CN109663524A

CN109663524A - The direct probe sensing temperature method that the speed of temperature-sensitive part for the melt blended batch of thermokinetics changes

Info

Publication number: CN109663524A
Application number: CN201710952394.4A
Authority: CN
Inventors: 克里斯·布鲁格
Original assignee: Diffusion technology co Ltd
Current assignee: Austin Pharmaceutical Co ltd
Priority date: 2017-10-13
Filing date: 2017-10-13
Publication date: 2019-04-23
Anticipated expiration: 2037-10-13
Also published as: CN109663524B

Abstract

Present disclose provides a kind of to the method for carrying out thermokinetics mixing comprising the components composition of at least one active pharmaceutical ingredient and at least one excipient or carrier, in the method, the thermokinetics mixing to components composition is carried out with lower first axle speed in thermokinetics mixer, the monitoring realization to batch for determining to carry out wherein is increased by temperature rate, and the judgement having occurred and that, the mixing of thermokinetics needed for being completed components composition using different axle speeds later are mixed to thermokinetics needed for a large portion.

Description

The speed of temperature-sensitive part for the melt blended batch of thermokinetics change it is direct into Sample probes sense temperature methods

Technical field

The disclosure relates generally to drug manufacturing fields, and relate more specifically to active pharmaceutical ingredient (active Pharmaceutical ingredient, API) thermokinetics mixing (thermokinetic mixing) to produce new agent Type.

Background technique

The molecule that the high-throughput molecule screening technique that current pharmaceuticals industry uses already leads to newfound poorly water-soluble is real Body ratio is substantially improved.Since the pharmacokinetic profile of difference is abandoned molecule in the process of development, or due to non- Optimal properties of product, many treatment potentialities usually cannot be realized sufficiently in these molecules.In addition, in recent years, due to salt Form and neutral or the chemical modification of faintly acid/alkalinity drug practical limitation, pharmaceuticals industry, which has begun, to be increasingly dependent on Preparation method improves drug solubility.Accordingly, it is intended to enhance the advanced preparation technique of the dissolution characteristics of the drug of poorly water-soluble Current Good conveying is become more and more important.

The U.S. Patent application No.8,486 submitted by inventor same as the present application and other co-inventor, 423 are related to (thermokinetic compounding) compound in drug manufacturing field application thermokinetics.Thermokinetics is compound Or " TKC " is thermokinetics mixing up to melt blended method.By the pharmaceutical composition of the compound preparation of thermokinetics or multiple Condensation material can be according to well known to a person skilled in the art methods to be further processed, these processing include but is not limited to that hot melt squeezes (hot melt extrusion), melt are granulated (melt granulation), compression molding (compression out Molding), tablet press (tablet compression), capsule filling (capsule filling), film coat (film- Coating) or injection moulding (injection molding) is final products.

Although being mentioned using thermokinetics is compound compared to other methods known in pharmaceutical field in drug manufacturing field Significant advantage has been supplied, but can improve mix certain temperature-sensitives using thermokinetics mixer continuous fusion in some cases Or the processing of thermo-labile component.This group of subassembly, which is blended, may require that using the axle speed or reduced axle speed of raising to extend The time is handled, to be enough to assign the complete amorphism of batch (amorphosity) sufficiently handled.It has been found that in certain situations Under, such processing may cause overstep the extreme limit temperature or heat input, and heat input may cause the degradation of thermo-labile component.It has seen Carrying out the big calorimetric that entire batch absorbs may cause thermo-labile component thermal degradation, rather than improve whole batch temperature.Substantially Complete amorphism is well known measurement in medicine preparation and process field, in the composition for lacking substantially completely amorphism In, bioavilability may be damaged.

Summary of the invention

The disclosure keep punching research and develop in relation to by thermokinetics Application of composite in drug composite and composition The application of production.It is introduced at the basic physics of the drug component in the thermokinetics mixing chamber of thermokinetics mixer as batch The Short Description of reason will be helpful to understand this processing.

Thermokinetics mixer is completely unique in processing equipment field.Heating during mixed process is by processing material Not (not the needing chemical reaction itself, but the structure of crystalline drug can change) that material itself generates, such as without external heat exchange By the indirect heat transfer of radiation or convection current, or even do not directly heat such as through direct flame contact yet.Thermokinetics is mixed Clutch has the proprietary extension extended from drive shaft, and wherein drive shaft extends through the axis of tubular mixing chamber.These are proprietary Extension be formed as providing the angled contact surface along the direction of angle driving direction orientation, wherein angled contact Surface is suitable for reducing or eliminating pressure break, tearing or the fracture of processing component molecular.It is sent out in thermokinetics mixer during processing Raw processing step is usual are as follows:

1. controlled sliding occurs between processing component particles and extension contact surface, frictionally heats and contacts, thus High transient temperature is generated (since particle can roll and can slide over contact table in the contacting side of processing component particles Face, therefore and cause to be heated side)；

2. in part high transient temperature can negatively affect the processing component particles of extended portion's heating chemical component it Before, these processing component particles are angularly sprayed the contact surface from extension, thus (due to mixing indoor extremely turbulent flow Condition) cause with mixing room air and other processing component particles it is instant cool down contact so that by by previous cunning Heat that is dynamic and frictionally heating contact generation is immediately assigned to the processing component particles of substantially entire batch；

3. the particle of angled deflection rubs each other, to generate the heating instantaneously spread, and reached in fusible particle In the case where melting temperature, melt granules are engaged and are opened with the non-melt particle of capture so that very crush or The non-melt particle of molecule dispersion is evenly distributed in melt granules；

4. the particle of angled deflection also from drive shaft axially and angularly outwardly, to cause sliding, friction It heats and is tangentially contacted with some of the inner surface of tubular mixing chamber, thus generated in the contacting side of processing component particles high Transient temperature so that particle due to it contacts with extension (direct or indirect) and when losing kinetic energy, particle quickly leaves The inner surface of mixing chamber and/or more there are the processing component particles of energy to push away or deviate the inner surface by other；

5. the instant cooling contact and mixing of above step 2 are repeated, with the particle for making to slide and frictionally heated It is disengaged with the contact of mixing chamber surface；And

6. since thermokinetics mixer connect at the end of thermokinetics mixing step thermokinetics mixer quilt Until closing, handle component particles violent and extreme turbulent flow be substantially it is instantaneous and substantially it is continuous (still It is not constant in the case where motor drive shaft velocity variations) so that the temperature of entire batch is substantially in entire mixing chamber Even, wherein temperature is surveyed at 1 centimetre to 2 centimetres of inner surface of the distance for frictionally heating surface and mixing chamber away from extension Amount.

It is heated to merge these processing component particles can one component particles will be handled using thermokinetics mixer Before the high temperature risen, thermokinetics mixer is mainly used for mixing, and fever is undesired side effect, thus by using mixing The coolant jacket of outdoor generates heat to reduce.The present inventor has been that the purposes that discovery thermokinetics is compound in pharmacy processing is made A part of isolated effort, wherein the disclosure is directed not only to chemical component-reservation mixing (chemical composition- Sparing field), and further relate to the structure change for causing thermally labile drug component.

This disclosure relates to be combined at least one excipient, polymer support or similar less activity or non-active ingredient At least one active pharmaceutical ingredient " API ", preferably at least part in crystal form active pharmaceutical ingredient (below In be known as components composition).Present disclose provides a kind of using following improved devices and/or method to the component in single batch The method that composition only mixes several seconds: when should terminate and incite somebody to action with determining that thermokinetics is mixed using only batch temperature measurement The thermokinetics mixed phase ratio that batch is removed from mixing chamber, the improved device and/or method shorten the batch processed time.

In the first embodiment of the disclosure, components composition mixing is carried out with lower first axle speed, wherein leading to Excess temperature rate increases the monitoring to batch for determining to carry out and realizes to the mixing of a large portion desired thermokinetics The judgement of generation completes the desired thermokinetics mixing of components composition using higher second axle speed later.

In second embodiment of the present invention, components composition mixing is carried out with lower first axle speed, wherein leading to The absolute value for crossing batch crystallinity determines or the reduction rate determination of batch crystallinity is monitored batch.In crystallinity or knot Brilliant degree reduces at the predetermined value of rate, and thermokinetics mixing is terminated, or using higher second axle speed in crystallinity or Crystallinity reduces the required thermokinetics mixing that components composition is completed at the second predetermined value of rate.

Inherence in the two embodiments is the discovery that, is widely tried in the thermokinetics mixing to components composition Test and mistake after, extend be exposed to realize needed for raised temperature needed for mixing time will lead to it is expensive and heat labile The degradation of drug molecule.The method that incorporation time needed for shortening must be found.The two embodiments meet these requirements.

The discovery result of first embodiment are as follows: lower first axle speed of components composition is blended in the processing and starts Only several seconds in provide a large portion components composition needed for mixing, but will lead to the extended of drug degradation Incorporation time is obviously needed, and has then used higher second axle speed later in this process.First embodiment packet Include such discovery: lower first axle velocity step only needs relatively short, and it terminates (and higher second axle speed The beginning of degree) it is triggered by sizable decline of the temperature increase rate of batch.When temperature increase rate in several seconds than initially counting The raised maximum temperature rate of the batch temperature of calculation it is small about 10% to 100% when, or when temperature increase rate have 1.5 degree/ Second to 0 degrees second increase rate (temperature (°F or DEG C)/time (second)) when, higher second axle speed will be started.Make us frightened It is odd, with the first reality all measured using individual temperature using individual axis velocity or only batch during entire mixed processing The mode of applying is compared, and can be realized as required mixing water under lower final batch temperature in a relatively short period of time and usually Flat (being determined by test and mistake, i.e., test mixed component composition after blending).The shorter place of first embodiment Reason time and lower final temperature make drug substantially non-degradable, and may be almost the same with the value of final products, And substantially eliminate the initial crystallinity of drug or pharmaceutical ingredients.Now to reduction crystallinity and increase mixed component combination The reason of amorphism of object, is described.

Structure change needed for hybrid medicine component is commonly known as amorphism or amorphous state.It is well known that The complex process almost all that solid particulate medicament is produced before final mixing or processing causes crystalline compounds.These purifying It closes object to be preferably amorphous before mixing with other components, to generate final desired composite medicine.It is well known that (Hancock et al. is in Pharm Res.2000 with the prediction solubility dramatically increased compared with its crystalline phase for amorphous drug April in year；17 (4): 397-404 deliver " what the real solubility advantage of amorphous drug is? (What is the true Solubility advantage for amorphous pharmaceuticals ?) "；www.ncbi.nlm.nih.gov/ pubmed/10870982).The biology that increased solubility only makes medical compounds be converted into amorphous state before administration is sharp One of expenditure advantage --- " importance of amorphous drug solid be its relative to corresponding crystal useful quality, generally send out Raw and physical chemistry unstability." (Yu, L. are Adv Drug Deliv Rev.2001 May 16；48 (1): 27-42 hair Table " amorphous drug solid: prepare, characterize and stabilize (Amorphous pharmaceutical solids: preparation,characterization and stabilization)"；www.ncbi.nlm.nih.gov/pubmed/ 11325475).Yu further illustrates by crystallization and heat labile medical compounds (such as protein and peptide) and reverts to effectively Amorphous state technology status --- melting quenching, cryospray be dry, grinding, wet granulation and solvated crystalline it is dry It is dry.These processing are time-consuming and labour-intensive, and must separately be completed with other components with final amorphous drug Solid mixing, and processed crystalline drug solid is made to be subjected to degrading and recrystallize.Need may be implemented single or multiple crystallizations The method for being blended to produce required final drug dose composition of medical solid, and at the same time realizing needed for medical solid The a part of desired amorphous state as required final drug dose composition.

Second embodiment includes a kind of completely new approach of thermokinetics mixing for monitoring components composition.The present inventor is It is found that the method that the crystallinity of the mixing batch in thermokinetics mixer can be measured.It is mixed in thermokinetics mixing periods Indoor environment is preferably dark and turbulent flow, and the duration no more than about 30 seconds.Although it is contemplated that can directly measure The crystallinity of batch is mixed, so that mixing can be terminated when crystallinity is sufficiently reduced or effectively eliminated, but can in the past It is unknown in the turbulent flow batch mixing field of dry particl in the method for realization.The present inventor's first discovery uses Raman spectrum Instrument come measure mixing static amount solid material crystallinity, therefore can be used Raman spectrometer measurement mixed component composition Crystallinity.When analyzing the static sample of unmixed and mixed components composition, the Raman spectrometer of business allows user All wavelength detected associated with the other components of components composition are filtered out, and allows user to detect and measures group The drug of subassembly object or the percent crvstallinity of drug.Inventors have discovered that a kind of Raman spectrum probe, the Raman Spectroscopic probe head includes relatively narrow pipe, which has the required lens oriented in inner axial tube, and the end of the pipe is unlimited, with It is suitable for the light wave of Raman spectrometer detection in reception and transmission.It is without being limited thereto, for the exemplary suitable of second embodiment Raman spectrometer can be Princeton instrument company, especially TriVista CRS (http: // Www.princetoninstruments.com/products/specsys/trivistacr s/), TriVista CRS's swashs Light and detection device have been suitable for this relatively narrow pipe, and (in the case where TriVista CRS, pipe is that the microscope of standard is saturating Mirror tube).Probe in second embodiment uses the lens extension of Raman spectrometer, so that the distal portion quilt of lens extension It is directed in mixing chamber, being preferably directed into so that popping one's head in can detecte the knot of the particle moved between rotation shaft extension Brilliant degree.The close end of Raman spectrum probe is connect with Raman spectrometer and device microprocessor, the equipment of the device microprocessor User interface allows to check that the crystallinity of Raman spectrometer determines data and/or the crystallinity of Raman spectrometer is determined number Microprocessor is controlled according to mixer is transmitted to.When Raman spectrometer has determined mixing batch crystallinity and is transmitted to the data mixed When clutch controls microprocessor, mixer control microprocessor can make the mixing of components composition batch terminate or make axle speed Degree improves and terminates mixing hereafter.In this second embodiment, when drug or drug change from crystallization amorphous form, from The Raman scattering of drug or drug crystal stops or cannot be detected, i.e., present energy is by different from drug or drug crystal Energy state absorbs.When Raman probe detection drug or drug crystal disappear substantially, so that not needing to components composition The processing control of thermokinetics mixing carries out temperature measurement.

It is of the invention in preceding general introduction

In contrast, the processing or thermo-labile drug component that thermo-labile drug component is mixed with other components are processed into itself The processing of powder type is all from being not intended to that thermo-labile drug component is made to reach its melting temperature.Instead, it is desirable to the result is that basic On be thoroughly mixed or powder type.It, will if amorphism substantially completely may be implemented in identical mixing step Avoid individual processing step.Inventors believe that since he is in terms of using thermokinetics mixer processing commercial polymer Many years of experience, thermokinetics mixer can be to avoid decomposition of the thermo-labile drug ingedient in required mixed processing.However, this It is also contemplated that even if heated very short time may also lead to the decomposition of component, these components usually require high-cost inventor Several preceding processing steps of special technology application.It is considered as desirable by the inventor to how further shorten mixing batch to exist The processing time in thermokinetics mixer, but still it is able to achieve the amorphism substantially completely of batch.

Additional general introduction to first embodiment and second embodiment of the invention

The present inventor observes when testing in thermokinetics mixer to the thermo-labile drug component of test batch The phenomenon that he is occurred when using thermokinetics mixer.After the initial mixing phase carried out with lower axle rotary speed, batch Secondary temperature will increase and stablize (plateau).It will be unable to produce in processing batch to be further processed compared with low velocity Raw amorphism substantially completely.The inventors discovered that axle rotary speed is increased to higher level and is continued extremely short Period can generate amorphism substantially completely in gained batch, and component is hardly processed heat and divides Solution.

However, it has been found by the present inventors that the above method of result needed for obtaining extends the processing time in which may not be necessary. In the present invention, with etc. temperature under lower axle rotary speed to be seen it is stable and then axle rotary speed is increased to it is higher Axle rotary speed compare, handle batch processing the time and by high temperature time shorten.In the present invention, high-speed temperature passes Sensor accurately and substantially immediately measures average batch temperature, which is stored in mixer or batch In microprocessor (including CPU, memory, clock and I/O unit), which controls under program in batch Operation.It calculates the temperature sensed and one or more previously stored temperature and its compared with the record time temperature and becomes Change rate.When detecting that rate temperature change is decreased or increases to required temperature raising triggering rate, axis rotation speed Degree is increased to higher axle rotary speed from lower axle rotary speed.

It is smaller near the distal portion of probe irradiated by laser beam that Raman spectrum probe is preferably positioned to detection The crystallinity of particle in the movement of sample space.The list that light from irradiation area is collected by lens and passes through Raman spectrometer Color instrument is sent.It is filtered close to the wavelength of laser and drug or drug due to elastic Rayleigh scattering, and the light that remaining is collected It is dispersed on detector.Lead to laser photon with molecular vibration, phonon or the laser of other excitation interactions in system Energy deviate upward or downward.The transfer of energy gives the information of vibration mode in system.In the feelings of second embodiment Under condition, these vibration modes are carried out to handle the average crystallite for determining mixing batch by the algorithm of temperature sensor manufacturer Degree.Since the detection time of mixing batch crystallinity can extend to about 3 seconds, device microprocessor or mixer control are micro- Processor selectively runs crystallinity set point program, which determines the fall off rate of batch crystallinity And it is stored for prediction and uses.Since over-mixed 3 seconds or more (the batch crystallinity detection carried out by Raman probe) can Can lead to drug or drug degradation, it is therefore preferred to the required components composition of testing experiment batch, with obtain terminate mixing or Speed improves triggering set point.These triggering set points are together with the crystallinity absolute value or crystallinity fall off rate that currently measure It uses, so that it is required to obtain to stop mixing (or axle speed raising) before currently detected required crystallinity level Thermokinetics mixing.

Referring now to first embodiment, the present inventors have additionally discovered that the rate temperature change at point on the first temperature platform The viscosity variation of the Best Times of axle rotary speed is improved corresponding to instruction.The present invention measures the temperature change speed of mixing batch Rate, and axle rotary speed is increased to higher level from reduced levels according to following processing methods: (1) change of average batch temperature Change rate to be calculated as having reached the triggering rate for the temperature change that instruction batch has been realized in required viscosity variation, In, required viscosity variation indicates that significantly improving for amorphism, or the rate of change of (2) average batch temperature have reached The expected triggering rate of temperature change, this shows after considering the processing speed of temperature detection and calculating, and batch will be realized Indicate the required viscosity variation that amorphism dramatically increases during short process phase.In the case where processing method (2), It is actually detected and calculate axle rotary speed is increased to higher level before desired rate temperature change, to avoid detecting And calculate the unnecessary incorporation time after desired rate temperature change.

In the present invention, obtained pharmaceutical composition due to substantially completely mixed and have amorphism and it is excellent Selection of land has increased bioavilability and stability.

It is blended and disperses to add certainly in the mixing chamber of super mixer as described above, a kind of thermokinetics mixer is provided The method of hot mixt, wherein First Speed is changed to the second speed in processes after reaching the first expectation processing parameter Degree.In another embodiment, second speed can be kept until reach final process parameter, axis rotation at that time be stopped and Melt blended batch is extracted out or is discharged from mixing chamber, with for further processing.It in another embodiment, can be Midrange speed change one or more times is made to axle rotary speed between two speed and stopping axis rotation.Determine that axle speed changes Processing parameter be scheduled, and can sense and show, calculate, speculating or otherwise true with reasonable certainty It is vertical, change so that making speed during single rotation continuous processing of the batch in the mixing chamber of super mixer.Another implementation Mode is the change of the shape, width and angle of the facial parts being projected into main process task volume using shaft extension or protruding portion Change to control and be transported to the rotary shaft energy of extension or protruding portion and be converted to and hit the part of extension or protruding portion Intragranular thermal energy.

Present inventors studied a variety of mixtures comprising thermo-labile component are melt blended in thermokinetics mixing chamber. Inventors have surprisingly discovered that using multistage speed in some lots of single rotation continuous operation containing thermo-labile component Degree is solved the problems, such as more than the limiting temperature of batch or excessive heat input.Inventor is also unexpectedly found that, changes axis and prolongs It extending portion or the shape of protruding portion, width and leaves the angle of axial plane of axis and provides the shearing that control is transported to particle Method, then provides the control to the axis energy for being converted to thermal energy, these thermal energy can be used in softening or melting heat power Learn the polymer moieties of particle in mixing chamber.

One embodiment of the disclosure be blended two or more ingredients composition method, wherein it is described at It point include one or more of temperature-sensitives or thermo-labile component, wherein resulting composition is amorphous, homogeneous (homogenous), heterogeneous (heterogenous) or heterogeneous uniform (heterogeneously homogenous), should Method, which is included in thermokinetics mixing chamber, mixes the ingredient, wherein thermokinetics mixer shafts are straight with First Speed operation To reaching predefined parameter, axle speed is adjusted to second speed at this time and continues second time period, wherein mixed processing is first It is substantially uninterrupted between period and second time period.In another embodiment of the disclosure, thermokinetics mixer shafts It is run with one or more speed up to reaching predefined parameter, axle speed is adjusted to different speed at this time and continues difference Period, wherein mixed processing is substantially uninterrupted between two or more periods.Such a embodiment Another example is the methods for the composition that two or more ingredients are blended, wherein thermokinetics mixer shafts are with First Speed Axle speed is adjusted to second speed at this time and continues second time period by operation up to reaching the first predefined parameter, wherein mixing Processing is substantially uninterrupted between first time period and second time period, and wherein, at the end of second time period, is reaching The rotation speed of axis is changed to third speed from second speed after to predefined parameter and continues the third period.Implement at one In mode, mixed processing is substantially uninterrupted between second time period and third period.

In some embodiments, temperature-sensitive or thermo-labile component may include one or more of active pharmaceutical ingredients, one Kind or more pharmaceutically acceptable excipient or one or more of pharmaceutically acceptable thermally sensitive polymerics.In other embodiments, hot Quick or thermo-labile component may include one or more of active pharmaceutical ingredients and one or more of pharmaceutically acceptable excipients or heat Photosensitive polymerization object.In other embodiments, active pharmaceutical ingredient and one or more of pharmaceutically acceptable excipients are respectively with about 1:2 Ratio to 1:9 is added.In yet other embodiments, active pharmaceutical ingredient and one or more of pharmaceutically acceptable thermally sensitive polymerics It is added respectively with the ratio of about 1:2 to 1:9.In some embodiments, second time period can be first time period at least About 5%, 10%, 15%, 20%, 25% or more.In other embodiments, with the speed phase during first time period Than, speed during second time period improve about 100 revolutions per minute (RPM), 200RPM, 300RPM, 400RPM, 500RPM, 600RPM、700RPM、800RPM、900RPM、1000RPM、1100RPM、1200RPM、1300RPM、1400RPM、1500RPM、 1600RPM、1700RPM、1800RPM、1900RPM、2000RPM、2100RPM、2200RPM、2300RPM、2400RPM、 2500RPM or more.For example, in one embodiment, First Speed is greater than 1000RPM, and second speed is than the first speed Spend big 200 to 400RPM.In another embodiment, First Speed is greater than 1000RPM, and second speed is bigger than First Speed 200 to 1000RPM.In other embodiments, First Speed be greater than 1000RPM, second speed bigger than First Speed 200 to 2500RPM。

In one embodiment, the end of first time period substantially reaches any reality in ingredient in mixing chamber temperature The shearing transition temperature (shear transition temperature) of matter component (substantial component) or Before person's fusing point.In another embodiment, the end of first time period is predetermined amount of time, and is terminated in first time period When second speed is automatically changed to by thermokinetics mixer.In another embodiment, the end of first time period is basic On before mixing chamber temperature reaches the shearing transition temperature of active pharmaceutical ingredient in ingredient.In another embodiment, first The end of period is substantially before mixing chamber temperature reaches the shearing transition temperature of the excipient in ingredient.In another implementation In mode, the end of first time period substantially reaches the shearing transition temperature of the thermally sensitive polymeric in ingredient in mixing chamber temperature Before.

In one embodiment, the end of second time period or any subsequent period are substantially in active pharmaceutical ingredient It is subjected to before significant thermal degradation.In another embodiment, the end of second time period or any subsequent period substantially exist Excipient ingredients are subjected to before significant thermal degradation.In another embodiment, the knot of second time period or any subsequent period Beam is substantially before thermally sensitive polymeric ingredient is subjected to a large amount of thermal degradations.In one embodiment, second time period or appoint How then at the end of the period, the active pharmaceutical ingredient and excipient of ingredient are substantially unbodied.In another embodiment party In formula, second time period or any subsequent period at the end of, the active pharmaceutical ingredient and thermally sensitive polymeric of ingredient are basic On be amorphous.In other embodiments, after reaching final process parameter, axis rotation be stopped and batch or Composite material is extracted out or is discharged from mixing chamber, with for further processing.In some embodiments, in batch or composite wood Under the glass transition temperature (glass transition temperature) of at least one component of material or lower than the glass Batch or composite material are extracted or are discharged at a temperature of change transition temperature.In other embodiments, it is squeezed by hot melt Out, melt granulation, compression molding, tablet press, capsule filling, film coating or injection moulding are further processed the batch or multiple Condensation material.In other embodiments, it when RPM platform starts, such as before batch or composite material are degraded, takes out Out or discharge batch or composite material.In other embodiments, it is adjusted before extracting out or batch or composite material is discharged RPM slows down to produce batch or composite material more evenly.

Another embodiment of the disclosure is related to compound one or more of active pharmaceutical ingredients and at least one polymer Method of the pharmaceutically acceptable excipient to produce unbodied, homogeneous, heterogeneous or heterogeneous uniform composition, the method includes The First Speed thermokinetics mixed active drug ingedient and at least one polymer of mixture temperature are effectively improved in room Pharmaceutically acceptable excipient, and temperature lower than in mixture any active pharmaceutical ingredient or polymer pharmaceutically acceptable excipient cut The time point for cutting transition temperature, the rotation of mixer is increased to second speed with generate it is unbodied, homogeneous, heterogeneous or Heterogeneous uniform composition, wherein the raising is realized in the case where both not needing and stopping and mix or do not need and open room 's.In another embodiment of the disclosure, the method includes the one of mixture temperature or more is effectively improved in room Multiple speed thermokinetics mixing, are adjusted to different speed for axle speed at this time and continue different time sections, and in temperature It will lower than at the time point of any active pharmaceutical ingredient in mixture or the shearing transition temperature of polymer pharmaceutically acceptable excipient The rotation of mixer is increased to one or more friction speeds, wherein it is described raising be both do not need stop mixing and also not It is realized in the case where needing to open room.

The certain embodiments of the disclosure are related to the thermokinetics mixer for producing pharmaceutical composition, the composition Include one or more of temperature-sensitives or thermo-labile component.Multiple embodiments of mixer may include one of following or more Any combination a variety of and below: (1) mixing chamber, such as generally cylindrical mixing chamber；(2) it is disposed through in mixing chamber The axis of mandrel line；(3) it is connected to the motor of axis, which for example effectively assigns axis rotary motion；(4) from axis and with the axis The vertical one or more protruding portions or extension of long axis；(5) one or more heat sensors, it is one or more Multiple heat sensors are for example attached to the wall of mixing chamber and operate at least part of heat or temperature inside at detection mixing chamber Degree；(6) converter plant, the converter plant are for example connect with motor；(7) door in the wall of mixing chamber is set, which for example exists Effectively the content of mixing chamber is allowed to come out from mixing chamber when program is opened during running；And (8) electronic controller.? In certain embodiments, moisture absorption is kept in thermokinetics mixer.In other embodiments, thermokinetics mixes Device is designed to make the shearing during batch processed to maximize.

In some embodiments, electronic controller and temperature sensor, door and converter plant communicate.In some embodiment party In formula, electronic controller includes user input apparatus, timer, electronic storage device and display, wherein Electronic saving dress Set the processing parameter for being configured to receive two or more stages for thermokinetics mixed processing of user's input or predetermined Parameter.In one embodiment, processing parameter or predefined parameter are saved in the storage device and are shown in for handling fortune On the monitor in capable one or more stages.In some embodiments, one is met during the stage of processing operation When a predefined parameter, processing operation is moved to the subsequent stage automatically by electronic controller.In other embodiments, mixing chamber Inside be lined with internal liner (interior liner piece).Liner can be by making any stickiness of batch during processing most The material of smallization is made, for example, as stainless steel and other as steel alloy, titanium alloy (such as nitridation or nitrogenate peptide), And wear-resistant and heat-resisting polymer (such as) be made.

In an embodiment of the disclosure, at least one temperature sensor in temperature sensor detects infrared ray spoke It penetrates, such as wherein, radiation level is exported over the display as temperature.In other embodiments, predefined parameter can be with Under any one or combination: temperature, rate temperature change, axle rotary speed (for example, the rate for accelerating and slowing down), motor The rate that ampere number (amperage draw), the time in stage or batch or composite material are extracted out or left.Ability Field technique personnel will change each following parameter by routine experiment to obtain the batch or composite wood with desired characteristic Material.In another embodiment, output display can be any one or combination below: room temperature, motor rpm, The ampere number of motor circulates through the time.

In the certain embodiments of the disclosure, one or more protruding portion or extension from axis include base Portion and end, and for example, end can be can from base portion remove and base portion can be can from axis remove.Another In some embodiments, protruding portion or extension in thermokinetics mixer can be replaced, such as based on wearing and tear It splits or different batches parameter.In one embodiment, one or more protruding portion from axis or extension include Width is at least about 0.75 inch, and the angle with the axial plane of axis is one or more interarea portion parts of 15 to 80 degree. In other embodiments, one or more protruding portion from axis or extension include following one or more Interarea portion part: the width of one or more interarea portion part is at least about 0.80 inch, 0.85 inch, 0.90 English It is very little, 0.95 inch, 1.0 inches, 1.1 inches, 1.2 inches, 1.3 inches, 1.4 inches, 1.5 inches, 1.6 inches, 1.7 inches, 1.8 inches, 1.9 inches, 2.0 inches, 2.1 inches, 2.2 inches, 2.3 inches, 2.4 inches, 2.5 inches, 2.6 inches, 2.7 English It is very little, 2.8 inches, 2.9 inches, 3.0 inches, 3.1 inches, 3.2 inches, 3.3 inches, 3.4 inches, 3.5 inches, 3.6 inches, 3.7 inches, 3.8 inches, 3.9 inches, 4.0 inches, 4.1 inches, 4.2 inches, 4.3 inches, 4.4 inches, 4.5 inches, 4.6 English Very little, 4.7 inches, 4.8 inches, 4.9 inches, 5.0 inches or bigger, the angle with the axial plane of axis is about 15 degree, 20 degree, 25 Degree, 30 degree, 35 degree, 40 degree, 45 degree, 50 degree, 55 degree, 60 degree, 65 degree, 70 degree, 75 degree or 80 degree.In some embodiments, One or more protruding portion or extension control from axis are transported to protruding portion or the rotary shaft energy of extension turns The intragranular thermal energy of protruding portion is hit in chemical conversion.

In other embodiments, these sizes of one or more protruding portion or extension from axis are set The shear property for improving resistant to shearing particle swarm in batch is counted into, such as to generate substantially unformed composite material.At certain In a little embodiments, one or more protruding portion or extension from axis are dimensioned to generate at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% unbodied composite material.

Detailed description of the invention

The following drawings forms a part of this specification, and the following drawings is to further show the certain of the disclosure Aspect and including.By the detailed description in conjunction with some specific embodiments being presented herein come referring to one in these figures A or more figure, the disclosure can be better understood.

The view of Fig. 1 thermokinetics mixer assembly.

The exploded view of Fig. 2 thermokinetics mixer.

The axis radial cross-section of Fig. 3 thermokinetics mixing chamber.

The exploded view of Fig. 4 thermokinetics mixing chamber.

The analysis of Fig. 5 batch sensing temperature, the axle rotary speed as unit of RMP and motor current amperage, conduct The directly proportional measurement of energy input that axle speed enters batch is rotated with one to any moment.

The analysis of Fig. 6 batch sensing temperature, the axle rotary speed as unit of RMP and motor current amperage, conduct The measurement directly proportional as two rotation axle speeds enter the energy input of batch to any moment.

The block diagram of the thermokinetics mixer processing of two or more rotation axle speeds of Fig. 7.

The cross section of the shaft extension interarea portion part of Fig. 8 prior art.

The axial plane of Fig. 9 and axis has the cross section of the shaft extension interarea portion part of about 15 degree of angles.

The axial plane of Figure 10 and axis has the cross section of the shaft extension interarea portion part of about 30 degree of angles.

The axial plane of Figure 11 and axis has the cross section of the shaft extension interarea portion part of about 45 degree of angles.

The axial plane of Figure 12 and axis has the cross section of the shaft extension interarea portion part of about 60 degree of angles.

The alternative designs of the cross section of Figure 13 shaft extension interarea portion part.

The alternative designs of the cross section of Figure 14 shaft extension interarea portion part.

The alternative designs of the cross section of Figure 15 shaft extension interarea portion part.

The alternative designs of the cross section of Figure 16 shaft extension interarea portion part.

The alternative designs of the cross section of Figure 17 shaft extension interarea portion part.

The alternative designs of the cross section of Figure 18 shaft extension interarea portion part.

Figure 19 shows the exploded view of the thermokinetics mixer of internal liner.

The diagrammatic side view of the shaft extension top surface of the inner surface of Figure 20 and mixing chamber interaction.

Figure 21 has the perspective view of the shaft extension of variable top surface path length.

The alternative designs of the forward face of Figure 22 shaft extension.

Figure 23 describes the flow chart of alternative embodiment of the invention.

Figure 24 is improved axle rotary speed using triggering set point and/or stops of the invention the replacing of thermokinetics mixing For the high level process flow diagram of property embodiment.

The analysis graph of Figure 25 individual axis velocity batch, show by °F as unit of the temperature sensed and with RPM be The axle rotary speed and the relationship of processing time of unit, stop at the temperature platform detected wherein handling.

The analysis graph of Figure 26 individual axis velocity batch, show by °F as unit of the temperature sensed and with RPM be The axle rotary speed and the relationship of processing time of unit, wherein handling in the temperature platform for detecting second time period or detecting Crystallinity stops after reducing.

The analysis graph of Figure 27 twin shaft speed batch, show by °F as unit of the temperature sensed and with RPM be The axle rotary speed and the relationship of processing time of unit, wherein axle speed improves at the temperature platform detected, and handles The stopping when detecting the temperature of second speed time or detecting that crystallinity reduces.

Specific embodiment

Although preparation and each embodiment using the disclosure has been discussed in detail below it should be appreciated that this public affairs Open many inventive concepts that provides and can implement with a variety of different situations.Particular aspects and embodiment party discussed herein Formula be only prepare and using the disclosure illustratively, without limiting the scope of the present disclosure.

In order to help to understand the disclosure, many terms are defined below.The term being defined herein has disclosure phase The normally understood meaning of pass field those of ordinary skill.The term for not having numeral-classifier compound to modify is not intended to only refer to single entity, and Being includes the general category that can be used for the specific example illustrated.For value described herein and range, term " about " is intended to Including the variation above and below the number pointed out, the variation can obtain essentially identical result with the number pointed out.? In the disclosure, each range in a variety of ranges pointed out is intended to continuously, so that including the minimum that each range is pointed out Each numerical parameter between value and maximum value.For example, the range of about 1 to about 4 includes about 1,1, about 2,2, about 3,3, about 4 and 4. Term herein is used to describe some specific embodiments of the disclosure, but it is not using the disclosure is limited, in addition to weighing What benefit was summarized in requiring.

Term " thermokinetics is compound " used herein or " TKC " refer to thermokinetics mixing up to melt blended side Method.TKC also can be described as thermokinetics mixed processing, wherein ending processing sometimes in the point earlier than reunion.

Term " interarea portion part " used herein refers to " top surface " of shaft extension.The top surface of shaft extension is Towards the face of thermokinetics mixer mixing chamber interior walls.

Term " shearing transition temperature " used herein refers to that further energy input does not cause temperature to increase immediately Point.

Term " homogeneous, heterogeneous or heterogeneous uniform composite material or amorphous composite material " as used in this article Refer to the numerous compositions that the preparation of TKC method can be used.

Term " heterogeneous homogeneous compositions " as used in this article refers to have and evenly and uniformly divide in whole volume The material compositions of at least two different materials of cloth.

The meaning of term " bioavilability " as used in this article is that target tissue can utilize drug after applying to body Degree.The bioavilability of difference is the exploitation of pharmaceutical composition (especially comprising those of non-highly soluble active constituent) In the prominent question that encounters.In certain embodiments (such as protein formulation), protein can be water-soluble, dissolubility It is difference, non-high soluble or insoluble.It will be recognized that a variety of methods can be used in improving the dissolution of protein Degree, such as use different solvents, excipient, carrier, targeting control, the glycosylation, rouge for forming fusion protein, amino acid sequence Change, degrade, combining and add a variety of salt with one or more of salt.

Phrase " pharmaceutically acceptable " as used in this article refers to does not generate allergia or similar bad generally when administering to the human Molecular entity, composition, material, excipient, carrier of reaction etc..

As used in this article term " active pharmaceutical ingredient " or " API " can with term " drug ", " drug products ", " drug ", " liquid ", " biological products (biologic) " or " active constituent " exchange." API " is intended to as used herein Diagnosis cures, mitigates, treating or preventing offer pharmacological activity or other direct effects in disease or influence people or other animals Any component of the structure of body or any function.In some embodiments, the water-soluble of API can be the dissolution of difference Property.

The example that can be used for the API of the disclosure includes but is not limited to antibiotic, analgestic, vaccine, anticonvulsant, anti-sugar Urinate sick agent, antifungal agent, antitumor agent, anti-Parkinson's disease agent, antirheumatic, appetite inhibitor, biological response modifier, painstaking effort Pipe agent, central nervous system stimulants, contraceptive, dietary supplements, vitamin, minerals, lipid, carbohydrate, metal, amino acid (and precursor), nucleic acid and precursor, contrast agent, diagnosticum, dopamine-receptor stimulant, erectile dysfunction medicine, pregnancy agent, stomach and intestine Agent, hormone, immunomodulator, the agent of hypercalcemia disease, mast cell stabilization agent, muscle relaxant, nutritional agents, ophthalmically acceptable dose, sclerotin Raising agent, psychotherapy agent, Parasympathomimetic, Parasympatholytic, respiratory system agent, sedative hypnotics, skin With mucous membrane agent, agent for stopping smoking, steroids, sympatholytic agent, urinary tract agent, uterine relaxant, vagina agent, vasodilator, anti- Hypertension agent, hyperthyroidism agent, anti-hyperthyroidism agent, antiasthmatics and dizziness agent.In some embodiments, API be poorly water-soluble medicine or With dystectic medicine.

API can be in the form of its one or more of officinal salts, ester, derivative, analog, prodrug and solvate In the presence of." officinal salt " used herein is understood to mean the compound formed by the interaction of bronsted lowry acids and bases bronsted lowry, acid Hydrogen atom by alkali cation substitute.The non-limiting example of officinal salt includes sulfate, citrate, acetate, grass Hydrochlorate, chloride, bromide, iodide, nitrate, disulfate, phosphate, acid phosphate, isonicotinic acid salt, lactate, Salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, biatrate, ascorbate, amber Amber hydrochlorate, maleate, gentisate, fumarate, gluconate, glucuronate salt, saccharate, formates, benzene first Hydrochlorate, glutamate, mesylate, esilate, benzene sulfonate, tosilate and pamoate.For defining ionic Another method of salt can be acid functional group, such as carboxylic acid functional and pharmaceutically acceptable inorganic or organic base.Alkali it is unrestricted Property example includes but is not limited to: the hydroxide of alkali metal (such as sodium, potassium and lithium)；The hydroxide of calcium and magnesium；Other metals The hydroxide of (such as aluminum and zinc)；Ammonia；And organic amine, such as unsubstituted or hydroxyl replace an alkylamine, dialkylamine, Or trialkylamine；Dicyclohexyl amine；Tri-n-butylamine；Pyridine；N- methyl-N- ethamine；Diethylamine；Triethylamine；One (2- hydroxy-lower alkane Base amine), two (2- hydroxy lower alkyl amine) or three (2- hydroxy lower alkyl amine), such as (2- ethoxy) amine, two (2- Ethoxy) amine or three (2- ethoxy) amine, 2- hydroxy-tert-butylamine or three-(methylol) methylamines, N, bis- low alkyl group-N- of N- (hydroxyl low-grade alkyl)-amine (such as N, N- dimethyl-N-(2- ethoxy) amine) or three-(2- hydroxyethyl) amine；N- methyl D- Aminoglucose；And amino acid (such as arginine, lysine) etc..

A variety of administration method can be used for being delivered to API in patient in need.Selected particular approach depends on Dosage needed for selected certain drug, the weight of patient and age and therapeutic effect.Pharmaceutical composition can be convenient ground Exist with unit dosage forms.It is suitable for the API used according to the disclosure and its officinal salt, derivative, analog, prodrug and solvent Closing object can be administered alone, but generally and according to the selected suitable medicinal tax of expected administration method and standard pharmaceutical practice Shape agent, diluent or carrier mixing application.

API can be used with a variety of application forms, including as tablet, capsule or suspension oral delivery；Lung and Nose delivering；Surface as emulsion, ointment or cream delivers；Dermal delivery；And as suspension, microemulsion or storage cavern Potential delivery.Term " parenteral " as used in this article includes subcutaneous, intravenous, intramuscular or infusion administration method.

Can be used for composition and composite material disclosed by the invention itself potentially has some active figurations simultaneously Agent and auxiliary material such as antioxidant are normally defined the efficiency of enhancing active constituent and/or the compound of effect in this application. Can also make to have in given solution is more than a kind of active constituent, so that the particle formed comprises more than a kind of active constituent.

As noted, excipient and auxiliary material can be used for enhancing the effect and efficiency of API.The compound that may include it is non- Limitative examples are binder, cryoprotector, frozen-dried protective base, surfactant, filler, stabilizer, polymer, albumen Enzyme inhibitor, antioxidant and absorption enhancer.Excipient be can choose to change by improving flowing or bioavilability The desired use of active constituent, or control or the release for delaying API.Specific non-limiting example includes: sucrose, seaweed Sugar, this disk (Span) 80, tween (Tween) 80, polyoxyethylene aliphatic alcohol ether (Brij) 35, Brij 98, pluronic (Pluronic), sucrose ester 7, sucrose ester 11, sucrose ester 15, NaLS, oleic acid, laureth -9, laruyl alcohol are poly- Ether -8, moon silicic acid, vitamin E TPGS, Gelucire 50/13, Gelucire 53/10, Labrafil, two palmityl phosphatide Phatidylcholine, glycolic and salt, deoxycholic acid and salt, sodium fusidate, cyclodextrin, polyethylene glycol, labrasol, polyvinyl alcohol, Polyvinylpyrrolidone and tyloxapol.Use disclosed method, thus it is possible to vary the form of active constituent obtains highly porous Particle and nano particle.

The exemplary hot binder that can be used for composition and composite material disclosed in the present invention includes but is not limited to: poly- Ethylene oxide；Polypropylene oxide；Polyvinylpyrrolidone；Polyvinylpyrrolidone -co- vinyl acetate；Acrylate and first Base acrylate copolymer；Polyethylene；Polycaprolactone；Polyethylene -co- polypropylene；Alkylcellulose, such as methylcellulose； Hydroxy alkyl cellulose, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose；Hydroxyl Alkyl-alkyl cellulose, such as hydroxyethylmethylcellulose and hydroxypropyl methyl cellulose；Starch, pectin；Polysaccharide, such as west are yellow Alpine yarrow glue, Arabic gum, guar gum and xanthan gum.One embodiment of binder is poly- (ethylene oxide) (PEO), and PEO can With commercially available from such as Dow Chemical Company company, the said firm is exemplary with POLY OX.TM. brand sales PEO Rank may include the WSR N80 that weight average molecular weight is about 200,000,1,000,000 and 2,000,000.

Suitable PEO rank can also be characterized by the viscosity of the solution of the PEO containing fixed concentration, say like:

May require or not that plasticizer suitable hot binder include such as Eudragit.TM.RS PO, Eudragit.TM.S100, Kollidon SR (poly- (vinyl acetate) -co- polyvinylpyrrolidone) copolymer), Ethocel.TM. (ethyl cellulose), HPC (hydroxypropyl cellulose), cellulose acetate-butyrate, polyvinylpyrrolidone) (PVP), poly(ethylene glycol) (PEG), poly- (ethylene oxide) (PEO), poly- (vinyl alcohol) (PVA), hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), sodium carboxymethylcellulose (CMC), dimethylaminoethyl acrylate methyl base Amino ethyl ester-methacrylate copolymer, EUDRAGIT NE 30 D (GAM-MA), C-5 or 60SH-50 (Shin-Etsu Chemical Corp.), cellulose acetate phthalate (CAP), trimellitic acid acetate fiber Element (cellulose acetate trimelletate, CAT), poly- (vinyl acetate) phthalic acid ester (PVAP), hydroxypropyl Ylmethyl cellulose phthalate (HPMCP), poly- (methacrylate acrylonitrile acetoacetic ester) (1:1) copolymer (MA-EA), Poly- (methacrylate methyl methacrylate) (1:1) copolymer (MA-MMA), poly- (methacrylate methyl methacrylate Ester) (1:2) copolymer, Eudragit L-30-D.TM. (MA-EA, 1:1), Eudragit L-100-55.TM. (MA-EA, 1: 1), hydroxypropylmethylcellulose acetate succinate (HPMCAS), Coateric.TM. (PVAP), Aquateric.TM. (CAP) and AQUACOAT.TM. (HPMCAS), polycaprolactone, starch, pectin；Polysaccharide, for example, tragacanth, Arabic gum, guar gum and Xanthan gum.

Stable and non-solubilization carrier can also include several functions excipient, such as: hydrophilic polymer, antioxidant, Super-disintegrant, the surfactant including amphipathic molecule, wetting agent, stabilizer, delayer, similar functions excipient or its Combination and plasticizer (including citrate, polyethylene glycol, PG, glyceryl triacetate, diethyl phthalate, castor-oil plant Oil) and other excipient well known by persons skilled in the art.Extruded material also may include: acidulant, adsorbent, basifier, Buffer, colorant, corrigent, sweetener, diluent, opacifier, complexing agent, fragrance, preservative or combinations thereof.

May be embodied in composite material or composition disclosed herein can be primary or secondary polymer carrier Exemplary hydrophilic polymer include poly(ethylene glycol) (PVA), polyethylene glycol propylene glycol (for example, POLOXAMER.TM.), Carbomer, Polycarbophil or chitosan.Hydrophilic polymer for the disclosure can also include: hydroxypropyl methyl cellulose, Carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, natural gum (such as guar gum, I One of primary glue, tragacanth or xanthan gum) and povidone or more.Hydrophilic polymer further include: polyethylene oxide, Sodium carboxymethylcellulose, hydroxyethylmethylcellulose, hydroxymethyl cellulose, carboxypolymethylene, polyethylene glycol, alginic acid, gelatin, poly- second Enol, polyacrylamide, polymethacrylamide, poly-phosphine piperazine, gathers polyvinylpyrrolidoneOxazolidine, poly- (hydroxyalkyl carboxylic Acid), carrageenan seaweed salt, carbomer, ammonium alginate, or mixtures thereof sodium alginate.

" releasing immediately (immediate release) " means to start once discharging, and activating agent is by the several seconds to being no more than About 30 minutes time can be discharged into environment, and discharges and start in no more than about 2 minutes after application.Release immediately not table Reveal the significant delay of drug release.

" discharging rapidly (rapid release) " means to start once discharging, activating agent by 1 minute to 59 minutes or 0.1 minute to three hours time can be discharged into environment, and discharges and can start to discharge with several minutes after application, or applying Start to discharge with after rear delay time (lag time).

It is extensive to use pharmaceutical science field for " sustained release (extended release) " curve as used in this article The definition recognized.Sustained release forms will be at an essentially constant rate by release of extended period drug (that is, activating agent Or API) or the drug of substantially constant amount will incrementally discharge by the extended period.With conventional pharmaceutical dosage forms (example Such as, solution or the conventional solid dosage forms discharged rapidly) present in drug compare, continuous release tablet generally result in administration frequency Rate reduces at least 2 times.

" control release (controlled release) " mean activating agent by about 8 hours to about 12 hours, 16 hours, 18 hours, 20 hours, 1 day or the time more than 1 day can be discharged into environment." sustained release release (sustained release) " meaning Refer to levels of drugs constant in blood or target tissue of the activating agent sustained release to keep the object of application device.

" control release " about drug release includes term " sustained release ", " extended release (prolonged Release) ", " sustained release release (sustained release) " or " slow release (slow release) ", such as these terms Used in pharmaceutical science.Control release can start to discharge with several minutes after application, or delay time is (stagnant after application Time afterwards) after start to discharge.

Slow release dosage form is to provide slow drug release rate, so that drug is slow and substantially continuous discharges example Such as the dosage form of the time in 3 hours, 6 hours, 12 hours, 18 hours, 1 day, 2 days or more, 1 week, 2 weeks or more weeks.

Term " mixing release " as used in this article refer to two kinds including one or more of active pharmaceutical ingredients or The medicament of more kinds of release profiles.For example, mixing release may include releasing immediately part and sustained release portion, release immediately Each of part and sustained release portion can have identical API or can have different API.

Time controlled released (timed release) dosage form is being measured such as since at the time of becoming exposed to use environment Start the dosage form of release drug after predetermined amount of time.

Targeting delivery (targeted release) dosage form generally refers to peroral dosage form, is designed to deliver drugs into The specific part of the gastrointestinal tract of object.Exemplary target is intestines dosage form to dosage form, deliver drugs into lower intestinal tract but not Into in the stomach or mouth of object.Other targeting dosage forms can be delivered to the other parts of gastrointestinal tract, such as stomach, jejunum, ileum, ten Two duodenum 12, caecum, large intestine, small intestine, colon or rectum.

" sustained release (delayed release) " means that the initial release of drug occurred in about delay (or lag) time After end.For example, the release of drug is in composition if the drug release from sustained-release composition postpones two hours Or dosage form to object apply after start within about 2 hours.In general, sustained release is opposite with releasing immediately, wherein in releasing immediately The release of drug is no more than several minutes of beginnings after application.Therefore, the drug release patterns from particular composition, which can be, prolongs Slow sustained release or delay discharges rapidly." postpone continue (delayed-extended) " release profiles are wherein drugs Sustained release starts after initial delay time." postpone rapidly (delayed-rapid) " release profiles are wherein drugs Discharge rapidly and start after initial delay time.

Pulse release (pulsatile release) dosage form is to provide the pulse of high active ingredient concentration, and is scattered with low The dosage form of concentration paddy (trough).Pulse curve including two peaks can be described as " bimodal (bimodal) ".More than two peaks Pulse curve can be described as multimodal.

False level-one (pseudo-first order) release profiles are the curves for being similar to first-order release curve.First-order release Curve characterizes such dosage form release profile, discharges the initial drug carrying capacity (drug of constant percentage per unit time charge)。

False zero order delivery profile is the curve for being similar to zero order delivery profile.Zero order delivery profile characterizes such dosage form and releases Curve is put, discharges the drug of constant basis per unit time.

Gained composite material or composition disclosed herein can also be configured to make the drug table for the poorly water-soluble prepared Reveal the dissolution rate of enhancing.

It is the example with the composition or preparation for stablizing release profiles below.Prepare two kinds of pieces with same recipe Agent.The first tablet stores one day under the first set of conditions, and the second tablet stores 4 months under the conditions of identical first group.1 The release profiles that the first tablet is determined after its Storage period, determine the release profiles of second of tablet after 4 months Storage periods. If the release profiles of the first tablet are roughly the same with the release profiles of second of tablet, then it is assumed that tablet/film preparation has Stablize release profiles.

It is another example with the composition or preparation for stablizing release profiles below.Preparation is respectively contained according to the disclosure Composition tablet A and B, and preparation respectively contain not the tablet C and D according to the composition of the disclosure.Tablet A and C is each From storing one day under the first set of conditions, stored three months under the conditions of each leisure of tablet B and D is first group identical.It was stored at 1 day The respective release profiles of tablet A and C are determined after phase, and are referred to as release profiles A and C.After trimestral Storage period really The respective release profiles of stator agent B and D, and it is referred to as release profiles B and D.It difference between release profiles A and B and releases Curve C is put to quantify as the difference between D.If the difference between release profiles A and B is less than between release profiles C and D Difference, then it is assumed that tablet A and B provide stable or more stable release profiles.

Particularly, TKC processing can be used for following one or more of medicinal applications.

The dispersion of one or more of API is used to API passing through oral, transpulmonary, parenteral, Via vagina, per rectum, warp Urethra, percutaneous or surface route of delivery are delivered to patient, wherein the API is small organic molecule, protein, peptide or multicore glycosides Acid, the dispersion is in polymer and/or the pharmaceutically acceptable material of non-polymer.

The dispersion of one or more of API be used for by improve API bioavilability, extend API release, will The privileged site of the release targeting gastrointestinal tract of API postpones the release of API or generates the pulse releasing system of API to improve API's Oral delivery, wherein the API is small organic molecule, protein, peptide or polynucleotides, the dispersion in polymer and/or In the pharmaceutically acceptable material of non-polymer.

The dispersion of one or more of API is used to generate the implantation of biological erodable, biodegradable or controlled release Delivery apparatus, wherein the API is small organic molecule, protein, peptide or polynucleotides, the dispersion in polymer and/or In the pharmaceutically acceptable material of non-polymer.

The solid dispersions of thermo-labile API are produced by handling the very short duration at low temperature.

The solid of API in thermo-labile polymer and excipient is produced by handling the very short duration at low temperature Dispersion.

Keep small organic API amorphous, while being dispersed in polymer, non-polymer or combination excipient carrier system.

Dry grinding crystalline A PI is to reduce the partial size of bulk material (bulk material).

The partial size of bulk material is reduced using acceptable solvent wet lapping crystalline A PI.

Utilize one or more of melting drug excipient fusing grinding knots with crystalline A PI with limited miscibility Brilliant API is to reduce the partial size of bulk material.

Crystalline A PI is ground in the presence of polymer or non-polymer excipient to generate ordered mixture, wherein thin medicine Composition granule is attached on the surface of excipient granule and/or excipient granule is attached on the surface of thin drug granule.

Generate the heterogeneous uniform composite wood for post-processing two or more drug excipients for example ground and sieved Material or amorphous composite material, are used subsequently to well known to a person skilled in the art secondary pharmaceutical operations, for example, film coating, system Piece (tableting), wet granulation and dry granulation roll (roller compaction), hot melt extrusion, melt granulation, molding Molding, capsule filling and injection moulding.

Generation is previously considered to be the single-phase of two or more immiscible drug materials and mixes composite material use In secondary treatment step, such as melt extrusion, film coating, film-making and granulation.

Preplasticizing polymer material is operated for subsequent use in film coating or melt extrusion.

Keep crystallization or the hypocrystalline pharmaceutical polymer of the carrier that may be used as API amorphous, wherein amorphous feature improves The dissolution rate of API- polymer composites, the stability of API- polymer composites and/or API and polymer can Combination.

Make to be engineered particle depolymerization and is dispersed in the characteristic in polymer support without changing engineering particle.

The API of powder type and one or more of drug excipient simple blends.

Without using the production of processing auxiliary agent comprising one or more high-melting-point API and one or more intolerant to thermopolymer Composite material.

It is dispersed in colorant or opacifiers in polymer support or excipient blend.

Disclosure preferred embodiment it is described in detail below in, with reference to the figure in attached drawing, wherein phase in different figures Same number refers to same or like part.

This disclosure relates to novel thermokinetics mixer and mixed method, temperature-sensitive or thermo-labile component can be blended and A large amount of thermal degradations do not occur.Particularly, the disclosure can be used in processing include thermo-labile component mixture, these thermo-labile group Divide the accumulation heat input for being exposed to fusion temperature or limiting time section and causes to degrade.One embodiment of the disclosure is related to using By the continuous melt blended method of self-heating mixture in the mixing chamber in high speed thermokinetics mixer, wherein reaching the After one expectation or predetermined process parameter, First Speed is changed to second speed in processes.In other embodiments, After reaching the second expectation or predetermined process parameter, second speed is changed to third speed in processes.Additional speed changes Also within the scope of this disclosure, several expectations as needed for it is expected composition or composite material by production or predetermined process are joined for change Indicated by number.

This method particularly suitable for: by under multistage speed with the low-temperature treatment very of short duration duration come produce intolerant to The solid dispersions of hot API；By thermo-labile poly- to produce with the low-temperature treatment very of short duration duration under multistage speed Close the solid dispersions of API in object and excipient；By under multistage speed with the low-temperature treatment very of short duration duration come Produce the solid dispersions of API in thermo-labile excipient；And by being held under multistage speed with low-temperature treatment is very of short duration The continuous time produces the solid dispersions of thermally sensitive polymeric.

One embodiment is to be reached in the thermokinetics processing of batch using two or more friction speeds with reducing The processing time needed for after to the shearing transition temperature of a part of batch.Another embodiment is the thermokinetics in batch The processing time needed for batch reaches after certain temperature is reduced using two or more friction speeds in processing, in the temperature Later, by causing the one of the batch with a large amount of thermal conductivities of shaft extension and/or the generation of the CONTACT WITH FRICTION of the inner surface of mixing chamber Kind or more component thermal degradation, and reduce speed.Another embodiment is used in the thermokinetics processing of batch Two or more friction speeds are passed through after the temperature with reducing the processing time needed for batch reaches after certain temperature The big calorimetric generated with shaft extension and/or the CONTACT WITH FRICTION of the inner surface of mixing chamber does not cause batch bulk temperature to change.Separately One embodiment provides the thermokinetics processing method using two kinds of speed, with reduce batch thermo-labile so handled or The thermal degradation of thermally sensitive polymeric or component.

In one embodiment, at least part of batch includes temperature-sensitive or thermo-labile group in super mixer mixing chamber Point, it is necessary to it basically prevents or limits it and be exposed to limiting temperature or the maximum cumulative heat Jing Guo limiting time section, to obtain The melt blended batch of the acceptable degradation of temperature-sensitive or thermo-labile component.In this embodiment, start and end in processing Between carry out at least once speed change so that be no more than limiting temperature or limit heat input, to save composition or compound Temperature-sensitive or thermo-labile component in material.

Thermo-labile component includes but is not limited to heat labile API, excipient or polymer.Thermally sensitive polymeric includes but unlimited In nylon, polypropylene terephthalate, PB Polybutene-1, polybutylene terephthalate (PBT), polyethylene terephthalate Ester, polyolefin (such as polypropylene and high density or low density polyethylene (LDPE)) and its mixture or copolymer, the polymer can be by It is formed on surface and bulk polymer defect and squeezes out limitation.Other thermally sensitive polymerics include poly- (methyl methacrylate), bunching Aldehyde, poly- ionomer, EVA copolymer, cellulose acetate, hard polyvinyl chloride and polystyrene or its copolymer.According to polymer Known degradation temperature, can be by selecting the temperature holding of batch sensed to be used for such heat within an acceptable range Limiting temperature in the disclosed method of photosensitive polymerization object, for example, about 5 DEG C, 10 DEG C, 20 DEG C, 25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80 DEG C, 85 DEG C, 90 DEG C, 95 DEG C or 100 DEG C, it is known in the art from described Degradation takes place in the expectation processing parameter that temperature starts thermally sensitive polymeric.

One embodiment of the disclosure is for being continuously blended in the mixing chamber of super mixer and melting self-heating The method of mixture, wherein First Speed to be changed to in processes after reaching the first expectation or predetermined process parameter Two speed.In one embodiment, second speed is kept until reaching final expectation or predetermined process parameter, axis rotates at that time It is stopped and melt blended batch is extracted out or is discharged from mixing chamber, with for further processing.It is being changed to second speed Axis is worked between stopping axis rotation with one or more intermediate rotation speeds.The processing parameter for determining that axle speed changes is pre- Fixed, and can sense and show, calculate, speculating or otherwise being determined with reasonable certainty, so that mixed in high speed Speed change is made during single rotation continuous processing of batch in the mixing chamber of clutch.Processing parameter include but is not limited to temperature, Motor RPM, ampere number and time.

Present disclosure also relates to thermokinetics mixer, which can be blended temperature-sensitive or thermo-labile component, Without a large amount of thermal degradations occur.One embodiment of thermokinetics mixer has high pass filter motor, the high pass filter motor The trunnion axis with dentation protruding portion is driven to rotate, wherein the dentation protruding portion extends outwardly along the rotation axis normal direction of axis. Axis is connect with drive motor.Being partly comprised in the closed container that composition operation occurs including protruding portion of axis, that is, be included in In thermokinetics mixing chamber.The high rotation speed of axis assigns processing material kinetic energy plus the design of axis protruding portion.Temperature sensor Sense the temperature in thermokinetics mixing chamber.Once having sensed set temperature, First Speed is just changed to second speed.

Fig. 1 shows the view of an embodiment of disclosed thermokinetics mixer assembly.Temperature sensor 20 It is connected to thermokinetics mixing chamber MC.Temperature sensor 20 provides information for programmable logic controller (PLC) 20a, these information are shown On programmable logic controller (PLC) display 20b.Drive motor 15 controls the speed across the mixing chamber MC axis rotated.Drive horse It is controlled up to 15 by variable frequency drives 20c.Variable frequency drives 20c also provides information for programmable logic controller (PLC) 20a, these information It is shown on programmable logic controller (PLC) display 20b.When meeting desired processing parameter, programmable logic controller (PLC) 20a It is signaled to variable frequency drives 20c to change the frequency for the electrical power for being supplied to driving engine 15.Drive motor 15 changes axis Axle speed.Temperature sensor 20 can be the sensor for distributing radiation out about sets of batches.

Fig. 2 shows the exploded views of an embodiment of thermokinetics mixer.Frame 1 support associated components so that Shaft assembly 2 is inserted in the axis hole by end plate 3 and the axis in the feed screw hole across end plate 4, the two end plates define The bottom of the closed end of mixing chamber cylinder, cylinder is limited by the inner surface of lower case 5.Lower case 5 is included in Dump gate The release opening that (discharge door) 6 is closed during working.Upper housing 7 includes the top of mixing chamber internal surface cylinder.Into Material shell body 8 is adapted to allow for supplying material to the feed screw of shaft assembly, so that these materials are with the rotation phase with feed screw In conjunction with mode by from external feeding device pressure be compressed in mixing chamber.Door 6 can be around Dump gate pivotal pin 9 with the side of rotation Formula is closed.End plate 3 has the rack gear-pinion gear cylinder 18 being attached to thereon, is equipped between end plate 3 and rack gear-pinion gear cylinder 18 Gasket 10.Peace turns have bracket 11 at the top of shell 7, and the bearing of bracket 11 is used for the infrared temperature sensor 20 of mixing chamber. Door protective device 12 protects the door 6 of sometimes high temperature to contact to avoid people with the accident of releasable material.Rotate 13 He of protective device Driving connection protective device 14 prevents human operator from contacting during operation with rotary part.Drive motor 15 is preferably to have Enough power completes the motor of disclosed operation.Axis platform 16 and 17 supports shaft assembly 2.

In the example of the system for the processing parameter that wherein measurement decision axle speed changes in mixing chamber and/or drive motor In, Fig. 7 shows the block diagram flow chart of disclosed processing, and wherein mixing chamber MC is by being pivotally connected to drive motor 42, wherein The rotation speed of the control drive motor 42 of variable frequency drives 41.In some embodiments, axle speed can from 0RPM to 5000RPM.In addition, programmable logic controller (PLC) 40 determines rotation axle speed using variable frequency drives 41 according to disclosed processing It spends and changes rotation axle speed.Programmable logic controller (PLC) 40 includes the set point of user's input, to change driving for determining The needs of the rotation axle speed of motor 42 and the rotation processing addition loaded to the transmission of variable frequency drives 41 instruction and in batch Change the speed after into mixing chamber.Programmable logic controller (PLC) may include the microprocessor containing memory, wherein this is deposited Reservoir includes suitable for reaching user's dependence by the setting of drive motor 42 and/or mixing chamber MC the sensing data input transmitted The control program acted on after point, and programmable logic controller (PLC) includes that user interface such as programmable logic controller (PLC) is shown Device, the user interface are observed for user by drive motor 42 and/or mixing chamber the MC duration of runs transmitted and sensing data.It can Programmed logic controller optionally includes following methods: this method for user in view of predetermined process parameter (such as operating when Between) after or by predetermined process parameter and sensing data (such as the batch that is transmitted by drive motor 42 and/or mixing chamber MC Temperature, ampere number and axle speed) conveying sensing data compare, be directly changed motor axle speed.Programmable logic control Device processed is optionally included in microprocessor with predetermined, storage processing parameter (such as duration of runs) operating or will make a reservation for, store up The processing parameter deposited and sensing data (such as the batch temperature, ampere transmitted by drive motor 42 and/or mixing chamber MC Several and axle speed) conveying sensing data relatively after change the autocontrol method of motor axle speed.

The component of an embodiment of the thermokinetics mixer for disclosed processing is shown in Fig. 3 and Fig. 4 Description.Fig. 3 shows the axis radial cross-section of the mixing chamber MC of the thermokinetics mixer for the disclosure, and half 5 and 7 engages And tubular mixing chamber is formed, axis 23 rotates on the axial length of room along direction of rotation 24.Shaft extension 30 is from it on axis 23 The place of being detachably connected extend close to the position of inner surface 19.Shaft extension 30 includes top surface 22 and forward face 21.Particle 26a to 26e shows shock of these particles on axis protruding portion 30 and inner surface 27, and such shock by such by being hit It hits the shearing of generation and particle is caused to crush and/or frictionally heat.In addition, Fig. 4 is extension and mixing chamber shown in Fig. 3 Exploded view, wherein shaft extension 30a, 30b and 30c respectively with top surface 22 and forward face 21 are limited on replaceable tooth, These replaceable teeth are suitable for being fixed to sufficient shape part part 31 by bolt 33.Part 31 is suitable for the bottom 32 via part 31 in slot Axis 23 (continuing from motor drive shaft 34) is fixed in replaceable mode at 35.Fig. 4 shows that particle is encountering shaft extension 30a extremely It is generally moved along direction 37 when 30c.Shaft extension 30a is shown as effective with the forward face relative to shaft extension 30b and 30c The forward face 21 of alignment.

For typical batch processing, user selects two kinds of components first, both components for example may include thermo-labile API And polymeric excipient.Then the shearing transition temperature of two kinds of components is empirically determined in user.User will be in programmable logic control Setting processing parameter (temperature, RPM, ampere number and time) is turned in device processed with the shearing for being suitable for component in the processing parameter First Speed is set to be changed to second speed when temperature.Any set point of user's input may be used as the second speed period Halt later.

Fig. 5 shows method of disclosure and using certain potential between the thermokinetics mixed method of substantially single axle speed Difference.Fig. 5 shows batch sensing temperature, the axle rotary speed as unit of RPM and any moment in processing and is input to The figure of the ampere number of the directly proportional measurement of energy in batch.As a specific example, the following combination of thermokinetics processing Object is to form griseofulvin: the batch of PVP (1:2 ratio), and batch size is 60 grams.Griseofulvin represents thermo-labile API.PVP Represent excipient.A series of three tests show thermokinetics in Fig. 5 and similar with shown in Fig. 3 and Fig. 4 in structure Carried out in mixer, wherein forward face 21 is prominent on direction of rotation forward and transverse width is about 1.0 inches, and keep with The plane and height that about 30 degree of leading edges for exiting through forward face 21 are stretched out from the axis of axis 23 are about 2.5 inches.Batch in Fig. 5 Secondary to handle under the conditions of thermokinetics self-heating, which use substantially single axle speeds.Y-axis is suitable for temperature (value is multiplied by 10) With the axle speed as unit of RPM (value is multiplied by 30).Time in x-axis is with 0.1 second for increment.If the composition of the batch with Be significantly higher than rotation axle speed --- that is, 2500RPM or higher --- the thermokinetics mixing of speed shown in Fig. 5, then it is final to produce The inspection of product is shown to be unacceptable crystallization and insufficient amorphous.Should the result is that those skilled in the art beyond expection 's.The thermokinetics higher axle speed of mixing art teaches ensures preferably to mix, but it is in the higher of these materials There is no occur under axle speed.When in lower rotation axle speed as shown in Figure 5 as processing example batch composition when, The inspection of final products shows that it is that abundant unbodied and bioavilability is abundant.But have occurred thermo-labile API can not The thermal degradation of receiving, this causes batch unacceptable.

In Fig. 5, in the zero-time, ampere number is increased to 35 amperes (1050 in figure) immediately.The discharge of batch is About 17.6 seconds, or when RPM is significantly reduced.Rotation axle speed is set as 1800RPM, and reaches in about 2 seconds of beginning The speed.In about 7 seconds, batch temperature reaches 260 °F, the shearing transition temperature of excipient.Change temperature higher than the shearing The shearing resistance of degree, excipient significantly reduces, and by particle and melted material to protruding portion surface and mixing chamber internal surface Shock and be transported to the energy in batch be then significantly reduced (when batch temperature reach shearing transition temperature when, electric current peace Training number is reduced to about half).From about 7 seconds to about 16 second, the batch temperature of composition while batch constant absorption big energy Degree does not increase.This raised energy conversion of temperature that do not result in is at thermo-labile or heat sensitive components thermal degradations.The test one As property confirmed the significant quantity component once in the melt blended batch of thermokinetics --- i.e. be greater than 5 weight percent, 10 weight Percentage, 20 weight percent or 30 weight percent --- reach it and shears transition temperature or fusing point, what entire batch absorbed A large amount of thermal conductivities cause thermo-labile or heat sensitive components thermal degradations, rather than increase entire batch temperature.This obviously shows 7 in Fig. 5 To 16 seconds time ranges, batch temperature actually reduced and has lasting energy input into batch at this time.

Use batch identical with Fig. 5 and thermokinetics mixer in Fig. 6, but used in continuous rotation batch processed Two speed.In Fig. 6, the programmable logic controller (PLC) for being connected to infrared sensor and variable frequency drives is used for detection batch Batch temperature is compared by secondary temperature with predetermined set-points, and the rotation axle speed of thermokinetics mixer is changed automatically Become another speed, lasting processing is until discharge batch by opening bottom release door.First Speed is set as 1800RPM, second speed are set as 2600RPM.The predetermined set-points of batch temperature are selected as substantially below excipient shearing and turn Horizontal 200 °F of temperature.It in the preferred embodiment, can be in the advance for the shearing transition temperature for reaching substantive component Scanning frequency degree changes, and system needs the batch temperature sensed to be sent to programmable logic controller (PLC) and the practical change of axle speed Between response time.As shown in Figure 6, there is no that the energy for being input to batch is not used in makes whole batch temperature liter It is high.The batch of processing shows substantially completely amorphism, and can not detect in about 6.5 seconds entire processing time API thermal degradation.The processing time of the time and 17.6 seconds in Fig. 5 form sharp contrast.

Fig. 6 shows substantive component or a part of the axle rotary speed in thermokinetics batch of certain thermo-labile components It when reaching shearing transition temperature or fusing point or should significantly improve before, the processing time later should minimize.In certain embodiment party In formula, First Speed should improve about 100RPM, 200RPM, 300RPM, 400RPM, 500RPM, 600RPM, 700RPM, 800RPM, 900RPM, 1000RPM or more and become second speed.In other embodiments, after second speed starts to batch from Mixing chamber release the processing time should be batch First Speed handle total time about 5%, 10%, 15%, 20%, 25% or More.

Well known in the art, the shock of particle on the surface assigns particle energies.Thermokinetics self-heating mixer One feature is to provide the shock to the particle containing polymer, thus the energy of imparting is partially converted into thermal energy with soften and/ Or melt these polymer.But thermokinetics mixing field general guide those skilled in the art are hit with that cannot finely control The mode of thermal energy can be converted to by, which hitting, provides shock of the particle in thermokinetics mixer.The disclosure is provided and is described for this The method of the control of sample.Highly cross-linked polymer and heat-curable compounds is very difficult to soften and melt, also exactly because of the original Cause is preferred, that is, highly cross-linked polymer and heat-curable compounds is resistant to breakage.But some dynamic using heat In some combinations of the component of mechanics mixed processing, highly cross-linked polymer and heat-curable compounds show bid value.It is true On, due to the fusing and blending of resistance to any other modes, thermokinetics mixing substantially handles high cross-linked polymer and thermosetting The unique method of property material.Field is mixed in thermokinetics, will improve rotation axle speed and/or processing Understanding Time is that can use Enough Impact energies are converted to thermal energy to cause softening or molten state for further processing in induction refractory fluidized polymer Method.Present embodiment, which discloses, can effectively control the device and method that Impact energy is converted to thermal energy.

Two main impact surfaces --- forward face and top surface of axis --- are controlled in thermokinetics mixer and are hit It hits and is converted to thermal energy.The two surfaces are that (volume is hereinafter also referred to as the volume for protruding outward mixing chamber of shaft extension " main process task volume " comprising from the inside cylindrical wall of mixing chamber radially-inwardly about 1 inch of most of confined area) 30% Or the facial parts of the internal cylindrical surface of less facial parts and mixing chamber itself.Change mixing chamber internal cylindrical surface Be not practicability selection, be since the surface is fixed, and the surface must keep smooth and keep uniform cylindricality with It resists the accumulation of melted material and allows to contact with movement by the self-heating that sliding and slidingtype occur for the particle of mixer room.

The disclosure is transported to extension using the variable for the top surface of shaft extension being projected into main process task volume to control The rotary shaft energy in portion is converted to the intragranular thermal energy hit with the part.It has been found that changing the width of interarea portion part Spend and leave axis axial plane angle provide be transported to the part hit particle shearing controllable variations, after And the axis energy for being converted to thermal energy is controlled, these thermal energy can be used in softening or melting the poly- of the particle in thermokinetics mixing chamber Polymer portion.

Referring again to Fig. 3 and Fig. 4, as long as discovery particle is in mixing chamber, accumulating the shearing being subjected to will lead to heat power Learn mixed self-heating phenomenon, the shearing by the shape and size on the direction of rotation facial parts surface of the extension from axis with And mixing chamber internal surface determines.Substantially all particles during axis rotates in mixing chamber are all in 30% volume of outside of inner space In, i.e. the centrifugal force holding particle and melted material of extension rotation leave the central volume of mixing chamber.Therefore, it is necessary to design The thermokinetics mixing chamber of effect, so that the distal portions of shaft extension are formed as realizing direct high shear (extension end front On face), indirect high shear (mixing chamber internal surface on) and material centrifugation is maintained at three kinds of functions in mixing chamber external volume.Axis The top surface of extension 30a to 30c forms generally vertical rectangular portion, the plane angulation of the rectangular portion and the axis by axis 23 Degree setting.It has been found that changing the simple rectangular portion of axis or width, angle or the unexpected improvement of shape of bow-shaped leaves and controlling The accumulation shearing for making the particle being transported in the mixing chamber of thermokinetics mixer is then provided to temperature-sensitive in processing batch Or the control of the assigned thermal energy of thermo-labile component and desired heat input.

For these specific comparisons of the operation of the heat power mixer with several interarea portion part configurations, it is assumed that logical Energy input and the axle rotary speed for crossing axis are roughly the same, and the number of shaft extension and its in mixing chamber along shaft length Interval it is essentially identical.Therefore, compare the influence that display is changed to interarea portion partial shape.

In general, the length relative to interarea portion part, which reduces width, improves the axis energy for being converted to thermal energy, these heat The polymer moieties of particle in thermokinetics mixing chamber can be used to soften or melt.Width has to be larger than minimal-contact width So that particle is subjected to hitting along the sliding of width, particle is induced " to slide " or assign the CONTACT WITH FRICTION of energy, is hitting institute The period for stating part rolls and sliding.Only normal graze of the particle on surface impinges upon the heat assigned for softening or melting Relative nullity in dynamics self-heating energy.But in some cases, sometimes with interarea portion part handle be easy fusing and Thermo-labile or thermally sensitive polymeric provides only such graze and hits (glancing inpact) with to being applied to the component Heat provides more controls.It is consistent with this introduction, usually using the axial plane minimum angles with axis (for example, at least 10 degree or extremely Few 15 degree) the interarea portion part processing of the minimum widith (at least 0.25 inch) of alignment is difficult to or resisted through application heat and softened Or fusing polymer, the time of contact with essentially identical energy input is provided, so as to by these energy be distributed into sliding and Rotary motion improves the self-heating of particulate polymers content.

At present in DraiswerkeThe design of the shaft extension found in thermokinetics mixer has Fig. 8 Shown in cross section 50, cross section 50 has the totality substantially spiral that circular interarea portion part 51 and width are about 2 inches Shape shape.The design it is not significant to be directed toward the relative shear 52 shown in several short arrows of interarea portion part 51.Therefore, this Device melts the molten of substantially resistance to softening or fusing to generate the heating of enough thermokinetics improving processing time and shaft power It is relatively expensive in terms of body polymer blend.Therefore, have the thermo-labile or thermally sensitive polymeric of such resistance opposite for handling It is insufficient.Thermokinetics mixing field does not propose the width that the axial plane relative to axis changes interarea portion part or angle to poly- The thermokinetics processing for closing object has any influence.The disclosure discloses such some embodiments in Fig. 9 to 12.

Fig. 9 to Figure 12 respectively illustrates interarea portion partial cross sectional 53 to 56, cross section 53 to 56 have it is of same size and With its represented by extension axis axial plane at 15 degree, 30 degree, 45 degree and 60 degree angles interarea portion part 57 to 60.It is main Projection width of the facial parts 57 to 60 on axis axial plane indicated respectively with length 65 to 68 and with relative shear 61 to 64 is directly related, wherein improve interarea portion part in the case where same widths reduces relative to the angle of the axial plane of axis Projection width in plane and unexpectedly improve same axis power input, on rotation axle speed and axis between extension Away from the relative shear in the case where with arrangement.Utilize the disclosure, it now is possible to control and pass through in thermokinetics mixer extension Convey the self-heating of shearing.Interarea portion partial width is reduced while keeping the angle relative to the axial plane of axis to maintain Thermokinetics handles total heat input in batch, and improves any list along the projection length of the axial plane of axis by reducing The shearing of only particle.

Therefore, now by thermokinetics self-heating be mixed and blended processing polymer shear strength can with pass through The relative shear energy that shaft extension assigns in mixer matches.As very common, when the polymers compositions packet in batch When both polymer containing high shear and low sheraing polymer, needs further to design and refine.It provides and is suitable for high shear component The shearing that interarea portion part assigns can convey too many thermal energy to low sheraing component.In this case, low sheraing component is inclined to It is rolled in softening and along the width of interarea portion part, so that the heat of generation is further improved, and high shear component is tended to It is easier to leave the surface.Such case may tend to cause not exclusively to mix, wherein the fusing of high shear component it is insufficient or Low sheraing component overheat.Still also need to realize the master of the high and low shearing component conveying optimizing shear into thermokinetics batch Facial parts design.

It has been found that increasing interarea portion partial width realizes the optimization.It is being 15 degree to 80 degree with the axial plane of axis Under angle, the interarea portion part that width is at least 0.75 inch is the traveling of both high and low shear polymer solution components in batch Enough paths are provided, so that high shear component is kept with the sliding of sufficiently long interarea portion part and gliding contact to generate heat And heat is absorbed to soften, to be blended with low sheraing component from low sheraing component.

The alternative designs of interarea portion part are shown in Figure 13 into Figure 17 respectively, and Figure 13 is to Figure 17 shows interarea portion portions Divide cross section 69,72,76,80,84 and 87.Figure 13 shows cross section 69, cross section 69 include forward position acute angle surface 70 backward Obtuse angle surface 71 is extended to, so that providing the first low shear surface is connected to high shear surface.Figure 14 shows cross section 72, horizontal Section 72 includes that forward position acute angle surface 73 extands rearward to 90 degree of surfaces 74, and the latter transfers to extand rearward to tail portion acute angle surface 75, so that providing the first low shear surface is connected to high shear surface and low shear surface.Figure 15 shows cross section 76, transversal Face 76 includes that forward position acute angle surface 77 extands rearward to obtuse angle surface 78, and obtuse angle surface 78 extands rearward to tail portion acute angle surface again 79, so that providing the first low shear surface is connected to high shear surface and low shear surface.Figure 16 shows cross section 80, transversal Face 80 includes that forward position obtuse angle surface 73 extands rearward to acute angle surface 74, and acute angle surface 74 extands rearward to tail portion obtuse angle surface again 75, so that providing the first high shear surface is connected to low shear surface and high shear surface.It is transversal Figure 17 shows cross section 84 Face 84 includes forward position and upward arcuate surfaces 85, arcuate surfaces 85 extand rearward to tail portion and downward 86 degree of tables of arcuate surfaces Face 71, arcuate surfaces 86 extand rearward to tail portion acute angle surface 75, so that providing the first low shear surface is connected to more high shear Surface and more low shear surface.Figure 18 shows cross section 87, and cross section 87 includes forward position acute angle surface 88 and tail portion acute angle table Face 89, so that providing the first low shear surface is connected to higher or lower shear surface --- the shearing depending on batch component.

According to the introduction of these above-mentioned embodiments, is contacted in offer with the thermokinetics of particle in mixing chamber and make it In impingement mix device internal cylindrical surface, the top surface 22 of Fig. 4 is important element.

Figure 19 shows another important embodiment of the dynamics mixer of the disclosure, and wherein half 5 and 7 and door 6 exist Inside is respectively lined with internal liner 5a, 7a and 6a.Liner is suitable in the operation process of mixer and in half 5 and 7 and door 6 Surface is closely positioned adjacently, to provide any in the acceleration desired many groups of thermokinetics frictional contact surfaces of particle One kind, the expectation surface are selected from the material of any suitable of liner 5a, 7a and 6a or optimization.Figure 19 shows adjacent thereto The exploded view of (when installation) part separated liner 5a, 7a and 6a.Half 5 and 7 is bolted together so that liner 5a It is fixed to serve as a contrast the inner surface in these half 5 and half 7 with 7a.The hole of the end of liner 6a allows liner 6a to be bolted To door 6.In thermokinetics mixer well known by persons skilled in the art, the inner surface of mixing chamber, which is limited to have, to be surrounded and closes Those of enough mechanical and calorific intensitys needed for the thermokinetics operating of such mixing chamber steel alloy.It is thus known that heat it is dynamic The processing capacity of mechanics mixer is only limitted to not attach to excessively the slippery inner surface of the steel alloy of mixing chamber and at the same time beneficial Ground, which is hit, those of frictionally heats mixture on these surfaces to provide for the particle in mixture.In addition, thermokinetics is mixed Even if relatively small slight abrasion, which may also be significantly changed, on clutch mixing chamber internal surface generates thermokinetics to indoor particle The efficiency of heating, wherein the distance between shaft extension and the inner surface of mixing chamber are specifically designed as optimization by mixing chamber The thermokinetics of the interaction of the particle moved between inner surface and shaft extension heats.Therefore, such mild wear can Need replacing the group of entire relatively expensive half 5 and half 7 in such thermokinetics mixer.Embodiment of the present invention disappears In addition to such expensive cost.Liner 5a, 7a and 6a are much more relatively cheap than half 5 and 7 and door 6 on replacement cost.Liner Replacement it is very simple and quick.Preferred liner composition comprising stainless steel (alloy with the chromium greater than 12 weight percent) with And other such steel alloys, titanium alloy (such as peptide nitrogenize or nitrogenate) and wear-resistant and hot polymer (ratio Such as).Another embodiment of the disclosure provides the non-smooth inner surface of liner 5a, 7a and 6a, for example, formed about Liner 5a, 7a be parallel with the internal cylindrical surface of 6a or helicla flute, surface texturizing (texturing) and/or electropolishing.Lining The such material and texture of piece 5a, 7a and 6a are intended to be optimized or desired balance of properties, and the balance of properties will reduce Thermokinetics fusing the undesirable of particle sticks and/or promotes between shaft extension and the inner surface of liner 5a, 7a and 6a The thermokinetics CONTACT WITH FRICTION of the mixing chamber particle of operation.

Passing through the material for selecting liner 5a, 7a and 6a or texture to obtain the another of the disclosure of thermokinetics mixing purpose It, can be by changing similar material with the inner surface those disclosed for being just directed to liner 5a, 7a and 6a in one embodiment Composition and/or texture adjust the shaft extension of preceding striking face including shaft extension and top striking face.

Another feature of the disclosure is, the top surface of shaft extension, at least a small amount of height that extends back and prolong higher than axis The height of the forward face of extending portion hits face (face 22 of Fig. 3 and Fig. 4) those of on it to form ramp structure and indoor particle It is to mix the main positions worn in chamber internal surface.Design of the consequence of the discovery for shaft extension in thermokinetics mixer It is meaningful.It has been found that such top surface has the function far different with forward face.The forward face of shaft extension along Its width being rearwardly directed to pulls particle, causes substantially to drive particle along the axis direction of drive shaft.Such axis drives Then dynamic particle tends to encounter another forward face of the shaft extension of another line behind shaft extension.By axis rotation driving with The movement of the particle of face contact is far different at the top of shaft extension, compared with the forward face of shaft extension, in such movement Impart the bigger friction thermokinetics energy of particle.

Figure 20 shows side view (the axis side for the axis that shaft extension 30 is installed of the removable portion of shaft extension 30 To view), the figure shows forward faces 21 and top surface 22.Reference altitude 30b to 30d is measured from datum level 30a.Before Portion face 21 or top surface 22 are not shown in the plan view, but are shown with its projection in the axis side view of axis.Top Face 22 includes leading edge, which is increased to height 30b from height 30c, and is hereafter bent upwards backward higher to having The similar inclined back edge of height 30d.The only a part inner surface of half 7 is shown as separating with top surface 22, and part P1 is extremely P4 indicates to impinge upon on top surface 22 and then impinge upon the path of the particle of the inner surface of half 7 first.Have been found that mixing chamber Greatest wear region in any interior surface is along the leading edge indicated by the line from height 30c to 30b --- that is, particle Rum point at the P1 of part --- region backward.Most of kinetic energy is obviously converted to friction of the particle in the region and adds Heat, as the noticeable wear by the hardened surface proves.Compared with starting along proximal edge at height 30c, top surface 22 increase at it along the distal edge of height 30b to 30d rapider, cause along part P2 and from height 30d to half 7 The relatively long friction travelling route of the particle of inner surface inclined-plane transmitting.In part the inner surface friction of P3 and half 7, rotate and drag After dragging contact, the particle heated extensively is rebounded from the inner surface of half 7 to be contacted again the top surface of another shaft extension.Portion The length of P2 is divided substantially to control the friction required for the thermokinetics mixing and fusing of granules batch in disclosure mixing chamber Heating time.The disclosure includes selection shaft extension, and the extension provides in thermokinetics mixing for shock particle longer Or the top face contact path of short length and the deviation angle, so that the significant or most of indoor particle is frictionally heated contact control In desired batch temperature.

Figure 21 shows the perspective view of the particular implementation of the shaft extension of Figure 20,21 He of forward face with spill Top surface 22, the forward face 21 and top surface 22 of spill can generate the part for being respectively used to the variable-length of part P3 ' and P3 " P2 ' (longer) and P2 " (shorter).In some embodiments, top surface 22 includes prolonging from its leading edge to its edge after The convex that the radius stretched is about 4.5 inches.

In some embodiments, the particle to be handled by the mixer of the disclosure provides relatively long CONTACT WITH FRICTION path Shaft extension for provide shorten the processing time be preferred, that is, batch is heated to preferred temperature as early as possible.Heating and place This control of reason time is directly applied for the published method of the continuous thermokinetics mixing of two steps, so that improving rotation axle speed will Assign frictional heat quickly with the melting capacity of the particle for being more difficult to or resisting low speed heating.Have been found that thermokinetics The inhomogeneities of material in the batch of processing --- i.e. in terms of composition or partial size --- causes bigger with mixing chamber interior contact Or smaller friction paths.It will be from thermokinetics mixer much more resistant to the particle melted by more high melting temperature or hardness It is faster sprung back in the CONTACT WITH FRICTION of inner surface, it is therefore desirable to which the particle for comparing not infusibility more handles the time.By thermo-labile or Can the component thermokinetics of pyrolytic damage mix to final desired processing consistency to typically facilitate and obtain object lot temperature as early as possible Degree.The certain embodiments of the disclosure provide short, medium, long or mixing by single treatment axle speed or multiprocessing axle speed The particle friction along shaft extension top surface of length contacts path, to realize the more effective mixing of certain thermo-labile components.

It is well known by those skilled in the art that the top surface of shaft extension is only in Draiswerke mixer The arch of the shaft extension of general bending is reduced and smooth end face.Therefore, such mixer is thermokinetics mixing chamber The ability that grain provides significant top surface shearing friction heating substantially minimizes.In order to realize additional top for the particle in mixing chamber Portion face sample friction paths and the other purposes for realizing the disclosure, Figure 22 disclose the front view of the extension of 30 axis of open type, institute Shaft extension is stated with central opening, particle in processes is passed through from it and is impinged upon is equally angled backward Surface is on A1/A2, B1/B2 and C1/C2.It should be appreciated that surface A 1/A2 acts on particle, surface B1/ together as top surface B2 and C1/C2 acts on particle as forward face.Figure 22 more typically disclose shaft extension can be formed as annulus (donut) or Anchor ring (toroid) shape or the diamond shape with central opening, to realize the more effective mixed of certain thermo-labile components It closes.

Specific descriptions to first embodiment and second embodiment of the invention

Figure 23 is the general machine figure of the processing of first embodiment and second embodiment.Figure 23 shows mixing chamber MC, mixing chamber MC include the temperature sensor or Raman spectrum probe 20 (as described above) in mixing transformation device MC, to divide It does not detect and averagely mixes batch temperature or laser is transmitted to lesser sample space and is collected from the lesser sample space The emitting substance of recycling, for detecting sample crystallinity by Raman spectrometer.The data that probe 20 is detected are transferred to Optional Raman spectrometer and device microprocessor RS/DMC (when probe 20 is Raman spectrum probe), or be transmitted directly to Mixer including microprocessor controls microprocessor MCM, wherein and the microprocessor has memory and I/O unit, The I/O unit is connect with the user interface for including input button and Output Display Unit.Mixer controls microprocessor MCM is operated in the case where the mixer of storage controls program, is used to receive and store the trigger data detected by probe 20, and Hereafter the axle speed and speed control 15 of thermokinetics mixer shafts motor are controlled.It includes for comparing that mixer, which controls program, The trigger data that detects or the trigger data rate calculated from trigger data and compare trigger data or trigger data rate Absolute value and predetermined trigger set point method.It is touched detecting that trigger data or trigger data rate have equalized or be higher than When sending out set point, mixer controls program makes the speed of mixer motors axis improve or make to mix after the starting of mixer motors axis It closes and terminates.

The additional information physically and thermally changed occurred in first embodiment and second embodiment is retouched now It states.Fig. 6 shows trigger data of the temperature relative to incorporation time of components composition, and wherein temperature platform extended from about 12 seconds To about 52 seconds, referred to herein as plateau.Think in experiment, plateau mixes thermokinetics horizontal needed for obtaining Reduction with drug or drug crystallinity is required.It has been found by the present inventors that entire plateau, Huo Zheke can not needed To be used to making motor axle speed to be increased to from lower first axle speed the triggering of higher second axle speed plateau Set point, the triggering set point can be scheduled batch temperature rate reduction, the absolute value of the crystallinity detected or crystallization The rate of decline is spent, this eliminates components composition plateau needed for thermokinetics mixing almost.

In slower second stage embodiment of the invention, the first stage is preferably completed in detection of platform, Second stage is then completed with lower axle speed, thus the final required reduction of the drug of crystal form or drug is being reduced Shearing and frictional strength under complete.It is the component that slower second stage embodiment has been applied successfully: [drug and tax below Shape agent/carrier name].

The second step of first step and higher axle speed for lower axle speed, it must be understood that thermokinetics mixing pair The Subtle differences of the influence of components composition.It is now clear that being mixed with the thermokinetics by being carried out with higher axle speed The higher batch temperature realized is compared, and lower axle speed step is at lower batch temperature (herein referred as phase first stage) in 9s A certain amount of hot (Fig. 6) is almost provided immediately to 11s, is become so as to cause 20% to 90% premixing crystalline drug without fixed Shape form is a large portion of desired crystallinity variation.But lower axle speed is mixed into what mixing batch provided Kinetic energy per unit time is less compared with the kinetic energy that higher axle speed mixes, so that temperature platform is generated, this is because crystallization The energy that component needs the per unit of remaining crystallographic component bigger realizes the conversion of crystal to amorphous structure.

Elimination may make the relatively long platform phase of required drug or drugs from degradation be that first embodiment and second are implemented The main purpose of mode, wherein even if 0.2% required drug or drug degradation can make thermokinetics mixing batch can not With.In specific example, the single low speed thermokinetics mixing that single-component composition needs 18 seconds, wherein by the first stage Predetermined temperature increase rate is used at the end of phase as set point is triggered to start the second stage of higher axle speed, required is complete Portion is 8 seconds the processing time.The first relatively low axle speed high 20% to 100% of preferably higher second axle speed, it is more excellent Selection of land is the relatively low first axle revolving speed high 40% to 80% of higher second axle speed.

In addition, the drug or drug of usually components composition are small molecules compared with its excipient, wherein drug is smaller Amorphous molecule be essentially acted as " lubricant " of bigger polymer.There is no high for the per unit energy input of components composition To the expectancy changes being enough to complete from crystallization to amorphous structure, until " lubricant " drug is captured to melting or " viscosity " In larger polymer aggregation.Useful analogy is: forming solid dispersions and is similar to drug dissolution in a liquid.In order to help It helps drug quickly to dissolve, temperature or stirring rate should be increased.It is uncertain to be, implement in first embodiment or second It can be obtained by the detection for the process points for preventing drug from degrading to motor axle speed should be improved in mode such aobvious Write effect.

Back to temperature increase rate is used, as the first embodiment of triggering set point, sensor 20 is fixed to make Obtaining port of the sensor 20 in mixing chamber MC, wherein the distal portion of sensor 20 is pointed generally in the axis of bearing shaft extension, The other end of sensor 20 is connected to batch microprocessor BMCRO.Batch microprocessor BMCRO (including CPU, memory, when Clock and I/O unit, CPU, memory, clock and I/O unit are all operated in the case where batch processed controls program) When receiving the temperature signal sensed by sensor 20, and these temperature signals and record time correlation being joined ground at a predetermined interval Between (preferably 500ms to 5ms) store in memory, therefore batch control program make storage temperature and record time number According to being used to calculate using arithmetic average, differential variation rate or other average computation methods calculated in period from 2s to 10ms Rate temperature change.When calculated rate temperature change is determined to be equivalent to or is become close to temperature stored in memory When the predetermined trigger value of change, batch control program acts on or postpones some effects immediately to send signal to the speed of motor 15 Controller preferably makes lower axis rotation speed so that lower axle rotary speed be made to rise to higher axle rotary speed Degree rises to higher axle rotary speed within a predetermined period of time, and hereafter batch control program stops motor 15.

Figure 24 describes the step of alternative embodiment of the invention, wherein will include components composition in step 102 Batch be added in the batch room exclusively for the thermokinetics mixer of this processing design, and make axis motor with lower First axle rotary speed starts.In step 104, temperature sensor or Raman spectrum probe (passing through its Raman spectrometer) are by signal It is sent to mixer control microprocessor and carries out memory storage as trigger data.

For first embodiment, in step 106, mixer controls microprocessor continually by temperature triggered data meter It calculates temperature increase rate and stores the values in memory, to calculate special speed.Mixer controls microprocessor packet The value that is stored in advance of the triggering set point of temperature increase rate is included, or including (preferably existing by obtaining in the previous period Between 0.5s and 1.0s) in maximum increase rate and by trigger set-point calculation be significantly less than triggering set point temperature liter High-speed and the triggering set point calculated.

For second embodiment, mixer control microprocessor continuously deposits the crystallinity value detected in mixing chamber Storage is trigger data, and optionally calculates crystallinity reduction rate in step 106 and store the values in memory.It is mixed Clutch control microprocessor include crystallinity value triggering set point be stored in advance value or as trigger set point crystallization Degree reduces rate.

In step 108, mixer control programmed microprocessor determines trigger data or is by the rate that trigger data calculates It is no to have reached triggering set point.In case of such case, then the phase makes axle speed to mixer microprocessor later in the first stage Degree improves or stops mixing at the end of the second stage phase.

In many methods of raising temperature for calculating first embodiment, a preferred method is to be detected and stored The mixing batch sensing temperature of 30ms to 0.5ms, and calculate being averaged for every 5 to every 10 previous record batch temperature values Value.For first embodiment, 1.5 degree to 0 degree of triggering set point preferably per second, wherein maximum temperature increase rate is not It is used to determine triggering set point.

For the triggering set point of second embodiment, preferably 20% to 0% crystallinity is more preferably tested The drug of amount or 2% to 0% detection crystallinity of drug.Crystallinity reduce triggering set point be preferably per second 20% to Per second 0%.

For first embodiment, the halt for carrying out thermokinetics mixing to specific components composition passes through test It determines, in experiments it is found that acceptable lower crystallinity level or the crystallinity level being not present, and drug or drug Degradation is within the acceptable limits.For second embodiment, for carrying out thermokinetics mixing to specific components composition Halt is determined by test, in experiments it is found that acceptable lower crystallinity level or the crystallinity level being not present, and And the degradation of drug or drug is within the acceptable limits or with scheduled low-level detection crystallinity.

Figure 25 shows the analysis graph of individual axis velocity batch, it illustrates relative to processing the time by °F as unit of Sensing temperature and the axle rotary speed as unit of RPM, wherein handle at about 15.3 seconds detect temperature platform (with Inclined dotted line is shown) at stop.In the processing of Figure 25, batch includes these components: Itraconazole；Utech (Eudragit) L100-55 (1:2 ratio).Figure grid block defines 25 °F of positive slope per second from opposite angle.Specifically show at this In example, detection of platform is preferably with about 15 °F per second or lower slope or more preferably with about 10 °F per second or lower Slope occurs.The processing of Figure 25 show terminated when mixer control programmed microprocessor detects temperature platform with single low The actual result for the thermokinetics mixing that axle speed (about 1900RPM) carries out.As in this case, some components compositions can To realize that enough crystallinity reduces in detection of platform step.The embodiment of the invention is referred to herein as single low axis Speed batch embodiment.

Figure 26 shows the analysis graph of individual axis velocity batch, it illustrates relative to processing the time by °F as unit of Sensing temperature and the axle rotary speed as unit of RPM, wherein handling the detection in second time period at about 15.8 seconds To temperature platform (being shown with inclined dotted line) after, stop at about 20.8 seconds, or at the crystallinity reduction detected Stop (if having used crystallinity probe).In the processing of Figure 26, batch includes these components: Itraconazole；Utech L100-55 (1:2 ratio).Figure grid block defines 10 °F of positive slope per second from opposite angle.In the specific example, platform is examined It surveys and preferably occurs with about 20 °F per second or lower slope or more preferably with about 10 °F per second or lower slope.Figure 26 processing shows the detection after mixer control programmed microprocessor detects temperature platform Jing Guo certain period of time Afterwards terminate (processing terminate indicate batch from mixing chamber remove or make thermokinetics mixing stop other effective ways) with list The actual result for the thermokinetics mixing that low axle speed (about 1600RPM) carries out.Such as in this case, some components compositions It can realize that enough crystallinity reduces in detection of platform step.In this case, the additional time after detection of platform Duan Weiyue 5 seconds.The embodiment of the invention is referred to herein as single low axle speed and adds batch embodiment additional time.

Figure 27 shows the analysis graph of twin shaft speed batch, it illustrates relative to processing the time by °F as unit of Sensing temperature and the axle rotary speed as unit of RPM, wherein at the temperature platform detected of the axle speed at about 9.5 seconds It improves, and handles and stop at second speed time (about 12.7 seconds), or stop (such as at the crystallinity reduction detected Fruit has used crystallinity detector).In the processing of Figure 27, batch includes these ingredients: griseofulvin；PVP K30 (1:3 Ratio).Figure grid block defines 25 °F of positive slope per second from opposite angle.In the specific example, detection of platform preferably with About 10 °F per second or lower slope or more preferably occur with about 5 °F per second or lower slope.The processing of Figure 27 is shown About 2250RPM is increased to the progress of lower first axle speed (about 1500RPM) and by axle speed and at about 12.5 seconds Stop the actual result of the heat power mixing of thermokinetics mixing.As in this case, many components compositions can be flat Realize that suitable crystallinity reduces in the period of higher axle speed after platform detecting step.In this case, platform is examined Additional time period after survey is about 3.2 seconds.The embodiment of the invention is referred to herein as low axle speed to high axle speed Spend batch embodiment.By the processing of Figure 27 compared with the processing of Figure 26, the processing of Figure 27 shortens total processing time about 30% to 40% processing realizes desired crystallinity and reduces in the case where stopping.

According to the disclosure, it can prepare and implement disclosed and claimed herein in the case where not needing and excessively testing All compositions and/or method.Although describing the composition and method of the disclosure according to preferred embodiment, for It will be apparent that for those skilled in the art, it, can be to this in the case where not departing from concept, the spirit and scope of the disclosure The sequence of the step of composition and/or method and method of described in the text or step makes modification.For those skilled in the art Apparent all these similar alternative solutions and remodeling are considered the essence in the disclosure being defined by the following claims for member In mind, range and concept.

Claims

1. a kind of carry out heat to comprising the components composition of at least one active pharmaceutical ingredient and at least one excipient or carrier The method of dynamics mixing, which comprises

(a) thermokinetics mixer, the thermokinetics mixer have mixing chamber, wherein the mixing chamber is contained in motor Thermokinetics extension on axis, and the motor drive shaft extends to axis motor, the rate of the rotation speed of the motor drive shaft by Mixer controls microprocessor control；

(b) batch of the components composition is added in the mixing chamber；

(c) thermokinetics mixing is carried out to the components composition, wherein

I. both temperature of the rate of the rotation speed of the motor drive shaft and the batch increase during the phase in the first stage,

Ii. the mean temperature of the batch is detected periodically at trigger data sensor, and

Iii. average temperature data is transferred into the mixer control microprocessor, controls microprocessor in the mixer In, it calculates temperature increase rate and compares the temperature increase rate and scheduled temperature increase rate triggering set point Compared with；And

(d) when Current Temperatures increase rate is less than or equal to the triggering set point, the mixer is controlled into microprocessor Operating into changes the rate of the rotation speed of the motor drive shaft and continues the second stage phase.

2. according to the method described in claim 1, wherein, the temperature increase rate passes through the average temperature to certain amount The value of degree evidence finally stored averagely calculates.

3. according to the method described in claim 1, wherein, the rotation speed of the motor drive shaft is held to be set with the triggering The identical speed predetermined hold-time section of rotation speed at fixed point, the batch is discharged from the mixing chamber later.

4. according to the method described in claim 3, wherein, the crystallinity of the batch is measured by Raman spectrometer.

5. according to the method described in claim 1, wherein, the rotation speed of the motor drive shaft is lowered in the second stage phase And predetermined hold-time section, the batch is discharged from the mixing chamber later.

6. according to the method described in claim 5, wherein, the crystallinity of the batch is measured by Raman spectrometer.

7. according to the method described in claim 1, wherein, the rotation speed of the motor drive shaft is mentioned in the second stage phase Height, during the second stage phase, the mean temperature of the batch is periodically examined at the trigger data sensor It surveys, average temperature data is transferred into the mixer control microprocessor, in mixer control microprocessor, calculates The temperature increase rate is simultaneously compared by temperature increase rate with scheduled second temperature increase rate triggering set point, and And when Current Temperatures increase rate is less than or equal to the second triggering set point, the batch is arranged from the mixing chamber Out.

8. according to the method described in claim 7, wherein, the crystallinity of the batch is measured by Raman spectrometer.

9. according to the method described in claim 7, wherein, the second temperature increase rate triggering set point by obtaining first This, is then averaged by the maximum value of the average value of the previously stored value of the temperature increase rate of the certain amount of previous time section The maximum value of value subtracts scheduled percentage to calculate.

10. according to the method described in claim 1, wherein, the rotation speed of the motor drive shaft is mentioned in the second stage phase Height, during the second stage phase, the mean temperature of the batch is periodically examined at the trigger data sensor It surveys, average temperature data is transferred into the mixer control microprocessor, in mixer control microprocessor, calculates The temperature increase rate is simultaneously compared by temperature increase rate with scheduled second temperature increase rate triggering set point, In, the rotation speed of the motor drive shaft is held at speed identical with the rotation speed at the second triggering set point and holds Continuous predetermined amount of time, the batch is discharged from the mixing chamber later.

11. according to the method described in claim 10, wherein, the crystallinity of the batch is measured by Raman spectrometer.

12. according to the method described in claim 10, wherein, the second temperature increase rate triggering set point by obtaining first The maximum value for obtaining the average value of the previously stored value of the temperature increase rate of the certain amount of previous time section, then puts down this The maximum value of mean value subtracts scheduled percentage to calculate.

13. according to the method described in claim 1, wherein, the temperature increase rate triggering set point by obtaining first first The maximum value of the average value of the previously stored value of the temperature increase rate of the certain amount of preceding period, then by the average value Maximum value subtract scheduled percentage to calculate.

14. according to the method described in claim 1, wherein, the triggering set point is 20 °F per second to 0 °F per second or per second 20 DEG C to 0 DEG C per second.

15. according to the method for claim 11, wherein the triggering set point is 15 °F per second to 0 °F per second or per second 15 DEG C to 0 DEG C per second.

16. according to the method for claim 12, wherein the triggering set point is 5 °F per second extremely 0 °F per second or per second 5 DEG C to 0 DEG C per second.

17. a kind of carry out heat to comprising the components composition of at least one active pharmaceutical ingredient and at least one excipient or carrier The method of dynamics mixing, which comprises

(a) thermokinetics mixer, the thermokinetics mixer have mixing chamber, wherein the mixing chamber is contained in motor Thermokinetics extension on axis, and the motor drive shaft extends to axis motor, and the rotation speed of the motor drive shaft is by mixer Control microprocessor control；

(b) batch of the components composition is added in the mixing chamber；

(c) thermokinetics mixing is carried out to the components composition, wherein

I. the temperature of the batch increases during the phase in the first stage,

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

Iii. crystallinity data is transferred into the mixer control microprocessor, in mixer control microprocessor, The current value of the crystallinity data is compared with scheduled crystallinity value triggering set point；And

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

18. according to the method for claim 17, wherein crystallinity is measured by Raman spectrometer.

19. according to the method for claim 18, wherein the trigger data sensor includes distal portion and close end Relatively narrow pipe, wherein the distal portion includes laser and at least one lens, and the laser is directed into carry out heat power In the sample space for learning the batch of mixing.

20. according to the method for claim 19, wherein the sensing emitting substance of the sample space is transferred to the Raman The crystallinity of spectrometer, the batch crystallographic component detected at the Raman spectrometer is calculated and is transmitted to the mixer Control microprocessor.

21. a kind of carry out heat to comprising the components composition of at least one active pharmaceutical ingredient and at least one excipient or carrier The method of dynamics mixing, which comprises

(a) thermokinetics mixer, the thermokinetics mixer have mixing chamber, wherein the mixing chamber is contained in motor Thermokinetics extension on axis, and the motor drive shaft extends to axis motor, and the rotation speed rate of the motor drive shaft is by mixing Clutch controls microprocessor control；

(b) batch of the components composition is added in the mixing chamber；

(c) thermokinetics mixing is carried out to the components composition, wherein

I. the temperature of the batch increases during the phase in the first stage,

Ii. the crystalline state of the batch is detected periodically at trigger data sensor to amorphous state data transfer, and

Iii. the crystalline state to amorphous state data transfer is transferred into the mixer control microprocessor, in the mixer It controls in microprocessor, the current value of the crystalline state to amorphous state data transfer and scheduled crystalline state to amorphous state is changed Data-triggered set point is compared；And

(d) when current crystalline state to amorphous state data transfer is less than or equal to the triggering set point, by the batch from institute State mixing chamber discharge.

22. according to the method for claim 21, wherein the crystallinity of the batch is measured by Raman spectrometer.