Implications of phase solubility/miscibility and drug-rich phase formation on the performance of co-amorphous materials: The case of Darunavir co-amorphous materials with Ritonavir and Indomethacin as co-formers

Shete, Sushant; Reddy, Sai Charan; Yarlagadda, Dani Lakshman; Vullendula, Sai Krishna Anand; Mehta, Chetan Hasmukh; Nayak, Usha Yogendra; Dengale, Swapnil J.

doi:10.1016/j.ijpharm.2021.121119

Cited by 4 publications

(6 citation statements)

References 35 publications

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“…This will inhibit supersaturation-driven recrystallization or phase separation in the liquid and solid states. As a result, the phase solubility of the drug and coformer pair is imperative which can be determined by computational, theoretical, and experimental approaches . Van Krevelen’s contribution values were considered to calculate drug–coformer miscibility by the Hildebrand and Hansen technique.…”

Section: Resultsmentioning

confidence: 99%

“…The detailed amorphous solubility methodology can be found in Shete et al (2021). 39 2.2.6.3. HPLC Method.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

“…As a result, the phase solubility of the drug and coformer pair is imperative which can be determined by computational, theoretical, and experimental approaches. 39 Van Krevelen's contribution values were considered to calculate drug− coformer miscibility by the Hildebrand and Hansen technique. The difference in Hildebrand solubility parameters of CRT and NRG is <7 MPa 1/2 , indicating that the system is single phase.…”

Section: Drug−coformer Miscibilitymentioning

confidence: 99%

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Computational-Based Polyphenol Therapy for Nonsmall Cell Lung Cancer: Naringin Coamorphous Systems for Solubility and Bioavailability Enhancement

Yarlagadda,

Das,

Anand Vullendula

et al. 2024

Mol. Pharmaceutics

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In this research, we utilized molecular simulations to create co-amorphous materials (CAMs) of ceritinib (CRT) with the objective of improving its solubility and bioavailability. We identified naringin (NRG) as a suitable co-former for CRT CAMs based on binding energy and intermolecular interactions through computational modeling. We used the solvent evaporation method to produce CAMs of CRT and NRG, expecting to enhance both solubility and bioavailability simultaneously. The solid-state characterization using techniques like differential scanning calorimeter, Xray powder diffraction, and Fourier-transform infrared spectroscopy affirmed the formation of a single amorphous phase and the presence of intermolecular interactions between CRT and NRG in the CAMs. These materials remained physically stable for up to six months under dry conditions at 40 °C. Moreover, the CAMs demonstrated significant improvements in the solubility and dissolution of CRT (specifically in the ratio CRT:NRG 1:2). This, in turn, led to an increase in cytotoxicity, apoptotic cells, and G0/G1 phase inhibition in A549 cells compared to CRT alone. Furthermore, CRT permeability is also improved twofold, as estimated by the everted gut sac method. The enhanced solubility of CAMs also positively affected the pharmacokinetic parameters. When compared to the physical mixture, the CAMs of CRT:NRG 2:1 exhibited a 2.1-fold increase in CRT exposure (AUC 0−t ) and a 2.4-fold increase in plasma concentration (C max ).

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Section: Resultsmentioning

confidence: 99%

“…The detailed amorphous solubility methodology can be found in Shete et al (2021). 39 2.2.6.3. HPLC Method.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Section: Drug−coformer Miscibilitymentioning

confidence: 99%

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Computational-Based Polyphenol Therapy for Nonsmall Cell Lung Cancer: Naringin Coamorphous Systems for Solubility and Bioavailability Enhancement

Yarlagadda,

Das,

Anand Vullendula

et al. 2024

Mol. Pharmaceutics

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“…There are various anti retrovirus drug products available including some fixed dose drug combination also. 1,2 Considering requirement of higher dosage regime of anti-retroviral product for HIV treatment, the formulation having two active in one tablet helps to maintain dose along with ease of therapy from patient perspective. Further refer to the literature reference on bioavailability, observed high relative bioavailability of Ritonavir in presence of other drug such as Darunavir, Atazanavir confirming better efficacy of fixed dose drug combination product.…”

Section: Introductionmentioning

confidence: 99%

Stability Indicating RP-UPLC Method for Impurity Profiling of Darunavir and Ritonavir in Fixed Dose Drug Combination Product

Buch,

Vaghani

2024

Ind. J. Pharm. Edu. Res

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Background:The goal of the proposed study was to develop and validate stability indicating mass compatible reverse phase UPLC method for impurity profiling of Darunavir Ethanolate and Ritonavir degradation impurities in fixed-dose drug combination products. Materials and Methods: The optimized chromatographic condition includes use of Zorbax Bonus C 18 column (150x2.1 mm, 1.8 µm) with mobile phase A (Buffer (55): Methanol ( 45)) and mobile phase B (Acetonitrile: (30) and Methanol ( 70)), flow rate of 0.22 mL/min and detection at 240 nm with gradient program of 50 min. The method was validated as per ICH quality guideline Q2 (R1) including specificity by forced degradation study to confirm suitability for intended use. Results: The observed retention time for Darunavir was 11.4 min and for Ritonavir was 30.0 min. The Limit of Quantitation (LOQ) for all degradation impurities found is 0.05%, equivalent to the reporting threshold level. The method was found linear and accurate in the range of LOQ to 150% with an observed range of % accuracy of 90.1 to 106.3 for all known impurities. The method was found precise based on less than 10.0% RSD and robust for deliberate changes. Considering the use of a volatile mobile phase, the method can be applied for LC-MS-based analysis for mass identification. Conclusion: The developed UPLC method was applied for impurity profiling during the release and stability study of Darunavir Ethanolate and Ritonavir in fixed-dose drug combination products.

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“…Quench-cooling is a commonly used technique to prepare CAMS, with approximately 48.8% of the studies following the thermodynamic pathway having used this method [ 3 ]. Using quench-cooling or hot-melt extrusion as preparation methods, a subsequent grinding or milling process is commonly performed to obtain finely powdered CAMS for later characterization or downstream manufacturing [ 15 , 16 ]. Despite the use of grinding in the preparation of CAMS, a dedicated investigation into the consequences of grinding for co-amorphous samples is missing.…”

Section: Introductionmentioning

confidence: 99%

Destabilization of Indomethacin-Paracetamol Co-Amorphous Systems by Mechanical Stress

Di,

Rades,

Grohganz

2023

Pharmaceutics

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Using co-amorphous systems (CAMS) has shown promise in addressing the challenges associated with poorly water-soluble drugs. Quench-cooling is a commonly used CAMS preparation method, often followed by grinding or milling to achieve a fine powder that is suitable for subsequent characterization or further down-stream manufacturing. However, the impact of mechanical stress applied to CAMS has received little attention. In this study, the influence of mechanical stress on indomethacin—paracetamol CAMS was investigated. The investigation involved thermal analysis and solid-state characterization across various CAMS mixing ratios and levels of mechanical stress. The study revealed a negative effect of mechanical stress on stability, particularly on the excess components in CAMS. Higher levels of mechanical stress were observed to induce phase separation or recrystallization. Notably, samples at the optimal mixing ratio demonstrated greater resistance to the destabilization caused by mechanical stress. These results showed the significance of careful consideration of processing methods during formulation and the significance of optimizing mixing ratios in CAMS.

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Implications of phase solubility/miscibility and drug-rich phase formation on the performance of co-amorphous materials: The case of Darunavir co-amorphous materials with Ritonavir and Indomethacin as co-formers

Cited by 4 publications

References 35 publications

Computational-Based Polyphenol Therapy for Nonsmall Cell Lung Cancer: Naringin Coamorphous Systems for Solubility and Bioavailability Enhancement

Computational-Based Polyphenol Therapy for Nonsmall Cell Lung Cancer: Naringin Coamorphous Systems for Solubility and Bioavailability Enhancement

Stability Indicating RP-UPLC Method for Impurity Profiling of Darunavir and Ritonavir in Fixed Dose Drug Combination Product

Destabilization of Indomethacin-Paracetamol Co-Amorphous Systems by Mechanical Stress

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