uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Bergström, ChristelORCID iD iconorcid.org/289172612
Alternative names
Publications (10 of 58) Show all publications
Bergström, C. A. & Larsson, P. (2018). Computational prediction of drug solubility in water-based systems: qualitative and quantitative approaches used in the current drug discovery and development setting. International Journal of Pharmaceutics, 540(1-2), 185-193
Open this publication in new window or tab >>Computational prediction of drug solubility in water-based systems: qualitative and quantitative approaches used in the current drug discovery and development setting
2018 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 540, no 1-2, p. 185-193Article, review/survey (Refereed) Published
Abstract [en]

In this review we will discuss recent advances in computational prediction of solubility in water-based solvents. Our focus is set on recent advances in predictions of biorelevant solubility in media mimicking the human intestinal fluids and on new methods to predict the thermodynamic cycle rather than prediction of solubility in pure water through quantitative structure property relationships (QSPR). While the literature is rich in QSPR models for both solubility and melting point, a physicochemical property strongly linked to the solubility, recent advances in the modelling of these properties make use of theory and computational simulations to better predict these properties or processes involved therein (e.g. solid state crystal lattice packing, dissociation of molecules from the lattice and solvation). This review serves to provide an update on these new approaches and how they can be used to more accurately predict solubility, and also importantly, inform us on molecular interactions and processes occurring during drug dissolution and solubilisation.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-342632 (URN)10.1016/j.ijpharm.2018.01.044 (DOI)000427584900019 ()
Funder
EU, European Research Council, 638965
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-04-05Bibliographically approved
Clulow, A. J., Parrow, A., Hawley, A., Khan, J., Pham, A. C., Larsson, P., . . . Boyd, B. J. (2017). Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid. Journal of Physical Chemistry B, 121(48), 10869-10881
Open this publication in new window or tab >>Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid
Show others...
2017 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 121, no 48, p. 10869-10881Article in journal (Refereed) Published
Abstract [en]

The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by the amount that can be dissolved by the endogenous fluids present in the gut. Human intestinal fluids (HIFs) comprise a complex mixture of bile salts, phospholipids, steroids and glycerides that vary in composition in the fed and fasted state and between subjects. A number of simulated intestinal fluid (SIF) compositions have been developed to mimic fasted and fed state intestinal conditions and allow the in vitro determination of drug solubility as a proxy for the maximum dissolved concentration it is possible to reach. In particular these solvents are used during the development of lipophilic and poorly water-soluble drugs but questions remain around the differences that may arise from the source and methods of preparation of these fluids. In this work, a range of SIFs were studied using small angle X-ray scattering (SAXS), cryogenic -transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations in order to analyze their structures. In-house prepared SIFs based on sodium taurodeoxycholate (NaTDC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) formed oblate ellipsoidal micelles irrespective of lipid concentration and preparation conditions. In contrast, commercially available SIFs based on sodium taurocholate and lecithin formed prolate ellipsoidal micelles in the fed state and vesicles in the fasted state. These structural variations are the likely reason for the dramatic differences sometimes observed in the solubility enhancements for hydrophobic drugs, nutrients and digestion products when using different SIFs. However, the structural homogeneity of the NaTDC/DOPC micelles makes them ideal candidates for standardizing SIF formulations as the structures of the solubilizing nanoaggregates therein are not sensitive to the preparation method.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-340253 (URN)10.1021/acs.jpcb.7b08622 (DOI)000417672200014 ()29090933 (PubMedID)
Funder
Australian Research Council, DP160102906, FT120100697EU, European Research Council, 638965Swedish Research Council, 2014-3309EU, Horizon 2020, 654000
Available from: 2018-01-31 Created: 2018-01-31 Last updated: 2018-01-31Bibliographically approved
Andersson, S. B. E., Alvebratt, C. & Bergström, C. (2017). Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds. Pharmaceutical research, 34(9), 1805-1816
Open this publication in new window or tab >>Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds
2017 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 9, p. 1805-1816Article in journal (Refereed) Published
Abstract [en]

Purpose: To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.

Methods: The IDR and apparent solubility (S-app) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the mu DISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.

Results: The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (mu g-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2-70.6 mu g/min/cm(2) and the IDR/S-app ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.

Conclusions: The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/S-app is proposed as a measure of particle size sensitivity when significant solubilization may occur.

Keywords
apparent solubility, controlled suspensions, dissolution-limited drug absorption, intrinsic dissolution rate, particle size reduction
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-333062 (URN)10.1007/s11095-017-2188-1 (DOI)000406495100006 ()28620887 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 115369
Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2018-01-13Bibliographically approved
Plum, J., Madsen, C. M., Teleki, A., Bevernage, J., Mathews, C. d., Karlsson, E. M., . . . Mullertz, A. (2017). Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method. Molecular Pharmaceutics, 14(12), 4161-4169
Open this publication in new window or tab >>Investigation of the Intra- and Interlaboratory Reproducibility of a Small Scale Standardized Supersaturation and Precipitation Method
Show others...
2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4161-4169Article in journal (Refereed) Published
Abstract [en]

The high number of poorly water-soluble compounds in drug development has increased the need for enabling formulations to improve oral bioavailability. One frequently applied approach is to induce supersaturation at the absorptive site, e.g., the small intestine, increasing the amount of dissolved compound available for absorption. However, due to the stochastic nature of nucleation, supersaturating drug delivery systems may lead to inter- and intrapersonal variability. The ability to define a feasible range with respect to the supersaturation level is a crucial factor for a successful formulation. Therefore, an in vitro method is needed, from where the ability of a compound to supersaturate can be defined in a reproducible way. Hence, this study investigates the reproducibility of an in vitro small scale standardized supersaturation and precipitation method (SSPM). First an intralaboratory reproducibility study of felodipine was conducted, after which seven partners contributed with data for three model compounds; aprepitant, felodipine, and fenofibrate, to determine the interlaboratory reproducibility of the SSPM. The first part of the SSPM determines the apparent degrees of supersaturation (aDS) to investigate for each compound. Each partner independently determined the maximum possible aDS and induced 100, 87.5, 75, and 50% of their determined maximum possible aDS in the SSPM. The concentration time profile of the supersaturation and following precipitation was obtained in order to determine the induction time (t(ind)) for detectable precipitation. The data showed that the absolute values of t(ind) and aDS were not directly comparable between partners, however, upon linearization of the data a reproducible rank ordering of the three model compounds was obtained based on the beta-value, which was defined as the slope of the In(t(ind)) versus In(aDS)(-2) plot. Linear regression of this plot showed that aprepitant had the highest beta-value, 15.1, while felodipine and fenofibrate had comparable beta-values, 4.0 and 4.3, respectively. Of the five partners contributing with full data sets, 80% could obtain the same rank order for the three model compounds using the SSPM (aprepitant > felodipine approximate to fenofibrate). The alpha-value is dependent on the experimental setup and can be used as a parameter to evaluate the uniformity of the data set. This study indicated that the SSPM was able to obtain the same rank order of the beta-value between partners and, thus, that the SSPM may be used to classify compounds depending on their supersaturation propensity.

Keywords
supersaturation, precipitation, oral drug delivery, variability
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-339902 (URN)10.1021/acs.molpharmaceut.7b00419 (DOI)000417342400005 ()29043811 (PubMedID)
Available from: 2018-01-23 Created: 2018-01-23 Last updated: 2018-03-08Bibliographically approved
Edueng, K., Mahlin, D., Larsson, P. & Bergström, C. (2017). Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways. Journal of Controlled Release, 256, 193-202
Open this publication in new window or tab >>Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways
2017 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 256, p. 193-202Article in journal (Refereed) Published
Abstract [en]

We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (mu DISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%-0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Amorphous, Crystallization, Solid-state, Dissolution, Stabilization, Polymer, Supersaturation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-329635 (URN)10.1016/j.jconrel.2017.04.015 (DOI)000403324800017 ()28412224 (PubMedID)
Funder
EU, European Research Council, 638965Swedish Research Council, 2014-3309
Available from: 2017-09-25 Created: 2017-09-25 Last updated: 2018-01-13Bibliographically approved
Larsson, P., Alskär, L. C. & Bergström, C. (2017). Molecular Structuring and Phase Transition of Lipid-Based Formulations upon Water Dispersion: A Coarse-Grained Molecular Dynamics Simulation Approach. Molecular Pharmaceutics, 14(12), 4145-4153
Open this publication in new window or tab >>Molecular Structuring and Phase Transition of Lipid-Based Formulations upon Water Dispersion: A Coarse-Grained Molecular Dynamics Simulation Approach
2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4145-4153Article in journal (Refereed) Published
Abstract [en]

The internal molecular structure of lipid-based formulations (LBFs) is poorly understood. In this work we aimed at establishing coarse-grained molecular dynamics simulations as a tool for rapid screening and investigation of the internal environment of these formulations. In order to study complex LBFs composed of different kinds of lipids we simulated a number of systems containing either medium-chain or long-chain lipids with varying proportions of tri-, di-, and monoglycerides. Structural and dynamic measurements and analyses identified that the internal environment in a mixture of lipids was locally ordered even in the absence of water, which might explain some of the previously reported effects on drug solubility in these systems. Further, phase changes occurring upon water dispersion are well captured with coarse-grained simulations. Based on these simulations we conclude that the coarse-grained methodology is a promising in silico approach for rapid screening of structures formed in complex formulations. More importantly it facilitates molecular understanding of interactions between excipients and water at a feasible time scale and, hence, opens up for future virtual drug formulation studies.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-332975 (URN)10.1021/acs.molpharmaceut.7b00397 (DOI)000417342400003 ()28799773 (PubMedID)
Funder
Swedish Research Council, 2014-3309EU, European Research Council, 638965
Available from: 2017-11-03 Created: 2017-11-03 Last updated: 2018-03-08Bibliographically approved
Pedersen, J. M., Khan, E. K., Bergström, C., Palm, J., Hoogstraate, J. & Artursson, P. (2017). Substrate and method dependent inhibition of three ABC-transporters (MDR1, BCRP, and MRP2). European Journal of Pharmaceutical Sciences, 103, 70-76
Open this publication in new window or tab >>Substrate and method dependent inhibition of three ABC-transporters (MDR1, BCRP, and MRP2)
Show others...
2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 103, p. 70-76Article in journal (Refereed) Published
Abstract [en]

Drug transport and drug-drug interactions (DDI) with human ABC transporters are generally investigated in mammalian cell lines or inverted membrane vesicles from insect cells (Sf9) overexpressing the transporter of interest. In this study, we instead used membrane vesicles from human embryonic kidney cells (HEK293) overexpressing wild type MDR1/Pgp (ABCB1), BCRP (ABCG2), and MRP2 (ABCC2) with the aim to study the concentration dependent inhibition of shared and prototypic probe substrates. We first investigated 15 substrates and identified estrone-17-beta-glucorinide (E17G) as shared substrate. Nine specific and general inhibitors were then studied using El7G and prototypic probe substrates. The results were compared with those previously obtained in Sf9 vesicles and cell lines of canine (MDCKII) and human (Saos-2) origin. For the majority of inhibitors, K-i; values differed <10-fold between EI7G and probe substrates. Significant differences in K-i; values were observed for about one third of the inhibitors. The transport inhibition potencies in HEK293 vesicles were in good agreement with those obtained in Sf9 vesicles. Large differences were found in the inhibition potencies observed in the vesicular systems compared to the cellular systems. Nevertheless, the rank order correlations between the different experimental systems were generally good. Our study provides further information on substrate dependent inhibition of ABC-transporters, and suggests that simple ranking of compounds can be used as a tier one approach to bridge results obtained in different experimental systems.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Transport protein, ATP binding cassette transporter, Transport inhibition, DDI drug-drug-interaction, Membrane vesicles, HEK293
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-326226 (URN)10.1016/j.ejps.2017.03.002 (DOI)000402349700009 ()28263911 (PubMedID)
Funder
Swedish Research Council, 521-2009-4085, 521-2009-2651
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-13Bibliographically approved
Edueng, K., Mahlin, D. & Bergström, C. (2017). The Need for Restructuring the Disordered Science of Amorphous Drug Formulations. Pharmaceutical Research, 34(9), 1754-1772
Open this publication in new window or tab >>The Need for Restructuring the Disordered Science of Amorphous Drug Formulations
2017 (English)In: Pharmaceutical Research, ISSN 0724-8741, Vol. 34, no 9, p. 1754-1772Article, review/survey (Refereed) Published
Abstract [en]

The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago. In this review we try to answer the following questions: What model compounds and excipients have been used in amorphous-based research? How were these two components selected and prepared? What methods have been used to assess the performance of amorphous formulation? What methodology have evolved and/or been standardized since amorphous-based formulation was first introduced and to what extent have we embraced on new methods? Is the extent of research mirrored in the number of marketed amorphous drug products? We have summarized the history and evolution of amorphous formulation and discuss the current status of amorphous formulation-related research practice. We also explore the potential uses of old experimental methods and how they can be used in tandem with computational tools in designing amorphous formulation more efficiently than the traditional trial-and-error approach.

Place, publisher, year, edition, pages
SPRINGER/PLENUM PUBLISHERS, 2017
Keywords
amorphous solid dispersion, computational tools, crystallization, dissolution, stability
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-341852 (URN)10.1007/s11095-017-2174-7 (DOI)000406495100002 ()
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-02-19Bibliographically approved
Feeney, O. M., Crum, M. F., McEvoy, C. L., Trevaskis, N. L., Williams, H. D., Pouton, C. W., . . . Porter, C. J. (2016). 50 years of oral lipid-based formulations: Provenance, progress and future perspectives. Advanced Drug Delivery Reviews, 101, 167-194
Open this publication in new window or tab >>50 years of oral lipid-based formulations: Provenance, progress and future perspectives
Show others...
2016 (English)In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 101, p. 167-194Article, review/survey (Refereed) Published
Abstract [en]

Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and pre-systemic metabolism are evident; however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained on-going solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with on-going solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but precludes enduring effects on receptor promiscuity and off target toxicity. Finally, recent efforts to generate solid LBF are briefly described as a means to circumvent the need to encapsulate in soft or hard gelatin capsules, although the latter remain popular with consumers and a proven means of LBF delivery.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-288001 (URN)10.1016/j.addr.2016.04.007 (DOI)000378667800013 ()27089810 (PubMedID)
Available from: 2016-04-27 Created: 2016-04-27 Last updated: 2018-01-10Bibliographically approved
Alhalaweh, A., Bergström, C. A. S. & Taylor, L. S. (2016). Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.. Journal of Controlled Release, 229, 172-182
Open this publication in new window or tab >>Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.
2016 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, p. 172-182Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-284963 (URN)10.1016/j.jconrel.2016.03.028 (DOI)000375218900016 ()27006280 (PubMedID)
Available from: 2016-04-27 Created: 2016-04-19 Last updated: 2018-01-10Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/289172612

Search in DiVA

Show all publications