Polymorphism in Pharmaceutical Drugs by Supercritical CO2 Processing

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Polymorphism in pharmaceutical drugs by supercritical CO processing – clarifying the role of anti-solvent effect and atomization enhancement Miguel A. Rodrigues, João M. Tiago, Andreia Duarte, Vitor Geraldes, Henrique A. Matos, and Edmundo Gomes Azevedo Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00697 • Publication Date (Web): 21 Sep 2016 Downloaded from http://pubs.acs.org on September 26, 2016

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Crystal Growth & Design

Polymorphism in pharmaceutical drugs by supercritical CO2 processing – clarifying the role of anti-solvent effect and atomization enhancement Miguel A. Rodrigues*, João M. Tiago, Andreia Duarte, Vítor Geraldes, Henrique A. Matos and Edmundo Gomes Azevedo Centro de Química Estrutural and CERENA, Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa Av. Rovisco Pais, 1049-001 Lisbon, Portugal * Miguel A. Rodrigues Centro de Química Estrutural, Department of Chemical Engineering Instituto Superior Técnico, Universidade de Lisboa Av. Rovisco Pais, 1049-001 Lisbon, Portugal E-mail: [email protected]

ABSTRACT Supercritical carbon dioxide (scCO2) induces polymorphism in pharmaceutical drugs. However, it is unclear whether polymorphism is induced by the CO2 anti-solvent effect or simply by the spray-drying step involved in the scCO2 anti-solvent processes. Herein, this effect is clarified by using supercritical enhanced atomization techniques assisted with scCO2 and scN2 and three drugs (indomethacin (IND), carbamazepine (CBZ) and theophylline (TPL)) that have already exhibited polymorphism when processed by classical Supercritical Anti-Solvent (SAS) processing. Polymorphs were obtained by Supercritical Enhanced Atomization (SEA) using either CO2 or N2 revealing that polymorphism was induced by atomization in all cases except for TPL, which was very sensitive to the CO2 anti-solvent action. The TPL polymorph was produced by Atomization of Supercritical Antisolvent Induced Suspensions (ASAIS) process, which enables to perform SAS in standard (atmospheric pressure) spray dryers. A Computational Fluid Dynamics (CFD) model was developed to understand the antisolvent-driven supersaturation of TPL inside the ASAIS nozzle. The significant solubility of TPL in CO2- tetrahydrofuran and its high sensitivity to the anti-solvent precipitation mechanism, limit the purity of this polymorph to a narrow range of process conditions. 1 ACS Paragon Plus Environment


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Polymorphism in pharmaceutical drugs by supercritical CO2 processing – clarifying the role of anti-solvent effect and atomization enhancement Miguel A. Rodrigues*, João M. Tiago, Andreia Duarte, Vítor Geraldes, Henrique A. Matos and Edmundo Gomes Azevedo Centro de Química Estrutural and CERENA, Department of Chemical Engineering, Instituto Superior Técnico, Universidade de Lisboa Av. Rovisco Pais, 1049-001 Lisbon, Portugal

* E-mail: [email protected]

ABSTRACT Supercritical carbon dioxide (scCO2) induces polymorphism in pharmaceutical drugs. However, it is unclear whether polymorphism is induced by the CO2 anti-solvent effect or simply by the spray-drying step involved in the scCO2 anti-solvent processes. Herein, this effect is clarified by using supercritical enhanced atomization techniques assisted with scCO2 and scN2 and three drugs (indomethacin (IND), carbamazepine (CBZ) and theophylline (TPL)) that have already exhibited polymorphism when processed by classical Supercritical Anti-Solvent (SAS) processing. Polymorphs were obtained by Supercritical Enhanced Atomization (SEA) using either CO2 or N2 revealing that 2 ACS Paragon Plus Environment

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polymorphism was induced by atomization in all cases except for TPL, which was very sensitive to the CO2 anti-solvent action. The TPL polymorph was produced by Atomization of Supercritical Antisolvent Induced Suspensions (ASAIS) process, which enables to perform SAS in standard (atmospheric pressure) spray dryers. A Computational Fluid Dynamics (CFD) model was developed to understand the antisolvent-driven supersaturation of TPL inside the ASAIS nozzle. The significant solubility of TPL in CO2- tetrahydrofuran and its high sensitivity to the anti-solvent precipitation mechanism, limit the purity of this polymorph to a narrow range of process conditions.

INTRODUCTION The properties of supercritical carbon dioxide (scCO2) have been explored for the production of particles by many authors.1,2 scCO2 antisolvent effect is the basis of the Supercritical Anti-Solvent (SAS) processing, which has been widely applied to comminute substances to micrometric and sub-micrometric sizes, with some control of morphology and size distribution, at moderate temperature and mechanical stress.2 SAS has also gained interest due to its potential to control the crystalline form of pharmaceutical substances. The singularity of the supercritical antisolvent mechanism induces polymorphism in substances that are not reproduced by other techniques.3,4 This is relevant because it is well-known the importance of polymorphs to the pharmaceutical industry, where it constitutes leverage tool to conquer a market share, but most importantly, because it also has the potential to transform physical-chemical characteristics of powders. Polymorphism has impact in the melting point, bulk density, chemical reactivity, apparent solubility and dissolution rate. In other words, polymorphism can affect drug stability, manipulation, and bioavailability.3,5 3 ACS Paragon Plus Environment


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Despite the SAS potential, it has several drawbacks that limit its industrial acceptance. In SAS, the antisolvent precipitation, the solvent extraction and the particle harvest occur simultaneously in the same unit (the high-pressure precipitator). Control of SAS is therefore challenging because the residence time distribution of the crystals in supercritical conditions is very wide, as crystals accumulate in the precipitator from the start of the run to its end. This lack of residence time control is problematic because the supercritical phase has significant solvent power, enabling crystal growth and crystal habit conversion. These issues, together with the scale-up of the high pressure volume and complex particle recovery by filtration, make it difficult to implement SAS at the industrial scale.6 In a previous work, a new version of SAS that restricts the use of CO2 at supercritical conditions (high-pressure) to a small volume (approximately 1 cm3) — the atomization of antisolvent induced suspensions (ASAIS) was developed.3 In this process the solution is mixed with scCO2 in a small volume mixer prior to its atomization to generate a suspension which is then immediately sprayed for solvent extraction by spray-drying at normal pressure. By restricting the high pressure exclusively to a small volume before the atomizer, the installation is simplified and becomes compatible with existing spray-drying equipment. On the contrary, in SAS the different particle-forming steps occur in the supercritical media (notably the atomization, the antisolvent crystallization, the solvent extraction and the particle separation). Consequently, ASAIS circumvents the high-volume equipment at high pressure and complex particle harvesting in filters, which is incompatible with continuous regime operation.

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Figure 1. Conceptual differences between SAS, ASAIS and SEA techniques, where the green represents an outer tube for the atomizing fluid (CO2 or N2), and red represents the liquid solution tubing. In ASAIS antisolvent precipitation occurs before the jet dispersion in a small volume. In addition, high-pressure is confined to a small equipment and the suspension spray is dried at normal pressure.

ASAIS has many similarities to other techniques that use scCO2 as an assisting fluid at the nozzle to enhance liquid jet break-up into very small droplets.7 In fact, in this work the same setup will be used for ASAIS and for Supercritical Enhanced Atomization (SEA)7–10 with the exception of the mixing chamber volume before the atomization (see Figure 1). However, this small difference is crucial, because depending of the mixing volume (and time), precipitation will occurs before or after the nozzle orifice, i.e. in ASAIS suspensions will be atomizing whereas in SEA homogeneous solutions are atomized. By comparing the crystal habit of the active pharmaceutical ingredients (APIs) obtained from ASAIS and SEA, it is expected to clarify whether the polymorphism observed using the SAS process was caused by the antisolvent action of CO2 or simply due to a high supersaturation or drying rate that could be reproduced by conventional spraydrying. Moreover this approach should also clarify the importance of CO2 for controlling the crystalline form of different APIs. Towards this goal, in this work a spray-drying setup was converted to ASAIS by assembling an ASAIS nozzle (including the mixer). The systems studied using this method were indomethacin (IND), 5 ACS Paragon Plus Environment


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carbamazepine

(CBZ),

non-steroidal anti-inflammatory drugs

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(NSAIDs),

and

theophylline (TPL), a bronchodilator. Other authors already processed these molecules by SAS,11–14 resulting in polymorphs, which provides a motivating background for discussion.7,12,13,15,16 A computational fluid dynamics (CFD) model previously developed by Rodrigues et al.3 was further adapted herein to simulate supersaturation and provide better insight of what is happening in the ASAIS mixing chamber. Several operating conditions associated to ASAIS processing, such as pressure, initial concentration of solution, liquid flow and nozzle diameter were explored to understand mechanisms involved in the formation of polymorphs by scCO2. The solubility of TPL mixtures in supercritical carbon dioxide-tetrahydrofuran (THF - scCO2) at different conditions was determined and solubility data was correlated to the molar fraction of CO2 in the mixture.17,18 The results discussed in this work provide an extended assessment of ASAIS comparatively to other scCO2-based techniques. The comparative analysis developed herein is a contribution to clarify the importance of scCO2 based technologies for controlling the crystalline form of APIs.

EXPERIMENTAL SECTION Materials. TPL and IND (minimum 99% of purity) were supplied by Sigma-Aldrich (Portugal), and CBZ (minimum 97% of purity) was purchased from Tokyo Chemical Industry (Belgium). THF was obtained from Panreac with a purity of 99.5% (wt.) and was used as received. Carbon dioxide (99.98% pure), nitrogen (99.98% pure) and liquid nitrogen were supplied by Air Liquide (Portugal).


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Experimental Setup. Figure 2 shows schematically the ASAIS setup. The liquid solution was pumped by a LKB metering pump (model 2150) into the ASAIS nozzle where it was mixed with a gaseous or supercritical fluid, (CO2 or N2). The gas (CO2 or N2) was compressed by a compressor (Newport, model 46-13421-2). The nozzle flow was measured by a mass flowmeter (Rheonik, model RHM007). Pressures were measured by transducers (Omega, model PX603) and temperatures were controlled, in the air chamber, by T-type thermocouples and Ero Electronic controllers (model LDS). Nozzle orifice diameter ranged from 50 µm to 150 µm. All nozzle discs (provided by Lenox Laser, USA) were 250 µm thick with laser-drilled orifices. The mixing volume was set by the height of the 1/16 inch tube inside the nozzle containing the liquid solution. A drying N2 flow at 323 K was set at approximately 30 normal liters per minute. The particles were collected in a BuchiTM cyclone and in a custom-built electrostatic precipitator (ESP) assembled in a single-stage tubular configuration and powered by an EMCO DX high voltage with 15 kV. TLP, IND and CBZ were processed by ASAIS and SEA using, separately, CO2 or N2 flow across the nozzle, under the conditions listed in Table 1.

Table 1. Experimental conditions used in ASAIS and SEA runs. Temperature was 323.15 K in all runs, pressure at the mixer was 9 MPa, diameter of nozzle was 150 µm and the liquid flow was 3mL/min. Vmixer: volume of the mixing chamber; C0: initial solution concentration; Rflow ratio: mass flow-rate ratio of the solution and the supercritical fluid. Sample TLP IND CBZ

Processing technique ASAIS ASAIS ASAIS

Vmixer (cm3) 0.3 0.3 0.3

C0 (mg/g) 5 5 100

Rflow ratio THF/scF 0.09 0.09 0.09



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TLP IND CBZ

SEA SEA SEA

0.01 0.01 0.01

2 2 2

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0.01 0.01 0.01

TPL: theophylline; IND: indomethacin; CBZ: carbamazepine.

(a)

(b)

Figure 2. (a) Schematic diagram of the ASAIS/SEA experimental setup. Pc, pressure controller; F, flowmeter; Tc, temperature controller. (b) ASAIS nozzle close-up. 1-Inner tube for the liquid solution; 2-Outer tube for CO2; 3-Heater cartridges; 4-Sealant O-ring; 5-nozzle disk.

Particles Characterization: Morphology and Solid State. The particles´ morphologies were analyzed by a Scanning Electron Microscope (SEM) JEOL JSM-7001F EDS Oxford INCA 250. Particle samples were coated prior to measurement with a gold film by electrodeposition in vacuum. The X-ray powder patterns for different samples were collected on a Bruker D8 Advance powder diffractometer using Cu Kα radiation (1.54056 Å) in Bragg Brentano geometry. The tube voltage and amperage was 40 kV and 40mA, respectively. The


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divergence slit and antiscattering slit settings were variable for illumination of the 20 mm sample. Each sample was scanned with 2θ between 5º and 35º with a step size of 0.02º and 0.5 s at each step. The TPL polymorphs were relatively quantified in the racemic mixtures by integrating the areas of the peaks at the angles (2θ) 13.9 and 14.8, which are characteristic of each polymorph and appear conveniently isolated in the powder diffractograms.

Equilibrium Solubility of TPL in THF-scCO2 System. The experimental measurements of TPL solubility in THF-scCO2 were carried out in a visual, variable volume high-pressure cell, as described elsewhere.19 Briefly, the visual cell consists of a stainless steel cylinder with a high-pressure glass window on the front side. This cell is divided into two chambers by a movable stainless steel piston with two O-ring seals. On the backside of the piston a pressuring fluid, water in this case, enables to drive the piston forward or backward. Each experimental run started by loading the cell (in the front side of the piston) with the solid powder whose solubility was to be determined and a magnetic stirrer for the sampling mixing at 700 rpm. After closing the cell the system was pressurized with CO2 and the air chamber was heated to the desired conditions (P, T). The mixture was left at these conditions overnight to ensure that the equilibrium solubility of solid components was established in the supercritical phase. Afterwards, a sample of the supercritical phase was loaded into a dead volume at the same P, T conditions by pushing the piston forward. The loop was then washed with a known mass of solution (phosphate buffer, pH 7.4). Each solubility measure was repeated at least three times and standard deviations were calculated.



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The TPL concentration in the washing solution was determined by high-performance liquid chromatography (HPLC) after filtration of the samples through a 0.20 µm membrane (Nylon). The HPLC system consisted of a Jasco HPLC-system provided with a Kromasil 2.1 x 150 mm C18 column and equipped with a variable UV detector (set at 254 nm). The column was kept at room temperature. The mobile phase - filtered by a 0.45 µm PVDF membrane and degassed by sonication prior to use - consisted of an acetate buffer:acetonitrile (95:5, pH 4), delivered at a flow rate of 0.3 mL/min. To determinate TPL concentration, the injection volume was 10 µL and the retention time was 11 min. Each sample was measured in triplicate.

Computational Fluid Dynamics Model. In this work it was extended a CFD model and solver previously used to simulate the mixing of a solvent with CO2 in the ASAIS conditions – coaxial mixing inside a small channel.3 Since the previous model did not consider the presence of the solute, it could not simulate the spatiotemporal supersaturation. Herein it was integrated in the model the solubility curve of TPL in CO2-THF mixtures, expressed by an empirical equation that was adjusted to the phase equilibria data determined experimentally for the ternary system TPL-THF-CO2. The model for unsteady-steady state laminar flow of an incompressible Newtonian fluid with a single phase can be described by the transport equations for total mass and momentum:

+ ∇ ∙ ρ = 0

(1)

+ ρ ∙ ∇ = −∇ + ∇ ∙ μ∇ + ρ

(2)

Considering the species mass composition and TPL supersaturation:


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+ ∇ ∙ = ∇ ∙ ∇

(3)

+ ∇ ∙ = ∇ ∙ ∇

(4)

where U is the velocity vector, P is the fluid pressure, wA is the mass fraction of THF, wS is the mass fraction of TPL and g is the gravitational acceleration vector. The viscosity (µ), density (ρ) and diffusivity (DAB) were assumed to depend linearly with wA. The physical properties and boundary conditions were identical to those described elsewhere.3 The transport equations were solved using the mesh and numerical parameters described in a previous work.3 The CFD solver was revised to solve the extra solute equation and to compute the supersaturation ratio. The supersaturation ratio was defined as the ratio of the computed TPL mass fraction by the corresponding equilibrium value. The mass fraction of TPL above the solubility limit was also computed and corresponds to the mass fraction of solute that would precipitate locally in equilibrium conditions.

RESULTS AND DISCUSSION A screening study was undertaken by processing all substances by ASAIS. The set of conditions (shown in Table 1) were based on a previous work3 in which the mixing conditions were defined to enabled polymorphism (in TPL) while not allowing nozzle blocking due to extended crystal growth. As Figure 3 shows, all substances processed by ASAIS originated polymorphs in accordance to those obtained by other authors using the SAS process.11–14 ASAIS processing of IND and CBZ led to “PXRD pure” polymorphs; the raw CBZ corresponds to the monoclinic form (form III) while processed CBZ to the trigonal form (form II) described by Grzesiak et al.20 The raw IND corresponds to γ-IND form,21 while the processed IND corresponds to α form 11 ACS Paragon Plus Environment


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reported by Varughese et al.14 The raw TLP corresponds to the orthorhombic form (form II), whereas the processed TPL was a mixture of polymorph with the unprocessed crystal form, reproducing the result previously described by Rodrigues et al.3 The diffraction peaks of the processed APIs are less intense, most likely due to the decrease in the particle size and crystallinity.3,22 Nevertheless, the screening results evidence that ASAIS is a supercritical anti-solvent process, with the advantage of being compatible with standard atmospheric pressure precipitators and cyclones. This has been previously suggested by Rodrigues et al.3 for TPL and is extended herein for other substances as well.

Figure 3. PXRD of raw and processed APIs by ASAIS: IND, CBZ and TPL. The symbols , and represent clear characteristic peaks of obtained polymorphs of IND, CBZ and TPL, respectively.

Nonetheless, the practical advantages of ASAIS or SAS to control the crystalline form of APIs cannot be clearly discerned without clarifying whether CO2 effect has any impact in the recrystallization mechanism and crystalline structure. This was addressed 12 ACS Paragon Plus Environment

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herein by processing the APIs in a SEA configuration, i.e. without the mixing required for anti-solvent precipitation. To further clarify if CO2 had any effect on the polymorphism, additional experiments with N2 were also carried out (conditions shown in Table 1). Figure 4 shows that the polymorph was still obtained for CBZ and IND even though the CO2 was not mixed with the liquid flow. Polymorphs of these two substances were produced in all conditions experimented regardless of the supercritical fluid used (N2 or CO2) revealing that in these cases polymorphism is essentially induced by the droplet formation and spray drying rather than a supercritical anti-solvent action. This suggests that crystalline forms obtained by supercritical anti-solvent processes can be, in many cases, also obtained by spray-drying, which is a simpler technique with widespread industrial implementation. TPL represents a different scenario and therefore constitutes the most interesting case. The results emphasize that only the TPL polymorph was not reproduced by the techniques that do not enable the CO2 antisolvent effect. Table 2 resumes qualitatively the polymorphism observation under ASAIS, SEA (with CO2 and N2) and also includes the SAS results reported by other authors.11–14



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Figure 4. Comparing PXRD of IND, CBZ and TPL produced by ASAIS and SEA (chosen conditions are described in experimental setup section) using CO2 and N2. White circles, squares and stars represent selected characteristic peaks of IND, CBZ and TPL polymorphs, respectively. Black star represent a characteristic peak of normal form TPL.

Regarding TPL, two crystalline forms were produced: the normal crystal form (form II), herein obtained by SEA with N2 and with CO2 (the same form of the unprocessed TPL)12 and the polymorph3 induced by scCO2 obtained by ASAIS. However, Figure 4 14 ACS Paragon Plus Environment

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also shows that the TPL polymorph processed by ASAIS (marked with

) was

contaminated with the normal crystal. This mixture may result from competing mechanisms, which could be more or less favored by different mixing conditions. A detailed study for TPL crystallization by ASAIS was developed towards understanding and optimizing the production of the polymorph, which involved more than 30 runs (results shown in Table 3).

Table 2. API’s crystal form (by PXRD) after processing with several atomization techniques. Process

CBZ

API’s crystal form IND

TLP

Unprocessed

III (Monoclinic)

γ

II (Orthorombic)

ASAIS

II (Trigonal)

α

scCO2 Polymorph3*

SEA-CO2

II (Trigonal)

α

II (Orthorombic)

SEA-N2

II (Trigonal)

α

II (Orthorombic)

SAS

II (Trigonal)11

α14

scCO2 Polymorph12,13

*

Mixture of polymorph with the unprocessed crystal form.

Table 3 shows the influence of mixing pressure (P), initial concentration of solution (C0), liquid flow (Fliquid), nozzle diameter (Dnozzle) and the mixing volume Vmixer on polymorph ratio (Y). Temperature was constant (323.15 K), mass flow-rate ratio of the solution to the supercritical fluid (Rflow ratio) was calculated using the CO2 flow rate, and TPL concentration in the mixing chamber and mixing time was calculated from the flow rates (considering the mixing volume).



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Table 3. Experimental conditions used in ASAIS runs for processing TPL in THF solution using scCO2. P: pressure at the mixer; C0: TPL concentration in the THF solution; C: TPL concentration in the mixer; Vmixer: volume of the mixing chamber; t: flow residence time in the mixer; Rflow ratio: mass flow-rate ratio of the solution to the supercritical fluid; Y: ratio of diffraction area of the polymorph and normal form selected peaks. Temperature was 323.15 K in all runs.

Run 1 2 3 4 5 6 7 8 9 10 11 12 13

P

Dnozzle

Fliquid

Vmixer

C0

C

t

Rflow ratio

YPolymorph/normal

(MPa)

(µm)

(mL/min)

(cm3)

100 100 100 150 150 150 150 150 150 150 50 50 50

1 1 1 1 1 1 1 1 3 5 1 3 5

0.9 0.9 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3

[TPL] mg/g 0.1 0.1 0.1 0.1 0.1 0.2 0.4 0.1 0.4 0.7 0.6 1.4 2

Residence time (s) 1.1 1.3 0.7 0.2 0.3 0.2 0.2 0.2 0.2 0.2 0.9 0.8 0.7

THF/SCF

15 11 10 9 9 9 9 9 9 9 9 9 9

[TPL] mg/g 2 2 2 4 2 4 4 5 5 5 5 5 5

diffraction area ratio 0.0 0.3 0.9 1.3 2.2 2.2 2.2 1.5 6.0 3.6 0 0.1 0.1

0.05 0.09 0.04 0.02 0.05 0.05 0.12 0.03 0.09 0.15 0.13 0.38 0.64

The results shown in Table 3 evidence that pressure is a critical variable affecting polymorph formation. The ratio between the areas of selected characteristic peaks “Y” shows that less polymorph is produced as the pressure increases. Pressure is directly related to the CO2 solvent power, suggesting that CO2 may start acting as a solvent rather than an anti-solvent (for the TPL-THF solution) at higher pressure. However, the solubility measurements shown in Table 4 apparently contradict this behavior, because as pressure and density of CO2 rise, the TPL solubility decreases, which in this case is explained by declining THF compositions for constant liquid flow rate. Alternatively, the reduction of polymorph observed with increasing pressure may be explained by its reconversion during the drying step. The magnitude of the Joule-Thompson cooling caused by the depressurization from higher pressure may slow the drying of the suspension, providing enough time for the antisolvent (CO2) to be released (at near


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atmospheric pressure) enabling the reversion of TPL to the crystal form II. Table 3 shows that increasing the concentration of TPL in the mixing chamber (at constant pressure) appears to favor TPL polymorphism, until a maximum is reached. Since this is achieved by increasing the liquid solution flow rate, the THF composition also increases in the mixing chamber, improving solubility. The variables that determine polymorphism under ASAIS configuration are intricate; it is therefore difficult to interpret which conditions are more favorable to induce polymorphism because the modification of one parameter – such as liquid flow rate or nozzle diameter acts on several variables. The understanding of the process can be much clarified if two questions are answered: should TPL supersaturate under the transient mixing conditions imposed by the ASAIS mixer? Can the ratio between polymorphs be explained by the amount of TPL that supersaturates inside the mixer and the amount that stays dissolved? The answers are pursued below by measuring and modelling the impact of THF-CO2 composition on TPL solubility and by running simulations (CFD) to predict local (microscale) mixing and supersaturation as the liquid solution and CO2 flow through the ASAIS mixer.

Table 4. Effect of pressure on the solubility of TPL in CO2-THF mixtures at 323.15 K within a range of different pressures. Pressure (MPa)

Solubility (10-2g kg-1)

9 10 12 15

10 ± 1 9.7 ± 0.8 8.2 ± 0.7 3.8 ± 0.9

Solubility (mol TPL/(mol THF+mol CO2))

(2.8 ± 0.3 )× 10-5 (2.4 ± 0.2) × 10-5 (2.0 ±0.2) × 10-5 (1.10 ± 0.07)× 10-5

THF molar fraction 0.16 0.12 0.10 0.07

The solubility of TPL as a function of CO2-THF composition was determined experimentally for the most favorable conditions for polymorph formation (9 MPa and



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323.15 K), shown in Table 5. The variation of TPL solubility with the molar fraction of CO2 can be described with an empirical equation previously proposed by Muntó et al.17 as shown in Figure 5. After fitting the experimental solubility data of TPL in “CO2THF” solvent mixture at 9 MPa and 323.15 K, the molar solubility of TPL (CS) can be expressed by the following equation (Eq. 5):

= × !"#$ %! − & ' (

).)#+.+"&'

+ !. , × !"#, & '

(5)

with xCO2 as CO2 molar fraction.

Table 5. Solubility of TPL as a function of CO2-THF composition determined experimentally at 9 MPa and 323.15 K. CO2 molar fraction 0.00 0.52 0.69 0.84 0.92 1.00

Phase Liquid Supercritical Supercritical Supercritical Supercritical Supercritical

Solubility 10-2g kg-1 ± 500 60 ± 10 12 ± 4 10 ± 1 3±1 1.4 ± 0.5

Solubility (molar) TPL/(THF + CO2)

2.00 × 10-3 1.82 × 10-4 3.50 × 10-5 2.8 × 10-6 6.6 × 10-6 1.6 × 10-6


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Figure 5. (a) Solubility curve (continuous line) of TPL obtained by fitting the experimental solubility data ( ) of drug in “CO2-THF” solvent mixtures at 9 MPa and 323.15 K. Dashed line: ideal dilution evolution; : experimental conditions used in ASAIS processing. (b) Close up of the ASAIS processing range.

Solubility data below approximately 0.5 of CO2 molar fraction was not obtained because the CO2 composition is difficult to determine in the vicinity of phase change from liquid to supercritical fluid (at 9 MPa). Nonetheless, as Figure 5 shows, the solubility curve (continuous line) is always below the dilution line (dashed line) at low CO2 concentrations. This behavior is consistent with a strong anti-solvent character of CO2 over the system.17 Consequently, CO2 acts as an anti-solvent for a saturated solution of TLP in THF in the entire range of CO2 composition. Moreover, the relation described by Eq. 5 provides an acceptable estimate to model by CFD the



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supersaturation within the ASAIS mixing chamber, allowing a better interpretation of the fast crystallization phenomena inside the small volume mixer. Despite the TPL polymorphism can be explained by the dissolution of CO2 in the liquid solution, it is unclear whether the boundary conditions for precipitation defined by Eq. 5, can be achieved in a residence time of a few tenths of a second and within a mixing volume smaller than 1 mL (as described in Table 3). Figures 6, 7 and 8 show still images of the CFD simulations for the ASAIS process under the conditions defined for RUN 9 in Table 3. Figure 6 shows the mixing of CO2 with the TPL-THF solution, evidencing that THF is rapidly diluted in the CO2 flow within the ASAIS static mixer. These results are in good agreement with the previously reported work3, which showed that the volume of 0.3 cm3 was adequate to achieve good mixing between THF and CO2. Yet, previously, the nonexistence of solubility data did not enable the simulation of local supersaturation of TPL, as presented in Figure 7. This figure clearly shows that TPL achieves high supersaturation in a fraction of a second, demonstrating the effectiveness of the small-volume static mixer to enable the anti-solvent action. Despite supersaturation is high all over the full domain, the solubility of TPL varies orders of magnitude depending of THF composition. Figure 8 shows a histogram of the quantity of supersaturated TPL, evidencing that most of the solute is located at the center of the mixer.


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Figure 6. THF mass fraction simulated by CFD, under the conditions defined in Table 3 for RUN 9.

The ratio between supersaturated and dissolved TPL can be calculated by considering the total TPL in the mixer and the residual solubility, which is defined by Eq. 5 assuming that mixing is complete (as the simulations anticipate). Table 6 shows that increasing ratios of saturated TPL correlate to increasing TPL polymorphism. Since the pure TPL polymorph could not be obtained by ASAIS, the ratio of the diffraction areas (of the characteristic peaks) cannot be converted to mass ratios, which would be easier to compare with the fraction of supersaturated TPL (in Table 6). Nonetheless, Table 6 shows that the supersaturated TPL is higher than 85% in all cases, including the results obtained with the 50 µm nozzle, which have not led to TPL polymorphism. Conversely, the TPL soluble fraction is relatively small in all cases and therefore the lower polymorphism observed for increasing THF composition cannot be justified only by the 21 ACS Paragon Plus Environment


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higher TPL solubility. Overall, the results show that the dualism observed in this system cannot be described without considering crystal growth rate, which is unknown and cannot be modelled. Despite supersaturation is expected to be very high, that will not necessarily result in the precipitation. Moreover, the nuclei or small crystals that can form inside the mixer may not be sufficiently stable and therefore may solubilize once the mixture exits the nozzle and the antisolvent is released by depressurization. This correlates with the observation that lower polymorph was obtained when drying was disfavored either by increasing the solvent quantity (THF) or by cooling the spray by Joule-Thompson effect, when the mixer pressure is higher. These results suggest that higher yield of polymorph may be achieved through the optimization of the residence time, to favor larger crystals (while not blocking the nozzle), and by abbreviating drying of the suspension.

Table 6. Ratio between saturated and dissolved TPL calculated using Eq. 5 (for runs at 9 MPa and 323.15 K). C: TPL concentration in the mixer; xCO2: CO2 molar composition CS: TPL solubility as defined by Eq. 5; Y: ratio of diffraction area of the polymorph and normal form selected peaks.

Run

Dnozzle

C

(µm)

4 5 6 7 8 9 10

150 150 150 150 150 150 150

[TPL] mg/g 0.1 0.1 0.2 0.4 0.1 0.4 0.7

11 12 13

50 50 50

0.6 1.4 2

xCO2

CS

YPolymorph/normal

0.99 0.97 0.97 0.93 0.98 0.95 0.92

[TPL] mg/g 0.009 0.015 0.015 0.030 0.011 0.024 0.036

Fraction of saturated TPL (C-CS)/C 0.91 0.85 0.93 0.92 0.89 0.94 0.95

0.93 0.81 0.72

0.032 0.072 0.107

0.95 0.95 0.95

0 0.1 0.1

diffraction area ratio 1.3 2.2 2.2 2.2 1.5 6.0 3.6


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Overall, the polymorphs of TPL exhibit the dualism of two distinct supersaturation mechanisms, in the first the solute supersaturates as it becomes increasingly diluted by dissolution of CO2, and the second in which the solute becomes increasingly concentrated by evaporation of the solvent. Nonetheless, this work also shows that this dualism between solid forms was not reproduced on other APIs. Moreover, polymorphs that are obtained using scCO2 techniques can be reproduced by simpler and widely implemented methods – such as spray drying.

Figure 7. TPL local saturation ratio (C/Cs) simulated by CFD, under the conditions defined in Table 3 for RUN 9, using the solubility curve defined by Eq. 5 (for 9 MPa; 323.15 K).



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Figure 8. Distribution of mass fraction of TPL above the solubility limit, predicted by CFD, under the conditions defined in Table 3 for RUN 9, using the solubility curve defined by Eq. 5 (for 9 MPa; 323.15 K).

CONCLUSION A typical spray-drying setup was transformed into a continuous supercritical antisolvent process (ASAIS) by replacement of the nozzle. The ASAIS setup was able to reproduce polymorph crystals of CBZ, IND and TPL — reported previously by conventional supercritical processing using SAS configuration. CBZ, and IND polymorphs were “PXRD pure”, however, they were also produced when the antisolvent (CO2) was not mixed with the liquid solutions before the orifice, or when it was replaced by N2 (under SEA configuration). These results suggest that some polymorphs formed using supercritical fluid technology may be replicated using classical spray-drying. Theophylline was the exception since the polymorph was only produced by the anti24 ACS Paragon Plus Environment

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solvent effect of CO2 enabled herein by the ASAIS process. The CFD simulation elucidated that the ASAIS process acts as a small-volume SAS, i.e. a high-pressure 0.3 cm3 antisolvent precipitator, which can be installed in normal pressure spray-dryers by replacement of the nozzle. This constitutes a major advantage because the highpressure, large-volume precipitator involved in SAS can be avoided, enabling to implement the essence of the CO2 Anti-Solvent process in existing facilities of conventional spray-drying industry. Nonetheless, TPL polymorphs produced by ASAIS were not pure, showing that crystal growth rate and spray-drying efficiency are important variables to consider for optimization. In this regard, the CFD tool presented here constitutes a major asset for interpretation and optimization of ASAIS, which can also be applied to any other crystallization process induced by the dissolution of an antisolvent.

ACKNOWLEDGMENTS The authors are grateful for financial support to Fundação para a Ciência e Tecnologia (FCT), Portugal (Grants SFRH/BD/39836/2007 and IF/01183/2013 and Projects PTDC/EQUFTT/099912/2008 and UID/QUI/00100/2013) and E.U. Program FEDER.



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REFERENCES (1)

Charbit, G.; Boutin, O.; Badens, E. In Supercritical Fluid Technology for Drug Product Development; York, P., Kompella, U. B., Shekunov, B. Y., Eds.; Drugs and the Pharmaceutical Sciences; Informa Healthcare: New York, 2004; Vol. 138, Chapter 4, pp 152–158.

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Reverchon, E.; Adami, R.; Caputo, G.; De Marco, I. J. Supercrit. Fluids 2008, 47, 70–84.

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Rodrigues, M. A.; Padrela, L.; Geraldes, V.; Santos, J.; Matos, H. A.; Azevedo, E. G. J. Supercrit. Fluids 2011, 58, 303–312.

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Rodrigues, M. A.; Tiago, J. M.; Padrela, L.; Matos, H. A.; Nunes, T. G.; Pinheiro, L.; Almeida, A. J.; Azevedo, E. G. Pharm. Res. 2014, 31, 3136–3149.

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Martín, Á.; Scholle, K.; Mattea, F.; Meterc, D.; Cocero, M. J. Cryst. Growth Des. 2009, 9, 2504–2511.

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Thiering, R.; Dehghani, F.; Foster, N. R. J. Supercrit. Fluids 2001, 21, 159–177.

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Padrela, L.; Rodrigues, M. A.; Velaga, S. P.; Fernandes, A. C.; Matos, H. A.; Azevedo, E. G. J. Supercrit. Fluids 2010, 53, 156–164.

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Rodrigues, M. A.; Figueiredo, L.; Padrela, L.; Cadete, A.; Tiago, J.; Matos, H. A.; Azevedo, E. G.; Florindo, H. F.; Gonçalves, L. M. D.; Almeida, A. J. Eur. J. Pharm. Biopharm. 2012, 82, 392–400.

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Tiago, J. M.; Padrela, L.; Rodrigues, M. A.; Matos, H. A.; Almeida, A. J.; Azevedo, E. G. Cryst. Growth Des. 2013, 13, 4940–4947.

(10) Padrela, L.; Rodrigues, M. A.; Tiago, J.; Velaga, S. P.; Matos, H. A.; Azevedo, E. G. J. Supercrit. Fluids 2014, 86, 129–136. (11)

Meng, D.; Falconer, J.; Krauel-Goellner, K.; Chen, J. J. J. J.; Farid, M.; Alany, R. 26 ACS Paragon Plus Environment

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G. AAPS PharmSciTech 2008, 9, 944–952. (12) Roy, C.; Vega-González, A.; Subra-Paternault, P. Int. J. Pharm. 2007, 343, 79– 89. (13) Subra, P.; Laudani, C. G.; Vega-González, A.; Reverchon, E. J. Supercrit. Fluids 2005, 35 (2), 95–105. (14) Varughese, P.; Li, J.; Wang, W.; Winstead, D. Powder Technol. 2010, 201, 64–69. (15) Franceschi, E.; Kunita, M. H.; Tres, M. V.; Rubira, A. F.; Muniz, E. C.; Corazza, M. L.; Dariva, C.; Ferreira, S. R. S.; Oliveira, J. V. J. Supercrit. Fluids 2008, 44 , 8–20. (16) Rodrigues, M.; Peiriço, N.; Matos, H.; Azevedo, E. G.; Lobato, M. R.; Almeida, A. J. J. Supercrit. Fluids 2004, 29, 175–184. (17) Muntó, M.; Ventosa, N.; Sala, S.; Veciana, J. J. Supercrit. Fluids 2008, 47, 147– 153. (18) Wubbolts, F. E.; Bruinsma, O. S. L.; Van Rosmalen, G. M. J. Supercrit. Fluids 2004, 32, 79–87. (19) Padrela, L.; Rodrigues, M. A.; Tiago, J.; Velaga, S. P.; Matos, H. A.; Azevedo, E. G. Cryst. Growth Des. 2015, 15, 3175–3181. (20) Grzesiak, A. L.; Lang, M.; Kim, K.; Matzger, A. J. J. Pharm. Sci. 2003, 92, 2260–2271. (21) Otsuka, M.; Kato, F.; Matsuda, Y. Analyst 2001, 126, 1578–1582. (22) Kayrak, D.; Akman, U.; Hortaçsu, Ö. J. Supercrit. Fluids 2003, 26, 17–31.



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TABLE OF CONTENTS USE ONLY

Polymorphism in pharmaceutical drugs by supercritical CO2 processing – clarifying the role of anti-solvent effect and atomization enhancement Miguel A. Rodrigues*, João M. Tiago, Andreia Duarte, Vítor Geraldes, Henrique A. Matos and Edmundo Gomes Azevedo

Synopsis The ASAIS process enabled to reproduce polymorphs of indomethacin, carbamazepine and theophylline, previously associated to processing by SAS. However, only theophylline crystal habit was sensitive to the CO2 anti-solvent mechanism, whereas other APIs were sensitive to atomization and fast drying. The CFD simulations elucidated that the ASAIS nozzle acts as a small-volume SAS, enabling Supercritical Anti-Solvent processing in standard spray-dryers.


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Conceptual differences between SAS, ASAIS and SEA techniques, where the green represents an outer tube for the atomizing fluid (CO2 or N2), and red represents the liquid solution tubing. In ASAIS antisolvent precipitation occurs before the jet dispersion in a small volume. In addition, high-pressure is confined to a small equipment and the suspension spray is dried at normal pressure. Figure 1 118x55mm (300 x 300 DPI)

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(a) Schematic diagram of the ASAIS/SEA experimental setup. Pc, pressure controller; F, flowmeter; Tc, temperature controller. (b) ASAIS nozzle close-up. 1-Inner tube for the liquid solution; 2-Outer tube for CO2; 3-Heater cartridges; 4-Sealant O-ring; 5-nozzle disk. Figure 2 193x112mm (300 x 300 DPI)


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PXRD of raw and processed APIs by ASAIS: IND, CBZ and TPL. The symbols represent clear characteristic peaks of obtained polymorphs of IND, CBZ and TPL. Figure 3 103x95mm (300 x 300 DPI)



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Comparing PXRD of IND, CBZ and TPL produced by ASAIS and SEA (chosen conditions are described in experimental setup section) using CO2 and N2. White circles, squares and stars represent selected characteristic peaks of IND, CBZ and TPL polymorphs, respectively. Black star represent a characteristic peak of normal form TPL. Figure 4 111x203mm (300 x 300 DPI)


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(a) Solubility curve (continuous line) of TPL obtained by fitting the experimental solubility data (triangles) of drug in “CO2-THF” solvent mixtures at 9 MPa and 323.15 K. Dashed line: ideal dilution evolution; (squares): experimental conditions used in ASAIS processing. (b) Close up of the ASAIS processing range. Figure 5 254x190mm (300 x 300 DPI)



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THF mass fraction simulated by CFD, under the conditions defined in Table 3 for RUN 9. Figure 6 160x167mm (300 x 300 DPI)


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TPL local saturation ratio (C/Cs) simulated by CFD, under the conditions defined in Table 3 for RUN 9, using the solubility curve defined by Eq. 5 (for 9 MPa; 323.15 K). Figure 7 164x166mm (300 x 300 DPI)



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Distribution of mass fraction of TPL above the solubility limit, predicted by CFD, under the conditions defined in Table 3 for RUN 9, using the solubility curve defined by Eq. 5 (for 9 MPa; 323.15 K). Figure 8 154x167mm (300 x 300 DPI)


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Polymorphism in Pharmaceutical Drugs by Supercritical CO2 Processing

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