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Chapter 6

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CHAPTER - 6

INFLUENCE OF SELECTED SOLVENTS AND SEEDING

TECHNIQUE ON THE NUCLEATION AND GROWTH OF

PARACETAMOL POLYMORPHS

6.1 Introduction

Single crystals have been the ultimate focus for potential applications in the

pharmaceutical industries especially for drug processing. The occurrence of different

polymorphic forms is associated with different solution environments and there is a need

to control the polymorph formation to ensure the production of desired polymorph [1-3].

Under laboratory conditions, several methods such as evaporative crystallization,

complex cooling, multicomponent crystallization and polymer heteronuclei have been

carried out selectively crystallize the preferred polymorph of paracetamol [4-9].

In addition to this, solvents have proved to be an important factor in influencing the

crystallization kinetics. The use of different solvents during crystallization profoundly

affects the crystal habit of the purified drug, leading to the variation in raw material

characteristics such as flowability, compaction, chemical stability, dissolution and

packing [3, 10]. Therefore habit modification seems to provide an alternative means for

designing the drugs with desired characteristics [11]. In order to achieve controlled

production of the desired polymorphic form, well-established seeding technique is used

in crystallization processes both in laboratories and industries [12]. In our present study,

the influence of ten different selected solvents such as polar protic (water, ethanol,

methanol, isopropyl alcohol), polar aprotic (cyclohexanone, acetone, ethyl acetate,

tetrahydrofuran, acetonitrile) and non-polar 1, 4-dioxane were investigated on the

nucleation and growth behaviour of paracetamol polymorphs. Among the ten different

selected solvents, two from polar aprotic (water, ethanol) and one from aprotic

(cyclohexanone) were chosen for investigation in the presence of seeding.

137


6.2 Nucleation and growth of monoclinic paracetamol single crystals

The solvents like polar protic, polar aprotic and one non-polar solvent were

selected based on their bonding characteristics and according to their solubility limits.

Saturated paracetamol solution prepared using different solvents on observing under

in-situ optical microscope reveals that the crystal nucleation of paracetamol has

undergone a change in the growth habit. The nucleation of paracetamol in different

solvents possesses different crystal habit such as prismatic, platy, and columnar like

crystals. It was observed that the nucleation induction time of paracetamol in the selected

solvents varies with significant variation in the rate of nucleation. The number of crystals

nucleated per unit area in different solvents was calculated from the captured microscopic

images. Paracetamol has polar functional groups such as hydroxyl, amide and carbonyl

groups and the non-polar as CH group. Among the selected solvents, polar protic solvents

such as water, ethanol, methanol and isopropyl alcohol strongly dissociate both the

positively and negatively charged species to participate in intermolecular force via

hydrogen bonding. Whereas the polar aprotic solvents such as cyclohexanone, acetone,

tetrahydrofuran, ethyl acetate and acetonitrile give only positive ions but not negative

ions which results in the absence of hydrogen bonding. Similarly for the non-polar

solvent 1, 4-dioxane, the bond between similar electronegative atoms in C-H will lack

partial charges. As a result the nucleation is faster and the rate of nucleated monoclinic

paracetamol polymorph is higher in polar protic solvents than in polar aprotic and non-

polar solvents. This result indicates that the type of solvent dramatically influences the

shape of paracetamol crystals with respect to the solubility of solute, solvent polarity,

evaporation number of solvent and rate of generation of supersaturation in the solution.

The dipole moment, evaporation number [13] and pH of the selected solvent are given in

Table 6.1. The microscopic image of the observed nucleation was photographed and it is

shown in the Fig. 6.1 (a-j).

138


Table 6.1 Dipole moment, Evaporation number and pH of the selected solvents

Selected solvents Dipole moment (Debye)

Evaporation number at room temp pH of the solvent

Water 1.87 1.0 7.0

Ethanol 1.69 8.3 6.8

Methanol 1.70 6.3 7.3

Isopropyl alcohol 1.66 11 7.1

Cyclohexanone 2.87 40 7.2

Acetone 2.88 2.1 6.4

Tetrahydrofuran 1.75 2.3 8.0

Ethyl acetate 1.78 2.9 5.5

Acetonitrile 3.20 2.1 5.9

1, 4-dioxane 0.45 7.3 5.1

Fig. 6.1 Optical micrographs of crystal habit of paracetamol nucleation observed in

different solvents (a) water (b) ethanol (c) methanol (d) isopropyl alcohol (e)

cyclohexanone (f) acetone (g) tetrahydrofuran (h) ethyl acetate (i) acetonitrile

and (j) 1, 4-dioxane

10µm

(b)

10µm

10µm

(e)

(h)

10µm

(i)

10µm

(g) (f)

10µm

(j)

10µm

(a)

10µm

(c)

10µm

(d)

10µm

139


The variation of growth habits observed in the nucleation of paracetamol with

different solvents was identified by subjecting the prepared saturated solution to slow

evaporation. Closed covering and uniform perforation on the top of a vessel gives

approximately the same growth rate for all the paracetamol crystals nucleated in a

particular solvent. It was found that there has been a drastic variation in the solubility,

apparent pH, nucleation time and number of nucleated paracetamol crystals in solution

under different solvents as shown in Table 6.2. The crystals grown by slow evaporation

also shows distinct variation in the growth habit as observed in in-situ optical

microscopy. The paracetamol single crystal grown by slow evaporation method and their

morphology is shown in the Fig. 6.2. It is observed that the growth morphology of

paracetamol single crystals from water is much different compared to the crystals grown

in other selected organic solvents such as ethanol, methanol, isopropyl alcohol, acetone,

ethyl acetate, cyclohexanone, tetrahydrofuran, acetonitrile and 1, 4- dioxane. It is seen

that the crystals grown in water possess columnar morphology having {110} as the

prominent face, { 201}, {001} and { 011} faces as the corner faces capping the ends of the

crystal and it is observed that the growth is prominent along the c-axis. Similarly, the

crystals grown in other organic solvents possess prismatic morphology showing { 001} as

the dominant faces and there is a decline in {110} faces as compared to the crystals

grown in water [11, 14]. Hence, there appears a demarcation between columnar crystals

and prismatic crystals in growth habits. The change in the relative area of the face mainly

depends on the polarity of the solvent and the effect of polarity can be understood by

examining the hydrogen bonding interaction between the emerging chemical groups from

the crystal surface and with that of the solvent molecules. Generally the face with greater

hydrogen bonding interaction binds strongly to solvent molecules and delays the growth

rate of the face. It is probable that for the growth of the face to occur, solute molecules

should dislocate the hydrogen bonding interaction with the solvent molecules.

10µm

140


Table 6.2 Solubility, apparent pH, nucleation time and number of nucleated paracetamol

crystals in the selected solvents

Solubility of paracetamol in g/100 mL at (305 K)

Apparent pH of the saturated paracetamol

solution

Nucleation time in h

Number of crystals per unit

area

2.1 g in Water 4.45 0.75 86

18 g in Ethanol 6.20 0.42 95

27.4 g in Methanol 6.04 0.50 7

9.5 g in Isopropyl alcohol 6.70 30 88

11 g in Cyclohexanone 4.65 120 76

9 g in Acetone 4.72 1.25 14

19.9 g in Tetrahydrofuran 7.85 96 47

1.1 g in Ethyl acetate 4.83 192 82

3.7 g in Acetonitrile 5.43 216 79

2.64 g in 1, 4-dioxane 2.64 984 32

141


Fig. 6.2 Crystal habit of paracetamol single crystals grown by slow evaporation method

in different solvents (a-d) polar protic, (e-i) polar aprotic and (j) non-polar

( )110( )001

( )011

( )201

c

b a ( )201

( )110

( )001

( )110

( )011( )011

b a

c

( )110

( )001

( )110

( )011 ( )011

( )111

( )201( )111

b a

c ( )001( )011 ( )011

( )111( )111

( )110( )110

b a

c

( )201

( )110 ( )110

( )011 ( )011

( )111( )111

( )001

b a

c ( )001( )011 ( )011

( )111( )111

( )110 ( )110

b a

c ( )111

( )001( )110

( )110

( )201

( )111 b a

c

Acetonitrile + Paracetamol

( )110

( )001

( )110

( )011 ( )011

( )111( )111

b a

c ( )111

( )110

( )201

( )110

( )111

( )001

b a

c

( )110

( )001

( )110

( )201

( )011 ( )011

b a

c

(f)

(a) (c)

(g)

(b) (d)

(e)

(i) (j)

(h)

142


6.3 Solute-solvent interaction on the crystal faces of the grown monoclinic

paracetamol

By examining the position of molecules in the crystal lattice relative to the crystal

faces we can qualitatively assess the particular preferred sites for hydrogen bonding

interaction. In our present study, the crystal structure information of paracetamol was

retrieved from single crystal X-ray diffraction. Paracetamol consists of a benzene ring

core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the

para position. The amide and hydroxyl groups act as hydrogen bond donors whereas the

carbonyl and hydroxyl group acts as hydrogen bond acceptors in the molecule.

The C=O···HO and OH···NH molecules of successive layers form head to tail sequence

using hydrogen bonds resulting in a network. The functional groups emerging from the

crystal surface of the grown paracetamol monoclinic crystal faces was constructed using

Mercury 3.0 software and relevant cif file obtained from single crystal X-ray diffraction

and is shown in the Fig. 6.3 (a-h).

The major crystal face ( 001) shows the hydroxyl and NH-CO-CH3 group as the

protruding group of paracetamol molecules from the surface, ( 201) with NH and OH

group projecting from the surface, ( 011), ( 011) and (110 ) with OH group projecting from

the surface, (110 ) and (110 ) with OH group from the surface, emergence of phenyl ring

together with NH-CO-CH3 projecting from the surface, (111) with CH, OH and NH

groups projecting from the surface, for the face (111) the emergence of phenolic OH

moiety and NH-CO-CH3 projecting from the surface. In general, stronger the hydrogen

bonding interaction of a face will be affected by the stronger hydrogen bonding solvents

i.e., the growth rate of a strongly hydrogen bonding face will be slowed. In the present

work, for the paracetamol crystallized from water, the growth is found to be prominent

along ‘c’ crystallographic axis with (110 ) as the prominent face and the remaining faces

(001), ( 201) and ( 011) as the smallest faces. It means the paracetamol molecule while on

interaction with water molecule, the hydroxyl group of the water molecule makes strong

hydrogen bonding interaction with the protruding groups of the amine and hydroxyl

group of the host molecule as NH···OH and OH···O=C hydrogen bonding interaction at

143


the face (110 ), whereas the remaining faces (001), ( 201) and ( 011) faces, there is less

interaction compared to (110 ) face. Therefore the face with (110 ) shows slower growth

speed along the ‘c’ direction due to strong interaction with solvent molecule and thus

induces the formation of large face while other faces grow faster without any disruption

of solvent molecule due to weak interaction. Faster the growth rate contributes less to the

morphology with lower morphological importance.

Fig. 6.3 Realization of different functional groups on the crystal faces of the grown

monoclinic paracetamol: (a) face ( 001), (b) face ( 201), (c) face ( 011), (d) face

( 011), (e) face (110 ), (f) face (110 ), (g) face (111) and (h) face (111)

(f)

a

c

b

(h)

a b

c

(b)

a

b c

(d)

a

c b

a b

c

(c)

a c

b

(g)

a

c b

(e)

a

b c

(a) (e)

(b)

(f)

(c)

(g)

(d)

(h)

144


In the case of polar protic solvents such as ethanol, methanol and isopropyl alcohol, it

is observed that the grown paracetamol crystal shows (001) as the prominent face. Since the

face (001) are populated with functional groups such as OH and NH-CO-CH3, the polar

hydroxyl group present in the solvent molecules strongly interacts with the amine

NH···OH and with carbonyl group as OH···O=C hydrogen bonding interaction. For the

face ( 201), there is only NH···OH interaction, for (011), (011) there is OH group and hence

only there is a possibility of O···HO hydrogen bonding interaction. For the faces such as

(110 ) and (110 ) there appears OH group and phenyl ring together with NH-CO-CH3 groups.

The overall surface of benzene ring is apolar as well as basic in nature there is a decrease

in the acidic nature. As a result, the growth rate of these two faces is faster showing weak

interaction and they appear as the smallest faces. This indicates that these faces grow

more relative to others on the crystal for the polar solvents, which is consistent with the

comparatively weak hydrogen bonding interaction of the faces.

In the case of polar aprotic solvents such as acetone, ethyl acetate, cyclohexanone

the C=O groups are very active and it is more polar in forming hydrogen bonding

interaction with paracetamol molecule. The grown paracetamol single crystal from these

solvents possesses ( 001) as the predominant face. As the face ( 001) is populated with

functional groups such as OH and NH-CO-CH3, the hydroxyl group of the host molecule

strongly interacts with the amide and carbonyl group of the guest molecule shows

NH···OH and OH···O=C hydrogen bonding interaction. Whereas in the face ( 201), there

is a weak hydrogen bonding interaction of OH···O=C compared to ( 001) face and for the

face ( 011), ( 011) there is only O···HO hydrogen bonding interaction. Similarly at the

face (110 ) and (110) there is a weak interaction due to the above said reason and hence

these faces grow faster and appear as a smaller faces.

The crystals obtained from the aprotic solvent tetrahydrofuran shows ( 001) and

(110 ) as the prominent faces and remaining faces as the smallest one. With respect to the

supersaturation of the solvent, these two corresponding crystal faces ( 001) and (110)

would be polar and it would have strong NH···OH and OH···O=C hydrogen bonding

interaction compared to other faces. For the face ( 201), there is only NH···OH

145


interaction and for the face (110 ) there exists weak hydrogen bonding interaction because

of the phenolic moiety. The remaining faces such as (111) there is only O···HO, CH···O

interactions and (111) face there exists weak hydrogen bonding interaction. In the case of

acetonitrile solvent, the crystals appeared with ( 001) as the prominent face and other

faces as the smallest face. Even though acetonitrile is a polar molecule with the triple

bond between C and N, nitrogen acts as an electronegative atom and are able to accept

the hydrogen bond, there exists only N···HO which is a weak interaction when compared

to O···HO interaction.

In the case of the non-polar solvent 1, 4-dioxane, the crystals obtained displays

( 001) as the largest face and other remaining faces capping as the smallest faces. Dioxane

is almost apolar and aprotic solvent but the ether oxygen’s of its molecule offer hydrogen

bonding acceptor sites and promotes the hydrogen bonding interaction with the host

molecule. For the prominent face ( 001), O···HO and O···HN interactions and the other

faces remains small due to weak hydrogen bonding interaction. It is observed that the

crystals grown from THF and 1, 4-dioxane, there is a disappearance of (011) faces which

means that those faces were grown out. Among the ten selected solvents used in this

study, solutions prepared with water yielded crystals with columnar morphology,

solutions prepared with polar protic, polar aprotic solvents like ethanol, methanol,

isopropyl alcohol, acetone, cyclohexanone, tetrahydrofuran, ethyl acetate and acetonitrile

and non-polar solvent 1, 4-dioxane yielded crystals with prismatic morphology. As on

overall assessment, each solvent used in this study affect the growth of different faces of

paracetamol crystals.

The grown paracetamol single crystal shows variation in the growth rate

dispersion in different solvents and hence it results in different crystal habits relative to

different growth rate. The growth habit of paracetamol single crystals observed in

different solvents varies as a function of various parameters such as solvent polarity,

evaporation number of solvent, pH of the solution, differences in solubility, rate of

generation of supersaturation and by solute-solvent interaction with different affinities

affecting the chain of bonds which runs through the structure. Thus, the growth

mechanism results in habit changes and growth rates of a crystal depend on both the

146


internal factors such as structure, bonds and external factor as solvent, solubility, pH and

supersaturation. Among the above-mentioned solvents, based on the better solubility

compared with other solvents, ethanol was selected as the best solvent and the growth of

bulk paracetamol single crystal was carried out. The growth of the monoclinic

paracetamol single crystal from ethanol by slow cooling method was photographed and

shown in Fig. 6.4 (a-d). The morphology of the grown paracetamol single crystal and its

morphological importance of different crystal faces are given in the Fig. 6.4 (e).

The grown bulk paracetamol single crystal in Fig. 6.4 (f) shows morphological

importance in the order { 001} > { 201} > { 011} > { 011} > {111} > {111} > {021}. The

{ 001} face had the greatest morphological importance representing the slower growth

rate and the other faces represent the sequential faster growth with respect to

supersaturation. One would expect that stirring must lead larger concentration of

paracetamol molecule in solution near the faces {021} than near the other faces thereby

promoting faster growth rate. Hence the growth rate of each crystal faces were probably

promoted by surface environment such as supersaturation and the supply of solute

concentration by solution flow around the crystal surface [15].

Fig. 6.4 Growth progression of paracetamol single crystals by slow cooling method

(a) initial stage (b) 14 days (c) 23 days (d) after harvesting stage (e) grown

morphology and (f) morphological importance

( )011

( )111

( )001( )011

( )201( )111c

b

a

0

100

200

300

400

500

600

700

Mor

phol

ogic

al Im

port

ance

(A

rea

in s

q.m

m)

Faces

(f) (c) (b) (a)

Paracetamol

(d) (e)

147


6.4 Crystallization of orthorhombic paracetamol by specially designed seeding technique

6.4.1 Seeding process

The design of seed preparation unit explained in section 2.2.7.1 is given in

Fig. 6.5. The variations in the pulling rate of the ampoule (Fig. 6.6) result in change in

temperature. It leads to a change in the cooling rate of the furnace with respect to

different rpms. The temperature profile of the furnace with respect to time for different

rpms is shown in Fig. 6.7. Crystallization under different cooling rates favours the

formation of different polymorphic seeds which are confirmed by PXRD shown in Fig.

6.8. PXRD patterns reveal that the prepared seeds A and D are the stable polymorphs of

monoclinic form I. The prepared seeds B, E, F, G, H and I shows the mixture of

monoclinic and orthorhombic polymorphic form whereas seed C confirms the metastable

orthorhombic polymorph. The grown paracetamol single crystals exhibit different

morphology in three different selected solvents such as water, ethanol and cyclohexanone

from slow evaporation. The growth rate of a crystal differs due to the variation in the

degree of supersaturation with respect to each of unseeded and seeded solution depending

on the evaporation of the solvent. The three selected solvents yield only monoclinic form

I paracetamol single crystals with columnar and prismatic morphology without seeding as

shown in Fig. 6.9 (a-c). Whereas on seeding the solvents, only monoclinic paracetamol

were obtained from water and ethanol with morphology similar to the crystals obtained

previously. The crystals obtained were confirmed by PXRD as monoclinic form I with

ICDD standard files (00-039-1503 for mono).

148


Fig. 6.5 Seed preparation unit

Fig. 6.6 Variation in pulling rate of the ampoule with respect to different rpms

Thermocouple

Sample

Pulley

Furnace end cap

Insulation

Heater winding

Power supply

Travelling rod

Digital temperature controller

Stepping motor controller

SMC

DTC

149


Fig. 6.7 Temperature profile of the furnace with time

Fig. 6.8 Powder X-ray diffraction pattern of paracetamol crystals

Seed I

Form I

Form II Seed A

Seed B

Seed C

Seed D

Seed E

Seed F

Seed H

Seed G

Form II

Form I

Observed

Form I+II

(-101)

(-101)

(-101)

(-101)

(-101)

(-101)

(-101)

(-101)

(-121)

(-121)

(-121)

(-121)

(-121)

(-121)

(-121)

(-311)

(-311)

(-311)

(-311)

(-311)

(-311)

(212)

(212)

(032)

(032)

(032)

(200)

(200)

(022)

(022)

(221)

(221)

(-311) (-121)

Form I

Form I+II

(140)

(140)

150


Grown crystals from cyclohexanone with seeds A, B, D, E, F, G, H and I yielded

only monoclinic paracetamol with prismatic morphology. It has {001} faces as the

greatest morphological importance as the prominent faces comprising {110}, {101},

{011} and {111} as the smallest end faces which are monoclinic form I. An exception

was observed in the case of seed C in cyclohexanone solvent. Here, the crystals show an

equant, squat prismatic habit of orthorhombic form II showing {211}, {200} and {210}

faces as the dominant. The obtained crystals were confirmed by PXRD with ICDD

standard files (00-087-9505 for ortho). Fig. 6.10 shows the photograph of the grown

monoclinic from seed A and orthorhombic paracetamol crystals from seed C and their

respective morphology. The dissimilarity showed by form II from form I could be the

effect of seed crystals of desired form as well as by the effect of solvent in the solution.

Fig. 6.9 Grown monoclinic paracetamol crystals without seeding in (a) water, (b) ethanol

and (c) cyclohexanone

Fig. 6.10 Grown monoclinic and orthorhombic paracetamol single crystals in

cyclohexanone with seeding using (a) seed A (b) seed C and (c) their

corresponding morphologies

(a) (b) (c)

Monoclinic Monoclinic Monoclinic

Monoclinic

Orthorhombic

(a)

(b)

b

a c

c

b a

(c)

151


Generally in the presence of seeding, metastable zone width (MSZW) of the

solution decreases when compared to the unseeded solution [16]. As a result, with the

stable polymorphic seeds, the generation of supersaturation in the solution on evaporation

favours the formation of stable secondary nuclei and enables the growth of stable

monoclinic paracetamol crystals. It can be noted that when water and ethanol used as a

solvent, seeding has no effect on the polymorph of the desired orthorhombic crystal by

slow evaporation. However the solution seeded with metastable polymorphic seed C in

cyclohexanone favours the necessary supersaturation for the formation of metastable

orthorhombic paracetamol single crystals by slow evaporation. These results lead to the

conclusion that the metastable seed C present in the solution of cyclohexanone reduces

the MSZW favourable for the desired polymorph or it may acts as a substrate for the

metastable secondary nuclei and accelerates the growth of metastable orthorhombic

crystals. Besides seeding, it is clear that the cyclohexanone solvent has specific solute-

solvent interaction effect compared to water and ethanol in polymorph formation during

crystallization.

6.4.2 Powder X-ray diffraction analysis

In Fig. 6.8, the grown paracetamol form I and form II single crystals have

distinctly different PXRD patterns. In terms of peak position and peak intensity profile,

the two XRD patterns agree well with ICDD standard files (00-039-1503 for mono and

00-087-9505 for ortho). The three strongest peak position 2θ of form I at 23.68° (121),

13.6° (101), 26.32° (311) reflections and largest peak position 2θ of form II at 24.10° (200),

18.22° (022), and 28.72° (221) reflections shows a distinguishable peak position of the

two forms. The determined lattice parameters a = 11.816 Å, b = 9.331 Å, c = 7.092 Å and

β = 97.12 ° for monoclinic form I and a = 7.396 Å, b = 11.664 Å and c = 16.972 Å for

orthorhombic form II paracetamol single crystals are in-line with the literature values [17].

6.4.3 Fourier Transform Infrared spectroscopic study

The frequencies of the mode of vibrations attributed to the paracetamol molecules

were identified for two polymorphs and from the recorded spectra shown in Fig. 6.11; a

small shift in the vibrational frequency of ortho polymorph was recognized.

The differences are observed as far as in amide stretching (3329 cm-1 for mono and

152


3330 cm-1 for ortho), O-H stretching (3182 cm-1 for mono and 3199 cm-1 for ortho), C=O

stretching (1649 cm-1 for mono and 1652 cm-1 for ortho), C-H symmetric stretching

(1506 cm-1 for mono and 1504 cm-1 for ortho). The shifting was also observed for skeletal

aryl C-C stretching vibrations (1435 cm-1 for mono and 1442 cm-1 for ortho), C-N

stretching mode vibration (1228 cm-1 for mono and 1220 cm-1 for ortho). The peaks

observed at 837, 686, 601 cm-1 for mono and 837, 686, 601 cm-1 for ortho are due to out

of plane C-H bending (aryl-1, 4 disubstituted) [18, 19].

Fig. 6.11 FTIR spectra of the grown paracetamol (a) form I and (b) form II

6.4.4. Differential Scanning Calorimetry analysis

Fig. 6.12 shows the DSC thermograms of the grown paracetamol mono and ortho

paracetamol single crystals. The sharp endothermic peak at 168.54 °C in Fig. 6.12 (a)

indicates the melting point of the monoclinic form I. DSC curve of the orthorhombic

form in Fig. 6.12 (b) shows an endothermic peak before its melting transition peaked at

89.44 °C followed by a sharp endothermic peak at 168.40 °C. This indicates that the

crystal undergoes a solid-state transformation of forms II to I at 89.44 °C, followed by the

melting of form I at 168.48 °C [20].

(a)

(b)

153


Fig. 6.12 DSC thermogram of the grown paracetamol crystals (a) form I and (b) form II

6.5 Conclusions

Crystallization of paracetamol from ten different solvents studied reveals that

polar protic, polar aprotic and non-polar solvents yielded only monoclinic paracetamol

single crystals. However the crystal faces of the grown paracetamol with different

solvents ends up with different growth rate, thus resulting in different external habit.

The changes in the growth habit of paracetamol single crystals caused by solvents of

varying chemical nature and polarity affects the solubility of the solute, pH of the

solution, evaporation number of solvent and rate of generation of supersaturation. These

are consistent with the interpretation that hydrogen bonding interaction between solvents

and crystal faces causes these changes resulting different habit modification. Good

quality large size paracetamol single crystal of size 36 mm × 39 mm × 22 mm was grown

from ethanolic solution for the first time. It is concluded that the solvents play a major role in

modifying the habit of the monoclinic paracetamol single crystals in accordance with their

hydrogen bonding ability with solute molecules. Without seeding, the three selected solvents

water, ethanol and cyclohexanone yielded only stable monoclinic form I paracetamol crystals

with different morphology. Whereas with seeding, only monoclinic paracetamol was

obtained from water and ethanol as solvents and only orthorhombic paracetamol single

crystals were obtained from cyclohexanone as a solvent. The influence of crystallization

condition on the polymorph is mainly attributed by seeding and different types of

intermolecular interaction of solute-solvent through hydrogen bonding.

(a)

(b)

154


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