A Process for Active Pharmaceutical Ingredient Recovery from Tablets

Subscriber access provided by The University of New Mexico

Full Paper

A Process for Active Pharmaceutical Ingredient Recovery from Tablets Using Green Engineering Technology Daniel S Hsieh, Mark Lindrud, Xujin J Lu, Christopher Zordan, Liya Tang, and Merrill L. Davies Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 19 Jun 2017 Downloaded from http://pubs.acs.org on June 19, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Organic Process Research & Development is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 39

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

Organic Process Research & Development

A Process for Active Pharmaceutical Ingredient Recovery from Tablets Using Green Engineering Technology Daniel S. Hsieh*1, Mark Lindrud2, Xujin Lu1, Christopher Zordan1, Liya Tang3, Merrill Davies3 1 Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States 2 API Operations, 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]

1 ACS Paragon Plus Environment


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 objective of this study is to recover Active Pharmaceutical Ingredient (API) from tablets via green engineering technology to meet material requirements for downstream formulation development. A separation train, using water as the separation media, includes dissolution, centrifugal phase separation, diafiltration, and reverse osmosis, has been developed based on the physical properties of the API and excipients. These properties include solubility, multiphase behaviors, particle densities and size differences between API and excipients. The recovered API both meets purity specifications and contains no polymer. It is suitable for reuse in formulation process development. The recovery of the API from tablets is over 90%. A green engineering technology using water and separation methods is successfully developed and used to recover API from tablets. KEY WORDS API, Solubility, Phase Separation, Diafiltration, Reverse Osmosis, Crystallization


Page 2 of 39

Page 3 of 39

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


1. INTRODUCTION During the development of solid dosage formulations, hundreds of kilograms or more of Active Pharmaceutical Ingredient (API) are mixed with excipients such as polymers and lubricant to produce tablets. In general, this development takes between one to two years to be completed. During this lengthy effort, additional supply of API is required. However, the production of API requires an investment of both time and financial resources, often costing several thousand dollars per kilogram of API. With this in mind, it is desirable that API could be recovered from tablets or off-spec tablets generated during the formulation development. Such recovered API could shorten the development time. If the recovered API is free from the excipients it can then be re-used for formulation development. The objective of this study is to provide a separation train to recover API from tablets. The development of this separation is based upon the physical properties of API and excipients such as solubility, phase separation, and size and density differences between API and polymers. Unit operations, including dissolution, diafiltration, reverse osmosis, and crystallization are utilized. The methodology used to develop the separation train is called the process synthesis;1-3 one example of which is its use in the chemical industry for chemical process design. The technology for this recovery is classified as green engineering for two reasons. First, water is used as the separation media for all of the necessary unit operations (dissolution, diafiltration and reverse osmosis) except crystallization where acetone is used as an anti-solvent. Second, no latent heat such as heat of vaporization is used for separation. Only mechanical force from pumps is used to provide the driving force for membrane separation. 1.1. Conceptual Process Design. In a chemical process, the chemical transformation of raw materials (tablets) via reaction or the separation of raw materials into desired products (API) usually cannot be achieved in a single step.1,2 Instead, the overall transformation/separation, which is called the process (as shown in Figure 1) is broken down into a number of steps that provide intermediate transformation/product. Once the individual steps are selected, they are linked to carry out the overall transformation/separation. Thus the synthesis of a chemical process involves two major activities: selection of individual steps and the interconnection of them to perform the overall transformation/separation. A process flow diagram is commonly used to represent the process steps with their interconnections.

Tablets

Process ?

API

Green Engineering Technology Figure 1. The synthesis of a process to convert tablets into API



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

1.2. Process Considerations. The process to convert tablets into pure API could be via chemical or physical methods, or the combination of both methods. However, some important considerations need to be taken into account for the process design. First, the process must be economical, which means the process yield must be high and both the fixed cost and operational cost must be low. Second, the impact of the process on the environment should be kept low. This means that the energy consumption and the waste generation from the process needs to be minimized. In other words, a green process is preferred. Third, health and safety criteria of the process and the product must be met.

On the basis of these considerations, the process proposed for the API recovery in this study is composed of several steps of physical separation and does not include any chemical transformations. Water is used as the separation media and each operation is selected based upon the interaction between water and excipient, various material solubilities as a function of temperature, gravimetric phase separations, molecular size difference, etc. Both theoretical approach and experimental approach of each step are presented. These steps are then interconnected as a separation train, presented by a process flow diagram for the transformation of the tablets into pure API.

1.3. Composition of Tablets. Table 1 shows the composition of Compound A tablet. Compound A, with a molecular weight less than 1,000 is the API. Its solubility in water is greater than 300 mg/mL at room temperature. Two major polymers, hydroxypropylmethylcelluslose (HPMC – DOW Methocel™) and hydroxypropylcelluslose (HPC – Ashland Klucel™), are used in the tablet and their molecular weights are both greater than 200,000. In formulation, HPMC provides the API’s controlled release and HPC serves as a binder. Small amounts of silicon dioxide and magnesium stearate are included in the tablet as lubricant and glidant. The tablet is coated with Colorcon Opadry II®, which is composed of PVA (polyvinyl alcohol), PEG (polyethylene glycol), and some inorganic component such as pigments.

Table 1. Composition of the Tablets Component

Wt. %

Notes

API, Compound A

~ 60

MW < 1,000

HPMC

~ 20

Mn ~ 200,000

HPC

~ 20

Mn ~ 800,000

Magnesium Stearate (MgSt)

low

Solid/Oil

Silicon Dioxide

low

Solid


Page 4 of 39

Page 5 of 39

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


Opadry II

low

Total

100.00

Solid

2. OVERVIEW Separation Train for Compound A Recovery. To recover API (Compound A) from the tablets, a separation train needs to be developed to meet the following objectives: •

The purity of the recovered API must be close to that of new API

•

The polymer concentration in the recovered API should be negligible

•

Physical properties of the recovered API, including but not limited to as flow ability, density, and cohesiveness, etc. must be as close as possible to those of new API

•

The maximum process temperature must be less than 70 °C to avoid chemical degradation of Compound A

•

The recovery yield of API should be high and the cost of the recovery must be kept low

•

The ideal recovery process should be as green as possible and avoid using any hazardous chemicals

On the basis of the physical properties of the components in Table 1, a separation train has been developed and proposed in Figure 2.

This separation train entails five primary steps (unit operations): 1. Tablet milling and dissolution 2. Solids-liquids separation via centrifugation 3. Filtration with ultrafiltration (UF) membranes 4. Filtration with reverse osmosis (RO) membranes 5. Recrystallization



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

Figure 2. Process flow diagram for the recovery of Compound A from tablets

3. THE STEPS OF THE RECOVERY PROCESS The five unit operations in the separation train shown in Figure 2 for Compound A recovery and the analytical tools during API recovery are described in this section. They include: 3.1. Step 1-Tablet Milling and dissolution 3.2. Step 2- Solids/Liquid Separation via Centrifugation 3.3. Step 3- Diafiltration via Ultrafiltration 3.4. Step 4-Reverse Osmosis membrane Operations 3.5. Step 5-Crystallization 3.6. Analytical Tools used during API Recovery Both theoretical and experimental approaches may include several subjects to illustrate the concepts and feasibility associated with each unit operation. The details of each unit operation are described below.

3.1. STEP 1 - TABLET MILLING AND DISSOLUTION. The first step in recovering the Compound A from tablets includes tablet milling and dissolution. This initial step does not remove any of the components from the process stream. The tablet milling is a purely physical process for both ease of handling the source material and accelerating the dissolution process. The dissolution activity solubilizes the tablets as much as possible. This dissolution required an analysis of the tablet solids in order to optimize the resulting process stream. Theoretical Approach The theoretical part of the dissolution includes three subjects: solubility of Compound A in water, polymer and water interactions, and solids and magnesium stearate in aqueous solution. Each is discussed in detail below. 6 ACS Paragon Plus Environment

Page 6 of 39

Page 7 of 39

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


Solubility of Compound A in Water Compound A is a salt and is very soluble in water. Its solubility in water is higher than 300 mg/mL (30 wt%) at room temperature. This high solubility of Compound A in water is advantageous for both the dissolution and RO membrane steps in the separation train as shown in Figure 2. During the dissolution step, the high solubility of Compound A in water creates a driving force to extract Compound A from tablets to the aqueous solution. For the RO step, the low concentration of Compound A in the aqueous solution as the feed to RO can be concentrated up to 300 mg/mL (30 wt%) without forming any solids which may cause some damage to the thin membrane surface. Two units for the solubility of Compound A in water are used in this study. The first is the weight percent of API in aqueous solution. The second is the mass (mg) of Compound A in one milliliter (mL) of water solution. These two units can be interchangeable when some assumptions are made. For example, when the solubility of Compound A in water is expressed as 30 wt%. this means that 30 g of Compound A is mixed with 70g of water to form an aqueous solution of 100 g. If the density of Compound A is assumed as 1 g/cc and there is no volume change upon mixing between water and Compound A, the solubility of Compound A can be expressed as 300 mg in one mL of aqueous solution. The use of wt% for the solubility of Compound A in water is commonly used for process development because no assumption of the volume change upon mixing needs to be made.

Polymer and Water Interaction There are four polymers in the tablet: DOW METHOCEL™ (HPMC), Ashland Klucel™ (HPC), Colorcon Opadry II (PVA & PEG). Both HPMC and HPC exhibit interesting precipitation behavior as a function of temperature in aqueous media. The solubility behavior for HPC is presented in Figure 3. As shown in this figure4, HPC precipitates around 45 °C, but this precipitation process is reversible. For example, the 10 mg/mL (1 wt%) of Klucel™ (H viscosity type) is completely soluble at 10 °C. As the temperature of this solution is gradually heated up from 10 °C to between 40 °C and 45 °C, the color of the solution turns cloudy and the viscosity (units [=] centipoise, cp) of the solution drops significantly from 1000 cp to 300 cp or even lower, indicating the precipitation of Klucel™. It is notable that when the temperature of the solution is lowered below 40 °C, the precipitated Klucel™ will re-dissolve. It should be noted that the precipitation temperature of Klucel™ is lower in the presence of relatively high concentrations of other dissolved materials that compete for the water in the system. It should also be noted that the transition from dissolved to precipitated polymer takes place without the formation of a gel.4



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

Figure 3. Effect of temperature on the viscosity of aqueous solution of Klucel™ branded HPC4

The precipitation temperature for HPC is around 45 °C - lower than 70 °C, the temperature constraint for the recovery process. Hence, it is feasible that HPC can be removed from the aqueous dissolved tablet solution via precipitation followed by a solid/liquid separation process.

HPMC exhibits thermal gelation in aqueous media.5,6 However, the solubility behavior for HPMC is different from that for HPC, previously discussed (Figure 3). First HPMC forms a gel when heated. The temperature at which this occurs is termed the gelation temperature. Second, the temperature window for gelation is very narrow. The gelation temperature of HPMC is dependent upon the type of HPMC and the presence of other additives.5 The gelation temperature for HPMC used in water without any other additives could be higher than 75 °C. As mentioned earlier in this study, the temperature of the recovery process should be less than 70 °C; hence, the removal of HPMC via the formation of gel at a temperature higher than 75 °C is not a feasible option due to the temperature constraint. The two other polymers used in the tablet, PVA and PEG, are at low concentrations and they are soluble in water. The viscosity is closely related to the heat transfer, mixing and mass transfer in the recovery process. When both HPMC and HPC, two major polymer components in the tablet, are dissolved in water, the viscosity of the aqueous solution will increase. Hence, the concentration of HPMC or HPC used in the aqueous solution should be less than 2% to minimize any processing difficulties.

Solids and Magnesium Stearate in Aqueous Solution


Page 8 of 39

Page 9 of 39

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


The components in the Compound A tablet other than API and polymers include magnesium stearate and some inorganic compounds, as shown in Table 2. They are not soluble in water and they could be removed either by centrifugation or phase separation. Table 2. Solids and Magnesium Stearate in Aqueous Solution – Methods for Removal Components

Property

Method for removal from water

Magnesium Stearate (MgSt)

Surfactant

Phase separation

Silicon Dioxide Particle size Centrifuge (Aerosil 200) D50 ~50µm Titanium Dioxide

Particle size Centrifuge < 5µm

Talc


Iron Oxide Yellow


Iron Oxide Red


Experimental Approach Tablet Milling Preliminary lab testing indicated that the tablets needed to be broken into small pieces in order to facilitate the API and polymer dissolution. Without milling, a significant amount of time (>10 hours) was required for the tablets to dissolve in water. A 650 gram supply of tablets was fed into a Fitzpatrick® branded hammer mill equipped with a 1/8 inch screen. The mill efficiently processed the tablets into small fragments: the fragments dissolved within 15 minutes. Dissolution Process This operation was performed in a jacketed 20 L ChemGlass™ reactor connected to an external heater-chiller. The dissolution steps are as follow: a. Charge 15 L deionized water (DI) to reactor; set agitator speed to 150 RPM b. Feed 300 g (20 mg/mL) milled Compound A tablets



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

Page 10 of 39

c. Stir contents for 15 minutes until no significant solids are observed. A yellow tinted solution results. Note: dissolution at room temperature ensures that polymer solids do not form and inhibit dissolution of the API. d. Heat contents to 52 °C to precipitate polymers.

3.2. STEP 2 – SOLIDS/LIQUID SEPARATION VIA CENTRIFUGATION Solids in the heated aqueous solution from the dissolution tank include the precipitated HPC and the materials shown in Table 2, with the exception of MgSt. To develop the removal of these solids from the aqueous solution, two kinds of centrifugation units were used: a test-tube centrifuge (Eppendorf model 5804) and a continuous disc centrifuge (GEA CTC-1, a.k.a. Whisperfuge). The Eppendorf centrifuge was used for the initial feasibility study and the verification of the clarity of the supernatant generated at larger scale. Large scale tests and production of centrate (clarified supernatant produced by the centrifuge) solutions were accomplished using the Whisperfuge. Below, the governing equations for the continuous disc centrifuge are presented in the section entitled, “Theoretical approach.” This derivation can be used as a basis for adjusting the control parameters to achieve the desired separation. The next section, entitled “Experimental Approach”, describes the equipment used for processing the stream from dissolution step. Theoretical Approach Continuous Disc Centrifuge The process flow profile in the continuous disc centrifuge used in this study is illustrated in Figure 4. As the centrifuge spins at an angular velocity ω, the heated feed slurry flows into the unit from the top. The centrate exits the separator from the top side port while the solids are discharged from the perimeter.


Page 11 of 39

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


Figure 4. Material flows through a GEA solids-liquids separator

To understand this solid-liquid separation, the governing equation for this unit operation is needed. The detailed derivation of this equation is provided by Coulson and Richardson.7 Only the figure for the derivation and the results of the derivation are provided in this study. Figure 5 shows the trajectory of particles through the separation channel with a width of a. As the slurry is passing through this channel, the particles are subjected to a centrifugal force in the radial direction which creates a radial sedimentation velocity. The resultant velocity from this sedimentation and the liquid velocity will force particles to travel a trajectory indicated by the dashed line in Figure 5. As shown in this figure, if a particle hits the disc at point B´ and loses its momentum, it will travel along the disc surface to move from point B´ to point B and then be removed from the side. However, if for one of three reasons (a particle size is too small, the liquid velocity is too high, or the angular velocity is too low) the particle will travel a distance in the y direction less than the distance between two discs in stack a. In this case the particle will escape from this disc centrifuge and exit the channel with the supernatant at section A´B´.

Figure 5. Material flow path within centrifuge channel

The governing equation for the disc centrifuge is provided in equation (1).

(1)

After the integration, equation (1) turns into the governing equation for the disc centrifuge and it is expressed in equation (2):

(2)

where

! "# $"

(3)

%&



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

Page 12 of 39

and Description

SI Units

Dimensions in M, L, T

a

Distance between disc in stack

m

L

d

Diameter (or equivalent diameter of particle)

m

L

g

Acceleration due to gravity

m/s2

LT-2

l

Distance particle travelling in the Y direction

m

L

n

Number of passages between discs in bowl

-

-

Q

Volumetric feed rate to centrifuge

m3/s

L3T-1

r1

Radius at inlet to disc bowl centrifuge

m

L

r2

Radius at outlet to disc bowl centrifuge

m

L

u0

Terminal falling velocity of particle

m/s

LT-1

µ

Viscosity of liquid

Ns/m2

ML-1T-1

ρ

Density of liquid

Kg/m3

ML-3

ρs

Density of particles

Kg/m3

ML-3

θ

Half included angle between discs

-

-

ω

Angular velocity

Rad/s

s-1

Σ

Capacity term for centrifuge

m2

L2

Symbol

As both sides of equation (2) is divided by a, equation (2) is turned into the following expression:

(4)

Equation (4) provides valuable guidelines for the design and operation of the disc centrifuge. Three cases are discussed in this study: 1, < 1 and > 1 Case (A)

1, equation (4) is turned into the following expression: 1

∗

(5)

After the rearrangement of equation (5), this equation can be expressed in the following form: ,

Σ


(6)

Page 13 of 39

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


-

(7)

! "# $"

(8)

%&

Equation (6) shows that the volumetric feed rate to centrifuge Q is equal to the product of the terminal falling velocity of particle u0 and the capacity term for centrifuge -. This means that the particle with particle size of d in the slurry at the volumetric feed flow rate Q will hit the disc before it exits from the outlet of the centrifuge which spins at the angular velocity of ω and has the physical dimensions including n, θ, r1, r2, etc. Equation (6) can be used for the scale up of the disc centrifuge because the term of u0 is the same and is independent of the scale; therefore,

.

(9)

.

Equation (9) means when the removal of solids from the slurry is successful with feed flow rate Q1 and by using a small disc centrifuge with the capacity term of Σ1. When this centrifuge operation is scaled up to a large scale and the feed flow rate to the larger centrifuge Q2 becomes higher than Q1, the capacity term for the larger centrifuge Σ2 should satisfy the relationship in equation (9) to maintain the same separation performance. It should be noted that the distance between discs in stack is kept the same during the scale-up when the volumetric percent solids in the feed is below 30%. However, when the solids load is over 30%, some adjustment of the distance between discs, the angular velocity or the feed flow rate may be needed to maintain the same separation efficiency. Case (B)

< 1, equation (4) is turned into the following expression:

< 1

(10)

Since the value of is less than 1, it means that the distance the designated particle travels is less than a. To increase the value of , equation (10) shows that there are two control parameters ω and Q can be adjusted. By either increasing the angular velocity or decreasing the volumetric flow rate, the distance the particle travels can be increased so the particle will hit the disc and hence, the separation efficiency can be achieved. Case (C)

> 1, equation (4) is turned into the following expression:

> 1

(11)

Since the value of is more than 1, the distance the designated particle travels is more than a. This means that the designated particle hits the disc before it exits from the centrifuge and some particles with the diameters less than that of the designated particle are also removed. If the objective of the separation is to remove the designated particles, the value of can be reduced by either decreasing the angular velocity or increasing the volumetric flow rate. 13 ACS Paragon Plus Environment


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

Page 14 of 39

Cases (B) and (C) are very useful for the tuning of the disc centrifuge to achieve the desired separation and the optimization of operating condition. A case study of this tuning will be illustrated in the session of results and discussion. Experimental Approach Preliminary Study Early studies of the dissolved tablet solutions used an Eppendorf model 5804 laboratory centrifuge. This unit is configured with tube adapters which can be spun up to 5000 RPM. This speed generates a force equivalent to 4200 * g. Vials containing dissolved and non-dissolved tablet solids in water were placed in the centrifuge and spun for up to 20 minutes. This study affirmed the concept that insoluble tablet solids could be separated from the solubilized API. Development Studies A CTC-1 (Whisperfuge) unit was obtained from GEA Westfalia Separator, Inc. for use in testing and scale-up of removing solids from a tablet slurry. This unit consists of a control panel and the operating unit, shown top (controller) to bottom (spinning unit) on the right-hand side of Figure 6a, respectively. The Whisperfuge was set up connected to the outlet of a 20 L ChemGlass reactor as shown in the schematic of Figure 6a.

Figure 6a. Schematic of Whisperfuge Integration with feed and product vessel

Figure 6b. Piping in to and out of Whisperfuge; note sight glasses (circled)

After the familiarization with the Whisperfuge, several tests were performed using a slurry prepared as described in the dissolution section above. The solids separation parameter evaluation experiments utilized the following procedures: a. Heat dissolved tablet slurry to desired temperature b. Preheat the distribution loop (insulated tubing, diaphragm pump, and centrifuge) with heated water (at 55 °C). Note: The circulation lines and centrifuge were preheated since the leased Whisperfuge was not jacketed. See Figure 6a, which shows the piping arrangement c. Pump dissolved tablet mixture to centrifuge


Page 15 of 39

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


d. Collect clarified solution under various operating conditions while ensuring clarity of centrate in product sightglass (Figure 6b). e. Change operating parameters as needed on the basis of the theoretical analysis of the centrifuge, equations (1) to (11), to evaluate process under various conditions

3.3 STEP 3 – DIAFILTRATION VIA ULTRAFILTRATION Theoretical Approach After the tablet dissolution and centrifugation steps, which removes all of the HPC, insoluble solids and magnesium stearate, the process stream contains dissolved API, PEG, PVA, HPMC and trace of HPC. The molecular weights of these components are listed in Table 3.

Table 3. Molecular Weight of Tablet Components and Method of Removal from Water Component Water

Molecular Weight, g/mole

Method of removal from Water

18

N/A

< 1,000

Crystallization

PEG

3,350

RO or UF

PVA

20,000

RO or UF

HPMC

~200,000

RO or UF

HPC

~800,000

RO or UF

Compound A

Selection of Ultrafiltration Membrane The objective of the ultrafiltration is to separate water and Compound A from the group of the components including PEG, PVA, HPMC and HPC. The aqueous solution containing the dissolved components shown in Table 3 is a conglomeration of materials with very different molecular weights (MW). Molecular weight cutoff is a convenient fiction that provides a rough guide to a membrane’s pore size.8 Molecular weight is but one of many factors including shape and affinity influencing retention. Ideally, to separate Compound A (MW $> >

1

>

(16)

>

where C1 is the Compound A concentration on the feed or concentrate side C2 is the Compound A concentration in the permeate Experimental Approach Selection of RO Membrane A DOW FILTEC® RO Membrane (2 m2 spiral wound cartridge model BW30-2540), made of Polyamide Thin-Film Composite, was selected for Compound A recovery.

Scale-up Study with GEA Membrane Filtration Unit



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

Page 22 of 39

The model L membrane filtration pilot plant unit from GEA, shown and illustrated in Figure 9, was used to generate the engineering data for scale up and concentrated streams of Compound A for subsequent processing. The operating pressure of this unit can go as high as 1,000 psig (69 bar) ideal for RO operation. As discussed previously, this unit can be equipped with a temperature bath so the temperature of the feed stream to the membrane can be controlled.

3.5. STEP 5 – CRYSTALLIZATION At the completion of the RO operation the Compound A concentration in water is at a concentration of 300 mg/ml (30 wt%). This stream can then crystallized to complete the recovery of high purity Compound A as a solid product. The crystallization utilizes a typical anti-solvent addition (with seeding when the solution is saturated). The process uses 21 volumes of acetone as the anti-solvent; Compound A seed crystals are added at a designated point; the resulting slurry is then filtered and dried. Since the solubility of Compound A in 90 wt% (acetone)/10 wt% (water) at 20⁰C is 2.1 mg/mL (0.21 wt%), the crystallization recovery of the Compound A is around 95%. This process has been demonstrated at pilot plant scale.

3.6. ANALYTICAL TOOLS USED DURING API RECOVERY HPLC Method A reversed-phase HPLC was used for quantitation of API (wt% assay). The method used an XBridge Phenyl column (150 mm x 4.6 mm ID, 3.5 µm particle size) from Waters with a gradient of acetonitrile-water with ammonium acetate buffer at pH 5.8. The column temperature was kept at 40 °C, flow rate pf mobile phases was kept at 1.0 mL/min, and UV wavelength at 302 nm was used as detection. The run time for each injection was 13 min. ELSD Method Analytical methods to quantify the levels of various polymers (PVA, PEG, HPMC, and HPC) were developed to determine the polymer levels at various stages of the recovery process. Specifically, the use of Evaporative Light Scattering Detection (ELSD) was applied to generate and analytical method to quantify the polymer levels during the ultrafiltration step. Samples at multiple DV were collected and analyzed for the presence of various polymers. By the end of the ultrafiltration, the polymer levels in the ultrafiltration product stream were determined to be below the level of detection. Multiple FOUV Technologies Fiber-Optic UV/Vis (FOUV) spectrophotometry was used to monitor the Compound A concentration and membrane integrity during the ultrafiltration (UF) and reverse osmosis (RO) steps of the API recovery process. A Rainbow FOUV system was made by pION Inc., Billerica, MA. This system provides multiple channels that can connect through optical fibers to both attenuated total reflectance (ATR) probes and transmission/reflectance (transflectance, or TF) probes, and meet the need for simultaneous monitoring of multiple spots and a wide 22 ACS Paragon Plus Environment

Page 23 of 39

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


range of concentration (from 250 mg/mL) anticipated during the API recovery operations. The ATR probes (Hellma, Mullhelm, Germany) were utilized for monitoring the high concentration regime ≥1 mg/mL. One of the ATR probe was mounted in the feed tank, and the others were mounted in the retentate output and the permeate output from the filter. The TF probes (pION Inc., Billerica, MA) were mounted in the retentate and permeate output streams for monitoring the very low concentration of the API in a range of 0.005 – 0.15 mg/mL. A spectrum in the range of 200 – 700 nm was recorded every 30 seconds for each of the channels during the operations. The Compound A concentration was determined using the absorbance at 305nm while the full spectra were examined periodically to monitor instrument drift. The data processing, curve fitting and integration of area under curve were performed using MATLAB® R2015a, version 8.5.0.197613, and the included Curve Fitting Toolbox, version 3.5.1. Parameterized functions for the concentration during process were fit in MATLAB® and then integrated over the appropriate time to calculate the area under the curve for the mass of API recovered.



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

Page 24 of 39

4. RESULTS AND DISCUSSION The results and discussion of each unit operation for Compound A recovery shown in Figure 2 and the analytical tools are presented in this section. 4.1 Recovery Process: Step 1-Tablet Milling and Dissolution Following milling, dissolution and precipitation, material sampled from the dissolution tank become two layers, as shown in Figure 10c. The major portion of the mixture (top layer) includes enough suspended solids to cloud the sample. The bottom layer contains the settled HPC and large insoluble tablet components; the top layer is yellowish due to the presence of Compound A, suspended small particles such as pigments and silicon dioxide, and other soluble polymers including HPMC, PVA and PEG. This material was next processed in the solids-liquids separator.

Tablets (a) Milling (b) Dissolution (c) Figure 10. Results of milling and dissolution

4.2 Recovery Process: Step 2-Solids/Liquid Separation via Centrifugation. Preliminary Study Vials containing dissolved and non-dissolved tablet solids in water were placed in the centrifuge and spun for up to 20 minutes. The effect of this centrifugation can be seen in Figure 13 (top). This study affirmed the concept that insoluble tablet solids could be separated from the solubilized API. Development Studies: Four tests at different operation conditions, shown in Table 5 were conducted. The changes in operating conditions produced solutions with distinct clarity – see Figure 11. Samples 2 and 3 both appeared cloudy. This is likely due to incomplete solids collection in the centrifuge. The final test (Sample 4) identified conditions which maximized the throughput while still producing a clear centrate. Table 5. Conditions and results of initial Whisperfuge tests Sample

RCF*

RPM

Feed rate, mL/min

Centrate Turbidity

Volume mL

1

12,000

11,960

350

Clear

5,000


collected,

Page 25 of 39

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


2

7,000

9,200

700

Slightly Turbid

4,000

3

12,000

9,200

700

Slightly Turbid

5,000

4

12,000

1,1960

500

Clear

10,000

*Radial Centrifuged Force (RCF) (G-force)

Figure 11. Product of centrifuge tests: Samples1-4

A phase diagram indicating the results of the different operating conditions is shown in Figure 12. The green is the area where a clear centrate can be achieved.

Figure 12. Centrate clarity shown as the result of Operating conditions

The separation of solids and liquids in the Whisperfuge is visually summarized in Figure 13. These images show the hazy input stream, the solids collected in the centrifuge, and the clear centrate which is the product of this step of the API recovery process. The scale up of the



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

Page 26 of 39

centrifuge operation using the operation condition located in the green area in Figure 12 was conducted to generate the feed material for the next unit operation: diafiltration.

Figure 13. Typical centrifuge input (top) and output streams (bottom)

4.3 Compound A Recovery Process: Step 3 – Diafiltration via Ultrafiltration. Feasibility Study: Two membranes 10 kDa and 30 kDa were tested using Pall TFF system for feasibility. The composition of the feed, retentate and permeate was analyzed by using two analytical methods, HPLC and evaporative light scattering detection (ELSD). The HPLC method was mainly applied for the analysis of Compound A while ELSD was mainly used for the analysis of polymers including PVA, PEG, HPMC and HPC. The details of these two methods are described in section 3.6. Only the results are summarized in Table 6. Note: ND = not detected. Table 6. Performance of Diafiltration for Two Ultrafiltration Membranes Concentration, wt % Sample

Compound A

PVA

PEG

HPMC

HPC

UFF Feed Stock

1.182

ND

0.1268

2.598

ND

10 kDa retentate

0.016

0.048

0.1233

2.355

ND

10 kDa permeate

0.122

ND

ND

ND

ND

30 kDa retentate

0.003

0.042

0.1178

2.103

ND

30 kDa permeate

0.115

ND

0.0011

ND

ND


Page 27 of 39

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


Using the analytical values shown in Table 6, Compound A recovery from diafiltration can be calculated in two ways. One is from the material balance in retentate and the other is from the material balance of permeate vs. retentate. The Compound A recovery calculated from the concentration of Compound A in retentate at the beginning of diafiltration (DV=0) and at the end of diafiltration (DV = 10) is equal to 98.6 %: .%$.A

[

.%

× 100% 98.6%]

The Compound A recovery can also be calculated from the concentration of permeate vs. retentate and its value is 98.7%: .

I. J .A × 100% 98.7%L Since the recovery of Compound A at 10 DV is close to 99%, this means that the permeability of Compound A through 10 kDa is close to 100%.

Results from 10 kDa Membrane Unit Since none of the polymers listed in Table 6 were detected in the permeate stream it can be claimed that they were fully rejected by the 10 kDa ultrafiltration membrane. As expected, the polymers with molecular weight significant higher than 10 kDa (HMPC, PVA and HPC) are rejected by 10 kDa membrane. Fortunately, the PEG, even with a MW = 3350 was also rejected. This is likely due to the low initial concentration level of PEG.

Results from 30 kDa Membrane Unit Table 6 indicates that PEG was not completely rejected by 30 kDa membrane. This result eliminated the 30 kDa membrane for further study. From the results of Compound A recovery and the rejection of polymer, the ultrafiltration membrane with 10 kDa was selected for scale up study.

Large Scale Operation: The large scale operation of diafiltration was conducted using GEA Model L unit.



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

Page 28 of 39

Feed Material Since HPC was completely removed via dissolution and centrifugation, the major polymer in the feed to the ultra-filtration unit is HPMC. As an initial test a synthetic solution made from Compound A, HPMC, and water was prepared to evaluate the diafiltration performance. The weight ratio of HPMC to Compound A is 0.3 in the tablet while that ratio is 0.5 in this synthetic solution. This variation from the actual ratio is because a higher HPMC concentration is needed to study the impact of viscosity on the diafiltration performance in terms of solute (Compound A) permeation rate.

Diafiltration Operation In order to maximize permeability of Compound A without impacting its stability, the diafiltration was performed at 40 °C. Coincidentally, this elevated temperature also reduced the viscosity of the process stream.

Table 7. Compound A Recovery from Discontinuous and Continuous Diafiltration Water added to retentate , Liter

Number of DV*

Compound A Recovery, %

0

0

47.25

16

0.87

87.81

24

1.30

94.63

32

1.75

97.38

40

2.18

98.66

48

2.62

99.22

56

3.06

99.54

64

3.49

99.68

72

3.93

99.73

80

4.36

99.80


Page 29 of 39

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


Figure 14. Compound A recovery as a function of volume collected from the permeate

Several interesting findings are noticed by Figure 14: 1. The Compound A recovery is 47.2% after the retentate volume changes from 17.2 liter to 9.16 liter, which is in a very good agreement with the theoretical Compund A recovery of 46.5% [calculated as (8.0/17.2)*100%]. This good agreement indicates that the permeability of Compound A is 100%. 2. The 99.2% recovery of Compound A after 2.62 DV is in a very good agreement with the theoretical prediction of Compound A recovery of 99.1% at 2.5 DV as shown in Table 7. 3. The diafiltration performance at 40 °C was not affected by the viscosity change due to the presence of HPMC during concentration, which at 20 °C is 1,500 cp (at 9 mg/mL) from 75,000 cp (at 18 mg/mL). The close agreement between the theoretical prediction and the actual reovery of Compound A after concentration supports this fact. The results of this diafiltration scale-up show that the diafiltration performance is unaffected at 40 °C even the HPMC concentration is as high as 18 mg/mL. Knowing this, if the initial HPMC concentration is less than 9 mg/mL, concentration of the feed is advantageous by lowering the diafiltration volume and the overall use of water to recover Compound A.

Suitability of FOUV in situ measurement: UV analysis of Compound A in water was found to be feasible due to a local absorption maximum at approximately 305 nm. Monitoring the UF and diafiltration processes at this wavelength is advantageous because this maximum is well away from possible interference of dissolved HPMC that is present in the feed stock during the UF operation. HPMC has some UV absorbance near 200nm and rapidly drops to zero beyond 230 nm (not shown).



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

Page 30 of 39

The pre-concentration step mass recovery was calculated by simple subtraction of the calibrated mass at 0:00 run time and the calibrated mass at 1:01 run time. The diafiltration mass recovered was calculated by integrating the area under the curve between 1:01 run time and 10:15 run time at the completion of the 8th DV. Table 8 shows the results for the mass recovered in absolute terms and as a percentage of the 320g of API charged into the solution to start the experiment. These are in good agreement with the quantitative HPLC results.

Table 8. API Recovery from UV Measurements Step(s) Pre-conc.Start Pre-conc. End Pre-conc. Diafiltration Step

-

Calculated Mass (g)

Cumulative Mass (g)

Recovery %

272

-

-

150

-

-

-

122

38

181

303

95

(DV 1-8)

4.4. Compound A Recovery Process: Step 4 – Reverse Osmosis Membrane Operation. Determination of Water Permeability Constant Feasibility tests of concentrating aqueous solutions of Compound A by RO were conducted at five different concentrations: Case I: 101.9 mg/mL (10.19 wt%); Case II: 152 mg/mL (15.2 wt%); Case III: 194.5 mg/mL% (19.45 wt%); Case IV: 229 mg/mL (22.9 wt%) and Case V: 282.0 mg/mL (28.2 wt%). The osmotic pressure at a dilute concentration (Case I, 101.9 mg/mL) can be calculated by using equation (13); this value is 117.41 psia. Based on this value the water permeate flux at various system pressures is plotted in Figure 19.


Page 31 of 39

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


Figure 15. The determination of the water permeability constant at 40 ⁰C

Figure 15 shows a linear fit between the water permeate flux and the pressure difference between the system pressure and the osmotic pressure at 101.9 mg/mL (10.19 wt%). The slope of this linear curve is the water permeability constant, Aw, and its value is 2.7685 mL / (min m2 psi). The water permeability constant is related to the water permeability and the membrane thickness; it is expected to be independent of the system pressure. If it is assumed that Aw is independent of Compound A concentration, then the value of Aw determined from Figure 15 can be used to determine the osmotic pressure at Compound A concentrations higher than 101.9 mg/mL (10.19 wt%) by using equation (15).

Determination of the Osmotic pressure at various Compound A concentrations As the system pressure was plotted against the ratio of the water permeate flux to the water permeability constant for Cases II to V, several, well-fitted linear relationships were obtained. This is shown in Figure 16.



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

Page 32 of 39

Figure 16. Determination of osmotic pressure from permeate flow measurements

The results of the linear regression for each of these cases are summarized in Table 9. By using equation (15), the osmotic pressure π for Cases II to V can be determined as the value for Q/AW becomes zero, as shown in Figure 15.

Table 9. Calculated Osmotic Pressure at Various Compound A Concentrations from Measurements Case

Compound A Conc, mg/mL

Linear Regression

R2

π, psia

II

152 (15.2 wt%)

-121.42 + 0.80423 P

0.998

150

III

194.6 (19.46 wt%)

-131.07 + 0.69795 P

0.997

187.8

IV

229 (22.9 wt%)

-129.14 + 0.57478 P

0.995

221.2

V

286 (28.6 wt%)

-116.54 + 0.45827 P

0.994

254.3

Comparison of Osmotic Pressure A comparison of the osmotic pressure between the predictions given by equation (13) and the empirical values obtained from the flow measurements is presented in Figure 16. It should be noted that the calculation of osmotic pressure from equation (13) is good for dilute water solutions. As the concentration of Compound A increases, the actual osmotic pressure is less than that predicted from equation (13). 32 ACS Paragon Plus Environment

Page 33 of 39

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


The osmotic pressure measured from the flow measurements, as shown in Figure 16 and Figure 17, can be correlated well with a second order polynomial. The result of this correlation is presented in Table 10.

Figure 17. Comparison of calculated and measured osmotic pressure for Compound A

Table 10. Regression of Osmotic Pressure at Various Compound A Concentrations Coefficient

Value

M0

1.4068

M1

11.698

M2

-0.099598

R

0.99852

Y = M0 + M1*x+M2*x2; Y = Osmotic pressure and x = Compound A concentration, mg/mL in water

Rejection of Compound A from RO Membrane The rejection of Compound A by the RO membrane (BW30-2540) for all five Cases I to V was investigated and the results are presented in Table 11. Table 11. Rejection of Compound A by RO 33 ACS Paragon Plus Environment


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

Page 34 of 39

Membrane C1a

C2b

Rejection, %

I

10.1937

0.0187

99.8

II

15.2

0.0184

99.87

III

19.4584

0.0167

99.91

IV

22.9

0.0182

99.92

V

28.6.0

0.0134

99.95

Case

a

Compound A concentration in the feed, wt%

b

Compound A concentration in the Permeate, wt%

Table 11 shows that the observed rejection of Compound A by the Dow RO Membrane (Model BM30-2540) is no less than 99.8%, resulting in a maximum loss of 0.2% Compound A from reverse osmosis concentration.

Design of Reverse Osmosis Membrane Unit for Compound A Recovery The results from this experimental approach show that the concentration, via reverse osmosis, of a dilute aqueous containing up to 300 mg/mL (30 wt%) Compound A is feasible. This is supported with following reasons: • The rejection of Compound A by RO membrane is over 99.8%. This means that the loss of Compound A from RO operation is less than 0.2%. • It has been demonstrated that the system pressure of 600 psi is much higher than the osmotic pressure of the concentrated (up to 30 wt %) Compound A solution. Hence, this system pressure provides enough driving force to concentrate the Compound A from a dilute solution to at least 30% for crystallization. • The information required to properly run and size the RO membrane unit design, including the water permeability constant, the osmotic pressure, the water permeation flux, and the rejection have been generated from these experiments. FOUV for Reverse Osmosis Concentration The FOUV probes were mounted in place as described in 3.6 for the reverse osmosis concentration of the solution from the UF process. The critical focus is to monitor the RO membrane for leaks. Figure 18 shows the FOUV trace of the transflectance probe in the RO membrane permeate. The shape of the UV absorption trace demonstrated the penetration of the API as the concentration increases in the stock solution.


Page 35 of 39

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


Figure 18. FOUV trace of the API in TF permeate stream during reverse osmosis

The API concentration in the permeate stream at the end of the experiment is approximately 0.05 mg/mL. From the FOUV-ATR data, an estimate of the API concentration in the feed hopper at the end of the RO process is between 220 - 280 mg/mL. A calculation of the RO rejection, R, using the values above with equation (16) gives: .M

2 1 ~% 1 0.022% This is equivalent to recovery of 99.98% of the API in the feed stream, which meets the performance expectation of the RO membrane and supports the previously reported high API recovery.

4.5. Compound A Recovery Process: Step 5 –Recrystallization The recrystallization of 300 mg/mL (30 wt%) Compound A aqueous solution has been performed at multi-kilogram scale and the recovery of Compound A is around 95%.

4.6. Overall Compound A Recovery from the Separation Train The feasibility and the recovery of Compound A from each unit operation of the Separation Train have been demonstrated and discussed above in Sections 4.1 to 4.5. Figure 19 illustrates both the unit operations and actual representative samples from each operation, which include: •

Dissolution: The tablets were milled and HPC precipitated in water at 50 °C as expected from the physical behavior of HPC.

•

Centrifuge: HPC and solids from the tablets not soluble in water were removed resulting in a clear centrate. Magnesium stearate can be removed via phase separation since it is immiscible in water and has a lower density than the aqueous layer.



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

Page 36 of 39

•

Diafiltration: Polymers in the tablets (HPMC, PVA and PEG) were completely separated from Compound A via diafiltration. The recovery of Compound A is over 99.2%.

•

Reverse Osmosis Membrane: the aqueous Compound A solution can be concentrated up to 300 mg/mL (30 wt%) and the rejection of Compound A is over 99.8%, resulting a loss of Compound A less than 0.2%.

•

Recrystallization: the anti-solvent crystallization recovery of Compound A is over 95%.

Figure 19. Recovery process schematic showing actual samples from each step of the separation train

Ultimately, the process outlined in Figure 19 efficiently produces Compound A with an overall recovery above 91%. The recovered material has high purity (>99%) and contains none of the polymers found in the original tablets.

CONCLUSIONS The impetus to find alternate sources of Compound A to support formulation development studies has led to the development of a process to recover API from tablets. Through combining multiple unit operations, an efficient technology which has many benefits was conceived, tested, and demonstrated. The recovery process began with identifying the materials present in the tablets and their physical properties. This was followed by identifying engineering processes which would separate these materials and yield pure API powder. A sequence of operations to remove 36 ACS Paragon Plus Environment

Page 37 of 39

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


different components other than Compound A was theorized, tested, and verified via experimentation. In the end, the process described in this report is successful in producing Compound A very efficiently (recovery > 91%) with very high purity (> 99%) and without the polymers used in the tablets which was the objective from the outset. The recovery process described herein presents the possibility of recycling API to accelerate development while reducing the expense of API synthesis. This project, in addition to enabling the recovery of high quality API, achieves significant milestones in various technological areas. These include: a green engineering process, demonstration of in situ UV technology to monitor API concentrations, novel HPLC and ELSD analyses, and a large scale plant design for recovery operations. Green engineering principles significantly impacted the design choices during the development of this process. Other than the final crystallization step, which does use acetone, the entire process is water based. There was a conscious decision to minimize non-aqueous based processes in order to maximize safe operating conditions, how the process streams could be handled, and where this process could be executed at larger scales. The process was also designed with a balance of yield and process time (especially for the filtration steps) for overall efficiency in mind. The process yield can be manipulated during the ultrafiltration operation by choosing how many diafiltration volumes (DV) are executed. High DV counts can produce nearly 100% recovery for the filtration at the expense of processing time and permeate volumes. In-situ UV technology was successfully used during the ultrafiltration and reverse osmosis operations. In theory, UV is a good means to quantitate the solute concentration in various aqueous solutions. Here, multiple FOUV technologies were successfully applied, demonstrating a new application for this technology. The development of the API recovery process required novel analytical methods for tracking the material of interest in various process streams. Specifically, the analytical methods HPLC and ELSD were used in unique ways to quantify both API and polymer levels in various process streams as the development continued.



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

Page 38 of 39

ACKNOWLEDGEMENTS The authors are grateful for the contributions from team members from Bristol-Myers Squibb and our external partners, including Ashland, Colorcon, DOW, GEA, and Pall.

REFERENCES (1)

Smith, R. Chemical Process Design, McGraw-Hill, New York, N.Y., 1995.

(2)

Douglas, J. M. Conceptual Design of Chemical Process, McGraw-Hill, New York, N.Y., 1988.

(3)

Hsieh, D.; Marchut A.; Wei C.; Zheng B.; Wang S-SY.; Kiang S. Org. Process Res. Dev. 2009, 13, 690-697.

(4)

Klucel™ hydroxypropylcellulose Physical and chemical properties, Ashland, 2012.

(5)

Methocel cellulose ethers technical handbook, Dow, 2000.

(6)

Using Dow excipients for controlled release of drugs in hydrophilic matrix systems, Dow, 2006.

(7)

Richardson, J. F. and Harker, J. H.; Coulson and Richardson’s Chemical Engineering Volume 2, fifth edition, Particle Technology and Separation Processes, ButterworthHeinemann, 2002.

(8)

Handbook of Separation Process, edited by Ronald W. Rousseau, John Wiley & Sons, Inc. 1987.

(9)

Membrane Handbook, edited by W. S. Winston Ho, and K. K. Sirkar, Chapman & Hall 1992.

(10) Schwartz, L., Diafiltration: A fast, efficient method for desalting, or buffer exchange of biological samples. PN 33289, Life Science Pall (11) Geankoplis C. J., Transport Processes and Unit Operations, Prentice Hall, 1983.


Page 39 of 39

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


Table of Contents Graphic

ACS Paragon Plus Environment

A Process for Active Pharmaceutical Ingredient Recovery from Tablets

Recommend Documents