Effects of Comilling on Final API Physical Attributes - Organic Process

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Organic Process Research & Development

EFFECTS OF COMILLING ON FINAL API PHYSICAL ATTRIBUTES Anne E. Mohan*, David J. Lamberto, Hirotaka Nakagawa, Rositza Petrova, Nicholas Rogus, Michael D. Ward Merck & Co., Inc. 126 East Lincoln Ave. Rahway, NJ 07065

* [email protected]

ACS Paragon Plus Environment

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For Table of Contents Use Only


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ABSTRACT Severe operational challenges were experienced during the delumping (via comilling) of a shear-sensitive active pharmaceutical ingredient (API) during a pilot plant campaign. During the in-line comilling operation from the dryer, the API melted and blinded the screen, which compromised the equipment and called the batch fitness for formulation into question. These challenges instigated the investigation of comilling parameters and API physical properties, and their respective effects on delumping performance as well as the final API attributes. Comil impeller speed, impeller type, screen hole size, and screen hole type were studied at both pilot plant and lab scale. The unique properties of the API were also studied in order to understand how this solid differed from others. Because solids with similar physical properties to the API in question are likely to behave in a similar way, the experimental approach described here for comil and solid characterization should be applicable to other projects as well. The optimal comilling conditions for the API were determined and demonstrated robustly at pilot scale.

KEYWORDS: Comilling, Delumping, Melting, Screen, Impeller


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INTRODUCTION Delumping operations are often used in the pharmaceutical industry to provide a homogenous, lump-free powder in either the drug substance or drug product space. Product powders in the drug substance space typically have some amount of heterogeneity when discharged from a dryer. The extent of this heterogeneity is dependent on a variety of factors such as the individual powder’s physical properties, dryer geometry and mixing efficiency, and solvent content. Comilling and sifting are some examples of “delumping” operations which can be used to normalize a powder’s physical properties. The terms “Comil” and “comilling” are product names from Quadro®. During comilling (shown in Figures 1 and 2), the rotation of an impeller creates a centrifugal acceleration force which pushes feed material toward the perforated surface of a conical screen. Particles are trapped between the edge of the impeller and the screen, causing breakage. The product is then discharged through the screen and out of the comil chamber.

Figures 1 and 2. Diagrams demonstrating the delumping process of a comil.

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The two studies described in this paper were conducted in response to a failure that occurred during in-line delumping of an active pharmaceutical ingredient (API) at pilot scale. This API is temperature and shear sensitive, and as such the physical properties of the API prior to comilling


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are heavily dependent on the dryer type and agitation protocol during the drying process. Previous pilot-scale experience had shown significant variability in flow properties from batch to batch (measured by Carr’s Index and FlodexTM). This inconsistency led to operational issues during downstream drug product formulation. A comilling operation was added to the API process in order to provide a homogenous powder with normalized physical properties, to ensure consistent flow properties from batch to batch regardless of dryer type, and to allow dryer equipment flexibility.

The API is isolated as an n-heptane channel solvate, dried to < 3.0 wt%, delumped, and then formulated into drug product. During a recent API production campaign in the pilot plant, the API melted during in-line comilling while being discharged from an agitated conical dryer, (known henceforth as the “Summix”) – melting images shown in Figure 3. The melted API seized the comil impeller, and caused serious operational challenges.

Figure 3. Images showing melted API blinding the Comil screen. Comil was operating using the 1905 micron round screen and the impeller speed was at 3600 rpm.


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Figure 4. Pictures and microscopy images displaying the API batch to batch variability observed for different dryer types. Note – microscopy images taken at 250x magnification.

This report summarizes the results of two studies – one conducted at pilot plant scale, and the other at lab scale. Comil conditions were tested in the pilot plant and then a more fundamental understanding of the comil operation, such as residence times in the screen and amorphous content changes leading up to API melting, was gained through experiments conducted in the lab. The objectives of these studies were to: (1) determine robust processing conditions for comilling that can support commercial demand for the API, (2) confirm that the comil normalizes the physical characteristics and flowability of API dried in different equipment, and (3) confirm that this normalized flowability is within the operational limits of formulation.

MATERIALS AND METHODS

The Quadro® U10 (pilot scale) and U3 (lab scale) under-driven comil units were used for these experiments. Process parameters of the comil which were varied to understand their effects on


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the final API attributes were: (1) the impeller rotational speed, (2) the impeller type, (3) the screen hole size, and (4) the screen hole shape. (1) The rotational speed of the impeller affects the apparent hole size, or the size of the hole in the screen that is experienced by the agglomerate or the clump. As the impeller speed increases, the apparent hole size decreases, leading to smaller particle sizes. Conversely, as the impeller speed decreases, the apparent hole size increases, leading to larger particle sizes. The impeller speed was varied from 1200 to 3600 rpm (U10 model) for the purposes of these studies.

(2) Round and square impellers were explored for this study. The round impeller, which is often used for dry milling, has a smaller nipping, or cutting, angle than the square, and compresses the API between the impeller and the screen. Square impellers have an effective cutting edge and a larger nipping angle than the round. Because of this, it has lower shear, and is used for both dry and wet milling.2 Due to the shear sensitivities of the API used in this study, the square impeller was chosen for the majority of the experiments because it imparts less shear than the round impeller. The direct comparison of these impeller types shown in Figure 5:

Figure 5. List of different impeller types and their properties. Impeller type numbers (i.e. 1601 and 1609) indicate the parts number. The round impeller has higher capacity for throughput, generates larger amount of fines, and imparts higher pressure on screen.3


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(3) The screen aperture size has the largest effect on milling time and the degree of particle size reduction.4 Because delumping results in approximately 50% size reduction, the target particle size should determine the screen size to be used. For this API, the specification on particle size was dictated by the physical parameters of the formulation, and there could not be any particles > 4mm in diameter. Table 1 lists the screen specifications which were tested in this work.

Table 1. Screen sizes and specifications which were tested in this study.

Mesh (um) 1905 4750 4750 4750 6350 6350

Hole Shape Round Round Grater Square Round Grater

Thickness 0.037'' (0.940mm) 0.037'' (0.940mm) 0.031'' (0.787mm) 0.050'' (1.27mm) 0.037'' (0.940mm) 0.031'' (0.787mm)

Open Area 51% 51% 23% 42% 59% 30%

Part ID 7A-075-R-037-51B 7A-187-R-037-51 7A-187-G-031-23-132 7A-187-Q-050-42 7A-250-R-037-59B 7A-250-G-031-30-071

(4) The screen type should be chosen according to the starting material and the desired final product.2 For example, screens with the grater (i.e. similar to cheese grater) hole type produce less fines compared to the round or square hole types during dry delumping. While all three screen types shown in Figure 6 were used is this study, the round screen type was used most frequently due to its availability both in the pilot plant and in the lab.


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Figure 6. Different screen types and their intended uses 3

In addition to the comil unit’s operational parameters, the feed rate of the API into the comil was also varied during these experiments. The feed rate had to be explored in order to confirm that the comil operation was not a bottleneck for the API process. It is believed that the melting phenomena seen in Figure 3 occurred due to over-feeding of the in-line comil because of insufficient control of the Summix discharge valves. During the pilot plant experimental work, over-feeding was prevented by controlling the feed rate with a combination of engineer/operator communications and recorded weights of the feed and receiving drums. At lab scale, the engineer had direct control over the feed rate. In both instances, feeding was stopped immediately if there was a detection of melted API or discoloration on the screen.

Temperature was a pivotal parameter which had to be monitored for true understanding of the cause of API melting. While over-feeding of the in-line comil is believed to be the “root cause” of the melting, the secondary cause is the increase of product temperature due to the extended residence time in the comil unit. In the pilot plant and lab, the temperature was studied by


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measuring the effective screen temperature using a thermocouple which was placed as close as possible to the screen outlet. Thermal imaging technology was also used to understand the temperature profile and how it is affected by impeller speed (note – thermal imaging was conducted using an empty comil unit, without active API comilling). The final optimized comil conditions for the API were chosen based on temperature data from these experiments. The maximum temperature allowable for this work was the API amorphous glass transition temperature, 45oC.

Off-line sample analyses of the API pre and post comilling were conducted to determine the impact of the delumping operation on product flowability, amorphous content, and solvent content. The Carr’s Index, described by the formula in Equation 15, was used to assess powder flowability. The general guideline is that a Carr’s Index value of 15% or less indicates good flow properties, whereas 25% or higher indicates poor flow properties.6 The three dryer types used produced API with drastically different Carr’s Indices – the Summix material had excellent flowability and the Carr Index was 5%, the agitated filter dryer had poorer flowability and the Carr’s Index was 30%, and the rotary dryer material had the worst flowability and the Carr’s Index was 45%.

( )

(

)

Eqn. 1

Another type of flowability test which was used was FlodexTM, or the flowability index measurement. This is the diameter of the smallest hole through which a sample will pass for three successive tests.7 It was determined that for this API, the Carr’s Index provided a better flow indicator than the FlodexTM and as such, only the Carr’s Index is discussed in this paper.


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The amorphous content was determined using differential scanning calorimetry (DSC). The measurements were performed on TA Instruments Q1000 and Q2000 differential scanning calorimeters in modulation mode with 3°C/min heating rate, 60 s modulation period, and 1°C modulation amplitude in a crimped Al pan under nitrogen flow. Calibration standards were prepared by adding the crystalline and amorphous components directly to the DSC pan and recording their individual weights. A calibration curve was built based on the enthalpy of melting of the crystalline component determined from the total heat flow curve. This calibration curve was used to assess the percent of crystalline and amorphous component of material generated in this study. Analysis of wet cakes was performed after the samples were dried in air right before the measurements.

RESULTS AND DISCUSSION – PILOT PLANT Prior to API delumping experiments, the pilot plant comil unit was run empty and monitored by thermal imaging in order to gain an understanding of how parameters such as time and impeller speed affected the temperature profile. This demonstrated that the heat generation in the comil originated from the bottom of the spindle, which is directly connected to the motor. This heat then traveled radially outward towards the screen. After 30 minutes, the temperature of the spindle reached 42.9C, which is very close to the API amorphous glass transition temperature. This imaging provided the clear correlation between comil run time and heat generation.


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Figure 7 . Thermal images showing heat flow over time. Note that temperature scales are varied in each image.

The full list of pilot scale comilling runs that were conducted is shown in Table 2. Conditions were chosen such that the 4 comil parameters, the feed rate, and the total run time would be sufficiently explored. Table 2: Complete list of comil runs conducted at pilot plant scale (note – runs are in chronological order). Run Conditions Results Screen Run Carr’s Screen Impeller Amorphous Run Name Size RPM Time Index Type Type Content (%) (micron) (min) (%) Summix Run 1 1905 Round Round 2400 15 25 24 Summix Run 2

1905

Round

Square

2400

11

30

33

Summix Run 3

6350

Round

Square

1200

30

26

18

Summix Run 4

6350

Round

Square

3600

28

24

28

Summix Run 5

6350

Round

Square

2400

25

25

36

Filter Dryer Run 1

6350

Round

Square

1200

12

34

29

Filter Dryer Run 2

6350

Round

Square

3600

12

41

33

Filter Dryer Run 3

6350

Grater

Square

1200

12

53

28

Rotary Dryer Run 1

4750

Square

Square

1200

11

7

47

Rotary Dryer Run 2

6350

Round

Square

3600

4

N/A

N/A

Rotary Dryer Run 3

6350

Grater

Square

1200

11

0

47

Rotary Dryer Run 4 Extended Filter Dryer Run 1 Extended Filter Dryer Run 2

6350

Round

Square

1200

11.6

5

47

6350

Round

Square

1200

80

42

25

6350

Round

Square

1200

50

46

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(1) The first comil parameter which was investigated was the impeller rotational speed. For Summix runs 3, 4, and 5, the speed was varied from 1200 to 3600 rpm and the effective screen temperature was tracked. The feed material (Summix), screen type and size (round, 6350), and


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impeller type (square) were held constant for these runs. As can be seen in Figure 8, there is a clear correlation between impeller speed and temperature – the frictional force of the spindle increases as the rotational speed is increased, and this causes the rate of increase in screen temperature to accelerate.

The screen temperature was also monitored for a period of time after the comil unit was turned off (denoted by the asterisk symbols in Figure 8). The temperature trend significantly deviates from the previous linear trend during this shut-off period, resembling a step change in temperature. This response can be attributed to the lack of cooling effect of air. When the comil is operating, the rotation of the impeller draws air through the screen, effectively cooling the unit. When the comil is turned off, this effective cooling is lost, and the screen temperature undergoes a step change.

Figure 8. Effective comil screen temperature over time as impeller speed is changed. The glass transition temperature (Tg) of the amorphous API material is shown for reference. This plot shows the data for Summix runs 3, 4 and 5.

(2) The round and square impellers were compared during Summix runs 1 and 2. While the comil unit was functioning, the screen temperature trends of the two impellers were similar. However, when the comil unit was turned off, the round impeller had a significant step change


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whereas the square impeller temperature remained relatively unchanged (Figure 9). This observation falls in-line with literature and vendor statements that the round impeller imparts more shear than the square impeller.

The temperature increase observed for the round impeller occurred after the comilling unit was turned off. When the comil is operating, the impeller spinning draws in a draft from the room, which in turn leads to convective cooling of the unit. Once the comil is turned off, this convective cooling is lost, and there is the observed step change in temperature.

Figure 9. Effect of impeller type (round or square) on effective comil screen temperature over time.

(3) The impact of screen aperture size on screen temperature was readily apparent after a very short period of time during Summix runs 1 and 2. The smallest screen size tested during pilot plant operation was 1905 (1.905mm). After ~10 minutes of comilling, API melting was observed on the underside of the comil screen (see Figure 10 below). In order to avoid such melting, the decision was made to only use the largest screen size available, which was the 6350 (6.350mm) screen. The 4750 (4.750mm) screen size was investigated during Rotary Dryer Run 1, but this size provided no added benefit.


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Figure 10. Melted API on the 1905 screen size after 10 minutes run time.

(4) Three different screen types were tested – the round screen, the square screen, and the grater screen. There was no added benefit of deviating from the typical round hole shape. In fact, the API had a tendency to coat the inner surface of the square and especially grater screen types. It is believed that this coating increased the residence time of the API inside the comil, thereby increasing its exposure to shear and temperature, leading to API glazing and melting. This glazing was limited to the API which was stuck, or had built up, on the screen. Complete melting would be likely if there was too much build up on the screen, as this would lead to increased residence time and temperature.

Figure 11. Picture which demonstrates the API glazing observed when the grater screen type was used.

The data from the above experiments of the 4 comil parameters allowed there to be a more informed decision about the optimal comilling conditions required for the API. The ideal conditions which were chosen were the 6350 round screen, with the square impeller operating at 1200 rpm. Based on the existing results, these conditions lead to minimal heat build-up on the screen, and therefore minimized the risk of API melting. The ideal conditions were


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demonstrated in the pilot plant via an extended run where the temperature was monitored. Figure 12 shows the clear benefits of the improved conditions – the comil was able to run for over an hour with little temperature increase, whereas with the original conditions, the temperature nearly reached the API amorphous glass transition temperature after only ~20 minutes.

Figure 12. Comparison of the heat generated in the old vs new comilling conditions.

An additional factor which impacts comil performance is the feed material and its physical properties. As previously mentioned, there were 3 different dryer types that had been used to dry the API, resulting in 3 different sets of physical properties (refer to Figure 4). The temperature profiles of these different feed materials in the comil are shown in Figure 13. Although there were minor changes in the temperature trends, the variation was < 4oC. In order to gain further understanding of the screen temperature dependence on material properties, lactose and sodium bicarbonate were comilled as surrogate materials. These temperature trends, which are shown in Figure 14, clearly demonstrate how the API has a different heat conductivity than the surrogates, leading to a steady temperature increase.


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Figure 13. Temperature trends of API which was dried in different dryer types.

Figure 14. Comparison of the impact of feed material on comilling temperature – API vs various other substrates.

When the API is compared to other solids such as lactose and sodium bicarbonate, the temperature trend clearly differs among those three materials. The API led to a substantial rise in the screen temperature, while sodium bicarbonate and lactose were comilled without a significant increase in temperature. This indicates that the API’s sensitivities to shear and temperature are somewhat unique, and pose certain challenges which may not be faced by every material comilled. The possibility of using lactose or sodium bicarbonate as surrogate solids for


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further development was therefore invalidated.

It is hypothesized that the extent of adhesion of solids onto the surface of the comil during delumping have a direct impact on the temperature trend and physical changes of the solids. The extent of adhesion decreases the efficacy of convective cooling (demonstrated by the control trend in Figure 14), and increases the time of exposure of the solids to shear and temperature. The physical properties which potentially result in melting include: 

High adhesive properties – for API, Carr’s Index  30%



Prone to amorphization under either shear or temperature – for API, minimum normal stress of 4 kPa required to generate amorphous



Low glass transition temperature – for API, Tg(amorphous)  45oC

Experimentation was scaled down to lab to generate further understanding of the specific physical properties of the API which increase the likelihood of melting in the comil unit (see point (3) of “Results and Discussion – Lab” section).

The target API feed rate range to meet commercial productivity requirements was 1 to 2 kg/min. In this range, there was no build-up of material in the comil chamber. The feed rate did not have a significant impact on the temperature trend, as shown in Figure 15. The increase in temperature was governed by the length of time the comil was run, not the feed rate. This indicated that the key route for API melting in the comil was passage through the screen, and not particle-particle collisions.


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Figure 15. Temperature trend for two runs with two different feed rates.

RESULTS AND DISCUSSION – LAB

From the pilot plant experiences, it was deduced that excessive melting of the API had occurred due to the combination of comil conditions (small screen, 1905, and high RPM), and product build up. These factors led to the increased temperature of the screen, which in turn led to the API melting. The melted API then hardened and completely plugged the comil screen, causing further build up in the comil unit and exacerbating the issue. The knowledge gained from the pilot plant was used to design a series of experiments at lab scale to achieve a more fundamental understanding of the API phase map and physical changes that occur during melting. The specific goals of the lab experiments were to: (1) understand how time to melt is influenced by the impeller speed, (2) understand how residence time varies with screen size and impeller speed, and (3) determine the key physical attributes that increase the risk of API melting.


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(1) The time required for API to melt as a function of impeller speed was determined in the lab by using the smallest screen size (156 screen, 0.156 mm pore size). This screen was so small that it acted as a barrier to the discharge of the product – thus, there could be no convective cooling of the powder within the delumping chamber. The lab comil was prefilled to ~30%, and then the comil was turned on at various impeller speeds. The time required for the API to melt was determined by visual and audible observations (there was a distinct change in the sound of the comil motor that indicated that the API was becoming “sticky” and causing the comil impeller to have difficulty rotating). Similar to the pilot plant experiments, the temperature of the screen as well as the API melting temperature was measured via thermocouples. This experimental set-up was artificially constrained in that there was no convective cooling from air draft, and many variables such as uniformity of mixing were not well controlled. However, this set-up was useful in achieving and exploring shear regimes that were inaccessible in other lab equipment.

Figure 16. Plot demonstrating the effect of impeller speed on API temperature and the time required to melt. The connected lines are the temperature of the screen, and individual points are the temperature of the melted API.

When the impeller speed was  2400 rpm, the temperatures increased significantly and the time to melt was extremely low, < 10 seconds. Also at these high speeds, the screen temperature and the API temperature differed significantly, indicating that the screen temperature may not be


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representative of the material. The mechanical energy input into the system was fast, but the heat transfer to the screen temperature probe may be delayed. Therefore, the screen temperature will provide little warning of imminent failure at high rotational speeds.

When the impeller speed was 1200 rpm, the time to melt increased dramatically, to > 180 seconds, and the screen temperature increased very gradually. Thus the temperature of the screen is more representative of the API temperature, and the process can be better controlled using a temperature data logger.

(2) In order to determine the residence time of the API in the screens used in the pilot plant study, the lab comil screen was completely filled with API and then the unit was turned on and a constant fill level was maintained. The graphical procedure is represented in Figure 17.

Figure 17. Set-up of lab comil used to determine the residence time of the API in the screen.

The residence time was calculated by dividing the volume of the material in the comil screen, V, by the volumetric feed rate, Fo. The residence time for 1143 and 1905 screens were 4.1 and 1.2 seconds, respectively. The residence time for 6350 screen could not be determined because it was too short to be measured accurately.


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The residence time for 1905 screen, which was 1.2 seconds, approached the time required to melt as seen in Figure 16 (5 seconds for 3600 rpm in the U10 unit). Operating in this narrow space increases the risk of API melting, and this explains why melting had occurred during in-line delumping (in-line comilling was conducted with the 1905 screen at 3600 rpm).

The 6350 screen was expected to have a residence time less than 1.2 seconds due to its larger aperture size. The 6350 screen at 1200 rpm provides the greatest buffer between the residence time in the unit and the time to melt, thereby mitigating the risk of API melting during the comil operation.

(3) The goal of the last set of lab experiments was to understand how changes in physical characteristics such as amorphous and solvent content lead up to catastrophic API melting. For these experiments, the 156 micron screen was used again to prevent the API from being discharged. The comil was run until the material started to catastrophically melt, and the time taken for this to occur was logged. Subsequent runs were conducted at the same comil conditions, but the runs were stopped prior to melting, and samples were collected. The results are shown in Figure 18.


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Figure 18. Graph showing changes in amorphous content and heptane content leading up to catastrophic melting. The heptane values were determined only for the red trend, shown in boxes located below each data point. Once the critical heptane content is lost (content < ~3.0wt%) the amorphous content increases more rapidly. Note that the red trend did not result in catastrophic API melt, but the impeller stopped rotating due to high compressibility of the material.

The amorphous content increases only approximately 20% throughout most of the run. This behavior is true for heptane content as well. There seems to be a critical point at which the material drastically loses heptane content and increases in amorphous content.

As previously mentioned, the API is prone to amorphization under exposure to shear and/or temperature. In order to correlate the shear force of the comil to impeller tip speed, the tangential force imparted by the impeller can be determined.

Figure 19. (left) Top view of the Comil; (right) Force body diagram on API particle.


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The tangential force of the comil provides the shear force to the API particle, and the normal force pushes the API through the comil screen hole. The equation for the tangential force, F, and normal force, FN can be determined by:

(

)

( )

Eqn. 3 Eqn. 4

√

Where:

Eqn. 2

m = mass of API particle (kg) d = impeller rotation diameter (mm) r = impeller rotation radius (mm) vtangential = tangential speed impeller pressure angle

Once the force on the body diagram is determined, shear stresses on material can be determined: Eqn. 5 Where:

Aimpeller = area of impeller facing the screen in contact with API normal = normal stress on the material

Using these equations, the shear stress that the API experiences as the impeller tip speed increases can be calculated: Table 3: Correlations between comil impeller speed and shear stress.

Comil Impeller Speed, rpm 1200 2400 3600

Shear Stress, kPa 2 8 18

According to previous characterization studies of the API (outside the scope of this article), amorphous material is generated when normal stress between 4kPa and 100MPa is applied. The


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shear applied by the comil can be enough to promote amorphorization, and the impeller speed directly impacts this shear force.

In order to understand which API physical attribute raises the risk of melting, the time required for melting was determined for various API lots with significantly different physical attributes. The set-up for these experiments was exactly the same as previously described – 156 micron screen size, comil pre-filled, and then run until melting observed. Several different material types were used for this experiment, as described in Figure 20. The last entry in Figure 20 describes material which was partially melted from the Summix, and then grinded into “powder” using a mortar and pestle.

Figure 20. Bar graph showing the dependence on time to melt on API physical attributes.

Before conducting the experiment, it was hypothesized that the material with the highest amorphous content would have the shortest time to melt because it was already partially melted. However, it was the material which had 0% amorphous content (the rotary dryer material), which melted the fastest. Additionally, the runs conducted using completely melted material from the


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in-line comilling operation did not undergo catastrophic melting, even when exposed to shear force for longer than 480 seconds. These results indicated that the rate of API melting is impacted by other physical attributes (besides amorphous) which affect the residence time inside the comil. These will be discussed in more detail later in this article.

RESULTS SUMMARY Table 3 summarizes the effect of comil conditions on key measures of success for the delumping step, which included lowering the risk of melting, minimizing the risk of amorphous formation, and normalizing powder flowability. The risk of melting and amorphous formation were separated into two categories because it was determined that material with high amorphous content does not necessarily melt the fastest (refer to previous section).

Table 4: Table summarizing the effect of Comil conditions on melting, screen temperature, and powder flowability

Risk of Melting

Risk of Amorphous Formation

Powder Flowability

High -For powder with poor flowability, high RPM creates turbulence that prevents the material from flowing down to the screen. -Some powder remains above the screen, causing melting. High -Smaller screens lead to longer residence times, and this increases the risk of melting.

High -Significant temperature rise with higher RPM (2400 and 3600) compared to lower RPM (1200). -Heat input increases the amorphous content. Low -No significant changes in amorphous content were observed. -Needs further investigation.

N/A -For runs using 6350 screens, RPM does not lead to significant changes in powder flowability. However, more data is needed to draw this conclusion. Low -The Carr’s Index values (flowability measure) are not significantly different based on screen sizes.

Screen Shape

Moderate -Grater screen led to coating of the API material on the screen.

Low -Screen shape does not seem to have a direct influence on amorphous formation.

Impeller Type

N/A -Only 2 runs comparing the effect of impeller type done in this study. -Melting observed in both runs because 1905 screen was used. -Needs further investigation to

N/A - Only 2 runs were conducted. -Amorphous content does not seem to be significantly affected based on impeller type. -Needs further investigation.

Low - The Carr’s Index values (flowability measure) are not significantly different based on screen types. N/A -Negligible difference in Carr’s Index values, but needs further investigation.

RPM

Screen Size


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Risk of Melting

Feed Rate Starting Material

understand the effect of impeller type on melting. High -In Lab study, overfeeding the system led to melting. Melting is a strong function of residence time. High -Although no melting was seen in the PILOT PLANT runs, the rotary dryer material was most susceptible to melting due to its unique physical attributes.

Risk of Amorphous Formation

Powder Flowability

N/A -Needs further investigation.

N/A -Not investigated.

Moderate -While there was no change in amorphous content for rotary dried material, for Summix dried material the amorphous content changed significantly (high granule strength of Summix material hypothesized to be cause).

High -The Comil is able to change the particle size and normalize flow properties if the starting material is large enough -The Summix material was large, so this applies -The rotary dryer material was small, so this does not apply.

As previously mentioned, the desolvated crystalline API is shear sensitive, causing it to readily convert to amorphous with heat (either frictional or mechanical) or shear stress from the comil impeller. The crystalline API is highly compressible and flows poorly compared to the amorphous material. Thus, it is hypothesized that the desolvated crystalline API is converted to heated amorphous material, which may immediately reach the glass transition point to melt. This may explain why poorly flowing API which has the highest Carr’s index value, has the shortest time to melt despite being low in amorphous content. The rotary-dried API had needle-like particles that were ungranulated. The high surface area of this material compared to the granulated material of the Summix caused this API to be prone to heating up faster and having a shorter time to melt.

The heat required to melt the amorphous material is speculated to come from frictional heat. When the material is already amorphous, the time to melt is significantly longer, which may be because the amorphous material has different heat transfer properties, good flow properties, and


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is less likely to be compressed to the comil screen. Thus the material requires more time to heat up, and is less likely to melt catastrophically compared to the shear sensitive, poorly-flowing anhydrous crystalline material.

CONCLUSIONS Through the use of temperature monitoring during API comilling, it was determined that the impeller speed and screen size are the key parameters which affect comil performance. The temperature data led to the development and demonstration of robust comil conditions at pilot scale. The 6350 round screen with impeller speed of 1200 rpm (U10 model) provided a stable delumping process that mitigated the risk of API melting. These comil conditions were used to successfully normalize powder flowability and remove batch to batch variability, thereby leading to less issues during downstream drug product manufacture. Additionally, these comil conditions allowed the target feed rate to be achieved which met the commercial productivity for this API – this was demonstrated by over 200 kg of API which was successfully delumped at pilot scale.

Successfully scaled-down experiments in the lab comil unit provided further understanding of the impacts of physical properties of the API on comil performance. Solids which (a) have greater adhesive properties, (b) are prone to amorphization, and (c) have a low glass transition temperature, are more likely to display an elevated temperature trend in the comil, potentially leading to melting. Any solid which demonstrates similar physical tendencies is expected to behave in a similar manner during comilling.


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ACKNOWLEDGEMENTS

This project was made possible through the support and execution of the pilot studies by the MSO pilot plant staff in Rahway, NJ. The staff involved in this project included Joram Kibuthu, David Lashen, Glenn Spencer, Anna Jenks, supervisors and operators. The Rahway PDM group provided the thermal imaging services of the empty pilot plant comil to understand temperature profiles in the unit. Elizabeth Fisher and Pedro Aresta provided support with the execution and set-up of the lab studies. Lisa Wright provided support for GC analysis of the solvent content of lab and pilot plant API samples.

Thank you to all involved parties. These experiments were iterative and required a great deal of oversight due to the unique challenges of the specific API in question. The dedication and willingness of the team to provide this oversight made the work shown here possible.

REFERENCES 1

Quadro® Comil® Underdriven Series Website and Product Bulletin, http://www.quadrocomil.com/documents/Flyer_Comil_Underiven.pdf 2

Quadro®. “Quadro Tech Tips: Solids Processing.” http://www.thurne.se/pdf/Welcome_to_the.pdf 3

Quadro® Comil® Tooling Selection Sales Technical Bulletin STB008, http://www.sawyerhanson.com/uploads/docs/Quadro%20catalog/Comil%20Tooling%20Selectio n.pdf 4

Samanta A. K., Ng K. Y., and Heng P.W.S. Int. J. Pharm. 2012, 17-23.

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Carr, R.L.; Chem. Eng. 1965, 72, 163-168.


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6

Kanig, J. L.; Lachman, L.; Lieberman, H. A. (1986). The Theory and Practice of Industrial Pharmacy (3 ed.). Philadelphia: Lea & Febiger. 7

©2004 Hanson Research Corporation, “Flodex Operation Manual”: Section 2, Page 6


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Effects of Comilling on Final API Physical Attributes - Organic Process

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