53 research outputs found
Studies of cocrystal-excipient interaction by a combination of experimental and computational approaches.
No full textHerein is presented a report on the study of a low-solubility active pharmaceutical ingredient (API), Leflunomide (LEF). Novel multi-component systems, both pharmaceutically and non-pharmaceutically acceptable, of LEF have been synthesised. Their multi-component nature was confirmed, and each system has been comprehensively characterised using X-ray Powder Diffraction (XRPD), Single-Crystal X-ray Diffraction (SCXRD) and detailed structural analysis.A cocrystal design approach, using judicious selection of coformers based upon crystal-engineering principles was taken for the cocrystal screening process. This resulted in five new cocrystal systems, four of which are pharmaceutically acceptable. All pharmaceutically acceptable cocrystals were subjected to a comprehensive evaluation of their physicochemical properties, such as thermal properties, stability, dissolution rate and solubility. These were performed alongside that of LEF, in order to compare the physicochemical behaviour of the cocrystals with their parent API. This been performed using a variety of techniques, including DSC, TGA, DVS, XRPD, HPLC, and FTIR.The two most promisingly performing cocrystals were then selected for further experimental formulation studies alongside complementary molecular dynamics simulations; providing a combined approach to probe the relationship between cocrystal-excipient interactions in water and the associated factors determining the dissolution properties of cocrystal formulations. These formulations, with the excipients lactose (LAC) or dibasic calcium phosphate (DCP), were experimentally evaluated for their dissolution rates and solubilities; properties which appeared to be influenced by their formulation. The parameters deduced from MD simulations, such as solvent accessible surface area (SASA), intermolecular hydrogen bonds among formulation ingredients and water, and interaction energy between the API (or cocrystal) and water were found to be essential indicators of cocrystal formulation dissolution performance.In order to strengthen the understanding of the impact of intermolecular and interparticular interactions on their physicochemical behaviour, the cocrystals subjected to formulation studies were also analysed through quantum crystallographic studies. Their related intermolecular interaction energies provide experimental insight into the role cocrystallisation plays in influencing solid-state stability, and therefore physicochemical performance.This was performed via theoretical computational calculations, using PIXEL and Crystal Explorer, of intermolecular interaction energies and their individual energetic contributions to relate these properties to structural assembly and physicochemical properties.<br/
Cocrystals of zonisamide: Physicochemical characterization and sustained release solid forms
No full textWe report four cocrystals of the antiepileptic drug, zonisamide (ZNS), which encounters half-life fluctuation when administered adjunctly with other antiepileptic drugs. Single crystals for two of the novel cocrystals of ZNS were successfully prepared from solvent evaporation experiments and their crystal structures were determined. Pharmaceutically acceptable cocrystals were analyzed for their dissolution rate, solubility and stability to draw conclusions on the impact of cocrystallization on the physicochemical properties of ZNS. It was found that the cocrystals showed lower solubility and dissolution rates and offer potential benefits in the development of sustained release formulations of ZNS which could address issues regarding its half-life fluctuation. Recent attempts to explore newer therapeutic applications have suggested ZNS as a potential drug for weight loss management. In this regard, the cocrystal of ZNS with caffeine, which has also been used in weight loss management, promises potential applications in the development of a novel fixed-dose combination drug which could offer synergistic therapeutic benefits in the treatment of obesity.</p
Cocrystals of leflunomide: Design, structural and physicochemical evaluation
No full textThe use of cocrystallisation as a tool to improve the pharmaceutical profile of the low-solubility drug leflunomide, used in the treatment of arthritis, is herein evaluated. Judicious selection of coformers based upon knowledge-based strategy and crystal engineering principles has resulted in new cocrystals with pyrogallol, 3-hydroxybenzoic acid, 2-picolinic acid, and 2-aminopyrimidine. Characterisation and structure determination of these systems was performed using X-ray diffraction. Crystal structure analysis revealed that the hydrogen bonding in the crystal structures corroborate well with the knowledge-based prediction tool. Physicochemical properties such as thermal behaviour, stability, solubility, and dissolution rate of the pharmaceutically acceptable cocrystals were evaluated to assess their impact on the pharmaceutical profile of leflunomide. When compared with their parent compound leflunomide and the physical mixtures, cocrystals were found to exhibit improved physicochemical properties, showing their potential for development of new solid dosage forms
Single crystal diffraction images for a room temperature data collection on the LEF-PG co-crystal.
No full textA set of diffraction images collected on a Rigaku FRE+ diffractometer, equipped with HF Varimax confocal mirrors and an AFC12 goniometer and HG Saturn 724+ detector diffractometer. The sample is an organic co-crystal that forms part of a study of the LEF active pharmaceutical ingredient with a range of coformers. The structure with the PG coformer shows strong signs of modulation in the diffraction pattern and structure refinement. The model presented in the paper (submitted to Crystal Growth and Design) does not account for any modulation and serves the purpose of a suitable degree of characterisation precision for this article. The authors wish to make the raw data available so that those with interest and experise in handling modulated structures can perform more detailed modelling studies and/or use the data to test software or for training examples.</span
Office based procedures
No full textThis unit of check looks at office based procedures with clinical scenarios demonstrating the important aspects of minor surgeryfor skin lesions, abscesses and ingrown toenails, intrauterine contraceptive device (IUCD) insertion, electrocautery and supraspinatus tendon injection. With any office based procedure it is important to accurately diagnose the problem, explore options for treatment, explain the procedure, and obtain informed consent Clinicians should ensure appropriate training, allow sufficient time, and carry out procedures in a stepwise fashion with adherance to aseptic technique where appropriate. Aftercare should be arranged at the time of the procedure and be clearly articulated to the patient.
The author, Associate Professor Frances Cadden, brings to this unit a wealth of clinical, research and teaching experience. Frances Cadden MBChB, FRACGP, Dip Health Informatics, Cert Skin Cancer Surgery, is General Practitioner and Adjunct Clinical Associate Professor at The University of Notre Dame, Fremantle, Western Australia. Her clinical and research interests include dermatology, office based procedures, computers in practice, women\u27s health, neurofibromatosis and management of cardiovascular risk factors.
Frances would like to thank Associate Professor Tom Brett, GP and Director, General Practice and Primary Health Care Research Unit School of Medicine, The University of Notre Dame, Fremantle, Western Australia for his assistance in producing this unit of check. [Exerpt from editorial by Kath O\u27Connor - published with permission
Insights into the structure-property relationship of pharmaceutical co-crystals: charge density and quantum chemical approaches
No full textA subset of co-crystal systems of the antipyretic and analgesic drug, propyphenazone, are used to probe the nature of the drug···co-former interactions. The experimental electron density distribution, based on very high-resolution single crystal diffraction, has been modelled and an analysis undertaken using Bader's Atoms in Molecules approach. Atomic charges, intermolecular interactions and their energies have been subsequently derived and compared between systems. Complementary theoretical calculations are used to derive interaction energies for intermolecular interactions beyond atom···atom contacts. These permit the deconvolution of the intermolecular interactions into their constituent energy components for a comprehensive analysis. This approach provides an insight into the factors affecting the assembly of the solid state, with the case of pharmaceutical co-crystals being highlighted in this work. Furthermore, this approach enables analysis of the effect of the co-former on various influencing factors that determine the physicochemical properties of these multi-component systems.</p
Cocrystal formulations: Evaluation of the impact of excipients on dissolution by molecular simulation and experimental approaches
No full textCocrystallization has matured into an established technique for fine-tuning the physicochemical properties of active pharmaceutical ingredients (APIs). This technique has been adopted by pharmaceutical drug companies, with increasing numbers of cocrystal-based drug products now entering the market. Surprisingly, however, studies into the formulation aspects of cocrystal-based drugs are relatively few and far between compared to the vast literature on their design, synthesis, and characterization. We herein report the results of our investigations into cocrystal–excipient interactions in water that determine the dissolution properties of cocrystals in formulation by a combination of molecular dynamics (MD) simulation and experimental approaches. Two cocrystals of an antirheumatic drug, leflunomide (LEF) with 3-hydroxybenzoic acid (HBA) and 2-picolinic acid (PIC), were assessed in formulation with the frequently used excipients lactose and dibasic calcium phosphate (DCP). For comparison, the dissolution of neat LEF formulations with these excipients was also evaluated. The parameters deduced from MD simulations, such as solvent-accessible surface area, intermolecular hydrogen bonds among formulation ingredients and water, and interaction energy between the API (or cocrystal) and water were found to be essential indicators in the prediction of cocrystal formulation dissolution trends. It was found that the presence of lactose as an excipient improved the dissolution of the cocrystal formulation compared to the neat cocrystals, most notably for the LEF-PIC cocrystal. In contrast, DCP was seen to have a detrimental effect on the dissolution of cocrystal formulations, all exhibiting lower dissolution than their neat cocrystal counterparts and LEF. Careful analysis of these results revealed that the nature of the excipient plays a significant role in the dissolution properties. While the improved dissolution of the lactose formulations was attributed to its hydrophilic nature, the ionic and hydrophobic nature of DCP was likely responsible for its detrimental effect. The results of the MD simulations were found to be in excellent agreement with the experimentally observed dissolution hierarchy
I¿M FINE, I¿M BETTER, DON¿T WORRY ABOUT ME A New Investigative Theater Piece About Student Mental Health
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Orpheus Retold: A History and A Journal
No full textAn exploration of the work of major artists and their use of Orpheus in their work, ending with Thomas Guthrie in his 12th &13th January 2018 performances. The first half of the paper looks at instances of generic creation or re-invention by an artist whose work centers on the figure of Orpheus. The second half is a rehearsal journal maintained by the author as he prepared to play Orpheus in 'L'Orfeo' by Monteverdi, directed by Thomas Guthrie
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