| 1. |
- Alhalaweh, Amjad, et al.
(författare)
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Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.
- 2016
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 229, s. 172-182
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Tidskriftsartikel (refereegranskat)abstract
- Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.
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| 2. |
- Alhalaweh, Amjad, et al.
(författare)
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Computational predictions of glass-forming ability and crystallization tendency of drug molecules
- 2014
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 11:9, s. 3123-3132
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Tidskriftsartikel (refereegranskat)abstract
- Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.
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| 3. |
- Alhalaweh, Amjad, et al.
(författare)
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Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions
- 2019
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Ingår i: Journal of Pharmaceutical Sciences. - : ELSEVIER SCIENCE INC. - 0022-3549 .- 1520-6017. ; 108:1, s. 252-259
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).
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| 4. |
- Alhalaweh, Amjad, et al.
(författare)
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Physical stability of drugs after storage above and below the glass transition temperature : Relationship to glass-forming ability
- 2015
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 495:1, s. 312-317
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Tidskriftsartikel (refereegranskat)abstract
- Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.
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| 5. |
- Alhalaweh, Amjad, et al.
(författare)
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Solubility behavior and solution chemistry of indomethacin cocrystals in organic solvents
- 2011
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 11:9, s. 3923-3929
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Tidskriftsartikel (refereegranskat)abstract
- The main objective of this study was to investigate the solubility behavior and solution chemistry of indomethacin-saccharin (IND-SAC) cocrystals in organic media. We also evaluated previously proposed models of cocrystal solubility in organic solvents. In addition, the solubility behavior of IND-SAC cocrystals was compared with that of indomethacin-nicotinamide (IND-NIC) cocrystals using the eutectic constant approach. Phase solubility diagrams of IND-SAC cocrystals in various solvents were generated and the transition concentrations, at which drug and cocrystals are in equilibrium with the solvents, were determined. The solubility of IND-SAC cocrystals was explained by the solubility product and solution complexation. The tested models were found to fit the experimental data and to adequately explain the solubility behavior of the cocrystals. The solution complexation of IND and SAC is negligible in ethyl acetate and low in methanol and ethanol. The IND-NIC cocrystals were more soluble than the IND-SAC cocrystals in all the solvents studied. The eutectic constants predicted both the solubility and the stability of the cocrystals. Understanding the solubility behavior and solution chemistry of cocrystals has important implications for the screening, scale-up, and formulation development of this solid form. Further, the determination of eutectic constants is a simple and resource sparing means of obtaining key information on cocrystal stability and solution behavior
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| 6. |
- Alzghoul, Ahmad, et al.
(författare)
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Experimental and Computational Prediction of Glass Transition Temperature of Drugs
- 2014
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Ingår i: JOURNAL OF CHEMICAL INFORMATION AND MODELING. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:12, s. 3396-3403
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Tidskriftsartikel (refereegranskat)abstract
- Glass transition temperature (T-g) is an important inherent property of an amorphous solid material which is usually determined experimentally. In this study, the relation between T-g and melting temperature (T-m) was evaluated using a data set of 71 structurally diverse druglike compounds. Further, in silico models for prediction of T-g were developed based on calculated molecular descriptors and linear (multilinear regression, partial least-squares, principal component regression) and nonlinear (neural network, support vector regression) modeling techniques. The models based on T-m predicted T-g with an RMSE of 19.5 K for the test set. Among the five computational models developed herein the support vector regression gave the best result with RMSE of 18.7 K for the test set using only four chemical descriptors. Hence, two different models that predict T-g of drug-like molecules with high accuracy were developed. If T-m is available, a simple linear regression can be used to predict T-g. However, the results also suggest that support vector regression and calculated molecular descriptors can predict T-g with equal accuracy, already before compound synthesis.
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| 7. |
- El Sayed, Mira, et al.
(författare)
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Impact of Simulated Intestinal Fluids on Dissolution, Solution Chemistry, and Membrane Transport of Amorphous Multidrug Formulations
- 2021
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 18:11, s. 4079-4089
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Tidskriftsartikel (refereegranskat)abstract
- The solution behavior and membrane transport of multidrug formulations were herein investigated in a biorelevant medium simulating fasted conditions. Amorphous multidrug formulations were prepared by the solvent evaporation method. Combinations of atazanavir (ATV) and ritonavir (RTV) and felodipine (FDN) and indapamide (IPM) were prepared and stabilized by a polymer for studying their dissolution (under non-sink conditions) and membrane transport in fasted state simulated intestinal fluid (FaSSIF). The micellar solubilization by FaSSIF enhanced the amorphous solubility of the drugs to different extents. Similar to buffer, the maximum achievable concentration of drugs in combination was reduced in FaSSIF, but the extent of reduction was affected by the degree of FaSSIF solubilization. Dissolution studies of ATV and IPM revealed that the amorphous solubility of these two drugs was not affected by FaSSIF solubilization. In contrast, RTV was significantly affected by FaSSIF solubilization with a 30% reduction in the maximum achievable concentration upon combination to ATV, compared to 50% reduction in buffer. This positive deviation by FaSSIF solubilization was not reflected in the mass transport-time profiles. Interestingly, FDN concentrations remain constant until the amount of IPM added was over 1000 mu g/mL. No decrease in the membrane transport of FDN was observed for a 1:1 M ratio of FDN-IPM combination. This study demonstrates the importance of studying amorphous multidrug formulations under physiologically relevant conditions to obtain insights into the performance of these formulations after oral administration.
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| 8. |
- El Sayed, Mira, et al.
(författare)
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Insights into Dissolution and Solution Chemistry of Multidrug Formulations of Antihypertensive Drugs
- 2020
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 17:10, s. 4018-4028
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Tidskriftsartikel (refereegranskat)abstract
- Using fixed dose combinations of drugs instead of administering drugs separately can be beneficial for both patients and the health care system, but the current understanding of how multidrug formulations work at the molecular level is still in its infancy. Here, we explore dissolution, solubility, and supersaturation of various drug combinations in amorphous formulations. The effect of chemical structural similarity on combination behavior was investigated by using structurally related compounds of both drugs. The effect of polymer type on solution behavior was also evaluated using chemically diverse polymers. Indapamide (IPM) concentration decreased when combined with felodipine (FDN) or its analogues, which occurred even when the IPM solution was undersaturated. The extent of solubility decrease of FDN was less than that of IPM from the dissolution of an equimolar formulation of the drugs. No significant solubility decrease was observed for FDN at low contents of IPM which was also observed for other dihydropyridines, whereas FDN decreases at high contents of IPM. This was explained by the complex nature of the colloidal precipitates of the combinations which impacts the chemical potential of the drugs in solution at different levels. The maximum achievable concentration of FDN and IPM during dissolution of the polyvinylpyrrolidone-based amorphous solid dispersion was higher than the value measured with the hydroxypropyl methylcellulose acetate succinate-based formulation. This emphasizes the significance of molecular properties and chemical diversity of drugs and polymers on solution chemistry and solubility profiles. These findings may apply to drugs administered as a single dosage form or in separate dosage forms and hence need to be well controlled to assure effective treatments and patient safety.
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| 9. |
- Rawas-Qalaji, Mutasem, et al.
(författare)
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Assessment of enhancing curcumin's solubility versus uptake on its anti-cancer efficacy
- 2024
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Ingår i: Colloids and Surfaces B. - : Elsevier. - 0927-7765 .- 1873-4367. ; 242
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Tidskriftsartikel (refereegranskat)abstract
- Curcumin (CUR) exhibits anti-inflammatory and anti-cancer activities. However, its poor solubility and bioavailability limit its therapeutic applications. Several CUR nano-formulations have been developed to enhance its solubility and uptake, thereby improving its anti-cancer activity. Despite this, studies comparing the effect of enhanced CUR solubility versus cellular uptake on its anti-cancer efficacy are lacking. Therefore, CUR nanofibers (CUR NF) were synthesized by electrospinning using a water-soluble polymer to enhance CUR solubility. While CUR nanoparticles (CUR NP) were synthesized by nanoprecipitation method using a waterinsoluble polymer to enhance CUR cellular uptake. Both nano-formulations aim to improve CUR cellular concentration and anti-cancer activity against various cancer cells. CUR NF and CUR NP were successfully synthesized at drug load (DL%) of 10 %, 20 %, and 40 % w/w. Both nano-formulations were characterized, and CUR dissolution, release, cytotoxicity, IC50, and cellular uptake were assessed. A gradual increase in NF diameter and NP size was observed as the drug load% increased compared to the placebo. NF showed a rapid CUR release and increased solubility by 16-38 fold. In contrast, NP sustained CUR release and resulted in only a 2-fold increase in solubility. Both formulations significantly reduced cell viability and IC50 compared to free CUR. However, CUR NP demonstrated higher cell toxicity (70-80 %) than CUR NF (60 %) and reduced IC50 up to 4 μM compared to 11 μM for NF. Enhancing CUR solubility or uptake can significantly increase its cellular concentration and anticancer activity. However, enhancing CUR cellular uptake by NP demonstrated superior anti-cancer effect compared to enhancing its solubility by NF.
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| 10. |
- Shojaee, Saeed, et al.
(författare)
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Investigation of Drug Release from PEO Tablet Matrices in the Presence of Vitamin E as Antioxidant
- 2015
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Ingår i: Current Drug Delivery. - : Bentham Science Publishers Ltd.. - 1567-2018 .- 1875-5704. ; 12:5, s. 591-599
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to investigate the influence of drug type on the release of drug from PEO matrix tablets accompanied with the impact of vitamin E succinate as antioxidant. The result showed that the presence of vitamin E promoted a stable release rate of soluble drug propranolol HCl from aged PEO matrix tablets, which was similar to fresh sample, regardless of molecular weight ( MW) of PEO. However, the influence of the presence of vitamin E on the release rate of partially soluble drug, theophylline, was dependent on the MW of PEO; i.e., fast and unstable drug release was obtained in the case of low MW PEO 750 whereas stable drug release was obtained in the case of high MW PEO 303. The release of low water-soluble drug zonisamide was stable regardless of both the presence of vitamin E and the MW of PEO. The presence of vitamin E slightly slowed the release of zonisamide from aged PEO 303 matrices but not PEO 750 matrices. Therefore, in order to achieve a suitable controlled release profile from PEO matrices, not only the presence of vitamin E but also the solubility of the drug and the MW of polyox should be considered.
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