Direct probe sensed temperature method for speed change for heat sensitive portions of a thermokinetically melt blended batch

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

(a) a thermokinetic mixer having a mixing chamber, where the mixing chamber contains thermokinetic extensions on a motor shaft and that motor shaft extends to a shaft motor, whose rate of rotation speed is controlled by a mixer control microprocessor;

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

(c) thermokinetic mixing of the component combination wherein:

i. the rate of rotation speed of the motor shaft and the temperature of the batch both increase during a first stage period,

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

iii. average temperature data is delivered to the mixer controller microprocessor, where a temperature increase rate is calculated and compared with a pre-determined temperature increase rate trigger setpoint; and

(d) when a current temperature increase rate equals or is less than the trigger setpoint, the mixer control microprocessor operates to change the rate of rotation speed of the motor shaft for a second stage period.

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

3. The method of claim 1 , wherein the rotation speed of the motor shaft is maintained at the same speed as the rotation speed at the trigger setpoint for a pre-determined period of time, after which the batch is ejected from the mixing chamber.

4. The method of claim 3 , wherein crystallinity of the batch is measured by Raman spectroscopy.

5. The method of claim 1 , wherein the rotation speed of the motor shaft is reduced in the second stage period for a pre-determined period of time, after which the batch is ejected from the mixing chamber.

6. The method of claim 5 , wherein crystallinity of the batch is measured by Raman spectroscopy.

7. The method of claim 1 , wherein the rotation speed of the motor shaft is increased in the second stage period, an average temperature of the batch is periodically detected at a trigger data sensor during the second stage period, average temperature data is delivered to the mixer controller microprocessor, where a temperature increase rate is calculated and compared with a pre-determined second temperature increase rate trigger setpoint, and when a current temperature rate increase equals or is less than the second trigger setpoint, the batch is ejected from the mixing chamber.

8. The method of claim 7 , wherein crystallinity of the batch is measured by Raman spectroscopy.

9. The method of claim 7 , wherein the second temperature increase rate trigger setpoint is calculated by first obtaining a maximum of an average of a certain number of previously stored values of temperature increase rates over a previous time period and then reducing that average by a pre-determined percentage.

10. The method of claim 1 , wherein the rotation speed of the motor shaft is increased in the second stage period, an average temperature of the batch is periodically detected at a trigger data sensor during the second stage period, average temperature data is delivered to the mixer controller microprocessor, where a temperature increase rate is calculated and compared with a pre-determined second temperature increase rate trigger setpoint, wherein the rotation speed of the motor shaft is maintained at the same speed as the rotation speed at the second trigger setpoint for a pre-determined period of time, after which the batch is ejected from the mixing chamber.

11. The method of claim 10 , wherein crystallinity of the batch is measured by Raman spectroscopy.

12. The method of claim 10 , wherein the second temperature increase rate trigger setpoint is calculated by first obtaining a maximum of an average of a certain number of previously stored values of temperature increase rates over a previous time period and then reducing that average by a pre-determined percentage.

13. The method of claim 1 , wherein the temperature increase rate trigger setpoint is calculated by first obtaining a maximum of an average of a certain number of previously stored values of temperature increase rates over a previous time period and then reducing that average by a pre-determined percentage.

14. The method of claim 1 , wherein the trigger setpoint is from 20 to 0 degrees F. or C. per second.

15. The method of claim 11 , wherein the trigger setpoint is from 15 to 0 degrees F. or C. per second.

16. The method of claim 12 , wherein the trigger setpoint is from 5 to 0 degrees F. or C. per second.

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

(a) a thermokinetic mixer having a mixing chamber, where the mixing chamber contains thermokinetic extensions on a motor shaft and that motor shaft extends to a shaft motor, whose rotation speed is controlled by a mixer control microprocessor;

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

(c) thermokinetic mixing of the component combination wherein:

i. the temperature of the batch increases during a first stage period,

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

iii. crystallinity data is delivered to the mixer controller microprocessor, where a current value of the crystallinity data is compared with a pre-determined crystallinity value trigger setpoint; and

(d) when current crystallinity data equals or is less than the trigger setpoint, the batch is ejected from the mixing chamber.

18. The method of claim 17 , wherein crystallinity is measured by Raman spectroscopy.

19. The method of claim 18 , wherein the trigger data sensor is a relatively narrow tube comprising a distal end and a proximal end, where the distal end comprises at least one lens and a laser which is directed into a sample space of the thermokinetically mixing batch.

20. The method of claim 19 , wherein sensed emissions of the sample space are transmitted to a Raman spectroscope, whereat a detected crystallinity of a batch crystalline component is calculated and transmitted to the mixer control microprocessor.

21. A method of thermokinetic mixing of a component combination comprising at least one active pharmaceutical ingredient and at least one excipient or carrier comprising:

(a) a thermokinetic mixer having a mixing chamber, where the mixing chamber contains thermokinetic extensions on a motor shaft and that motor shaft extends to a shaft motor, whose rate of rotation speed is controlled by a mixer control microprocessor;

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

(c) thermokinetic mixing of the component combination wherein:

i. the temperature of the batch increases during a first stage period,

ii. crystalline to amorphous transformation data of the batch is periodically detected at a trigger data sensor, and

iii. crystalline to amorphous transformation data is delivered to the mixer controller microprocessor, where a current value of the crystalline to amorphous transformation data is compared with a pre-determined crystalline to amorphous transformation value trigger setpoint; and

(d) when current crystalline to amorphous transformation data equals or is less than the trigger setpoint, the batch is ejected from the mixing chamber.

22. The method of claim 21 , wherein crystallinity of the batch is measured by Raman spectroscopy.