Pyrazinamide Polymorphs: Relative Stability and Vibrational Spectroscopy

Cherukuvada, Suryanarayan; Thakuria, Ranjit; Nangia, Ashwini

doi:10.1021/cg1004424

Cited by 105 publications

(122 citation statements)

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“…Melting point by DSC Differential Scanning Calorimetry (DSC) can confirm the purity and monitor phase transformations. [58][59] The melting point of the cocrystals was found to be lower than that of SMT except that for SMT-OA, which is higher because it is a salt ( Table 6). Aromatic acids and amide group containing coformers, e.g.…”

Section: Ft-ir Spectroscopymentioning

confidence: 98%

Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

Suresh

Minkov

Namila

et al. 2015

Crystal Growth & Design

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The sulfamethizole antibiotic drug has rich hydrogen bond functionalities (donors: amine NH 2 and imine NH; acceptors: sulfonyl O, thiazolidine N and S, and imidine N) which makes it a functionally diverse molecule to form cocrystals. A cocrystal screen of sulfamethizole (SMT) with COOH, NH 2 , pyridine and CONH 2 functional group containing coformers, e.g.paminobenzoic acid (PABA), vanillic acid (VLA), p-aminobenzamide (ABA), 4,4-bipyridine (BIP), suberic acid (SBA), oxalic acid (OA), and adipic acid (ADP), resulted in six cocrystals and one salt namely, SMT-ADP (1:0.5), SMT-PABA (1:1), SMT-VLA (1:1), SMT-ABA (1:1), SMT-BIP (1:1), SMT-SBA (1:0.5), and SMT-OA (1:1). The novel crystalline adducts were synthesized by liquid-assisted cogrinding and isothermal solvent crystallization. In addition to single-crystal X-ray diffraction, the phase composition of the powder samples was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Hydrogen bonding interactions between the coformers and SMT are analyzed as six different synthons. In addition to strong N-H···O and O-H···N H-bonds, the cocrystal structures are sustained by weak C-H···O hydrogen bonds. The not so common chalcogen-chalcogen (S···O) type II intermolecular interaction in SMT-ADP cocrystal and chalcogen-nicogen (S···N) type II interaction in SMT-BIP cocrystal were observed. The products were characterized by vibrational spectroscopy to obtain information on the strengths of the intermolecular interactions. Solubility and dissolution experiments on SMT-ADP, SMT-SBA and SMT-OA showed lower intrinsic dissolution rate (IDR) and equilibrium solubility compared to SMT in 0.1N HCl medium, which is ascribed to stronger N-H···O, N-H···N, and O-H···O hydrogen bonds and better crystal packing. The decreased IDR could be useful in controlled/extended release of SMT to improve therapeutic activity of the drug by minimizing its fast systemic elimination in vivo. Furthermore, we observed that SMT-OA salt is formed spontaneously when the components were mixed in acidic medium (0.1N HCl), whereas in neutral medium (phosphate buffer) no SMT-OA salt formation was observed.

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Section: Ft-ir Spectroscopymentioning

confidence: 98%

Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

Suresh

Minkov

Namila

et al. 2015

Crystal Growth & Design

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Section: What Factors Lead To Different Polymorphs?mentioning

confidence: 99%

“…A complicating factor in the search for commercially viable solid phases is that the stable forms of a material can change based on external factors such as temperature [18,46,[92][93][94][95][96][97][98][99][100][101][102][103], pressure [76][77][78][79][80][81] and humidity [47,82,83,200]. A complete experimental mapping of all possible solid forms for a given material would therefore require screening at every condition the material will encounter.…”

Section: Introductionmentioning

confidence: 99%

“…Temperature-mediated polymorphic transformations involve a crystal structure that is globally stable at low temperatures becoming metastable at higher temperatures and subsequently restructuring to a more stable form. Polymorphs that reversibly change stability order as a function of temperature in this manner are referred to as enantiotropically related forms and have been observed experimentally for a number of real organic molecules [18,46,[92][93][94][95][96][97][98][99][100][101][102][103].…”

Section: Introductionmentioning

confidence: 99%

“…Structures that can be isolated at one temperature may become kinetically unstable at higher temperatures. Furthermore, the thermodynamically most stable structure can also change with the temperature [18,46,[92][93][94][95][96][97][98][99][100][101][102][103] or pressure [76][77][78][79][80][81] leading to new observable forms.The complete set of all 'observable polymorphs' for a given material therefore consists of all structures that can be produced from any crystallization method in any thermodynamic state of practical interest to the material. The challenge for experimental polymorph screening procedures is to cover a large enough range within this multidimensional space to achieve high confidence that another undiscovered form, which could compromise the performance of the product, will not be observed.…”

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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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Solid‐State Form Screen of Cardiosulfa and Its Analogues

Kumar

Rana

Nangia

2013

Chemistry An Asian Journal

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Cardiosulfa is a biologically active sulfonamide molecule that was recently shown to induce abnormal heart development in zebrafish embryos through activation of the aryl hydrocarbon receptor (AhR). The present report is a systematic study of solid-state forms of cardiosulfa and its biologically active analogues that belong to the N-(9-ethyl-9H-carbazol-3-yl)benzene sulfonamide skeleton. Cardiosulfa (molecule 1; R(1) = NO2, R(2) = H, R(3) = CF3), molecule 2 (H, H, CF3), molecule 3 (CF3, H, H), molecule 4 (NO2, H, H), molecule 5 (H, CF3, H), and molecule 6 (H, H, H) were synthesized and subjected to a polymorph search and solid-state form characterization by X-ray diffraction, differential scanning calorimetry (DSC), variable-temperature powder X-ray diffraction (VT-PXRD), FTIR, and solid-state (ss) NMR spectroscopy. Molecule 1 was obtained in a single-crystalline modification that is sustained by N-H⋅⋅⋅π and C-H⋅⋅⋅O interactions but devoid of strong intermolecular N-H⋅⋅⋅O hydrogen bonds. Molecule 2 displayed a N-H⋅⋅⋅O catemer C(4) chain in form I, whereas a second polymorph was characterized by PXRD. The dimorphs of molecule 3 contain N-H⋅⋅⋅π and C-H⋅⋅⋅O interactions but no N-H⋅⋅⋅O bonds. Molecule 4 is trimorphic with N-H⋅⋅⋅O catemer in form I, and N-H⋅⋅⋅π and C-H⋅⋅⋅O interactions in form II, and a third polymorph was characterized by PXRD. Both polymorphs of molecule 5 contain the N-H⋅⋅⋅O catemer C(4) chain, whereas the sulfonamide N-H⋅⋅⋅O dimer synthon R2(2)(8) was observed in polymorphs of 6. Differences in the strong and weak hydrogen-bond motifs were correlated with the substituent groups, and the solubility and dissolution rates were correlated with the conformation in the crystal structure of 1-6. Higher solubility compounds, such as 2 (10.5 mg mL(-1)) and 5 (4.4 mg mL(-1)), adopt a twisted confirmation, whereas less-soluble 1 (0.9 mg mL(-1)) is nearly planar. This study provides practical guides for functional-group modification of drug lead compounds for solubility optimization.

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Pyrazinamide Polymorphs: Relative Stability and Vibrational Spectroscopy

Cited by 105 publications

References 52 publications

Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

Novel Synthons in Sulfamethizole Cocrystals: Structure–Property Relations and Solubility

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

Solid‐State Form Screen of Cardiosulfa and Its Analogues

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