JP7376220B2 - Method for speed variation via direct probe sensed temperature for thermosensitive portions of thermodynamically melt blended batches - Google Patents

Description

This application is a continuation-in-part of Application No. 13/190,176, filed July 25, 2011, entitled: Multirate Process for Preserving Heat-Sensitive Portions of Thermodynamically Melt-Blended Batches. Yes, and claim that benefit.

1. Field of the Invention The present disclosure relates generally to the field of pharmaceutical manufacturing, and more specifically to thermodynamic mixing of active pharmaceutical ingredients (APIs) to produce novel dosage forms.

2. Background Current high-throughput molecular screening methods used by the pharmaceutical industry have resulted in a tremendous 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 because the molecules are abandoned during development due to poor pharmacodynamic properties or because the performance of the products is suboptimal. Also, in recent years, the pharmaceutical industry has begun to rely more heavily on formulation methods to improve drug solubility due to practical limitations on salt formation and chemical modification of neutral or weakly acidic/basic drugs. As a result, advanced formulation techniques aimed at enhancing the solubility properties of poorly water-soluble drugs are becoming increasingly important for modern drug delivery.

US Pat. No. 6,001,300, which names the same inventors and further co-inventors as the present application, is directed to the application of thermodynamic compounding in the field of pharmaceutical manufacturing. Thermodynamic compounding or "TKC" is a method of thermodynamic mixing until melt blended. Pharmaceutical compositions or complexes made by thermodynamic compounding include hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film coating, or injection molding into the final product. Further processing may be performed according to methods well known to those skilled in the art, including, but not limited to, those skilled in the art.

Although the application of thermodynamic compounding in the field of pharmaceutical manufacturing offers significant advantages over other methods known in the pharmaceutical field, certain heat-sensitive or heat-labile components can be easily combined using thermodynamic mixers. The continuous melt blending process may be improved in certain cases. Blending such combinations of components requires the use of high shaft speeds or low shaft speeds over long processing times sufficient to impart fully amorphous character to a fully processed batch. sell. It has been found that in certain cases, such processing results in exceeding critical temperatures or heat inputs, which can result in decomposition of thermally unstable components. It appears that the substantial amount of heat absorbed by the entire batch may result in thermal decomposition of the thermally unstable components rather than increasing the overall batch temperature. Substantially complete amorphity is a well-known measure in the pharmaceutical preparation and processing arts; compositions that lack substantially complete amorphity may have compromised bioavailability.

U.S. Patent No. 8,486,423

BRIEF SUMMARY OF THE INVENTION The present disclosure continues efforts in research and development regarding the application of thermodynamic formulation to produce pharmaceutical conjugates and compositions. A brief description of the basic physical handling of the drug components introduced as a batch into the thermodynamic mixing chamber of a thermodynamic mixer will aid in understanding this process.

Thermodynamic mixers are quite unique in the world of process equipment. Heating during the mixing operation occurs from the process material itself (although structural changes are contemplated for crystalline drugs) without external heat exchange, such as indirect heat transfer by radiation or convection or direct heating, such as by direct flame contact. (without a chemical reaction itself). The thermodynamic mixer has its own extension extending from the drive shaft, where the drive shaft extends through the axis of the cylindrical mixing chamber. These unique extensions are shaped to provide an angled contact surface oriented in the driving angular direction, where the angled contact surface reduces fragmentation, tearing, or destruction of the component molecules being processed. or modified to remove it. The process steps that occur within a thermodynamic mixer during processing are generally:
1. A controlled sliding, frictional, exothermic contact between the processing component particles and the extension contact surface, whereby the processing component particles roll and slide on the contact surface. can produce multiple heating surfaces, thus generating high transient temperatures at multiple “surfaces”);
2. Before localized high transient temperatures can adversely affect the chemical composition of the processing component particles heated by the extension, they are discharged at an angle from the contact surface of the extension (in the mixing chamber). Due to the extremely turbulent flow conditions of the mixing chamber), there is immediate cooling contact with the air and other processing component particles, such that the heat generated by the previous sliding, frictional exothermic contact is transferred to the processing component. Immediate distribution to essentially the entire batch of elementary particles;
3. The angularly deflected particles rub against each other, creating an immediate, diffusive heat generation in which the meltable particles reach their melting point, and the melted particles join and separate from the captured non-melted particles. resulting in very finely ground or molecularly dispersed unfused particles that are homogeneously distributed within the molten particles;
4. The angularly deflected particles are also directed axially and angularly outward from the drive shaft, resulting in sliding, frictional heating contact and some slight contact with the inner surface of the cylindrical mixing chamber. , thereby generating high transient temperatures at the contact surfaces of the component particles to be processed, and therefore increasing the temperature significantly from the inner surfaces of the mixing chamber as the particles lose kinetic energy from their contact (direct or indirect) with the extension. falls rapidly and/or is pushed or deflected from its inner surface by other, more energetic processing component particles;
5. Repeat the immediate cooling contact and mixing of step 2 above for sliding, frictional heating particles that leave contact with the mixing chamber surface; and
6. Process so that the temperature of the entire batch is essentially homogeneous throughout the mixing chamber when the temperature is measured at a distance of 1 to 2 cm from the frictional heating surface of the extension and the inner surface of the mixing chamber. The intense and extremely turbulent flow of component particles is essentially instantaneous and essentially persistent ( However, it is not constant if there is a change in motor shaft speed).

Before using a thermodynamic mixer to heat the component particles to be processed to such high temperatures that they melt together, the unwanted side effect of heat production is reduced using a cooling jacket outside the mixing chamber. A thermodynamic mixer was used primarily for mixing. The inventors are part of an independent effort to find applications for thermodynamic compounding in pharmaceutical processing, and the present disclosure provides not only chemical composition-preserving mixing but also structural changes in thermolabile drug components. Aim for the field that causes.

The present disclosure is directed to at least one active pharmaceutical ingredient "API", preferably in at least partially crystalline form, in combination with at least one excipient, polymeric carrier or similar less active or inactive ingredient. This is hereinafter referred to as a combination of constituent elements. The present disclosure provides improved equipment and/or batch processing compared to thermodynamic mixing that uses only batch temperature measurements to determine when thermodynamic mixing should be stopped and the batch removed from the mixing chamber. A method is provided for thermodynamically mixing a combination of components in a single batch in a relatively short number of seconds in a time saving manner.

A first aspect of the present disclosure provides for mixing a combination of components at a first lower shaft speed, wherein a substantial portion of the desired thermodynamic mixing is achieved by monitoring the batch by determining the rate of temperature rise. has occurred, and then a second, higher shaft speed is used to complete the desired thermodynamic mixing of the component combination.

A second aspect of the invention involves mixing a combination of components at a first lower shaft speed, wherein the monitoring of the batch is a determination of the absolute value of the batch crystallinity or a reduction in the batch crystallinity. Depends on speed judgment. At a predetermined crystallinity value or crystallinity reduction rate, the thermodynamic mixing is stopped or the components are stopped at a second predetermined crystallinity value or crystallinity reduction rate. A second higher shaft speed is used to complete the desired thermodynamic mixing of the combination.

The discoveries surrounding these two embodiments, after extensive trial and error in the thermodynamic mixing of component combinations, resulted in expensive This is due to the decomposition of heat-labile drug molecules. A way had to be found to reduce the required mixing time. These two embodiments meet those needs.

Mixing of the component combinations at the first lower shaft speed provides a substantial portion of the desired mixing of the component combinations within just a few seconds of process initiation, but later in the process the mixing of the component combinations at the second higher shaft speed The first aspect is a result of the discovery that even when speeds were used, long mixing times were clearly required leading to drug degradation. The first aspect incorporates the discovery that the first, lower shaft speed phase requires only a relatively short time, and that the end of the phase (and the beginning of the second, higher shaft speed) , triggered by a relatively substantial reduction in the rate of temperature rise of the batch. If the temperature rise rate is approximately 10% to 100% lower than the calculated maximum rate of temperature rise for the batch temperature during the first few seconds, or if the temperature rise rate is between 1.5 and 0 degrees/second (temperature (degrees Fahrenheit or (degrees Celsius)/time (seconds)), start the second, higher shaft speed. Surprisingly, the desired mixing level (determined by trial and error, i.e. by testing combinations of mixing components after mixing) can be determined by using a single shaft speed for the entire mixing process or by using a single shaft speed for the batch. According to the first aspect, this is accomplished in a shorter time and generally at lower final batch temperatures than using temperature measurements alone. The shorter processing time and lower final temperature of the first embodiment result in essentially no degradation of the drug, which is likely to be approximately equivalent to the final product, and the initial crystallinity of the drug or drug component is essentially removed. The reasons for the decreased crystallinity and increased amorphousness of mixed component combinations are currently debated.

The desired structural change in the mixed drug component is commonly referred to as amorphous or amorphous state. It is well known that almost all sophisticated processes that produce solid particulate drugs prior to final mixing or processing result in crystalline compounds. These pure compounds are preferably rendered amorphous before being mixed with other components to produce the final desired drug composition. It is well known that amorphous drugs have dramatically higher predicted solubility compared to their crystalline phase (Hancock et al.; What is the true solubility advantage for amorphous pharmaceuticals?; Pharm Res. 2000 Apr. ;17(4):397-404); www.ncbi.nlm.nih.gov/pubmed/10870982). Increased solubility is just one of the bioavailability benefits of rendering pharmaceutical compounds amorphous prior to administration-''The importance of amorphous pharmaceutical solids lies in their useful properties, common occurrence, and physicochemical instability relative to corresponding crystals.'' (Yu, L.; Amorphous pharmaceutical solids: preparation, characterization and stabilization.; Adv Drug Deliv Rev. 2001 May 16;48(1):27-42; www.ncbi.nlm .nih.gov/pubmed/11325475). Yu further describes the latest techniques to bring crystalline, heat-labile pharmaceutical compounds (such as proteins and peptides) into an effective amorphous state - liquid quenching, freezing and spray drying, milling, wet granulation, and solvents. The drying of Japanese crystals is further explained. These processes are time and labor intensive, must be accomplished separately from other components that mix with the final amorphous drug solid, and subject the treated crystalline drug solid to decomposition and recrystallization. The mixing of single or multiple crystalline drug solids to produce the desired final drug dose composition, while simultaneously containing the desired amorphous form of the drug solid as part of the desired final drug dose composition. What is needed is a process that can obtain state.

The second embodiment incorporates an entirely novel method of monitoring thermodynamic mixing of a combination of components. The inventor has discovered a method by which it is possible to measure the crystallinity of a mixed batch in a thermodynamic mixer. The atmosphere within the mixing chamber during thermodynamic mixing is at best dark and turbulent and does not last more than about 30 seconds. Although it would be desirable to be able to directly measure the crystallinity of a mixed batch so that mixing could be stopped when crystallinity is sufficiently reduced or effectively removed, conventional turbulent batch mixing of dry particles In the field, there is no known method by which this can be achieved. The inventors first discovered the use of Raman spectroscopy to measure the crystallinity of a fixed amount of mixed solid material, in this case a combination of mixed components. When analyzing static samples of unmixed and mixed component combinations, commercially available Raman spectrometers allow the user to remove all of the detection wavelengths associated with other components of the component combination and It makes it possible to detect and measure the percent crystallinity of a drug or drug in a combination of components. A Raman spectroscopic probe comprising a thin tube with a requisite lens oriented axially within the tube, the ends of which are open to receive and transmit light waves suitable for detection by a Raman spectrometer. The inventor has discovered a probe. For example, without intending to be limited thereby, a suitable Raman spectrometer for the second embodiment is from Princeton Instruments, specifically TriVista CRS (http://www.princetoninstruments.com/products/specsys /trivistacrs/), whose laser and detection equipment have already been modified for use in such thin tubes (in the case of TriVista CRS, the tube is a standard microscope lens tube). The probe of the second aspect is configured for Raman spectroscopy, the tip of which is directed into the mixing chamber, preferably such that it can detect the crystallinity of moving particles between the rotating shaft extensions. Use the lens extension tube of the device. The proximal end of the Raman spectrometer probe is connected to the Raman spectrometer and the instrument's microprocessor, and the instrument's user interface allows Raman spectrometer crystallinity determination data to be reviewed and transmitted to the mixer control microprocessor. When the Raman spectrometer determines the mixed batch crystallinity and sends that data to the mixer control microprocessor, the mixer control microprocessor either stops mixing the combined batch of components or increases the shaft speed and then restarts the mixing. It can be activated to stop. In a second embodiment, when the drug or drug is converted from crystalline to amorphous form, Raman scattering from the drug or drug crystal stops or becomes undetectable, i.e., the energy is not that of the drug or drug crystal. , absorbed from different energy states. Raman probes detect when the drug or drug crystals essentially disappear, so temperature measurements are not required for process control of thermodynamic mixing of component combinations.

SUMMARY PRIOR TO THE INVENTION In contrast, the processing of a heat-labile drug component for mixing with other components or processing into a powder form by itself requires that the component reach a temperature at which it melts. is not intended. Rather, the desired result is an essentially complete mix or powder form. If essentially complete amorphism is obtained in the same mixing step, a separate processing step will be avoided. The inventor's long experience in processing commercially available polymers with thermodynamic mixers has led the inventors to believe that thermodynamic mixers can avoid degradation of thermolabile drug components during the necessary mixing process. However, the inventors have demonstrated that exposure to heat, even for very short periods of time, typically requires several prior processing steps of special technology application at high cost, resulting in component decomposition. I also thought that it could cause The inventor considered how it might be possible to further reduce the processing time of a mixed batch in a thermodynamic mixer and still obtain essentially complete amorphousness of the batch.

FURTHER SUMMARY OF THE INVENTION FOR FIRST AND SECOND EMBODIMENTS In proceeding to experiments with test batches of thermolabile drug components in thermodynamic mixers, the inventors have discovered that, in their years of work with thermodynamic mixers, , observed a certain phenomenon. After an initial mixing period at a lower shaft rotation speed, the temperature of the batch increases and reaches a plateau. Further processing at that lower rate would not be able to produce essentially complete amorphism in the processed batch. The inventors have found that increasing the shaft rotational speed to higher levels for a fairly short period of time results in essentially complete amorphism in the resulting batch, with virtually no degradation of the components due to exposure to the heat of the process. I found that there is almost no difference.

However, the inventor has found that the above-described method of achieving the desired result may unnecessarily lengthen processing time. The present invention reduces processing time and exposure of the processing batch to high temperatures compared to waiting for a temperature plateau at a lower shaft rotational speed and then increasing to a higher shaft rotational speed. In the present invention, a high-speed temperature sensor accurately and essentially instantaneously measures the average batch temperature, and the sensed temperature is connected to a mixer or batch microprocessor (CPU, memory, clock, and inputs) operating under a batch control program. / output unit). The sensed temperature is immediately compared to one or more already stored temperatures and their recording times, and the rate of temperature change is calculated from that data. The shaft rotational speed is increased from the lower shaft rotational speed to the higher shaft rotational speed when it is detected that the rate of temperature change has decreased or increased to the desired activation rate of temperature increase.

The Raman spectroscopy probe is preferably positioned to detect the crystallinity of a small sample volume of particles moving near the tip of the probe illuminated by the laser beam. Light from the illuminated area is collected by a lens and sent through the monochromator of the Raman spectrometer. Wavelengths near the laser and drug or drug due to elastic Rayleigh scattering are filtered out, while the remainder of the collected light is dispersed onto the detector. The laser beam interacting with molecular vibrations, phonons, or other excitations in the system causes the energy of the laser photon to shift up or down. The energy shift provides information about the vibrational modes in the system. In the second embodiment, those vibrational modes are processed by the temperature sensor manufacturer's algorithm to determine the average crystallinity of the mixed batch. Because the detection time for mixed batch crystallinity can extend to approximately 3 seconds, the instrument microprocessor or mixer control microprocessor optionally determines the rate of batch crystallinity decline and determines the rate of crystallinity that is saved for predictive use. Operate the setpoint program. Test batches of the desired component combinations are preferably mixed at either a stop mixing or a speed up start setting, as over-mixing for more than 3 seconds (for detection of batch crystallinity by Raman probes) can result in drug or agent degradation. Test to get value. These start-up setpoints are used in conjunction with the currently measured absolute value of crystallinity or rate of decline in crystallinity, so that the desired thermodynamic Mixing would be stopped (or shaft speed increased) to obtain mixing.

Now with respect to the first aspect, the inventor has also found the rate of temperature change at a point on the first temperature plateau corresponding to the change in viscosity, which indicates the optimal time to increase the shaft rotation speed. 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 when: (1) the viscosity exhibits a significant increase in amorphousness; (2) if the rate of change in average batch temperature is calculated to have reached a "temperature change startup rate" indicating that the batch has achieved the required change; or (2) if there is a significant The rate of change in average batch temperature reaches the expected start-up rate of temperature change, which indicates (taking into account the processing speed of temperature sensing and calculations) that the batch will achieve the required change in viscosity, which indicates a significant increase in viscosity. If it is calculated that For process method (2), before the desired rate of temperature change is actually detected and calculated, the shaft rotational speed is increased to a higher level so that after the detection and calculation of that desired rate of temperature change Avoid unnecessary mixing times.

In the present invention, the resulting pharmaceutical composition preferably has high bioavailability and stability due to essentially complete mixing and amorphous nature.

As described above, thermodynamic mixers provide blending and dispersion of self-heating mixtures in the mixing chamber of a high speed mixer, where a first speed achieves a first desired process parameter. When the second speed is changed during processing. In another embodiment, the second speed may be maintained until the final process parameters are achieved, after which the shaft rotation is stopped and the melt-blended batch is withdrawn or discharged from the mixing chamber for further processing. do. In another embodiment, one or more intermediate speed changes may be made to the shaft rotational speed between the second speed and the cessation of shaft rotation. The process parameters governing shaft speed changes are predetermined and sensed and displayed, calculated, inferred, or otherwise established with reasonable certainty, thereby controlling the mixing chamber of the high speed mixer. Speed changes may be made during a single rotational continuous process of a batch. Another aspect includes an intrusion into the main processing volume for controlling the conversion of rotational shaft energy applied to the extension or protrusion into heating energy within the particles impinging on the portion of the extension or protrusion. The use of variations in the shape, width and angle of the surface portions of shaft extensions or protrusions.

We investigated melt blending in a thermodynamic mixer of various mixtures containing thermolabile components. By using multiple speeds during a single continuous rotational operation for a given batch containing thermally unstable components, we address the problem of exceeding batch temperature limits or excessive heat input. It was unexpectedly discovered that the problem can be solved. The inventors have also surprisingly found that by varying the shape, width, and angle of the shaft extension or protrusion from the plane of the shaft axis, a method of controlling the shear force exerted on the particles is obtained, which then It has also been found that the shaft energy that is converted into thermal energy available to soften or melt the polymer portion of the particles in the thermodynamic mixing chamber is controlled.

One embodiment of the present disclosure is a method of blending a composition of multiple components, wherein the components include one or more heat-sensitive or heat-labile components, and wherein the resulting composition is non-component. crystalline, homogeneous, heterogeneous, or heterogeneously homogeneous, the method includes the step of mixing the components in a thermodynamic mixing chamber, where the shaft of the thermodynamic mixer has predetermined parameters. the shaft speed is adjusted to a second speed for a second time period, at which point the mixing process is substantially reduced between the first and second time periods. It is continuous. In another aspect of the disclosure, the shaft of the thermodynamic mixer is operated at one or more speeds until achieving predetermined parameters, at which point the shaft speed is changed to different speeds for different time periods. regulated, where the mixing process is substantially continuous over multiple time periods. An example of such an embodiment is a method of blending a composition of multiple components, wherein the shaft of the thermodynamic mixer is operated at a first speed until achieving predetermined parameters; the shaft speed is adjusted to a second speed for a second time period at which the mixing process is substantially continuous between the first time period and the second time period; At the end of the period, after achieving the predetermined parameters, the rotational speed of the shaft is changed from the second speed to a third speed for a third period. In one embodiment, the mixing process is substantially continuous between the second period and the third period.

In certain embodiments, the thermosensitive or thermolabile component is one or more pharmaceutically active ingredients, one or more pharmaceutically acceptable excipients, or one or more pharmaceutically acceptable It may also contain a heat-sensitive polymer. In other embodiments, the thermosensitive or thermolabile component may include one or more pharmaceutically active ingredients and one or more pharmaceutically acceptable excipients or thermosensitive 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 one or more pharmaceutically acceptable heat-sensitive polymers are added in a ratio of about 1:2 to 1:9, respectively. In certain embodiments, the second period may be at least about 5%, 10%, 15%, 20%, 25% or more of the first period. In other embodiments, the speed during the second period is about 100 revolutions per minute (“RPM”), 200 RPM, 300 RPM, 400 RPM, 500 RPM, 600 RPM, 700 RPM, 800 RPM, compared to the speed during the first period. 900RPM, 1000RPM, 1100RPM, 1200RPM, 1300RPM, 1400RPM, 1500RPM, 1600RPM, 1700RPM, 1800RPM, 1900RPM, 2000RPM, 2100RPM, 2200RPM, 2300RPM, 2400RPM, 2500RPM or more increase For example, in one embodiment, the first speed is higher than 1000 RPM and the second speed is 200-400 RPM higher than the first speed. In another embodiment, the first speed is higher than 1000 RPM and the second speed is 200-1000 RPM higher than the first speed. In yet another embodiment, the first speed is higher than 1000 RPM and the second speed is 200-2500 RPM higher than the first speed.

In one embodiment, the end of the first period is substantially before the temperature of the mixing chamber reaches the shear transition temperature or melting point of any substantial constituent of the ingredients. In another embodiment, the end of the first period is a predetermined period and the change to the second speed is automatically performed by the thermodynamic mixer at the end of the first period. In yet another embodiment, the end of the first period is substantially before the temperature of the mixing chamber reaches the shear transition temperature of the active pharmaceutical ingredient in the ingredients. In yet another embodiment, the end of the first period is substantially before the temperature of the mixing chamber reaches the shear transition temperature of the excipients in the ingredients. In another embodiment, the end of the first period is substantially before the temperature of the mixing chamber reaches the shear transition temperature of the heat sensitive polymer in the components.

In one embodiment, the end of the second or any subsequent period is substantially before the active pharmaceutical ingredient undergoes substantial thermal decomposition. In another embodiment, the end of the second or any subsequent period is substantially before the excipient component has undergone substantial thermal decomposition. In yet another embodiment, the end of the second or any subsequent period is substantially before the heat-sensitive polymer component undergoes substantial thermal decomposition. In one embodiment, at the end of the second or any subsequent period, the active pharmaceutical ingredients and excipients of the ingredients are substantially amorphous. In another embodiment, at the end of the second or any subsequent period, the component pharmaceutically active ingredient and heat sensitive polymer are substantially amorphous. In other embodiments, after achieving the final process parameters, shaft rotation is stopped and the batch or composite is withdrawn or discharged from the mixing chamber for further processing. In certain embodiments, the batch or composite is recovered or discharged at or below the glass transition temperature of at least one of the components 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 complex is withdrawn or discharged at the onset of the RPM plateau, eg, before degradation occurs in the batch or complex. In other embodiments, the RPM deceleration prior to withdrawal or discharge of the batch or composite is adjusted to produce a more homogeneous batch or composite.

Another aspect of the disclosure provides one or more pharmaceutically active ingredients and at least one pharmaceutically acceptable ingredient to produce an amorphous, homogeneous, heterogeneous, or heterogeneously homogeneous composition. A method of compounding a polymeric excipient, comprising: thermodynamically combining a pharmaceutically active ingredient and at least one pharmaceutically acceptable polymeric excipient in a chamber at a first rate effective to increase the temperature of the mixture; and at a point where the temperature is below the shear transition temperature of any active pharmaceutical ingredient or pharmaceutically acceptable polymeric excipient in the mixture, increasing the rotation of the mixer to a second speed. The method is directed to a method comprising producing an amorphous, homogeneous, heterogeneous, or heterogeneously homogeneous composition, where the ascent is accomplished without stopping mixing or opening the chamber. In another aspect of the disclosure, a method includes thermodynamically mixing in a chamber at one or more speeds effective to increase the temperature of the mixture, wherein the shaft speed is set for different periods of time. The mixer revolutions are adjusted to one or more different speeds, and at points where the temperature is below the shear transition temperature of any active pharmaceutical ingredient or pharmaceutically acceptable polymeric excipient in the mixture. and ramping up to speed, where ramping is accomplished without stopping the mixing or opening the chamber.

Certain embodiments of the present disclosure are directed to thermodynamic mixers for use in producing pharmaceutical compositions that include one or more thermosensitive or thermolabile components. Various embodiments of mixers may include one or more and any combination of the following: (1) a mixing chamber, e.g., a substantially cylindrical mixing chamber; (2) a central axis of the mixing chamber; a shaft disposed through; (3) an electric motor connected to the shaft, e.g., effective to impart rotational motion to the shaft; (4) an electric motor extending from the shaft and perpendicular to the longitudinal axis of the shaft; or a plurality of protrusions or extensions; (5) one or more thermal sensors, e.g., mounted on the wall of the mixing chamber and operative to sense heat or temperature of at least a portion inside the mixing chamber; 6) a variable frequency device, e.g. connected to a motor; (7) a door located in the wall of the mixing chamber, effective to open during a process, e.g. to allow the contents of the mixing chamber to leave the mixing chamber; ; and (8) electronic controller. In certain embodiments, hygroscopic conditions are maintained within the thermodynamic mixer. In other embodiments, thermodynamic mixers are designed to maximize shear forces 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 configured to receive user input of process parameters or predetermined parameters for multiple stages of the thermodynamic mixing process; and display. In one embodiment, process parameters or predetermined parameters are stored in storage and displayed on a monitor for one or more stages of process execution. In certain embodiments, the electronic controller automatically advances process execution to the next stage if one of the predetermined parameters is met during a stage of process execution. In other embodiments, the mixing chamber is internally lined with an internal liner piece. The liner pieces are made of materials that minimize any stickiness of the batch during processing, such as stainless steel and other such alloy steels, titanium alloys (such as titanium nitride or nitride-containing titanium), and wear-resistant It may be made of a flexible and heat resistant polymer (such as Teflon®).

In one embodiment of the present disclosure, at least one of the plurality of temperature sensors detects infrared radiation, eg, where the radiation level is output as temperature on a display. In other embodiments, the predetermined parameter may be any one or combination of the following: temperature, rate of temperature change, shaft rotational speed (e.g., acceleration and deceleration rates), electric motor current consumption. , stage time, or rate of batch or complex collection or release. Those skilled in the art will be able, through routine experimentation, to vary each of the following parameters to obtain a batch or complex with the desired characteristics. In another embodiment, the output display may be any one or combination of the following: chamber temperature, motor revolutions per minute, motor current consumption, or cycle elapsed time.

In certain aspects of the present disclosure, the one or more protrusions or extensions from the shaft include a base and an end, e.g., the end may be removable from the base, and the base may be removable from the shaft. It may be possible. In other embodiments, the projections or extensions are replaceable in the thermodynamic mixer, eg, based on wear or different batch parameters. In one embodiment, the one or more protrusions or extensions from the shaft have one or more major surface portions having a width of at least about 0.75 inches at an angle between 15 and 80 degrees from the shaft axial plane. including. In other embodiments, the one or more projections or extensions from the shaft are about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 from the shaft axial plane. , or at an 80 degree angle, at least approximately 0.80", 0.85", 0.90", 0.95", 1.0", 1.1", 1.2", 1.3", 1.4", 1.5", 1.6", 1.7", 1.8", 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", 3.7", 3.8", 3.9", 4.0", 4.1", 4.2", 4.3", 4.4", 4.5", 4.6", 4.7", 4.8", 4.9", 5.0" or wider width one or more major surface portions having. In certain embodiments, the one or more protrusions or extensions from the shaft control the conversion of rotational shaft energy applied to the protrusions or extensions into heating energy in particles that impinge on the protrusions. do.

In other embodiments, these dimensions of the one or more protrusions or extensions from the shaft are adjusted to accommodate the shear-resistant particles in the batch, e.g., to produce a substantially amorphous composite. Designed to increase shear properties. In certain embodiments, the one or more projections or extensions from the shaft have dimensions that are at least about 60, 65, 70, 75, 80, 85, 90, 95, or 99% amorphous. Designed to generate a body.

More specifically, the invention provides:
[1] A method for thermodynamic mixing of a combination of components comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, comprising:
(a) a thermodynamic mixer having a mixing chamber, the mixing chamber including a thermodynamic extension on a motor shaft, the motor shaft extending to a shaft motor, the rate of rotational speed of which is controlled by a mixer control microcontroller; said mixer controlled by a processor;
(b) adding a batch of said combination of components to a mixing chamber;
(c) thermodynamic mixing of said combination of components,
i. Both the rate of rotational speed of the motor shaft and the temperature of the batch increase during the first stage,
ii. The average temperature of the batch is detected periodically by a start-up data sensor, and
iii. the average temperature data is delivered to a mixer controller microprocessor that calculates a temperature rise rate and compares it to a predetermined temperature rise rate activation setpoint;
said mixing; and (d) if the current rate of temperature rise is equal to or less than the startup set point, the mixer control microprocessor changes the rate of rotational speed of the motor shaft for a second stage period; It works like this;
[2] The method of [1], in which the temperature increase rate is calculated by averaging a certain number of recently stored values of average temperature data;
[3] The method of [1], wherein the rotational speed of the motor shaft is maintained at the same speed as the start-up setpoint rotational speed for a predetermined period of time, after which the batch is discharged from the mixing chamber;
[4] The method of [3], wherein the crystallinity of the batch is measured by Raman spectroscopy;
[5] The method of [1], wherein during the second stage period, the rotational speed of the motor shaft is reduced for a predetermined period of time, after which the batch is discharged from the mixing chamber;
[6] The method of [5], wherein the crystallinity of the batch is measured by Raman spectroscopy;
[7] The rotational speed of the motor shaft is increased during the second stage,
The average temperature of the batch is detected periodically by the start-up data sensor during the second stage period,
The average temperature data is delivered to a mixer controller microprocessor that calculates and compares the temperature rise rate to a predetermined second temperature rise rate activation setpoint, and the current temperature rise rate is matched to the second temperature rise rate activation setpoint. the batch is ejected from the mixing chamber when equal to or less than
Method [1];
[8] The method of [7], wherein the crystallinity of the batch is measured by Raman spectroscopy;
[9] First, by obtaining the maximum value of a fixed number of averages of the already stored values of the temperature rise rate of the preceding period, and then reducing that average by a predetermined percentage, the second temperature rise rate is determined. The method of [7] in which the startup settings are calculated;
[10] The rotational speed of the motor shaft is increased during the second stage,
The average temperature of the batch is detected periodically by the start-up data sensor during the second stage period,
the average temperature data is delivered to a mixer controller microprocessor that calculates a temperature rise rate and compares it to a predetermined second temperature rise rate activation setpoint;
wherein the rotational speed of the motor shaft is maintained at the same speed as the rotational speed of the second startup set point for a predetermined period of time, after which the batch is ejected from the mixing chamber;
Method [1];
[11] The method of [10], wherein the crystallinity of the batch is measured by Raman spectroscopy;
[12] A second temperature increase rate is determined by first obtaining the maximum value of a fixed number of averages of the already stored values of the temperature increase rate for the preceding period and then reducing that average by a predetermined percentage. The method of [10] in which the startup settings are calculated;
[13] The temperature rise rate activation setpoint is determined by first obtaining the maximum value of a fixed number of averages of the already stored values of the temperature rise rate for the preceding period and then reducing that average by a predetermined percentage. is calculated, the method of [1];
[14] The method of [1], where the startup setting value is 20 to 0 degrees Fahrenheit or degrees Celsius per second;
[15] The method of [11], where the startup setting value is 15 to 0 degrees Fahrenheit or degrees Celsius per second;
[16] The method of [12], wherein the startup setting value is 5 to 0 degrees Fahrenheit or degrees Celsius per second;
[17] A method for thermodynamic mixing of a combination of components comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, comprising:
(a) a thermodynamic mixer having a mixing chamber, the mixing chamber including a thermodynamic extension on a motor shaft, the motor shaft extending to a shaft motor, the rotational speed of which is controlled by a mixer control microprocessor; the mixer being controlled;
(b) adding a batch of said combination of components to a mixing chamber;
(c) thermodynamic mixing of said combination of components,
i. The temperature of the batch increases during the first stage,
ii. Crystallinity of the batch is detected periodically by the start-up data sensor and
iii. the crystallinity data is delivered to a mixer controller microprocessor that compares the current value of the crystallinity data to a predetermined crystallinity value activation setpoint;
said mixing; and (d) the batch is ejected from the mixing chamber if the current crystallinity data is equal to or less than the startup set point;
[18] The method of [17], in which crystallinity is measured by Raman spectroscopy;
[19] of [18], wherein the activation data sensor is a relatively thin tube including a distal and proximal end, the tip including at least one lens and a laser directed into the sample space of the thermodynamically mixed batch. Method;
[20] The method of [19], wherein the sensed sample space emission is transmitted to a Raman spectrometer, where the detected crystallinity of the batch crystalline component is calculated and transmitted to a mixer control microprocessor;
[21] A method for thermodynamic mixing of a combination of components comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, comprising:
(a) a thermodynamic mixer having a mixing chamber, the mixing chamber including a thermodynamic extension on a motor shaft, the motor shaft extending to a shaft motor, the rate of rotational speed of which is controlled by a mixer control microcontroller; said mixer controlled by a processor;
(b) adding a batch of said combination of components to a mixing chamber;
(c) thermodynamic mixing of said combination of components,
i. The temperature of the batch increases during the first stage,
ii. Batch crystalline to amorphous conversion data is periodically detected by a start-up data sensor, and
iii. A mixer in which the crystalline to amorphous conversion data compares the current value of the crystalline to amorphous conversion data with a predetermined crystalline to amorphous conversion value activation setpoint. delivered to the controller microprocessor,
said mixing; and (d) the batch is ejected from the mixing chamber if the current crystalline to amorphous conversion data is equal to or less than the startup set point; and [22] The method of [21], where crystallinity is measured by Raman spectroscopy.

The following drawings form part of the present specification and are included to further illustrate certain aspects of the disclosure. The present disclosure may be better understood by reference to one or more of these drawings in conjunction with the detailed description of specific embodiments presented herein.
FIG. 1 is a diagram of a thermodynamic mixer assembly. Figure 2 is an exploded three-dimensional view of the thermodynamic mixer. FIG. 3 is a shaft radial cutaway view of the thermodynamic mixing chamber. Figure 4 is an exploded three-dimensional view of the thermodynamic mixing chamber. Figure 5 is an analysis of batch sensed temperature, shaft rotational speed (RPM), and motor current consumption as a directly proportional measure of energy input to the batch at any instant at one shaft rotational speed. Figure 6 is an analysis of batch sensed temperature, shaft rotational speed (RPM), and motor current consumption as a directly proportional measure of energy input to the batch at any instant at two shaft rotational speeds. FIG. 7 is a graphical block diagram of a thermodynamic mixer process at multiple shaft rotational speeds. FIG. 8 is a cross-sectional view of a major surface portion of a prior art shaft extension. FIG. 9 is a cross-sectional view of a major surface portion of a shaft extension having a shaft axis plane at an angle of approximately 15 degrees. FIG. 10 is a cross-sectional view of a major surface portion of a shaft extension having a shaft axis plane at an angle of approximately 30 degrees. FIG. 11 is a cross-sectional view of a major surface portion of a shaft extension having a shaft axis plane at an angle of approximately 45 degrees. FIG. 12 is a cross-sectional view of a major surface portion of a shaft extension having a shaft axis plane at an angle of approximately 60 degrees. FIG. 13 is an alternative design of a cross-sectional view of a major surface portion of a shaft extension. FIG. 14 is an alternative design of a cross-sectional view of a major surface portion of a shaft extension. FIG. 15 is an alternative design of a cross-sectional view of a major surface portion of a shaft extension. FIG. 16 is an alternative design of a cross-sectional view of a major surface portion of a shaft extension. FIG. 17 is an alternative design of a cross-sectional view of a major surface portion of a shaft extension. FIG. 18 is an alternative design of a cross-sectional view of a major surface portion of a shaft extension. FIG. 19 is an exploded view of the thermodynamic mixer showing the internal liner pieces. FIG. 20 is a generalized side view of the interaction of the upper surface of the shaft extension with the inner surface of the mixing chamber. FIG. 21 is a perspective view of a shaft extension with variable upper surface path length. FIG. 22 is an alternative design of the front surface of the shaft extension. FIG. 23 is a flow chart describing an alternative embodiment of the invention. FIG. 24 is a high-level process flow diagram of an alternative embodiment of the present invention using activation settings to increase shaft rotational speed and/or stop thermodynamic mixing. FIG. 25 is an analysis graph of a single shaft speed batch showing sensed temperature (degrees Fahrenheit) and shaft rotational speed (RPM) versus process time, where the process is stopped at a detected temperature plateau. FIG. 26 is an analysis graph of a single shaft speed batch showing sensed temperature (degrees Fahrenheit) and shaft rotational speed (RPM) versus process time, where a second period of time after a detected temperature plateau. Stop the process when or upon detected crystallinity loss. FIG. 27 is an analysis graph of two shaft speed batches showing sensed temperature (degrees Fahrenheit) and shaft rotational speed (RPM) versus process time, where increasing shaft speed at a sensed temperature plateau and The process is stopped at the second rate at the detected temperature or at the detected crystallinity decrease.

DETAILED DESCRIPTION OF THE INVENTION Although the making and use of various aspects of the present disclosure are discussed in detail below, it should be understood that the present disclosure provides a number of inventive concepts that may be embodied in a variety of contexts. The particular 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 understanding of this disclosure, several terms are defined below. Terms defined herein have meanings as commonly understood by one of ordinary skill in the areas to which this disclosure relates. Terms such as "a" and "the" are not intended to refer only to a singular entity, but are inclusive of the general class and specific examples thereof are used for illustrative purposes. It's okay. With respect to values or ranges recited herein, the term "about" is intended to encompass variations above and below the stated number that may achieve substantially the same result as the stated number. . In this disclosure, each of the variously stated ranges is intended to be continuous to include each numerical parameter between the stated minimum and maximum values of each range. For example, the range from about 1 to about 4 includes about 1, 1, about 2, 2, about 3, 3, about 4, and 4. Although the terms herein are used to describe particular embodiments of the disclosure, their use does not delimit the scope of the disclosure other than as outlined in the claims.

As used herein, the term "thermodynamic compounding" or "TKC" refers to a method of thermodynamic mixing until melt blended. TKC may be described as a thermodynamic mixing process where processing ends some time before agglomeration.

As used herein, the term "major surface portion" refers to the "upper surface" of a shaft extension. The upper surface of the shaft extension is the surface facing the inner wall of the mixing chamber of the thermodynamic mixer.

As used herein, the term "shear transition temperature" means the point at which further energy input does not result in an immediate increase in temperature.

As used herein, the phrase "homogeneous, heterogeneous, or heterogeneously homogeneous or amorphous composite" refers to a variety of compositions that can be made using the TKC method.

As used herein, the term "heterogeneously homogeneous composition" refers to a material composition having at least two different materials evenly and homogeneously distributed throughout a volume.

As used herein, "bioavailability" refers to the extent to which a drug is available to target tissues after administration to the body. Poor bioavailability is a serious problem encountered during the development of pharmaceutical compositions, especially those containing active ingredients that are not highly soluble. In certain embodiments, such as protein formulations, the protein may be water soluble, sparingly soluble, not highly soluble, or insoluble. Those skilled in the art will be aware of various methods to increase protein solubility, such as the use of different solvents, excipients, carriers, generation of fusion proteins, targeted manipulation of amino acid sequences, glycosylation, lipid modification, degradation. , combinations with one or more salts and the addition of various salts may be used.

As used herein, the term "pharmaceutically acceptable" refers to a molecular entity, composition, material, excipient, which generally does not produce an allergic or similar adverse reaction when administered to humans. Means a carrier, etc.

As used herein, the term "active pharmaceutical ingredient" or "API" is interchangeable with "drug," "drug product," "drug," "liquid," "biologic," or "active ingredient." be. As used herein, "API" means a drug that has pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or that affects the structure or any function of the human or other animal body. Any component that is intended to be influenced. In certain embodiments, the API has poor solubility in water.

Examples of APIs that may be used in this disclosure include antibiotics, analgesics, vaccines, anticonvulsants, antidiabetics, antifungals, antineoplastics, antiparkinsonian drugs, antirheumatic drugs, appetite suppressants, biological biological response modifiers, cardiovascular therapeutics, central nervous system stimulants, contraceptives, nutritional supplements, vitamins, minerals, lipids, sugars, metals, amino acids (and precursors), nucleic acids and precursors, contrast agents, diagnostic agents , dopamine receptor agonists, erectile dysfunction drugs, fertility drugs, gastrointestinal drugs, hormones, immunomodulators, anti-hypercalcemic drugs, mast cell stabilizers, muscle relaxants, nutritional supplements, eye drops, osteoporosis drugs, psychiatric drugs Therapeutic drugs, parasympathomimetic drugs, parasympathetic depressants, respiratory drugs, sedative-hypnotics, skin and mucous membrane drugs, smoking cessation drugs, steroids, sympatholytic drugs, urinary tract drugs, uterine relaxants, vaginal drugs , vasodilators, antihypertensive drugs, hyperthyroid drugs, anti-hyperthyroid drugs, anti-asthma drugs and anti-vertigo drugs. In certain embodiments, the API is a poorly water soluble drug or a high melting point drug.

API can be found in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. A "pharmaceutically acceptable salt" as used herein is understood to mean a compound formed by the interaction of an acid and a base, in which the hydrogen atom of the acid is replaced by a cation of the base. Non-limiting examples of pharmaceutically acceptable salts include sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates. , isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisic acid Salt, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfone Includes acid salts, and pamoate salts. Another way to define an ionic salt can be as an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Non-limiting examples of bases include hydroxides of alkali metals such as sodium, potassium and lithium; hydroxides of calcium and magnesium; hydroxides of other metals such as aluminum and zinc; ammonia; substituted mono-, di-, or trialkylamine; dicyclohexylamine; tributylamine; pyridine; N-methyl-N-ethylamine; diethylamine; triethylamine; mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert- butylamine, or mono-, bis- or tris-(2-hydroxy-lower alkylamine) such as tris-(hydroxymethyl)methylamine, N,N- such as N,N-dimethyl-N-(2-hydroxyethyl)amine Di-lower alkyl-N-(hydroxy-lower alkyl)-amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and organic amines such as amino acids such as arginine and lysine. It is not limited to them.

Various routes of administration are available to deliver APIs to patients in need. The particular route chosen will depend on the particular drug chosen, the weight and age of the patient, and the dose required for therapeutic effect. Pharmaceutical compositions may conveniently be presented in unit dosage form. APIs suitable for use in accordance with the present disclosure, and their pharmaceutically acceptable salts, derivatives, analogs, prodrugs, and solvates, can be administered alone, but generally by the intended route of administration and It will be administered in admixture with appropriate pharmaceutical excipients, diluents, or carriers selected according to standard pharmaceutical practice.

The API is suitable for oral delivery as a tablet, capsule or suspension; pulmonary and nasal delivery; topical delivery as an emulsion, ointment or cream; transdermal delivery; and parenteral delivery as a suspension, microemulsion or depot. May be used in a variety of application modes, including. 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 complexes of the present disclosure may have some activity of their own, such as antioxidant activity, but generally for purposes of this application the efficiency of the active ingredient is and/or efficacy-enhancing compounds. 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 mentioned above, excipients and adjuvants may be used to enhance the effectiveness and efficiency of the API. Non-limiting examples of compounds that may be included are binders, cryoprotectants, lyoprotectants, surfactants, fillers, stabilizers, polymers, protease inhibitors, antioxidants and absorption enhancers. Excipients may be selected to modify the intended function of the active ingredient by improving flow, or bioavailability, or to control or delay release of the API. Specific non-limiting examples include: sucrose, trehalose, Span 80, Tween 80, Brij 35, Brij 98, Pluronic, Sucroester 7, Sucroester 11, Sucroester 15, Sodium Lauryl Sulfate, Oleic Acid, Laureth-9, Laureth-8, Lauric Acid, Vitamin E TPGS, Guelsia 50/13, Guelsia 53/10, Labrafil, Dipalmitoylphosphaditylcholine, Glycolic Acid and Salts, Deoxycholic Acid and Salts, Sodium Fusidate, Cyclodextrin, Polyethylene Glycol , labrasol, polyvinyl alcohol, polyvinylpyrrolidone and tyloxapol. Using the process of the present disclosure, the morphology of the active ingredient can be modified to obtain highly porous microparticles and nanoparticles.

Exemplary thermal binders that may be used in the compositions and composites of this disclosure include polyethylene oxide; polypropylene oxide; polyvinylpyrrolidone; polyvinylpyrrolidone-co-vinyl acetate; acrylate and methacrylate copolymers; polyethylene; polycaprolactone; polypropylene; alkylcelluloses such as methylcellulose; hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose; hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose; starch, pectin; tragacanth, gum arabic polysaccharides such as, but not limited to, guar gum, and xanthan gum. One embodiment of the binder is poly(ethylene oxide) (PEO), which is commercially available from companies such as Dow Chemical Company, which sells PEO under the trademark POLY OX(TM); Exemplary grades include WSR N80, which has an average molecular weight of about 200,000; 1,000,000; and 2,000,000.

A suitable grade of PEO can be characterized by the viscosity of a solution containing a fixed concentration of PEO, such as:

Suitable thermal binders that may or may not require plasticizers 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), hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), hydroxyethylcellulose (HEC), carboxymethyl-cellulose (CMC) sodium salt, dimethylaminoethyl methacrylate-methacrylate ester copolymer, ethyl acrylate-methyl methacrylate copolymer (GA-MMA), C-5 or 60 SH-50 (Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), cellulose acetate trimelletate (CAT), poly(vinyl acetate) phthalate ( PVAP), hydroxypropyl methyl cellulose phthalate (HPMCP), poly(methacrylate ethyl acrylate) (1:1) copolymer (MA-EA), poly(methacrylate methyl methacrylate) (1:1) copolymer (MA-MMA), poly(methacrylate) Methyl methacrylate) (1:2) copolymer, Eudragit L-30-D(TM) (MA-EA, 1:1), Eudragit L-100-55(TM) (MA-EA, 1:1), Hydroxypropyl Methylcellulose acetate succinate (HPMCAS), Coateric(TM) (PVAP), Aquateric(TM) (CAP), and AQUACOAT(TM) (HPMCAS), polycaprolactone, starch, pectin; tragacanth, gum arabic, guar gum, and xanthan gum Contains polysaccharides such as

Stabilizing and non-stabilizing carriers may contain a variety of functional excipients, such as: hydrophilic polymers, antioxidants, superdisintegrants, surfactants including amphiphilic molecules, wetting agents, etc. agents, stabilizers, retarders, similar functional excipients, or combinations thereof, as well as citric acid esters, polyethylene glycols, PG, triacetin, diethyl phthalate, castor oil, and others known to those skilled in the art. Contains plasticizer. The extruded material may contain acidifying agents, adsorbents, alkalizing agents, buffering agents, coloring agents, flavoring agents, sweetening agents, diluents, opacifying agents, complexing agents, fragrances, preservatives or combinations thereof. It's okay to stay.

Exemplary hydrophilic polymers that can be the first or second polymer carriers that can be included in the conjugates or compositions disclosed herein include poly(vinyl alcohol) (PVA), polyethylene-polypropylene glycol (e.g., POLOXAMER(TM)), carbomer, polycarbophil, or chitosan. Hydrophilic polymers for use in the present disclosure also include one or more of hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, natural gums such as guar gum, acacia gum, tragacanth gum, or xanthan gum, and povidone. may be included. Hydrophilic polymers include polyethylene oxide, sodium carboxymethycellulose, hydroxyethylmethylcellulose, hydroxymethylcellulose, carboxypolymethylene, polyethylene glycol, alginic acid, gelatin, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylamide, polymethacrylamide, polyphosphazine, polyoxazolidine, Also included are poly(hydroxyalkyl carboxylic acids), carrageenate alginates, carbomers, ammonium alginate, sodium alginate, or mixtures thereof.

"Immediate release" means release of the active agent into the environment over a period of time from a few seconds to within about 30 minutes after release begins, with release beginning within about 2 minutes after administration. Immediate release shows no significant delay in drug release.

"Rapid release" means the release of active agent into the environment over a period of 1 to 59 minutes or 0.1 minutes to 3 hours after release begins, with release occurring within minutes after administration or delayed after administration. It can begin after the end of the period (time lag).

As used herein, the term "extended release" properties assumes the widely recognized definition in the pharmaceutical field. Extended release dosage forms release drug (ie, active agent or API) at a substantially constant rate over an extended period of time, or a substantially constant amount of drug is released incrementally over an extended period of time. Extended release tablets generally reduce dosing frequency by at least a factor of two compared to drugs provided in conventional dosage forms (eg, liquids or rapid-release conventional solid dosage forms).

"Controlled release" means release of the active agent 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. "Sustained release" refers to an extended release of the active agent to maintain constant drug levels in the blood or target tissue of the subject to whom the device is administered.

The term "controlled release" with respect to drug release includes the terms "extended release," "sustained release," "sustained release," or "slow release," as they are used in pharmacy. Controlled release may begin within minutes after administration or after the end of a post-administration delay period (time lag).

Slow release dosage forms are those in which the drug is released slowly and nearly continuously over a period of time, e.g., 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 or more days, 1 week, or 2 weeks or more. As such, it provides a slow rate of drug release.

The term "mixed release" as used herein refers to a medicament that includes multiple release profiles for one or more active pharmaceutical ingredients. For example, a mixed release may include an immediate release and an extended release portion, each of which may be the same API, or each of which may be a different API.

Timed release dosage forms are those that begin to release drug after a predetermined period of time, measured from the moment of first exposure to the environment of use.

Targeted release dosage form generally refers to an oral dosage form that is designed to deliver drug to a specific portion of a subject's gastrointestinal tract. An exemplary targeted dosage form is an enteric-coated dosage form that delivers drug from the midsection to the lower intestinal tract rather than into the subject's stomach or mouth. Other targeted dosage forms can be delivered to other sites in the gastrointestinal tract, such as the stomach, jejunum, ileum, duodenum, cecum, large intestine, small intestine, colon, or rectum.

"Delayed release" means that the first release of drug occurs after the approximate delay (or lag) period has expired. For example, if the release of drug from an extended release composition is delayed by 2 hours, the release of drug begins about 2 hours after administration of the composition or dosage form to a subject. Generally, delayed release is the opposite of immediate release, where release of drug begins within minutes after administration. Thus, the drug release characteristics from a particular composition can be delayed-extended release or delayed-rapid release. A "delayed-extended" release profile is one in which extended release of the drug begins after the end of the initial delay period. A "delayed-rapid" release profile is one in which rapid release of drug begins after the end of the initial delay period.

Pulsatile release dosage forms provide pulses of high active ingredient concentration interspersed with lower concentration troughs. A pulsatile characteristic that includes two peaks may be described as "bimodal." Pulsatility characteristics of three or more peaks may be described as multimodal.

A pseudo-first-order release profile is one that approximates a first-order release profile. The primary release profile characterizes the release profile of a dosage form that releases a constant percentage of the initial dose of drug per unit time.

A pseudo zero-order emission characteristic approximates a zero-order emission characteristic. Zero-order release characteristics characterize the release characteristics of a dosage form that releases a fixed amount of drug per unit time.

The resulting conjugates or compositions disclosed herein may be formulated to exhibit enhanced dissolution rates of formulated poorly water-soluble drugs.

Examples of compositions or formulations with stable release characteristics are as follows. Make two tablets with the same formulation. The first tablet is stored under the first conditions for 1 day and the second tablet is stored under the same first conditions for 4 months. The release profile of the first tablet is determined after 1 day of storage and the release profile of the second tablet is determined after 4 months of storage. A tablet/film formulation is considered to have stable release characteristics if the release characteristics of the first tablet are approximately the same as the release characteristics of the second tablet.

Another example of a composition or formulation with stable release characteristics is as follows. Tablets A and B are made, each containing a composition according to the present disclosure, and tablets C and D, each containing a composition not according to the present disclosure, are made. Tablets A and C are each stored for 1 day under the first conditions, and tablets B and D are each stored for 3 months under the same first conditions. The respective release profiles of tablets A and C were determined after one day of storage and are referred to as release profile A and C, respectively. The respective release profiles of tablets B and D were determined after storage for 3 months and are referred to as release profiles B and D, respectively. The difference between release profiles A and B is quantified similarly to the difference between release profiles C and D. If the difference between release profiles A and B is less than the difference between release profiles C and D, tablets A and B are understood to provide stable or more stable release profiles.

Specifically, the TKC process can be used for one or more of the following pharmaceutical applications:

1 into polymeric and/or non-polymeric pharmaceutically acceptable materials for the purpose of delivering the API to a patient by oral, pulmonary, parenteral, vaginal, rectal, urethral, transdermal, or topical delivery routes. A dispersion of one or more APIs, where the APIs are small organic molecules, proteins, peptides, or polynucleic acids.

improving the bioavailability of the API, prolonging the release of the API, targeting the release of the API to specific sites in the gastrointestinal tract, delaying the release of the API, or creating a pulsatile release system for the API. Dispersion of one or more APIs in polymeric and/or non-polymeric pharmaceutically acceptable materials for the purpose of improving the oral delivery of APIs by making A dispersion that is a molecule, protein, peptide, or polynucleic acid.

Dispersion of one or more APIs in polymeric and/or non-polymeric pharmaceutically acceptable materials for the purpose of creating bioerodible, biodegradable, or controlled release implantable delivery devices, comprising: , a dispersion where the API is a small organic molecule, protein, peptide, or polynucleic acid.

Producing a solid dispersion of thermolabile API by processing at low temperatures for a very short period of time.

Producing a solid dispersion of API in a thermolabile polymer and excipient by processing at low temperatures for a very short period of time.

Making a small molecule organic API amorphous while dispersing it in an excipient carrier system that is polymeric, non-polymeric, or a combination thereof.

Dry milling of crystalline API to reduce particle size of bulk raw materials.

Wet milling of crystalline API with a pharmaceutically acceptable solvent to reduce particle size of bulk raw materials.

Melt milling of the crystalline API with one or more molten pharmaceutical excipients having limited miscibility with the crystalline API to reduce the particle size of the bulk raw material.

The presence of polymeric or non-polymeric excipients to create an ordered mixture in which fine drug particles adhere to the surface of excipient particles and/or excipient particles adhere to the surface of fine drug particles. Milling the crystalline API under.

For post-processing, e.g. milling and sieving, to produce heterogeneous homogeneous or amorphous complexes of multiple pharmaceutical excipients, which are subsequently It is used in well-known secondary pharmaceutical operations such as film coating, tabletting, wet and dry granulation, roller compaction, hot melt extrusion, melt granulation, compression molding, capsule filling, and injection molding.

Single-phase miscible composites of multiple pharmaceutical materials previously considered to be immiscible for use in secondary processing steps, such as melt extrusion, film coating, tabletting, and granulation. to generate.

Preplasticizing the polymeric material for subsequent use in film coating or melt extrusion operations.

Making crystalline or semi-crystalline pharmaceutical polymers amorphous so that they can be used as carriers for APIs, where the amorphous characteristics affect the dissolution rate of the API-polymer complex, the API -Improve the stability of the polymer complex and/or the miscibility of the API and polymer.

Deagglomeration and dispersion of particles made in a polymeric carrier without changing the properties of the particles made.

Simple blending of powdered API with one or more pharmaceutical excipients.

Producing a composite comprising one or more high melting point API and one or more thermolabile polymers without the use of processing agents.

Uniformly dispersing the colorant or opacifier in the polymeric carrier or excipient blend.

In the following detailed description of preferred embodiments of the present disclosure, reference is made to the drawings, where like numbers refer to the same or similar parts in different figures.

The present disclosure is directed to novel thermodynamic mixers and mixing processes that can blend heat-sensitive or heat-labile components without substantial thermal decomposition. In particular, the present disclosure is useful in processing mixtures containing thermally unstable components that undergo decomposition when exposed to melting temperatures or cumulative heat input for a defined period of time. One aspect of the present disclosure is a method of continuously melt blending a self-heating mixture in the mixing chamber of a high speed thermodynamic mixer, the method comprising: after achieving a first desired or predetermined process parameter; The present invention is directed to a method of changing one speed to a second speed during processing. In other embodiments, the second speed is changed to a third speed during processing after achieving a second desired or predetermined process parameter. Additional rate variations are also within the scope of this disclosure, as defined by the desired or predetermined number of processing parameters necessary to produce the desired composition or complex.

This process is particularly applicable to: producing solid dispersions of thermolabile APIs by processing at low temperatures for very short periods of time at multiple rates; producing solid dispersions of API in thermolabile polymers and excipients by processing at high speed; producing a solid dispersion of an API; and producing a solid dispersion of a thermosensitive polymer by processing at low temperatures and at multiple rates for relatively short periods of time.

One embodiment is to use multiple different rates during thermodynamic processing of the batch after reaching the shear transition temperature of a portion of the batch to reduce the required processing time. Another aspect is the processing time required, after the batch has reached a certain temperature, after which the significant amount of heat generated by frictional contact with the shaft extension and/or the internal surfaces of the mixing chamber The use of a plurality of different rates during the thermodynamic processing of the batch is to reduce the processing time, resulting in thermal decomposition of one or more components of the batch and reducing the rate. A further aspect is that the batch reaches a certain temperature, after which a significant amount of heat generated by frictional contact with the shaft extension and/or the internal surface of the mixing chamber is required which does not result in an overall temperature change of the batch. In order to shorten the processing time, several different speeds are used during the thermodynamic processing of the batch. A further embodiment is to provide a thermodynamic processing method that uses two rates to reduce thermal instability or thermal decomposition of a thermally sensitive polymer or component of a batch processed thereby.

In one embodiment, at least a portion of the batch in the mixing chamber of the high-speed mixer is at its critical temperature or at a specified temperature to obtain a melt-blended batch with acceptable decomposition of heat-sensitive or heat-labile components. Contains heat-sensitive or heat-labile components whose exposure to cumulative heat input limits for a period of time must be substantially prevented or limited. In this embodiment, at least one rate change is made between the start and end of the process such that critical temperatures or heat input limits are not exceeded, thereby causing thermosensitive or thermolabile compositions in the composition or composite. Protect elements.

Thermolabile components include, but are not limited to, thermolabile APIs, excipients or polymers. Heat sensitive polymers include, but are not limited to, polyolefins such as nylon, polytrimethylene terephthalate, polybutene-1, polybutylene terephthalate, polyethylene terephthalate, polypropylene and high or low density polyethylene, and mixtures or copolymers thereof. These polymers may be susceptible to surface and bulk polymer defects and extrusion limitations. Other heat sensitive polymers include poly(methyl methacrylate), polyacetals, polyionomers, EVA copolymers, cellulose acetate, rigid polyvinyl chloride and polystyrene or copolymers thereof. Critical temperatures in the disclosed process for such heat-sensitive polymers are about 5, 10, 20, 25, 30 from the temperatures at which heat-sensitive polymers begin to undergo decomposition of the desired process parameters in the art. , 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100°C, within an acceptable range from the known decomposition temperature for the polymer, The selection may be made by maintaining a sensed temperature of the batch.

One aspect of the present disclosure is a method of continuously blending and melting a self-heating mixture in the mixing chamber of a high-speed mixer, the method comprising: after achieving a first desired or predetermined process parameter, a first speed This is a method of changing the speed to the second speed during processing. In one embodiment, the second speed is maintained until the final desired or predetermined process parameters are achieved, after which the shaft rotation is stopped and the melt-blended batch is transferred to the mixing chamber for further processing. collected or discharged from The shaft operates at one or more intermediate rotational speeds between changing to the second speed and ceasing shaft rotation. The process parameters governing shaft speed changes are predetermined and sensed and displayed, calculated, inferred, or otherwise established with reasonable certainty, thereby controlling the mixing chamber of the high speed mixer. Speed changes may be made during a single rotational continuous process of a batch. Process parameters include, but are not limited to, temperature, motor RPM, motor current draw, and time.

The present disclosure is also directed to thermodynamic mixers that can blend heat-sensitive or heat-labile components without substantial thermal decomposition. One embodiment of a thermodynamic mixer has a high horsepower motor driving the rotation of a horizontal shaft with tooth-like protrusions extending outwardly perpendicular to the axis of rotation of the shaft. The shaft is connected to a drive motor. The portion of the shaft containing the protrusion is contained within a closed vessel, ie a thermodynamic mixing chamber, in which the blending operation takes place. The high rotational speed of the shaft combined with the design of the shaft protrusion imparts kinetic energy to the material being processed. A temperature sensor senses the temperature within the thermodynamic mixing chamber. When the set temperature is detected, the first speed is changed to the second speed.

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

FIG. 2 shows an exploded view of one embodiment of a thermodynamic mixer. The frame 1 supports the relevant components and connects the two ends so that the shaft assembly 2 is inserted into the axis of the shaft hole through the end plate 3 and into the feed screw hole through the end plate 4. The plate defines the closed end of the mixing chamber cylinder, the bottom of which is defined by the inner surface of the lower housing 5. The lower housing 5 includes a dropout opening that is closed by an ejection door 6 during operation. The upper housing 7 constitutes the upper part of the cylinder, which is the inner surface of the mixing chamber. The feed housing 8 is adapted to enable feeding of material to the feed screw of the shaft assembly such that, in combination with rotation of the feed screw, the material is compressed and forced into the mixing chamber from the external feed. . The door 6 pivots closed around the discharge door pivot pin 9. The end plate 3 is attached to the rack and pinion cylinder 18 with a spacer 10 in between. A bracket 11 is fixed to the upper part of the housing 7 for supporting an infrared temperature sensor 20 of the mixing chamber. The door guard 12 protects the sometimes hot door 6 from accidental human contact with the dropout material. The rotary guard 13 and drive coupling guard 14 protect the operator from contact with the rotating components being operated. Drive motor 15 is preferably an electric motor with sufficient power to accomplish the disclosed operations. Axles 16 and 17 support shaft assembly 2.

In an example of a system in which process parameters defining changes in shaft speed are measured in a mixing chamber and/or a drive motor, FIG. 7 shows a block diagram of the disclosed process, where the mixing chamber MC is driven by a shaft driven motor The variable frequency drive device 41 controls the rotational speed of the drive motor 42. In certain embodiments, the shaft speed can be between 0 and 5000 RPM. Additionally, programmable logic controller 40 defines and implements shaft rotational speed changes using variable frequency drive 41 in accordance with the disclosed process. A programmable logic controller 40 includes set points input by the user to determine the need to change the shaft rotational speed of a drive motor 42 and provides a variable frequency drive 41 with a rotational process for batch loads added to the mixing chamber. Send a command to change such speed after the The programmable logic controller includes a microprocessor that includes a memory incorporating a control program adapted to operate upon attainment of a set point entered by the user in dependence on sensor data transmitted from the drive motor 42 and/or the mixing chamber MC. may be incorporated and may include a user interface, such as a programmable logic controller display for the user to observe operating times and/or sensor data transmitted from the drive motor 42 and/or the mixing chamber MC. The programmable logic controller can be configured based on consideration of predetermined process parameters (such as operating time) or sensor data sent from the drive motor 42 and/or the mixing chamber MC for predetermined process parameters (batch temperature, Optionally includes a method for the user to directly change the motor shaft speed based on a comparison of the motor shaft speed (e.g., current consumption, and shaft speed). The programmable logic controller can control the drive motor 42 and/or mix based on microprocessor operation at the time of predetermined and stored process parameters (such as operating time) or with predetermined and stored process parameters. Optionally includes an automatic control method for changing motor shaft speed based on comparison with sensor data sent from the chamber MC (such as batch temperature, current consumption, and shaft speed).

A description of the components of one embodiment of a thermodynamic mixer for the disclosed process is shown in FIGS. 3 and 4. FIG. 3 is a shaft radial cutaway view of the mixing chamber MC of the thermodynamic mixer of the present disclosure, where halves 5 and 7 together have a shaft 23 rotating in a direction of rotation 24 of the axial length of the chamber. , forming a cylindrical mixing cavity. Shaft extensions 30 extend from their releasable connection on shaft 23 to a location proximal to interior surface 19. Shaft extension 30 includes an upper surface 22 and a front surface 21. Particles 26a-26e exhibit impingement of such particles on shaft extension 30 and inner surface 27, which impingement causes fragmentation of the particles and/or frictional heating due to the resulting shear forces. Additionally, FIG. 4 is an exploded three-dimensional view of the extension and mixing chamber shown in FIG. It has an upper surface 22 and an anterior surface 21 defined on the replaceable tooth. The foot 31 is adapted to be exchangeably fixed to the shaft 23 (continuing from the motor shaft 34) in a slot 35 by a bottom 32 of the foot 31. Figure 4 shows that particles are generally moving in direction 37 when impacting shaft extensions 30a-30c. Shaft extension 30a is shown having a front surface 21 arranged substantially opposite the front surfaces of shaft extensions 30b and 30c.

In a typical batch process, the user will first select two components, which may include, for example, a thermolabile API and a polymeric excipient. The user then empirically determines the shear transition temperature of the two components. The user then controls the process parameters (temperature, RPM, current consumption, and time) in the programmable logic controller to change from the first speed to the second speed as appropriate to the shear transition temperature of the component. Set. Any set point entered by the user can be used as the stopping point after the second speed period.

FIG. 5 illustrates certain differences that may exist between the methods of the present disclosure and thermodynamic mixing methods that use substantially a single shaft speed. Figure 5 shows a graph of batch sensed temperature, shaft rotational speed (RPM), and motor current consumption as a directly proportional measure of energy input to the batch at any instant during processing. As a specific example, the following composition was thermodynamically processed to produce a batch of griseofulvin:PVP (1:2 ratio) with a batch size of 60 grams. Griseofulvin is a thermolabile API. PVP is an excipient. A series of three tests is shown in Figure 5, carried out on a thermodynamic mixer similar in construction to those shown in Figures 3 and 4, in which the front surface 21 has a width of approximately 1.0 inches in the positive rotational direction, and they are maintained approximately 30 degrees from a plane extending from the axis of shaft 23 through the tip of front surface 21, which is about 2.5 inches tall. The batch of Figure 5 was processed under thermodynamic, self-heating conditions using essentially a single shaft speed. The y-axis corresponds to temperature (value x 10) and shaft speed (RPM, value x 30). Time on the x-axis is in 0.10 second increments. When the composition of this batch is thermodynamically mixed at shaft rotational speeds substantially higher than those shown in Figure 5, i.e., greater than 2500 RPM, inspection of the final product reveals that the composition becomes unacceptably crystalline. It was found to be sexually and poorly amorphous. This result would be unexpected to those skilled in the art. Although higher shaft speeds are taught in the thermodynamic mixing art to ensure better mixing, better mixing did not occur at higher shaft speeds with these materials. When the exemplary batch composition was processed at lower shaft rotational speeds, as shown in Figure 5, examination of the final product revealed that the composition was sufficiently amorphous and suitable for bioavailability. . However, unacceptable thermal decomposition of the thermolabile API occurred, rendering the batch unacceptable.

At time zero in Figure 5, the current consumption immediately increased to 35 amps (1050 on the graph). Batch discharge was approximately 17.6 seconds or the point at which a significant drop in RPM was exhibited. I set the shaft rotation speed to 1800 RPM and reached that speed within about 2 seconds of starting. Within about 7 seconds, the batch temperature reached 260°F, the shear transition temperature of the excipients. Above the shear transition temperature, the resistance of the excipients to shear was significantly reduced, and the energy imparted to the batch by collisions of particles and molten material on the extension surfaces and on the internal surfaces of the mixing chamber was also significantly reduced as a result. (When the batch temperature reached the shear transition temperature, the current consumption decreased by about half). From about 7 seconds to 16 seconds, the batch temperature of the composition did not increase, but substantial energy continued to be absorbed by the batch. Energy that did not result in such a temperature increase was converted into thermal instability or thermal decomposition of heat sensitive components. This test is generally performed once a significant amount of the components in a thermodynamically melt-blended batch, i.e., greater than 5%, 10%, 20%, or 30% by weight, undergoes that shear. It confirms that once the transition or melting point is reached, a significant amount of the heat absorbed by the entire batch causes thermal instability or thermal decomposition of the thermally sensitive components instead of increasing the overall batch temperature. . This is clearly shown in the time range from 7 to 16 seconds in Figure 5, where the batch temperature actually decreased with continuous energy input to the batch.

The same batch and thermodynamic mixer as in Figure 5 was used in Figure 6, but two speeds were run during continuous rotation batch processing. In Figure 6, the batch temperature is sensed, the batch temperature is compared to a predetermined set point, and the shaft rotation speed of the thermodynamic mixer is adjusted until the batch is discharged by opening the bottom dropout door. A programmable logic controller connected to an infrared sensor and a variable frequency drive was used to automatically change to different speeds during the process. The first speed was set at 1800 RPM and the second speed was set at 2600 RPM. A predetermined set point for batch temperature was selected to be 200° F. as a substantial level below the shear transition temperature of the excipients. In a preferred embodiment, the speed change may occur before the shear transition temperature of the substantial component is reached, and the system is configured such that the shaft speed is actually changed between the moment the sensed batch temperature is sent to the programmable logic controller. Reaction time is required before the reaction occurs. As shown in Figure 6, no substantial energy input to the batch was used other than to raise the temperature of the entire batch. The processed batch exhibited virtually complete amorphism with no detectable thermal decomposition of the API over a total processing time of approximately 6.5 seconds. This time contrasts dramatically with the 17.6 second processing time in Figure 5.

FIG. 6 increases the shaft rotational speed for a particular thermolabile component substantially at or before the shear transition temperature or melting point of a substantial component or portion of the thermodynamic batch. This indicates that the processing time should be minimized. In certain embodiments, the first speed should increase to the second speed by about 100 RPM, 200 RPM, 300 RPM, 400 RPM, 500 RPM, 600 RPM, 700 RPM, 800 RPM, 900 RPM, 1000 RPM, or more. In other embodiments, the processing time after the second speed starts until the batch is discharged from the mixing chamber is about 5%, 10%, 15% of the total time processing the batch at the first speed, Should be 20%, 25% or more.

It is well known in the art that the impact of particles onto a surface imparts energy to the particles. Thermodynamic, self-heating mixers are characterized by providing collisions with polymer-containing particles, whereby the imparted energy is partially converted into thermal energy, softening and/or melting those polymers. It is. However, the thermodynamic mixing technology field generally guides those skilled in the art to provide collisions to particles in thermodynamic mixers in a manner that lacks fine control of the conversion of collision energy to thermal energy. There is. This disclosure provides and describes methods for such control. Highly crosslinked polymers and thermosetting compounds are highly refractory to softening and melting for the same reason they are preferred: they are resistant to degradation. Furthermore, they have been shown to be of value in some combinations of components treated by thermodynamic mixing. In fact, thermodynamic mixing is essentially the only way to process highly crosslinked polymers and thermosets since they are resistant to melting and blending in any other manner. In the field of thermodynamic mixing technology, increasing the shaft rotation speed and/or processing time ensures that the melt-resistant polymer converts enough impact energy into thermal energy to soften or melt to a molten state for further processing. It was understood to be a method that could be induced to bring about. This aspect discloses an apparatus and method that can effectively control the conversion of collision energy to thermal energy.

The two main impact surfaces, the front and top surfaces of the shaft, control the conversion of impact into thermal energy in a thermodynamic mixer. Those two surfaces are the outermost part of the volume of the mixing chamber (hereinafter referred to as the "primary processing volume", which includes the most confined area at a radius approximately 1 inch inward from the cylindrical interior wall of the mixing chamber). The surface part of the shaft extension penetrating up to 30% and the cylindrical inner surface of the mixing chamber itself. Modification of the cylindrical inner surface of the mixing chamber is not a practical option - this surface is fixed and thus prevents the accumulation of molten material and prevents skidding and sliding self-heating contact with particles moving in the mixing chamber. To be possible, it must remain smooth and cylindrically homogeneous.

The present disclosure utilizes variations in the upper surface of a shaft extension penetrating into a main processing volume to control the conversion of rotational shaft energy imparted to the extension into thermal energy within particles impinging on the extension. use Varying the width of the major surface section and its angle from the shaft axis plane provides a controllable variation in the shear force imparted to the particles impinging on the section, which in turn It has been shown to provide control of the shaft energy that is converted into heat energy that can be used to soften or melt the polymer portion.

Referring again to Figures 3 and 4, by providing the particles in the mixing chamber with a cumulative experienced shear force defined by the rotational surface of the extension from the shaft and the shape and dimensions of the internal surface of the mixing chamber, the thermal power It has been shown that a self-heating phenomenon of chemical mixing is caused. Substantially all the particles in the mixing chamber during shaft rotation are present in the outer 30% of the volume of the internal space, i.e. the centrifugal force of the rotation of the extension moves the particulates and molten material into the central volume of the mixing chamber. Keep away from. Therefore, an effective thermodynamic mixer requires that the end of the shaft extension undergoes direct high shear (at the end front surface of the extension), indirect high shear (at the inner surface of the mixing chamber), and into the outer volume of the mixing chamber. must be designed to accomplish three functions: centrifugal retention of materials; The upper surfaces of shaft extensions 30a-30c form substantially vertical rectangles oriented at an angle away from a plane passing through the axis of shaft 23. Unexpected improvements and control over the cumulative shear forces imparted to the particles in the mixing chamber of a thermodynamic mixer by changing the width, angle, or varying the shape of a simple rectangular or arcuate paddle on the shaft This, in turn, has been shown to provide control of the thermal energy imparted and the desired heat input to heat-sensitive or heat-labile components in the processed batch.

For these specific comparisons of thermodynamic mixer operation and some configurations of the main surface parts, the energy input through the shaft and the shaft rotational speed are approximately the same, and the number of shaft extensions and the mixing chamber Assume that their spacing along the shaft length within is substantially the same. The comparison will therefore show the effect of changing the shape of the major surface portions.

In general, decreasing the width relative to the length of the major surface portion increases the shaft energy that is converted into thermal energy available to soften or melt the polymeric portion of the particle within the thermodynamic mixing chamber. . The width has minimal contact so that the particle experiences sliding collisions along the width, and the particle is induced into frictional contact, rolling and sliding, which gives "skid" or energy to the duration of the collision on that part. Must be larger than width. Mere normal grazing impact of particles on surfaces is relatively ineffective in providing thermodynamic, self-heating energy for softening or melting. Additionally, in some cases, readily melting, thermolabile or thermosensitive polymers are sometimes treated with only major surface portions that provide such grazing impact that heat application to such components is not possible. Provides further control over Consistent with this teaching, polymers that are refractory or resistant to softening or melting by the application of heat can be made at a minimal angle back from the shaft axis plane ( (e.g., at least 10 degrees or at least 15 degrees) with a minimally wide (at least 0.25 inch) major surface portion, such that the distribution of that energy into side-slipping and rotational motion is controlled by the particle's polymer content. Often improves the self-heating of objects.

The shaft extension design currently found in Draiswerke Gelimat® thermodynamic mixers has a cross section 50 shown in FIG. It has a spiral shape. Relative shear forces 52, shown by several short arrows directed at major surface portions 51, are not critical to this design. Therefore, this equipment is relatively expensive in terms of processing time and increased shaft forces to produce sufficient thermodynamic heating for the molten blend polymers, which are fairly resistant to softening or melting. It is therefore relatively unsuitable for processing thermolabile or thermosensitive polymers with such resistance. It has never been suggested in the art of thermodynamic mixing that changing the width and angle of the major surface portion relative to the shaft axis plane has any effect on the thermodynamic mixing of polymers. The present disclosure discloses such embodiments in FIGS. 9-12.

Figures 9-12 each have major surface portions 57-60 of equal width at angles of approximately 15 degrees, 30 degrees, 45 degrees and 60 degrees rearward from the shaft axis plane of the extension they represent. Sections 53-56 are shown. The width of the protrusion of the major surface portions 57-60 in their shaft axial plane is indicated by lengths 65-68, respectively, and is directly related to the relative shear forces 61-64, where the major surface portions 57-60 with respect to the shaft axial plane of the same width are Increasing the angle of the surface portion reduces the width of the projection relative to the plane and unexpectedly increases the relative shear force for the same shaft force input, shaft rotational speed and extension spacing and alignment on the shaft. With the present disclosure, it is possible to control self-heating by the shear force applied to the extension of the thermodynamic mixer. Reducing the width of the major surface area while maintaining the angle to the shaft axis plane maintains the total heat input to the thermodynamically processed batch in the mixer, but reduces the protrusion along the shaft axis plane. Reducing the length increases the shear force on any individual particle.

Thus, the shear strength of polymers processed by thermodynamic, self-heating mixing and blending can be matched to the relative shear energy imparted by the shaft extension in the mixing chamber. Of course, further design improvements are desirable when the polymer components in the batch include both high shear and low shear polymers. Providing a major surface portion suitable for high shear components imparts shear energy that can add too much thermal energy to low shear components. In such cases, the low shear components tend to soften and roll along the width of the major surface portion, further increasing heat production, while the high shear components tend to leave that surface more easily. be. Such situations tend to cause incomplete mixing, with insufficient melting of high-shear components or overheating of low-shear components. There is a further need for designs of major surface portions that achieve optimal shear loading for high and low shear components in thermodynamic batches.

It has been shown that this optimization is achieved by increasing the width of the main surface portion. A major surface portion having a width of at least 0.75 inches at an angle between 15 and 80 degrees from the shaft axis plane provides sufficient distance for both high and low shear polymer components in the batch, thus providing a high shear configuration The element remains in sliding and sliding contact with the major surface portion long enough to generate heat and absorb heat from the low shear component to soften and thereby blend with the low shear component.

Alternative designs for major surface portions are shown in FIGS. 13-17, showing major surface portion cross-sections 69, 72, 76, 80, 84, and 87, respectively. FIG. 13 shows a cross-section 69 that includes a distal acute surface 70 extending rearward to an obtuse surface 71, first providing a low shear surface and then a high shear surface. FIG. 14 includes a distal sharp surface 73 extending rearwardly to a 90 degree surface 74, which in turn extends rearwardly to a distal acute surface 75, first forming a low shear surface, followed by a high shear surface and a low shear surface. A cross-section 72 is shown, providing a shear plane. FIG. 15 includes a distal acute surface 77 extending rearwardly to an obtuse surface 78, which in turn extends rearwardly to a distal acute surface 79, first forming a low shear surface, followed by a high shear surface and a low shear surface. A cross-section 76 is shown, providing . FIG. 16 includes a distal obtuse surface 73 extending rearwardly to an acute surface 74, which in turn extends rearwardly to a distal obtuse surface 75, first forming a high shear surface, followed by a low shear surface and a high shear surface. A cross-section 80 is shown. FIG. 17 includes a distal ascending arcuate surface 85 extending posteriorly to a distal reducing arcuate surface 86 degree surface 74, which in turn extends posteriorly to a distal acute angle surface 75, first forming a low shear surface; A cross section 84 is then shown which provides a high shear surface and a low shear surface. FIG. 18 shows a cross-section 87 that includes a leading acute surface 88 and a distal acute surface 89 to provide an initial low shear surface followed by a high or low shear surface depending on the shear forces of the batch components.

In view of the foregoing teachings of these embodiments, the top surface 22 of FIG. It is.

Figure 19 shows another important embodiment of the thermodynamic mixer of the present disclosure, where halves 5 and 7 and door 6 are lined with internal liner pieces 5a, 7a and 6a, respectively. The liner pieces are adapted to sit closely adjacent to the inner surfaces of halves 5 and 7, as well as door 6, during operation of the mixer, thereby providing any variety of thermodynamic friction desired for the accelerated particles. Providing contact surfaces, such desired surfaces are selected among materials suitable or optimized for liner pieces 5a, 7a and 6a. Figure 19 shows the liner pieces 5a, 7a and 6a separated from their adjacent (installed) parts in an exploded view. Bolting halves 5 and 7 together ensures that liner pieces 5a and 7a line the inner surfaces of those halves 5 and 7. A hole in the end of the liner piece 6a allows for a bolted connection to the door 6. In thermodynamic mixers, which are well known to those skilled in the art, the inner surface of the mixing chamber is made of an alloy having sufficient mechanical and thermal strength required to contain and seal the thermodynamic operation of such mixers. Limited to steel. Thus, known thermodynamic mixers, at their capacity, do not stick excessively to the smooth inner surfaces of the alloy steel of the mixing chamber, and at the same time advantageously impinge on those surfaces, resulting in friction of the particles in the mixture. Limited to only mixtures that provide heat. Additionally, the distance between the shaft extension and the inner surface of the mixing chamber is specifically designed to optimize thermodynamic heating due to the interaction of moving particles between the inner surface of the mixing chamber and the shaft extension. In that respect, even relatively slight wear on the inner surface of the mixing chamber of a thermodynamic mixer can dramatically alter the effectiveness of producing thermodynamic heating of the encapsulated particles. Therefore, even such slight wear may require replacing the entire relatively expensive set of halves 5 and 7 in such thermodynamic mixers. This aspect reduces such excessive costs. The liner pieces 5a, 7a and 6a are relatively much less costly to replace than the halves 5 and 7 and the door 6. Replacing liner pieces is quite simple and fast. Preferred liner strip compositions include stainless steel (greater than 12% alloy by weight) and other such alloy steels, titanium alloys (such as titanium nitride or nitride-containing titanium), and wear- and heat-resistant polymers. (such as Teflon®). Another aspect of the present disclosure provides for non-smooth inner surfaces of liner pieces 5a, 7a and 6a, such as parallel or helical grooving, surface texturing, and/or electropolishing around the cylindrical inner surfaces of liner pieces 5a, 7a and 6a. The goal is to provide the following. Such materials and texturing for the liner pieces 5a, 7a and 6a reduce undesired adhesion of thermodynamically molten particles and/or for the shaft extensions and liner pieces 5a, 7a and 6a. It is intended to obtain an optimal or desired balance of characteristics that promote thermodynamic frictional contact of the mixing chamber particles in their movement within the interior surface.

In a further aspect of the present disclosure whereby the material or texturing of the liner pieces 5a, 7a and 6a is selected to obtain a target for thermodynamic mixing, the shaft extension including the front and upper impingement surfaces of the shaft extension is , by material composition and/or texturing similar to the changes disclosed for the inner surfaces of liner pieces 5a, 7a and 6a.

Another feature of the present disclosure is that the upper surface of the shaft extension, i.e., extends with a slight rearward rise at least above the height of the front surface of the shaft extension, on which the encapsulated particles are exposed. What forms the impinging ramp structure (surface 22 in Figures 3 and 4) is the main site of wear within the internal surface of the mixing chamber. The results of this discovery should be considered with respect to the design of shaft extensions in thermodynamic mixers. It has been shown that such a top surface has a very different function than the front surface. The front surface of the shaft extension drags the particles along its rearward width, displacing the particles substantially in the direction of the axis of the drive shaft. Such shaft-driven particles then lead to interlocking with yet another front surface of the next row of shaft extensions behind the shaft extension. The movement of particles in contact with the upper surface of the shaft extension driven by shaft rotation is very different, and in such movement it exerts substantially more frictional, thermodynamic energy than the front surface of the shaft extension. give to the particles.

FIG. 20 shows a side view (in the direction of the axis of the shaft to which it is fixed) of the removable part of the shaft extension 30, showing the front surface 21 and the top surface 22. Measure reference altitudes 30b to 30d from base level 30a. Neither the front surface 21 nor the upper surface 22 are shown in plan view, but are shown with their projections in shaft axial side view. The upper surface 22 includes a leading edge rising from an elevation 30c-30b and then extending rearward and upward to a similarly sloped trailing edge having the highest elevation 30d. Only part of the inner surface of half 7 is shown away from upper surface 22, parts P1 to P4 representing the path of particles impinging first on upper surface 22 and then on the inner surface of half 7. It has been revealed that the area of maximum wear on any internal surface of the mixing chamber is along the area from the front end to the rear, represented by the line from altitude 30c to 30b, i.e. at the point of impact of the particles at part P1. . As evidenced by the substantial wear on such hardened surfaces, a major portion of the kinetic energy is clearly converted into frictional heat to the particles in that area. The upper surface 22 rises more steeply at its far end along altitudes 30b to 30d than along its near edge starting at altitude 30c, resulting in a relatively long frictional migration path of particles along portion P2. , and is launched from an altitude of 30d to the inner surface of half 7 by inclination. After friction, rotation and drag contact with the inner surface of half 7 in part P3, the extensively heated particles bounce off the inner surface of half 7 and contact again the upper surface of another shaft extension. The length of portion P2 substantially controls the frictional heating time required for thermodynamic mixing and melting of the batch of particles within the mixing chamber of the present disclosure. The present disclosure provides for selecting shaft extensions that provide longer or shorter length top surface contact paths and deflection angles for impinging particles during thermodynamic mixing, thereby achieving a desired batch of encapsulated particles. controlling substantial or major frictional heating contact to temperature.

FIG. 21 shows a concave front surface 21 and an upper surface 22 that can produce sections P2' (longer) and P2'' (shorter) of various lengths for sections P3' and P3'', respectively. 21 shows a perspective view of certain embodiments of the shaft extension of FIG. 20 having . In certain embodiments, upper surface 22 includes a convex surface with a radius of approximately 4.5 inches extending from its forward tip to its most rearward edge.

In certain embodiments, a shaft extension that provides a relatively long frictional contact path for the particles being processed by the mixer of the present disclosure provides a reduction in processing time, i.e., heating the batch to the desired temperature as quickly as possible. preferred for. Such control of heating and processing times is directly applicable to the disclosed process of two-stage continuous thermodynamic mixing, whereby increasing the shaft rotational speed makes it more refractory to slower rates of heating or Particles that are resistant will be more quickly exposed to frictional heat for melting energy. Inhomogeneity of the material in the thermodynamically processed batch, i.e., either by composition or particle size, can result in greater or lesser frictional path contact with the inside of the mixing chamber. It has been revealed. Particles that are more resistant to melting, either due to higher melting temperature or hardness, will bounce back from frictional contact with the inner surface of the thermodynamic mixer more rapidly than less refractory particles. also requires long processing times. Thermodynamic mixing of heat-labile or heat-damageable components to the final, desired processing consistency is generally preferred to reach the target batch temperature as quickly as possible. Certain embodiments of the present disclosure provide a method for achieving more effective mixing of certain thermally labile components along the upper surface of the shaft extension by either single or multiple processing shaft speeds. Provide particle frictional contact paths of short, medium, long, or mixed lengths.

It is well known to those skilled in the art that the top surface of the shaft extension of a Draiswerke mixer is simply an arcuately tapered smooth end of a generally undulating shaft extension. Accordingly, the ability of such mixers to provide substantial surface shear, frictional heat to the thermodynamic mixing chamber particles is essentially minimal. To achieve an additional upper surface-like frictional path for the particles in the mixing chamber, and to achieve other objects of the present disclosure, FIG. Discloses a front view of an aperture 30 shaft extension with a central opening for passage during processing and collision on /A2, B1/B2 and C1/C2. It will be understood that the surfaces A1/A2 together act on the particle as a top surface, and the surfaces B1/B2 and C1/C2 act on the particle as a front surface. Figure 22 discloses that, more generally, the shaft extension may be formed in a donut or toroid shape or a diamond shape with a central opening to achieve more effective mixing of certain thermally labile components. ing.

DETAILED DESCRIPTION OF THE INVENTION OF THE FIRST AND SECOND EMBODIMENTS FIG. 23 is a schematic diagram of the process of the first and second embodiments. In Figure 23, the mixing chamber MC is configured to transmit the laser into a small sample space and then collect the collected luminescence for individual detection of the average mixed batch temperature or for detection of sample crystallinity by Raman spectroscopy. includes a temperature sensor or Raman spectroscopy probe 20 (as described above) located within the mixing chamber MC. Probe 20 sends its detection data to any Raman spectrometer and instrument microprocessor RS/DMC (if probe 20 is a Raman spectroscopy probe) or directly to the mixer control microprocessor MCM, which It includes a microprocessor having an input/output unit connected to a user interface including input buttons and an output display. The mixer control microprocessor MCM operates under a stored mixer control program, and the program receives and stores the detected start-up data from the probe 20 and then the shaft motor of the thermodynamic mixer and the shaft of the speed controller 15. Works to control speed. The mixer control program includes means for comparing the detected activation data or activation data rate calculated from the activation data, and compares the absolute value of the activation data or activation data rate with a predetermined activation set point. When it is detected that the startup data or startup data rate equals or exceeds the startup setpoint, the mixer control program increases the speed of the mixer motor shaft or causes the mixer to stop mixing after it has started. Work.

Further information about the physical and thermal changes that occur in the first and second embodiments is now described. FIG. 6 shows temperature start-up data versus mixing time for a combination of components, with a temperature plateau extending from about 12 seconds to about 52 seconds, referred to herein as the plateau period. At the time of that experiment, a plateau period was considered necessary to obtain the desired level of thermodynamic mixing and reduction of drug or drug crystallinity. The inventors have discovered that a full plateau period may not be necessary or that a predetermined period of in-batch temperature may be required to increase the motor shaft speed from a first lower shaft speed to a second higher shaft speed. We have found that this can be used as a start-up setpoint, which can be either the rate of decline, the absolute value of detected crystallinity, or the rate of crystallinity, and this indicates that the heat required for the combination of components Almost eliminates plateau periods in kinetic mixing.

In the low speed second stage embodiment of the invention, the first stage is completed upon plateau detection, followed by a second stage of lower shaft speed, such that the ultimate need for the drug or drug in crystalline form Preferably, the stated reduction is achieved with low shear and frictional strengths. Below are the components for which the slow second stage embodiment has been found to be successfully applied: [Name of drug and excipient/carrier].

For the first stage at lower shaft speeds and the second stage at higher shaft speeds, a slight difference must be recognized in the effect of thermodynamic mixing on the combination of components. The lower shaft speed stage provides a constant amount of heat almost instantly in 9-11 seconds at a lower batch temperature than the higher batch temperatures achieved by thermodynamic mixing at higher shaft speeds. (Figure 6) (referred to herein as the first stage period), resulting in 20-90% conversion of the premixed crystalline drug to the amorphous form, which is a substantial portion of the desired crystallinity change. One thing is clear. However, mixing at lower shaft speeds provides substantially less kinetic energy per unit of time than that at mixing at higher shaft speeds, which suggests that the amorphous structure of crystals The crystalline component requires more energy per unit of the remaining crystalline component to achieve the conversion to , resulting in a temperature plateau.

The elimination of long plateau periods during which degradation of the desired drug or drug may occur is the main objective of the first and second embodiments, as even 0.2% degradation of the desired drug or drug is thermodynamically Can render mixed batches unusable. In a specific example, one combination of components requires a single low speed thermodynamic mixing of 18 seconds, the end of the first stage period to start the second stage of higher shaft speed. By using a predetermined temperature rise rate as the start-up set point, the total process time required was 8 seconds. Preferably, the second higher shaft speed is 20-100% greater than the first lower shaft speed, and the second higher shaft speed is 40-80% greater than the first lower shaft speed. It is more preferable.

Additionally, the drug or drug in the component combination is generally a small molecule compared to its excipients, where the smaller amorphous molecule of the drug essentially acts as a "lubricant" for the much larger polymer. It acts in a certain way. The energy input per unit of the combination of components increases the desired conversion from crystalline to amorphous structure until the "lubricant" drug is captured in the melted or "sticky" larger polymer aggregates. Not high enough to complete the change. A useful analogy is that making a solid dispersion is similar to dissolving a drug in a liquid. Either the temperature or stirring speed should be increased to help the drug dissolve faster. It was unexpected that such a significant effect could be obtained in the first or second embodiment by detecting the process point at which the motor shaft speed should be increased to prevent drug degradation.

Returning to the first embodiment using the rate of temperature rise as the start-up set point, the tip is generally directed toward the shaft supporting the shaft extension, and the other end of the sensor 20 is connected to the batch microprocessor BMCRO. It is fixed so that it passes through the port of the mixing chamber MC. The batch microprocessor BMCRO (contains CPU, memory, clock, and input/output units, all operating under a batch control program) senses from sensor 20 at predetermined intervals (preferably from 500 to 5 ms). The batch control program then uses the stored temperature and recorded time data to calculate an arithmetic average, differential rate of change calculation, or other average A computational method will be used to calculate the rate of temperature change over a period of 2 seconds to 10 milliseconds. If it is determined that the calculated rate of temperature change is equal to or close to the predetermined starting value of the rate of temperature change stored in memory, the batch control program immediately or after some delay adjusts the speed of motor 15. The batch control program is operative to signal the controller to increase the lower shaft rotational speed to the higher shaft rotational speed, preferably for a predetermined period of time, after which the batch control program is operative to stop the motor 15.

FIG. 24 describes the steps of an alternative embodiment of the invention, in step 102 adding a batch containing a combination of components to the batch chamber of a thermodynamic mixer specifically designed for such processing; Starting the shaft motor at a first lower shaft rotation speed. At step 104, the temperature sensor or Raman spectroscopy probe (with its Raman spectrometer) sends a signal to the mixer control microprocessor for storage in memory as startup data.

For the first embodiment, the mixer control microprocessor continuously calculates the rate of temperature rise from the temperature start-up data, stores those values in memory, and calculates a certain rate at step 106. The mixer control microprocessor determines a pre-stored value of a temperature rise rate start-up setpoint or a maximum rise rate for a preceding period (preferably between 0.5 seconds and 1.0 seconds) that is substantially lower than the start-up setpoint. The start-up setpoint is calculated by calculating the start-up setpoint as the rate of temperature rise.

For the second embodiment, the mixer control microprocessor persistently stores the crystallinity values detected in the mixing chamber as start-up data and optionally calculates the crystallinity reduction rate in step 106 and converts those values into Save in memory. The mixer control microprocessor includes either a pre-stored value of a crystallinity value activation setpoint or a crystallinity reduction rate as a activation setpoint.

At step 108, the mixer control program microprocessor determines whether the start-up set point has been reached by the start-up data or their calculated speed. If that condition occurs, the mixer microprocessor operates to either increase the shaft speed after the first stage period or stop mixing at the end of the second stage period.

Among the many methods of calculating the rate of temperature rise for the first embodiment, one preferred method is to detect and store the sensed temperature of the mixed batch for 30 to 0.5 milliseconds, and then The next step is to calculate the average of each value of batch temperature. A start-up setpoint of 1.5 to 0 degrees/second is preferred for the first embodiment, where the maximum temperature rise rate is not used to determine the start-up setpoint.

The activation set point for the second embodiment is preferably an absolute value of 20-0% crystallinity, more preferably a detected crystallinity of 2-0% of the drug or drug being measured. The starting set point for crystallinity reduction rate is preferably between 20%/sec and 0%/sec.

For the first embodiment, a stop point for thermodynamic mixing of a particular combination of components is determined by testing, at which an acceptably low or non-existent level of crystallinity is observed and the drug or the degradation of the drug is within acceptable limits. For the second embodiment, a stop point for thermodynamic mixing of a particular combination of components is determined by testing, at which an acceptably low or non-existent level of crystallinity is observed and the drug or the degradation of the drug is within acceptable limits, or the stopping point is determined by a predetermined low level of detected crystallinity.

Figure 25 shows an analytical graph of a single shaft speed batch showing sensed temperature (degrees Fahrenheit) and shaft rotational speed (RPM) versus process time, with a temperature plateau detected at approximately 15.3 seconds (indicated by the sloping dashed line). ) to stop the process. In the process of Figure 25, the batch contains these components: itraconazole; Eudragit L100-55 (1:2 ratio). The grid blocks of the graph define a positive slope of 25 degrees Fahrenheit/sec from diagonal to diagonal. Detection of a plateau is preferably seen in this embodiment at a slope of about 15 degrees Fahrenheit/second or less, or more preferably about 10 degrees Fahrenheit/second or less. The process in Figure 25 shows the actual results of thermodynamic mixing at a single low shaft speed (approximately 1900 RPM), stopping upon detection of a temperature plateau by the mixer control program microprocessor. Some combinations of components may achieve sufficient reduction in crystallinity at the plateau detection step, as in this case. This aspect of the invention is referred to herein as the single low shaft speed batch aspect.

Figure 26 is an analytical graph of a single shaft speed batch showing sensed temperature (degrees Fahrenheit) and shaft rotational speed (RPM) versus process time, with a temperature plateau (indicated by a sloped dashed line) detected at approximately 15.8 seconds. ), then stop the process at a second period of approximately 20.8 seconds or at the detected decrease in crystallinity (if using a crystallinity probe). In the process of Figure 26, the batch contains these components: itraconazole; Eudragit L100-55 (1:2 ratio). The grid blocks of the graph define a positive slope of 10 degrees Fahrenheit/sec from diagonal to diagonal. Detection of a plateau is preferably seen in this embodiment at a slope of about 20 degrees Fahrenheit/second or less, or more preferably about 10 degrees Fahrenheit/second or less. The process of Figure 26 is terminated upon detection by the mixer control program microprocessor of a period of time following detection of a temperature plateau (process termination - either by removal of the batch from the mixing chamber or by any other valid termination of thermodynamic mixing). ), showing the actual results of thermodynamic mixing at a single low shaft speed (approximately 1600 RPM). Some combinations of components may achieve sufficient reduction in crystallinity in the period after the plateau detection step, as in this case. In this case, the additional period after plateau detection is approximately 5 seconds. This aspect of the invention is referred to herein as the single low shaft speed plus additional time batch aspect.

Figure 27 is an analysis graph of a batch of two shaft speeds showing sensed temperature (degrees Fahrenheit) and shaft rotational speed (RPM) versus process time, increasing shaft speed with a temperature plateau detected at approximately 9.5 seconds. , stop the process at the second speed at the detected temperature (approximately 12.7 s), or at the detected decrease in crystallinity (if using a crystallinity probe). In the process of Figure 27, the batch contains the following components: griseofulvin; povidone K30 (1:3 ratio). The grid blocks of the graph define a positive slope of 25 degrees Fahrenheit/sec from diagonal to diagonal. In this embodiment, plateau detection preferably occurs with a slope of about 10 degrees Fahrenheit/second or less, or more preferably about 5 degrees Fahrenheit/second or less. The process in Figure 27 actually results in thermodynamic mixing at a first low shaft speed (approximately 1500 RPM), an increase in shaft speed to approximately 2250 RPM, and termination of thermodynamic mixing at approximately 12.5 seconds. shows. Many combinations of components may achieve sufficient reduction in crystallinity during periods at higher shaft speeds after the plateau detection phase, as in this case. In this case, the additional period after plateau detection is approximately 3.2 seconds. This aspect of the invention is referred to herein as the low to high shaft speed batch aspect. In comparing the process of Figure 27 with that of Figure 26, the process of Figure 27 achieves the desired reduction in crystallinity for process stop with approximately 30-40% reduction in total process time. .

All of the compositions and/or methods disclosed and claimed herein can be made and practiced without undue experimentation with reference to this disclosure. Although the compositions and methods of the present disclosure have been described in terms of preferred embodiments, it is important to note the concept, spirit and scope of the present disclosure in terms of the compositions and/or methods and method steps or order of steps described herein. It will be obvious to those skilled in the art that variations may be applied without departing from the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of this disclosure as defined by the appended claims.

1 frame
2 Shaft assembly
3 End plate
4 End plate
5 Lower housing/half
5a liner piece
6 doors
6a liner piece
7 Upper housing/half
7a liner piece
8 Feed housing
9 Pivot pin
10 spacer
12 Door guard
13 Rotary Guard
14 Drive coupling guard
15 Drive motor/speed controller
16 spindle
17 Axle head
18 rack pinion cylinder
20 sensors/probes
20a programmable logic controller
20b programmable logic controller display
20c variable frequency drive
21 Front surface
22 Top surface
23 Shaft
24 Rotation direction
26a particle
26b particles
26c particles
26d particles
26e particles
27 Inner side
30 Shaft extension
30a shaft extension/base level
30b shaft extension/altitude
30c shaft extension/altitude
30d altitude
31 Foot
32 Bottom
33 volts
34 motor shaft
35 slots
37 directions
50 cross section
51 Rounded main surface area
52 Relative shear force
53 Main surface partial cross section
54 Main surface partial cross section
55 Main surface partial cross section
56 Main surface partial cross section
57 Main surface area
58 Main surface area
59 Main surface part
60 Main surface area
61 Relative shear force
62 Relative shear force
63 Relative shear force
64 Relative shear force
65 length
66 length
67 length
68 length
69 cross section
70 Sharp tip
71 Obtuse surface
72 cross section
73 sides
74 sides
75 sides
76 cross section
77 Sharp tip surface
78 Obtuse surface
79 Sharp end face
80 cross section
84 cross section
85 Arcuate surface with rising tip
86 Distal reducing arcuate surface
87 cross section
88 Sharp tip surface
89 Sharp end face

Claims (19)

A method for thermodynamic mixing of a combination of components comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, comprising the steps of:
(a) a thermodynamic mixer having a mixing chamber, the mixing chamber including a thermodynamic extension on a motor shaft, the motor shaft extending to a shaft motor, the rotational speed of which is controlled by a mixer control microprocessor; adding the combination of components to the mixing chamber of the mixer in a controlled manner;
(b) thermodynamically mixing the combination of components, the step of:
i. includes a first stage period during which both the rotational speed of the motor shaft and the temperature of the mixture of said component combinations increase;
ii. the average temperature of the mixture of said component combinations is periodically detected by a startup data sensor;
iii. said average temperature data is delivered to a mixer control microprocessor, a rate of temperature rise is calculated, and
iv. a second stage in which the mixer control microprocessor operates to increase the rotational speed of the motor shaft if the current temperature rise rate is less than or equal to a predetermined temperature rise rate activation setpoint; including the period,
The step characterized in that: 2. The method of claim 1, wherein the temperature increase rate is calculated by averaging recently stored values of average temperature data. The method of claim 1, wherein the rotational speed of the motor shaft is maintained at the same speed as the start-up setpoint rotational speed for a predetermined period of time, after which the mixture of component combinations is discharged from the mixing chamber. . 4. The method of claim 3, wherein the crystallinity of the mixture of component combinations is determined by Raman spectroscopy. 2. The method of claim 1, wherein during the second stage, the rotational speed of the motor shaft is reduced for a predetermined period of time, after which the mixture of component combinations is discharged from the mixing chamber. 6. The method of claim 5, wherein the crystallinity of the mixture of component combinations is determined by Raman spectroscopy. The rotational speed of the motor shaft is increased during the second stage,
an average temperature of the mixture of said component combinations is periodically detected by a start-up data sensor during a second stage;
the average temperature data is delivered to a mixer control microprocessor, a temperature rise rate is calculated, and the current temperature rise rate is equal to or less than a predetermined second temperature rise rate activation setpoint; In some cases, the mixture of the combinations of components is discharged from the mixing chamber;
The method according to claim 1. 8. The method of claim 7, wherein the crystallinity of the mixture of component combinations is determined by Raman spectroscopy. The rotational speed of the motor shaft is increased during the second stage,
an average temperature of the mixture of said component combinations is periodically detected by a start-up data sensor during a second stage;
the average temperature data is delivered to a mixer control microprocessor to calculate a rate of temperature rise;
wherein the rotational speed of the motor shaft is maintained at the same speed as the rotational speed of the predetermined second temperature rise rate activation setpoint for a predetermined period of time, after which the mixture of said component combinations is discharged from the mixing chamber,
The method according to claim 1. 10. The method of claim 9, wherein the crystallinity of the mixture of component combinations is determined by Raman spectroscopy. 2. The method of claim 1, wherein the start-up set point is 20 to 0 degrees Fahrenheit per second. 2. The method of claim 1 , wherein the start-up set point is 15 to 0 degrees Fahrenheit per second. 2. The method of claim 1 , wherein the start-up set point is 5 to 0 degrees Fahrenheit per second. A method for thermodynamic mixing of a combination of components comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, comprising the steps of:
(a) a thermodynamic mixer having a mixing chamber, the mixing chamber including a thermodynamic extension on a motor shaft, the motor shaft extending to a shaft motor, the rotational speed of which is controlled by a mixer control microprocessor; adding the combination of components to the mixing chamber of the mixer in a controlled manner;
(b) thermodynamically mixing the combination of components, the step of:
i. comprising a first stage period during which the temperature of the mixture of said combination of components increases;
ii. Crystallinity of the mixture of said combinations of components is periodically detected by an activation data sensor; and
iii. said crystallinity data is delivered to a mixer control microprocessor;
and (c) when the current crystallinity data is equal to or less than a predetermined crystallinity value activation set point, the mixture of the component combinations is mixed. Ejected from the chamber, stage. 15. The method of claim 14, wherein crystallinity is measured by Raman spectroscopy. the activation data sensor is a relatively thin tube including a distal and proximal end, the tip including at least one lens and a laser directed into the sample space of the combination of components thermodynamically mixed; 16. The method according to claim 15. 16. The sensed sample space emission is transmitted to a Raman spectrometer where the detected crystallinity of the crystalline component of the mixture of component combinations is calculated and transmitted to a mixer control microprocessor. Method described. A method for thermodynamic mixing of a combination of components comprising at least one active pharmaceutical ingredient and at least one excipient or carrier, comprising the steps of:
(a) a thermodynamic mixer having a mixing chamber, the mixing chamber including a thermodynamic extension on a motor shaft, the motor shaft extending to a shaft motor, the rotational speed of which is controlled by a mixer control microprocessor; adding the combination of components to the mixing chamber of the mixer in a controlled manner;
(b) thermodynamically mixing the combination of components, the step of:
i. comprising a first stage period during which the temperature of the mixture of said combination of components increases;
ii. crystalline to amorphous conversion data of the mixture of said component combinations is periodically detected by an activation data sensor; and
iii. the crystalline to amorphous conversion data is delivered to a mixer control microprocessor;
and (c) the current crystalline to amorphous conversion data is equal to or less than a predetermined crystalline to amorphous conversion value activation set point. , the mixture of said component combinations is discharged from the mixing chamber. 19. The method of claim 18, wherein the crystallinity of the mixture of component combinations is determined by Raman spectroscopy.

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