Polymorphisms and Patent, Market, and Legal Battles:  Cefdinir Case Study

Cabri, Walter; Ghetti, Paolo; Pozzi, Giovanni; Alpegiani, Marco

doi:10.1021/op0601060

Cited by 76 publications

(56 citation statements)

References 8 publications

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“…[2][3][4][5] The choice of the wrong crystal form thus causes severe problems and can cost the pharmaceutical company large amounts of money in 'damage limitation'. 6,7 In additional to 'pure' polymorphs, crystals may contain solvent of crystallisation resulting in various solvate forms, or hydrates in the special case of the inclusion of water. 8 The incorporated solvent can vary in its interaction with the host molecules in the crystal and exhibit varying stability towards desolvation.…”

Section: Introductionmentioning

confidence: 99%

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

Fucke

McIntyre

Wilkinson

et al. 2012

Crystal Growth & Design

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'New insights into an old molecule : interaction energies of theophylline crystal forms.', Crystal growth design., 12 (3). pp. 1395-1401. Further information on publisher's website:http://dx.doi.org/10.1021/cg201499sPublisher's copyright statement:This document is the Accepted Manuscript version of a Published Work that appeared in nal form in Crystal growth design, copyright c American Chemical Society after peer review and technical editing by the publisher. To access the nal edited and published work see http://dx.doi.org/10.1021/cg201499sAdditional information:Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO• the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. The asthma therapeutic theophylline exists in at least three anhydrous polymorphs and a monohydrate. The single-crystal X-ray structure of the high-temperature polymorph form I is presented for the first time and the energetic relationship between forms I and II is investigated using the partial charges and chemical hardness analysis (PACHA) algorithm. It is shown that the interactions in the form I crystal network are stronger, especially the hydrogen bond. The singlecrystal neutron structure of the monohydrate demonstrates static disorder of the water molecule as well as dynamic disorder of the methyl groups. PACHA investigations based on the neutron coordinates reveal that the homomeric interactions in this form are stronger than the interaction of the water with the host molecules. The dehydration of the hydrate should thus leave the theophylline network intact, explaining the isomorphic powder X-ray diffractograms of the monohydrate and its dehydrated form III.

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Section: Introductionmentioning

confidence: 99%

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

Fucke

McIntyre

Wilkinson

et al. 2012

Crystal Growth & Design

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“…In fact API exhibiting structural polymorphism received regulatory approval for only one single crystal form or a specific polymorph. An example is Cefdinir, broad-spectrum antibiotic, for which a lot of companies (Fujisawa, Biochemie, ACS Dobfar, Orchid, Abbott, Aurobindo, Novartis, Lupin, Rambaxy) patented 11 polymorphs related to 5 crystalline forms [118], atorvastatin calcium -a statin lowering blood cholesterol, for which more than 60 solid forms have been patented [119], piroxicam -a non-steroidal antiinflammatory drug, synthesized in more than 50 forms [120] and sulfathiazole a local antimicrobial agent for which more than 100 forms have been described [121]. From among multicomponents the one showing the optimum properties from the biological activity point of view is chosen.…”

Section: Polymorphismmentioning

confidence: 99%

“…However, sometimes the estimation of the amount of polymorphs in a mixture on the basis of these parameters can be misleading [156]. It is known that in some cases SS NMR was helpful in explaining contradictions concerning polymorphism following from IR, XRD and DSC studies [118]. A briliant example indicating the usefulness of SS NMR is cefinidir, a broad-spectrum antibiotic, proven effective for common bacterial infections of the ear, sinus, throat, and skin.…”

Section: Form II Form Iiimentioning

confidence: 99%

“…The use of XRPD and IR was not sufficient and Abbott's 'new polymorph' discovered using these techniques in 2003 was proved to be not a polymorph, but a pyridinium salt. [118]. Up to now no examples of such spectacular NQR applications had been given, but it does not mean that the potential of this method will not be exploited for this purpose in future.…”

Section: Form II Form Iiimentioning

confidence: 99%

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Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

Latosińska¹,

Latosińska²

2011

Drug Discovery and Development - Present and Future

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“…Similar examples of patent extension through discovering a new crystal form have been reported for Paroxentine Hydrochloride (Paxil R ) [60] and Cefdinir [61]. Large pharmaceutical companies are actively looking for new crystal structures to extend patents for this reason.…”

Section: Legal Controversy and Disappearing Polymorphsmentioning

confidence: 63%

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

Dybeck

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AcknowledgementsI would like to acknowledge the guidance and support provided by my advisor MichaelShirts. I would also like to thank Levi Naden, Natalie Schieber, Nate Abraham and the entire Shirts group for their help and technical support during my research. I also would like to acknowledge the UVA high performance computing team for the computational resources necessary to complete this work. Finally, I would like to acknowledge the endless love and support that my friends and family provided me during this challenging Ph.D. journey.iii AbstractThe presence of multiple stable crystal structures in solid organic materials can limit their commercial viability when two or more observable polymorphs exhibit markedly different physical properties. Unintended restructuring events have hindered pharmaceutical solid form development in numerous therapeutic candidates and have led to costly market recalls.Conversely, intentional synthesis of a metastable form has led to significantly more favorable performance in numerous materials.Current computational methods for predicting polymorphic behavior evaluate candidate crystal structures based on the minimized lattice energy. However, these static lattice energybased approaches generate far more lattice energy minima than there are experimentally observed structures. Thermal motion of the crystals under working conditions has the potential to explain why many of these lattice minima are not observed experimentally. Lattice minima that are identified from a static crystal structure prediction can ultimately be unstable at experimental conditions through either temperature-mediated stability reranking, kinetic interconversion of multiple minima, or inaccuracies of the energy function in producing the real crystal ensemble.In this work, we explore the role of thermal motion in eliminating candidate crystal structures using fully atomistic molecular dynamics simulations. Enthalpically favorable structures with low entropy will become unfavorable at high temperatures through temperaturemediated stability reranking. Our simulations correctly identify the high temperature solid form as having a larger entropy than the low temperature form in twelve small molecule organic systems with known temperature-mediated transformations. The estimated entropy differences in the classical point-charge potential are significantly closer to experimental measurements than estimated enthalpy differences. This result suggests that entropy difference estimates are less sensitive to the complexity of the simulation potential than the corresponding enthalpy estimates. We additionally find that a cheaper harmonic approximation provides a sufficient estimate of entropic contributions in small rigid molecules. However, entropies with iv the harmonic approximation diverge from molecular dynamics-derived entropies in systems with multiple rotatable degrees of freedom or dynamically disordered crystalline structures.We additionally probe the sensitivity of the stability estimates to the energy function ...

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Polymorphisms and Patent, Market, and Legal Battles: Cefdinir Case Study

Abstract: The ongoing patent battle relating to Cefdinir polymorphism and crystalline forms is described from a scientific point of view. This case study illustrates some of the strategies adopted by generic bulk manufacturers to challenge originator's patents on polymorphic forms.

Cited by 76 publications

References 8 publications

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

New Insights into an Old Molecule: Interaction Energies of Theophylline Crystal Forms

Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

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