Discovered two polymorphs and two solvates of lamotrigine-tolfenamic acid salt: Thermal behavior and crystal morphological differences

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In this study, the crystal structures of 1:1 theophylline–ferulic acid cocrystal polymorphs are reported for the first time. Interestingly, both forms crystallize in the same space group but with a different number of molecules in the asymmetric unit (form I = 2; form II = 4). The two polymorphs show distinct crystal morphology, demonstrating prism and rod single crystals, respectively. Theoretical calculations are performed to predict their morphology and thermodynamic stability (form I > form II). The prediction result agrees well with the measured pharmaceutical properties. Form I presents better hygroscopic stability (RH < 95%), slower dissolution, and lower solubility (1.06 ± 0.03, 1.63 ± 0.01, 1.30 ± 0.08 and 4.09 ± 0.05 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions) over form II (8.45 ± 0.33, 2.41 ± 0.17, 3.46 ± 0.26 and 28.71 ± 0.87 mg/mL in water, pH = 1.2, pH = 4.5 and pH = 6.8 buffered solutions). In summary, this work elucidates the experimental findings with relevant predictions systematically and enriches our understanding of the structure–property relationship of the theophylline cocrystal system.

Section: Thermodynamic Relationship Of the Cocrystal Polymorphs 331 T...mentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Two Polymorphic Cocrystals of Theophylline with Ferulic Acid

Liu

Chan²,

et al. 2023

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“…Crystalline polymorphism originating from multiple packing arrangements or different configurations of the same compound is a crucial and ubiquitous phenomenon of the active pharmaceutical ingredients (APIs), and about 80% of APIs have been estimated to possess more than one polymorph. − Polymorphism has a profound impact on the solubility, dissolution rate, stability, and also on efficacy properties of APIs and the formulated products. − Some polymorphic APIs, such as carbamazepine in Tegretol, mebendazole in Vermox, warfarin in Coumadin, and ritonavir in Norvir, are known to undergo crystalline phase transformation during their processing and formulation. − Hence, it is vital to explore and identify possible polymorphs as early as possible and confirm the preponderant crystalline form, which provides a stable baseline for subsequent drug development. Furthermore, exploring and understanding the relationship between polymorphic structures and properties facilitate the medications better in clinical trials and marketing, which is the tireless driving force for the pharmaceutical industry.…”

Section: Introductionmentioning

confidence: 99%

Toltrazuril Polymorphs and the Effect on Hygroscopicity and Dissolution Rate

Zhang,

Chen,

Lin

et al. 2024

The different arrangement and/or conformation polymorphs frequently generate a pivotal difference in hygroscopicity, stability, and dissolvability. For the purpose of screening the preponderant polymorphs of toltrazuril (Tol) with the desired physicochemical property, two polymorphs (Forms I and II) are screened out, and structure−property relationships are meticulously explored. Interaction energy analyses show that Form II is not stronger than Form I in packing due to the lower intermolecular lattice energy. And the dissolution rate of Form II is higher than that of Form I because the loosened packing in Form II would facilitate diffusion and dissolution. The percentage of mass change of Forms I and II in hygroscopicity at 95% RH is less than 0.2%, and they are both nonhygroscopic crystalline forms. Interestingly, the weight increase of Form II at 95% RH is about twice that of Form I, which might be due to plentiful −CF 3 groups exposed on the facet (001) (about 72% area ratio) of Form II possessed a weakly negatively charged region to capture a few H 2 O molecules in surroundings. Overall, Form II not only exhibits higher solubility and dissolution rate relative to Form I, but also possesses good stability (high temperature, humidity, and light); hence, Form II might be an advantageous candidate crystalline form. This work may provide inspirational thinking for predicting the trends in hygroscopicity and dissolvability of polymorphic APIs and avoiding compromising upcoming pharmaceuticals.

“…However, the research on complex salt polymorphs systems is still lacking. 14 Nicorandil (2-[(pyridine-3-yl) formamide] ethyl nitrate, NIC), an orally efficacious vasodilatory drug being used to treat angina, acts as the opener of ATP-sensitive potassium channels through the nicotinamide group and the NO donor by nitrate moiety. 15 The dual-mechanism action makes NIC both an arterial and a venous dilator.…”

Section: Introductionmentioning

confidence: 99%

Insight into the Structure and Property Diversity of Four Nicorandil Oxalate Salt Polymorphs Based on Experiments and Quantum Chemistry Study

Wang,

Guo,

et al. 2024

This contribution presents a novel and comparative study on the relationship between the crystal structure and the property diversity of a complex polymorph system of nicorandil oxalate (NIC-OA) salts. Single-crystal structures of four salt polymorphs with 1:1 stoichiometry were prepared, and crystal structure analysis revealed the difference of configuration and tautomer structure among those polymorphs. Bulk samples of three polymorphs (S1, S3 and S4) were successfully isolated from ethanol/water solution, while the metastable form S2 could not be obtained. Detailed property studies including solvent-mediated polymorph transformation, physical-chemical stability, and intrinsic dissolution of those polymorphs were conducted. Phase transformation from S3 to S4 in high-humidity conditions and accelerated conditions was driven by lowering of lattice energy. High hygroscopicity would accelerate the process. All polymorphs showed better chemical stability and greater dissolution rate compared to NIC. The binding energy between NIC and oxalate acid and crystal-solvent interaction were studied to investigate the correlation between polymorph packing and bulk property. The chemical stability of NIC was affected by the diversity in cation–anion binding modes, while the dissolution process of the polymorphs was influenced by the crystal face differences and the interaction between the crystal and solvent. It is the first time that four crystalline forms of NIC-OA are reported, and the structure and property diversity among these salt polymorphs are revealed with experiments and the quantum chemistry method, which provided new insights into the NIC-OA polymorphs in the crystal engineering field and might contribute to the property research of the complex pharmaceutical polymorphism system.