European Journal of Pharmaceutical Sciences 17 (2002) 13–21 www.elsevier.nl / locate / ejps Effects of harvesting and cooling on crystallization and transformation of orthorhombic paracetamol in ethanolic solution * N. Al-Zoubi, K. Kachrimanis, S. Malamataris Department of Pharmaceutical Technology, School of Pharmacy, University of Thessaloniki, Thessaloniki 54006, Greece Received 17 January 2002; received in revised form 18 June 2002; accepted 3 July 2002 Abstract Orthorhombic paracetamol (form II) can be obtained from ethanolic solution when seeding technique is applied although it converts to monoclinic (form I) upon contact with the solvent. In the present work different cooling temperature T ( 220, 210 and 0 8C) was C applied under fixed agitation (700 rpm) and the crystalline product was harvested after different crystallization time t (20, 30 and 40 H min). Crystal yield ( Y%), micromeritic properties and orthorhombic content of the crystalline product were evaluated and related to T C and t . Conditions for optimal crystal yield and orthorhombic content were elucidated and kinetic parameters of solvent mediated H transformation (induction times, t , and activation energy, E ) were determined. It was found that crystal yield ( Y%) increases with t and it a H decreases with T . The mean crystal size and size distribution is affected linearly by T , probably due to alterations in the nucleation and C C growth processes. The effects on the crystal shape can be elucidated only after size classification. As the crystals grow, they become more elongated, with rougher surface due to secondary nucleation and alteration in growth rate of different crystal faces. Induction times for solvent mediated transformation ( t ), were remarkably longer than those corresponding to appearance of monoclinic form, when large it scale collection and drying of crystalline product was applied, probably due to residual solvent evaporation. The activation energy of solvent mediated transformation ( E 562.9 kJ / mol) is between those for nucleation in the solid state and in a solvent, indicating the a operation of a mixed mechanism.  2002 Published by Elsevier Science B.V. Keywords: Orthorhombic paracetamol; Crystal morphology; Solvent mediated transformation 1. Introduction cooling of melts and from ethanolic solution when seeding technique is applied under controlled conditions (Di Mar- Three polymorphs of paracetamol are reported in the tino et al., 1997; Nichols and Frampton, 1998). The melt- literature, the monoclinic (form I), the orthorhombic (form crystallization is not reproducible and unsuitable for large- II) and a very unstable one (form III) (Di Martino et al., scale production (Di Martino et al., 1997), while the 1997). The monoclinic form, which is used for pharma- crystallization from ethanolic solution with seeding needs ceutical tablet preparation, lacks slip planes in its crystal optimisation (Nichols and Frampton, 1998). It is because structure and therefore requires addition of plasticisers and the yield is low (less than 30%) and in addition the a wet granulation process. In contrast, orthorhombic ‘metastable’ orthorhombic paracetamol easily converts to paracetamol (form II) is composed of anti-parallel rows of monoclinic (form I) upon contact with the solvent even hydrogen-bonded molecules, which form relatively planar when small-scale crystallization process is applied (Nich- sheets and, as a result, it undergoes plastic deformation ols and Frampton, 1998). Therefore, the harvesting pro- upon compaction (Haisa et al., 1974, 1976; Boldyrev et al., cedure is very important and would need to be optimised 1997; Nichols and Frampton, 1998; Joiris et al., 1998). as well. In a recent attempt to elucidate the effects of the Consequently, the ability to produce orthorhombic para- crystallization conditions, it was found that the content of cetamol (form II) in quantity has attracted much interest. orthorhombic form increases in the final crystalline product Orthorhombic paracetamol can be obtained by slow with the agitation rate (AR) and the cooling temperature ( T ) while crystal yield ( Y%) increases with AR but C decreases with T . At 700 rpm the orthorhombic content is *Corresponding author. Tel.: 130-31-997-651; fax: 130-31-997-652. C E-mail address: smalam@pharm.auth.gr (S. Malamataris). maximised and becomes independent to T (Al-Zoubi et C 0928-0987 / 02 / $ – see front matter  2002 Published by Elsevier Science B.V. PII: S0928-0987(02)00129-X