Polymer-Induced Selective Nucleation of Mono or Ortho Polymorphs

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Polymer-Induced Selective Nucleation of Mono or Ortho Polymorphs of Paracetamol through Swift Cooling of Boiled Aqueous Solution C. Sudha, R. Nandhini, and K. Srinivasan* Crystal Growth Laboratory, Department of Physics, School of Physical Sciences, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India ABSTRACT: A novel method of inducing the preferred polymorph of paracetamol through swift cooling of boiled aqueous solution in the presence of selective polymers has been identified. Depending upon the molecular interaction between the selected polymers such as nylon 6/6, polypropylene, and polyvinylchloride and the paracetamol, nucleation of either mono or ortho or both polymorphic forms of paracetamol were induced at well-distinguished supersaturation regions, whereas in the absence of the polymers, pure aqueous solution yielded only stable mono form. Nucleations induced by three different polymers have different induction periods. The percentage of mono, ortho, and mixed polymorphs nucleated at different supersaturation regions was estimated. Their external morphologies were identified through optical in situ microscopy, and their internal crystallographic structure was confirmed by powder X-ray diffraction (PXRD). It is found that the specific polymer−solute interaction induces nucleations with preferential growth of crystal facets having specific crystallographic orientations which is evident from the PXRD patterns of the grown crystals in which the prominent reflections observed corresponded to the crystal planes with which the nucleation began. Differential scanning calorimetry analysis revealed that the grown metastable ortho polymorph undergoes phase transformation at 89.35 °C, whereas the mono form does not show any phase transformation throughout the experimental temperature range of 40−190 °C.

1. INTRODUCTION The control of polymorphism is a long-standing bottleneck issue in solid-state chemistry which has significant importance especially in pharmaceutical industries, and it creates a troubling situation for the production of high purity drugs.1,2 The pharmaceutical properties, including the physical and chemical properties, and the bioavailability are greatly influenced by their polymorphism. This crucial issue has promoted the intense search of specific crystal polymorphs which offers a potential route for the drug development process through its intellectual property such as faster dissolution, higher solubility, and better compressibility.2,3 The precise control over nucleation is often the critical step in determining the ultimate solid-state form produced.4 As such, desired techniques are necessary for the degree of control of polymorphism of the target compound and strategies for selectively crystallizing the desired polymorphs.5 Paracetamol, an important analgesic and antipyretic drug, crystallizes in three polymorphic forms: stable monoclinic form I,6 metastable orthorhombic form II,7 and unstable form III.8 The commercially available stable mono polymorph form I has poor compressibility and low solubility, whereas the metastable polymorph ortho form II has remarkable advantages over form I with better compressibility, dissolution rate, etc., and it remains as a promising drug candidate for pharmaceutical industries.6,7,9,10 Form III polymorph has been shown to be highly unstable and has only been crystallized in confined environments.11,12 However, recently, by a swift cooling © XXXX American Chemical Society

crystallization process, we isolated the highly unstable polymorph form III from pure aqueous solution and were unable to resolve its crystal structure because of its high instability.13 Different crystallization parameters such as multicomponent crystallization,10 solvent,14 seeding strategy,15 complex cooling,16 and high throughput screening using polymer heteronuclei4,17−19 were employed for controlling the paracetamol polymorphs. Despite considerable efforts, the methods adopted in previous reports were complex for controlling the crystal polymorphism of paracetamol, and still a thirst exists for identifying reliable methodology for the separation of the nucleation region of paracetamol polymorphs. Recently, it was reported that the heteronucleation approach with the use of particular polymers to single crystal production and new form selection have met with considerable success in crystallization of selective polymorph form II from aqueous solution,17,18 and the authors postulate that the molecular functionality of the polymers plays a significant role in promoting the nucleation of desired polymorph form II paracetamol.17 In our present work, a systematic insight on the nucleation control and separation of mono and ortho paracetamol polymorphs was studied by adopting a laboratory-scale novel swift cooling crystallization process. The experiment has been Received: October 24, 2013 Revised: December 23, 2013

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dx.doi.org/10.1021/cg401588j | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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each of the four glass vials which were kept at 1 °C. The solutions in the vials were carefully monitored through the full-visibility window of the bath under bright-light illumination for nucleation, and the events were recorded over time. The solution was clear and transparent initially for short period of time (15 min) known as the induction period, that is, time interval between the attainment of supersaturation and nucleation, after which it yielded tiny crystalline particles. The nucleated particles were identified as one of the polymorphs of paracetamol based on their morphology. Growth of different polymorphs nucleated in pure and polymer-added solution was examined, and the images are captured at different time frames by in situ optical microscopy. Polymorph characterization was instantly carried out to scrutinize the formation of nucleated crystalline products. The experiment was repeated by varying the initial saturation of the mother solution corresponding to the saturation temperatures in the range from 32 to 52 °C. From the data obtained, the types of nucleation were identified, and their corresponding induction period was deduced at different initial saturated levels of the mother solution. 2.2. Powder X-ray Diffraction (PXRD). In order to confirm the internal structure of the harvested crystalline samples, they were loaded immediately after the harvestment from the mother solution to the panel of the sample holder, and PXRD patterns of the nucleated paracetamol polymorphs were recorded at room temperature from 10 to 60° 2θ with a step size 0.05° 2θ using a Bruker D8 Advance diffractometer with Cu Kα source (λ = 1.5406 Å) at 40 kV, 40 mA. 2.3. Differential Scanning Calorimetry (DSC). In order to observe the possible polymorphic phase transformation of the harvested polymorphic sample in the temperature range of 40−190 °C, the DSC thermogram was recorded. Thermograms of the nucleated polymorphs were recorded on a TA Instruments DSC Q20 V24. The thermal behavior of samples, placed in sealed aluminum pans, was studied under a nitrogen purge with a heating rate of 1 °C/ min covering a temperature from 40 to 190 °C.

carried out with boiled aqueous solution of pure paracetamol as well as with selected polymers such as nylon 6/6, polypropylene and polyvinylchloride added, at different supersaturation ranges. Pure aqueous paracetamol solution yields thermodynamically stable monoclinic polymorph, whereas the polymer-added paracetamol solution suppresses the stable mono polymorphs and yields the metastable ortho polymorphs at particular supersaturation regions. The induction period of the nucleated polymorphs of paracetamol was determined for different supersaturation ranges. From the result, we found that different polymers induce nucleation of different crystal polymorphs and end up with different crystal orientation after its growth. The powder X-ray diffraction study reveals that the crystallization of desired polymorph nucleated on the polymer surface mainly depends on the interaction of the particular polymer surface with the solute molecule in addition to the supersaturation of the mother solution. Also it is evident from the PXRD study that the specific crystallographic orientation of the induced crystal nucleation depends very much on the interaction between specific polymer surfaces with solute molecule.

2. EXPERIMENTAL SECTION 2.1. Materials and Methods. Acetaminophen (C8H9NO2), commercially known as paracetamol, purity (assay 98.0−101.0%) and selected polymers such as nylon 6/6 (C12H22N2O2)n, polypropylene (C3H6)n, and polyvinylchloride (C2H3Cl)n were purchased from the Sigma Aldrich (product name: A5000, CAS number: 103-902). The polymers were used as received and therefore were in several different physical forms that include pellets and powder form. Laboratory double-distilled water was used for solution preparation. The chemical structure of paracetamol and the selected polymers of nylon 6/6, polypropylene, and polyvinylchloride is shown in Figure 1a−d.

3. RESULTS AND DISCUSSION 3.1. Polymer Impact and the Effect of Supersaturation on the Nucleation of Paracetamol Polymorphs. The pure aqueous paracetamol solution yields only stable monoclinic paracetamol polymorphs at all supersaturation ranges from σ = 1.11−1.92 as shown in Figure 2, whereas the experiment

Figure 1. Chemical structures of (a) paracetamol, (b−d) polymers. Acetaminophen (1.8 g/100 mL solubility at 32 °C) was dissolved in 100 mL of laboratory double-distilled water in an airtight ampule and boiled at 100 °C with stirring for about 30 min. Four screw-capped glass vials of each volume 5 mL were selected and 0.05 g of each of the three selected polymers such as nylon 6/6, polypropylene, and polyvinylchloride was added in the three of the glass vials. All the four vials were precooled at 1 °C for about 15 min in the digitally controlled constant temperature bath (CTB) with inbuilt cryostat facilities, which have a temperature-controlling accuracy of ±0.01 °C. About 1 mL of the aqueous paracetamol solution which was at boiled condition at 100 °C was pipetted out and transferred immediately into

Figure 2. Variation in % of nucleation with respect to supersaturation.

performed in the presence of polymer induces the nucleation of mono and ortho paracetamol polymorphs in the solution. This is because the pure paracetamol solution has no kinetic effect, and hence it exhibits random orientation producing the thermodynamically stable mono form I. The photographs are shown in Figure 3. However, the presence of selected polymers in the aqueous mother solution of paracetamol acts as a B



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Figure 3. Snapshot of the mono nucleation form I in pure aqueous solution.

nucleation site in facilitating the nucleation and growth of preferred polymorph in different supersaturation regions in the range σ = 1.11−1.92. In the case of the polymer-added solution, the polymer explicitly targets the preferred nucleation by producing a kinetic effect and affects the crystal nucleation by aligning the solute molecules along the polymer chain via specific polymer−solute interaction. In our experimental investigation, we observed that the use of ortho inducing polymer17 such as nylon 6/6, polypropylene, and polyvinylchloride is capable of yielding both stable monoclinic form I and metastable orthorhombic form II polymorphs in different supersaturation regions. It also results in an increase in the nucleation rate compared to pure aqueous solution. Therefore, in addition to the polymer templating effect, the supersaturation also plays a key role in inducing the preferred polymorphs. In the presence of nylon 6/6 polymer, the solution at the supersaturation range σ = 1.11−1.40 yields 100% monoclinic form I paracetamol polymorph on the polymer surface with prismatic morphology. As the supersaturation increases from σ = 1.44−1.51, mixture of mono and ortho polymorphs was observed on the polymer surface. The percentage of mono polymorph decreases with increase in the percentage of ortho polymorph as the supersaturation increases. An increase in the supersaturation range from σ = 1.55−1.71 favors 100% needleshaped orthorhombic form II polymorph. This nucleated orthorhombic paracetamol polymorph remains stable for about 5 h in solution in our experimental observation. A further increase in the supersaturation range from σ = 1.74−1.92 leads to the mono form I polymorph with platelike morphology. The variation in percentage of nucleation of paracetamol polymorphs with respect to supersaturation in the presence of nylon polymer is shown in Figure 4. The photographs of the growth progression of mono, mono−ortho mixed, and ortho paracetamol polymorphs are shown in Figures 5, 6, and 7, respectively. Similarly, in the presence of polypropylene polymer, the supersaturation range σ = 1.11−1.31 favors 100% mono form I polymorph, σ = 1.35−1.58 favors both monoclinic and orthorhombic polymorphs, σ = 1.62−1.74 favors 100% ortho polymorph form II, and the next higher supersaturation range from σ = 1.77−1.92 favors the mono form I polymorph. The variation in percentage of nucleation of paracetamol polymorphs with respect to supersaturation in the presence of polypropylene is shown in Figure 8. The photograph of the nucleated mono, mono−ortho mixed, and ortho polymorphs of paracetamol on the polypropylene surface is shown in Figures 9, 10, and 11, respectively. In the case of polyvinylchloride, the nucleation heteronucleated on the polymer surface at the lower supersaturation range from σ = 1.11−1.48 favors 100% mono polymorph form I. The next supersaturation range σ = 1.51−1.58 favors a mixture of monoclinic and orthorhombic paracetamol polymorphs. Further increase in the supersaturation range from σ =

Figure 4. Variation in % of nucleation with respect to supersaturation in the presence of nylon 6/6 polymer.

1.62−1.71 favors 100% ortho polymorph form II and in the next higher supersaturation range σ = 1.74−1.92 again favors 100% mono form I polymorph. The variation in the percentage of nucleation of paracetamol polymorphs with respect to supersaturation in the presence of polyvinylchloride is shown in Figure 12. The photograph of the nucleated mono, mono− ortho mixed, and ortho polymorphs of paracetamol on the polyvinylchloride surface is shown in Figures 13, 14, and 15, respectively. This result obeys the Ostwald rule that the higher supersaturation favors metastable orthorhombic polymorph, and lower supersaturation favors stable monoclinic paracetamol polymorph. It clearly elucidates that with respect to the necessary driving force created in the solution and based on the functional group on the polymer surface, the solute molecule makes alignment on the polymer chain favoring mono and ortho polymorphs. 3.2. Role of Polymer−Solute Interaction on Specific Crystal Faces of the Nucleated Paracetamol Polymorphs. In addition to this, the specific polymer−solute interaction was studied realistically; we choose to determine the crystal facets preferentially grown from a polymer surface and infer the complementary functional group interactions by examining the molecular structure of surface in contact.19 Molecular models of each crystal surface were constructed using Mercury 3.0 software and the relevant cif file. Nylon 6/6 preferentially templated the growth of smaller reflection peaks in 2θ at 20.32° (1̅20), 23.32° (1̅21), 48.32° (1̅33), and higher reflection peak at 26.38° (2̅21) planes of monoclinic paracetamol in the supersaturation range from σ = 1.11−1.40 judging from the relative peak intensities in the PXRD patterns shown in Figure 16 a. It is evident from the photographic images shown in Figure 16c that the prismatic-shaped paracetamol crystals exhibited a certain plane orientation when nucleated on the respective polymer surface, judging from similar crystal morphology compared to the grown mono paracetamol crystal from pure aqueous solution. Figure 17a−f C



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Figure 5. Snapshot of the mono polymorph form I at σ = 1.22 in the presence of nylon 6/6 polymer.

Figure 6. Snapshot of the mono−ortho mixed nucleation of paracetamol at σ = 1.48 in the presence of nylon 6/6 polymer.

Figure 7. Growth progression of ortho polymorph form II at σ = 1.62 in the presence of nylon 6/6 polymer surface.

planes expose the amide group, carbonyl group, and methyl groups to the surface. Among the four crystal planes mentioned, the (2̅21) plane interacts mainly with the nylon polymer because of high densities of amide and carbonyl groups on the surface, whereas in (1̅21) the phenyl ring together with NH−CO−CH3 groups shows a decrease in polar nature because of the apolar and basic nature of overall benzene ring surface. This indicates that the nylon polymer strengthens its hydrogen bonding interaction with both amide and carbonyl groups of paracetamol as NH···OC and with methyl groups as CH···OC. This provides a possible pathway of monoclinic form I on nylon 6/6 in the presence of water as a solvent at low supersaturation from σ = 1.11−1.40. In the case of higher supersaturation σ = 1.55−1.71, the ortho form II polymorph nucleated on nylon 6/6 surface yields a diffractogram with reflection peaks at 14.51° (020), 15.25° (111), and 36.99° (126) planes in 2θ judging from the PXRD patterns shown in Figure 16b. It is observed from Figure 16f that the needle-shaped orthorhombic crystals stood tilted on nylon surface with preferred crystal orientation via the (111) plane, and growth of the nucleated crystal was perpendicular to the (111) plane on the polymer surface and elongated along the

Figure 8. Variation in % of nucleation with respect to supersaturation in the presence of polypropylene polymer.

shows the molecular structure of the templated crystal facets of the monoclinic paracetamol on the polymer surface. Comparing the molecular structures of the templated crystal facets such as (1̅20), (1̅21), (1̅33), and (2̅21) planes, it is observed that all D



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Figure 9. Snapshot of the mono polymorph form I at σ = 1.22 in the presence of polypropylene polymer.

Figure 10. Snapshot of the mono−ortho mixed nucleation of paracetamol at σ = 1.48 in the presence of polypropylene polymer.

Figure 11. Growth progression of ortho polymorph form II at σ = 1.62 in the presence of polypropylene polymer surface.

presence of amide, carbonyl, and methyl groups, whereas in the (126) plane the presence of methyl and carbonyl groups forms has only weak CH···OC interactions. Moreover, in the next supersaturation range from σ = 1.74−1.92 paracetamol polymorph heteronucleated on nylon 6/6 surface present a platelike monoclinic form I. At this higher supersaturation region, there may be the occurrence of metastable form II or unstable polymorph form III paracetamol with very short period of time, and it was not visible in our experimental condition. This would be the reason for the occurrence of mono polymorph at this higher supersaturation.13 On analyzing the preferred crystal orientation of mono paracetamol nucleation in the supersaturation range σ = 1.11− 1.31, the polypropylene initiates the growth with multiple reflection peaks at 12.16° (1̅10), 13.84° (1̅01), 15.64° (011), 18.16° (111), 24.4° (2̅20), and 26.62° (2̅21), respectively. Among such planes, the higher index plane (111) mainly interacts with the polypropylene polymer surface. Comparing the molecular structure of such crystal facets, the (1̅10) plane has a hydroxyl group, (1̅01) plane has OH and CH groups, (011) plane has a phenyl ring together with NH−CO−CH3 groups, the (111) plane has amide and methyl groups, (2̅20)

Figure 12. Variation in % of nucleation with respect to supersaturation in the presence of polyvinylchloride polymer.

c axis. Figure 18a−e shows the molecular structure of templated crystal facets of nucleated orthorhombic paracetamol on the polymer surface. The functional groups present in the (111) plane shows strong NH···OC interaction and weak CH···OC hydrogen bonding interaction with the nylon polymer because of the E



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Figure 13. Snapshot of the mono polymorph form I at σ = 1.31 in the presence of polyvinylchloride polymer.

Figure 14. Snapshot of the mono−ortho mixed nucleation of paracetamol at σ = 1.55 in the presence of polyvinylchloride polymer.

Figure 15. Growth progression of ortho polymorph form II at σ = 1.65 in the presence of polyvinylchloride polymer surface.

has carbonyl and methyl groups, and the (2̅21) plane has amide, carbonyl, and methyl groups on the plane surface. The only possibility of hydrogen bonding interaction of paracetamol with the polypropylene polymer is CH···OH and CH···OC. It is evident from the PXRD that the higher index plane (111) plane ensures the preferred orientation of the nucleated mono paracetamol crystal. This (111) plane has only CH···CH interactions with CH or methyl hydrogen groups of polypropylene which are much weaker than other hydrogen bonding, yet it is found to be abundant between the polymer/ crystal interface. Similarly, in the case of supersaturation range σ = 1.62−1.74, the nucleated ortho polymorph has a preferred orientation on the polymer surface via the (020) plane, which shows hydrogen bonded molecular sheets lay planar along (020) with the OH, NH, and CO functional groups. Morphology predictions suggest that {100}, {010}, and {001} are the fast-growing faces of orthorhombic paracetamol.20 On the basis of these predictions and the obtained results of the PXRD, it suggests that when the polypropylene is utilized as the heteronucleant in aqueous media, it has the capability to secure the hydrogen bonded molecular sheets of paracetamol that form along the fast growing {010}. It is observed that

similar hydrogen bond pairings are formed between the adjacent molecules resulting in planar sheets parallel to the ab plane. However, the functional groups present are fully engaged in intraplanar hydrogen bonding; no groups, especially -OH groups are free to interact with external molecules. This makes the possibility of yielding this polymorph against the thermodynamically more stable monoclinic form. Similarly, in the PXRD pattern of mono and ortho polymorphs of paracetamol templated on polyvinylchloride, the preferred crystal nucleation with the (1̅21) plane in monoclinic and the (111) face in orthorhombic would have strong C−Cl···OC halogen bond interactions with the polymer surface due to the presence of NH−CO−CH3 groups of paracetamol and has weak CH···OC hydrogen bonding interactions.21,22 3.3. Effect of Polymer on Induction Time. The time taken for the nucleation of monoclinic paracetamol polymorph in pure aqueous solution varies from about 14 min initially in the supersaturation range σ = 1.11, and as the supersaturation increases the induction time is about 1 min in the supersaturation range σ = 1.92. In the case of the polymer-added solution, the addition of polymers profoundly impacts F



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Figure 16. Preferred orientation of paracetamol crystals on polymer surfaces. Comparison of PXRD pattern of paracetamol (a) form I, (b) form II. (c−e) Photographic images of mono paracetamol form I nucleated from nylon 6/6 (c), polypropylene (d), and polyvinylchloride (e). (f−h) Photographic images of ortho paracetamol form II nucleated from nylon (f), polypropylene (g), and polyvinylchloride (h).

induction time in each system. For the solution with nylon 6/6 polymer, the induction time for the nucleation of mono polymorph takes 34 min initially in the supersaturation range σ = 1.11 and gradually decreases to 15 min as the supersaturation increases to σ = 1.40. Moreover, the induction time for ortho polymorph in the supersaturation range σ = 1.55−1.71 is shorter, about 9 to 5 min, when compared to the stable monoclinic form I.

It is interesting to note that the presence of polymer in the solution acts as the nucleation inhibitor by enhancing the induction time compared to pure aqueous system, and it paves the way resulting in different polymorphs. Similarly, the solution with polypropylene shows shorter induction time for nucleation of metastable ortho polymorph of about 4−2 min in the supersaturation range σ = 1.62−1.74. The lower supersaturation region which prefers the monoclinic nucleation G



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Figure 17. Molecular structure of templated crystal facets of the nucleated monoclinic paracetamol (a) face (22̅ 1), (b) face (1̅21), (c) face (111), (d) face (1̅33), (e) face (1̅01), and (f) face (2̅20).

shows a larger induction time of about 23 min initially at supersaturation σ = 1.11, and it decreases to 13 min as the supersaturation increases to σ = 1.31. In the case of polyvinylchloride-added solution, it is found that the induction time varies from 34 to 14 min for mono polymorph in the supersaturation range σ = 1.11−1.48. A further increase in supersaturation range σ = 1.62−1.71 results in ortho polymorph, which has the minimum induction time of about 3−0.3 min. The induction time of the nucleated paracetamol polymorphs in pure solution and in the presence of selected polymers is shown in Figure 19. 3.4. Confirmation of Lattice Parameters of the Grown Polymorphs. The PXRD pattern of the nucleated mono and ortho paracetamol polymorphs shown in Figure 16, panels a and b, were well distinguished with different reflection peaks

corresponding to different crystallographic planes in the respective crystal systems. The diffraction peaks in the XRD patterns were indexed with the standard ICDD files (00-0391503 for mono and 00-087-9505 for ortho), and the determined lattice parameter values for mono and ortho polymorphs are in-line with the literature values.11,13,20 The determined lattice parameter values are given in Table 1. It is obvious that there is no much variation in the lattice parameter values determined for paracetamol polymorphs grown from both pure aqueous solution as well as on the polymer surface. 3.5. Analysis of the Phase Transformation of the Grown Polymorphs by DSC. Figure 20 displays the DSC thermogram recorded for mono and ortho paracetamol polymorphs. The sharp endothermic peak that appears at 168.81 °C (Figure 20a) indicates the melting point of the H



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Figure 18. Molecular structure of templated crystal facets of nucleated orthorhombic paracetamol (a) face (111), (b) face (020), (c) face (126), (d) face (202), and (e) face (321).

solid-state phase transformation of form II to I, followed by the melting of form I at 168.89 °C.23,24 The nucleated paracetamol polymorphs obtained using polymer as heteronuclei were characterized by PXRD and DSC analysis. From this result, we observed that the preferred crystal orientation induced by specific polymer solute interaction provides strong evidence for the templating effect of polymer surface on nucleation. Since nylon 6/6 is a

monoclinic form I. Before melting, neither endothermic nor exothermic peaks were observed, which indicates that the material is quiet stable in this temperature range. Likewise, the DSC thermogram of the orthorhombic form II (Figure 20b) shows an endothermic peak before its melting transition at 89.35 °C, followed by a sharp endothermic peak at 168.89 °C. The peak at 89.35 °C20 indicates that the crystal undergoes I



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its hydrogen bonding interaction with polypropylene and polyvinyl chloride is much weaker due to the hydrophobic nature of the polymer. All the three selected polymers of nylon 6/6, polypropylene, and polyvinyl chloride could act like a “catalyst” for crystal nucleation, which leads to the selective nucleation of polymorph facilitating by hydrogen bonding interaction. Results indicate that the phase selection mechanism not only depends on polymer surface functional groups, but in addition to this, the supersaturation generated in the solution also acts as a key factor for facilitating the nucleation of polymorphs.

4. CONCLUSIONS The polymer-induced crystallization technique offers a novel and effective way of obtaining stable and metastable paracetamol polymorphs with high purity at various supersaturation ranges. Without the addition of polymers, pure paracetamol solution yields only stable mono polymorph in all the supersaturation regions. The existence of polymer in the crystallizing solution triggers the metastable polymorph in a particular supersaturation range. The three selected polymers tested in this study have the capability of templating the nucleation and growth of stable mono as well as the elusive metastable ortho polymorph of paracetamol at respective supersaturation ranges. Each of the selected polymers nucleate the paracetamol polymorphs at well-distinguished supersaturation regions which favor the nucleation of the most wanted metastable ortho polymorph. The nucleated polymorphs grown on these different types of polymers adopt a specific crystal orientation, which reflect their preferred geometry at the nucleation as well as growth stages. Nylon 6/6 polymer induces stable mono polymorph in supersaturation range σ = 1.11−1.40 and metastable ortho polymorph in supersaturation range σ = 1.55−1.71. The polymer polypropylene templates the nucleation and growth of mono polymorph in supersaturation range σ = 1.11−1.31 and ortho polymorph in supersaturation range σ = 1.62−1.74. Likewise, the polymer polyvinylchloride prompts the nucleation and growth of mono polymorph in the supersaturation range σ = 1.11−1.48 and induces the nucleation and growth of ortho polymorph in the supersaturation range σ = 1.62−1.71 on its surface. This investigation demonstrates that the crystal nucleation and polymorph selectivity very much depend on the selected polymer surface which is mainly related to the intermolecular interactions at the polymer/crystal interface as well as the driving force created in the mother solution. It is also observed that the presence of polymer in the solution increases the nucleation rate in all three cases. It is obvious from the results obtained that the induction time of metastable ortho polymorph is comparatively shorter than the stable mono polymorph. Also it is noted that the unstable polymorph form III is not at all observed in any of the supersaturation levels employed in the present study. The crystal structure of the nucleated paracetamol polymorphs was confirmed by PXRD. DSC analysis revealed that the grown metastable ortho polymorph undergoes phase transformation from form II to I at 89.35 °C, while the grown mono form I retains its phase until melting.

Figure 19. Variation in induction time of the nucleated paracetamol polymorphs.

Table 1. Crystallographic Information of the Grown Polymorphs lattice parameter (Å) type of polymorphs

mono

ortho

space group

P21/n

Pbca

samples obtained

a

b

c

literature value13 from pure aqueous solution with nylon with polypropylene with polyvinylchloride literature value13 from pure aqueous solution with nylon with polypropylene with polyvinylchloride

11.751 11.657

9.413 9.397

7.122 7.109

11.973 11.695

9.745 9.380

7.080 7.107

11.496

9.428

7.106

7.178 7.245

11.767 11.814

17.273 17.123

7.201 7.117

11.824 12.041

16.924 17.052

7.254

12.125

17.220

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Figure 20. DSC thermogram of the grown paracetamol single crystals (a) form I, (b) form II.

AUTHOR INFORMATION

Corresponding Author

*Tel.: +91- 422-2428442. Fax: +91-422-2422387. E-mail: [email protected].

hydrophilic polymer, paracetamol interacts with nylon through strong NH···OC and weak CH···OC interaction, whereas J



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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors wish to acknowledge the financial support provided for this work by the University Grants Commission through its Special Assistance Programme (SAP) to the Department of Physics, Bharathiar University, Coimbatore.

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ABBREVIATIONS PXRD, powder X-ray diffraction; DSC, differential scanning calorimetry REFERENCES

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Polymer-Induced Selective Nucleation of Mono or Ortho Polymorphs

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