Polymer Templated Structural Evolution of a Poorly Water-Soluble

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Polymer Templated Structure Evolution of a Poorly Water-Soluble Active Pharmaceutical Ingredient from Nanoparticles to Hierarchical Crystals Fei Sheng, Pui Shan Chow, Yuancai Dong, and Reginald B. H. Tan Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00233 • Publication Date (Web): 09 Apr 2018 Downloaded from http://pubs.acs.org on April 9, 2018

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Crystal Growth & Design

Polymer Templated Structure Evolution of a Poorly Water-Soluble Active Pharmaceutical Ingredient from Nanoparticles to Hierarchical Crystals Fei Sheng, †,*, Pui Shan Chow†, Dong Yuancai†, Reginald B. H. Tan†‡,* †

Institute of Chemical and Engineering Sciences, A*STAR (Agency for Science, Technology and Research), 1 Pesek Road, Jurong Island, Singapore 627833, Singapore

‡

Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 119260, Singapore

Key worlds, Nanoparticle growth, Self-assembly superstructure, Hollow crystal, Hydrate, Antisolvent precipitation, Poorly water-soluble API

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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

Abstract The hydrate form of a poorly water-soluble active pharmaceutical ingredient (API), spironolactone (SP), was produced using antisolvent precipitation in the presence/absence of polymer templates and stirring. Different crystal habits were observed depending on the polymer added. Superstructures consisting of primary constituent units were obtained in the presence of hydroxypropyl methylcellulose (HPMC), while tubular crystals with highly fused surfaces were observed in the presence of polyvinyl pyrrolidone (PVP). In contrast, tubular and dendritic crystals were obtained in the absence of polymer. The structure evolution of particle formation process was monitored by scanning electron microscope (SEM), which reveals the growth mechanisms leading to different crystal habits. Superstructures are attributed to self-assembly growth, while tubular and dendritic crystals are formed under diffusion limited growth. The results suggest a potential way to produce crystals with the desired crystal habit by appropriate selection of polymer additive and precipitation conditions.


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Introduction Size reduction to the submicron level is an effective approach to increase the bioavailability of poorly water-soluble drugs

1

. The common techniques include milling, high pressure

homogenization, supercritical fluid technology and antisolvent precipitation. In comparison with other techniques, antisolvent precipitation is a simple, cost effective approach to produce submicron particles 2. At the same time, antisolvent precipitation can offer a greater flexibility in controlling particle morphology 3. In a typical antisolvent precipitation, the poorly water-soluble drug is first dissolved in a water-miscible organic solvent, and then rapidly mixed with the antisolvent, which is commonly water. High supersaturation is generated after the mixing of solvent and antisolvent, resulting in fast nucleation rate and producing a large number of nuclei. Stabilizers such as polymer or surfactant are usually used to inhibit the particle growth and amorphous transition in aqueous solutions 4. The hydrophobic portion of stabilizer can be adsorbed on the hydrophobic drug surface while the hydrophilic portion provides steric and/or electrostatic stabilization 5. Hydrogen bonding formed between stabilizer and drug molecules can also inhibit particle growth, facilitating the formation of submicron particles. In spite of the simple processing, there are debates over the mechanism of particle formation during precipitation, especially under high supersaturation. The classical crystallization theory suggests that small nuclei formed in the solution first and subsequently grow into final crystals through diffusional growth of the formed nuclei via molecular addition 6. From the perspective of classical crystallization, the crystal morphology is related to the intrinsic structure of the nuclei, and driven by surface energy of crystal faces 7. However, this classical mechanism is unable to explain the crystal growth phenomenon in the case of kinetic driven crystallization. In contrast, the non-classical crystallization pathway introduced by Cöelfen et al. considers crystal 3 ACS Paragon Plus Environment


growth as a mesoscale assembly process through nanocrystals aggregation that results in mesocrystals 8. Mesocrystals are ordered mesoscale superstructures composed of individual nanocrystals with similar scattering properties of single crystal 9. Mesocrystals have been widely studied in biominerals 10-11, inorganic materials 12-13 and metals 14. Hierarchical structures can be obtained through self-organization of mesocrystals, which offers an alternative approach to modify crystal habit. In comparison with inorganic materials, the study of mesocrystals in organic compounds is rare, especially for pharmaceutical ingredients 3, 15. Spironolactone (SP) is a poorly water-soluble steroidal diuretic that transforms to the hydrate form upon prolonged contact with water 16. Unexpected hydrate formation during manufacturing, storage and delivery would cause issues in drug processing, such as inaccurate weighing during quantitative analysis

17-18

. It is critical to identify the potential hydrate content in drug samples

before analysis as one-third of drugs are capable of forming hydrate 19. Hydrate is also known to be more thermodynamically stable than anhydrate when the water activity is above the critical water activity value for hydrate formation

20

. In this study, the antisolvent precipitation of

spironolactone hydrate (SPH) was carried out in ethanol/water system with/without the presence of different polymers, i.e. hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP). To achieve a better understanding of the hydrate formation process, we monitored the structure evolution during antisolvent precipitation. Based on the particle habit, the growth mechanisms from nanoparticles to hierarchically structured crystals were investigated. We propose that the non-classical crystallization pathway is followed during SPH antisolvent precipitation to produce superstructures and diffusion limited growth leading to the formation of tubular and dendritic crystals.


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Experimental Section Materials Spironolactone (SP) was purchased from Wuhan Hezheng Biochemical Manufacture CO. Ltd, China. Hydroxylpropylmethyl cellulose (HPMC E3) and polyvinyl pyrrolidone (PVP K30) were obtained from Sigma-Aldrich. Reagent grade ethanol from Fisher Scientific and deionized water were used as the solvent and antisolvent, respectively. Molecular structures of SP, HPMC and PVP are presented in Figure 1. Antisolvent Precipitation of SPH Nanoparticles SP was dissolved in ethanol at a concentration of 10 mg/ml, polymer was dissolved in antisolvent (water) at a concentration of 1 mg/ml. 1 ml of drug solution was rapidly injected into 10 ml of antisolvent with or without stirring in a 20 ml glass sample bottle to produce nanosuspension using the volume ratio of drug solution:antisolvent at 1:10. Nanosuspensions were maintained at ambient temperature with or without stirring after mixing. Morphology A field emission scanning electron microscope (FESEM, JEOL JSM-6700F) was used to analyze particle morphology. Droplets collected from suspensions at different times after precipitation were deposited onto copper grids, and the droplets were instantly dried using filter paper to avoid any change in morphology during the drying process. The samples were sputter coated with gold for 120 s at 20 mA, and the scanning was performed at 5.0 kV. Powder X-ray Diffraction (PXRD)



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The precipitated suspensions at different times were rapidly filtrated and air dried for 24 h. A D8-ADVANCE powder X-ray diffractometer (Bruker AXS GmbH, Germany) with 30 kV voltage and 40 mA current was used to obtain the PRXD patterns. The scan range was from 5 to 40° (2θ) at a scan rate of 2°/min. Fourier Transformed InfraRed (FTIR) A FTS 3000MX FTIR (Bio Rad) spectrometer with the scanning range from 400-4000 cm-1 was used. 30 scans were acquired for each sample with a spectral width of 1 cm-1 at a speed of 5 kHz. Results and Discussion Crystal identification using PXRD and FTIR Spironolactone is known to exist in two polymorphs, several solvates and one hydrate

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.

PXRD was used to identify the crystal form produced from our experiments. The final crystals obtained with or without stirring presented the same PXRD pattern. Therefore, only the PXRD patterns of crystals obtained under stirring are shown here (Figure 2). It can be seen that all the samples corresponded to the hydrate form and the PXRD patterns were consistent with simulated pattern from reference 23. This suggests that the polymeric additives used here have no effect on the final polymorphic outcome. The slight peak shift was attributed to the difference in experimental temperature between PXRD and single-crystal XRD. HPMC and PVP are both in amorphous state. Figure 3 presents the evolution of PXRD patterns of the samples taken at different times after mixing of antisolvent and drug solution. SP particles possessed very low crystallinity in the initial period of precipitation in the presence of HPMC, indicating that amorphous particles were


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first formed before transforming to the crystalline form (Figure 3a-b). The low crystalline particles persisted for a longer time in the absence of stirring. This suggests that stirring enhances the nucleation and leads to faster crystallization. In the cases of precipitation with PVP and without polymer (shown in Figure 3 c-d and e-f), high crystalline particles were observed in early stage of precipitation from the PXRD results. We believe that this is due to the fast amorphous to crystalline transformation rate. In all the experiments, no polymorphic change took place once the crystals were formed and they corresponded to the hydrate form. FTIR spectra of SPH crystals precipitated in the presence of HPMC, PVP and precipitated without polymer are presented in Figure 4. In the case of precipitation with HPMC, the characteristic peaks at 1640 cm-1 corresponding to the stretching vibration of C-O embedded in hexatomic ring and the peaks at 1350-1500 cm-1 corresponding to the bending vibrations of methoxy group were observed. This indicates that HPMC was precipitated out together with SPH particles and played a possible role in particle stabilization and superstructure formation. On the other hand, the characteristic peaks of PVP were not observed in the FTIR spectrum, suggesting that PVP was not present in the precipitated particles. Structure monitoring using SEM The evolution of particle growth was monitored by SEM and various habits were observed at different polymer addition and stirring condition. The SEM images of SPH precipitated in the presence of HPMC and stirring are presented in Figure 5. At 1 min after precipitation, the particles were amorphous without specific shape (Figure 5 a-b) as supported by the XRD results shown in Fig 3. At 5 min (Figure 5 c-d), agglomerates of prismatic crystals dominated the suspension system, which were arranged layer by layer and less fused on the surface. At 1 h after



precipitation (Figure 5 e-f), it can be observed clearly that the primary prismatic units were around 300 nm in length and highly homogeneous in size. The surface of crystals was clearly highly fused as enough time was provided for crystal growth. Because the primary units with high shape anisotropy would spontaneously align to produce crystals with similar morphologies 10

, the superstructures also presented an analogous prismatic morphology. In the case of

precipitation with HPMC but without stirring, particles grew following a similar pathway but at a much slower rate, which is shown in Figure 6. At 1 min after antisolvent precipitation (Figure 6 a-b), spherical amorphous nanoparticles of size around 100-200 nm were obtained, some of the nanoparticles were end to end attached while single particles were still visible. At 5 min (Figure 6 c-d), most of the nanoparticles were end to end attached to reduce surface energy. Submicron particles of varying shapes were formed with lateral dimension equal to the size of primary nanoparticles. These submicron particles were still unstable and continued to form larger particles by side-by-side assembly. As the experiments were carried out without any turbulence, the particles can be maintained as amorphous for a longer time compared to experiment performed with stirring, in agreement with the PXRD results shown earlier (Figure 3a-b). At 1 h after precipitation, superstructures of self-assembled crystals emerged (Figure 6 e-f), which had similar prismatic constituent units as the particles precipitated in presence of HPMC and stirring. In contrast to the amorphous superstructures formed in the early stage (Figure 6 c-d), the crystalline superstructures presented entirely different morphologies, implying the formation of crystalline structures occurred via a dissolution-renucleation process. In the case of precipitation in presence of PVP, no sign of nanocrystal agglomerates can be observed. In contrast, tubular crystals were obtained independent of stirring condition (Figure 7 and 8). These tubular crystals were believed to form under diffusion-limited growth mechanism 8 ACS Paragon Plus Environment

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24-26

. As it is more convenient for SP molecules to diffuse to the edge of the fast growing face

than the center, according to the Berg effect 27, a concentration gradient is generated, leading to faster growth at the edge of the face than the center. While the concentration in the center decreases to the equilibrium state and growth stops, the edges of the face continue to grow and form the hollow in the crystal 24. Previous research demonstrated that supersaturation is a critical factor for the formation of tubular crystal with high anisotropy, and the flaws on the crystal surface become apparent when the solution supersaturation is above a critical value further increase in supersaturation, crystals would split and dendritic growth occurs

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. Upon

. In the

case of precipitation under stirring, prismatic crystals with uneven growth at the ends were obtained at 1 min after precipitation (Figure 7 a-b), which became the precursors of the tubular crystals (Figure 7 c-f). In the case of SPH particles precipitated with PVP but without stirring, SPH grew into tubular crystals at a slower growth rate. Figure 8 shows the formation of small prismatic crystals, which is the early stage of tubular crystals. It can be seen that spherical nanoparticles of 100 nm were embedded in large particles with various shapes at 1 min after precipitation (Figure 8 a-b). These large particles were still visible at 5 min shown in Figure 8 cd. However, at 1 h after precipitation, small prismatic crystals emerged without any large particles remaining (Figure 8 e-f), which confirmed the prismatic crystals were obtained through a dissolution-renucleation process. The small prismatic crystals continue to grow into tubular crystals possessing similar crystal habit as the crystals precipitated in the presence of PVP and stirring. Figure 9 and Figure 10 illustrate the evolutions of SPH particles precipitated without polymer. It can be seen that precipitation under stirring yielded tubular crystals (Figure 9). However, in comparison with the tubular crystals precipitated in the presence of PVP, these crystals have 9 ACS Paragon Plus Environment


elongated openings that extend to the prismatic walls and some openings have edges that are parallel to the crystallographic directions. This can be explained by the difference in local supersaturation in the vicinity of the particle surface. PVP is reported to lower the interfacial energy which in turn leads to an enhanced nucleation rate 29. With the enhanced nucleation rate in the presence of PVP, supersaturation was consumed rapidly to produce a large number of nuclei. Therefore, the concentration gradients surrounding the particles surface was higher in the case of precipitation without polymer, which resulted in the apparent flaws on the crystal surface 30

. This can also be confirmed by the crystal size precipitated under different conditions. For

instance, the crystals precipitated without polymer were typically 30-40 µm in size (Figure 9), while the crystal size was around 10 µm when precipitated in the presence of PVP (Figure 7). In the case of precipitation in the absence of both polymer and stirring, dendritic crystals were obtained (shown in Figure 10 c-d). This dendritic structures were resulted from diffusion-limited growth mechanism due to the high concentration gradients surrounding particle surface without stirring

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. From the SEM images of SPH particles precipitated after 1 hour, it can be seen that

the branches of the dendrites grew to tubular crystals due to diffusion-limited growth (shown from Figure 10 e-f). Proposed evolution mechanism The proposed growth mechanisms of SPH nanocrystals are illustrated in Figure 11 for crystal formation under different polymer addition. In the case of precipitation in the presence of polymer (either HPMC or PVP), crystal habit was independent of stirring condition, but nucleation rate is enhanced by stirring. However, in the case of precipitation without polymer, stirring resulted in different habits which are presented separately in Figure 11. Based on the results of SEM and XRD, we postulate that amorphous SPH were first obtained and followed a 10 ACS Paragon Plus Environment

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dissolution-renucleation process to form primary crystal units. Thereafter, the crystals grew into different habits depending on the polymer added. In the presence of HPMC (Figure 11 a), nanosize prismatic SPH primary crystal units were surrounded by HPMC molecules through hydrogen bonding, which inhibited the growth of SPH particles and resulted in the agglomeration of the SPH primary crystal units. These agglomerates were formed by end to end and side-by-side assemblies of the primary crystal units and the final agglomerates present a similar habit as the primary units. In contrast, no agglomeration phenomena were observed in case of PVP as stabilizer (Figure 11 b). The primary crystal units grew to micron size through molecule-by-molecule addition and the expansion of flaws on crystal surface resulted in tubular crystals as crystal grew under diffusion limited crystallization condition. Since PVP is incapable of forming hydrogen bonding with SP molecules to inhibit particle growth, the only notable effect that PVP has on the precipitation was to increase the nucleation rate and faster supersaturation consumption. In the case of no polymer addition but with stirring (Figure 11 c), tubular crystals formed but with more apparent flaws on the crystal surface that expand and eventually destroy the crystallographic symmetry. When polymer and stirring were both absent (Figure 11 d), no crystallographic primary crystal units were observed. Micron-sized crystals branched off rapidly and resulted in dendritic crystals. After enough crystallization time, the branches formed tubular crystals under diffusion limited crystallization condition. Conclusions Antisolvent precipitation of spironolactone hydrate was carried out to understand the effect of polymer additives on the crystal growth mechanism. Structure evolution of the precipitated



particles was monitored by SEM. In the presence of HPMC, self-assembled superstructures consisting of prismatic primary crystals were observed, which can be explained by a nonclassical growth mechanism. In contrast, tubular single crystals with highly fused crystal surfaces were obtained when PVP was added, which was attributed to the diffusion-limited growth mechanism. In the presence of polymer additives, stirring only enhanced the nucleation but did not change the habit of the final crystals. However, in the case of precipitation without polymer, the presence/absence of stirring led to the formation of tubular and dendritic crystals, respectively. The understanding of particle formation in spironolactone hydrate system suggests a potential application to produce crystals with the desired habit through polymer additive selection using antisolvent precipitation.

*Corresponding author: E-mail address: [email protected] (F. Sheng) E-mail address: [email protected] (R.B.H. Tan)

Acknowledgments This work was supported by project grant ICES/16-22KA01 from A*STAR (Agency for Science, Technology, and Research) of Singapore.


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Spironolactone

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Figure 1 Molecular structures of Spironolactone, HPMC and PVP


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Figure 2 PXRD patterns of (a) Crystals precipitated with HPMC (b) Crystals precipitated with PVP (c) Crystals precipitated without polymer (d) PXRD pattern calculated from the singlecrystal data of SPH 23 (e) HPMC and (f) PVP


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Figure 3 Evolution of PXRD patterns of (a) SPH crystals precipitated with HPMC and under mixing (b) SPH crystals precipitated with HPMC and without mixing (c) SPH crystals precipitated with PVP and under mixing (d) SPH crystals precipitated with PVP and without mixing (e) SPH crystals precipitated without polymer and under mixing (f) SPH crystals precipitated without polymer and without mixing 17 ACS Paragon Plus Environment


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Figure 4 FTIR spectra of (a) SPH crystals precipitated with HPMC (b) SPH crystals precipitated PVP and (c) SPH crystals precipitated without polymer


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Figure 5 Evolution of SPH particles precipitated with HPMC and stirring at 1 min (a-b), 5 min (c-d) and 1 h (e-f), respectively 19 ACS Paragon Plus Environment


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Figure 6 Evolution of SPH particles precipitated with HPMC and without stirring at 1 min (a-b), 5 min (c-d) and 1 h (e-f), respectively 20 ACS Paragon Plus Environment

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Figure 7 Evolution of SPH particles precipitated with PVP and stirring at 1 min (a-b), 5 min (c-d) and 1 h (e-f), respectively 21 ACS Paragon Plus Environment


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Figure 8 Evolution of SPH particles precipitated with PVP and without stirring at 1 min (a-b), 5 min (c-d) and 1 h (e-f), respectively 22 ACS Paragon Plus Environment

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Figure 9 Evolution of SPH particles precipitated without polymer and with stirring at 1 min (ab), 5 min (c-d) and 1 h (e-f), respectively 23 ACS Paragon Plus Environment


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(f)

Figure 10 Evolution of SPH particles precipitated without polymer and without stirring at 1 min (a-b), 5 min (c-d) and 1 h (e-f), respectively 24 ACS Paragon Plus Environment

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HPMC molecules

(a)

HPMC

Primary SPH crystal unit in nanosize

(b)

PVP

No polymer

(c)

Precipitated in absence (d) of polymer and stirring

Time evolution

Figure 11 Illustration of growth mechanisms of SPH nanocrystals (a) in presence of HPMC and stirring, (b) in presence of PVP and stirring, (c) in absence of polymer but in presence of stirring and (d) in absence of polymer and stirring



For Table of Contents Use Only

Polymer Templated Structure Evolution of a Poorly Water-Soluble Active Pharmaceutical Ingredient from Nanoparticles to Hierarchical Crystals

Proposed growth mechanisms of spironolactone hydrate


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Polymer Templated Structural Evolution of a Poorly Water-Soluble

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