Research

12 pages, 4209 KiB

Open AccessArticle

Physical Characteristics of Cilostazol–Hydroxybenzoic Acid Cocrystals Prepared Using a Spray Drying Method

by Maho Urano, Megumi Kitahara, Kae Kishi, Eiichi Goto, Tatsuaki Tagami, Toshiro Fukami and Tetsuya Ozeki

Crystals 2020, 10(4), 313; https://doi.org/10.3390/cryst10040313 - 17 Apr 2020

Cited by 11 | Viewed by 3072

Abstract

The cocrystal formation of pharmaceuticals can improve the various physical properties of drugs, such as solubility, without the need for chemical modification of the drug substances. In the present study, we prepared cocrystals of cilostazol and additive coformers (derivatives of hydroxybenzoic acid) using [...] Read more.

The cocrystal formation of pharmaceuticals can improve the various physical properties of drugs, such as solubility, without the need for chemical modification of the drug substances. In the present study, we prepared cocrystals of cilostazol and additive coformers (derivatives of hydroxybenzoic acid) using a spray drying method. Based on the preparation of the cocrystals of cilostazol and the coformers as reported previously, the characteristics of the cilostazol cocrystals prepared using solvent evaporation, slurry, and spray drying methods were compared. The physical characterization revealed that the spray drying method successfully produced cilostazol–4-hydroxybenzoic acid and cilostazol–2,4-dihydroxybenzoic acid cocrystals, whereas samples of cocrystals of cilostazol and 2,5-dihydroxybenzoic acid produced via the spray drying process appeared to contain coformer polymorphs. The dissolution of cilostazol was improved using the spray-dried cocrystal samples composed of coformers compared to samples prepared using cilostazol alone or a physical mixture. The present results provide useful information regarding the manufacture of cilostazol cocrystals and pharmaceutical cocrystals via spray drying in large-batch production. Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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18 pages, 3304 KiB

Open AccessArticle

Pharmaceutical Cocrystal Development of TAK-020 with Enhanced Oral Absorption

by Kouya Kimoto, Mitsuo Yamamoto, Masatoshi Karashima, Miyuki Hohokabe, Junpei Takeda, Katsuhiko Yamamoto and Yukihiro Ikeda

Crystals 2020, 10(3), 211; https://doi.org/10.3390/cryst10030211 - 18 Mar 2020

Cited by 24 | Viewed by 5010

Abstract

The objective of this study was to improve the solubility of poorly water-soluble drugs by pharmaceutical cocrystal engineering techniques and select the best pharmaceutical forms with high solubility and solubilized formulations for progress from the early discovery stage toward the clinical stage. Several [...] Read more.

The objective of this study was to improve the solubility of poorly water-soluble drugs by pharmaceutical cocrystal engineering techniques and select the best pharmaceutical forms with high solubility and solubilized formulations for progress from the early discovery stage toward the clinical stage. Several pharmaceutical cocrystals of TAK-020, a Bruton tyrosine kinase inhibitor, were newly discovered in the screening based on the solid grinding method and the slurry method, considering thermodynamic factors that dominate cocrystal formation. TAK-020/gentisic acid cocrystal (TAK-020/GA CC) was selected based on a physicochemical property of enhanced dissolution rate. TAK-020/GA CC was proven to be a reliable cocrystal formation with a definitive stoichiometric ratio by a variety of analytical techniques—pKa calculation, solid-state nuclear magnetic resonance, and single X-ray structure analysis from the view of regulation. Furthermore, its absorption was remarkable and beyond those achieved in currently existing solubilized formulation techniques, such as nanocrystal, amorphous solid dispersion, and lipid-based formulation, in dog pharmacokinetic studies. TAK-020/GA CC was the best drug form, which might lead to good pharmacological effects with regard to enhanced absorption and development by physicochemical characterization. Through the trials of solid-state optimization from early drug discovery to pharmaceutical drug development, the cocrystals can be an effective option for achieving solubilization applicable in the pharmaceutical industry. Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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14 pages, 8450 KiB

Open AccessArticle

Synthesis, X-ray Single Crystal, Conformational Analysis and Cholinesterase Inhibitory Activity of a New Spiropyrrolidine Scaffold Tethered Benzo[b]Thiophene Analogue

by Assem Barakat, Saied M. Soliman, Saeed Alshahrani, Mohammad Shahidul Islam, M. Ali, Abdullah Mohammed Al-Majid and Sammer Yousuf

Crystals 2020, 10(2), 120; https://doi.org/10.3390/cryst10020120 - 15 Feb 2020

Cited by 11 | Viewed by 2596

Abstract

Described herein is a one-pot protocol for the synthesis of a substituted spiropyrrolidine scaffold tethered benzo[b]thiophene analogue from (E)-3-(benzo[b]thiophen-2-yl)-1-(4-fluoro- phenyl)-prop-2-en-1-one. The described protocol has the advantage of the high purity of the cyclized adduct and high chemical [...] Read more.

Described herein is a one-pot protocol for the synthesis of a substituted spiropyrrolidine scaffold tethered benzo[b]thiophene analogue from (E)-3-(benzo[b]thiophen-2-yl)-1-(4-fluoro- phenyl)-prop-2-en-1-one. The described protocol has the advantage of the high purity of the cyclized adduct and high chemical yield. To assign the chemical structure, different spectrophotometric tools have been applied, including ¹H-NMR, ¹³C-NMR, FTIR, and the X-ray single crystal technique. The X-ray structure showed that the studied compound exist in two disordered parts with equal partial occupancies. The energies of the two conformers were found to be very similar and not exceed 1 kcal/mol, which justifies their coexistence in the crystal with equal percentage. The molecular packing in the crystal was analyzed using Hirshfeld topology analysis. The packing described as two dimensional hydrogen bond network extended along the ac-plane in both conformers but the intermolecular interactions included in each conformer are not similar. The synthesized spiropyrrolidine scaffold tethered benzo[b]thiophene analogue was examined against cholinesterase inhibitory activity and show moderate activity compared to standard drug galantamine. Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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14 pages, 4936 KiB

Open AccessArticle

Crystal Structural Analysis of DL-Mandelate Salt of Carvedilol and Its Correlation with Physicochemical Properties

by Nanami Hata, Takayuki Furuishi, Majid I. Tamboli, Momiji Ishizaki, Daiki Umeda, Kaori Fukuzawa and Etsuo Yonemochi

Crystals 2020, 10(1), 53; https://doi.org/10.3390/cryst10010053 - 20 Jan 2020

Cited by 2 | Viewed by 3603

Abstract

A 1:1 salt of carvedilol (CVD), an anti-hypertensive drug, with DL-mandelic acid (DL-MA) was crystallized from ethanol and the structure was characterized by X-ray single-crystal diffraction, revealing salt formation by transfer of an acidic proton from the COOH group of MA to the [...] Read more.

A 1:1 salt of carvedilol (CVD), an anti-hypertensive drug, with DL-mandelic acid (DL-MA) was crystallized from ethanol and the structure was characterized by X-ray single-crystal diffraction, revealing salt formation by transfer of an acidic proton from the COOH group of MA to the aliphatic (acyclic) secondary amino NH group of CVD. The crystal structure is triclinic, with a P-1 space group and unit cell parameters a = 9.8416(5) Å, b = 11.4689(5) Å, c = 14.0746(7) Å, α = 108.595(8), β = 95.182(7), γ = 107.323(8), V = 1406.95(15) Å³, and Z = 2. The asymmetric unit contained one protonated CVD and one MA anion, linked via an N⁺–H∙∙∙O¯ strong hydrogen bond and a ratio of 1:1. As previously reported, the thermal, spectroscopic, and powder X-ray diffraction properties of the salt of CVD with DL-MA (CVD_DL-MA) differed from CVD alone. The intrinsic dissolution rate of CVD_DL-MA was about 10.7 times faster than CVD alone in a pH 6.8 buffer. Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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13 pages, 4668 KiB

Open AccessArticle

Three Multi-Components Reaction: Synthesis and X-Ray Single-Crystal of Hydroacridinone-Based Hydrazino-S-Triazine Derivative as a New Class of Urease Inhibitor

by Assem Barakat, Saied M. Soliman, Ayman El-Faham, M. Ali, Abdullah Mohammed Al-Majid, Sammer Yousuf and M. Iqbal Choudhary

Crystals 2020, 10(1), 14; https://doi.org/10.3390/cryst10010014 - 30 Dec 2019

Cited by 7 | Viewed by 2580

Abstract

The one-pot fashion of three multi-component reaction provides the desired hydroacridinone-based hydrazino-s-triazine scaffold 4. Compound 4 was crystallized in an orthorhombic crystal system and Pbca space group with a = 11.6271(2) Å, b = 18.2018(4) Å, c = 32.4721(6) Å, [...] Read more.

The one-pot fashion of three multi-component reaction provides the desired hydroacridinone-based hydrazino-s-triazine scaffold 4. Compound 4 was crystallized in an orthorhombic crystal system and Pbca space group with a = 11.6271(2) Å, b = 18.2018(4) Å, c = 32.4721(6) Å, and α = β = γ = 90° with one formula unit per asymmetric unit and eight molecules per unit cell. Additionally, structural features, Hirshfeld surfaces, and DFT studies were also investigated. Its packing in the crystal is controlled by H…H (63.4%), O…H (12.7%), Cl…H (7.2%), N…H (4.7%), and C…H (10.2%) contacts, where the O…H and Cl…H contacts were found the strongest. In vitro urease inhibition evaluation showed that the hydroacridinone-based hydrazino-s-triazine is more active (IC₅₀ = 17.9 ± 0.47 µM) than the standard acetohydroxamic acid (IC₅₀ = 20.3 ± 0.43 µM). Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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11 pages, 1462 KiB

Open AccessArticle

Effect of Solid Forms on Physicochemical Properties of Valnemulin

by Jinbo Ouyang, Jian Chen, Limin Zhou, Fangze Han and Xin Huang

Crystals 2019, 9(12), 675; https://doi.org/10.3390/cryst9120675 - 16 Dec 2019

Cited by 5 | Viewed by 2403

Abstract

To improve the physicochemical properties of valnemulin (VLM), different solid forms formed by VLM and organic acids, including tartaric acid (TAR), fumaric acid (FUM), and oxalic acid (OXA), were successfully prepared and characterized by using differential scanning calorimetry (DSC), scanning electron microscope (SEM), [...] Read more.

To improve the physicochemical properties of valnemulin (VLM), different solid forms formed by VLM and organic acids, including tartaric acid (TAR), fumaric acid (FUM), and oxalic acid (OXA), were successfully prepared and characterized by using differential scanning calorimetry (DSC), scanning electron microscope (SEM), X-ray powder diffraction (XRPD), and Fourier-transform infrared spectroscopy (FT-IR). The excess enthalpy H_ex between VLM and other organic acids was calculated by COSMOthermX software and was used to evaluate the probability of forming multi-component solids between VLM and organic acids. By thermal analysis, it was confirmed that multi-component solid forms of VLM were thermodynamically more stable than VLM itself. Through dynamic vapor sorption (DVS) experiments, it was found that three multi-component solid forms of VLM had lower hygroscopicity than VLM itself. Furthermore, the intrinsic dissolution rate of VLM and its multi-component forms was determined in one kind of acidic aqueous medium by using UV-vis spectrometry. It was found that the three multi-component solid forms of VLM dissolved faster than VLM itself. Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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13 pages, 4659 KiB

Open AccessArticle

Isomorphous Crystals Formed by the Similar Supramolecular Motifs in Sorafenib Hydrochloride and Regorafenib Hydrochloride Salts

by Chi Uyen Phan, Jie Shen, Jiyong Liu, Jianming Mao, Xiurong Hu and Guping Tang

Crystals 2019, 9(12), 649; https://doi.org/10.3390/cryst9120649 - 06 Dec 2019

Cited by 9 | Viewed by 3049

Abstract

Sorafenib and regorafenib (or fluoro-sorafenib) are multikinase inhibitors active in the treatment of various human cancers, but their solubilities are very poor. To improve their solubilities, in this study, sorafenib hydrochloride (Sor·HCl, I) and regorafenib hydrochloride (Reg·HCl, II) have been prepared and their [...] Read more.

Sorafenib and regorafenib (or fluoro-sorafenib) are multikinase inhibitors active in the treatment of various human cancers, but their solubilities are very poor. To improve their solubilities, in this study, sorafenib hydrochloride (Sor·HCl, I) and regorafenib hydrochloride (Reg·HCl, II) have been prepared and their crystal structures were characterized. Their solubility properties in water were evaluated. Intriguingly, they are isomorphous crystal structures with the same space group and the similar unit cell dimensions, which were caused by the similar supramolecular patterns resulted by the formation of N–H···Cl⁻ hydrogen bond instead of hydrogen bond between the protonated pyridinium cation and counterion. Moreover, the solubility properties displayed identical profiles. It may be concluded that a similar crystal structure leads to a comparable solubility profile. Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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16 pages, 4273 KiB

Open AccessArticle

Synthesis, Single Crystal X-Ray Analysis, Prediction and Study of Pharmacological Activity of 4-(1H-Benzo[d]imidazol-2-yl)-1-Phenyl-1H-1,2,3-triazol-5-Amine and Its Solvates

by Alexandre V. Ivachtchenko, Oleg D. Mitkin, Dmitry V. Kravchenko, Sergiy M. Kovalenko, Svitlana V. Shishkina, Natalya D. Bunyatyan, Irina S. Konovalova, Vladimir V. Ivanov, Olena D. Konovalova and Thierry Langer

Crystals 2019, 9(12), 644; https://doi.org/10.3390/cryst9120644 - 05 Dec 2019

Cited by 2 | Viewed by 2423

Abstract

A method for the synthesis of 4- (1H-benzo[d]imidazole-2-yl)-1-phenyl-1H-1,2,3-triazole-5-amine was developed, and the electronic and spatial structure of this molecule was studied theoretically and experimentally. The study of interaction energies between molecules by quantum-chemical calculations allows us to recognize different [...] Read more.

A method for the synthesis of 4- (1H-benzo[d]imidazole-2-yl)-1-phenyl-1H-1,2,3-triazole-5-amine was developed, and the electronic and spatial structure of this molecule was studied theoretically and experimentally. The study of interaction energies between molecules by quantum-chemical calculations allows us to recognize different levels of crystal structure organization and describe the interaction types causing their formation. The classic N-H…N and C-H…N hydrogen bonds play the main role in all the studied crystals forming the primary basic structural motif. Their role is comparable with the role of the stacking interactions. The molecular docking study predicted that the studied compound may exhibit anti-hepatitis B activity, and experimental in vitro studies confirmed that it is a potent HBV inhibitor with IC₅₀ in a low micromolar range. Full article

(This article belongs to the Special Issue Pharmaceutical Crystals and Its Application)

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