Effects of crystal habit on the sticking propensity of ibuprofen—A case study

Hooper, Debbie; Clarke, Fiona; Docherty, R.; Mitchell, John C.; Snowden, Martin J.

doi:10.1016/j.ijpharm.2017.08.091

Cited by 31 publications

(21 citation statements)

References 35 publications

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“…The recent development of digital design workflows based upon computational molecular modelling (11)(12)(13)(14)(15) have highlighted their potential utility in terms of assessing directed assembly and solvation (10)(11)(12); solid-state and surface properties (13)(14)(15)(16)(17) and formulation properties (18)(19)(20) and, through this, have provided a holistic framework for pharmaceutical product design encompassing molecular, solid-state, surface and particulate properties. This study builds upon and integrates these capabilities through a detailed examination of the structure and energetics associated with the polymorphic behavior of ritonavir forms I and II.…”

Section: Introductionmentioning

confidence: 99%

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties

et al. 2021

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Purpose Application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing. Methods Molecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields. Results The form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability. Conclusion Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

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Section: Introductionmentioning

confidence: 99%

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties

et al. 2021

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“…Samples of the active substance may differ in the degree of wettability, compressibility, hygroscopicity, stability, solubility and other physicochemical properties, which ultimately affects the quality of the final product. That is why these moments are currently receiving a lot of attention [4,5,11,12,18,20]. The crystalline modifications of N-(4-trifluoromethylphenyl)-4-methyl-2.2dioxo-1H-2λ6.1-benzothiazine-3-carboxamide presented in this work are unique in that they differ only in appearance, whereas the X-ray diffraction analysis showed their identical molecular and crystalline structure.…”

Section: №41 Page 46-51mentioning

confidence: 88%

“…Different in strength and toxicity, different polymorphs and stereoisomers are able to form antibacterial drugs (chloramphenicol, ampicillin, tetracycline), local anesthetics and analgesics (ibuprofen, ketoprofen), hormonal and cardiovascular drugs methylprednisolone, insulin, progesterone [2,4,9,10,11,20]. However, in recent years, no less important characteristic that significantly affects the properties of biologically active substances and drugs, their habit (appearance) -needles, plates, cubes, prisms, shapeless crystals and others.…”

Section: №41 Page 46-51mentioning

confidence: 99%

Investigation of pharmacokinetics of N-(4-trifluoromethylphenyl)-4-methyl-2.2-dioxo-1H-2λ6.1-benzothiazine-3-carboxamide various crystalline modifications in vivo

Bondarenko

Волощук

Ларіонов

et al. 2020

Biomed. and Biosoc. Anthrop.

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The phenomenon of polymorphism, inherent in many biologically active substances, including drugs, is an extremely serious problem that requires close attention and comprehensive study. Various crystalline modifications of biologically active compounds, as well as excipients can dramatically change the biopharmaceutical properties and pharmacological characteristics of already known drugs. The bioactive compound N-(4-trifluoromethylphenyl)-4-methyl-2.2-dioxo-1H-2λ6.1-benzothiazine-3-carboxamide was obtained by bioisosterical substitution in the molecule of known non-steroidal anti-inflammatory drugs of the oxycam group in the form of three polymorphic modifications of the crystal. sticks (form A), plates (form B) and blocks (form C) with varying degrees of analgesic and anti-inflammatory effects. The aim of the study was to investigate the pharmacokinetic profile of these polymorphic forms of benzothiazine-3-carboxamide derivative by their oral administration in vivo. The concentration of compounds in the blood of mice was determined by HPLC and the main pharmacokinetic parameters were calculated. It was found that the polymorphic form in the form of plates (form B), in particular, having the largest surface area of crystals, has differences mainly at the stage of absorption with corresponding changes in absorption values, maximum concentration and time of its achievement, has the highest bioavailability and rapid elimination which correlates with the most optimal pharmacological and toxicological characteristics of this compound in comparison with other crystalline forms. This makes it possible to recommend the most active and safe polymorphic form of the compound (form B) for in-depth preclinical study and possible clinical trials as an analgesic and anti-inflammatory agent.

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“…All these parameters one way or another inevitably affect the quality of the final product. Hence, apparently, there is the increased attention to their study [32][33][34][35][36][37][38]. At the same time, no less interesting, and in some ways even a more important medical aspect of the problem we are considering remains in the background.…”

Section: Evaluation Of the Biological Propertiesmentioning

confidence: 99%

Crystal Habits and Biological Properties of N-(4-Trifluoromethylphenyl)-4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamide

et al. 2019

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In order to study polymorphic modifications of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide, which is of interest as a promising analgesic, its three colorless crystal forms with different habitus have been obtained: sticks of ethyl acetate, plates of meta-xylene and blocks of ortho-xylene. However, the X-ray diffraction analysis has shown that all the forms studied have the identical molecular and crystal structure in spite of such significant differences in appearance. Moreover, pharmacological tests have revealed significant differences in the analgesic activity in these samples (a total of five experimental models were used: “acetic-acid-induced writhing”, “hot plate”, “thermal irritation of the tail tip” (tail-flick), “tail electric stimulation” and “neuropathic pain”), acute toxicity and the ability to cause gastric damage. As a result, only the plate crystal form of N-(4-trifluoromethylphenyl)-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide is recommended for further studies. Thus, it has been proven that the habitus of crystals is an important characteristic of the drug substance and is able to have a noticeable effect on its biological properties. Changes in habitus should be considered as a guide to the mandatory verification of at least the basic pharmacological parameters of the new form regardless of whether the molecular and crystal structure changes.

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Effects of crystal habit on the sticking propensity of ibuprofen—A case study

Cited by 31 publications

References 35 publications

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties

Molecular, Solid-State and Surface Structures of the Conformational Polymorphic Forms of Ritonavir in Relation to their Physicochemical Properties

Investigation of pharmacokinetics of N-(4-trifluoromethylphenyl)-4-methyl-2.2-dioxo-1H-2λ6.1-benzothiazine-3-carboxamide various crystalline modifications in vivo

Crystal Habits and Biological Properties of N-(4-Trifluoromethylphenyl)-4-Hydroxy-2,2-Dioxo-1H-2λ6,1-Benzothiazine-3-Carboxamide

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