| 1. |
- Alhalaweh, Amjad, et al.
(författare)
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1:1 and 2:1 urea-succinic acid cocrystals : structural diversity, solution chemistry, and thermodynamic stability
- 2010
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 10:11, s. 4847-4855
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to study the crystal structures of 1:1 and 2:1 urea-succinic acid (U-SA) cocrystals and to investigate the role of solution chemistry in the formation and stability of different stoichiometric cocrystals. The structural diversity of other urea-dicarboxylic acid cocrystals is also discussed. The 1:1 U-SA cocrystal was stabilized by an acid-amide heterosynthon while acid-amide heterosynthons and amide-amide homosynthons stabilized the 2:1 cocrystals. The hydrogen bonding motifs in 1:1 and 2:1 U-SA cocrystals were consistent with other urea-dicarboxylic acid systems with similar stoichiometries. The 1:1 cocrystals were transformed to 2:1 cocrystals upon slurrying in various solvents at 25 °C. The phase solubility diagram was used to define the stability regions of different solid phases in 2-propanol at 25 °C. While no phase stability region for 1:1 cocrystal could be found, the stable regions for the 2:1 cocrystals and their pure components were defined by eutectic points. The solubility of the 2:1 cocrystals was dependent on the concentration of the ligand in the solution and explained by the solubility product and 1:1 solution complexation. The mathematical models predicting the solubility of the 2:1 cocrystals were evaluated and found to fit the experimental data
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Alhalaweh, Amjad, et al.
(författare)
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Data mining of solubility parameters for computational prediction of drug–excipient miscibility
- 2014
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Ingår i: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:7, s. 904-909
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Tidskriftsartikel (refereegranskat)abstract
- Computational data mining is of interest in the pharmaceutical arena for the analysis of massive amounts of data and to assist in the management and utilization of the data. In this study, a data mining approach was used to predict the miscibility of a drug and several excipients, using Hansen solubility parameters (HSPs) as the data set. The K-means clustering algorithm was applied to predict the miscibility of indomethacin with a set of more than 30 compounds based on their partial solubility parameters [dispersion forces , polar forces and hydrogen bonding ]. The miscibility of the compounds was determined experimentally, using differential scanning calorimetry (DSC), in a separate study. The results of the K-means algorithm and DSC were compared to evaluate the K-means clustering prediction performance using the HSPs three-dimensional parameters, the two-dimensional parameters such as volume-dependent solubility and hydrogen bonding , and selected single (one-dimensional) parameters. Using HSPs, the prediction of miscibility by the K-means algorithm correlated well with the DSC results, with an overall accuracy of 94%. The prediction accuracy was the same (94%) when the two-dimensional parameters or the hydrogen-bonding (one-dimensional) parameter were used. The hydrogen-bonding parameter was thus a determining factor in predicting miscibility in such set of compounds, whereas the dispersive and polar parameters had only a weak correlation. The results show that data mining approach is a valuable tool for predicting drug–excipient miscibility because it is easy to use, is time and cost-effective, and is material sparing.
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| 5. |
- Alhalaweh, Amjad, et al.
(författare)
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Effects of polymer and surfactant on the dissolution and transformation profiles of cocrystals in aqueous media
- 2014
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 14:2, s. 643-648
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Tidskriftsartikel (refereegranskat)abstract
- Capturing solubility advantages of cocrystals is of great interest, and thus to understand the mechanism by which different excipients could maintain the supersaturation generated by cocrystals at the course of absorption in aqueous media is essential. To achieve this aim, the impact of different excipients on dissolution behavior of indomethacin-saccharin (IND-SAC) were monitored by measuring the concentrations of cocrystal components in the absence and presence of various concentration of excipients by HPLC, and solid phases were analyzed by differential scanning calorimetry after each experiment and the potential of Raman spectroscopy for monitoring phase transformations in situ was tested. No dissolution advantage was offered by cocrystals in the absence of any solution additive. The polymer and surfactant used in the study increased the solubility of IND but not SAC. This differential solubilization effect is believed to have stabilized the cocrystals for a relevant period for the absorption to take place. This could be attributed to either decreased gap between supersaturation and saturation of the drug or drug interaction with the additives. Understanding the effects of excipients type and concentration on the transformation profile is vital for designing enabling formulations for cocrystals. The eutectic constant may be useful in selecting excipients for stabilizing cocrystals.
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| 6. |
- Alhalaweh, Amjad, et al.
(författare)
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Formation of cocrystals by spray drying
- 2010
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Ingår i: Journal of Pharmacy and Pharmacology (JPP). - : Oxford University Press (OUP). - 0022-3573 .- 2042-7158. ; 62:10 - Special issue, s. 1332-1333
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Spray drying is a widely used technique for material processing and scale-up. The cocrystals formation by spray drying is studied. In contrast to solvent evaporation method, spray drying of stiochiometric solutions of incongruently saturating cocrystals had generated pure cocrystals. The formation phenomena in spray drying could be kinetically controlled or mediated by glassy state.
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| 7. |
- Alhalaweh, Amjad, et al.
(författare)
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Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying
- 2010
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 10:8, s. 3302-3305
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Tidskriftsartikel (refereegranskat)abstract
- Spray drying is a well established technique for material processing and scale-up. This study investigated the formation of pharmaceutical cocrystals by spray drying. The cocrystal formation mechanisms in spray-drying and solution methods, based on triangular phase diagrams, are discussed. The solvent evaporation of stoichiometric solutions of incongruently saturating cocrystals resulted in a mixture of phases, as dictated by the thermodynamic phase diagram. In contrast, spray drying of similar solutions of incongruently saturating systems generated pure cocrystals. It is thus suggested that the formation of cocrystals by spray drying could be kinetically controlled and/or mediated by the glassy state of the material.
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| 8. |
- 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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| 9. |
- Alhalaweh, Amjad, et al.
(författare)
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pH-dependent solubility of indomethacin-saccharin and carbamazepine-saccharin cocrystals in aqueous media
- 2012
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 9:9, s. 2605-2612
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Tidskriftsartikel (refereegranskat)abstract
- Cocrystals constitute an important class of pharmaceutical solids for their remarkable ability to modulate solubility and pH dependence of water insoluble drugs. Here we show how cocrystals of indomethacin-saccharin (IND-SAC) and carbamazepine-saccharin (CBZ-SAC) enhance solubility and impart a pH-sensitivity different from that of the drugs. IND-SAC exhibited solubilities 13 to 65 times higher than IND at pH values of 1 to 3, whereas CBZ-SAC exhibited a 2 to 10 times higher solubility than CBZ dihydrate. Cocrystal solubility dependence on pH predicted from mathematical models using cocrystal K(sp), and cocrystal component K(a) values, was in excellent agreement with experimental measurements. The cocrystal solubility increase relative to drug was predicted to reach a limiting value for a cocrystal with two acidic components. This limiting value is determined by the ionization constants of cocrystal components. Eutectic constants are shown to be meaningful indicators of cocrystal solubility and its pH dependence. The two contributions to solubility, cocrystal lattice and solvation, were evaluated by thermal and solubility determinations. The results show that solvation is the main barrier for the aqueous solubility of these drugs and their cocrystals, which are orders of magnitude higher than their lattice barriers. Cocrystal increase in solubility is thus a result of decreasing the solvation barrier compared to that of the drug. This work demonstrates the favorable properties of cocrystals and strategies that facilitate their meaningful characterization.
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| 10. |
- Alhalaweh, Amjad
(författare)
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Pharmaceutical cocrystals : formation mechanisms, solubility behaviour and solid-state properties
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The primary aim of pharmaceutical materials engineering is the successful formulation and process development of pharmaceutical products. The diversity of solid forms available offers attractive opportunities for tailoring material properties. In this context, pharmaceutical cocrystals, multicomponent crystalline materials with definite stoichiometries often stabilised by hydrogen bonding, have recently emerged as interesting alternative solid forms with potential for improving the physical and biopharmaceutical properties of a drug substance. There are, however, gaps in our understanding of the screening, scale-up and formulation operations required for effective use of cocrystals in drug product development. The objective of this thesis was to improve fundamental understanding of the formation mechanisms, solution behaviour and solid-state properties of pharmaceutical cocrystals. The solution chemistry and solubility behaviour of a diverse set of cocrystals were studied. It was found that the thermodynamic stability regions of the cocrystals and their components were defined by the phase solubility diagrams. Spray drying was introduced as a new method of preparing cocrystals; the formation mechanisms are illustrated. The cocrystals were more soluble than the respective drugs alone and the solubility-pH profiles were able to be predicted by mathematical models using a eutectic point determination approach. The cocrystal solubility was pH-dependent and could be engineered by the choice of coformers; this is valuable information for designing robust formulations. The solubility advantage of cocrystals was retained by the use of excipients that imparted kinetic and thermodynamic stability. The retention of drug-coformer association in processed cocrystals has been revealed, introducing a novel concept with potential implications for solid dosage form development. The final study demonstrated that the structure of the crystals and the particle engineering processes affected the solidstate and bulk particle properties of the cocrystals.This thesis contributes to the field of pharmaceutical science by advancing our understanding of crystallization processes and formulation development, thus enabling pharmaceutical cocrystals into drug products.
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