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School of Pharmacy and Chemistry, Li6erpool John Moores Uni6ersity, Byrom Street, Li6erpool L3 3AF, UK
b
School of Pharmacy, Mashhad Uni6ersity of Medical Sciences, Mashhad, Iran
Received 5 October 1998; received in revised form 21 April 1999; accepted 2 May 1999
Abstract
Prismatic polyhedral crystals of paracetamol were prepared by cooling an aqueous saturated solution of paracetamol from 65 to 25C. Thin plate-like crystals were prepared by adding a concentrated solution of paracetamol in hot
ethanol to water at 3C. Infrared (IR), X-ray powder diffraction (XPD) and differential scanning calorimetry (DSC)
studies confirmed that these two forms of crystals were structurally similar, therefore polymorphic modifications were
ruled out. The crystal habit influenced the compression properties during axial compression of paracetamol at
different constant rates in a compaction simulator, the Heckel plots and their associated constants being dependent
on the habits. The correlation coefficient of the initial part of the Heckel plots, and also the values of strain rate
sensitivity (SRS), were lower for thin plate-like crystals, indicative of greater fragmentation for the thin plate-like as
compared to polyhedral crystals. Compacts made from thin plate-like crystals exhibited higher elastic recoveries and
elastic energies indicating that these crystals underwent less plastic deformation during compression than the
polyhedral crystals. 1999 Elsevier Science B.V. All rights reserved.
Keywords: Paracetamol; Crystallisation; Crystal habit; Compaction; Apparent mean yield pressure; Plastic deformation; Elastic
deformation; Fragmentation
1. Introduction
Crystallisation from solution is used widely for
the purification of drugs during their final stages
* Corresponding author. Tel.: +44-151-2312096; fax: +
151-2312170.
E-mail address: j.l.ford@livjm.ac.uk (J.L. Ford)
1
Present address: School of Pharmacy, Mashhad University
of Medical Sciences, Mashhad, Iran.
0378-5173/99/$ - see front matter 1999 Elsevier Science B.V. All rights reserved.
PII: S 0 3 7 8 - 5 1 7 3 ( 9 9 ) 0 0 1 5 7 - X
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2.6. Compression
Sieved fractions of paracetamol (105 210 mm)
were used to achieve approximate equivalency of
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(1)
(2)
From B, the place where the Heckel plot intercepts the ln 1/1 D axis (Fig. 2), the density of
powder at zero pressure, Do, is obtained (Eq. (3)).
Do can be defined as the densification due to die
filling or to initial powder packing.
Do = 1e B
(3)
(4)
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Fig. 3. Scanning electron micrographs of paracetamol particles crystallised by the (a) watering-out method at 3C; (b) watering-out
method at 25C; (c) from a mixture of ethanol/water at 3C; (d) at 25C; (e) from ethanol at 3C; (f) at 25C; (g) from water at 3C
and (h) at 25C (all magnifications 200).
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Thin plate-like
crystals
Polyhedral
crystals
171.879 0.14
179.359 10.47
171.91 90.21
176.759 4.82
a
Results are the means and standard deviations of four
determinations.
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Fig. 4. Size distributions of (a) thin plate-like and (b) polyhedral crystals of paracetamol. The thickness of polyhedral crystals were
approximately equal to their width.
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Fig. 5. The X-ray powder diffraction spectra of (a) polyhedral and (b) thin plate-like crystals of paracetamol.
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Table 2
The values derived from the Heckel plots of Fig. 6 of polyhedral and thin plate-like crystals of paracetamol compressed at a
compression speed of 10 mm s1 to a maximum 30 kN compression force
Crystal type
K (slope)
Da
Do
r*
r**
Polyhedral
Thin plate-like
0.0367
0.0285
27.5
35.3
0.71
0.69
0.66
0.53
0.965
0.925
0.9989
0.997
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Table 3
The values derived from the Heckel plots of polyhedral and thin plate-like crystals of paracetamol compressed at 10, 50, 100 or 250
mm s1 up to a maximum 30 kN compression force
Polyhedral crystals
Plate crystals
Compression speed
(mm s1)
Da
Do
Db
Da
Do
DB
10
50
100
250
0.7039 0.009
0.0709 0.007
0.6809 0.005
0.6609 0.004
0.6509 0.005
0.650 90.077
0.640 90.004
0.620 90.005
0.050 9 0.005
0.050 90.007
0.040 90.004
0.037 90.004
0.693 9 0.005
0.665 9 0.005
0.657 9 0.004
0.598 9 0.001
0.525 9 0.006
0.515 9 0.005
0.515 9 0.011
0.505 9 0.005
0.165 90.013
0.150 90.010
0.143 90.008
0.088 90.008
10
50
100
250
a
Thin plate-like
crystals
28.2 91.6
30.5 91.4
36.9 91.4
38.9 90.8
35.1 9 1.8
37.3 9 2.6
41.9 9 1.3
40.8 9 1.6
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(5)
PY1 and PY2 are the apparent mean yield pressure at 10 and 250 mm s 1 speed, respectively.
The calculated values of SRS for polyhedral and
thin plate-like crystals were 27 and 14%, respectively. It has been reported that, due to the time
dependent nature of plastic flow, the apparent
mean yield pressures increase with increasing
punch velocity for plastic materials which consequently show higher value of SRS (Roberts and
Rowe, 1985, 1986). Therefore these results indicate that polyhedral crystals were more sensitive
to compression speed suggesting that they were
more plastic than the thin plate-like crystals which
were more brittle.
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4. Conclusions
References
Armstrong, N.A., Haines-Nutt, R.F., 1972. Elastic recovery
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