Cocrystallization of lenvatinib and temozolomide to improve the performance in terms of stability, dissolution, and tabletability

Wang, Zhi-Qing; Dai, Xia-Lin; Gu, Dai-Lin; Wu, Chao; Lu, Tong-Bu; Long, Xiang-Tian; Chen, Jia-Mei

doi:10.1039/d3ce00473b

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…Combinational therapies [ 1,2 ] are increasingly becoming a trend in clinic due to the improvement of the therapeutic effect and reduction of patient medication costs. Salt formation between two ionizable drugs, as one of the common strategies for combination medication, could enhance the therapeutic effect of the drugs, allow for combination of two drugs in a single preparation with lowering the frequency of drug administration, [ 3,4 ] and modulate their physicochemical properties such as stability, solubility and bioavailability etc. [ 5,6 ] Thus, salt formation between two ionizable drugs is a hot research topic in the field of crystallization.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Improvements of Physicochemical Properties and Anti‐Microbial Activity of Berberine via Forming Salt with Gallic Acid

Chen,

Yang,

Ren

et al. 2024

Cryst. Res. Technol.

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Implementing combination medication through crystal engineering technology receives increasing attention from researchers due to improvements in the clinical treatment effects as well as the physicochemical properties of the drug. Berberine (BER) is commonly used to treat gastroenteritis and bacterial diarrhea, with the problems of poor solubility and low oral bioavailability. Recently, it is found that gallic acid (GA) also has anti‐inflammatory and anti‐bacterial activities. Therefore, if the above‐mentioned two ingredients can be combined, it is possible to enhance the therapeutic effects and physicochemical properties of BER. Inspired by this, 8‐hydroxy‐7,8‐dihydroberberine (8H‐HBER) in this study is employed to react with gallic acid to yield BER gallate dihydrate (2BER‐2GA‐2 W). Furthermore, dissolution experiments demonstrate that the maximum apparent solubility (MAS) of 2BER‐2GA‐2 W in dilute hydrochloric acid solution medium (pH 1.2) has increased by 7 times compared to the commercial form of BER, because of avoiding the common‐ion effect. Moreover, 2BER‐2GA‐2 W has also obviously enhanced stability relative to the commercial form of BER. In addition, 2BER‐2GA‐2 W has a better inhibitory effect on Staphylococcus aureus (S. aureus) relative to the commercial form of BER. Hence, 2BER‐2GA‐2 W will be a promising solid‐state form of BER for its further development.

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Section: Introductionmentioning

confidence: 99%

Simultaneous Improvements of Physicochemical Properties and Anti‐Microbial Activity of Berberine via Forming Salt with Gallic Acid

Chen,

Yang,

Ren

et al. 2024

Cryst. Res. Technol.

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“…Beyond the fact that cocrystals are solid forms different from the solid reactants they originate, literature also lately reported several examples of polymorphic cocrystals − and solvate cocrystals. − These are mostly produced by conventional methods. Though the potentiality of scCO 2 -based techniques to control polymorphism has been addressed for homocrystals, − only few articles reported polymorphism of cocrystals, , one for the production of a solvate, and none has ever reported the obtention of a cocrystal solvate.…”

Section: Introductionmentioning

confidence: 99%

Unraveling a Unique Metastable Phase of a Proxyphylline Cocrystal Exclusively Produced by Compressed Carbon Dioxide

Ercicek,

Marchivie,

Nimod

et al. 2024

Crystal Growth & Design

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In this work, racemic proxyphylline ((±)-PXL, a chiral drug) was cocrystallized for the first time with 4-hydroxybenzoic acid (4-HBA) from three solvents (acetone, ethyl acetate, and isobutanol) and using CO2 as an antisolvent. The obtained solid forms were compared to those produced by liquid-assisted grinding (LAG). It is shown that though both methods produce a racemic compound (±)-PXL1:4-HBA1 cocrystal, LAG promotes the crystallization of an orthorhombic Pna21 form (Phase I), whereas CO2-assisted crystallization gives rise to an original monoclinic C2/c form with partial inclusion of CO2 and water molecules (Phase II). The structure of Phase II originates from this inclusion since this phase is never obtained in the absence of CO2. Concomitant cocrystallization of Phase I and Phase II occurs during CO2-assisted crystallization in proportions that vary with solvents and temperature. Our study shows that Phase II transforms progressively into Phase I upon storage or heating.

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“…Additionally, multicomponent solvates are also applied to improve the API’s physiochemical properties, such as hydration stability, enhanced dissolution, low melting point, and enhanced solubility . Therefore, if the multicomponent solvates are the final solid forms, the investigation of stability and desolvation conditions of the solvates may need important and crucial attention. It is necessary to explore the formation mechanism, interaction structure features, and physiochemical properties to design rationally the formation of the multicomponent solvates.…”

Section: Introductionmentioning

confidence: 99%

Weak but Vital: The Role of Solvents in Crystal Packing and Coassembly for the Formation of Multicomponent Salt Solvates of Clozapine with Oxalic Acid

Li,

Zhang,

Wang

et al. 2024

Crystal Growth & Design

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In order to explore the role of solvent molecules (acetonitrile and ethanol) in crystal packing and coassembly for the formation of three multicomponent salt solvates of clozapine (CLZ) with oxalic acid (OXA), i.e., CLZ-OXA1 ([CLZ2+]:[HOXA–]:[OXA2–]:acetonitrile = 1:1:0.5:1), CLZ-OXA2 ([CLZ2+]:[HOXA–]:[OXA2–]:ethanol = 1:1:0.5:1), and CLZ-OXA3 ([CLZ+]:[OXA2–]:ethanol = 1:0.5:1), experimental and computational studies via density functional theory and molecular dynamics were employed to relate intermolecular interactions to packing arrangements, formation mechanism, stability, and the desolvation process of CLZ salt solvates. The crystal structures of three CLZ salt solvates were analyzed to show that both weak interactions C–H···X (X = O, N, or π) and van der Waals forces were of great importance in the process of self-assembly as well as strong and conventional hydrogen bonds (N–H···O and O–H···O), leading to a stable and diverse multidimensional supramolecular architecture. The packing arrangement and crystal assembly analysis implied that CLZ-OXA1 and CLZ-OXA2 were isostructural. Furthermore, solvent molecules were classified as isolated sites in the packing cages consisting of CLZ and OXA to fill the vacancies in the framework and compensate for the weak interactions or charges. Particularly, ethanol molecules in CLZ-OXA3 also acted as very important bridge-builders, contributing to the formation of the multicomponent crystals. The thermal analysis results indicated that the solvent molecules cannot easily escape from their sites; however, when desolvation occurred, the CLZ multicomponent crystal structures collapsed immediately, indicating the critical role of solvent molecules in stabilizing the crystal structure via intermolecular interactions. After filling the void space, the relatively more negative lattice energy than pure CLZ and the increased packing coefficients may also be the important driving forces for the solvation formation. The present study might provide an opportunity to further reveal the role of solvent molecules in the solid form of the antipsychotic drug CLZ.

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Cocrystallization of lenvatinib and temozolomide to improve the performance in terms of stability, dissolution, and tabletability

Abstract: Two anti-melanoma drugs, lenvatinib and temozolomide, were cocrystallized to obtain two drug-drug cocrystal solvates, TMZ-LEN·MeOH (1:1:1) and TMZ-LEN·EtOH (1:1:1). They were fully characterized by XRD and thermal analyses, NMR and...

Cited by 6 publications

References 34 publications

Simultaneous Improvements of Physicochemical Properties and Anti‐Microbial Activity of Berberine via Forming Salt with Gallic Acid

Simultaneous Improvements of Physicochemical Properties and Anti‐Microbial Activity of Berberine via Forming Salt with Gallic Acid

Unraveling a Unique Metastable Phase of a Proxyphylline Cocrystal Exclusively Produced by Compressed Carbon Dioxide

Weak but Vital: The Role of Solvents in Crystal Packing and Coassembly for the Formation of Multicomponent Salt Solvates of Clozapine with Oxalic Acid

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