Mechanistic Elucidation of Hard Agglomerate Formation from Drying

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Mechanistic Elucidation of Hard Agglomerate Formation from Drying Kinetics in the Integrated Sorption Chamber Daniel S Hsieh, Mark Lindrud, Ming Hsing Huang, Steven H. Chan, Deniz Erdemir, and Joshua D. Engstrom Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00052 • Publication Date (Web): 25 Apr 2018 Downloaded from http://pubs.acs.org on April 26, 2018

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Organic Process Research & Development

Mechanistic Elucidation of Hard Agglomerate Formation from Drying Kinetics in the Integrated Sorption Chamber Daniel S. Hsieh*1, Mark Lindrud2, Ming Huang3, Steven H. Chan1, Deniz Erdemir1, and Joshua D. Engstrom1 1 Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States 2 Research & Development External Manufacturing, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States 3 Chemical & Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States * E-mail: [email protected]

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ABSTRACT The formation of hard agglomerates during drying has impacts on the product quality, particle size distribution and downstream formulation. Hence, understanding the cause of hard agglomerates and determining a remedy or prevention of such formation are necessary. The integrated sorption chamber (ISC) has been successfully applied for the study of the formation of hard agglomerates. The design and the development of this ISC are briefly described. The vapor phase profile of a binary mixture of acetone and water without active pharmaceutical ingredient (API) was predicted using an analytical solution of a batch distillation and verified via mass spectrometry (MS). The drying of the API wet cake, which is very soluble in water, using a starting point of 5 wt% water in acetone was conducted in the ISC. A significant delay in water removal was observed from both the weight measurement and from the MS signal. The slow removal of water was attributed to the diffusion of water from a thin crust layer induced by the solution of API in water and drying, resulting in forming hard agglomerates at the end of drying. A wet cake solvent composition change following a cake wash with acetone reduced the initial water content from 5.5 wt% to 0.5 wt%. This altered wet cake solvent composition changed the behavior of water removal, leading to a significant reduction of the diffusion time. The dried API contained soft lumps without hard agglomerates.

KEY WORDS API, Drying, Sorption Chamber, Raman, Mass Spectroscopy, Hard Agglomerates


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1. INTRODUCTION Approximately 30% of active pharmaceutical ingredients (API) experience agglomeration, granulation, and breakage during agitated drying.1 There are several laboratory tools to study the formation of agglomerates. These, include, but are not limited to a small-scale mixer-torque rheometer (MTR),2 which help predict particle properties upon scale-up, and acoustic mixers,1 which aid in the assessment of granulation behavior. The results of testing materials in such equipment have been successfully used to define suitable plant-scale drying conditions which avoid agglomeration.3-4 It should be noted however, that the above mentioned laboratory tools focus on the impact of shear forces on the morphology of a wet cake upon drying. For the case studied here, the mechanism which causes formation of hard agglomerates is best understood when determined in the early stage of drying process development by using a static method such as a drying chamber. Such a chamber has been described in a paper5 published by the Enabling Technologies Consortium6 (ETC). The paper introduced a custom drying chamber designed by Bristol-Myers Squibb (BMS), but no details of its design and development were provided. This drying chamber was used to investigate a case where hard agglomerates formed during the drying of an API wet cake which had been washed with a mixture of acetone and water.7 The objective of this study is to communicate both the theoretical and experimental approaches used to understand the formation of such hard agglomerates and how to avoid such process challenges by using an integrated process development plan for crystallization, filtration, washing, and drying of APIs. The experimental approach described includes the design of the integrated sorption chamber (ISC), the use of process mass spectroscopy (MS) to verify the pattern of vapor concentration profiles (both with API and without API), and the use of gravimetric drying curves to elucidate drying mechanisms. In addition, the method used to characterize the hard agglomerates is documented.8 The theoretical approach includes the prediction of the concentration profile of the vapor phase and the diffusion model for the removal of water from a thin layer of hard cake. Since the solvent mixture includes both acetone and water, an analytical solution of batch distillation is used to establish the composition trend in the vapor phase. A Fickian diffusion model9 is used to characterize the mass transfer of water through the thin layer of the hard cake. The results from both experimental and theoretical approaches provides a fundamental understanding of the formation of the hard agglomerates upon drying. On the basis of this understanding, a washing protocol is proposed to eliminate hard agglomerate formation. The development of the optimal drying protocol5,10 requires a fundamental mechanistic understanding of the drying process and the impact of shear forces on particle morphology. The formation of hard agglomerates is closely related to the interaction between API and the solvent and the shear force during drying. The use of the ISC (static method) provides the basic drying curves, vapor phase composition, and the potential structure change. The ISC approach presented in this study is a static method to elucidate the mechanism of the formation of hard agglomerates. The focus of this approach is placed on the interaction between API and solvent, but the effect of the shear forces on such formation needs to be investigated by using dynamic methods such as a 3 ACS Paragon Plus Environment


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mixer-torque rheometer which are documented in the literature. Each is critical to the mechanistic understanding of the drying process. The use of an agitated filter dryer or acoustic mixer (a dynamic method)1-4 identifies the impact of the shear forces on particle morphology on drying. Hence the static method using ISC and the dynamic methods are complimentary and important for understanding and estimating the formation of hard agglomerates during drying. The elucidation of the mechanism of hard agglomerate formation is closely related to the design and the development of the Integrated Sorption Chamber (ISC). The intent of developing the ISC was to enable collection of engineering data for drying process development as well as providing large enough samples for downstream formulation development. A brief comparison between the design of the ISC vs Thermogravimetric Analysis (TGA) and Dynamic Vapor Sorption (DVS) is provided to support the design and use of the ISC. Appendix 1 includes a history of the development of the ISC as investigative opportunities revealed the need for additional capabilities.

2. THEORETICAL AND EXPERIMENTAL APPROACH 2.1.

Prediction of the Vapor Phase Concentration Profile for Acetone and Water

As a solvent mixture is removed from material surfaces (in this case API) upon drying, this mass transfer can be characterized by using a batch distillation model. The purpose of setting up a model is to provide an understanding of the physical significance of the process. This modeling can be carried out either by using an analytical method or a method using a computer software package such as ASPEN™ Plus. Regardless of which method is used for a batch distillation, the physical properties of the acetone and water mixture in terms of the vapor liquid equilibrium as a function of temperature, pressure and concentration need to be evaluated to ensure the physical properties of this mixture are accurate. The importance of this evaluation has been documented in details in the literature.11,12 There are several simulation programs such as ASPEN™ Plus, DynoChem®, etc. that predict the vapor phase composition for batch distillations. However, this study utilizes a simple analytical solution, which provides sufficient physical insight into the batch distillation of a mixture of acetone and water and predicts the vapor phase concentration profile. It should be noted that the results of modeling from either an analytical method or a computer simulation program need to be verified with experimental data. Relative volatility of the mixture of acetone and water The concept of the relative volatility (i.e. separation factor) is commonly used to describe the behavior of the separation of a mixture by distillation12. The relative volatility is defined by , where =

/

(1)

/


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where y and x are the mole fractions of components i and j in the vapor phase and in the liquid phase at equilibrium respectively. The subscript i is for the light component (acetone) and the subscript j is for the heavy component (water). The value of the relative volatility is related to the vapor pressure of each component. Large relative volatilities (separation factors) imply large difference in boiling point and easy separation. Close boiling points imply relative volatilities (separation factors) closer to unity and difficult separation. Since the drying of a liquid mixture from the API surface can be simulated via a batch distillation, the results of the derivation of the liquid phase composition as a function of the relative distillate at a constant relative volatility for a batch distillation are available13 and they are expressed as:

= 1

∗

(2)

The notation for the parameters and variables used in eq 1 and eq 2 are listed in Table 1 for clarity. Table 1. Parameters and variables used in eq 1 and eq 2

αij xi or x yi or y xF F D D/F

Relative volatility of compound i with respect to compound j Acetone concentration in the liquid phase, mole fraction Acetone concentration in the vapor phase, mole fraction Concentration of acetone at the beginning of drying, mole fraction Liquid amount in its initial state, mole Amount of overhead product, mole Relative distillate

The value of x as a function of D/F can be found by solving eq 2 using the built-in Excel data analysis Solver14. After the value of x is determined from eq 2, the acetone concentration in the vapor phase, y, can be obtained from eq 3 below. =

∗

(3)

∗

As the acetone and water vapor phase concentrations are determined, a figure of the vapor phase composition as a function of D/F can be established. 2.2. Diffusion of Water from a Layer of Hard Cake The mathematical Fickian diffusion model, as shown in Figure 1, is set up to describe the removal of water from a layer of hard cake:

Figure 1 - Geometry of the slab and the schematic of the drying process.



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The Fick’s law expression, by assuming a constant diffusion coefficient and one-dimensional diffusion, is written as follows:

=

(4)

Initial Condition: C = C0, t =0, - ! < Z < ! Boundary Conditions: 1.

Z = !, C=0, t > 0

2.

Z = -!, C=0, t > 0

where D is the diffusion coefficient, C is the concentration of solvent, Z is the direction of the diffusion, t is time, and C0 is the initial concentration of water before drying. The thickness of the plane sheet is 2!. To solve eq 4, four assumptions are made. First, a uniform water concentration is present through the slab at the beginning of the drying. Second, the diffusion occurs in Z direction. Third, the diffusion coefficient is not a function of water concentration and fourth, the slab is indefinitely long and no end effect occurs. The partial differential eq 4 can be solved by the method of separation of variables and its solution is available in the literature.10,15 The solution of eq 4 in terms of concentration as a function of time and location can be integrated from −! to +! to provide the measurable quantity in terms of weight loss as a function of drying time as follows: "#

"$

&

= ∑* (+, '( ) exp 0

'( ) 12

3

(5)

where M0 is the weight of water before the diffusion process, Mt is the weight of water at drying time t, and n is an integer. Although eq 5 provides the relationship between the weight change and drying time, it does not offer a clear analytical relationship between the weight loss and the drying time at the beginning of drying when t is small. This kind of relationship can be obtained from the solution of eq 4 via the Laplace transformation, as described in the literature.10,15 The solution from this transformation is provided as follows: "#

"$

= 1 2 )2

'

5

'

(6)

Equation 6 offers two useful features of Fickian diffusion. First, the plot of dimensionless weight loss 6 ⁄6, vs. the square root of drying time is linear when time is small. This linear relationship is valid when the value of 6 ⁄6, is less than 0.5. Second, the value of the diffusion coefficient can be determined from eq 6 if the diffusion length 2! is known. 2.3.

Material and Methods

The Integrated Sorption Chamber (ISC) designed and constructed by authors and presented here is a tool for drying process development. A history of the development of the ISC is provided in 6 ACS Paragon Plus Environment

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Appendix 1. The difference between this sorption chamber and TGA16 or DVS,17,18 which are primarily used for the characterization of API, can be summarized in the following two areas: sample size and bulk powder property responses, and engineering data generation. These two areas are described below. A. Sample size and bulk property determination. The ISC is equipped with a load cell to monitor the weight change of the analyte. The sample size range in this chamber can be from 10 to 50 grams, or ever higher with a modified sample holder. In contrast, microbalances used for both TGA and DVS generally limit the sample size to less than a few hundred milligrams or grams, respectively. For example, the sample mass range for the DVS Adventure19 instrument is from 1 mg to 5000 mg. In contrast, the sample size for flowability measurements of dried product, which is a common critical quality attribute6 (CQA) for downstream drug product formulation, requires more than 40 grams of dried product. This quantity of dried API can be produced by the ISC in one operation. For drying process development, the focus is on bulk powder properties which involve the interaction between particles in the presence of solvent mixture. In addition, some properties, such as the formation of hard agglomerates, are observed only in bulk materials since they are dependent upon the bulk packing of the wet cake and can be better determined when generated by drying large amounts of material. B. Engineering data generation. The drying of API involves both heat transfer into the material and the mass transfer of the solvents. These two activities are coupled together and determine the cycle time of the drying process. High vacuum levels typically used in commercial size dryers result in most heat transfer for API drying to occur via conduction. Nearly all commercial size dryers for API drying such as the filter dryers, tumbler dryers or conical dryers11 have heated jacketed walls for providing heat to the API. Heat transfer in the ISC is very similar to that in a static commercial dryer. The types of mass transfer for API drying involve constant rate period and falling rate period6 and these two types of mass transfer coupled with heat transfer can be monitored in the ISC. During development of an API drying process the effect of temperature on either type of mass transfer needs to be studied to determine the major mass transfer resistance as a function of temperature. The ISC can be utilized for such studies because the operating temperature of the ISC can be 90 °C or higher. In fact, API thermal stability limits usually determine the maximum temperature settings of the ISC in such development studies.10 Additional material characterization, such as measuring the hardness of the observed agglomerates, was performed using a TA TXPlus Texture Analyzer (Texture Technologies Corp., Hamilton, MA/ Stable Micro Systems, Godalming, Surrey, UK). The hardness of a material is determined by placing a sample on a flat stable surface. Data collection occurs as a ball probe with a diameter of 0.125 inches (TA-8A) travels vertically downward in the compressive mode with a constant speed of 0.01 mm/sec until the agglomerate is broken, as evidenced from the abrupt drop in the force profile. Further technical details in the calculation of Young’s Modulus, defined as the mechanical strength of the material, have been discussed previously.8 Note that prior to performing any measurements with the TA TXPlus Texture 7 ACS Paragon Plus Environment


Analyzer, a calibration without any sample is performed in order to know the exact position of the ground surface. With an agglomerate placed on this surface, the Texture Analyzer starts taking measurements when a trigger force of 0.5 gm is sensed and this distance value is set to zero.


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3. RESULTS AND DISCUSSION 3.1.

Hard Agglomerate Formation

Compound A is an API currently under development which is crystallized from an acetone:water 90:10 (wt:wt) solvent system. During early development, the wet cake of Compound A was found to form hard agglomerates after drying; and a chisel was required to break and remove the dried cake from the laboratory filter. The evidence for the formation of hard crust can be obtained from the results by using the TXPlus Texture Analyzer as shown in Figure 2.

Figure 2. Force vs. the penetration distance from a Texture Analyzer

Figure 2 shows a typical breakage profile when a ball probe is in contact with an agglomerate as it moves vertically in the downward direction. In the above example, the agglomerate height is determined to be 1.831 mm (x-axis), which is determined from the distance when the force on the agglomerate is triggered with respect to the ground surface. The crust thickness is defined as the distance between when there is a sudden change in the force profile to the zero position. The sudden drop in force is indicative of a change in the mechanical properties of the material. In this example, the crust thickness is determined to be 0.36 mm. The hardness of these agglomerates was measured using the previously described TXPlus Texture Analyzer. Typical values of Young’s Modulus for the agglomerates of Compound A ranged from 3.8 to 5.3 MPa. In terms of mechanical strength, values of Young’s Modulus exceeding 3.5 MPa are generally considered hard in the pharmaceutical industry. The formation of such hard agglomerates in the batch is unacceptable because such materials would have a negative impact on both the powder properties and the drug content uniformity. Since these hard lumps were formed during drying the ISC was utilized to understand the mechanism of agglomerate formation and accordingly identify a means to prevent it from occurring. A systematic approach to understand API drying has been adopted. This approach includes the prediction of evaporation of a binary mixture, the measurement of vapor composition by using MS, the determination of the drying curve from weight loss measurements during drying, and the elucidation of agglomerate formation. 9 ACS Paragon Plus Environment


The wet cake of Compound A after filtration contains both water and acetone. Water is the solvent and acetone is the anti-solvent used in the course of Compound A crystallization. The API surface is wetted with both water and acetone. It is expected that the removal of acetone and water will follow the predicted evaporation behavior of a binary mixture of acetone and water. 3.2.

Batch Distillation of the Solvent Mixture of Acetone and Water

Since the drying of API can be conducted at various pressures, the separation of acetone from water becomes easier when the drying pressure is reduced. This is expected because the value of the relative volatility (separation factor) become higher with the reduction of pressure. This relationship between the acetone concentration in the liquid phase and the separation factor is illustrated in Figure 3.

Figure 3. Relative volatility of acetone wrt water at various pressures and liquid composition

It should be noted that the separation of acetone from water is also dependent upon the liquid composition of the water and acetone mixture, as shown in Figure 3. For example, the value of the relative volatility is equal to 5.45 at 100 mmHg for pure acetone while the value of relative volatility is equal to 46 for water alone. This means that at this pressure it is difficult to separate acetone from the acetone rich region (xacetone is close to 1), but it becomes easy to separate acetone from water rich region (xacetone is close to 0). The drying of API is normally carried out at a reduced pressure such as 100 mmHg. This pressure lowers the wet cake temperature and increases the temperature gradient, and hence increases the heat transfer rate, between the jacket wall and the bulk of wet cake. The pressure value of 100 mmHg is used here to simulate the separation of acetone from water to illustrate the physical insight of this separation.


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The relative volatility for acetone and water binary mixture at various pressures and liquid compositions can be calculated from the VLE (vapor liquid equilibrium) data from the Dortmund Data Bank.20 Results of this calculation are shown in Figure 3. Two conditions of batch distillation are presented here: one is for the batch distillation at α = 5 to mimic the acetone separation from the feed composition (xF=0.73, 90 wt% of acetone) and the other is for the batch distillation at α = 40 to mimic the acetone separation from pure water. Since the relative volatility of acetone in these mixtures increases from 5 to 40 as the batch distillation progresses these two values of α represent the vapor phase composition profile at the start and end of the drying process. The results of the calculation using eq 2 show in Figures 4(a) and 4(b) that the vapor phase composition of the batch distillation (evaporation) can be approximately described by using three step functions. The step function is defined by a slowly changing concentration value when D/F is low; then, as the value of D/F increases, the component concentration either rapidly decreases to zero or increases to a higher value. By using this definition, the first two step functions occur at the beginning of evaporation, one for acetone at a high concentration and the other for water at a low concentration. The remaining step function applies to the system when the water concentration is high. This third step function emerges when xacetone= 0.

Figure 4(a). Vapor phase composition as a function of relative distillate (α = 5)

Figure 4(b). Vapor phase composition as a function of relative distillate (α = 40)

The results from this simulation show a very interesting evaporation behavior: after the acetone is completely removed (xacetone= 0), there is still some water left on API surface. This phenomenon occurs when the value of D/F is equal to 0.95 (α = 5) and 0.8 (α = 40). The prediction pattern of the vapor phase composition shown in Figures 4(a) and 4(b) can be verified using the capability of the ISC to monitor the vapor phase composition using MS. 11 ACS Paragon Plus Environment


MS Pattern of Evaporation of Acetone and Water Mixture Three step functions are used in Figure 4 to predict the vapor phase composition. This prediction can be verified by using MS in the ISC. As illustrated in Figure 5, an acetone and water mixture (90:10 wt.%) is placed inside the oven at 55 °C and 100 mmHg. The ISC oven can be treated as a plug flow tank reactor (PFTR). The vapor generated from the sample can be treated as the input to the PFTR which is mixed first and the output from the oven is monitored by MS. The results of this evaporation are presented in Figure 6.

Figure 5. The setup for the evaporation in the ISC

Figure 6. Vapor phase composition of acetone and water during evaporation from MS at T = 55 ⁰C and P = 100 mmHg

The composition of the vapor phase of acetone and water collected by MS as shown in Figure 6 is consistent with the prediction of the batch distillation shown in Figure 4. Note that the acetone and water trends use different y-axis scales. Two solvent trend step functions emerge at the beginning of drying. As the step function of acetone goes to zero, the step function for water at a higher concentration emerges and then also gradually goes to zero when water in the cup has completely evaporated. It should be noted that the concentration profile in the effluent from the oven is not a perfect step function because of two possible reasons. First, at the beginning of drying, the pressure in the oven was slightly higher than the set point pressure which resulted in a higher concentration of acetone or water. Second, the oven is not a perfect plug flow reactor; therefore, some mixing would occur in the oven resulting in slight decay of the concentration profile as the concentration of each component drops from the peak to the bottom.


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It should be noted that the signal from MS is the response intensity of the solvent, not the concentration. A calibration is usually needed to convert the signal intensity to a concentration value. In this study, such a conversion is not necessary because the results from the MS are used for a qualitative pattern recognition. The pattern shown in Figure 6 presents the evaporation behavior (drying behavior) of the mixture of acetone and water. If the drying behavior deviates from the pattern in Figure 6, the drying mechanism is caused by a mechanism other than evaporation. 3.3.

Drying Experiment

To understand the drying mechanisms of Compound A, a wet cake (111.6 g), which was recovered from slurry with a solvent mixture of water (10 Vol%) and acetone (90 Vol%) and subsequently washed with the same solvent composition was dried in the oven (tray drying) at 55 ºC and 100 mmHg. The initial water content of the wet cake was measured as 5.5 wt% by Karl Fischer (KF) analysis. The oven was equipped with a balance to measure the wet cake weight change as a function of time. The vapor composition during drying was analyzed with mass spectroscopy (MS). MS Pattern for Drying of Wet Cake Figure 7(a) shows the acetone and water MS responses from Figure 6. In this instance, the yaxis scaling for each component is the same. The magnitude of each trends is approximately proportional to the vapor phase composition. Figure 7(b) shows the MS trends of the drying of the wet cake of Compound A after acetone and water wash. The MS pattern for water in Figure 7(b) is different in two aspects in comparison with the one in Figure 7(a). First, as the acetone intensity goes to zero at 100 minutes in Figure 7(b), the water intensity in Figure 7(b) does not rise as sharply as that shown in Figure 7(a). Second, the water trend from the wet cake takes longer to drop to zero. As illustrated in Figure 7(a), the drying time for water, 90 minutes, is almost twice as much as that for acetone, 50 minutes. However, the drying time (300 minutes) for water in the presence of Compound A is almost three times longer than that for acetone, which is 100 minutes. This difference indicates that the removal of water from the wet cake does not follow the typical evaporation behavior and that a drying mechanism other than evaporation needs be taken into account.

(a)

(b)

Figure 7. MS of drying in the oven at 55°C and 100 mmHg (a) acetone/water (b)acetone/water/API 13 ACS Paragon Plus Environment


Drying Curve for the Removal of Acetone and Water from the Wet Cake of Compound A As mentioned previously, mass transfer during API drying may include both a constant rate period and a falling rate period6. The constant rate period is attributed to the removal of solvent from the API surface. The falling rate period may be due to the removal of solvent from the interior of the material being dried (which can be spray dried dispersion (SDD) drug product, a solvate form of API or non-solvated API). Both types of mass transfer were observed by using the ISC and published earlier.9,10. The gravimetric drying curve for Compound A is presented in Figure 8; it shows the weight change as a function of time. From Figure 7(b), it is known that acetone can no longer be detected from MS after 100 minutes and it is assumed that acetone is completely removed from the API surface. Hence, the weight loss in Figure 8 can be divided into two stages. In Stage I both acetone and some water are removed from the API surface and in Stage II only water is removed from the API. Both stages are discussed below.

Figure 8. Weight loss as a function of time during drying and mass transfer via evaporation

Stage I: Removal of Acetone and Water from API Surface At the beginning of Stage I, the rate of weight loss is constant which indicates the removal of mainly acetone from the API surface since acetone is much more volatile than water. As the drying process continues, the water concentration in the liquid increases, causing the boiling temperature of the liquid mixture and the heat of vaporization to increase and therefore the heat transfer rate to decrease. Hence, the rate of the weight loss decreases as shown in Figure 8. Stage II: Water Removal from API The early drying trends above (Figure 8) show that the rate of weight loss is constant when a single solvent is removed from the API surface at a constant temperature and pressure. This statement is true when the drying mechanism is accomplished solely through evaporation. From Figures 7 and 8 it can be seen that after 100 minutes only water is removed from API, but the rate of weight loss is not constant. Instead it is changing with time. This indicates that the removal of water from API in Stage II proceeds through a mechanism other than evaporation. 14 ACS Paragon Plus Environment

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This finding is consistent with the results of the diagnosis by the using the pattern recognition from MS. Drying Mechanisms of Stage II The drying mechanism in Stage II can be classified as solvent diffusion in the solid because the relationship between the weight change and the square root of time is linear at the beginning of drying (Figure 9). This linear behavior is characteristic of a Fickian diffusion process.10

Figure 9. Weight loss as a function of square root of time and mass transfer via diffusion

Efforts have been made to simulate the diffusion of water from API. The mathematical expressions in eq 5 and eq 6 were used for this simulation. A comparison between the collected drying data and the prediction from the diffusion model is shown in Figure 10. A good agreement between the data and the modelled prediction was observed. However, it should be noted that this good agreement shows that the drying curve exhibits some Fickian diffusion behavior and can be approximately described by using eq 5 and eq 6.

Figure 10. Comparison between the drying data and the prediction from diffusion model

Agglomerate Formation



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The drying mechanism change from evaporation in Stage I to diffusion in Stage II is due to agglomerate formation illustrated in Figure 9 and Figure 10. When acetone is completely removed from the API surface, pure water remains on the API surface. Since Compound A is very soluble in water, a paste on the API surface forms immediately. As water is removed from the paste during drying, a thin continuous crust layer forms on the outer surface of the paste. As water continues to be removed by diffusion through the paste, the crust thickens and hard agglomerates of API particles are formed, as shown in Figure 11. It should be noted that when a bundle of API particles is packed together in the pan used for drying in the integrated sorption chamber, the formation of hard agglomerates is easily observed. This agglomerate formation may not be observed when the sample size is small (e.g. mg range). Stage I • Water left on API surface. • API soluble in water and a mixture of API and water forms.

Stage II • A thin crust (barrier) forms on surface. • Water trapped inside the barrier, water removal through diffusion, not evaporation.

Water Removal

Water Removal

API

API

Drying Time

Stage III • Water removal is complete. • API particles are fused together and hard agglomerates form.

API

API

Key: API Paste (API and water) Crust (Dried API) Figure 11. Stages of hard agglomerate formation upon water removal


API

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3.4.

Proposed Route to Prevent Hard Agglomerate Formation

The formation of the agglomerates is attributed to the high residual water content remaining in the wet cake (5.5 wt%) which acts as the binding agent during drying as depicted in Figure 11. The agglomerates were also noticeable in the SEM images (Figure 12). In order to determine the minimum amount of acetone wash required to effectively remove water and prevent agglomerate formation, a series of wash studies were performed. The cake was washed with different volumes of acetone and the water content of the cake was measured by KF analysis. It was observed that the water content of the cake decreased with an increased wash volume (1 wt% with a 5 volume wash and 0.6 wt% with a 10 volume wash). After 15 volumes of acetone wash, the water content of the wet cake only slightly decreased to 0.5 wt%. Therefore, any additional acetone wash was ineffective in reducing the water content further.

(a)

(b)

Figure 12. SEM Images of (a) dried material with initial water content of 5.5 wt% prior to drying, (b) dried material with initial water content of 0.5wt% prior to drying.

Accordingly, wet cake was washed with 15 volumes of acetone to reduce the initial water content to 0.5 wt%. The dried product was a loose powder, free of any hard agglomerates. In addition, no agglomeration was observed in SEM images (Figure 12(b)). This resulted in a change in vapor phase profile as shown in Figure 13. As the vapor phase profile in Figure 13 is compared with those in Figures 7(a) and 7(b), some interesting observations are made. The acetone vapor phase profiles in these three figures are very similar, typical evaporation behavior. However, the water vapor phase profile in Figure 13 can be described as the combination of evaporation and diffusion. Before the acetone vapor concentration drops to zero, the water vapor phase behavior (Figure 13) is very similar to that of evaporation described in Figure 7(a). However, after the water concentration rises, it does not drop rapidly; instead it decreases gradually and levels off, similar to the water vapor phase behavior in Figure 7(b), caused by the diffusion constraint. However, the time required from the rise at 110 minutes to a point where it no longer changes at 200 minutes is only 90 minutes (Figure 13). This time is much less than when the initial wet cake water content is 5.5 wt% (Figure 7 (b)), where the complete water 17 ACS Paragon Plus Environment


removal takes approximately 200 minutes (experiment drying time from t=100 minutes to t=300 minutes).

Figure 13. Vapor phase profile during drying for wet cake with initial water content of 0.5 wt%

CONCLUSIONS The integrated sorption chamber (ISC) has been successfully applied for the study of the formation of hard agglomerates. The vapor phase profile of a binary mixture of acetone and water without API was demonstrated and established via MS, which is in a good agreement with the prediction from a batch distillation of this binary mixture. The vapor phase profile of the wet cake of API with acetone and water with the initial water content 5.5 wt% during drying was established. A significant delay in water removal from Compound A wet cake was observed from weight measurement and from MS. The slow removal of water was attributed to the diffusion of water from a thin layer of crust induced by the solution of Compound A in water and drying, resulting in the formation of hard agglomerates at the end of drying. A thorough acetone washing reduced the initial water content from 5.5 wt% to 0.5 wt% and changed the behavior of water removal, resulting in significant reduction of the diffusion time and producing dried API that contained soft lumps but no hard agglomerates.

ACKNOWLEDGEMENTS The authors would like to thank project team members for providing technical discussions.


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APPENDIX 1 Development Timeline for the Integrated Sorption Chamber The development of the ISC can be divided into three phases. These phases are summarized in Table A1 and further described below. Table A1 – Phases of ISC development

Development I phase of ISC Early development of a Description Functionality Purpose

sorption chamber Primitive, with a Sartorius balance placed inside a vacuum oven Gravimetric and MS data collection Elucidation of hard lump agglomerate formation (current study) Maximum drying temperature is ~50 °C

Documented application Limitation identified

II Upgrade of the sorption chamber Balance electronics isolated from heated chamber Expand temperature operating range up to 90 °C Secondary drying for Spray Dried Dispersive (SDD) drug product.9 Limited application of PAT

III Formation of ISC Probe well installed

Collection of Raman and/or IR spectra of drying samples Optimal drying protocol for solvate drying.10 N/A

Phase I: Early development of a sorption chamber The drying of API is an important unit operation, but it is often overlooked and not fully investigated until later in the development cycle. This frequently occurs because many drying related issues are only discovered upon scale up or the drying process is transferred from one type of dryer to another.6 Therefore, the understanding of the drying mechanism and the need of a large quantity of sample such as 40 g for testing flow ability for downstream formulation development in the early phase of the API process become critical and required. On the basis of these requirements, a simple sorption chamber incorporating the primary drying tools shown in Figure A1 was designed and constructed.7 This sorption chamber is composed of three elements: vacuum oven (Figure A1(a)), electronic balance (Figure A1(b)) and mass spectrometer (MS) (Figure A1 (c)). The balance is placed in the oven and the oven equipped with vacuum pumps is connected to the MS.

(a)

(b)

(c) 19

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Figure A1. A simple sorption chamber is composed of (a) oven (b) balance and (c) MS

This simple sorption chamber developed at this phase was used for the study of agglomerate formation during drying7 and the details of this study will be presented in the current paper. Phase II: Upgrade of the Sorption Chamber The simple sorption chamber developed in Phase I has one major drawback: a limited temperature range due to the placement of the balance inside the heated drying chamber. The balance manufacturer’s specified operating temperature range for the electronic balance is from 5 °C to 40 °C. This temperature range significantly limits the usefulness of the sorption chamber due to the potential need to dry API at temperatures up to 90 °C. Hence, the simple sorption chamber developed in Phase I needed to be modified. The updated specifications for a revised sorption chamber therefore included a potential operating temperature range from ambient temperature up to 90 °C, a weighing capacity higher than 100 g, and an accurate weight readability of 1 mg. To meet those requirements, a load cell (Sartorius WZA523-CW) with a weighing capacity of 520 g and a weight readability resolution of 1 mg was selected and sealed in a housing. This housing is mounted above the oven and is connected to the oven via a pipe with a diameter less than 1 inch as shown in Figure A2. The housing design and connection to the oven serves a few purposes. First, the load cell in the housing can be connected to the weighing pan in the oven with a wire through the pipe. Second, the conduit allows the load cell housing to have the same pressure levels as the oven. Third, even at high oven operating temperatures, the load cell operating temperature can be maintained below 40 °C by means of limited conduction, nitrogen sweep, or active cooling. Finally, the diameter of the pipe is chosen to be large enough to allow the wire connecting between the load cell and the weighing pan without any interference yet small enough to maintain a high surface to volume ratio for cooling purpose as mentioned previously. The sorption chamber developed in this phase was used for the study of the removal of solvent from SDD drug product.9 Phase III: The Formation of Integrated Sorption Chamber The inability to directly observe potential polymorph or structure changes of API via Raman and the surface temperature of API via IR during drying was identified as a limitation of the early design of the Sorption Chamber. In addition to recording the weight change and the vapour phase solvent composition profile, collection of Raman data and surface temperature would enable the establishment of the drying model for scale-up of the drying process.6 Having identified these requirements, a Sorption Chamber design which enabled these technologies was considered and implemented. An angled probe well with a two inch internal diameter which accommodates both Raman and IR probes was added to the vacuum oven. This well holds and orients various instrument probes at the suspended sample tray. The name of the Integrated Sorption Chamber is used because it is capable of integrating up to 4 technologies in one sorption chamber. The use of Raman spectroscopy is illustrated in an application involving the desolvation.10


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A microprocessor controlled vacuum oven (VWR Model 1430M) was modified and converted to an Integrated Sorption Chamber. This chamber is equipped with a load cell (Sartorius WZA523CW) and a Raman (Kaiser Model PhAT™ System Analyzer). The vacuum oven vent line was connected to a mass spectrometer (Ametek ProMaxion™), as shown in Figure A2. Note that, as in the previous design, the weigh cell is connected to the sample tray within the oven chamber with a wire fed through a pipe. During operation the oven was set at the desired drying temperature. Wet cake is placed on the suspended weighing pan in the chamber. Sample weight is automatically recorded to generate basic weight change curves for use in elucidating drying mechanisms. In the course of drying, the vapour phase composition was also monitored via MS. The drying process was determined to be complete when no further changes were observed in both the weight curve and the vapor phase composition. For certain applications, a Raman probe (Figure A2) or IR camera can be installed in the probe well with a fixed window installed at the bottom of the well. This well was designed and constructed so that the laser beam from the probe selected is directed at the sample in the sample pan. The probe well window is fabricated from ZnSe and allows transmission of wavelengths used for both Raman and IR systems.

Figure A2. Schematic diagram of the Integrated Sorption Chamber



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(13) Stichlmair,J. and James R. F., Distillation: Principles and Practice, Wiley; 1998 (14) Gottfried, Byron S., Spreadsheet Tools for Engineers, WCB/McGraw-Hill, 1998 (15) Vrentas J.S. and Vrentas CM. Diffusion and Mass Transfer. Florida: Taylor & Francis/CRC; 2013 (16) Cypes, S. H.; Wenslow, R. M.; Thomas, S. M.; Chen, A. M.; Dorwart, J. G.; Corte, J. R.; Kaba, M. Drying an Organic Monohydrate: Crystal Form Instabilities and a Factory-Scale Drying Scheme to Ensure Monodydrate Preservation. Org. Process Res. Dev. 2004, 8, 576582.


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(17) Khoo, J. Y.; Heng, J. Y. Y.; Williams, D. R. Agglomeration Effects on the Drying and Dehydration Stability of Pharmaceutical Acicular Hydrate: Carbamazepine Dihydrate. Ind. Eng. Chem. Res. 2010, 49, 422-427. (18) Khoo, J. Y.; Williams, D. R.; Heng, J. Y. Y. Dehydration Kinetics of Pharmaceutical Hydrate : Effects of Environmental Conditions and Crystal Forms. Dry. Technol. 2010, 28, 1164-1169. (19) DVS Adventure, product bulletin, Surface Measurement Systems, 2017 (20) Dortmund Data Bank, www.ddbst.com/ddb.html

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