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Dr. Christian Lübbert studied chemical engineering at TU Dortmund University and finished his PhD in 2018. During his PhD, he successfully predicted the long-term stability of hundreds of pharmaceutical formulations via thermodynamic modeling. He developed methods to measure and to predict unwanted changes in amorphous formulations during long-term storage, e.g., phase separation and crystallization. His work was awarded as the best German PhD thesis in thermodynamics in 2018 and he received the TU Dortmund PhD award. During a postdoc, he intensified his work in the field of thermodynamic modeling in various fields of pharmaceutical formulation development and manufacturing. He founded with Prof. Gabriele Sadowski the company amofor in 2019, which provides in silico development tools for customers from the pharmaceutical industry.
The formulation of active pharmaceutical ingredients (APIs) as pharmaceutical co-crystals (CCs) is a promising way to overcome the poor aqueous solubility and therewith poor bioavailability of many APIs. Identifying suitable coformers (CFs) that form CCs with the API is a major challenge during CC development. In this work, we developed a material-sparing and simple approach to identify whether a certain API/CF combination can form CCs. This approach is based on the solvent vapor sorption of API/CF combinations in a dynamic vapor-sorption apparatus. CC formation is detected based on the solvent vapor uptake behavior of an API/CF crystal mixture. This screening approach was applied for carbamazepine (CBZ)/nicotinamide and CBZ/acetylsalicylic acid systems using ethanol and methanol as the volatile solvents. CC formation was observed for both systems with both solvents used. Additionally, the process and success of CC formation by vapor sorption is explained by predicted phase diagrams using the Perturbed-Chain Statistical Associating Fluid Theory. The developed approach is beneficial over co-grinding and other batch crystallization approaches in that it can be performed with only a few milligrams of the API, low solvent consumption, and a solvent sorption versus time behavior for identifying CC formation.
Heiner Veith; Christian Luebbert; Naír Rodríguez-Hornedo; Gabriele Sadowski. Co-Crystal Screening by Vapor Sorption of Organic Solvents. Crystal Growth & Design 2021, 1 .
AMA StyleHeiner Veith, Christian Luebbert, Naír Rodríguez-Hornedo, Gabriele Sadowski. Co-Crystal Screening by Vapor Sorption of Organic Solvents. Crystal Growth & Design. 2021; ():1.
Chicago/Turabian StyleHeiner Veith; Christian Luebbert; Naír Rodríguez-Hornedo; Gabriele Sadowski. 2021. "Co-Crystal Screening by Vapor Sorption of Organic Solvents." Crystal Growth & Design , no. : 1.
Hydrogels are one of the emerging classes of materials in current research. Besides their numerous applications in the medical sector as a drug delivery system or in tissue replacement, they are also suitable as irrigation components or as immobilization matrices in catalysis. For optimal application of these compounds, knowledge of the swelling properties and the diffusion mechanisms occurring in the gels is mandatory. This study is focused on hydrogels synthesized by radical polymerization of imidazolium-based ionic liquids. Both the swelling and diffusion behavior of these hydrogels were investigated via gravimetric swelling as well as sorption experiments implemented in water, ethanol, n-heptane, and tetrahydrofuran. In water and ethanol, strong swelling was observed while the transport mechanism deviated from Fickian-type behavior. By varying the counterion and the chain length of the cation, their influences on the processes were observed. The calculation of the diffusion coefficients delivered values in the range of 10−10 to 10−12 m2 s−1. The gravimetric results were supported by apparent diffusion coefficients measured through diffusion-weighted magnetic resonance imaging. A visualization of the water diffusion front within the hydrogel should help to further elucidate the diffusion processes in the imidazolium-based hydrogels.
Ann Jastram; Tobias Lindner; Christian Luebbert; Gabriele Sadowski; Udo Kragl. Swelling and Diffusion in Polymerized Ionic Liquids-Based Hydrogels. Polymers 2021, 13, 1834 .
AMA StyleAnn Jastram, Tobias Lindner, Christian Luebbert, Gabriele Sadowski, Udo Kragl. Swelling and Diffusion in Polymerized Ionic Liquids-Based Hydrogels. Polymers. 2021; 13 (11):1834.
Chicago/Turabian StyleAnn Jastram; Tobias Lindner; Christian Luebbert; Gabriele Sadowski; Udo Kragl. 2021. "Swelling and Diffusion in Polymerized Ionic Liquids-Based Hydrogels." Polymers 13, no. 11: 1834.
The presence of water in the form of relative humidity (RH) may lead to deliquescence of crystalline components above a certain RH, the deliquescence RH (DRH). Knowing the DRH values is essential, e.g., for the agrochemical industry, food industry, and pharmaceutical industry to identify stability windows for their crystalline products. This work applies the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) to purely predict the DRH of single components (organic acids, sugars, artificial sweeteners, and amides) and multicomponent crystal mixtures thereof only based on aqueous solubility data of the pure components. The predicted DRH values very well agree with the experimental ones. In addition, the temperature influence on the DRH value could be successfully predicted with PC-SAFT. The DRH prediction also differentiates between formation of hydrates and anhydrates. PC-SAFT-predicted phase diagrams of hydrate-forming components illustrate the influence of additional components on the hydrate formation as a function of RH. The DRH prediction via PC-SAFT allows for the determining of the stability of crystals and crystal mixtures without the need for time-consuming experiments.
Heiner Veith; Christian Luebbert; Gabriele Sadowski. Predicting Deliquescence Relative Humidities of Crystals and Crystal Mixtures. Molecules 2021, 26, 3176 .
AMA StyleHeiner Veith, Christian Luebbert, Gabriele Sadowski. Predicting Deliquescence Relative Humidities of Crystals and Crystal Mixtures. Molecules. 2021; 26 (11):3176.
Chicago/Turabian StyleHeiner Veith; Christian Luebbert; Gabriele Sadowski. 2021. "Predicting Deliquescence Relative Humidities of Crystals and Crystal Mixtures." Molecules 26, no. 11: 3176.
Knowledge of the stability of pharmaceutical formulations against relative humidity (RH) is essential if they are to become pharmaceutical products. The increasing interest in formulating active pharmaceutical ingredients as stable co-crystals (CCs) triggers the need for fast and reliable in-silico predictions of CC stability as a function of RH. CC storage at elevated RH can lead to deliquescence, which leads to CC dissolution and possible transformation to less soluble solid-state forms. In this work, the deliquescence RHs of the CCs succinic acid/nicotinamide, carbamazepine/nicotinamide, theophylline/citric acid, and urea/glutaric acid were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These deliquescence RH values together with predicted phase diagrams of CCs in water were used to determine critical storage conditions, that could lead to CC instability, that is, CC dissolution and precipitation of its components. The importance of CC phase purity on RH conditions for CC stability is demonstrated, where trace levels of a separate phase of active pharmaceutical ingredient or of coformer can significantly decrease the deliquescence RH. The use of additional excipients such as fructose or xylitol was predicted to decrease the deliquescence RH even further. All predictions were successfully validated by stability measurements at 58%, 76%, 86%, 93%, and 98% RH and 25 °C.
Heiner Veith; Maximilian Zaeh; Christian Luebbert; Naír Rodríguez-Hornedo; Gabriele Sadowski. Stability of Pharmaceutical Co-Crystals at Humid Conditions Can Be Predicted. Pharmaceutics 2021, 13, 433 .
AMA StyleHeiner Veith, Maximilian Zaeh, Christian Luebbert, Naír Rodríguez-Hornedo, Gabriele Sadowski. Stability of Pharmaceutical Co-Crystals at Humid Conditions Can Be Predicted. Pharmaceutics. 2021; 13 (3):433.
Chicago/Turabian StyleHeiner Veith; Maximilian Zaeh; Christian Luebbert; Naír Rodríguez-Hornedo; Gabriele Sadowski. 2021. "Stability of Pharmaceutical Co-Crystals at Humid Conditions Can Be Predicted." Pharmaceutics 13, no. 3: 433.
In this work we investigated the solubilities of 10 active pharmaceutical ingredients (APIs), namely, fenofibrate, ibuprofen, cinnarizine, carbamazepine, indomethacin, naproxen, griseofulvin, glibenclamide, felodipine, and praziquantel in the pharmaceutically relevant excipients tricaprylin, Lauroglycol FCC, Capryol 90, Kolliphor TPGS, ethanol, and monolaurin. API solubilities were either determined gravimetrically, with high-performance liquid chromatography, or with differential scanning calorimetry. Mutual solubilities in the three possible mixtures out of Kolliphor TPGS, tricaprylin, and carbitol as well as the vapor sorption of ethanol in tricaprylin were determined experimentally. The Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) pure-component parameters for seven APIs were determined via fitting to vapor pressures and liquid densities or to solubilities in organic solvents. In total, 80 binary interaction parameters were fitted to the investigated binary mixtures. They can be used in the future to improve the accuracy of lipid-based drug delivery systems in-silico screenings with PC-SAFT.
Joscha Brinkmann; Lara Exner; Sergey P. Verevkin; Christian Luebbert; Gabriele Sadowski. PC-SAFT Modeling of Phase Equilibria Relevant for Lipid-Based Drug Delivery Systems. Journal of Chemical & Engineering Data 2021, 66, 1280 -1289.
AMA StyleJoscha Brinkmann, Lara Exner, Sergey P. Verevkin, Christian Luebbert, Gabriele Sadowski. PC-SAFT Modeling of Phase Equilibria Relevant for Lipid-Based Drug Delivery Systems. Journal of Chemical & Engineering Data. 2021; 66 (3):1280-1289.
Chicago/Turabian StyleJoscha Brinkmann; Lara Exner; Sergey P. Verevkin; Christian Luebbert; Gabriele Sadowski. 2021. "PC-SAFT Modeling of Phase Equilibria Relevant for Lipid-Based Drug Delivery Systems." Journal of Chemical & Engineering Data 66, no. 3: 1280-1289.
Purpose This work proposes an in-silico screening method for identifying promising formulation candidates in complex lipid-based drug delivery systems (LBDDS). Method The approach is based on a minimum amount of experimental data for API solubilites in single excipients. Intermolecular interactions between APIs and excipients as well as between different excipients were accounted for by the Perturbed-Chain Statistical Associating Fluid Theory. The approach was applied to the in-silico screening of lipid-based formulations for ten model APIs (fenofibrate, ibuprofen, praziquantel, carbamazepine, cinnarizine, felodipine, naproxen, indomethacin, griseofulvin and glibenclamide) in mixtures of up to three out of nine excipients (tricaprylin, Capmul MCM, caprylic acid, Capryol™ 90, Lauroglycol™ FCC, Kolliphor TPGS, polyethylene glycol, carbitol and ethanol). Results For eight out of the ten investigated model APIs, the solubilities in the final formulations could be enhanced by up to 100 times compared to the solubility in pure tricaprylin. Fenofibrate, ibuprofen, praziquantel, carbamazepine are recommended as type I formulations, whereas cinnarizine and felodipine showed a distinctive solubility gain in type II formulations. Increased solubility was found for naproxen and indomethacin in type IIIb and type IV formulations. The solubility of griseofulvin and glibenclamide could be slightly enhanced in type IIIb formulations. The experimental validation agreed very well with the screening results. Conclusion The API solubility individually depends on the choice of excipients. The proposed in-silico-screening approach allows formulators to quickly determine most-appropriate types of lipid-based formulations for a given API with low experimental effort. Graphical abstract
Joscha Brinkmann; Lara Exner; Christian Luebbert; Gabriele Sadowski. In-Silico Screening of Lipid-Based Drug Delivery Systems. Pharmaceutical Research 2020, 37, 1 -12.
AMA StyleJoscha Brinkmann, Lara Exner, Christian Luebbert, Gabriele Sadowski. In-Silico Screening of Lipid-Based Drug Delivery Systems. Pharmaceutical Research. 2020; 37 (12):1-12.
Chicago/Turabian StyleJoscha Brinkmann; Lara Exner; Christian Luebbert; Gabriele Sadowski. 2020. "In-Silico Screening of Lipid-Based Drug Delivery Systems." Pharmaceutical Research 37, no. 12: 1-12.
Many amorphous solid dispersions (ASDs) are thermodynamically unstable. Thus, the active pharmaceutical ingredient (API) might crystallize over time. The crystallization kinetics and therewith the long-term stability of ASDs depends on the storage conditions temperature and relative humidity (RH) as they determine the molecular mobility of the API in the polymer. To quantify the molecular mobility, the rheological behavior of two different ASDs with ibuprofen and either poly(vinyl acetate) or poly(vinylpyrrolidone-co-vinyl acetate) was analyzed as function of temperature and relative humidity by means of an oscillatory rheometer. The plasticizing effect of ibuprofen and absorbed water on the zero-shear viscosity of the polymer could be fully explained by the reduction of the glass-transition temperature of the mixture compared to the one of the pure polymer. Moreover, this work proposes an approach to predict the zero-shear viscosity of an ASD based on only the temperature dependence of the zero-shear viscosity of the pure polymer as well as the predicted water content in the ASD at certain RH using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT).
Friederike Wolbert; Joel Stecker; Christian Luebbert; Gabriele Sadowski. Viscosity of ASDs at humid conditions. European Journal of Pharmaceutics and Biopharmaceutics 2020, 154, 387 -396.
AMA StyleFriederike Wolbert, Joel Stecker, Christian Luebbert, Gabriele Sadowski. Viscosity of ASDs at humid conditions. European Journal of Pharmaceutics and Biopharmaceutics. 2020; 154 ():387-396.
Chicago/Turabian StyleFriederike Wolbert; Joel Stecker; Christian Luebbert; Gabriele Sadowski. 2020. "Viscosity of ASDs at humid conditions." European Journal of Pharmaceutics and Biopharmaceutics 154, no. : 387-396.
Amorphous solid dispersions (ASD) are state-of-the art enabling formulations for poorly water-soluble active pharmaceutical ingredients (APIs). Depending on the relative humidity (RH), temperature, and API content, ASDs are often metastable against crystallization of the API or even against the formation of API hydrates in the ASD. Knowing the conditions at which API crystals or API hydrate formation may occur in ASDs therefore is an important prerequisite for developing a suitable formulation strategy for APIs. ASDs containing hydrate-forming APIs (carbamazepine/polyvinylpyrrolidone, carbamazepine/hydroxypropylmethylcellulose acetate succinate, and theophylline/polyvinylpyrrolidone) were investigated in this work. The influence of polymer type, RH, API content, and water sorption on the ASD stability was determined via phase diagrams predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These predictions were successfully validated by long-term stability tests at 295 K and 0%, 58%, 76%, 86%, and 93% RH. Hydrate crystals are formed above their critical RH. Thus, ASDs with carbamazepine (critical RH 65% at 295 K) as well as theophylline (critical RH 58% RH) showed hydrate crystals at 76%, 86% and 93% RH, no matter which polymer was used for preparing the ASD.
Heiner Veith; Erol Turan; Christian Luebbert; Gabriele Sadowski. Hydrate formation in polymer-based pharmaceutical formulations. Fluid Phase Equilibria 2020, 521, 112677 .
AMA StyleHeiner Veith, Erol Turan, Christian Luebbert, Gabriele Sadowski. Hydrate formation in polymer-based pharmaceutical formulations. Fluid Phase Equilibria. 2020; 521 ():112677.
Chicago/Turabian StyleHeiner Veith; Erol Turan; Christian Luebbert; Gabriele Sadowski. 2020. "Hydrate formation in polymer-based pharmaceutical formulations." Fluid Phase Equilibria 521, no. : 112677.
Understanding and prevention of unwanted changes of a pharmaceutical formulation during the production process is part of the critical requirements for the successful approval of a new drug product. Polymer-based formulations, so-called amorphous solid dispersions (ASDs), are often produced via solvent-based processes. In such processes, active pharmaceutical ingredient (API) and polymers are first dissolved in a solvent or solvent mixture, then the solvent is evaporated e.g. via spray drying or rotary evaporation. During the drying step, unwanted liquid-liquid phase separation may occur, leading to polymer rich and API rich regions with crystallization potential, and thus, heterogeneities and a two-phasic system in the final ASD. Phase separation in ASDs may impact their bioperformance due to the locally higher degree of API supersaturation. Although it is known that the choice of the solvent plays an important role in the formation of heterogeneities, solvent-impact on ASD drying and eventual product quality is often neglected in the process design. This study aims to investigate for the first time the phase behavior and drying process of API/polymer/solvent(s) systems from a thermodynamic perspective. Unwanted phase changes during the drying process of the ASD containing hydroxypropyl methylcellulose acetate succinate and naproxen prepared from acetone/water or ethanol/water solvent mixtures were predicted using the thermodynamic model PC-SAFT. The predicted phase behavior and drying curves were successfully validated by confocal Raman spectroscopy.
Stefanie Dohrn; Philipp Reimer; Christian Luebbert; Kristin Lehmkemper; Samuel O. Kyeremateng; Matthias Degenhardt; Gabriele Sadowski. Thermodynamic Modeling of Solvent-Impact on Phase Separation in Amorphous Solid Dispersions during Drying. Molecular Pharmaceutics 2020, 17, 2721 -2733.
AMA StyleStefanie Dohrn, Philipp Reimer, Christian Luebbert, Kristin Lehmkemper, Samuel O. Kyeremateng, Matthias Degenhardt, Gabriele Sadowski. Thermodynamic Modeling of Solvent-Impact on Phase Separation in Amorphous Solid Dispersions during Drying. Molecular Pharmaceutics. 2020; 17 (7):2721-2733.
Chicago/Turabian StyleStefanie Dohrn; Philipp Reimer; Christian Luebbert; Kristin Lehmkemper; Samuel O. Kyeremateng; Matthias Degenhardt; Gabriele Sadowski. 2020. "Thermodynamic Modeling of Solvent-Impact on Phase Separation in Amorphous Solid Dispersions during Drying." Molecular Pharmaceutics 17, no. 7: 2721-2733.
Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, HPLC, and Raman spectroscopy. Further this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Further, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.
Joscha Brinkmann; Frauke Rest; Christian Luebbert; Gabriele Sadowski. Solubility of Pharmaceutical Ingredients in Natural Edible Oils. Molecular Pharmaceutics 2020, 17, 2499 -2507.
AMA StyleJoscha Brinkmann, Frauke Rest, Christian Luebbert, Gabriele Sadowski. Solubility of Pharmaceutical Ingredients in Natural Edible Oils. Molecular Pharmaceutics. 2020; 17 (7):2499-2507.
Chicago/Turabian StyleJoscha Brinkmann; Frauke Rest; Christian Luebbert; Gabriele Sadowski. 2020. "Solubility of Pharmaceutical Ingredients in Natural Edible Oils." Molecular Pharmaceutics 17, no. 7: 2499-2507.
In the pharmaceutical industry, polymers are used as excipients for formulating poorly water-soluble active pharmaceutical ingredients (APIs) in so-called “amorphous solid dispersions” (ASDs). ASDs can be produced via solvent-based processes, where API and polymer are both dissolved in a solvent, followed by a solvent evaporation step (e.g. spray drying). Aiming at a homogeneous API/polymer formulation, phase separation of the components (API, polymer, solvent) during solvent evaporation must be avoided. The latter is often determined by the phase behavior of polymer/solvent mixtures used for ASD processing. Therefore, this work investigates the polymer-solvent interactions in these mixtures. Suitable polymer/solvent combinations investigated in this work comprise the pharmaceutically relevant polymers poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA64), and hydroxyppropyl methylcellulose acetate succinate 126G (HPMCAS) as well as the solvents acetone, dichloromethane (DCM), ethanol, ethyl acetate, methanol, and water. Based on vapor-sorption experiments demixing of solvents and polymers were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These were found to be correct for all investigated solvent/polymer mixtures. Acetone, DCM, ethanol, methanol, and water were found to be completely miscible with PVPVA64. DCM, ethanol, methanol, and water were found to be completely miscible with PVP K90, while none of the investigated solvents was appropriate for avoiding immiscibility with HPMCAS. In addition, the impact of temperature, polymer molecular weight, and solvent-mixture composition on miscibility was successfully predicted using PC-SAFT. Thus, the proposed methodology allows identifying suitable solvents or solvent mixtures relevant for solvent-based preparations of pharmaceutical ASD formulations with low experimental effort.
Stefanie Dohrn; Christian Luebbert; Kristin Lehmkemper; Samuel O. Kyeremateng; Matthias Degenhardt; Gabriele Sadowski. Phase behavior of pharmaceutically relevant polymer/solvent mixtures. International Journal of Pharmaceutics 2020, 577, 119065 .
AMA StyleStefanie Dohrn, Christian Luebbert, Kristin Lehmkemper, Samuel O. Kyeremateng, Matthias Degenhardt, Gabriele Sadowski. Phase behavior of pharmaceutically relevant polymer/solvent mixtures. International Journal of Pharmaceutics. 2020; 577 ():119065.
Chicago/Turabian StyleStefanie Dohrn; Christian Luebbert; Kristin Lehmkemper; Samuel O. Kyeremateng; Matthias Degenhardt; Gabriele Sadowski. 2020. "Phase behavior of pharmaceutically relevant polymer/solvent mixtures." International Journal of Pharmaceutics 577, no. : 119065.
The formation of solvates, hydrates, or different polymorphs significantly alters the physico-chemical properties of a target component (TC) (e.g. active pharmaceutical or agrochemical active ingredient), such as solubility and dissolution behavior. Thus, it is very important to know under which conditions a certain solvate, hydrate, or polymorph is formed. This information can be obtained from phase diagrams which are usually based on solubility measurements. Possible pitfalls in measuring the solubility of TC hydrates or solvates in solvents and solvent mixtures are discussed and strategies for obtaining reliable solubility data are proposed. To substantiate the proposed solubility-measurement strategies, a thermodynamic approach based on the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) for modeling solvate/hydrate solubilities was developed. This approach allows identifying stability regions of solvates/hydrates and predicting solubilities of solvates/hydrates or of polymorphs in pure solvents and solvent mixtures. It was successfully verified for modeling the solubility of the indomethacin-methanol solvate in methanol and of the carbamazepine dihydrate in water. Furthermore, the solubility of carbamazepine dihydrate and theophylline monohydrate in water/ethanol mixtures was predicted in excellent agreement with experimental data.
Heiner Veith; Christian Luebbert; Gabriele Sadowski. Correctly Measuring and Predicting Solubilities of Solvates, Hydrates, and Polymorphs. Crystal Growth & Design 2020, 20, 723 -735.
AMA StyleHeiner Veith, Christian Luebbert, Gabriele Sadowski. Correctly Measuring and Predicting Solubilities of Solvates, Hydrates, and Polymorphs. Crystal Growth & Design. 2020; 20 (2):723-735.
Chicago/Turabian StyleHeiner Veith; Christian Luebbert; Gabriele Sadowski. 2020. "Correctly Measuring and Predicting Solubilities of Solvates, Hydrates, and Polymorphs." Crystal Growth & Design 20, no. 2: 723-735.
Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8–18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU = 10.5 wt% at 25 °C in tricaprylin) TGs compared to unsaturated ones (wIBU = 4.0 wt% at 25 °C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures. API solubilities in TGs and TG mixtures (mixtures of tricaprylin and tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility.
Joscha Brinkmann; Fabian Huxoll; Christian Luebbert; Gabriele Sadowski. Solubility of pharmaceutical ingredients in triglycerides. European Journal of Pharmaceutics and Biopharmaceutics 2019, 145, 113 -120.
AMA StyleJoscha Brinkmann, Fabian Huxoll, Christian Luebbert, Gabriele Sadowski. Solubility of pharmaceutical ingredients in triglycerides. European Journal of Pharmaceutics and Biopharmaceutics. 2019; 145 ():113-120.
Chicago/Turabian StyleJoscha Brinkmann; Fabian Huxoll; Christian Luebbert; Gabriele Sadowski. 2019. "Solubility of pharmaceutical ingredients in triglycerides." European Journal of Pharmaceutics and Biopharmaceutics 145, no. : 113-120.
Vapor pressures for the saturated triglycerides (TGs) tricaprylin, tricaprin, and liquid densities of tricaprylin were experimentally determined. TG pure-component parameters for the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) were fitted to that data and validated with densities of the binary mixtures octanol/tricaprin and octanol/trilaurin at different temperatures and TG mass fractions. Furthermore, pure-component parameters of the unsaturated TGs triolein and trilinolein were estimated by a group-contribution method. Correctly predicted solid–liquid equilibria of mixtures containing the before-mentioned TGs revealed that intermolecular interactions among TGs are quantitatively described by PC-SAFT.
Joscha Brinkmann; Christian Luebbert; Dzmitry H. Zaitsau; Sergey P. Verevkin; Gabriele Sadowski. Thermodynamic Modeling of Triglycerides using PC-SAFT. Journal of Chemical & Engineering Data 2019, 64, 1446 -1453.
AMA StyleJoscha Brinkmann, Christian Luebbert, Dzmitry H. Zaitsau, Sergey P. Verevkin, Gabriele Sadowski. Thermodynamic Modeling of Triglycerides using PC-SAFT. Journal of Chemical & Engineering Data. 2019; 64 (4):1446-1453.
Chicago/Turabian StyleJoscha Brinkmann; Christian Luebbert; Dzmitry H. Zaitsau; Sergey P. Verevkin; Gabriele Sadowski. 2019. "Thermodynamic Modeling of Triglycerides using PC-SAFT." Journal of Chemical & Engineering Data 64, no. 4: 1446-1453.
Amorphous solid dispersions (ASD) are often used for formulating poorly-water-soluble active pharmaceutical ingredients (APIs). In an ASD, the amorphous API is embedded in a suitable matrix excipient in order to stabilize the amorphous state and control the dissolution performance. ASDs can be prepared by commonly dissolving the API and the polymer in a suitable organic solvent which is evaporated afterwards (e.g. via spray drying) aiming at a homogeneous API distribution in the polymer matrix. Sometimes, unexpected solvent influences on the heterogeneity of the dry ASD are observed. Thermodynamic predictions using the Perturbed-Chain Statistical Associating Fluid Theory combined with experimental investigations via Raman spectroscopy, differential scanning calorimetry and microscopy performed in this work, revealed the amorphous phase separation (APS) between the solvent and the polymer as causing the ASD heterogeneities. It will be shown that thermodynamic modeling allows for identifying appropriate solvents that will neither show APS with the polymeric excipient nor at any time of the drying process of ASD formulations.
Christian Luebbert; Daniel Real; Gabriele Sadowski. Choosing Appropriate Solvents for ASD Preparation. Molecular Pharmaceutics 2018, 15, 5397 -5409.
AMA StyleChristian Luebbert, Daniel Real, Gabriele Sadowski. Choosing Appropriate Solvents for ASD Preparation. Molecular Pharmaceutics. 2018; 15 (11):5397-5409.
Chicago/Turabian StyleChristian Luebbert; Daniel Real; Gabriele Sadowski. 2018. "Choosing Appropriate Solvents for ASD Preparation." Molecular Pharmaceutics 15, no. 11: 5397-5409.
Amorphous solid dispersions (ASD) are intended to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients. However, the development of long-term stable ASDs is often limited by the unwanted crystallization of the incorporated active pharmaceutical ingredient. Robust detection and quantification of crystal formation - especially at temperatures and humidites relevant for long-term storage tests - are essential for understanding crystallization phenomena. In this work, the crystallization kinetics in spray-dried nifedipine/poly (vinyl acetate) ASDs was investigated by measuring the time-dependent water sorption behavior at constant storage conditions. By coupling these experiments with thermodynamic predictions of the water sorption in amorphous and crystallized ASDs using the Perturbed-Chain Statistical Associating Fluid Theory, the amount of crystallized nifedipine as function of time could be determined in-situ just by weighing the ASD samples and without any calibration. The experimental findings were validated by X-ray diffraction measurements. Metastable ASDs with nifedipine contents between 70 wt% and 90 wt% were investigated at relative humidities between 60% RH and 90% RH and in a temperature range between 30 °C and 40 °C. Storage at high temperature and at high RH, and high nifedipine contents dramatically increased the crystallization rates.
Christian Luebbert; Gabriele Sadowski. In-situ determination of crystallization kinetics in ASDs via water sorption experiments. European Journal of Pharmaceutics and Biopharmaceutics 2018, 127, 183 -193.
AMA StyleChristian Luebbert, Gabriele Sadowski. In-situ determination of crystallization kinetics in ASDs via water sorption experiments. European Journal of Pharmaceutics and Biopharmaceutics. 2018; 127 ():183-193.
Chicago/Turabian StyleChristian Luebbert; Gabriele Sadowski. 2018. "In-situ determination of crystallization kinetics in ASDs via water sorption experiments." European Journal of Pharmaceutics and Biopharmaceutics 127, no. : 183-193.
The molecular integration of poorly-water-soluble active pharmaceutical ingredients (APIs) in a suitable polymeric matrix is a possible approach to enhance the dissolution behavior and solubility of these APIs. Like all newly-developed pharmaceutical formulations, these formulations (often denoted as amorphous solid dispersions (ASDs)) need to undergo storage stability tests at defined relative humidity (RH) and temperature conditions. In a previous work (Int. J. Pharm. 532 (2017) 635-646), it was shown that thermodynamic modeling can be successfully used to predict the long-term stability of ASDs against API crystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This works in turn demonstrates the prediction of water sorption in ASDs accounting for potentially occurring API-crystallization and MIAPS. The water sorption and phase behavior of ASDs containing the APIs felodipine and ibuprofen incorporated in three different hydrophilic polymers poly(vinyl pyrrolidone), poly(vinyl acetate), and poly(vinyl pyrrolidone-co-vinyl acetate) at the conditions 25 °C/60% RH and 40 °C/75% RH was predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). The predictions were successfully validated via two-years-lasting water-sorption experiments. It was shown that crystallization of the API and MIAPS on the one hand and water sorption in the ASDs on the other hand dramatically influence each other and that this behavior can even be quantitatively predicted by PC-SAFT which provides valuable insights already at early stages of formulation development.
Christian Luebbert; Maximilian Wessner; Gabriele Sadowski. Mutual Impact of Phase Separation/Crystallization and Water Sorption in Amorphous Solid Dispersions. Molecular Pharmaceutics 2018, 15, 669 -678.
AMA StyleChristian Luebbert, Maximilian Wessner, Gabriele Sadowski. Mutual Impact of Phase Separation/Crystallization and Water Sorption in Amorphous Solid Dispersions. Molecular Pharmaceutics. 2018; 15 (2):669-678.
Chicago/Turabian StyleChristian Luebbert; Maximilian Wessner; Gabriele Sadowski. 2018. "Mutual Impact of Phase Separation/Crystallization and Water Sorption in Amorphous Solid Dispersions." Molecular Pharmaceutics 15, no. 2: 669-678.
Active Pharmaceutical Ingredients (APIs) are often dissolved in polymeric matrices to control the gastrointestinal dissolution and to stabilize the amorphous state of the API. During the pharmaceutical development of new formulations, stability studies via storage at certain temperature and relative humidity (RH) have to be carried out to verify the long-term thermodynamic stability of these formulations against unwanted recrystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This study focuses on predicting the MIAPS of API/polymer formulations at elevated RH. In a first step, the phase behavior of water-free formulations of ibuprofen (IBU) and felodipine (FEL) combined with the polymers poly(vinyl pyrrolidone) (PVP), poly(vinyl acetate) (PVAC) and poly (vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) was determined experimentally by differential scanning calorimetry (DSC). The phase behavior of these water-free formulations was modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). Based on this, the API solubility and MIAPS in the above-mentioned formulations at humid conditions was predicted in perfect agreement with the results of two-year lasting stability studies at 25°C/0% RH and 40°C/75% RH. MIAPS was predicted and also experimentally found for the FEL/PVP, FEL/PVPVA64 and IBU/PVP formulations, whereas MIAPS was neither predicted nor measured for the IBU/PVPVA64 system and PVAC-containing formulations. It was thus shown that the results of time-consuming long-term stability tests can be correctly predicted via thermodynamic modeling with PC-SAFT.
Christian Luebbert; Gabriele Sadowski. Moisture-induced phase separation and recrystallization in amorphous solid dispersions. International Journal of Pharmaceutics 2017, 532, 635 -646.
AMA StyleChristian Luebbert, Gabriele Sadowski. Moisture-induced phase separation and recrystallization in amorphous solid dispersions. International Journal of Pharmaceutics. 2017; 532 (1):635-646.
Chicago/Turabian StyleChristian Luebbert; Gabriele Sadowski. 2017. "Moisture-induced phase separation and recrystallization in amorphous solid dispersions." International Journal of Pharmaceutics 532, no. 1: 635-646.
The long-term stability of pharmaceutical formulations of poorly-soluble drugs in polymers determines their bioavailability and therapeutic applicability. However, these formulations do not only often tend to crystallize during storage, but also tend to undergo unwanted amorphous-amorphous phase separations (APS). Whereas the crystallization behavior of APIs in polymers has been measured and modeled during the last years, the APS phenomenon is still poorly understood. In this study, the crystallization behavior, APS, and glass-transition temperatures formulations of ibuprofen and felodipine in polymeric PLGA excipients exhibiting different ratios of lactic acid and glycolic acid monomers in the PLGA chain were investigated by means of hot-stage microscopy and DSC. APS and recrystallization was observed in ibuprofen/PLGA formulations, while only recrystallization occurred in felodipine/PLGA formulations. Based on a successful modeling of the crystallization behavior using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the occurrence of APS was predicted in agreement with experimental findings.
Christian Luebbert; Fabian Huxoll; Gabriele Sadowski. Amorphous-Amorphous Phase Separation in API/Polymer Formulations. Molecules 2017, 22, 296 .
AMA StyleChristian Luebbert, Fabian Huxoll, Gabriele Sadowski. Amorphous-Amorphous Phase Separation in API/Polymer Formulations. Molecules. 2017; 22 (2):296.
Chicago/Turabian StyleChristian Luebbert; Fabian Huxoll; Gabriele Sadowski. 2017. "Amorphous-Amorphous Phase Separation in API/Polymer Formulations." Molecules 22, no. 2: 296.
Amorphous formulations of APIs in polymers tend to absorb water from the atmosphere. This absorption of water can induce API recrystallization, leading to reduced long-term stability during storage. In this work, the phase behavior of different formulations was investigated as a function of relative humidity. Indomethacin and naproxen were chosen as model APIs and poly(vinyl pyrrolidone) (PVP) and poly(vinyl pyrrolidone-co-vinyl acetate) (PVPVA64) as excipients. The formulations were prepared by spray drying. The water sorption in pure polymers and in formulations was measured at 25°C and at different values of relative humidity (RH=25%, 50% and 75%). Most water was absorbed in PVP-containing systems, and water sorption was decreasing with increasing API content. These trends could also be predicted in good agreement with the experimental data using the thermodynamic model PC-SAFT. Furthermore, the effect of absorbed water on API solubility in the polymer and on the glass-transition temperature of the formulations was predicted with PC-SAFT and the Gordon-Taylor equation, respectively. The absorbed water was found to significantly decrease the API solubility in the polymer as well as the glass-transition temperature of the formulation. Based on a quantitative modeling of the API/polymer phase diagrams as a function of relative humidity, appropriate API/polymer compositions can now be selected to ensure long-term stable amorphous formulations at given storage conditions.
Anke Prudic; Yuanhui Ji; Christian Luebbert; Gabriele Sadowski. Influence of humidity on the phase behavior of API/polymer formulations. European Journal of Pharmaceutics and Biopharmaceutics 2015, 94, 352 -362.
AMA StyleAnke Prudic, Yuanhui Ji, Christian Luebbert, Gabriele Sadowski. Influence of humidity on the phase behavior of API/polymer formulations. European Journal of Pharmaceutics and Biopharmaceutics. 2015; 94 ():352-362.
Chicago/Turabian StyleAnke Prudic; Yuanhui Ji; Christian Luebbert; Gabriele Sadowski. 2015. "Influence of humidity on the phase behavior of API/polymer formulations." European Journal of Pharmaceutics and Biopharmaceutics 94, no. : 352-362.