 60 on the axial plane of the shaft are indicated by lengths 65 to 68 respectively and are directly related to the relative shears 61 to 64, wherein increasing the angle of the main face portions with respect to the axial plane of the shaft at the same width reduces the projected width on the plane and unexpectedly increases the relative shears at the same shaft power input, rotational shaft speed and spacing and arrangement of the extensions on the shaft. With the present disclosure, it is now possible to control the self-heating in the extension of the thermodynamic mixer by transport shear. Reducing the major face portion width while maintaining the angle relative to the axial plane of the shaft maintains the overall heat input in the thermodynamic processing batch, while increasing the shear of any individual particle by reducing the projected length along the axial plane of the shaft.

Thus, the shear strength of the polymer now processed by thermokinetic self-heating mixing and blending can be matched to the relative shear energy imparted by the axial extension in the mixer. As is very common, further design refinement is required when the polymer components in the batch contain both high shear polymers and low shear polymers. Providing shear energy imparted by the major face portion suitable for the high shear component would transfer too much thermal energy to the low shear component. In this case, the low shear component tends to soften and roll along the width of the major face portion, further increasing the heat generated, while the high shear component tends to leave the surface more readily. This situation may tend to result in incomplete mixing, where the high shear component is under melted or the low shear component is overheated. There remains a need for major face portion designs that achieve optimal shear for delivery of high and low shear components in a thermodynamic batch.

It has been found that increasing the width of the main face portion achieves this optimization. At an angle of 15 to 80 degrees to the axial plane of the shaft, a major face portion having a width of at least 0.75 inches provides sufficient path for the travel of both the high and low shear polymer components in the batch such that the high shear component remains in sliding and sliding contact with a major face portion of sufficient length to generate heat and absorb heat from the low shear component to soften and thereby blend with the low shear component.

Alternative designs for the main face portion are shown in fig. 13-17, respectively, with fig. 13-17 showing main face

portion cross sections

69, 72, 76, 80, 84 and 87. Fig. 13 shows a cross-section 69, the cross-section 69 including a leading acute angled surface 70 extending rearwardly to an obtuse angled surface 71, thereby providing a first low-shear surface followed by a high-shear surface. Fig. 14 shows a cross-section 72, the cross-section 72 including a leading acute angled surface 73 extending rearwardly to a 90 degree surface 74 which in turn extends rearwardly to a trailing acute angled surface 75, thereby providing a first low shear surface followed by a high shear surface and a low shear surface. Figure 15 shows a cross-section 76, the cross-section 76 including a leading acute angled surface 77 extending rearwardly to an obtuse angled surface 78, the obtuse angled surface 78 in turn extending rearwardly to a trailing acute angled surface 79, thereby providing a first low shear surface followed by a high shear surface and a low shear surface. Figure 16 shows a cross-section 80 where the cross-section 80 includes a leading obtuse angled surface 73 extending rearwardly to an acute angled surface 74 and the acute angled surface 74 extending rearwardly to a trailing obtuse angled surface 75, thereby providing a first high shear surface with a low shear surface and a high shear surface. Fig. 17 shows a cross-section 84, the cross-section 84 including a leading and upwardly arcuate surface 85, the arcuate surface 85 extending rearwardly to a trailing and downwardly arcuate surface 86 surface 71, the arcuate surface 86 extending rearwardly to a trailing acute angle surface 75, thereby providing a first low shear surface followed by a higher shear surface and a lower shear surface. Fig. 18 shows a cross-section 87, the cross-section 87 including a leading acute surface 88 and a trailing acute surface 89, thereby providing a first low-shear surface followed by a higher or lower shear surface-depending on the shear of the batch components.

In accordance with the teachings of these embodiments described above, the top face 22 of FIG. 4 is an important element in providing thermodynamic contact with the particles in the mixing chamber and causing them to impinge upon the mixer internal cylindrical surface.

Fig. 19 shows another important embodiment of the dynamic mixer of the present disclosure, in which the

halves

5 and 7 and the door 6 are internally lined with

internal linings

5a, 7a and 6a, respectively. The liners are adapted to be positioned in close proximity to the

halves

5 and 7 and the inner surface of door 6 during operation of the mixer to provide any one of a number of sets of thermodynamic frictional contact surfaces desired to accelerate particles, the desired surfaces being selected from any suitable or optimized material of

liners

5a, 7a and 6 a. Figure 19 shows an exploded view of the

linings

5a, 7a and 6a partially separated from their neighbours (when installed). The

halves

5 and 7 are bolted together so that the

linings

5a and 7a are fixed to line the inner surfaces of these

halves

5 and 7. Holes in the end of the lining 6a allow the lining 6a to be bolted to the door 6. In the thermodynamic mixers known to those skilled in the art, the inner surfaces of the mixing chamber are limited to those steel alloys having sufficient mechanical and thermal strength required for thermodynamic operation surrounding and enclosing such a mixing chamber. Thus, known thermodynamic mixtures The processing capacity of the adapter is limited to only those mixtures that do not excessively adhere to the smooth inner surfaces of the steel alloy of the mixing chamber and at the same time beneficially impinge on these surfaces to provide frictional heating of the particles in the mixture. Furthermore, even relatively minor wear on the inner surface of the mixing chamber of the thermodynamic mixer may significantly change the efficiency of the thermodynamic heating of the particles in the chamber, wherein the distance between the shaft extension and the inner surface of the mixing chamber is specifically designed to optimize the thermodynamic heating by interaction of the particles moving between the inner surface of the mixing chamber and the shaft extension. Such slight wear may therefore require replacement of the entire set of relatively

expensive halves

5 and 7 in such a thermodynamic mixer. Embodiments of the present invention eliminate such expensive expenses. The

linings

5a, 7a and 6a are relatively much cheaper in terms of replacement costs than the

halves

5 and 7 and the door 6. The replacement of the lining is very simple and quick. Preferred liner compositions include stainless steel (alloys with greater than 12 weight percent chromium) and other such steel alloys, titanium alloys (such as nitrided or nitride-containing peptides), and wear and heat resistant polymers (such as

). Another embodiment of the present disclosure provides a non-smooth inner surface of the

facings

5a, 7a, and 6a, such as forming parallel or spiral grooves with respect to the inner cylindrical surface of the

facings

5a, 7a, and 6a, surface texturing, and/or electropolishing. Such materials and textures of the facing

sheets

5a, 7a and 6a are intended to achieve an optimized or desired balance of properties that will reduce undesirable adhesion of the thermodynamically fused particles and/or promote thermodynamic frictional contact of the mixing chamber particles operating between the shaft extension and the inner surfaces of the facing

sheets

5a, 7a and 6 a.

In another embodiment of the present disclosure by selecting the material or texture of the

facings

5a, 7a and 6a for purposes of thermodynamic mixing, the shaft extensions of the front and top striking surfaces, including the shaft extension, may be adjusted by material composition and/or texture similar to those variations just disclosed for the inner surfaces of the

facings

5a, 7a and 6 a.

Another feature of the present disclosure is that the top face of the shaft extension, i.e., the face that extends rearward at least a small amount of height above the height of the front face of the shaft extension to form a ramp structure and those faces (faces 22 of fig. 3 and 4) on which the chamber particles impinge are the primary location of wear in the mixing chamber interior surface. The consequences of this finding are significant for the design of the shaft extension in a thermodynamic mixer. Such a top face has been found to have a very different function than the front face. The front face of the shaft extension drags the particles along its rearwardly directed width, causing the particles to be driven in a direction substantially along the axis of the drive shaft. Such axis-driven particles then tend to encounter another forward face of the shaft extension that is another line behind the shaft extension. The motion of particles in contact with the top face of the shaft extension, driven by the rotation of the shaft, is quite different, imparting greater tribo-thermodynamic energy to the particles in such motion than to the front face of the shaft extension.

Fig. 20 shows a side view of the removable portion of the shaft extension 30 (a view of the axial direction of the shaft to which the shaft extension 30 is mounted), showing the front face 21 and the top face 22. The reference heights 30b to 30d are measured from the reference plane 30 a. Neither the front face 21 nor the top face 22 is shown in plan view, but in its projection in the axial side view of the shaft. Top face 22 includes a front edge that rises from a height 30c to a height 30b and thereafter curves back upward to a similarly sloped rear edge having a higher height 30 d. Only a portion of the inner surface of half 7 is shown separated from top face 22, with portions P1 through P4 representing the paths of particles that first impinge on top face 22 and then impinge on the inner surface of half 7. It has been found that the area of greatest wear on any interior surface of the mixing chamber is the area rearward along the leading edge represented by the line from height 30c to 30b, i.e., the point of impact of the particles at portion P1. A large portion of the kinetic energy is significantly converted into frictional heating of the particles in the region, as evidenced by significant wear of the hardened surface. Top face 22 rises more rapidly at its distal edge along heights 30b through 30d than along the proximal edge starting at height 30c, resulting in a relatively long frictional travel path for particles emitted along portion P2 and from height 30d to the inner surface slope of half 7. After portion P3 is in frictional, rotational and dragging contact with the inner surface of half 7, the extensively heated particles bounce back from the inner surface of half 7 to again contact the top face of the other shaft extension. The length of portion P2 substantially controls the frictional heating time required for the thermodynamic mixing and melting of the batch of particles in the mixing chamber of the present disclosure. The present disclosure includes selecting shaft extensions that provide a longer or shorter length and deflection angle top face contact path for impinging particles in thermodynamic mixing, thereby controlling significant or majority of frictional heating contact of the particles within the chamber at a desired batch temperature.

Fig. 21 shows a perspective view of a particular embodiment of the shaft extension of fig. 20, with concave front and top faces 21, 22, the concave front and top faces 21, 22 being able to produce portions P2 '(longer) and P2 "(shorter) of variable length for portions P3' and P3", respectively. In certain embodiments, top face 22 comprises a convex face extending from its leading edge to its rearmost edge with a radius of about 4.5 inches.

In certain embodiments, a shaft extension that provides a relatively long frictional contact path for particles processed by the mixer of the present disclosure is preferred to provide a shortened processing time, i.e., heating a batch to a desired temperature as quickly as possible. This control of heating and processing times is directly applicable to the disclosed method of two-step continuous thermokinetic mixing, such that increasing the speed of the rotating shaft will impart frictional heat more quickly for melting energy of particles that are more difficult or resistant to low-speed heating. It has been found that non-uniformity of the material in the thermodynamically processed batch, i.e., in composition or particle size, results in larger or smaller frictional paths in contact with the interior of the mixing chamber. Particles that are more resistant to melting by higher melting temperatures or hardnesses will rebound more quickly from frictional contact with the inner surfaces of the thermodynamic mixer, thus requiring more processing time than less refractory particles. Thermodynamic mixing of thermolabile or thermally damaging components to the final desired process consistency generally helps to achieve the target batch temperature as quickly as possible. Certain embodiments of the present disclosure provide short, medium, long, or mixed length particle frictional contact paths along the top face of the shaft extension by single or multiple process shaft speeds to achieve more efficient mixing of certain thermolabile components.

It is well known to those skilled in the art that the topmost surface of the shaft extension in the Draiswerke mixer is simply the arcuate tapered and smooth end face of the generally curved shaft extension. Thus, the ability of such a mixer to provide significant top-face shear friction heating to the thermodynamic mixing chamber particles is substantially minimized. To achieve an additional top facing frictional path for the particles in the mixing chamber and to achieve other objects of the present disclosure, fig. 22 discloses a front view of an extension of the open 30 shaft having a central opening so that the particles can pass therethrough and impinge on the likewise rearwardly angled surface pairs a1/a2, B1/B2 and C1/C2 during processing. It will be appreciated that surface A1/A2 together act as the top face to the particle, and surfaces B1/B2 and C1/C2 act as the front face to the particle. Fig. 22 more generally discloses that the shaft extension may be formed in a donut or torus (toroid) shape, or a diamond shape with a central opening to achieve more efficient mixing of certain thermolabile components.

Detailed description of the first and second embodiments of the invention

Fig. 23 is an overall mechanical diagram of the processes of the first embodiment and the second embodiment. Fig. 23 shows a mixing chamber MC comprising a temperature sensor or raman spectroscopy probe 20 (as described above) located in the mixing transformer MC to detect the average mixed batch temperature, or to transmit laser light to and collect recovered emissions from a smaller sample space, respectively, for detection of sample crystallinity by raman spectroscopy. The probe 20 transmits its detected data to an optional raman spectrometer and device microprocessor RS/DMC (when the probe 20 is a raman spectroscopy probe) or directly to a mixer control microprocessor MCM comprising a microprocessor with memory and an input/output unit connected to a user interface comprising input buttons and an output display. The mixer control microprocessor MCM operates under a stored mixer control program for receiving and storing trigger data detected by the probe 20 and thereafter controlling the shaft speed of the thermodynamic mixer shaft motor and the speed controller 15. The mixer control program includes a method for comparing detected trigger data or a trigger data rate calculated from the trigger data and comparing the absolute value of the trigger data or trigger data rate with a predetermined trigger set point. Upon detecting the trigger data or the trigger data rate has become equal to or higher than the trigger set point, the mixer control program causes the speed of the mixer motor shaft to increase or causes the mixing to terminate after the mixer motor shaft is started.

Additional information of the physical and thermal variations that occur in the first and second embodiments will now be described. Fig. 6 shows trigger data for temperature versus mixing time for the component compositions, where the temperature plateau extends from about 12 seconds to about 52 seconds, referred to herein as the plateau. In the experiments it was thought that a plateau was necessary to obtain the desired level of thermodynamic mixing and reduction of the crystallinity of the drug or drug. The inventors have discovered that the entire plateau may not be required, or that the plateau may be used as a trigger set point for increasing the motor shaft speed from a lower first shaft speed to a higher second shaft speed, which may be a predetermined batch temperature rate decrease, an absolute value of the detected crystallinity, or a rate of crystallinity decrease, that nearly eliminates the plateau required for the component compositions in thermodynamic mixing.

In the slower second stage embodiment of the present invention, it is preferred to complete the first stage in a flat bed test followed by a second stage at a lower spindle speed, whereby the final desired reduction of the drug or pharmaceutical product in crystal form is accomplished with reduced shear and friction intensity. The following are the components that successfully employed the slower second stage embodiment: [ drug and excipient/carrier name ].

The subtle differences in the effect of thermodynamic mixing on the composition of the set must be understood for the first step at lower shaft speeds and the second step at higher shaft speeds. It is now clear that the lower shaft speed step provides an amount of heat at 9s to 11s almost immediately at the lower batch temperature (referred to herein as the first stage) resulting in 20% to 90% of the premixed crystalline drug substance becoming amorphous, which is a significant fraction of the desired crystallinity change, as compared to the higher batch temperature achieved by thermodynamic mixing at higher shaft speeds (fig. 6). But the lower shaft speed mixing provides less kinetic energy per unit time for the mixed batch than the higher shaft speed mixing, creating a temperature plateau because the crystalline component requires more energy per unit of the remaining crystalline component to effect the conversion of the crystal to an amorphous structure.

Eliminating a long plateau that may degrade the desired drug or drugs is a primary objective of the first and second embodiments, wherein even 0.2% degradation of the desired drug or drug renders the thermokinetic mixing batch unusable. In a specific example, a single-component composition requires 18 seconds of single low-speed thermo-kinetic mixing, where the total processing time required is 8 seconds by starting the second stage of higher shaft speed using a predetermined rate of temperature rise as a trigger set point at the end of the first stage period. Preferably the higher second shaft speed is 20% to 100% higher than the lower first shaft speed, more preferably the higher second shaft speed is 40% to 80% higher than the lower first shaft rotational speed.

Furthermore, often the drug or pharmaceutical product of the component composition is a small molecule as compared to its excipients, with the smaller amorphous molecule of the pharmaceutical product essentially acting as a "lubricant" for the larger polymer. The energy input per unit of the component composition is not high enough to accomplish the desired change from crystalline to amorphous structure until the "lubricant" drug is captured in the molten or "sticky" larger polymer aggregates. Useful analogies are: forming a solid dispersion is analogous to dissolving a drug in a liquid. To help the drug dissolve faster, the temperature or agitation rate should be increased. It is unpredictable that such a remarkable effect can be obtained by the detection of the treatment point at which the motor shaft speed should be increased to prevent the degradation of the drug in the first embodiment or the second embodiment.

Returning to the first embodiment using the rate of temperature rise as the trigger set point, the sensor 20 is fixed such that the sensor 20 passes through a port in the mixing chamber MC with the distal end of the sensor 20 pointing generally towards the shaft supporting the shaft extension and the other end of the sensor 20 connected to the batch microprocessor BMCRO. The batch microprocessor BMCRO (comprising a CPU, a memory, a clock and an input/output unit all operating under a batch process control program) receives the temperature signals sensed by the sensor 20 and stores these temperature signals in the memory at predetermined intervals (preferably 500ms to 5ms) in association with the recording time, so that the batch control program uses the stored temperature and recorded time data to calculate the rate of change of temperature over a period of time from 2s to 10ms using an arithmetic mean, a differential rate of change calculation or other mean calculation method. When the calculated rate of temperature change is determined to be at or near the predetermined trigger value for the temperature change stored in the memory, the batch control program acts immediately or with some delay to send a signal to the speed controller of the motor 15 to increase the lower shaft rotation speed to a higher shaft rotation speed, preferably for a predetermined period of time, after which the batch control program stops the motor 15.

FIG. 24 depicts the steps of an alternative embodiment of the present invention wherein at step 102, a batch comprising a component composition is added to a batch chamber of a thermodynamic mixer specifically designed for such processing, and a spindle motor is activated at a lower first spindle rotational speed. At step 104, the temperature sensor or raman spectroscopy probe (through its raman spectrometer) sends a signal to the mixer control microprocessor for memory storage as trigger data.

For the first embodiment, the mixer control microprocessor continuously calculates the rate of temperature increase from the temperature trigger data and stores these values in memory, at step 106, to calculate the specific rate. The mixer control microprocessor includes a pre-stored value for the trigger set point for the rate of temperature increase, or a trigger set point calculated by obtaining a maximum rate of increase over a previous time period (preferably between 0.5s and 1.0 s) and calculating the trigger set point as a rate of temperature increase that is significantly less than the trigger set point.

For the second embodiment, the mixer control microprocessor continuously stores the crystallinity values detected in the mixing chamber as trigger data, and optionally calculates the rate of crystallinity decrease and stores these values in memory at step 106. The mixer control microprocessor includes a pre-stored value for the trigger set point of the crystallinity value or a rate of crystallinity decrease as the trigger set point.

At step 108, the mixer control program microprocessor determines whether the trigger data or the rate calculated from the trigger data has reached the trigger set point. If this occurs, the mixer microprocessor increases the shaft speed after the first phase or stops mixing at the end of the second phase.

Among the many methods of calculating the elevated temperature of the first embodiment, one preferred method is to detect and store 30ms to 0.5ms of the mixed batch sensed temperature, and calculate the average of the previous values of every 5 to every 10 recorded batches of temperature. For the first embodiment, a trigger set point of 1.5 to 0 degrees per second is preferred, where the maximum rate of temperature increase is not used to determine the trigger set point.

For the trigger set point of the second embodiment, a crystallinity of 20% to 0% is preferred, and a detected crystallinity of 2% to 0% of the drug or pharmaceutical product being measured is more preferred. The trigger set point for crystallinity reduction is preferably 20% per second to 0% per second.

For the first embodiment, the stopping point for thermodynamic mixing of a particular component composition is determined by testing where an acceptable lower level or an absent level of crystallinity is found and degradation of the drug or pharmaceutical product is within acceptable limits. For the second embodiment, the stopping point for thermodynamic mixing of the particular component compositions is determined by testing where an acceptable lower level or an absent level of crystallinity is found and the degree of crystallinity is detected with degradation of the drug or pharmaceutical product within acceptable limits or at a predetermined low level.

Fig. 25 shows an analytical graph of a single axis speed batch showing sensed temperature in ° F and axis rotational speed in RPM versus process time, with the process stopped at a detected temperature plateau (shown in a sloped dashed line) at about 15.3 seconds. In the process of fig. 25, the batch contains these components: itraconazole; eudragit L100-55(1:2 ratio). The grid blocks define a positive slope of 25 ° F per second from opposite angles. In this particular example, the plateau detection preferably occurs at a slope of about 15 ° F or less per second, or more preferably at a slope of about 10 ° F or less per second. The process of FIG. 25 shows the actual results of thermodynamic mixing at a single low axis speed (about 1900RPM) terminated when the mixer control program microprocessor detects a temperature plateau. As in this case, some component compositions may achieve sufficient crystallinity reduction in the plateau detection step. This embodiment of the invention is referred to herein as a single low shaft speed batch embodiment.

Fig. 26 shows an analytical graph of a single axis velocity batch showing sensed temperature in ° F and axis rotation speed in RPM versus processing time, where processing stopped at about 20.8 seconds after a detected temperature plateau (shown in the sloped dashed line) at about 15.8 seconds, or stopped at a detected decrease in crystallinity (if a crystallinity probe is used) at a second time period. In the process of fig. 26, the batch contains these components: itraconazole; eudragit L100-55(1:2 ratio). The grid blocks define positive slopes of 10 ° F per second from opposite angles. In this particular example, the plateau detection preferably occurs at a slope of about 20 ° F or less per second, or more preferably at a slope of about 10 ° F or less per second. The process of FIG. 26 shows the actual results of thermodynamic mixing at a single low axis speed (about 1600RPM) that terminates after a certain period of detection has elapsed after the temperature plateau is detected by the mixer control program microprocessor (process termination means batch removal from the mixing chamber or other effective method of stopping thermodynamic mixing). As in this case, some of the component compositions may achieve sufficient crystallinity reduction in the plateau detection step. In this case, the additional period of time after the platform detection is about 5 seconds. This embodiment of the invention is referred to herein as a single low axis speed plus additional time batch embodiment.

Fig. 27 shows an analytical graph of a two-axis speed batch showing sensed temperature in ° F and axis rotation speed in RPM versus processing time, where the axis speed is increased at a detected temperature plateau at about 9.5 seconds, and the processing is stopped at a second speed time (about 12.7 seconds), or at a detected crystallinity decrease (if a crystallinity detector is used). In the process of fig. 27, the batch contains these components: griseofulvin; povidone K30(1:3 ratio). The grid blocks define a positive slope of 25 ° F per second from opposite angles. In this particular example, the platform detection preferably occurs at a slope of about 10 ° F or less per second, or more preferably at a slope of about 5 ° F or less per second. The process of FIG. 27 shows the actual results of thermodynamic mixing that is performed at a lower first shaft speed (about 1500RPM) and increases the shaft speed to about 2250RPM and stops the thermodynamic mixing at about 12.5 seconds. As in this case, many component compositions can achieve a suitable reduction in crystallinity over a period of higher axis velocity following the plateau detection step. In this case, the additional period of time after the platform detection is about 3.2 seconds. This embodiment of the invention is referred to herein as a low shaft speed to high shaft speed batch embodiment. Comparing the process of fig. 27 with the process of fig. 26, the process of fig. 27 achieves the desired reduction in crystallinity with the process stopping, which shortens the total process time by about 30% to 40%.

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

Claims

1. A method of thermokinetic mixing of a component composition comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, the method comprising:

(a) a thermodynamic mixer having a mixing chamber, wherein the mixing chamber houses a thermodynamic extension on a motor shaft and the motor shaft extends to a shaft motor, the rate of rotational speed of the motor shaft being controlled by a mixer control microprocessor;

(b) adding batches of the component compositions to the mixing chamber;

(c) Subjecting the component compositions to thermodynamic mixing, wherein,

i. both the rate of rotation speed of the motor shaft and the temperature of the batch are increased during the first phase,

the average temperature of the batch is periodically detected at a trigger data sensor, and

average temperature data is transmitted to the mixer control microprocessor where the rate of temperature rise is calculated and compared to a predetermined rate of temperature rise trigger set point; and

(d) operating the mixer control microprocessor to vary the rate of rotation speed of the motor shaft for a second phase period when the current rate of temperature increase is less than or equal to the trigger set point.

2. The method of claim 1, wherein the rate of temperature increase is calculated by averaging a last stored value of a number of the average temperature data.

3. The method of claim 1, wherein the rotational speed of the motor shaft is maintained at the same speed as the rotational speed at the trigger set point for a predetermined period of time before the batch is discharged from the mixing chamber.

4. The method according to claim 1, wherein the rotational speed of the motor shaft is reduced during the second phase for a predetermined period of time, after which the batch is discharged from the mixing chamber.

5. The method of claim 1, wherein the rotational speed of the motor shaft is increased during the second phase during which the average temperature of the batch is periodically detected at the trigger data sensor, average temperature data is transmitted to the mixer control microprocessor where the rate of temperature increase is calculated and compared to a predetermined second rate of temperature increase trigger set point, and the batch is discharged from the mixing chamber when the current rate of temperature increase is less than or equal to the second rate of temperature increase trigger set point.

6. The method of claim 5, wherein the second rate of temperature rise trigger set point is calculated by first obtaining a maximum value of an average of previously stored values of a number of rates of temperature rise for a previous time period, and then subtracting a predetermined percentage from the maximum value of the average.

7. The method of claim 1, wherein the rotational speed of the motor shaft is increased during the second phase during which the average temperature of the batch is periodically detected at the trigger data sensor, average temperature data is transmitted to the mixer control microprocessor where the rate of temperature increase is calculated and compared to a predetermined second rate of temperature increase trigger set point, wherein the rotational speed of the motor shaft is maintained at the same speed as the rotational speed at the second rate of temperature increase trigger set point for a predetermined period of time before the batch is discharged from the mixing chamber.

8. The method of claim 7, wherein the second temperature rise rate trigger set point is calculated by first obtaining a maximum value of an average of a number of previously stored values of the temperature rise rate for a previous time period, and then subtracting a predetermined percentage from the maximum value of the average.

9. The method of claim 1, wherein the temperature increase rate trigger set point is calculated by first obtaining a maximum value of an average of previously stored values of a number of temperature increase rates for a previous time period, and then subtracting a predetermined percentage from the maximum value of the average.

10. The method of claim 1, wherein the trigger set point is 20 ° F per second to 0 ° F per second, or 20 ℃ per second to 0 ℃ per second.

11. The method of claim 7, wherein the trigger set point is 15 ° F per second to 0 ° F per second, or 15 ℃ per second to 0 ℃ per second.

12. The method of claim 8, wherein the trigger set point is 5 ° F per second to 0 ° F per second, or 5 ℃ per second to 0 ℃ per second.

13. A method of thermokinetic mixing of a component composition comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, the method comprising:

(a) a thermodynamic mixer having a mixing chamber, wherein the mixing chamber houses a thermodynamic extension on a motor shaft and the motor shaft extends to a shaft motor, the rotational speed of the motor shaft being controlled by a mixer control microprocessor;

(b) adding batches of the component compositions to the mixing chamber;

(c) subjecting the combination of components to thermodynamic mixing, wherein,

i. the temperature of the batch is increased during the first phase,

the crystallinity of the batch is periodically detected at a trigger data sensor, and

The crystallinity data is transmitted to the mixer control microprocessor where the current value of the crystallinity data is compared to a predetermined crystallinity value trigger set point; and

(d) discharging the batch from the mixing chamber when the current crystallinity data is less than or equal to the trigger set point.

14. The method of claim 13, wherein crystallinity is measured by raman spectroscopy.

15. The method of claim 14, wherein the trigger data sensor is a relatively narrow tube comprising a distal portion and a proximal portion, wherein the distal portion comprises a laser and at least one lens, the laser being directed into the batch of sample spaces undergoing thermodynamic mixing.

16. The method of claim 15, wherein the sensed emissions of the sample space are transmitted to the raman spectrometer, and the crystallinity of the batch crystalline component detected at the raman spectrometer is calculated and transmitted to the mixer control microprocessor.

17. A method of thermokinetic mixing of a component composition comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, the method comprising:

(a) A thermodynamic mixer having a mixing chamber, wherein the mixing chamber houses a thermodynamic extension on a motor shaft and the motor shaft extends to a shaft motor, the rotational speed rate of the motor shaft being controlled by a mixer control microprocessor;

(b) adding a batch of the component composition to the mixing chamber;

(c) subjecting the combination of components to thermodynamic mixing, wherein,

i. the temperature of the batch is increased during the first phase,

the crystalline-to-amorphous transition data of the batch is periodically detected at the trigger data sensor, and

said crystalline-to-amorphous state transition data is communicated to said mixer control microprocessor where a current value of said crystalline-to-amorphous state transition data is compared to a predetermined crystalline-to-amorphous state transition data trigger set point; and

(d) discharging the batch from the mixing chamber when the current crystalline-to-amorphous state transition data is less than or equal to the trigger set point.

18. The method of claim 17, wherein the crystallinity of the batch is measured by a raman spectrometer.