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New cocrystals of ezetimibe with L-proline and imidazole

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New cocrystals of ezetimibe with L-proline and imidazole

 

CrystEngComm, 2014, Advance Article
DOI: 10.1039/C4CE01127A, Paper
Manishkumar R. Shimpi, Scott L. Childs, Dan Bostrom, Sitaram P. Velaga
 
 *Corresponding authors
aDepartment of Health Sciences Luleå University of Technology, Luleå, Sweden 
bRenovo Research, Atlanta, USA 
cThermal Energy Conversion Laboratory, Department of Applied Physics and Electronics, Umeå University, Umeå S-90187, Sweden
 
Two new cocrystals of ezetimibe were identified and scale-up. Ezetimibe-proline cocrystal showed improved apparent solubility and physical stability.
 
 
The objectives of the study were to screen and prepare cocrystals of anti-cholesterol drug ezetimibe (EZT) with the aim of increasing its solubility and dissolution rate. Thermodynamic phase diagram based high throughput screening was performed using wet milling/grinding or solution crystallization methods. A large number of coformers were tested and the resulting solids were preliminarily characterized using X-ray powder diffraction (PXRD) and Raman spectroscopy. Potential cocrystals of EZT with L-proline and imidazole and a solvate formamide were identified in the screening experiments. The cocrystal hits were further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solution Proton nuclear magnetic resonance spectroscopy (1H-NMR) and single crystal XRD. The dissolution properties and stability of cocrystals were determined. Single-crystal X-ray diffraction data were obtained for EZT, EZT-IMI cocrystal and formamide solvate of ezetimibe. All three systems were crystallized in non-centrosymmetric orthorhombic space group P212121 with Z = 4. Robust O–HO, O–HN, N–HO and C–HO hydrogen bonds played an important role in all these crystal structures. EZT-PRO cocrystal showed improved apparent solubility and solid state stability.
 

1 Comment

  1. larryhbern says:

    Reblogged this on Leaders in Pharmaceutical Business Intelligence and commented:
    Interesting explanation of improvement in an existing drug.

    Larry H Bernstein, MD, FCAP

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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