Crystallization from solution is an important unit operation widely used in food, cosmetics, agrochemical, chemical and pharmaceutical industries. It is a crucial step especially for pharmaceutical industries since the shape, size and polymorphic form of the obtained crystals will strongly influence the properties of the final drug as well as downstream operations such as filtering, washing and drying. These properties can be controlled by an opportune selection of solvents or antisolvent, pH, cooling profiles or additives. Furthermore, in situ monitoring and control can be performed using process analytical technology (PAT) tools in batch or continuous crystallizers (Saleemi et al. 2012, Barrett et al. 2010, Kee et al. 2009, Alatalo et al. 2010). The use of additives for tailoring the polymorphic form nucleated, as well as the morphological properties of the crystals is being largely studied. Additives can be used to control the shape of the final crystals (Majumder, Nagy 2013), their size (Garnier et al. 2002) and crystal structure (Price et al. 2005). The molecular structure of an impurity or a specific substrate (templates characterized by a film of molecules are often used) can influence the polymorphic form nucleated: a correspondence between the molecular lattice of the substrate/impurity and the target polymorph usually facilitates its nucleation and the presence of opportune functionality group in the substrate can also cause the nucleation of a specific polymorphic form (Chadwick, et al. 2011, Kulkarni et al. 2014). Structurally related additives can inhibit the nucleation or the growth of a certain polymorph stabilizing another form (Davey et al. 2002, Mo et al. 2011): they can be incorporated in the crystal lattice and slow down nucleation or growth of the stable polymorph favouring the metastable form.
In this work, the effect of different additives on the crystallization of ortho-aminobenzoic acid (OABA) will be studied. The compound is a derivative of benzoic acid used mainly for the production of dyes, perfumes, cosmetics and as an intermediate for the production of few drugs. The chosen additives belong to three different categories: (1) Ionic small molecules that can change the solution equilibria but could also interfere with the growth of the OABA crystals (2) Molecules with molecular structure similar to OABA which usually strongly influence the shape and size of the produced crystals (3) Polymeric additives which also have a strong effect on size and morphology of the crystals. Several spectroscopic (Raman, ATR-FTIR and UV) and laser techniques (FBRM) will be used.
Materials and Methodology
OABA has three known different polymorphic forms: (i) Form I is the stable form which is also the only one that presents zwitterions in the crystal structure, (ii) Form II is the most metastable form, it is enantiotropically related to form I and monotropically related to the more stable form III (iii) Form III it is usually very difficult to nucleate during cooling crystallization from solution, it is normally produced by sublimation or by polymorphic transformation of form I at high temperatures (form I and III are enantiotropically related), (Jiang et al. 2010b, Jiang et al. 2010a).
Benzoic acid was used in the experiments as the structurally related additive while sodium hexametaphosphate and aluminium sulfate octadecahydrate were used as salts. For the experiments with a polymeric additive, Hydroxy Propyl Methyl Cellulose (HPMC) was chosen. Three different solvents were used for the experiments: pure water, water and 10% IPA w/w and water and 20% IPA w/w. From a previous study it was found that water favours the crystallization of the zwitterionic polymorph Form I while mixtures of IPA and water favour nucleation of the metastable form II. Form III was never observed during the cooling crystallization experiments conducted during that particular study. Two level of OABA saturation temperature were used (about 35 and 45°C referred to form I) for each solvent. Solid OABA was added to the solvent and the temperature was raised to 50°C in order to dissolve all the particles. The solution was kept at high temperature for 20-30 minutes and then cooled down at a rate of -1°C/min to 10 or 20°C depending on the initial saturation temperature. After that a small amount of additive was added to the slurry and the solution was heated up again and then cooled down with the previous cooling rate. More consecutive additions of additive in the same solution were performed maintaining the same kinetic conditions (initial temperature and cooling rate) but increasing the ratio of additive and ortho-aminobenzoic in solution. Particle vision and measurement (PVM), focused beam reflectance measurement (FBRM) and UV spectroscopy were used to detect nucleation and monitor OABA concentration and crystals during the experiment while online Raman spectroscopy was used to determine the polymorphic form nucleated. On and off-line images of the crystals will also be analysed in order to determine the effect of additives on the crystals (size, shape, agglomeration, breakage). Additional off-line techniques such as SEM, XRD and DSC will also be used.
Results and discussion
Benzoic acid: this structurally related additive has an effect on both the morphology and polymorphism of OABA. It can be easily incorporated in the crystal structure of both form II and III but not in form I and it was found to increase the time of polymorphic conversion of both the metastable forms (II and III) into the stable form I. At BA/OABA ratios smaller than 0.1 no change in the polymorphic form nucleated was observed: form I was always nucleated from water while form II or mixture of II and I were nucleated in water and 10% IPA. At IPA concentration of 20% w/w in solution and BA/OABA<0.1 pure form II was consistently nucleated. The morphology of form II was not strongly affected by the presence of small concentrations of benzoic acid while a higher aspect ratio of form I was observed. However, a higher tendency to agglomeration was noticed for both polymorphs in the presence of this additive. For BA/OABA ratios higher than 0.1 form III started nucleating in all the tested solvents. Pure form III was obtained for BA/OABA ratios higher than 0.3-0.4 (depending on the solvent), while mixtures of form III and I or form III and II were nucleated for ratios between 0.1 and 0.3.
Ionic salts: these additives seem not to affect significantly nucleation or polymorphism of OABA. The nucleation temperature did not change even at high salt concentration as well as the polymorph nucleated. A change in morphology of form I crystals was observed using sodium hexametaphosphate while the shape of form II was not affected by this additive. Aluminium sulfate did not affect morphology of any polymorph nucleated.
HPMC: this compound was found to increase induction time as well as to affect morphology of form I in water. Both growth and nucleation of this polymorph were strongly inhibited by HPMC even at very low concentration. The compound did not seem to affect significantly the morphology of form II but its transformation time into form I was considerably increased (probably as a result of the nucleation inhibition of the stable polymorph).
Several additives were tested in the cooling crystallization of OABA. It was found that ionic additives have only a small effect on the morphology of the zwitterionic form I while they don’t seem to significantly affect nucleation temperature or polymorphism. The polymeric additive HPMC could strongly inhibit both growth and nucleation of form I causing a significant change in its morphology. Benzoic acid instead, was found to inhibit growth of form I in water at low concentrations. At high ratios BA/OABA in solution form III was nucleated regardless of the solvent used. This compound also favoured agglomeration of OABA and stabilized the metastable forms.
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