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Chapter 4

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CHAPTER - 4

NUCLEATION BEHAVIOUR OF PARACETAMOL POLYMORPHS

ON POLYMER TEMPLATES

4.1 Introduction

In order to modify the crystal properties of paracetamol and to improve its

tableting characteristics, different crystallization parameters such as using different

solvents, additives, melts and solutions at different cooling rates have been employed by

several researchers to study their profound effect on nucleation and crystal growth

kinetics [1-12]. Despite considerable efforts, all the methods adopted 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 by the use of soluble polymeric additives and

insoluble polymer heteronuclei some attempts were made to discover and control the

production of crystal modifications by several research groups [13-17]. In the present

work, to investigate the nucleation behaviour of paracetamol, we have selected the water

soluble polymers such as agar, gelatin, polyvinyl alcohol (PVA), polyvinylpyrrolidone

(PVP) and hydroxypropylmethylcellulose (HPMC) and insoluble polymers such as nylon

6/6, polypropylene, polyvinyl chloride, alginic acid and polymethylmethacrylate as

additives and templates respectively.

4.2 Effect of soluble polymeric additives on the nucleation of paracetamol

Soluble polymeric additives added in saturated aqueous paracetamol solution

induce only the nucleation of stable monoclinic form I with different morphologies at all

the concentration range from 0.01-0.1 g/1 mL of solution by fast evaporation method.

Role of agar in solution medium is such that at lower additive concentration levels

i.e., 0.01 and 0.02 g/1 mL of solution yields mono paracetamol with columnar habit, at

intermediate concentration levels 0.03-0.07 g/1 mL of solution yields prismatic habit and

at the concentration above 0.07 g/1 mL of solution, plate-like habit dominates.

The preferential growth of certain crystal faces in the presence of agar upon indexing

shows that the nucleated mono paracetamol at lower concentration of additive have {110}

78


as high index face parallel to ‘c’ axis and { 201}, { 011} faces are present at either end of

the crystal as obtained from pure aqueous solution indicating that agar is less effective at

lower additive concentration levels in the solution. However crystals nucleated at higher

additive concentrations have consistently different habits showing prismatic and plate-

like morphology. When the additive concentration of agar was increased above 0.02 g/1 mL

of solution, the growth morphology of the nucleated mono paracetamol with { 001} face

was observed to be the prominent. Further increase in additive concentration in the range

0.08-0.1 g/1 mL of solution results in {101} as the dominant face. It was observed that

the induction time of nucleation increased as the additive concentration increased.

Increasing the concentration of additive, however increased the crystal size with decrease

in the number of nucleation. The photograph of the nucleated mono paracetamol in the

presence of agar at different concentration and their corresponding morphologies are

shown in Fig. 4.1.

Fig. 4.1 Nucleated monoclinic paracetamol in the presence of agar with concentrations at

(a) 0.01 g (b) 0.03 g (c) 0.08 g and (d-f) their respective growth morphologies

Nucleation of paracetamol from pure aqueous solution in the presence of gelatin

at the concentration range 0.01-0.1 g/1 mL of solution shows prismatic morphology with

{ 001} as the prominent face and remaining faces as the fast growing faces due to lesser

a

b c

b a c a

b c

10 µm 10 µm 10 µm

(a) (b) (c)

(d) (e) (f)

79


interaction. Variation in additive concentration alters the growth rate of the nucleated

mono paracetamol polymorph. The photograph of the nucleated paracetamol in the

presence of gelatin at different concentrations and their corresponding morphologies are

shown in Fig. 4.2.

Fig. 4.2 Nucleated monoclinic paracetamol in the presence of gelatin with concentrations

at (a) 0.01 g and (b) 0.1 along with their growth morphologies

In the case of polyvinylpyrrolidone (PVP), large spike-like trenches were

observed at lower concentration in the range 0.01-0.06 g/1 mL of solution whereas

agglomerate (clusters) of numerous spike-like microcrystals which had stuck together

appears at higher concentration in the range 0.07-0.1 g/1 mL of solution. Therefore, PVP

has strong inhibitory effect on nucleation due to their high mobility of functional groups

involved in hydrogen bonding interaction with crystal surface. It can interact with

paracetamol in their aqueous solution and they can bind together via. formation of

hydrogen bonding. It acts as strong crystal growth inhibitor for paracetamol by

adsorption onto the crystal surface. The photograph of the nucleated paracetamol in the

presence of PVP at different concentrations is shown in Fig. 4.3.

Fig. 4.3 Nucleated monoclinic paracetamol in the presence of PVP with concentrations

at (a) 0.01 g and (b) 0.1 g

10 µm 10 µm

(a) (b)

a b c

a

b c 10 µm

10 µm

(a) (b)

80


In the case of polyvinyl alcohol (PVA), at lower concentration levels 0.01 and

0.02 g/1 mL of solution, the nucleated mono paracetamol crystals are much longer along

‘c’ axis with rectangular block shaped morphology. It shows {100} faces as dominant

and similarly the growth of {110}, {110} faces also relatively get enlarged along ‘c’ axis

and {101} face get reduced compared to other two {110} and {110} faces as shown in

Fig. 4.4 (a). As the additive concentration of PVA was increased above 0.02 g/1 mL of

solution, the growth morphology of the nucleated mono paracetamol shows the trend that

growth along ‘b’ axis is enhanced as shown in Fig. 4.4 (b). In fact in Fig. 4.4 (c), it was

observed that the overall growth rate was decreased as the additive concentration was

increased from 0.07-0.1 g/1 mL of solution.

Fig. 4.4 Nucleated monoclinic paracetamol in the presence of PVA with concentrations at

(a) 0.01 g, (b) 0.05 g, (c) 0.1 g and (d-f) their respective growth morphologies

a

b

c

(a) (b) (c)

(d) (e) (f)

10 µm 10 µm 10 µm

81


Fig. 4.5 Nucleated monoclinic paracetamol in the presence of HPMC with concentrations

at (a) 0.01 g, (b) 0.05 g, (c) 0.1 g and (d-f) their respective growth morphologies

Similarly in the case of polymeric additive HPMC shown in Fig. 4.5, at lower

concentration levels 0.01 and 0.02 g/1 mL of solution, the nucleated mono paracetamol

crystals shows columnar morphology with {100} faces as dominant and {110}, {110} faces

also get enlarged along ‘c’ axis. Further increase in additive concentration HPMC above

0.03 g/1 mL of solution, it reduces the growth rate of {100} faces and enhances {110} faces

of the nucleated paracetamol. At higher additive concentration levels 0.08-0.1 g/1 mL of

solution, the size of the nucleated mono paracetamol crystals decreases with increase in

the nucleation rate. The polymeric additives of PVA and HPMC increases the nucleation

induction time and also reduces the crystal growth rate. These effects can be attributed by

the adsorption of additives onto the surface of growing crystal.

4.3 Insoluble polymers as template on the nucleation of paracetamol polymorphs at

different supersaturation levels

To explore the utility of the polymer-induced heteronucleation approach for

selectively crystallizing polymorphs of the paracetamol facilitating single crystal growth,

crystallization was performed in the presence of polymer heteronuclei. The chemical

structure of the selected insoluble polymers is shown in Fig. 4.6 (a-e).

b c

a

(a) (b) (c)

10 µm 10 µm 10 µm

(f) (e) (d)

82


Fig. 4.6 Chemical structure of polymers

C

CH3

H

C

H

H

C

CH3

H

C

H

H

C

CH3

H

C

H

H

C

H

CH3

C

H

H

C

CH3

H n

Polypropylene

C

H

H

C

H

Cl

C

H

H

C

Cl

H

C

H

H

C

Cl

H

C

H

H

C

H

Cl

n

Polyvinylchloride

(a)

(b)

(c)

O

OH

OH

O

OHO

OO

OH

O

O

n

C

CH3

H2C

O

CH3

C On

(e)

(d)

Polymethylmethacrylate

C

CH2

H2C

CH2

H2C

C

HN

CH2

H2C

CH2

H2C

CH2

H2C

NH

O

O

n

Nylon (6/6)

Alginic acid

83


The pure aqueous paracetamol solution yields only stable monoclinic paracetamol

polymorphs at all supersaturation ranges from σ = 1.11-1.92 as shown in Fig. 4.7,

whereas the experiment 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 Fig. 4.8.

However, the presence of selected polymers in the aqueous mother solution of

paracetamol acts as a nucleation site in facilitating the nucleation and growth of preferred

polymorph in different supersaturation regions in the range σ = 1.11-1.92.

Fig. 4.7 Variation in % of nucleation with respect to supersaturation

Fig. 4.8 Snapshot of the mono nucleation form I in pure aqueous solution

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

polymer [14] such as nylon 6/6, polypropylene, polyvinylchloride, alginic acid and

0 min 30 min 1 h 2 h

84


polymethylmethacrylate 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 favours 100 % needle shaped 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 plate-like morphology.

The variation in percentage of nucleation of paracetamol polymorphs with respect to

supersaturation in the presence of nylon polymer is shown in Fig. 4.9. The photographs

of the growth progression of mono, mono-ortho mixed, and ortho paracetamol

polymorphs are shown in Fig. 4.10 (a-c).

Fig. 4.9 Variation in % of nucleation with respect to supersaturation in the presence of

nylon 6/6 polymer

M M+O O M

85


Fig. 4.10 (a) Snapshot of the mono polymorph form I at σ = 1.22 in the presence of

nylon 6/6 polymer

Fig. 4.10 (b) Snapshot of the mono-ortho mixed nucleation of paracetamol at σ = 1.48 in

the presence of nylon 6/6 polymer

Fig. 4.10 (c) Growth progression of ortho polymorph form II at σ = 1.62 in the presence

of nylon 6/6 polymer surface

0 min 30 min 1 h 2 h

0 sec 660 sec 780 sec

840 sec

800 sec

820 sec 860 sec

380 sec 370 sec

400 sec 410 sec 390 sec 420 sec

0 sec 360 sec

86


Similarly, in the presence of polypropylene polymer, the supersaturation range

σ = 1.11-1.31 favours 100 % mono form I polymorph, σ = 1.35-1.58 favours both

monoclinic and orthorhombic polymorphs, σ = 1.62-1.74 favours 100 % ortho polymorph

form II, and the next higher supersaturation range from σ = 1.77-1.92 favours 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 Fig. 4.11.

The photograph of the nucleated mono, mono-ortho mixed, and ortho polymorphs of

paracetamol on the polypropylene surface is shown in Fig. 4.12 (a-c) respectively.


polypropylene polymer


polypropylene polymer

M M M+O O

0 min 5 min 15 min 30 min

87



the presence of polypropylene polymer


of polypropylene polymer surface

In the case of polyvinylchloride, the nucleation heteronucleated on the polymer

surface at the lower supersaturation range from σ = 1.11-1.48 favours 100 % mono

polymorph form I. The next supersaturation range σ = 1.51-1.58 favours a mixture of

monoclinic and orthorhombic paracetamol polymorphs. Further increase in the

supersaturation range from σ = 1.62-1.71 favours 100 % ortho polymorph form II and in

the next higher supersaturation range σ = 1.74-1.92 again favours 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 Fig. 4.13.

The photograph of the nucleated mono, mono-ortho mixed, and ortho polymorphs of

paracetamol on the polyvinylchloride surface is shown in Fig. 4.14 (a-c) respectively.

420 sec 600 sec 660 sec

680 sec 700 sec 720 sec

0 sec

400 sec 380 sec 0 sec 360 sec

420 sec 440 sec 460 sec 480 sec

88



polyvinylchloride polymer


polyvinylchloride polymer


the presence of polyvinylchloride polymer

0 min 20 min 25 min 30 min

M M+O O M


660 sec 680 sec 700 sec

89



of polyvinylchloride polymer surface

The solution in the presence of alginic acid polymer heteronucleates 100 % mono

form I polymorph on the polymer surface with prismatic shaped at lower supersaturation

range σ = 1.11-1.31 and rectangular block shaped at σ = 1.35-1.44. With increase in

supersaturation range σ = 1.48-1.62 mixture of mono and ortho was observed. The percentage

of mono polymorph decreases with increase in the ortho polymorph as the supersaturation

increases and favours 100 % needle shaped ortho polymorph form II at σ = 1.65-1.74.

Further increase in supersaturation range σ = 1.77-1.92 leads to mono form I with plate-

like morphology. The variation in percentage of nucleation of paracetamol polymorphs

with respect to supersaturation in the presence of alginic acid polymer is shown in

Fig. 4.15. The photograph of mono, mono-ortho mixed and ortho paracetamol

polymorphs on alginic acid polymer surface is shown in Fig. 4.16 (a-c).


480 sec 500 sec 520 sec 540 sec

90



alginic acid polymer

Fig. 4.16 (a) Snapshot of mono polymorph form I at σ = 1.11 in the presence of alginic

acid polymer

Fig. 4.16 (b) Snapshot of mono-ortho polymorph of paracetamol at σ = 1.48 in the

presence of alginic acid polymer

M+O M O M

0 min 30 min 1h 10 min

0 sec 320 sec 300 sec

400 sec 360 sec

340 sec

380 sec

91


Fig. 4.16 (c) Snapshot of ortho polymorph form II at σ = 1.74 in the presence of alginic

acid polymer

Similarly in the presence of polymethylmethacrylate polymer, the nucleation

templated on the polymer surface at the lower supersaturation range σ = 1.11-1.26

favours 100 % mono form I polymorph, σ = 1.31-1.48 yields both mono and ortho

polymorphs. In the next supersaturation range from σ = 1.51-1.62 favours the ortho form II

polymorph and further increase in supersaturation leads to mono form I polymorph at

σ = 1.65-1.92. The variation in percentage of nucleation of paracetamol polymorphs with

respect to supersaturation in the presence of polymethylmethacrylate polymer is shown in

Fig. 4.17. The photograph of mono, mono-ortho mixed and ortho paracetamol polymorphs

on polymethylmethacrylate polymer surface is shown in Fig. 4.18 (a-c).


polymethylmethacrylate polymer

280 sec

200 sec 220 sec 180 sec

260 sec 240 sec

0 sec

M+O M M O

92


Fig. 4.18 (a) Snapshot of mono polymorph form I at σ=1.11 in the presence of


Fig. 4.18 (b) Snapshot of mono-ortho polymorph of paracetamol at σ=1.31 in the

presence of polymethylmethacrylate polymer

Fig. 4.18 (c) Snapshot of ortho polymorph form II at σ=1.62 in the presence of


0 min 40 min 1h 2h

0 sec

700 sec 680 sec

640 sec

660 sec

620 sec 600 sec

0 sec 1500 sec

1650 sec

1630 sec

1660 sec 1680 sec

1610 sec

93


This result obeys the Ostwald rule that the higher supersaturation favours

metastable orthorhombic polymorph, and lower supersaturation favours 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 favouring

mono and ortho polymorphs.

4.4 Quantification of polymer-solute interactions 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 [16]. 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° (120 ),

23.32° (121), 48.32° (133 ), and higher reflection peak at 26.38° ( 221) 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 Fig. 4.19 (a). It is evident from

the photographic images shown in Fig. 4.19 (c) 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. Fig. 4.20 (a-j) 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 (120 ),

(121), (133 ), and ( 221) planes, it is observed that all planes expose the amide group,

carbonyl group, and methyl groups to the surface. Among the four crystal planes

mentioned, the ( 221) plane interacts mainly with the nylon polymer because of high

densities of amide and carbonyl groups on the surface, whereas in (121) 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

94


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 range

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 Fig. 4.19 (b). It is observed from

Fig. 4.19 (i) 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

‘c’ axis. Fig. 4.21 (a-k) 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 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 plate-like 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 [18].

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° (110 ), 13.84° (101), 15.64° (011), 18.16° (111),

24.40° ( 220 ), and 26.62° ( 221), 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 (110 ) plane has a hydroxyl group, (101)

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, ( 220 ) has carbonyl and methyl

groups, and the ( 221) plane has amide, carbonyl, and methyl groups on the plane surface.

95


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 [1].

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 (121) 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 [19, 20].

Alginic acid at lower concentration σ = 1.11-1.31 heteronucleates the growth of

prismatic mono form I with higher reflection peak in 2θ at 48.10° (133 ) and smaller

reflection peaks at 20.32° (120 ) and 23.32° (121) planes with amide, carbonyl and

methyl as the exposing groups to the surface. Among the three crystal planes, the higher

index plane (133 ) strengthens its hydrogen bonding interaction with the alginic acid

96


polymer surface as NH···OH, NH···O=C, NH···O, CH···O=C whereas the (120 ) and

(121) planes has weak hydrogen bonding interaction due to the decrease in polar nature

of the phenyl ring together with NH-CO-CH3 by the apolar and basic nature of overall

benzene ring surface. Similarly at the intermediate supersaturation range σ = 1.35-1.44,

rectangular block shaped mono crystal nucleated with multiple refection peaks at 13.96°

(101), 16.96° (111), 18.28° (111), 23.56° (121), 26.62° ( 221) and 37.72° (312) judging

from the relative peak intensities in the PXRD patterns. Among such planes higher index

plane (101) mainly interacts with alginic acid polymer surface. Comparing the molecular

structure of such crystal facets, the (101) plane has OH and CH group, (111) and (111)

plane has amide and methyl groups, (121) has phenyl ring together with NH-CO-CH3 and

( 221) plane has amide, carbonyl and methyl groups on the plane surface. At this

supersaturation range it is observed that (101) plane assures the preferred orientation with

both oxygen and carbonyl group of alginic acid polymer as OH···O and CH···O=C

interaction which is evident from PXRD.

In the case of higher supersaturation σ = 1.65-1.74, the needle shaped ortho form II

polymorph nucleated on the alginic acid surface yields a diffraction peaks at 15.35°

(111), 26.10° (211) and 48.30° (216) planes in 2θ from the PXRD pattern. Crystal facet

(111) plane has high densities of amide and methyl groups, (211) has phenyl ring

together with NH-CO-CH3 group and (216) plane has NH-CO-CH3 group on the plane

surface. The higher index plane (111) shows strong NH···OH, NH···O=C interaction and

weak CH···OH, CH···O=C hydrogen bonding interaction with alginic acid polymer

because of high densities of amide and methyl groups on the plane surface when compared to

other two crystal planes. In the next supersaturation range from σ = 1.77-1.92, alginic acid

polymer heteronucleates the plate-like monoclinic paracetamol polymorph.

On examining the preferred crystal orientation of mono and ortho paracetamol

polymorphs templated on the polymethylmethacrylate polymer, PXRD shows the

reflection peaks in 2θ at 20.32° (120 ), 23.32° ( 211) and 26.38° ( 221) for mono at the

supersaturation range σ = 1.11-1.26 and at 15.50° (111), 18.20° (022), 24.55° (200),

27.85° (132) and 29.20° (221) for ortho nucleated at the supersaturation range σ = 1.51-1.62.

97


Comparing the molecular structure of the crystal facets (120 ), ( 211) and ( 221) planes of

mono, the functional groups of amide, carbonyl and methyl present in ( 221) plane shows

strong NH···O=C interaction and weak CH···O=C hydrogen bonding interaction with the

polymethylmethacrylate polymer whereas in (120 ), the presence of phenyl ring with

NH-CO-CH3 and in ( 211) plane the CH group has only weak interactions compared to

( 221) plane. Similarly the molecular structure of the crystal facets the ortho polymorph

(111) plane has high densities of NH-CO-CH3 groups, the plane (022) and (221) has

phenyl ring together with NH-CO-CH3 group, (200) has phenolic ring and methyl group

and (132) has carbonyl and methyl group on the plane surface. Among such planes the

nucleated ortho polymorph has preferred orientation on the polymer surface via (111)

plane and would have strong NH···O=C interaction and has weak CH···O=C hydrogen

bonding interaction.

98


(a) (b)

c b a

(c)

a

b c

a b

c

a b

c

a b

c

(d)

a b

c

(e)

(i)

(j)

(k)

99


Fig. 4.19 Preferred orientation of paracetamol crystals on polymer surfaces. Comparison

of PXRD pattern of paracetamol (a) form I, (b) form II. (c-h) Photographic images

of mono paracetamol form I nucleated from nylon 6/6 (c), polypropylene (d),

polyvinylchloride (e), alginic acid (f, g) and polymethylmethacrylate (h). Photographic

images of ortho paracetamol form II nucleated from nylon (i), polypropylene (j),

polyvinylchloride (k), alginic acid (l) and polymethylmethacrylate (m)

a

b c

300 μm

a

b

c 400 μm

a b

c 400 μm

(f)

(h)

(g)

(m)

c

a

b

250 μm

(l)

c

a b 250 μm

100


(a)

a

b c

(b)

a

b

c

a

b c

(c) (d)

a

b c

a b

c

(e)

c

b

a

(f)

(f)

101


Fig. 4.20 Molecular structure of templated crystal facets of the nucleated monoclinic

paracetamol (a) face ( 221), (b) face (121), (c) face (111), (d) face (133 ),

(e) face (101), (f) face ( 220 ), (g) face (120 ), (h) face ( 221), (i) face (211)

and (j) face (312)

(g) (h)

(i)

(j)

a

b

c

a c

b

a

b c

b a

c

102


(a)

a b

c

(b)

a c

b

a

c b

(c) (d)

a

b c

(e)

a b c

a

c b

(f)

103


Fig. 4.21 Molecular structure of templated crystal facets of nucleated orthorhombic

paracetamol (a) face (111), (b) face (020), (c) face (126), (d) face (202),

(e) face (321), (f) face (022), (g) face (132), (h) face (200), (i) face (211),

(j) face (216) and (k) face (221)

a

c

b

c b

a

b c a

b c a

a

c

b

(i)

(h) (g)

(j)

(k)

104


4.5 Effect of polymer on induction time of the nucleated polymorphs

The impact of polymer has profound effect on induction time of the nucleated

paracetamol polymorphs in pure aqueous solution. The time taken for the nucleation of

monoclinic paracetamol polymorph in pure aqueous solution varies from about 14 min

initially in the supersaturation level σ = 1.11, and as the supersaturation increases the

induction time is about 1 min in the supersaturation level σ = 1.92. In the case of the

polymer added solution, the addition of polymers profoundly impacts 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 level 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 ranges 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.

Fig. 4.22 Variation in induction time of the nucleated paracetamol polymorphs

Similarly, the solution with polypropylene shows shorter induction time for

nucleation of metastable ortho polymorph of about 4 to 2 min in the supersaturation range

σ = 1.62-1.74. The lower supersaturation region which prefers the monoclinic nucleation

shows a larger induction time of about 23 min initially at supersaturation level σ = 1.11,

and it decreases to 13 min as the supersaturation increases to σ = 1.31. In the case of

105


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 to 0.3 min. It is noted that the time taken for the nucleation of

mono polymorph in the solution with alginic acid polymer is about 10 to 5 min in the

supersaturation range σ = 1.11-1.48 which is less as the induction time for nucleation in pure

system took about 14 min. Whereas in the case of solution with polymethylmethacrylate

polymer shows larger induction time of about 40 min initially at supersaturation level

σ = 1.11 and it decreases to 10 min for the nucleation of ortho polymorph and finally

decreases to 0.7 min as the supersaturation increases as compared to the case of alginic

acid polymer. The induction time of the nucleated paracetamol polymorphs in pure

solution and in the presence of selected polymers is shown in Fig. 4.22.

4.6 Confirmation of lattice parameters of the grown polymorphs by PXRD

The PXRD pattern of the nucleated mono and ortho paracetamol polymorphs

shown in Fig. 4.19, 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

(00-039-1503 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 [1, 18, 21].

The determined lattice parameter values are given in Table 4.1. 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.

106


Table 4.1 Crystallographic information of the grown polymorphs

Type of polymorphs

Space group Samples obtained

Lattice parameter (Å)

a b c

Literature value [18]

from pure aqueous solution

11.751

11.657

9.413

9.397

7.122

7.109

Mono P21/n with nylon 11.973 9.745 7.080

with polypropylene 11.695 9.380 7.107

with polyvinylchloride 11.496 9.428 7.106

with alginic acid 11.647 9.681 7.121

with polymethyl

-methacrylate

11. 785 9.574 7.100

Literature value [18]

from pure aqueous solution

7.178

7.245

11.767

11.814

17.273

17.123

Ortho Pbca with nylon 7.201 11.824 16.924

with polypropylene 7.117 12.041 17.052

with polyvinylchloride 7.254 12.125 17.220

with alginic acid 7.138 11.981 17.135

with polymethyl

-methacrylate

7.147 11.799 17.113

107


4.7 Analysis of the phase transformation of the grown polymorphs by DSC

Fig. 4.23 displays the DSC thermogram recorded for mono and ortho paracetamol

polymorphs. The sharp endothermic peak that appears at 168.81 °C (Fig. 4.23 a) indicates

the melting point of the 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 (Fig. 4.23 b)

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 °C [1] indicates that the crystal

undergoes solid-state phase transformation of forms II to I, followed by the melting of

form I at 168.89 °C [22, 23].

Fig. 4.23 DSC thermogram of the grown paracetamol single crystals (a) form I and (b) form II

4.8 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 presence of

soluble polymeric additives in the pure aqueous solution significantly modified the

crystal habit of monoclinic paracetamol. The existence of insoluble polymers in the

crystallizing solution triggers the metastable polymorph in a particular supersaturation

108


range. The five 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 nucleates the paracetamol polymorphs at well-distinguished supersaturation

regions which favour 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. 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 five 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.

109


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