Crystallization is an essential step in many processes in chemical industries, ranging from bulk chemicals to special products. It is a separation and purification technique that results in a solid particulate product, which is generally preferred in the pharmaceutical industry. The crystal product quality is determined by the specific crystal form (polymorph) crystallized, and by the crystal size, morphology and purity. It depends heavily on the process conditions under which crystal nucleation occurs. During the crystal nucleation event, parameters that are essential for the product quality, in particular the polymorph formed, are not very well established. The nucleation event is still poorly understood and is therefore difficult to control and optimize. Crystal nucleation sets the initial crystal size distribution at the start of unseeded batch crystallization processes and is the first and most important step in this process (Chapter 1). A fundamental understanding of crystal nucleation is needed for the rigorous control and prediction of the crystalline product quality of any crystallization processes on industrial scale. Also the lead compounds in pharmaceutical industry become more and more complex. As a result crystallization research becomes increasingly fundamental while model compounds have shifted from bulk chemicals to high added-value chemicals. A fundamental understanding of molecular processes during crystallization is becoming increasingly important not in the least when applied on an industrial scale. In this thesis we improve the knowledge and understanding of crystal nucleation of organic compounds from solution. The research starts with comparing two newly developed methods to measure heterogeneous nucleation kinetics by determining crystal nucleation rates in stirred solutions (Chapter 2). Both methods make use of the stochastic nature of crystal nucleation by determining and analysing the variation in nucleation kinetic measurements. The values of the kinetic parameter (A) obtained in the present thesis are low compared to the theoretical values. This could be due to both a lower than expected attachment frequency of building units to the nucleus and a lower than expected concentration of active nucleation sites (heterogeneous particles) in the solution. It was further identified that the single nucleus mechanism, in which all crystals in the suspension originate from the same parent single crystal, might occur more generally than is currently recognized, even in larger volumes. In this thesis we used concomitant polymorphism as a tool to validate this single nucleus mechanism (Chapter 3). The single nucleus mechanism has important implications for the control of industrial crystallization processes of polymorphic compounds. In terms of crystal size distribution, control can be obtained by controlling the secondary rather than the primary nucleation event for which completely different control procedures are needed. In terms of polymorphism, the control can be achieved by controlling the primary nucleation event that leads to the single crystal, which in turn defines the crystal form of the secondary nuclei. One of the major challenges the pharmaceutical industry is faced in production, where often during cooling crystallization the product separates not as crystals but as a viscous liquid. This phenomenon is referred to as oiling out or liquid-liquid phase separation (LLPS). The effect of LLPS on the crystallization of 4-hydroxyacetophenon (4HAP) in water, water-ethanol mixtures and ethyl acetate solutions were shown in Chapter 4. For HAP, the LLPS is a stable region above the saturation temperature of 52 °C, 36 °C and 30 °C of 4HAP in water, water-ethanol (90-10 wt%) and water-ethanol (80-20 wt%) mixtures, respectively. Cooling crystallization experiments always resulted into mixtures of polymorphic fractions if the LLPS preceded 4HAP crystallization. The results suggest that the crystallization behavior is strongly influenced by the presence of this LLPS. Due to the LLPS the nucleation may proceed on the droplet surface and the single nucleus mechanism does not hold anymore. The crystallization within the LLPS region seems to lead to agglomeration of the particles. One of the causes for the low kinetic parameter A of the nucleation rate equation was identified in Chapter 3 to be the building units that attach to the nucleus and thus determine the attachment frequency. The effect of these solution-building units or associates in solution was investigated in Chapter 5. The model compound used was isonicotinamide, which has an amide group that can form both homosynthons and heterosynthons by self-association. We show that, in a controlled and reproducible way, specific solvents lead to specific polymorphic forms of isonicotinamide. We argue on the basis of Raman and FTIR spectroscopy that the hydrogen bonding (self-association) in solution kinetically drives the nucleation towards a specific form. The self-association in solution reflects the crystal structure of the obtained polymorph. The method based on self-association of molecules in solution may help in reproducible production of polymorphs. In chapter 6 we propose a polymorph screening method based on the identification of crystal building units using Raman, FTIR and NMR techniques. We demonstrated this new approach by relating the structural outcome of the crystallization process of Isonicotinamide (INA), Nicotinamide (NA), Picolinamide (PA), Carbamazepine (CBZ) and Diprophylline (DPL) to the association and self-association processes in solutions, which are largely influenced by the hydrogen bonding capacity of the solvent. The screening method based on the identification of crystal building units may help to discover new polymorphs. The self-association method offers the ability to identify solvents or solvent mixtures that promote or avoid the presence of specific building units and in this way control the building unit towards polymorphs having specific structural features. As identified in chapter 3, another cause for the low kinetic factor in nucleation is the heterogeneous particle. Nothing is known about the actual concentration and functionality of these heterogeneous particles while they tremendously affect nucleation behavior. We therefore investigated the interplay between self-associates in solution and well-defined heterogeneous template surface by studying the crystallization behavior of isonicotinamide (INA) and 2,6-dihydroxy benzoic acid (DHB) (Chapter 7). Well-defined templates were prepared by making Self-Assembled Monolayers (SAM) onto a gold surface. The self-association of INA and DHB were investigated using spectroscopic techniques. Raman spectroscopy of the crystal-template surface after template crystallization suggests that molecular interactions between INA or DHB associates and the SAM are responsible for the formation of specific polymorphs. XRPD helped in the identification of the crystal orientation on the template surface further verifying the importance of solute interactions with the functionalized template surface. The systematic analysis of the association processes in solutions and the interplay with well-defined templates is beneficial in the development of polymorph discovery and preparation methods as well as control over crystallization processes. Industrially, the thesis results may not only help to discover new polymorphs but can also help in reproducible industrial production of polymorphs. On Industrial scale seeding approaches using only a single crystal can lead to the avoidance of primary nucleation and thus control over the polymorph obtained. The combination of well-defined template surfaces and the self-association method can be used as a screening method in the early drug discovery and development phase but also define robust conditions for industrial crystallization of polymorphs. This will not only help to discover and reproducibly prepare polymorphs, but a more comprehensive screening can be performed at reduced cost. Industries can implement the results to improve crystal product qualities and can also discover and optimize the quality of new crystal products by incorporating the methods in the development process. Scientifically, this thesis opened the route towards a thorough study of heterogeneous nucleation of polymorphic compounds taking into account self-association, template effects and relative stability of polymorphs. Such a study would result in an accurate molecular interpretation of crystal nucleation and would finally enable the validation of heterogeneous nucleation theories. As analytical techniques become more and more powerful, finding new and better ways to powerful insights in the crystal nucleation research become easier. Utilization of these principles and tools not only allow studying crystal nucleation, but also allows the understanding of nucleation processes to a new level. Molecular simulations are still needed to bridge the gap between solution chemistry and crystal nucleation rate analysis to come to a molecular interpretation of crystal nucleation of organic compounds. The new experimental approaches described in this thesis will boost the existing methods for polymorph prediction and in particular for predicting the conditions for polymorph formation.