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Role of Hydrogen Bonding Lifetime and Complementarity in Heterogeneous Nucleation

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Role of Hydrogen Bonding Lifetime and Complementarity in Heterogeneous Nucleation ROLE OF HYDROGEN BONDING LIFETIME AND COMPLEMENTARITY IN HETEROGENEOUS NUCLEATION Vivek Verma, Int. BS-MS Thesis presented for the award of Doctor of Philosophy (PhD.) Supervisor: Prof. B. Kieran Hodnett, Dr. Sarah Hudson, Dr. Peter Davern Submitted to the Faculty of Science and Engineering, University of Limerick, Ireland. Submitted: September 2018 ABSTRACT This work investigates the mechanism for the heterogeneous nucleation of active pharmaceutical ingredients (APIs) in the presence of different excipient heterosurfaces. By elucidating this mechanism for a range of API molecules, the appropriate crystallisation conditions and heterosurfaces can be selected in silico for individual APIs to then generate API crystals of the desired size and morphology via controlled heterogeneous crystallisation processes, thus facilitating control over the API dissolution process. The crystallisation of seven APIs (acetaminophen (AAP), carbamazepine (CBMZ), caffeine (CAF), phenylbutazone (PBZ), risperidone (RIS), clozapine base (CPB) and fenofibrate (FF)) was studied in the absence and presence of the excipients α/β-lactose (α/β-lac), β-D-mannitol (β-D-man), dextran (DEX), chitosan (CHT), carboxymethyl cellulose (CMC) and microcrystalline cellulose (MCC), each of which acted as a heterosurface. Two of the APIs, namely AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) functionalities whereas the other five only possess HBA functionality. The crystallisation experiments for all seven APIs were carried out within or at the limit of their respective metastable zones at supersaturation ratios in the range of 1.08 to 1.50. A novel methanol solvate of CPB was also discovered during these crystallisation experiments. API crystallisations in the presence of a heterosurface were accompanied by a more pronounced acceleration of the crystallisation for those APIs possessing only HBA functionality relative to the acceleration observed for the APIs possessing HBA and HBD functionalities. The smallest heterosurface acceleration of crystallisation was observed for CBMZ at 1.4 times and the largest was observed for FF at 16 times. For all the APIs studied, the interfacial energy was similar for crystallisations carried out in the presence and absence of the heterosurface; by contrast, the pre-exponential factor was generally larger for crystallisations carried out in the presence of the heterosurface than in its absence. Density i Functional Theory (DFT) and Molecular Density calculations complemented the above experimental study. Thereafter, a model of heterogeneous crystallisation was developed wherein two factors were identified. The first of these was the complementarity of hydrogen bonding between the heterosurface and the APIs. Hence the crystallisation of APIs without HBD functionality was accelerated more strongly than for those with HBA and HBD functionality because the heterosurface provided the HBD functionality lacking in these APIs which allowed them to attach or adsorb to the heterosurface and thus act as nucleation points for the API’s crystallisation. The second factor identified was that the hydrogen bonding lifetime of the individual API molecules or small API clusters attached to a heterosurface is much longer (up to 1000 times) than (i) the lifetime of API-API interactions in the solution phase, or (ii) the time required for an API molecule to add to a growing crystal. This lifetime effect arises from the greater stability of an adsorbed species, and this extended lifetime increases the probability that molecules or small clusters of the API in solution will add to the adsorbed or attached species thus favouring the heterogeneous route to crystallisation. In addition to enhanced control over nucleation and particle growth, the resultant API- excipient composites from this heterogeneous nucleation process were shown to demonstrate improved dissolution profiles and could be directly tableted, with lower downstream processing requirements than homogeneously crystallised API. Specifically, a pronounced improvement in the dissolution of CBMZ FIII and desolvated CPB was observed when crystallised in the presence of excipients when compared with the physical mix of API- excipient. The isolated solids were mixed with disintegrant and lubricant, and were tabletted by direction compression to confirm the tabletability. Hence heterogeneous nucleation can potentially help in reducing the downstream processing. ii Graphical abstract: SEM micrograph of CBMZ crystallised on the surface of MCC iii iv DECLARATION I declare that the work presented in this thesis herein, is entirely my own work and has not be been submitted to this or any other university. Due references and acknowledgement has been made, when necessary, to the work of others. Vivek Verma (Candidate) Prof. B. Kieran Hodnett (Supervisor) Dr. Sarah Hudson (Co-supervisor) Dr. Peter Davern (Co-supervisor) This Thesis was defended on 12th October, 2018 Examination Committee Chairperson Dr. Tadgh Keneddy University of Limerick External Examiner Dr. Jerry Heng Imperial College London Internal Examiner Dr. Emmet O’Reilly University of Limerick v vi Acknowledgements At the very outset, I would like to convey my deepest regards to my research supervisors Prof. Kieran Hodnett, Dr. Sarah Hudson and Dr. Peter Davern, who has continuously encouraged me in the last four years. I firmly believe that their inspiring guidance has been a key factor behind the wholesome learning process throughout my PhD tenure. I would like to thank to the whole staff of Materials and Surface Science Institute, for helping me with PXRD, SEM, DSC and TGA. Next I would like to thank the entire staff of the Chemical and Environmental Science department in the University of Limerick for all their help throughout the course of my research, especially James Kelly, Brian O’Shaughnessy and Bridget Hogan, Chief Technical Officer Maria Munroe, Departmental Coordinator Ciara Tuohy and Departmental Head Prof Tony Pembroke. It is my immense pleasure to thank all the lovable and dear members of the “Synthesis and Solid State Pharmaceutical Centre (SSPC)” team I belong to. My special thanks to Dr. Clare Crowley, for series of fruitful long discussions with respect to my project and for sharing of her work-experiences combined with assimilation of individual ideas that has helped me a lot to expand the horizon of scientific knowledge. I would also like to thank Dr. Raquel Arribas-Bueno for time to time discussion on the project and also teaching me Spanish. Next I would like to thanks Dr. Manik Ghosh for helping me with DFT calculations, Dr. Jacek Zeglinski for his help with molecular modelling, Dr. Matteo Lusi for his support with solving crystal structures and Pauric Bannigan for his help in single crystal data collection. vii I would also like to thank all the administrative staff members of SSPC, especially the senior administrator Rosaleen Archbold for her constant support with all the administrative processing. I would like to thank all my friends, Amrit, Dipali, Shubhangi, Rodrigo, Yara, Shiv, Deepam, Pauric, Michael, Killian, Sarah, Teri, Kata, Ajay, Barry, Naveen, Kiran, Vasanth, Anurag, Prabal, Priyank, Akash, Shraddha, Juhi, Parul, Ankit, Vikas and others. I apologize beforehand for not being able to take all of your names, but am sure; it would not offend you to a great extent. Without them the journey would not have been as exciting as it has been. Finally, I would like to thank my family; my parents R K Verma and J Verma, my brothers; Deepak and Shubham my sister-in-law Rashmi and my niece Shradha for their constant support over the years and for keeping faith in me to carry on with everything I have set out to do in life. I would definitely not be here today without your help and support over the years. viii to my family for their understanding, encouragement and support… ix x LIST OF PUBLICATIONS This thesis is based on the work of the following papers: I. V. Verma, R. V. G. Peddapatla, C. M. Crowley, A. M. Crean, P. Davern, S. Hudson and B. K. Hodnett, “Experimental Study on the Influence of Excipients on the Heterogeneous Crystallisation and Dissolution Properties of an Active Pharmaceutical Ingredient”, Crystal Growth & Design, 2018, 18, 338-350. II. V. Verma, P. Bannigan, M. Lusi, C. Crowley, S. Hudson, B. K. Hodnett and P. Davern, “The Heterogeneous Crystallisation of a Novel Solvate of Clozapine Base in the Presence of Excipients,” CrystEngComm, 2018, 20, 4347-4516. (Accepted for front cover page) III. V. Verma, and B. K. Hodnett, “A Basis for Kinetic Selection of Polymorphs,” CrystEngComm, 2018, 20, 5551-5561. IV. V. Verma, J. Zagelinski, S. Hudson, P. Davern and B. K. Hodnett, “Dependence of Heterogeneous Nucleation on Hydrogen Bonding Lifetime and Complementarity.” Crystal Growth & Design, 2018, DOI: 10.1021/acs.cgd.8b01302 Related Conference contributions and oral presentations (not included in thesis): V. Verma, R. Arribas-Bueno, J. Zeglisnki, C. M. Crowley, S. Hudson, P. Davern, B. K. Hodnett, “Role of Hydrogen Bonding in reducing the Barrier in Heterogeneous Nucleation.” Oral and Poster presentation at: 49th British Association of Crystal Growth (BACG), June 2018, Limerick, Ireland. V. Verma, P. Bannigan, M. Lusi, C. M. Crowley, S. Hudson, B. K. Hodnett, P. Davern, “Dissolution behaviour of a novel solvate of Clozapine base crystallised in the presence of excipients.” Poster presentation at: United Kingdom and Ireland Controlled Release Society (UKICRS), May 2018, Belfast,
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