Disappearing Polymorphs Revisited

Bučar, Dejan‐Krešimir; Lancaster, Robert W.; Bernstein, Joel

doi:10.1002/anie.201410356

Cited by 303 publications

(281 citation statements)

References 120 publications

(107 reference statements)

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“…4 Polymorphic purity is essential for quality control, as the presence of any undesirable polymorphs or polymorphic transformation during manufacturing processes induces substantial economic loss (for example, more than $250 million loss due to an unknown more stable form of ritonavir, an antiviral compound for AIDS). 5 The evaporation crystallisation processes of butyl paraben in liquid-liquid phase separation are very different on glass, metal and PTFE surfaces, 6,7 and ibuprofen changes morphology on Al, Au or self-assembled -CH 3 , -OH, and -COOH monolayers. 8 On a siloxane monolayer template, a metastable polymorph of 1,3-bisĲm-nitrophenyl)urea appeared.…”

Section: Introductionmentioning

confidence: 99%

Selective crystallisation of carbamazepine polymorphs on surfaces with differing properties

et al. 2017

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Surface-induced nucleation of carbamazepine (CBZ) in ethanol was investigated with different surface materials: glass, polytetrafluoroethylene (PTFE) and tin. The introduction of foreign surfaces with different areas and surface chemistries into the solution has an impact on the crystal morphology and polymorphic form (Form II or III). With an increase in supersaturation, a higher possibility of crystallisation of CBZ metastable Form II was observed, as expected. Increasing the number of inserts resulted in a direct increase in the surface area available for heterogeneous nucleation. The increase in surface area resulted in the greater possibility of obtaining the metastable Form II of CBZ. The stable Form III preferred to nucleate on tin rather than on glass and PTFE. The results indicate that the two different polymorphs of CBZ can be selectively crystallised out from solution with the aid of a foreign surface. The kinetic mechanism of heterogeneous nucleation of the different polymorphs induced by foreign surfaces was discussed. The potential applications will be used to control and design the crystallisation process.

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Section: Introductionmentioning

confidence: 99%

Selective crystallisation of carbamazepine polymorphs on surfaces with differing properties

et al. 2017

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“…This behavior suggests a delicate balance in the reaction kinetics and thermodynamics that govern the formation of one phase over the other. 16 The sheets within this crystal structure are comprised of pentagonal bipyramidal Ca 2+ ions, which are each coordinated to two water molecules in a cis geometry and five carboxylate oxygen atoms from the bridging olsalazine units.…”

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confidence: 99%

Calcium Coordination Solids for pH‐Triggered Release of Olsalazine

et al. 2017

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Calcium coordination solids were synthesized and evaluated for delivery of olsalazine (H4olz), an anti‐inflammatory compound used for treatment of ulcerative colitis. The materials include one‐dimensional Ca(H2olz)⋅4 H2O chains, two‐dimensional Ca(H2olz)⋅2 H2O sheets, and a three‐dimensional metal‐organic framework Ca(H2olz)⋅2DMF (DMF=N,N‐dimethylformamide). The framework undergoes structural changes in response to solvent, forming a dense Ca(H2olz) phase when exposed to aqueous HCl. The compounds Ca(H2olz)⋅x H2O (x=0, 2, 4) were each pressed into pellets and exposed to simulated gastrointestinal fluids to mimic the passage of a pill from the acidic stomach to the pH‐neutral intestines. All three calcium materials exhibited a delayed release of olsalazine relative to Na2(H2olz), the commercial formulation, illustrating how formulation of a drug within an extended coordination solid can serve to tune its solubility and performance.

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“…These disappearing polymorphs have led to legal controversy regarding how broadly a patent's protection extends when multiple crystal structures exist [57]. In general, one patents a particular crystallization process which therefore patents a particular crystal form of an API.…”

Section: Legal Controversy and Disappearing Polymorphsmentioning

confidence: 99%

“…When the form 1 crystal patent expired, generic companies following the original patent always produced form 2, which was still patented by Glaxo. As a result, generic production was prevented until the second patent expired in 2002 [57]. Glaxo effectively extended the patent on their lucrative drug Zantac by 7…”

Section: Legal Controversy and Disappearing Polymorphsmentioning

confidence: 99%

“…The most famous case of this late appearance was Abbott's HIV drug ritonavir. The drug was originally formulated in a semisolid gel capsule based on the only known solid form at the time (Form I) [50,57]. However, the globally stable Form II crystal ultimately precipitated out of the capsule due to a lower solubility in the hydroalcoholic solution and led to failed dissolution in patients.…”

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confidence: 99%

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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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Disappearing Polymorphs Revisited

Cited by 303 publications

References 120 publications

Selective crystallisation of carbamazepine polymorphs on surfaces with differing properties

Selective crystallisation of carbamazepine polymorphs on surfaces with differing properties

Calcium Coordination Solids for pH‐Triggered Release of Olsalazine

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

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