HK1234360A1 - Multiple speed process for preserving heat sensitive portions of a thermokinetically melt blended batch - Google Patents

Description

Multi-speed processing for protecting heat sensitive portion of thermodynamic melt blending batch

RELATED APPLICATIONS

Background

1. Field of the invention

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

2. Background of the invention

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

U.S. patent No.4,789,597 to Gupta relates to the incorporation of chemical reactants (chemical reactive agents) on resin particles. Simply stated, the chemical reactants are locked onto the appropriate synthetic resin particles without the need to completely melt (fluoring) the resin. The high-quality intermediate product obtained does not undergo premature reaction and is suitable for further technology. The method comprises intimately mixing and thermodynamically heating a batch (batch) of finely divided resin particles and a chemical reactant in a closed mixing chamber having a plurality of blades (blades) attached to an arm that rotates about a central axis (central axis) within the chamber, the blade tip speed being at least about 18 m/s; mixing the batch until the chemical reactant is locked to the resin particles; ensuring that the temperature of the batch remains just below the decomposition temperature of the reactants and below the melting temperature of the resin particles; the batch is discharged from the mixing chamber and the discharged batch is cooled to avoid agglomeration (agglomeration) of the resin particles.

U.S. patent No.5,895,790 to Good relates to the thermal curing of a wide range of polymer blends. Briefly, a wide range of polymer blends and waste thermosets can be recycled. A method of thermally curing a wide range of polymer blends forms a uniform and tunable (adapt) material. This material has a zero melt index (meltdex) and a relatively predictable density. Very high levels of fibrous non-polymer may be added to the first material.

U.S. patent No.6,709,146 to Little relates to a thermodynamic mixer and a method of using the mixer. Briefly stated, a thermodynamic mixer has a mixing chamber with an at least partially removable and replaceable shaft (draft) projection (projection) without the need to cut the projection from the shaft. In one embodiment, only the tip of such a protrusion is removable and replaceable without the need for such cutting. In another embodiment, the shaft protrusion into the mixing chamber comprises a tooth having a substantially mesh-shaped face forming a deflecting surface such that substantially all mixing chamber particles encountering the impact of the tooth are deflected away from the deflecting surface (deflecting surface) with an incidence of substantially the outside angle (lateral angle).

U.S. patent No.4,764,412 to Burns discloses the use of a high speed mixer with a heated jacket (heated jack) surrounding its vertical mixing chamber to first mix a set of components at 1700 rpm. The high speed mixer was stopped and after the addition of additional components, the rotational speed of the mixer was increased to 3400 rpm. Running the high speed mixer at a rotational speed of 3400rpm generates heat which is advantageous for further processing the mixture.

U.S. patent application No.12/196,154, filed by the same inventor as the present application and by another co-inventor, relates to the application of thermodynamic compounding in the field of pharmaceutical manufacturing. Thermodynamic compounding is a process of thermodynamic mixing until melt blending. Pharmaceutical compositions or composites (composites) prepared by thermodynamic compounding may be further processed according to methods well known to those skilled in the art, including but not limited to hot melt extrusion (hot melt extrusion), melt granulation (melt granulation), compression molding (compression molding), tablet compression (tablet compression), capsule filling (capsule filling), film-coating (film-coating), or injection molding (injection molding) into the final product. One embodiment relates to a method of preparing a pharmaceutical composition comprising one or more active pharmaceutical ingredients and one or more pharmaceutically acceptable excipients by a thermodynamic compounding process. Another embodiment relates to a composite material comprising one or more APIs and one or more pharmaceutically acceptable excipients prepared by thermodynamic compounding into a final product.

While the use of thermodynamic compounding in the pharmaceutical manufacturing field provides significant advantages over other methods known in the pharmaceutical field, problems can arise when using thermodynamic mixers to continuously melt blend certain heat-sensitive or thermolabile components with certain non-thermolabile components. Blending such a combination of components typically requires the use of increased or decreased shaft speeds to extend processing time sufficient to impart fully processed batches with complete amorphicity (amorphocity). In some cases, this results in heat input exceeding a threshold temperature or an unacceptable duration. The batch is thus subject to unacceptable degradation of the thermolabile component because the large amount of heat absorbed throughout the batch causes the thermolabile component to thermally degrade rather than increasing the overall batch temperature. Substantially completely amorphous is a well-known measure in the art of pharmaceutical preparation and processing, and in compositions lacking substantially completely amorphous, bioavailability can be significantly compromised.

Brief description of the invention

The present disclosure unexpectedly solves the problems associated with blending certain heat sensitive or thermolabile components in a thermodynamic mixer by using multiple speeds in a single, continuous rotation of batches containing thermolabile components. Identified herein are novel thermodynamic mixers and mixing methods that can blend heat-sensitive or thermolabile components while minimizing any significant thermal degradation. In particular, the present disclosure can be used to process mixtures containing thermolabile components that are exposed to melting temperatures or cumulative heat inputs for defined periods of time resulting in significant degradation. The obtained pharmaceutical composition has improved bioavailability and stability. Furthermore, the methods disclosed herein are readily extended to the commercial production of pharmaceutical compositions.

One embodiment of the present disclosure is a method for continuously blending and melting a self-heated mixture in a mixing chamber of a high-speed mixer, wherein after a first desired processing parameter is reached, the first speed is changed in-process to a second speed. In another embodiment, the second speed may be maintained until the final processing parameters are reached, at which time the shaft rotation is stopped and the melt-blended batch is withdrawn or ejected from the mixing chamber for further processing. In another embodiment, one or more intermediate speed changes may be made to the shaft rotation speed between the second speed and stopping the shaft rotation. The process parameters that determine the change in shaft speed are predetermined and may be sensed and displayed, calculated, inferred or otherwise established with reasonable certainty such that the speed change is made in a single rotation continuous process of a batch in the mixing chamber of the high speed mixer. Another embodiment is to use changes in the shape, width and angle of the face (facial portion) of the shaft extension or protrusion that intrudes into the main processing volume to control the conversion of the rotational shaft energy delivered to the extension or protrusion into thermal energy within the particles impacting the portion of the extension or protrusion.

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

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

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

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

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

Another embodiment of the present disclosure is directed to a method of compounding one or more active pharmaceutical ingredients and at least one polymeric pharmaceutically acceptable excipient to produce an amorphous, homogeneous, heterogeneous, or heterogeneously homogeneous composition, the method comprising thermodynamically mixing the active pharmaceutical ingredients and the at least one polymeric pharmaceutically acceptable excipient in a chamber at a first speed effective to increase the temperature of the mixture, and increasing the rotation of the mixer to a second speed to produce an amorphous, homogeneous, heterogeneous, or heterogeneously homogeneous composition at a point in time at which the temperature is below the shear transition temperature of any active pharmaceutical ingredient or polymeric pharmaceutically acceptable excipient in the mixture, wherein the increase is achieved without either stopping the mixing or opening the chamber. In another embodiment of the present disclosure, the method comprises thermodynamically mixing in a chamber at one or more speeds effective to increase the temperature of the mixture, at which time the shaft speed is adjusted to different speeds for different time periods, and increasing the rotation of the mixer to one or more different speeds at a point in time at a temperature below the shear transition temperature of any active pharmaceutical ingredient or polymeric pharmaceutically acceptable excipient in the mixture, wherein the increase is achieved without either stopping the mixing or opening the chamber.

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

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

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

In certain embodiments of the present disclosure, the one or more protrusions or extensions from the shaft comprise a base and an end, and for example, the end is detachable from the base and the base is detachable from the shaft. In other embodiments, the projections or extensions in the thermodynamic mixer are replaceable, e.g., based on wear and tear or different batch parameters. In one embodiment, the one or more protrusions or extensions from the shaft comprise one or more major face portions having a width of at least about 0.75 inches and an angle to the axial plane of the shaft of 15 to 80 degrees. In other embodiments, one or more protrusions or extensions from the shaft comprise one or more major faces having a width of at least about 0.80 inch, 0.85 inch, 0.90 inch, 0.95 inch, 1.0 inch, 1.1 inch, 1.2 inch, 1.3 inch, 1.4 inch, 1.5 inch, 1.6 inch, 1.7 inch, 1.8 inch, 1.9 inch, 2.0 inch, 2.1 inch, 2.2 inch, 2.3 inch, 2.4 inch, 2.5 inch, 2.6 inch, 2.7 inch, 2.8 inch, 2.9 inch, 3.0 inch, 3.1 inch, 3.2 inch, 3.3 inch, 3.4 inch, 3.5 inch, 3.6 inch, 3.7 inch, 3.8 inch, 3.9 inch, 4.0 inch, 4.1 inch, 4.2 inch, 4 inch, 4.5 inch, 4.6 inch, 4 inch, 4.7 inch, 4 inch, 4.9 inch, 4.0 inch, 4.1 inch, 4.2 inch, 4 inch, 4.5 inch, 4 inch, 4.6 inch, 5 inch, 4 inch, 5 inch, 25.5 inch, 25 inch, 40 inch, or more with a planar axis of the shaft axis being at an angle of a, 55. 60, 65, 70, 75, or 80 degrees. In certain embodiments, one or more projections or extensions from the shaft control the conversion of the rotational shaft energy delivered to the projections or extensions into thermal energy within the particles impacting the projections.

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

Brief description of the several views of the drawings

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

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

FIG. 2 is an exploded view of a thermodynamic mixer (expanded view).

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

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

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

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

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

FIG. 8 is a cross-section of a major face portion of a prior art shaft extension.

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

Fig. 10. a cross-section of a main face of the shaft extension at an angle of about 30 degrees to the axial plane of the shaft.

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

FIG. 12 is a cross section of a main face portion of the shaft extension at an angle of about 60 degrees from the axial plane of the shaft.

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

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

FIG. 15. alternative design of the cross section of the main face portion of the shaft extension.

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

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

FIG. 18. alternative design of the cross section of the main face portion of the shaft extension.

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

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

FIG. 21 is a perspective view of a shaft extension having a variable top surface path length.

FIG. 22. alternative design of front face of shaft extension (front face).

Detailed Description

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

To facilitate an understanding of the present disclosure, several terms are defined below. Terms defined herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. Nouns without quantitative modification mean one or more. For values and ranges recited herein, the term "about" is intended to include variations above and below the indicated number which can achieve substantially the same result as the indicated number. In the present disclosure, each of the various indicated ranges is intended to be continuous, such that each numerical parameter between the minimum and maximum values indicated for each range is included. For example, a range of about 1 to about 4 includes about 1, about 2, about 3, about 4, and 4. Certain specific embodiments of the present disclosure are described herein using terminology, but its use is not limiting of the disclosure, except as outlined in the claims.

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

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

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

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

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

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

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

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

Examples of APIs that may be used in the present disclosure include, but are not limited to, antibiotics, analgesics, vaccines, anticonvulsants, antidiabetic agents, antifungal agents, antineoplastic agents, anti-parkinson agents, antirheumatic agents, appetite suppressants, biological response modifiers, cardiovascular agents, central nervous system stimulants, contraceptives, dietary supplements, vitamins, minerals, lipids, carbohydrates, metals, amino acids (and precursors), nucleic acids and precursors, contrast agents, diagnostic agents, dopamine receptor agonists, erectile dysfunction agents, fertility agents (fertility agents), gastrointestinal agents, hormones, immunomodulators, antihypercalcemic agents, mast cell tranquilizers, muscle relaxants, nutritional agents, ophthalmic agents, osteoporosis agents, psychotherapeutic agents, parasympathomimetic agents (parasympatholytic agents), parasympathetic nerve blocking agents (parasympathetic agents), respiratory agents (respiratory agents), hypnotic agents (hypnotic agents), hypnotic agents, Skin and mucoadhesive agents, smoking cessation agents, steroids, sympathetic blockers (sympathogens), urinary tract agents (urinary tract agents), uterine relaxants, vaginal agents, vasodilators, antihypertensive agents, hyperthyroid agents (hyperthyroids), anti-hyperthyroid agents, antiasthmatic agents, and vertigo agents. In certain embodiments, the API is a poorly water soluble drug or a drug with a high melting point.

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

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

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

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

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

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

Suitable PEO grades can also be characterized by the viscosity of solutions containing a fixed concentration of PEO, for example:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The following is another example of a composition or formulation having a stable release profile. Tablets a and B were prepared each comprising a composition according to the present disclosure, and tablets C and D were prepared each comprising a composition not according to the present disclosure. Tablets a and C were each stored under the first set of conditions for one day, and tablets B and D were each stored under the same first set of conditions for three months. The release profiles of each of tablets a and C were determined after a1 day storage period and are referred to as release profiles a and C, respectively. The release profiles of each of tablets B and D were determined after a three month storage period and are referred to as release profiles B and D, respectively. The difference between release profiles a and B is quantified as the difference between release profiles C and D. Tablets a and B are considered to provide a stable or more stable release profile if the difference between release profiles a and B is less than the difference between release profiles C and D.

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

A dispersion of one or more APIs, wherein the APIs are small organic molecules, proteins, peptides, or polynucleotides, in a polymeric and/or non-polymeric pharmaceutically acceptable material for delivery of the APIs to a patient via oral, pulmonary, parenteral, vaginal, rectal, urethral, transdermal, or topical delivery routes.

A dispersion of one or more APIs, wherein the APIs are small organic molecules, proteins, peptides or polynucleotides, in a polymeric and/or non-polymeric pharmaceutically acceptable material for improving oral delivery of the APIs by increasing bioavailability of the APIs, prolonging release of the APIs, targeting release of the APIs to specific sites in the gastrointestinal tract, delaying release of the APIs, or creating a pulsatile release system of the APIs.

A dispersion of one or more APIs, wherein the APIs are small organic molecules, proteins, peptides, or polynucleotides, in a polymeric and/or non-polymeric pharmaceutically acceptable material for producing a bioerodible, biodegradable, or controlled release implantable delivery device.

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

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

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

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

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

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

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

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

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

Preplasticizing the polymeric material, which is subsequently used in film coating or melt extrusion operations.

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

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

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

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

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

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

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

The process is particularly suitable for producing solid dispersions of thermolabile APIs by cryogenic treatment at multistage speeds for a very brief duration, for producing solid dispersions of APIs in thermolabile polymers and excipients by cryogenic treatment at multistage speeds for a very brief duration, for producing solid dispersions of APIs in thermolabile excipients by cryogenic treatment at multistage speeds for a very brief duration, and for producing solid dispersions of thermosensitive polymers by cryogenic treatment at multistage speeds for a very brief duration.

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

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

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

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

The present disclosure also relates to thermodynamic mixers that can blend heat-sensitive or thermolabile components without substantial thermal degradation. One embodiment of the thermodynamic mixer has a high horsepower motor that drives a horizontal shaft with tooth-like projections (teeth-like projections) that extend outwardly normal to the axis of rotation of the shaft. The shaft is connected with a driving motor. The portion of the shaft comprising the projection is contained in a closed container where the compounding operation takes place, i.e. a thermo-dynamic mixing chamber. The high rotational speed of the shaft plus the design of the shaft projections imparts kinetic energy to the work material. A temperature sensor senses a temperature in the thermodynamic mixing chamber. Once the set temperature is sensed, the first speed is changed to a second speed.

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

FIG. 2 illustrates an exploded view of one embodiment of a thermodynamic mixer. The frame 1 supports the relative components so that the shaft assembly 2 is inserted in an axis passing through the axial hole of the end plate 3 and the feed screw hole of the end plate 4, both end plates defining the closed end of the mixing chamber cylinder, the bottom of the cylinder being defined by the inner surface of the lower casing 5. The lower case 5 includes a discharge opening (discharging opening) that is closed during operation of a discharge door 6. The upper housing 7 contains the upper part of the mixing chamber inner surface cylinder. The feed housing 8 is adapted to allow the supply of materials to the feed screw of the shaft assembly, in combination with the rotation of the feed screw, such that these materials are forcibly compressed into the mixing chamber from an external feed. The door 6 is rotatable closed about a discharge door pivot pin (pivotpin) 9. The end plate 3 has a rack (rack) and pinion cylinder (pinion) 18 attached thereto with the spacer 10 disposed therebetween. On top of the housing 7a bracket 11 is mounted, which supports an infrared temperature sensor 20 for the mixing chamber. A door guard (door guard)12 protects the door 6, which is sometimes at a high temperature, from accidental contact by a person with the release material. The rotation protection 13 and the drive coupling protection 14 prevent the human operator from coming into contact with the rotating parts during operation. The drive motor 15 is preferably a motor of sufficient power to carry out the disclosed operation. Pillow blocks 16 and 17 support the axle assembly 2.

In one example of a system in which process parameters that determine shaft speed changes are measured in the mixing chamber and/or drive motor, fig. 7 shows a block flow diagram (block flow diagram) of the disclosed method in which the mixing chamber MC is connected to the drive motor 42 by a shaft, with the variable frequency drive 41 controlling the rotational speed of the drive motor 42. In certain embodiments, the shaft speed may be 0 to 5000 RPM. In addition, according to the disclosed method, programmable logic controller 40 uses variable frequency drive 41 to determine and vary the speed of the rotating shaft. The programmable logic controller 40 contains a user-entered set point (setpoint) for determining the need to change the speed of the rotating shaft in the drive motor 42 and sending instructions to the variable frequency drive 41 to change the speed after the rotational processing of the batch load added to the mixing chamber. The programmable logic controller may incorporate a microprocessor containing a memory incorporating a control program adapted to act upon reaching a set point entered by the user in dependence upon sensor data delivered by the drive motor 42 and/or the mixing chamber MC, and containing a user interface such as a programmable logic controller display with which the user observes the run time and sensor temperature delivered by the drive motor 42 and/or the mixing chamber MC. The programmable logic controller optionally includes a method that the user uses to directly change the motor shaft speed after considering predetermined processing parameters (e.g., run time) or after comparing the predetermined processing parameters to sensor data conveyed by the sensor data (e.g., batch temperature, current amperage, and shaft speed) transmitted by the drive motor 42 and/or the mixing chamber MC. The programmable logic controller optionally includes an automatic control method that varies the motor shaft speed after the microprocessor is run at a predetermined, stored process parameter (e.g., run time) or after comparing the predetermined, stored process parameter to sensor data conveyed by the sensor data (e.g., batch temperature, current amperage, and shaft speed) delivered by the drive motor 42 and/or the mixing chamber MC.

A description of the components of one embodiment of a thermodynamic mixer for use in the disclosed method is shown in fig. 3 and 4. FIG. 3 shows an axial radial cross-sectional view of a mixing chamber MC for use in the thermodynamic mixer of the present disclosure, with halves 5 and 7 joined to form a cylindrical mixing chamber, with shaft 23 rotating in direction of rotation 24 over the axial length of the chamber. The shaft extension 30 extends from its detachable connection on the shaft 23 to a position proximate the inner surface 19. The shaft extension 30 includes a top surface 22 and a front surface 21. Particles 26a-26e illustrate the impact of the particles on the shaft protrusions 30 and inner surface 27, which results in particle comminution and/or frictional heating by the shear created by such impact. Additionally, FIG. 4 is an exploded view of the extension and mixing chamber shown in FIG. 3, wherein shaft extensions 30a, 30b, and 30c, each having a top surface 22 and a front surface 21, are defined on replaceable teeth adapted to be secured to feet 31 by bolts 33. Portion 31 is adapted to be replaceably secured to shaft 23 (continuing from motor shaft 37) by a bottom 32 of portion 31 at slot 35. Fig. 4 shows that the particles move generally in direction 38 as they encounter the shaft extensions 30 a-30 c. Shaft extension 30a is shown having a front face 21 that is effectively aligned with respect to the front faces of shaft extensions 30b and 30 c.

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

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

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

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

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

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

The two major impingement surfaces in a thermodynamic mixer are the front and top surfaces of the shaft, which control the conversion of impingement into heat energy. These two surfaces are the faces of the shaft extensions that protrude into the mixing chamber by 30% or less of the volume outside the mixing chamber (said volume is also referred to hereinafter as the "main process volume" which includes the most restricted area about 1 inch radially inward from the inner cylindrical wall of the mixing chamber) and the inner cylindrical surface of the mixing chamber itself. It is not a practical option to modify the internal cylindrical surface of the mixing chamber, which is fixed and must remain smooth and cylindrically uniform to resist the accumulation of molten material and to allow self-heating contact with the sliding and sliding of the particles moving through the mixer chamber.

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

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

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

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

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

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

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

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

Alternative designs for the main face are shown in fig. 13 to 17, respectively, which show main face cross sections 69, 72, 76, 80, 84 and 87. Fig. 13 shows a cross-section 69 comprising a leading acute angled surface (70) extending back to an obtuse angled surface 71, providing a first low shear surface followed by a high shear surface. Fig. 14 shows a cross-section 72 comprising a leading acute surface 73 extending rearwardly to a 90 degree surface 74 which in turn extends rearwardly to a trailing acute surface 75, providing a first low shear surface followed by a high shear surface and a low shear surface. Fig. 15 shows a cross-section 76 comprising a leading acute angled surface 77 extending rearwardly to an obtuse angled surface 78 which in turn extends rearwardly to a trailing acute angled surface 79 providing a first low shear surface followed by a high shear surface and a low shear surface. Fig. 16 shows a cross-section 80 comprising a leading obtuse angled surface 73 extending rearwardly to an acute angled surface 74 which in turn extends rearwardly to a trailing obtuse angled surface 75, providing a first high shear surface followed by a low shear surface and a high shear surface. Fig. 17 shows a cross-section 84 containing a leading and upwardly arcuate surface 85 extending rearwardly to a trailing and downwardly arcuate surface 86 degree surface 74, the latter continuing rearwardly to a trailing acute angle surface 75, providing a first low shear surface followed by a higher shear surface and a lower shear surface. Fig. 18 shows a cross-section 87 comprising a leading acute surface 88 and a trailing acute surface 89, providing a first low shear surface followed by a higher or lower shear surface (depending on the shear of the batch components).

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

Fig. 19 shows another important embodiment of the dynamic mixer of the present disclosure, in which the halves 5 and 7 and the door 6 are internally lined with internal linings 5a, 7a and 6a, respectively. The liners are adapted to be positioned in close proximity to the inner surfaces of halves 5 and 7 and door 6 during operation of the mixer to provide any one of a number of sets of thermodynamic frictional contact surfaces desired to accelerate particles, the desired surfaces being selected from any suitable or optimized material of liners 5a, 7a and 6 a. Figure 19 shows an exploded view of the linings 5a, 7a and 6a partially separated from their neighbours (when installed). Bolting the halves 5 and 7 together results in the linings 5a and 7a being secured to line the inner surfaces of these halves 5 and 7. Holes in the end of the facing 6a allow it to be bolted to the door 6. In the thermodynamic mixers known to those skilled in the art, the inner surfaces of the mixing chamber are limited to those steel alloys having sufficient mechanical and thermal strength required for the thermodynamic operation of enclosing and closing such a mixing chamber. Thus, the processing capabilities of known thermodynamic mixers are limited to those mixtures that do not excessively adhere to the smooth inner surfaces of the steel alloys of the mixing chamber and at the same time beneficially impinge on these surfaces to provide frictional heating of the particles in the mixture. In addition, even relatively minor wear on the interior surfaces of the mixing chamber of the thermodynamic mixer may significantly alter the pairingThe chamber particles produce an efficiency of thermodynamic heating, wherein the distance between the shaft extension and the inner surface of the mixing chamber is specifically designed to optimize thermodynamic heating by interaction of the particles moving between the inner surface of the mixing chamber and the shaft extension. Such slight wear may therefore require replacement of the entire set of relatively expensive halves 5 and 7 in such a thermodynamic mixer. Embodiments of the present invention eliminate such expensive expenses. The linings 5a, 7a and 6a are relatively much cheaper in terms of replacement costs than the halves 5 and 7 and the door 6. The replacement of the lining is very simple and quick. Preferred liner compositions include stainless steel (alloys with greater than 12 weight percent chromium) and other such steel alloys, titanium alloys (e.g., nitrided or nitride-containing peptides), and wear and heat resistant polymers (e.g.,). Another embodiment of the present disclosure provides a non-smooth inner surface of the liners 5a, 7a and 6a, such as forming parallel or spiral grooves with respect to the inner cylindrical surface of the liners 5a, 7a and 6a, surface texturing and/or electropolishing. Such materials and textures of the linings 5a, 7a and 6a are intended to obtain an optimized or desired balance of properties that will reduce undesirable adhesion of the thermokinetic molten particles and/or promote thermokinetic frictional contact of the mixing chamber particles traveling between the shaft extension and the inner surfaces of the linings 5a, 7a and 6 a.

In other embodiments of the present disclosure in which the materials or textures of the facings 5a, 7a, and 6a are selected to achieve thermodynamic mixing objectives, the shaft extensions of the front and top impact surfaces containing the shaft extensions are adjusted by material composition and/or texture similar to those variations just disclosed for the inner surfaces of the facings 5a, 7a, and 6 a.

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

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

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

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

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

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

Claims (25)

1. A method of blending a composition of two or more ingredients, wherein the ingredients comprise one or more thermolabile components, wherein the resulting composition is amorphous or heterogeneously homogeneous, the method comprising mixing the ingredients in a thermodynamic mixing chamber, wherein a thermodynamic mixer shaft is operated at a first speed until a predetermined parameter is reached, at which time the shaft speed is adjusted to a second speed for a second period of time, wherein the mixing process is uninterrupted between the first and second periods of time.

2. The method of claim 1, wherein the thermolabile component comprises one or more active pharmaceutical ingredients or one or more pharmaceutically acceptable excipients.

3. The method of claim 1, wherein the composition comprises at least one thermosensitive polymer.

4. The method of claim 1, wherein the second period of time is 5% or more of the first period of time.

5. The method of claim 1, wherein the second period of time is 10% or more of the first period of time.

6. The method of claim 1, wherein the end of the first period of time is substantially before the mixing chamber temperature reaches the shear transition temperature or melting point of any substantial component in the ingredients.

7. The method of claim 1, wherein the end of the first period of time is a predetermined period of time and the second speed is automatically changed by the thermodynamic mixer at the end of the first period of time.

8. The method of claim 1, wherein at the end of the second time period, the rotational speed of the shaft is changed from the second speed to a third speed for a third time period after reaching a predetermined parameter.

9. The method of claim 8, wherein the mixing process is uninterrupted between the second and third time periods.

10. The method of claim 1, wherein the end of the first period of time is substantially before the mixing chamber temperature reaches the shear transition temperature of the active pharmaceutical ingredient in the composition.

11. The method of claim 1, wherein the end of the first period of time is substantially before the mixing chamber temperature reaches the shear transition temperature of the pharmaceutically acceptable excipients in the ingredients.

12. The method of claim 1, wherein the end of the second time period is substantially before an active pharmaceutical ingredient of the ingredients undergoes substantial thermal degradation.

13. The method of claim 12, wherein at the end of the second period of time, the active pharmaceutical ingredient and pharmaceutically acceptable excipients of the ingredient are substantially amorphous.

14. The method of claim 1, wherein the first speed is greater than 1000 revolutions per minute and the second speed is 200 to 400 revolutions per minute greater than the first speed.

15. The method of claim 1, wherein the first speed is greater than 1000 revolutions per minute and the second speed is 200 to 1000 revolutions per minute greater than the first speed.

16. The method of claim 1, wherein the first speed is greater than 1000 revolutions per minute and the second speed is 200 to 2500 revolutions per minute greater than the first speed.

17. A method of compounding an active pharmaceutical ingredient with at least one polymeric pharmaceutically acceptable excipient to produce a heterogeneous homogeneous composition, said method comprising thermodynamically mixing said active pharmaceutical ingredient and at least one polymeric pharmaceutically acceptable excipient in a chamber at a first speed effective to increase the temperature of the mixture, and increasing the rotation of said mixer to a second speed to produce a heterogeneous homogeneous composition at a point in time at which the temperature is below the shear transition temperature of any active pharmaceutical ingredient or polymeric pharmaceutically acceptable excipient in the mixture, wherein said increase is achieved without either stopping said mixing or opening said chamber.

18. A thermokinetic mixer for producing a pharmaceutical composition comprising a heat sensitive ingredient, the mixer comprising:

(a) a substantially cylindrical mixing chamber;

(b) a shaft disposed through a central axis of the mixing chamber;

(c) a motor coupled to the shaft effective to impart rotational motion to the shaft;

(d) one or more projections from the shaft and perpendicular to a long axis of the shaft;

(e) one or more thermal sensors attached to a wall of the mixing chamber and operative to detect heat or temperature of at least a portion of the interior of the mixing chamber;

(f) the frequency conversion device is connected with the motor;

(g) a door disposed in a wall of the mixing chamber effective to allow contents of the mixing chamber to exit the mixing chamber when opened during a process run; and

(h) an electronic controller in communication with said temperature sensor, said door and said variable frequency device;

wherein the electronic controller comprises a user input device, a timer, an electronic storage device configured to accept user input of process parameters for two or more stages in a thermo-dynamic hybrid process, and a display; wherein predetermined process parameters are stored in the storage device and displayed on a monitor for one or more phases of a process run; and wherein the electronic controller automatically moves a process run to a subsequent stage when one of the predetermined parameters is satisfied during a stage of the process run.

19. The thermodynamic mixer of claim 18 wherein at least one of the temperature sensors detects infrared radiation and wherein a level of the radiation is output as a temperature on the display.

20. The thermodynamic mixer of claim 18 wherein the interior of the mixing chamber is lined with an internal liner.

21. The thermodynamic mixer of claim 18, wherein the predetermined parameter is selected from the group consisting of temperature, shaft rotational speed, current amperage of the motor, time of the phase, and any combination thereof.

22. The thermodynamic mixer of claim 18, wherein the output display comprises a chamber temperature, a motor rpm, a motor current amperage, a cycle elapsed time, or any combination thereof.

23. The thermodynamic mixer of claim 18 wherein the one or more projections from the shaft include a base and an end, the end being detachable from the base and the base being detachable from the shaft.

24. The thermodynamic mixer of claim 18 wherein the one or more projections from the shaft comprise one or more major faces having a width of at least about 0.75 inches and an angle to the axial plane of the shaft of 15 to 80 degrees.

25. The thermodynamic mixer of claim 23 wherein the one or more projections from the shaft control the conversion of rotational shaft energy delivered to the projections into thermal energy within particles impacting the projections.