Green Technology for Salt Formation: Slurry Reactive Crystallization

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Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 Haloperidol-Maleic Acid Salt Jeanne Dewi Damayanti, Dhanang Edy Pratama, and Tu Lee Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00098 • Publication Date (Web): 12 Apr 2019 Downloaded from http://pubs.acs.org on April 16, 2019

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Crystal Growth & Design

Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 Haloperidol-Maleic Acid Salt

Jeanne Dewi Damayanti, Dhanang Edy Pratama, and Tu Lee,* Department of Chemical and Materials Engineering, National Central University, 300 Zhongda Road, Zhongli District, Taoyuan City 32001, Taiwan, R.O.C.

ABSTRACT: Papaverine HCl was successfully suspended by slurry reactive crystallization with the use of isopropyl alcohol (IPA) at 25C, a solid-to-liquid ratio of 0.19 g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 200-400 µm, and the value for enthalpy of fusion of 154.5 J/g.

The poor solubility of papaverine

in IPA and better solubility of papaverine HCl in water-containing IPA had made the homogeneous nucleation of papaverine HCl dominate. of papaverine HCl were time and temperature dependent.

Crystal size and crystallinity On the other hand, the 1:1

haloperidol-maleic acid salt was also successfully suspended and generated by slurry reactive crystallization with the use of water at 25C, a solid-to-liquid ratio of 0.18

*

Corresponding Author. Tel: +886-3-4227151 ext. 34204. E-mail: [email protected].

Fax: +886-3-4252296. 1

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Crystal Growth & Design 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

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g/mL, an aging time of 8 h, a yield of 82.0 w/w %, crystal sizes of 500-1000 µm, and the value for enthalpy of fusion of 84.9 J/g.

The poor solubility of haloperidol and

1:1 haloperidol-maleic acid salt in water had made the heterogeneous nucleation of 1:1 haloperidol-maleic acid salt dominate.

Crystal size and crystallinity of 1:1

haloperidol-maleic acid salt became less sensitive to time and temperature. Comparing with grinding, solution reactive crystallization by cooling and solution recrystallization by cooling, slurry reactive crystallization was a simple, robust, straightforward, low-constant-temperature, low-solvent-volume and environmentally benign process giving comparable yield, particle size distribution, and crystallinity. Moreover, the use of a poor solvent in the slurry reactive crystallization enabled the recycling of the mother liquor without any significant loss in yield and crystallinity up to three cycles.

INTRODUCTION Cooling crystallization and antisolvent addition crystallization in a common stirred tank are the two most common conventional solution crystallization methods for inducing homogeneous nucleation and crystal growth in a supersaturated solution.1 Those two conventional approaches are widely used in the penultimate and final steps for the manufacturing of active pharmaceutical ingredients (APIs).2

In general, 2


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conventional solution crystallization offers a seamless integration with the chemical reaction step of

A + B  C + D, which takes place prior to crystallization.3,4

If

properly designed, the clever choice of solvent can dissolve the unwanted by-product molecules, C, in the solution phase and keep them away from the desired API solutes, D, which are being densified into solids by crystallization.

The phase separation

between liquid and solid then happens naturally by the free pulling of gravity. Moreover, if crystallization in the solution phase is controlled either by cooling or by anti-solvent addition or by both ways, the API attributes such as purity, yield, polymorphism, crystallinity, crystal habit, and particle size distribution (PSD) can be tailor-made.4-7

Those physicochemical properties are patentable and essential for

quality control in the final step.8 Despite of the advantages for the two conventional solution crystallization approaches, their prerequisite for concocting a homogenous solution phase in the beginning could be troublesome.

Normally, a large volume of organic solvent is

required to achieve a homogeneous phase.

Finding a common solvent for both

reactants, A and B, and by-product, C, but not for the API solutes, D, could be timeconsuming and sometimes impossible.9

Screening solvents for dissolving reactants,

A and B, separately, and wishing a complete miscibility upon mixing of the two separate solutions of A and B could be very difficult.

The situation becomes worse 3



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when the API solutes, D, are highly soluble in the resulting co-solvent medium. Evaporation is usually employed to concentrate the solution, which will bring an undesirable variation to the co-solvent makeup, and complicate the conventional solution crystallization afterwards. Although those solvent related problems may potentially be eliminated by mechanochemical synthesis involving the use of manual grinding,10 ball milling10-13 and twin screw melt extrusion,14 those solvent-less methods are mainly restricted to the use of solid reactants.

The lack of understanding for the formation mechanism,

and the uncontrollable particle size of API further complicate the implementation of those methods.

Therefore, looking into slurry reactive crystallization with  = 1 to

10, which is between the two extremes of solution reaction with  > 10, and mechanochemistry with  = 0 to 1, where  is the ratio of the liquid volume in µL to the solid mass in mg,15,16 may be necessary for robust manufacturability, mass efficiency and process greenness.

Two important precedents related to slurry reactive

crystallization had been reported, one for an API17 and the other for a ceramic material of barium titanate (BaTiO3).18-23

For the crystallization of a potent oncology drug

candidate under development at GlaxoSmithKline,17 the free base solvate was initially dissolved in 2-methyltetrahydrofuran (MeTHF).

The free base solvate slurry was then

generated by the addition of an anti-solvent acetonitrile (MeCN) followed by cooling. 4 ACS Paragon Plus Environment

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The acid counter ion dissolved in MeTHF was then charged to the free base solvate containing MeTHF solution at a controlled rate to form salt crystals.

This approach

involved the co-existence of crystals for both parent free base solvate and salt. secondary nucleation dominated.

The

As for the hydrothermal synthesis of sub-

micrometer BaTiO3 powders, crystalline or hydrous titania (TiO2) in aqueous slurries was reacted with the dissolved barium hydroxide (Ba(OH)2) near the boiling point of water.18-23

At the early stage of BaTiO3 formation, a dissolution-precipitation

mechanism dominated, but at longer reaction times, the mechanism was switched over to an in-situ transformation mechanism.20 Therefore, the aim of our study is to come up with a more robust method, namely slurry reactive crystallization, based on the selection of only one poor solvent for both the reactant, A, and the API product, D.

Consequently, the yield of the product will

be comparable with the one of solution reactive crystallization by cooling, and will depend solely on the initial solid-to-solvent loading ratio.

The particle size

distribution (PSD) of the API product, if necessary, will later be tuned by a separate step of solution re-crystallization for the product alone.24,25

The advantages of slurry

reactive crystallization include: solvent reduction, easy scale-up, constant operating temperature, minimum control on reactant addition, repeated use of the mother liquor, and reproducibility of the API powder properties.

This strategy can also be used to 5



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replace conventional salt screening procedures,9,26-29 and expedite the production of chemical intermediates and generic drugs. To demonstrate the concept of slurry reactive crystallization, salt formation of papaverine free base (pKa = 6.4)30 suspension with the presence of aqueous solution of hydrochloric acid, and salt preparation of haloperidol free base (pKa = 8.3)14,30 suspension with the addition of aqueous solution of maleic acid, were investigated. Papaverine HCl was chosen as a model API because it was so difficult to be crystallized in water.

It took days to precipitate it by cooling.

Peculiarly, the solubility of

papaverine HCl in water was enhanced upon the addition of anti-solvent acetone (Figure S1(a)) or isopropyl alcohol (Figure S1(b))! was selected as another model API.

1:1 haloperidol-maleic acid salt

Although 1:1 haloperidol-maleic acid salt was

successfully prepared by us before through the solvent-less twin screw extrusion method,14 the extruder itself is neither a common lab tool nor a common unit operation in a chemical plant.

There is a need to develop a more simple, and general protocol

using a common stirred tank. Apparently, slurry reactive crystallization could serve the purpose.

Consequently, initial solvent screening was performed to identify the poor

solvents for the API free base and its salt.

Slurry reactive crystallization could be

started by adding the aqueous acidic solution into the free base, which was suspended in the poor solvent at a given temperature.

Time studies from t = 0 to 20 min at T = 6


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25C, and temperature studies at T = 5, 25, and 60C for t = 20 min, were carried out to figure out the mechanism for slurry reactive crystallization.

The attributes of salt

crystals from slurry reactive crystallization at T = 25C for t = 8 h were fully characterized, and compared with the ones from grinding, solution reactive crystallization by cooling, and re-crystallization in a good solvent by cooling. Finally, the mother liquor after slurry reactive crystallization was separated and recycled to test for the feasibility of solvent reduction.

MATERIALS AND METHODS Materials.

Papaverine HCl (C20H21NO4.HCl, 98% assay, MW : 375.85, mp : 226oC,

Lot : SLBN9986V) and maleic acid (C4H4O4, ≥ 99% purity, MW : 116.07, mp : 137140oC, Lot : 055K5429) were purchased from Sigma-Aldrich (St. Louis, MO, USA). Haloperidol (C21H23ClFNO2, > 98% purity, MW : 375.87, mp : 151oC, Lot : B3REDEK) was obtained from Tokyo Chemical Industry Co. (TCI, Tokyo, Japan).

Hydrochloric

acid 37% (HCl 37%, MW : 36.46, bp : 50.5oC, Lot : UN1789) was purchased from Johnson Matthey Co. (UK).

Sodium hydroxide (NaOH, 96% assay, MW : 40.00, mp

: 318oC, Lot : KX-2842A) was received from Showa Chemical Co. Ltd. (Tokyo, Japan). Solvents.

n-heptane (CH3(CH2)5CH3, 99% purity, Lot: EA8351), toluene (C6H5CH3,

100% purity, Lot: ETA140403), chloroform (CHCl3, 99.99% purity, Lot: E554180), 7 ACS Paragon Plus Environment


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tetrahydrofuran (THF) (C4H8O, 99% purity, Lot: E704198), ethanol (CH3CH2OH, 99.5% purity, Lot: 262611) and dimethyl sulfoxide (DMSO) ((CH3)2SO, 99.8% purity, Lot: EA3M741) were purchased from Echo Chemical Co. Ltd. (Taiwan).

Xylene

(C6H4(CH3)2, 98.5% purity) and 1,4-dioxane (C4H8O2, 98% purity, Lot: SP-34332R) were purchased from Avantor Performance Materials Co. Ltd. (USA). p-xylene (C6H4(CH3)2 , 99% purity, Lot: 802551), ethyl acetate (CH3COOC2H5, 99.5% purity, Lot: 711912), methyl tert-butyl ether (MTBE) ((CH3)3COCH3, 99.9% purity, Lot: 1005355), benzene (C6H6, 99% purity, Lot: 310008), methyl ethyl ketone (MEK) (C2H5COCH3, 99.6% purity, Lot: SMEI40421), acetone (CH3COCH3, 99.5% purity, Lot: EB8N311), n-butyl alcohol (CH3(CH2)3OH, 99.4% purity, Lot: 205027), isopropyl alcohol (IPA) ((CH3)2CHOH, 99.8% purity, Lot: 14030108), benzyl alcohol (C6H5CH2OH, 99.8% purity, Lot: 70950), acetonitrile (CH3CN, 99.96% purity, Lot: 14050419), N,N-dimethylformamide (DMF) (HCON(CH3)2, 99.8% purity, Lot: 912313), and methanol (CH3OH, 99.9% purity, Lot: 14050368) were obtained from TEDIA company (USA).

N,N-dimethylaniline (DMA) (C6H5N(CH3)2, 99% purity,

Lot: A0213203001), and nitrobenzene (C6H5NO2, 99% purity, Lot: A0282673) were received from Acros Organics company (USA).

Water was clarified by reverse

osmosis (RO) through a water purification system (model Milli-RO Plus) bought from Millipore (Billerica, MA, USA). 8 ACS Paragon Plus Environment

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Preparation of Papaverine Free Base.

Due to the unavailability of papaverine free

base commercially, it was synthesized by reacting papaverine HCl with NaOH at room temperature.

About 0.3 g of papaverine HCl was dissolved in a 15 mL of water

followed by the addition of 0.80 mL of 1 M NaOH (aq), resulting in a 1:1 molar ratio of papaverine HCl to NaOH.

The crystals formed were filtered, rinsed by water, oven

dried at 40oC for 24 h, and characterized. Preparation of 1:1 Haloperidol-Maleic Acid Salt. was unavailable commercially. outlined by Lee et al.14

1:1 Haloperidol-maleic acid salt

The salt was synthesized following the procedure

Equal molar amount of haloperidol (0.94 g, 2.5 mmol) and

maleic acid (0.29 g, 2.5 mmol) were dissolved together in a 15 mL of ethyl acetate at 65oC.

The solution was heated briefly to 68oC to ensure complete dissolution, and

then cooled to room temperature.

The resulting 1:1 haloperidol-maleic acid salt

crystals were filtered, oven dried at 70oC for 24 h to prevent hydrate formation and characterized. Initial Solvent Screening. followed.

The procedure for initial solvent screening31 was

There were 23 solvents used for initial solvent screening: n-heptane, xylene,

p-xylene, ethyl acetate, toluene, methyl tert-butyl ether (MTBE), benzene, methyl ethyl ketone (MEK), chloroform, tetrahydrofuran (THF), N,N-dimethylaniline (DMA), acetone, 1,4-dioxane, nitrobenzene, n-butyl alcohol, isopropyl alcohol (IPA), benzyl 9 ACS Paragon Plus Environment


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alcohol, acetonitrile, N,N-dimethylformamide (DMF), ethanol, dimethyl sulfoxide (DMSO), methanol, and water. scintillation vial.

30 mg of a powder sample were placed into a 7 mL

A chosen solvent was added dropwise into the vial with an

intermittent stirring at 25C.

If all powders were dissolved within 6 mL of addition

by eye, the solvent was regarded as a good solvent (solubility ≥ 5 mg/mL) with respect to the powder sample, otherwise the solvent was regarded as a bad solvent (solubility < 5 mg/mL).

This procedure was performed for all powder samples of papaverine

free base, papaverine HCl salt, haloperidol free base, maleic acid, and 1:1 haloperidolmaleic acid salt.

The solubility of each compound in those 23 common solvents was

summarized and depicted in a form space. Slurry Reactive Crystallization of Papaverine HCl at T = 25C for t = 0.5, 1, 2, 3, 5, 7, 10, 15 and 20 min.

0.12 g (0.35 mmol) of papaverine free base was placed in a

20 mL scintillation vial, followed by the addition of 0.5 mL of isopropyl alcohol (IPA). 0.13 mL (0.38 mmol) of 3 M HCl aqueous solution was added dropwise to prepare an equal molar ratio of papaverine free base to HCl suspension at 25oC as illustrated in Figure S2(a).

The vial was capped, intermittently agitated by hand instead of using a

spin bar, to avoid powder attrition.

The resulting slurry was allowed to stand still for

up to 20 min, during which time powder samples were withdrawn at 0.5, 1, 2, 3, 5, 7, 10, 15, and 20 min.

The harvested powders were filtered, oven dried at 40oC for 24 10 ACS Paragon Plus Environment

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h, and characterized. Slurry Reactive Crystallization of Papaverine HCl at T = 5 and 60C for t = 20 min.

The procedures were the same as the ones in the last section.

However, the

temperatures used were 5 and 60oC, and the reaction time was up to 20 min. Slurry Reactive Crystallization of Papaverine HCl at T = 25C for t = 8 h. procedures were the same as the ones in the last section.

The

The temperature used was

25C and the total reaction and crystallization time was 8 h. Crystallization of Papaverine HCl by Grinding.

0.12 g (0.35 mmol) of papaverine

free base was placed in a mortar, which was oven heated at 60oC for 1 h.

The sample

was then taken out from the oven and 0.03 mL of concentrated 12 M HCl (0.38 mmol) was added to the mortar and ground together for 10 min while the mortar was hot before the next heating period at 60oC for 30 min. completing the reaction while the mortar was hot.

The sample was ground again for Finally, the product was oven dried

at 40oC for 24 h and characterized. Solution Reactive Crystallization of Papaverine HCl by Cooling.

0.12 g (0.35

mmol) of papaverine free base in 20 mL of scintillation vial was dissolved in 10 mL of acetone at 50oC.

0.13 mL (0.38 mmol) of 3M HCl aqueous solution was added into

the saturated papaverine free base solution, cooled to room temperature and stood for 8 h.

The solids were filtered and oven dried at 40oC for 24 h and characterized. 11 ACS Paragon Plus Environment


Re-crystallization of Papaverine HCl by Cooling.

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About 30 mg of papaverine free

base powder were prepared in a 7 mL scintillation vial, followed by an addition of 0.09 mL of water and placed in a water bath at 60oC. the solution was cooled to 4oC.

After the powders were dissolved,

The crystals were precipitated out after ~1 week,

which were then filtered, oven dried at 40oC for 24 h, and characterized. Recycling Mother Liquor for Slurry Reactive Crystallization of Papaverine HCl. 0.24 g of papaverine free base, 0.27 mL of 3 M HCl (aq), and 1 mL of IPA were introduced and mixed in a 20 mL scintillation vial at 25C for 8 h. suspension was centrifuged at 6000 rpm for 5 min. and placed in another 20 mL scintillation vial.

After that, the

The supernatant was withdrawn

This mother liquor was then treated as

if it was the IPA poor solvent for the subsequent slurry reaction.

Therefore, this

supernatant was used to suspend 0.24 g of papaverine HCl free base powders in a 20 mL scintillation vial. papaverine HCl salt.

0.27 mL of 3 M HCl (aq) was added dropwise to make new This cycle was repeated three times.

All crystals obtained were

filtered, oven dried at 40C for 24 h, and characterized. Slurry Reactive Crystallization of 1:1 Haloperidol-Maleic Acid Salt at T = 25C for t = 0.5, 1, 2, 3, 5, 7, 10, 15 and 20 min.

0.52 M aqueous solution of maleic acid

for making haloperidol salt was prepared.

0.037 g of maleic acid was dissolved in

0.68 mL of water at 25oC.

The aqueous maleic acid solution was introduced dropwise 12 ACS Paragon Plus Environment

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to 0.12 g (0.32 mmol) of haloperidol free base which was placed in a 20 mL scintillation vial to make a suspension at 25oC as shown in Figure S2(b).

The vial was capped,

intermittently agitated by hand instead of using a spin bar, to avoid powder attrition. The resulting slurry was allowed to stand still for up to 20 min, during which time powder samples were withdrawn at 0.5, 1, 2, 3, 5, 7, 10, 15, and 20 min.

The obtained

powders were filtered, oven dried at 70oC for 24 h to dehydrate the salt, and characterized. Slurry Reactive Crystallization of 1:1 Haloperidol-Maleic Acid Salt at T = 5 and 60C for t = 20 min. The procedures were the same as the ones in the last section.

The temperatures used

were 5 and 60oC, and the reaction time was up to 20 min. Slurry Reactive Crystallization of 1:1 Haloperidol-Maleic Acid Salt at T = 25C and t = 8 h. The procedures were as same as the ones in the last section.

The temperature used

was 25C and the total reaction and crystallization was 8 h. Crystallization of 1:1 Haloperidol-Maleic Acid Salt by Grinding.

0.12 g (0.32

mmol) haloperidol free base, and 0.04 g (0.35 mmol) maleic acid were placed in a mortar and pestle and preheated at 60oC for 30 min. ground together for 10 min.

After that, those powders were

The resulting 1:1 haloperidol-maleic acid salt crystals 13 ACS Paragon Plus Environment


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were oven dried at 70oC min for 24 h and characterized. Solution Reactive Crystallization of 1:1 Haloperidol-Maleic Acid Salt by Cooling. The synthesis of 1:1 haloperidol-maleic acid salt was carried out by following the procedures outlined by Lee et al.14

0.94 g (2.5 mmol) haloperidol free base and 0.32

g (2.8 mmol) maleic acid were dissolved together in a 15 mL of ethyl acetate at 60C. The temperature was raised briefly to 68C to ensure complete dissolution. solution was then cooled to room temperature.

The

The resulting salt crystals were filtered,

oven dried at 70oC for 24 h to prevent hydrate formation and characterized. Re-crystallization of 1:1 Haloperidol-Maleic Acid Salt by Cooling.

About 30 mg

of 1:1 haloperidol-maleic acid salt crystals were introduced in a 7 mL scintillation vial, followed by an addition of 0.19 mL n-butyl alcohol as a good solvent. placed in a water bath at 60C.

The vial was

After the powders were dissolved, the solution was

cooled to room temperature and stood for 8 h.

The crystals were precipitated, filtered,

oven dried at 70oC for 24 h, and characterized. Recycling Mother Liquor for Reactive Slurry Crystallization of 1:1 HaloperidolMaleic Acid Salt.

The procedure of making 1:1 haloperidol-maleic acid salt by slurry

reactive crystallization was followed.

0.24 g of haloperidol free base was suspended

in 1.4 mL of 0.52 M maleic acid aqueous solution for 8 h. was centrifuged at 6000 rpm for 5 min.

After that, the suspension

The supernatant was withdrawn, and placed 14


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in another 7 mL scintillation vial.

This mother liquor was treated as if it was the

solvent water for the subsequent slurry reactive crystallization.

Therefore, this mother

liquor was used to prepare 0.52 M maleic acid aqueous solution.

The solution was

added dropwise into a 20 mL scintillation vial containing haloperidol free base powders to make new 1:1 haloperidol-maleic acid salt.

This cycle was repeated four times.

The harvested crystals from each cycle filtered, oven dried at 70C for 24 h to dehydrate the salt and characterized.

Instruments.

Fourier-Transform Infrared (FTIR) Spectroscopy.

FTIR

spectroscopy was utilized to monitor the conversion of solid reactant during slurry reactive crystallization.

The FTIR spectrometer used was Perkin Elmer Spectrum One

(Norwalk, CT, USA).

About 1 mg of sample was gently ground with dry potassium

bromide (KBr) powders with a ratio of about 1 to 100 in an agate mortar. press was used to turn the powder into a pellet.

A manual

The pellet was scanned in the region

of 4000-400 cm-1 with a resolution of 2 cm-1. Differential Scanning Calorimetry (DSC).

DSC was used to measure the solid-solid

transition temperature, solid-liquid melting point, and heat of fusion.

The DSC

instrument used was Perkin Elmer DSC-7 calorimeter (Perkin Elmer Instruments LLC, Shelton, CT, USA).

The temperature scanning rate was 10oC/min from 40o to 150oC 15 ACS Paragon Plus Environment


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under a constant 99.99% pure nitrogen purge. Powder X-Ray Diffraction (PXRD).

PXRD was used to determine the crystal form of

the samples by comparing the XRD pattern of the samples with the reference obtained from Cambridge Crystallography Data Center (CCDC).

The PXRD pattern was

collected from a sample by using a Bruker Axs D8 Advance PXRD (Karlsruhe, Germany).

X-ray radiation Cu Kα1 (λ = 1.5405 Å) was set at 40 kV and 25 mA

passing through a nickel filter.

Samples were subjected to powder X-ray diffraction

analysis with a sampling width of 0.01o in a continuous mode with a scanning rate of 2o/min over an angular range of 5o to 35o. Optical Microscopy (OM).

The crystal habit and particle size distribution were

observed by Olympus BX-51 (Tokyo, Japan) equipped with a digital camera made by Moticam 2000 (Hong Kong, China).

About 3 mg of sample was used for each OM

characterization, and several micrographs were taken for the same sample.

The

obtained images were transformed by Motic Image Plus (version 2.0) into a digital photograph.

Analysis of the photograph was done by ImageJ 1.51g software equipped

with Microscope Measurement Tools v1 plugin. Scanning Electron Microscopy (SEM).

Surface morphology of the crystals were

observed by Hitachi S-800 instrument operated at an accelerating voltage of 20 keV. Analysis of the photographs were done by ImageJ 1.51g software equipped with 16 ACS Paragon Plus Environment

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Microscope Measurement Tools v1 plugin.

RESULTS AND DISCUSSION

Preparation of Papaverine Free Base and 1:1 Haloperidol-Maleic Acid Salt as Starting Materials.14

Since papaverine free base was unavailable commercially,

it was made in-house by us.

Papaverine HCl (Figure S3(a)) was successfully

converted into the free base (Figure S3(b)) by solution reactive crystallization with NaOH aqueous solution at room temperature as evidenced by the disappearance of the IR characteristic amine salt peaks at 2500, 1993, and 1956 cm-1.32

Different from the

purchased papaverine HCl having a melting point of 225.3C (Figure S4(a)),30,33 the synthesized papaverine free base exhibited a melting endotherm at 147.6C in the DSC scans (Figure S4(b)).30,34

The PXRD pattern of the synthesized papaverine free base

(Figure S5(a)) also matched well with the calculated PXRD pattern based on a single crystal X-ray diffraction standard (Figure S5(b)).35

1:1 haloperidol-maleic acid salt

was also successfully prepared through solution reactive crystallization by cooling.14 The IR spectrum showed the appearance of the NH+ tertiary amine salt characteristic bands from 2770 to 2380 cm-1 (Figure S6(c))14,32 which was absent in the IR spectrum for haloperidol free base (Figure S6(a)).14

The DSC scans revealed that the 1:1

haloperidol-maleic acid salt displayed a melting endoderm at 127.2C (Figure S7(b))14 17 ACS Paragon Plus Environment


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whereas the free base had a melting point at 154.2C (Figure S7(a)).14,30

The PXRD

pattern of the synthesized 1:1 haloperidol-maleic acid salt (Figure S8(a)) matched well with the calculated PXRD pattern based on a single crystal X-ray diffraction standard (Figure S8(b)).14

In addition, all the starting materials prepared in-house should be

pure, and their stability was checked by the use test for experimental use.

Initial Solvent Screening of Papaverine Free Base, Papaverine HCl, Haloperidol Free Base, and 1:1 Haloperidol-Maleic Acid Salt.31

The solubility of

papaverine free base, papaverine HCl, haloperidol free base, maleic acid, and haloperidol-maleic acid salt in 23 common solvents were summarized in the form spaces in Table S1-S5, respectively.

Based on the form spaces for papaverine free

base and papaverine HCl (Table S1 and S2), poor solvents for both papaverine free base and papaverine HCl salt were n-heptane, MTBE, n-butyl alcohol, IPA, and ethanol. Any of those five solvents could facilitate slurry reactive crystallization, and IPA was chosen for this study, because it is relatively safe, less hazardous, and environmentally benign.36

For haloperidol free base, maleic acid, and 1:1 haloperidol-maleic acid salt,

the solvent used for slurry reactive crystallization must be poor for dissolving the free base and the salt, but good for dissolving maleic acid, because maleic acid would be introduced as a solution form with the presence of haloperidol free base powders. Based on those requirements and the solubility properties provided by the form spaces 18 ACS Paragon Plus Environment

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for haloperidol free base, maleic acid, and haloperidol-maleic acid salt (Tables S3, S4 and S5), three solvent candidates: MTBE, IPA, and water, were found.

Water was

chosen because of its environmental benignity.37

Slurry Reactive Crystallization of Papaverine HCl.

The dissolution of

papaverine free base and the formation mechanism of papaverine HCl were monitored by samples collected at different time points during the 20 min reaction period at 25C by OM, SEM, and DSC.

The OM image at t = 0 min revealed that papaverine free

base originally existed as a 600-µm sized aggregate (Figure 1).

The SEM image

further showed that the aggregates actually composed of numerous 2- to 5-µm sized, needle-like primary crystals (Figure 1).30

Because of the hydrophobic nature of

papaverine free base,38 it was quite difficult for the polar IPA solvent39 to wet all the crystal surfaces in the suspended aggregates and to disperse the primary crystals into the IPA medium.

Therefore, the OM images from t = 0.5 to 7 min illustrated that the

aggregates were still holding together (Figure 1).

The DSC scans indicated that the

aggregates as a whole were mainly papaverine free base with a melting endotherm at 147.5C (Figures 2(a) to 2(c)).30,34

The appearance of an etched and gritty

morphology in the SEM images from t = 1 to 7 min (Figure 1) suggested that the needlelike primary free base crystals were later truncated into pieces.

This was due to the

local neutralization of free base with HCl, and the leaching of the randomly formed 19 ACS Paragon Plus Environment


papaverine HCl molecules.

Page 20 of 55

Having a higher solubility in water than the free base, the

newly formed papaverine HCl salt molecules (i.e. solubility in water at 25C was near 33.3 mg/mL, and practically insoluble in anhydrous IPA) tended to dissolve in watercontaining IPA, which contained a trace amount of water from the HCl aqueous solution.

However, no papaverine HCl crystals were precipitated at this point.

After

t = 7 min, the water-containing IPA had become saturated or even supersaturated with papaverine HCl.

Since then, approximately from t = 10 to 20 min, all papaverine free

base was completely converted as revealed by the diminishing melting endotherm near 149.7C (Figure 2(e)), and precipitated out as papaverine HCl crystals as evidenced by the appearance of an endotherm from 217.4 to 223.8C in the DSC scans (Figures 2(e) and 2(f)).30,33

The OM images from t = 7 to 10 min (Figure 1) suggested that

homogeneous nucleation of papaverine HCl crystals might have dominated the formation mechanism. clustered.

Many tiny prismatic crystals existed and were loosely

The SEM images from t = 10 to 15 min (Figure 1) further displayed the

clustering of many prismatic crystals, and at t = 20 min, aggregates had begun to fuse into larger crystals with a smoother surface.

Therefore, the crystallinity of papaverine

HCl was ameliorated during this crystal alignment process as reflected by the increasing values in enthalpy of fusion31,40 from 92.1 to 139.8 J/g under the endothermic peaks of melting near 217.4 to 223.8C in Figures 2(e) and 2(f).30,33 20 ACS Paragon Plus Environment

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Temperature Effect on Slurry Reactive Crystallization of Papaverine HCl. The DSC scans of papaverine HCl crystals produced by slurry reactive crystallization at 5, 25, and 60C for 20 min were shown in Figure 3.

Reaction kinetics of

neutralization was known to be increased with the increase of temperature,41 which is in agreement with Arrhenius equation.42 completely converted to papaverine HCl.

At 60C, papaverine free base was Only the melting point of papaverine HCl

at 226.0C was observed in Figure 3(d).30,33

As for 5C, a trace amount of papaverine

free base with a melting point of 150C was still observed in the DSC scan (Figures 3(b)).

Obviously, neutralization was incomplete for 20 min at a lower temperature.

The largest crystal size of 600 to 800 µm obtained at 60C (Figure 3(d)) as compared to the smaller ones of 80 and 100 µm for 5 and 25C (Figures 3(b) and 3(c)), respectively, verified the domination of homogeneous nucleation mechanism again. At a higher temperature, the degree of supersaturation was lowered because of the increase in the solubility of papaverine HCl in the water-containing IPA.

Therefore,

the number of nuclei formed would decrease, and given with a fixed amount of solutes, crystals could grow to larger sizes.43

The enthalpy values of fusion of 99.1, 139.9 and

123.3 J/g in Figures 3(a), 3(b) and 3(c), implied that the 20-min slurry reactive crystallization at 5, 25 and 60C, gave the lowest, highest and the medium degree of crystallinity for papaverine HCl, respectively.

The 5C slurry reactive crystallization 21



Page 22 of 55

produced crystals with the lowest degree of crystallinity because of incomplete neutralization.

Since the mass transfer rate was highly temperature dependent,42,44

the 60C slurry reactive crystallization gave crystals with a second best degree of crystallinity due to the fastest crystal growth rate.

Apparently, the best crystallinity

achieved by the 25C slurry reactive crystallization was mainly due to the balance of complete neutralization, and the not too rapid crystal growth rate.

Time Effect on Slurry Reactive Crystallization of Papaverine HCl.

Even

though neutralization was finished in 20 min at 25C, and the crystallinity of papaverine HCl at 25C was the highest among the other samples prepared at 5 and 60C, the crystallinity of papaverine HCl could be enhanced by aging the salt crystals in the slurry for 8 h by the mechanism of Ostwald ripening.

The resulting dissolution-and-

precipitation events of Ostwald ripening provided the physical means for lattice editing and alignment.42

This was verified by the increase in the enthalpy value of fusion

from 139.8 to 154.5 J/g for prolonging the contact time from 20 min to 8 h, respectively, for the slurry reactive crystallization at 25C as shown by the DSC scans in Figures 4(a) and 4(b).

After aging, the particle size distribution was increased from an average of

80 µm to 150 µm, and became more monodispersed as demonstrated by a comparison between the OM images in Figures 4(a) and 4(b).

22 ACS Paragon Plus Environment

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Comparisons with Papaverine HCl Produced by Other Methods.

The OM

images and DSC scans of papaverine HCl produced by different methods were summarized in Figures 4(a) to 4(e). from 218.3 to 225.3C.30,33 J/g.

All crystals had similar melting points ranging

The enthalpy values of fusion fell between 129.3 to 154.5

No new polymorphs were found because samples from all methods gave the same

characteristic peaks in the PXRD patterns (Figure S9).

Therefore, the difference in

melting points in the DSC scans was due to the difference of particle size which affected the kinetics of phase transition,45 and the difference in peak shape and width in PXRD patterns were either due to the difference in crystallite sizes or the presence of defects.45

The size of papaverine HCl crystals of 200 µm obtained from slurry reactive crystallization (Figure 4(b)) was smaller than the prismatic crystal sizes of 400 to 800 µm grown from conventional solution reactive crystallization by cooling (Figure 4(d)), and solution re-crystallization by cooling (Figure 4(e)).

However, crystals from slurry

reactive crystallization gave the highest enthalpy value of fusion of 154.5 J/g indicating of having a highest degree of crystallinity.

A relatively lower degree of

supersaturation during homogeneous nucleation was maintained with the presence of plentiful of IPA poor solvent.

As for the other solution crystallization methods taking

place in either acetone or water, the sudden rise of the papaverine HCl concentration in the good solvent gave a much higher degree of supersaturation upon cooling, and 23 ACS Paragon Plus Environment


Page 24 of 55

therefore, produced crystals having a relatively lower crystallinity due to a high mass transfer rate during crystal growth (Tables S1 and S2).

The grinding method gave the

smallest crystals and lowest enthalpy of fusion of 129.3 J/g due to crystal attrition and shear induced lattice defects, respectively (Figure 4(c)).46

Poor mixing for the

grinding method also prevented neutralization from completion as indicated by the endotherm at 146.8C for the presence of traces of unreacted papaverine free base (Figure 4(c)).

This pointed to the necessity of having a liquid phase in the process as

a medium for efficient mass transfer47 and purification.

Slurry Reactive Crystallization of 1:1 Haloperidol-Maleic Acid Salt. Similar to papaverine free base, the reaction mechanism of haloperidol slurry was monitored at different time points by using OM, SEM, and DSC, and those results were displayed in Figures 5 and 6.

The DSC scans in Figure 6 illustrated that the acid-base

reaction kinetics of haloperidol slurry proceeded at a faster rate than the one of papaverine free base.

Haloperidol free base was totally consumed at t = 7 min (Figure

6(d)) whereas it took more than t = 10 min to deplete all papaverine free base (Figure 2(f)).

It was because the surface areas per volume of haloperidol free base needles

were larger than those of the papaverine free base agglomerates.


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At t = 0 min, the free base crystals were small 50 µm-sized needles (Figure 5) with a layered surface structure.

1:1 haloperidol-maleic acid salt began to grow to 200

µm-sized agglomerates at t = 0.5 to 1 min as indicated by the morphological change in the OM images (Figure 5), and supported by the appearance of the melting endotherm of 1:1 haloperidol-maleic acid salt at 124.0oC in the DSC scan14 at t = 1 min (Figure 6(b)).

At t = 1 min, no needle-shaped crystals were observed by OM, and yet, the free

base was still present according to DSC, which displayed a small melting endotherm of haloperidol free base at 144.2C (Figure 6(b)).14,30

This implied that the round-shaped

salt crystals were actually grown on the surface of the free base needle crystals. remaining free base was trapped in the newly-formed salt crystals.

The

Hence, free base

conversion from t = 1 to 7 min had become a diffusion-limiting process.

After t = 7

min, the reaction was complete, as indicated by the disappearance of the melting endotherm for the free base near 142C in the DSC scan (Figure 4(d)).

All SEM

images for the 1:1 haloperidol-maleic acid salt crystals after t = 7 min showed some sort of layering texture (Figure 5).

Temperature Effect on Slurry Reactive Crystallization of 1:1 HaloperidolMaleic Acid Salt.

The DSC scans of slurry reactive crystallization of haloperidol

slurry at 15, 25, and 60oC for 20 min were shown in Figure 7.

At 5oC, traces of

haloperidol free base having a melting endotherm at 139.7C were remaining, while at 25 ACS Paragon Plus Environment


Page 26 of 55

25 and 60oC, reaction was complete and all free base was depleted.

The incomplete

reaction at the low temperature was due to the relatively low solubility of free base, and low reaction rate, which was in agreement with Arrhenius equation.42

Besides

reaction rate, the temperature effect on PSD and enthalpy of fusion for 1:1 haloperidolmaleic acid salt, seemed to be insignificant in Figure 7.

Since water was a poor

solvent for both haloperidol free base and 1:1 haloperidol-maleic acid salt, salt formation was most likely taking place very near to the free base surface.

When

heterogeneous nucleation occurred and dominated, daughter salt crystals tended to anchored onto the mother free base particles through the hydrogen bonding of the carboxylic acid groups of maleic acid molecules.

Crystal lattice editing and re-

alignment became difficult because of the poor solubility of salt42 and the strong adhesion among crystal planes.48 were generated.

Consequently, agglomerates with random sizes

The enthalpy of fusion remained around 83.5 to 87.8 J/g.

Time Effect on Slurry Reactive Crystallization of 1:1 Haloperidol-Maleic Acid Salt.

The poor solubility of 1:1 haloperidol-maleic acid salt and the strong

adhesion among their crystal planes in the agglomerates had prevented the enhancement of crystallinity by aging the salt crystals in the slurry for even up to 8 h.42,48

The

relatively close enthalpy values of fusion of 83.5 J/g, and 84.9 J/g, for salt agglomerates formed at 25C for 20 min, and 8 h, respectively (Figures 8(a) and 8(b)), had 26 ACS Paragon Plus Environment

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demonstrated the failure of Ostwald’s ripening in a poor solvent environment.

Time

did not have any influence on crystal lattice editing and alignment.

Comparisons of 1:1 Haloperidol-Maleic Acid Salt Produced by Other Methods.

The OM images and DSC scans of 1:1 haloperidol-maleic acid salt

produced by different methods were summarized in Figures 8(a) to 8(e). had similar melting points ranging from 125.7 to 130.0C.14 fusion were in the range of 83.5 to 92.5 J/g.

All crystals

The enthalpy values of

No new polymorphs were detected.

All

samples gave the same characteristic peaks in the PXRD patterns (Figure S10). Therefore, the slight difference in the melting point values in the DSC scans was due to crystallite size differences,49 and the various peak intensities in the PXRD patterns were due to the difference in crystallite size and the presence of lattice strain.45 PSDs of salts obtained from various methods were different.

The

The slurry reactive

crystallization method gave 600 to 800 µm sized agglomerates (Figures 8(a) and 8(b)). The grinding method gave 200 µm sized aggregates composing of mechanically attrited crystals (Figure 8(c)).

Since ethyl acetate was a good solvent for haloperidol and

maleic acid but a poor solvent for the 1:1 haloperidol-maleic acid salt only (Tables S3, S4 and S5), doing solution reactive crystallization by cooling would give a sudden very high degree of supersaturation for the salt.

This process would give 20 µm sized 1:1

haloperidol-maleic acid salt crystals (Figure 8(d)).

If a solvent was changed to n-butyl 27



Page 28 of 55

alcohol, which was a good solvent for the free base, maleic acid and the salt (Tables S3, S4 and S5), solution recrystallization by cooling would then give a relatively low degree of supersaturation, which would produce a 1000 µm sized large crystals (Figure 8(e)).

Recycling of the Mother Liquor for Slurry Reactive Crystallization. Recycling of the mother liquor for slurry reactive crystallization on both systems of papaverine HCl and 1:1 haloperidol-maleic acid salt were carried out at 25C for 8 h, and repeated for four times to test for its feasibility.

The DSC scans in Figure 9

showed the melting point of papaverine HCl ranged from 223.1 to 226.8C,30,33 but the crystallinity related enthalpy value of fusion dropped from 160.3 J/g in the first run to 147.7 J/g in the third cycle (Figures 9(a) to 9(d)). to 1:1 haloperidol-maleic acid salt.

A similar situation also happened

The DSC scans in Figure 10 exhibited the melting

point of the salt ranging from 127.0 to 128.7C.14

However, the enthalpy values of

fusion did decrease from 97.6 J/g in the first run to 80.8 J/g in the third cycle.

Since

the recycled mother liquor contained either a large amount of very tiny papaverine HCl crystals or 1:1 haloperidol-maleic acid salt crystals, the secondary nucleation became more and more dominant as the number of cycle increased, due to microattrition of salt crystals from the previous cycle which later acted as seeds.50

This would bring a

negative effect to crystallinity, because seeds formed from crystal fracture tended to 28 ACS Paragon Plus Environment

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have many dislocations and mismatched surfaces, resembled more of the amorphous than crystalline conditions.42

The OM images also illustrated the increase of crystal size from 15 µm in the first run to 1000 µm in the third cycle (Figures 9(a) to 9(d)).

Every time a fresh dose

of HCl aqueous solution was introduced into the mother liquor to start slurry reaction crystallization, the amount of traced water would be accumulated.

This would

increase the solubility of the recycled water-containing IPA and lower the degree of supersaturation upon cooling.

The number of nuclei would drop and the crystals

grown would become larger as shown by the trend in the OM images (Figures 9(a) to 9(d)).43

However, the OM images of 1:1 haloperidol-maleic acid salt agglomerates

maintained the same size of 1200 µm after three cycles (Figures 10(a) to 10 (d)) due to (1) water was a poor solvent to both the free base and salt, (2) the dominance of secondary nucleation, and (3) the binding of particles by maleic acid.

CONCLUSIONS

Slurry reactive crystallization of papaverine HCl and 1:1 haloperidol-maleic acid was successfully carried out. free base.

The chosen IPA was a poor solvent for papaverine

The addition of HCl aqueous solution would introduce trace amount of 29 ACS Paragon Plus Environment


water into IPA. HCl salt.

Page 30 of 55

The resulting water-containing IPA was a good solvent for papaverine

Those solubility properties had turned this system to be homogeneous

nucleation dominant (Figure 11).

Therefore, salt crystal size increased as the slurry

reactive crystallization temperature rose because of the low degree of supersaturation in the diffuse layer near the free base crystal surface (Figure 11).

For 1:1 haloperidol-

maleic acid salt, the selected water was a poor solvent for both haloperidol free base and 1:1 haloperidol-maleic acid salt.

Those poor solubility properties would make

this system heterogeneous nucleation dominant.

The carboxylic groups of maleic acid

could also strengthen the binding of the crystals at the crystal surfaces through hydrogen bonding (Figure 11).

Consequently, the size of the agglomerates of 1:1 haloperidol-

maleic acid should be less temperature sensitive.

The results of the two salts were

summarized and compared with the ones prepared by grinding, solution reactive crystallization by cooling and solution re-crystallization by cooling in Tables 1 and 2, respectively.

Slurry reactive crystallization operated safely at 25C, with a relatively

high solid-to-liquid ratio of 0.18 to 0.19 g/mL, high yield of 82.0%, large crystal size and high crystallinity.

Moreover, slurry reactive crystallization enabled the recycling

of the mother liquor, with the results summarized in Table 3. and energy used could be reduced drastically.

The amount of solvent

Apparently, there should be no

challenge for scale-up in a common stirred tank as long as the solid-to-liquid ratio stays 30 ACS Paragon Plus Environment

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low enough to avoid from having a thick slurry.

As the pharmaceutical industry is

shifting towards continuous manufacturing, it will be possible to implement slurry reactive crystallization continuously.

For the future study, we would look into the

possibility of applying slurry reactive crystallization to (1) co-crystallization, (2) other chemical reactions, (3) process development and scale-up, and (4) salt and co-crystal screening with the use of water only in early drug discovery.

ASSOCIATED CONTENT

Supporting Information. This material is available free of charge via the Internet at http://pubs.acs.org.

1. Solubility curves of papaverine HCl salt in acetone (antisolvent) / water (solvent) and IPA (antisolvent) / water (solvent) systems with various w/w %,

2. Experimental schemes of slurry reactive crystallization,

3. FTIR, DSC, and PXRD of the prepared papaverine free base and 1:1 haloperidol-maleic acid salt,



Page 32 of 55

4. FTIR, DSC, and PXRD of papaverine HCl and 1:1 haloperidol-maleic acid salt obtained from slurry reactive crystallization, grinding, solution reactive crystallization, and solution recrystallization, and

5.

Form spaces of papaverine free base, papaverine HCl, haloperidol free base, maleic acid, and haloperidol-maleic acid salt.

AUTHOR INFORMATION Corresponding Author * Tel: +886-3-4227151 ext. 34204. Fax: +886-3-4252296. Email: [email protected]. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

This research was supported by the grants from the Ministry of Science and Technology of Taiwan R.O.C. (MOST 104-2221-E-008-070-MY3 and 107-2221-E008-037-MY3). We are also greatly indebted for the assistance provided by Li-Fan Chen for the DSC, Chin-Chuan Huang for the PXRD, and Ching-Tien Lin for the SEM at Precious Instrumentation Center of National Central University.


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For Table of Contents Use Only

Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 Haloperidol-Maleic Acid Salt

Jeanne Dewi Damayanti, Dhanang Edy Pratama, and Tu Lee†

Slurry reactive crystallization, defined as a system in between grinding and solution reactive crystallization, was demonstrated for the formation of papaverine HCl and 1:1 haloperidol-maleic acid salt, dominated by homogeneous nucleation, and heterogeneous nucleation, respectively. The nucleation mechanism was determined by the solubility properties of the reactant and product in a selected solvent, which would affect the particle size distribution and crystallinity of the salt crystals in response to the reaction temperature and aging time. The greenness of slurry reactive crystallization was evidenced by the use of environmentally benign solvent, high solidto-liquid ratio, high yield, relatively low constant temperature, and recycling of the mother liquor for up to three cycles (OM image scale: 200 µm).

†

Corresponding Author. Tel: +886-3-4227151 ext. 34204. E-mail: [email protected].

Fax: +886-3-4252296. 40


Page 41 of 55 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


Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 HaloperidolMaleic Acid Salt

Jeanne Dewi Damayanti, Dhanang Edy Pratama, and Tu Lee*

Department of Chemical and Materials Engineering, National Central University, 300 Zhongda Road, Zhongli District, Taoyuan City 32001, Taiwan, R.O.C.

Corresponding Author. Tel: +886-3-4227151 ext. 34204. Fax: +886-3-4252296. E-mail: [email protected]. *



Figure 1.

OM and SEM images of crystals or aggregates produced by slurry reactive

crystallization at different time points of 0, 0.5, 1, 2, 3, 5, 7, 10, 15 and 20 min (OM image scale bar: 200 µm, and SEM image scale bar: 10 µm).


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Figure 2. DSC scans of crystals produced by slurry reactive crystallization at 25C at different time points of (a) 0 min, (b) 1 min, (c) 5 min, (d) 7 min, (e) 10 min, and (f) 20 min ((): papaverine, and (): papaverine HCl).



Figure 3. OM images and DSC scans of (a) initial papaverine, and crystals produced by slurry reactive crystallization for 20 min at different temperatures of (b) 5oC, (c) 25oC, and (d) 60oC ((): papaverine, and (): papaverine HCl; OM image scale bar: 200 µm).


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Figure 4. OM images and DSC scans of papaverine HCl produced by: (a) slurry reactive crystallization at 25C for 20 min, (b) slurry reactive crystallization at 25C for 8 h, (c) grinding for 10 min, (d) solution reactive crystallization in acetone by cooling from 50C to room temperature and kept for 8 h, and (e) solution re-crystallization in water by cooling from 60 to 5oC and kept for 1 week ((): papaverine, and (): papaverine HCl; OM scale bar: 200 µm).



Figure 5.

OM and SEM images of crystals or agglomerates produced by slurry reactive

crystallization at 25C at different time points of 0, 0.5, 1, 2, 3, 5, 7, 10, 15 and 20 min (OM image scale bar: 200 µm, and SEM image scale bar: 10 µm).


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Figure 6. DSC scans of crystals produced by slurry reactive crystallization at 25C at different time points of (a) 0 min, (b) 1 min, (c) 5 min, (d) 7 min, (e) 10 min, and (f) 20 min ((): haloperidol, and (): 1:1 haloperidol-maleic acid salt).



Figure 7. OM images and DSC scans of (a) haloperidol, and (b) crystals produced by slurry reactive crystallization for 20 min at (b) 5oC, (c) 25oC, and (d) 60oC ((): haloperidol, and (): 1:1 haloperidol-maleic acid salt; OM image scale bar: 200 µm).


Page 48 of 55

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Figure 8. OM images and DSC scans of 1:1 haloperidol-maleic acid salt produced by (a) slurry reactive crystallization for 20 min, (b) slurry reactive crystallization for 8 h, (c) grinding for 10 min, (d) solution reactive crystallization in ethyl acetate by cooling from 60 to room temperature, and (e) solution recrystallization in n-butyl alcohol from 60 to 25oC, and kept for 8 h (OM scale bar: 200 µm).



Figure 9. OM images and DSC scans of papaverine HCl salt produced by slurry reactive crystallization at 25C for 8 h of (a) the first run, and recycled slurry reactive crystallization at 25C for 8 h of (b) first cycle, (c) second cycle, and (d) third cycle (OM image scale bar: 200 µm).


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Figure 10. OM images and DSC scans of 1:1 haloperidol-maleic acid salt produced by slurry reactive crystallization at 25C for 8 h of (a) the first run, and recycled slurry reactive crystallization at 25C for 8 h of (b) first cycle, (c) second cycle, and (d) third cycle (OM image scale bar: 200 µm).



Figure 11. Mechanism of slurry reactive crystallization method (OM scale bar: 200 µm).


Page 52 of 55

Page 53 of 55 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


Green Technology for Salt Formation: Slurry Reactive Crystallization Studies for Papaverine HCl and 1:1 HaloperidolMaleic Acid Salt

Jeanne Dewi Damayanti, Dhanang Edy Pratama, and Tu Lee*

Department of Chemical and Materials Engineering, National Central University, 300 Zhongda Road, Zhongli District, Taoyuan City 32001, Taiwan, R.O.C.

Corresponding Author. Tel: +886-3-4227151 ext. 34204. Fax: +886-3-4252296. E-mail: [email protected]. *



Page 54 of 55

Table 1. Comparisons of grinding, slurry reactive crystallization, solution reactive crystallization, and solution recrystallization for papaverine HCl production. Production Methods Variables Grinding

Slurry Reactive Crystallization

Solution Reactive Crystallization

Solution Recrystallization

Temperature (C)

60

25

50 to 25

60 to 4

Solid-to-liquid ratio (g/mL)

4

0.19

0.01

0.33

Time

10 min

8h

8h

~1 week

Yield (w/w %)

82.7

82.0

87.9

25.0

Crystal size (µm)

10-100

200-400

200-400

400-600

Enthalpy of fusion (J/g)

129.3

154.5

140.7

145.2

Table 2. Comparisons of grinding, slurry reactive crystallization, solution reactive crystallization, and solution recrystallization for 1:1 haloperidol-maleic acid salt production. Production Methods Variables Grinding

Slurry Reactive Crystallization

Solution Reactive Crystallization

Solution Recrystallization

Temperature (C)

60

25

60 to 25

60 to 25

Solid-to-liquid ratio (g/mL)

∞

0.18

0.08

0.25

Time

10 min

8h

8h

8h

Yield (w/w %)

64.6

82.0

88.6

42.4

Crystal size (µm)

10-400

500-1000

10-100

300-500


89.1

84.9

92.5

88.1


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Table 3. Yield comparisons of papaverine HCl and 1:1 haloperidol-maleic acid salt produced by the first and recycled runs.

Papaverine HCl

1:1 Haloperidolmaleic acid salt

First Run

First Cycle

Second Cycle

Third Cycle

Yield (w/w %)

83.0

78.2

76.6

81.2

Crystal size (µm)

10-100

100-700

200-800

500-800


160.3

152.7

150.1

147.7

Yield (w/w %)

76.2

84.5

89.9

85.7

Crystal size (µm)

500-1000

500-1000

500-1000

500-1000


97.6

91.4

88.7

80.8


Green Technology for Salt Formation: Slurry Reactive Crystallization

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