Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption

Hatanaka, Yuta; Uchiyama, Hiromasa; Kaneko, Shun; Ueda, Keisuke; Higashi, Kenjirou; Moribe, Kunikazu; Furukawa, Shingo; Takase, Mai; Yamanaka, Shinya; Kadota, Kazunori; Tozuka, Yuichi

doi:10.1021/acs.molpharmaceut.3c00226

Cited by 11 publications

(3 citation statements)

References 67 publications

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“…Coamorphous systems are homogeneous single amorphous systems comprised by two or more low-molecular-weight molecules. , For pharmaceutical formulation development, coamorphous systems are remarkably interesting since they increase the solubility of the API without the stability problems associated with amorphous materials. , In this work, a new coamorphous of RIF with TRIS with a RIF–TRIS ratio of 2:1 (Figure ) was developed and characterized. RIF is a low-solubility API and therefore a suitable candidate for a solubility increase.…”

Section: Discussionmentioning

confidence: 99%

Preparation and Characterization of a Rifampicin Coamorphous Material with Tromethamine Coformer: An Experimental–Theoretical Study

Queiroz,

Barros,

de Sousa

et al. 2024

Mol. Pharmaceutics

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Rifampicin (RIF) is an antibiotic used to treat tuberculosis and leprosy. Even though RIF is a market-available drug, it has a low aqueous solubility, hindering its bioavailability. Among the strategies for bioavailability improvement of poorly soluble drugs, coamorphous systems have been revealed as an alternative in the increase of the aqueous solubility of drug systems and at the same time also increasing the amorphous state stability and dissolution rate when compared with the neat drug. In this work, a new coamorphous form from RIF and tromethamine (TRIS) was synthesized by slow evaporation. Structural, electronic, and thermodynamic properties and solvation effects, as well as drug−coformer intermolecular interactions, were studied through density functional theory (DFT) calculations. Powder X-ray diffraction (PXRD) data allowed us to verify the formation of a new coamorphous. In addition, the DFT study indicates a possible intermolecular interaction by hydrogen bonds between the available amino and carbonyl groups of RIF and the hydroxyl and amino groups of TRIS. The theoretical spectra obtained are in good agreement with the experimental data, suggesting the main interactions occurring in the formation of the coamorphous system. PXRD was used to study the physical stability of the coamorphous system under accelerated ICH conditions (40 °C and 75% RH), indicating that the material remained in an amorphous state up to 180 days. The thermogravimetry result of this material showed a good thermal stability up to 153 °C, and differential scanning calorimetry showed that the glass temperature (T g ) was at 70.0 °C. Solubility studies demonstrated an increase in the solubility of RIF by 5.5-fold when compared with its crystalline counterpart. Therefore, this new material presents critical parameters that can be considered in the development of new coamorphous formulations.

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Section: Discussionmentioning

confidence: 99%

Preparation and Characterization of a Rifampicin Coamorphous Material with Tromethamine Coformer: An Experimental–Theoretical Study

Queiroz,

Barros,

de Sousa

et al. 2024

Mol. Pharmaceutics

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“…WO/2007/147889 and US 6737432 described the preparation of telmisartan salt with sodium [16] and organic acids [17]. Recently, Hatanaka et al reported a co-amorphous drug-drug salt between telmisartan and amlodipine with an improved solubility and permeability for oral absorption [18]. Research has also been conducted to investigate the formation of telmisartan salt with the addition of hydrochloric acid (HCl), which shows an increase in solubility [19].…”

Section: Introductionmentioning

confidence: 99%

Structural Characterization and Pharmaceutical Evaluation of Telmisartan Hydrochloride Salts

Nugraha,

Unique,

Miyake

et al. 2024

Crystals

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Telmisartan is an anti-hypertensive drug that exhibits poor aqueous solubility. In this work, salt formation was utilized to address this issue. Three hydrochloride salts of telmisartan (TELHCl), a trihemihydrate hydrochloride salt (TELHCl-Hyd), and two anhydrate forms (TELHCl-A and TELHCl-B) were obtained. The crystal structures of TELHCl-Hyd and TELHCl-A were determined using single-crystal structure analysis. TELHCl-Hyd is a channel hydrate that has structural similarities with TELHCl-A. The structures of both crystals are mainly composed of chain structures formed by centrosymmetric dimers connected via carboxylic–benzimidazole hydrogen bonding. Despite their structural similarities, the dehydration of TELHCl-Hyd led to the formation of TELHCl-B. The solubility, intrinsic dissolution rate (IDR), powder flowability, and tabletability of TELHCl-Hyd and TELHCl-B were characterized and compared with those of the telmisartan free base form (TEL). The hydrochloride salts enhanced the solubility of telmisartan approximately 10 to 20 times and maintained the spring parachute effect up to 24 h. The IDR was also improved due to the existence of a hydrophilic channel that facilitates the dissolution of telmisartan cations. The resulting salts had a larger particle size and a more favorable crystal morphology that led to a better powder flowability. However, the tabletability was not improved by salt formation. The TEL exhibited a defined slip plane and a higher specific surface area that may assist the tableting process.

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“…TEL (Figure ), characterized by high permeability and pH-dependent low aqueous solubility (0.09 μg/mL), belongs to the BCS class II drug category, with a dissolution rate-limited oral bioavailability of 40–58% . TEL is considered as a high glass forming molecule with a moderate glass stability and several strategies like use of polymers in conjunction with alkalizers, , antisolvent crystallization, development of cocrystals, − and coamorphous systems have been investigated to inhibit recrystallization of amorphous TEL (AM-TEL) to maximize its solubility and dissolution profile. Most recently, Bennett et al and Sharma et al .…”

Section: Introductionmentioning

confidence: 99%

Molecular Insights from Spectral and Computational Studies on Crystalline and Amorphous Telmisartan

Singh,

Murugan,

Kongsted

et al. 2024

Crystal Growth & Design

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Suboptimal aqueous solubility of drugs is one of the key challenges in early pharmaceutical development. To overcome this issue, alternative solid-state forms, including polymorphs, salts, cocrystals, and amorphous solids, are explored to enhance aqueous solubility. Despite the advantages of amorphous solids, their pharmaceutical application is limited due to the thermodynamic instability, unpredictability of the crystallization potential, and a lack of comprehensive molecular-level understanding. Herein, we explore the differential molecular interactions between the crystalline and amorphous forms of telmisartan, a nonpeptide angiotensin II receptor antagonist and a BCS class II drug, using spectroscopies and computational simulations. The amorphous phase of telmisartan was prepared through the quench cooling of the melt. From spectral techniques and computational tools, we observed the altered behavior in the molecular interactions of amorphous telmisartan compared to its crystalline counterpart. Through molecular dynamics simulations of both amorphous and crystalline forms, we identified that the amorphous structure maintained some of its molecular interactions within the disordered molecular arrangement. Notably, the amorphous form exhibited a relatively weaker (indicated by an increase in bond length) yet less extensive (constituting only 2.6% of the total population) hydrogen bonding network when contrasted with the crystalline counterpart, where the hydrogen bonding network constituted up to 76% of the total population with stronger hydrogen bonds.

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Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption

Cited by 11 publications

References 67 publications

Preparation and Characterization of a Rifampicin Coamorphous Material with Tromethamine Coformer: An Experimental–Theoretical Study

Preparation and Characterization of a Rifampicin Coamorphous Material with Tromethamine Coformer: An Experimental–Theoretical Study

Structural Characterization and Pharmaceutical Evaluation of Telmisartan Hydrochloride Salts

Molecular Insights from Spectral and Computational Studies on Crystalline and Amorphous Telmisartan

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