Industrial Challenges of Crystallization, Nucleation, and Solubility: Perspectives from Industry, Experiment and Simulation

June 9, 2015 to June 12, 2015
Location : CECAM-IRL, University College Dublin, Ireland UCD O'Brien Centre for Science - Science South Room S3.56 Third floor of Science South (Centre for Pharmaceutical Science), Belfield Dublin 4


  • Donal Mac Kernan (University College Dublin, Ireland)
  • Brian Glennon (University College Dublin & SSPC, Ireland)
  • Baron Peters (University of California, Santa Barbara, USA)
  • Ake Rasmuson (University of Limerick, Ireland)
  • Zaworotko Michael (University of Limerick & SSPC, Ireland)
  • Jean-Christophe Jacquier (UCD Institute of Food and Health, Ireland)



   Irish Higher Education Authority

   Science Foundation Ireland


Some of the key scientific and processing issues faced by the pharmaceutical and food for health industries involve molecular scale mechanisms, such as the purification of active pharmaceutical ingredients (API) & nutraceuticals (NU) through crystallization[22], solubility of API & NU and delivery mechanisms including:
1. their co-crystal[23, 24, 25] embedding with physiological safe agents;
2. the use of anti-solvents to promote nucleation/crystallization[26, 27] ;
3. continuous [28, 29] rather than traditional batch manufacturing, where frequently the system is kept in a state of non-equilibrium through a flow reactor or the application of shear stress[30, 31];
4. continuous measurement using methods such as real-time infrared and Raman spectroscopy and control of the system[32, 33] through accessible control parameters such as effective temperature, density, and flow rate.

Many of these methods can be, and frequently are combined. One particular attraction of continuous manufacturing is that it gives in principle both greater control of the final product (for example crystal size distribution important for bio-availability), and allows demand driven cost efficient production of tailored quantities of the desired product (rather than fixed batch sizes).

Co-crystals are emerging as a very important technology allowing the modification of solubility for example of target API’s, nutraceuticals, and other agents through non-covalent bonding with appropriately selected coformers. Key findings concerning pharmaceutical co-crystallization have thus far tended to concentrate on gaining a better understanding of co-crystals from the materials design and structural
perspectives. The role of co-crystals as potential APIs suitable for use in drug products is less well delineated and, to the best of our knowledge, common Pharmacokinetics (PK) parameters are only reported for 64 co-crystals. Nevertheless, the high potential of co-crystals to fine-tune physicochemical and PK properties for a given API is becoming crystal clear and it seems that co-crystals are poised to become a platform technology that can be adapted across the full range of drug molecules and Biopharmaceutics Classification System (BCS) classes. The motivation for many researchers in this field, systematic commercialization of co-crystal drug products with advantageous clinical safety and efficacy, has coincided with development of the intellectual property landscape. In one of the early contributions to the field of pharmaceutical co-crystals, the following question[34] was asked in 2004: do pharmaceutical co-crystals represent a new path to improved medicines ? In essence, we are once again asking the same question through analysis of PK data that was unavailable in 2004. We conclude that the goal of researchers in this field is coming closer to fruition. However, there remain some obstacles, including (1) there is limited PK information in the public domain and the effects of co-crystallization upon BCS class I, III and IV drug substances remain understudied; and, (2) a far greater range of coformer types remain to be subjected to systematic study, especially ionic co-crystals.



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