Scope for application of template chemistry for nucleation control

With precise knowledge on the fundamental mechanism of template- induced nucleation, this approach can be used to control crystal nucleation in various technological applications. Some of the possible applications that could be foreseen with template-induced nucleation approach are highlighted here.

7.3.1. Polymorph screening

Polymorph screening is an essential step in crystallisation process development of any new drug molecule that needs to be formulated as a solid dosage form. At this stage, the operating and solution conditions influencing polymorphic crystallisation are screened by conducting hundreds of small- volume batch crystallisation experiments simultaneously (Cross et al., 2002). High-throughput crystallisation experiments using well plate method is commonly used in polymorph screenings (Morissette et al., 2004). The surface functionality of these well plates could be modified to induce heterogeneous nucleation under the influence of a wide range of properties such surface energy, polarity, hydrogen-donating or accepting functional groups. The small volume (typically <0.5 ml) of these wells make it ideal for template-induced nucleation due to the high surface area to volume ratio. Medium-throughput multi-batch crystallisers (such as Avantium Crystal16® or CrystalBreeder®

systems) commonly used for early stage crystallisation studies could also be modified to incorporate the templating effect on nucleation. Such crystallisers typically use glass vessels which can be silanised to produce the desired surface chemistry. As revealed through this study, surface interactions at the walls of the vessel could potentially nucleate either metastable or stable polymorphs. Furthermore, interactions with the template surface may stabilise metastable polymorphs, which otherwise could have been missed in the screening process due to fast solution-mediated polymorphic conversions.

7.3.2. Polymorphic purity

Nucleation of polymorphs under the influence of template surfaces could be utilised for either promoting or hindering the formation of specific polymorphs. The latter strategy is particularly helpful in avoiding unwanted nucleation during crystallisation which might affect product purity. Surface chemistry at interfaces in contact with the solution could be analysed and modified towards this goal. Molecular modelling could be used as a tool for predicting the effect of surface chemistry in promoting or inhibiting nucleation of specific polymorphs.

In small scale, template-induced nucleation could be achieved through immersing functionalised template surfaces in crystallising solution. However, with the development of new crystallisation reactor systems, the application of surface chemistry for polymorph control could take up new scenarios as discussed below.

7.3.2.1. Continuous crystallisation

Development of continuous crystallisation has received much attention recently. Many different configurations of continuous crystallisers have been

proposed for achieving consistent product quality in terms of crystal size distribution, polymorphism and yield (Zhang et al., 2014). Two of the promising continuous crystalliser configurations are plug flow crystalliser and continuous oscillatory baffled crystalliser (Alvarez & Myerson, 2010; Zhao et

al., 2014). The walls of these crystallisers comprising of long tubes can act as

templates that could trigger heterogeneous nucleation. Fouling or encrustation at the wall surface due to crystal growth has been reported as an obstacle in developing continuous flow crystallisation systems (Jiang et al., 2014). Modelling approach used for template-induced nucleation could be used for screening suitable surface chemistry either for promoting nucleation of suitable polymorphs or for hindering nucleation. By functionalising the wall surfaces with suitable chemistry further control on crystallisation could be obtained in continuous crystallisers.

7.3.2.2. Producing nanocrystals

Formulation of drug crystals in the size range less than 100 nm is suggested to significantly improve the bioavailability of poorly water-soluble drugs (Elsayed et al., 2014). With a significant proportion of the new drugs in pharmaceutical development pipeline possessing low aqueous solubility, methods for producing nanocrystal is becoming more and more significant (Keck & Müller, 2006). Several production routes such as precipitation, milling and high pressure homogenisation have been adopted by pharmaceutical industries for producing drug nanocrystals (Junghanns & Müller, 2008). Nonetheless, direct synthesis of nanoscale crystals through controlled crystallisation could overcome limitations of high energy input, multiple processing stages and low yield associated with top-down approaches

where the larger sized crystals are broken down to nano-scale particles (de Waard et al., 2008). In thin-film crystallisation methods commonly used for producing inorganic nanocrystals, surface chemistry of the evaporating surface is known to play a significant role in controlling nucleation kinetics. On adapting this method for organic systems, knowledge developed through template-induced nucleation studies could be utilised for selective nucleation of nanocrystals polymorphs.

7.3.3. Seeding

Seeding is the most commonly used industrial practice to ensure polymorphic selectivity. The process involves addition of small seed crystals of the required polymorphic form into the crystallising solution to grow and/or nucleate the same crystal form. However, it is known that different processing routes used for generating seed crystals can produce crystals with different surface properties (Shah et al., 2014). Milling of crystals could expose inner planes of crystals which are otherwise inaccessible and can modify the surface polarity of seed crystals (Ho et al., 2012). In such cases, the effect of seed surface properties on polymorph control could be better understood by tracking the polymorphic domains via template-induced nucleation approach, i.e. by plotting TiPoD for various surface chemistries. Moreover, in cases where heterogeneous seeding is acceptable, template particles with different surface chemistries could be used to produce different polymorphs under identical crystallization conditions. For instance, crystal surfaces of excipient molecules such as mannitol could themselves act as heterogeneous seeds or could be functionalised to exhibit different surface chemistries. However, it is to be acknowledged that usage of heterogeneous seeds for pharmaceutical

crystallisation could be a major challenge due to regulatory issues. Nonetheless, heterogeneous seeding could be adopted in other industrial crystallisations such as agrochemical industry where the use of appropriate heterogeneous seeds would not be a serious roadblock for development and commercial approval.