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Mahlin, D
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Publications (10 of 18) Show all publications
Edueng, K., Bergström, C., Gråsjö, J. & Mahlin, D. (2019). Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties. Pharmaceutics, 11(9), Article ID 425.
Open this publication in new window or tab >>Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties
2019 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 9, article id 425Article in journal (Other academic) Published
National Category
Social and Clinical Pharmacy
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-390255 (URN)10.3390/pharmaceutics11090425 (DOI)000489151700053 ()31438566 (PubMedID)
Funder
Swedish Research Council, 621-2011-2445Swedish Research Council, 621-2014-3309
Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-11-08Bibliographically approved
Edueng, K., Mahlin, D., Gråsjö, J., Nylander, O., Thakrani, M. & Bergström, C. (2019). Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage. Molecules, 24(15), Article ID 2731.
Open this publication in new window or tab >>Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage
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2019 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 24, no 15, article id 2731Article in journal (Refereed) Published
Abstract [en]

This study explores the effect of physical aging and/or crystallization on the supersaturation potential and crystallization kinetics of amorphous active pharmaceutical ingredients (APIs). Spray-dried, fully amorphous indapamide, metolazone, glibenclamide, hydrocortisone, hydrochlorothiazide, ketoconazole, and sulfathiazole were used as model APIs. The parameters used to assess the supersaturation potential and crystallization kinetics were the maximum supersaturation concentration (Cmax,app), the area under the curve (AUC), and the crystallization rate constant (k). These were compared for freshly spray-dried and aged/crystallized samples. Aged samples were stored at 75% relative humidity for 168 days (6 months) or until they were completely crystallized, whichever came first. The solid-state changes were monitored with differential scanning calorimetry, Raman spectroscopy, and powder X-ray diffraction. Supersaturation potential and crystallization kinetics were investigated using a tenfold supersaturation ratio compared to the thermodynamic solubility using the µDISS Profiler. The physically aged indapamide and metolazone and the minimally crystallized glibenclamide and hydrocortisone did not show significant differences in their Cmax,app and AUC when compared to the freshly spray-dried samples. Ketoconazole, with a crystalline content of 23%, reduced its Cmax,app and AUC by 50%, with Cmax,app being the same as the crystalline solubility. The AUC of aged metolazone, one of the two compounds that remained completely amorphous after storage, significantly improved as the crystallization kinetics significantly decreased. Glibenclamide improved the most in its supersaturation potential from amorphization. The study also revealed that, besides solid-state crystallization during storage, crystallization during dissolution and its corresponding pathway may significantly compromise the supersaturation potential of fully amorphous APIs.

Keywords
physical aging, crystallization, amorphous, supersaturation potential, crystallization kinetics, nucleation pathway, crystal growth, dissolution, solvent shift, spray-drying
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-389887 (URN)10.3390/molecules24152731 (DOI)000482441100054 ()31357587 (PubMedID)
Funder
EU, European Research Council, 63896Swedish Research Council, 621-2014-330Swedish Research Council, 621-2011-2445
Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-10-02Bibliographically approved
Hellrup, J. & Mahlin, D. (2017). Confinement of Amorphous Lactose in Pores formed upon Co-Spray-Drying with Nanoparticles. Journal of Pharmaceutical Sciences, 106(1), 322-330
Open this publication in new window or tab >>Confinement of Amorphous Lactose in Pores formed upon Co-Spray-Drying with Nanoparticles
2017 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 106, no 1, p. 322-330Article in journal (Other academic) Published
Abstract [en]

This study aims at investigating factors influencing humidity induced recrystallization of amorphous lactose, produced by co-spray-drying with particles of cellulose nanocrystals (CNC) or sodium montmorillonite (Na-MMT). In particular, the focus is on how the nanoparticle shape and surface properties influence the nano- to micrometer length scale nanofiller arrangement in the nanocomposites and how the arrangements influence the mechanisms involved in the inhibition of the amorphous to crystalline transition. The nanocomposites were produced by co-spray-drying. Solid-state transformations were analyzed at 60-94% relative humidity using X-ray powder diffraction, microcalorimetry, and light microscopy. The recrystallization rate constant for the lactose/CNC and lactose/Na-MMT nanocomposites was lowered at nanofiller contents higher than 60% and were stable for months at 80% nanofiller. The most likely explanation to these results is spontaneous formations of mesoporous particle networks that the lactose is confined within upon co-spray-drying at high filler content. Compartmentalization and rigidification of the amorphous lactose proved to be less important mechanisms involved in the stabilization of lactose in the nanocomposites.

National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-300153 (URN)10.1016/j.xphs.2016.09.032 (DOI)000393920500035 ()27836110 (PubMedID)
Available from: 2016-08-03 Created: 2016-08-03 Last updated: 2017-04-18Bibliographically 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: 2019-08-14Bibliographically approved
Hellrup, J., Nordström, J. & Mahlin, D. (2017). Powder compression mechanics of spray-dried lactose nanocomposites. International Journal of Pharmaceutics, 518(1-2), 1-10
Open this publication in new window or tab >>Powder compression mechanics of spray-dried lactose nanocomposites
2017 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 518, no 1-2, p. 1-10Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to investigate the structural impact of the nanofiller incorporation on the powder compression mechanics of spray-dried lactose. The lactose was co-spray-dried with three different nanofillers, that is, cellulose nanocrystals, sodium montmorillonite, and fumed silica, which led to lower micron sized nanocomposite particles with varying structure and morphology. The powder compression mechanics of the nanocomposites and physical mixtures of the neat spray-dried components were evaluated by a rational evaluation method with compression analysis as a tool using the Kawakita equation and the Shapiro-Konopicky-Heckel equation. Particle rearrangement dominated the initial compression profiles due to the small particle sizes of the materials. The strong contribution of particle rearrangement in the materials with fumed silica continued throughout the whole compression profile, which prohibited an in-depth material characterization. However, the lactose/cellulose nanocrystals and the lactose/sodium montmorillonite nanocomposites demonstrated increased yield pressure compared with the physical mixtures indicating increased particle hardness. This increase has likely to do with a reinforcement of the nanocomposite particles by skeleton formation of the nanoparticles. In summary, the rational evaluation applying compression analysis proved to be a valuable tool for mechanical evaluation for this type of materials unless they demonstrate particle rearrangement throughout the whole compression profile.

Keywords
Amorphous, Nanocomposite, Powder compression, Lactose, Spray-drying, Yield pressure
National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-300156 (URN)10.1016/j.ijpharm.2016.12.041 (DOI)000394402100001 ()28007544 (PubMedID)
Available from: 2016-08-05 Created: 2016-08-03 Last updated: 2018-08-20
Hellrup, J., Rooth, M., Johansson, A. & Mahlin, D. (2017). Production and characterization of aluminium oxide nanoshells on spray dried lactose. International Journal of Pharmaceutics, 529(1-2), 116-122
Open this publication in new window or tab >>Production and characterization of aluminium oxide nanoshells on spray dried lactose
2017 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 529, no 1-2, p. 116-122Article in journal (Refereed) Published
Abstract [en]

Atomic layer deposition (ALD) enables deposition of dense nanometer thick metal oxide nanoshells on powder particles with precise thickness control. This leads to products with low weight fraction coating, also when depositing on nano- or micron sized powder particles. This study aimed at investigating the aluminium oxide nanoshell thickness required to prevent moisture sorption. The nanoshells were produced with ALD on spray-dried lactose, which is amorphous and extremely hygroscopic. The particles were studied with dynamic vapor sorption between 0 and 50% RH, light scattering, scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and polarized light microscopy. The ALD did not induce any recrystallization of the amorphous lactose. The dynamic vapor sorption indicated that the moisture sorption was almost completely inhibited by the nanoshell. Neat amorphous lactose rapidly recrystallized upon moisture exposure. However, only ca. 15% of the amorphous lactose particles recrystallized of a sample with 9% (by weight) aluminium oxide nanoshell at storage for six months upon 75% RH/40 degrees C, which indicate that the moisture sorption was completely inhibited in the majority of the particles. In conclusion, the aluminium oxide nanoshells prevented moisture sorption and dramatically improved the long term physical stability of amorphous lactose. This shows the potential of the ALD-technique to protect drug microparticles.

Keywords
Atomic layer deposition, Dynamic vapor sorption, Amorphous, Gas barrier, Physical stability, Solid state
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-333962 (URN)10.1016/j.ijpharm.2017.06.046 (DOI)000408009200011 ()28645629 (PubMedID)
Available from: 2017-12-13 Created: 2017-12-13 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
Hellrup, J., Holmboe, M., Nartowski, K. P., Khimyak, Y. & Mahlin, D. (2016). Structure and mobility of lactose in lactose/sodium montmorillonite nanocomposites. Langmuir, 32(49), 13214-13225
Open this publication in new window or tab >>Structure and mobility of lactose in lactose/sodium montmorillonite nanocomposites
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2016 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 32, no 49, p. 13214-13225Article in journal (Refereed) Published
Abstract [en]

This study aims at investigating the molecular level organization and molecular mobility in montmorillonite nanocomposites with the uncharged organic low-molecular-weight compound lactose commonly used in pharmaceutical drug delivery, food technology, and flavoring. Nanocomposites were prepared under slow and fast drying conditions, attained by drying at ambient conditions and by spray-drying, respectively. A detailed structural investigation was performed with modulated differential scanning calorimetry, powder X-ray diffraction, solid-state nuclear magnetic resonance spectroscopy, scanning electron microscopy, microcalorimetry, and molecular dynamics simulations. The lactose was intercalated in the sodium montmorillonite interlayer space regardless of the clay content, drying rate, or humidity exposure. Although, the spray-drying resulted in higher proportion of intercalated lactose compared with the drying under ambient conditions, nonintercalated lactose was present at 20 wt % lactose content and above. This indicates limitations in maximum loading capacity of nonionic organic substances into the montmorillonite interlayer space. Furthermore, a fraction of the intercalated lactose in the co-spray-dried nanocomposites diffused out from the clay interlayer space upon humidity exposure. Also, the lactose in the nanocomposites demonstrated higher molecular mobility than that of neat amorphous lactose. This study provides a foundation for understanding functional properties of lactose/Na-MMT nanocomposites, such as loading capacity and physical stability.

National Category
Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-300158 (URN)10.1021/acs.langmuir.6b01967 (DOI)000389866300029 ()
Available from: 2016-08-05 Created: 2016-08-03 Last updated: 2017-11-28
Hellrup, J., Alderborn, G. & Mahlin, D. (2015). Inhibition of Recrystallization of Amorphous Lactose in Nanocomposites Formed by Spray-Drying. Journal of Pharmaceutical Sciences, 104(11), 3760-3769
Open this publication in new window or tab >>Inhibition of Recrystallization of Amorphous Lactose in Nanocomposites Formed by Spray-Drying
2015 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 104, no 11, p. 3760-3769Article in journal (Refereed) Published
Abstract [en]

This study aims at investigating the recrystallization of amorphous lactose in nanocomposites. In particular, the focus is on the influence of the nano- to micrometer length scale nanofiller arrangement on the amorphous to crystalline transition. Further, the relative significance of formulation composition and manufacturing process parameters for the properties of the nanocomposite was investigated. Nanocomposites of amorphous lactose and fumed silica were produced by co-spray-drying. Solid-state transformation of the lactose was studied at 43%, 84%, and 94% relative humidity using X-ray powder diffraction and microcalorimetry. Design of experiments was used to analyze spray-drying process parameters and nanocomposite composition as factors influencing the time to 50% recrystallization. The spray-drying process parameters showed no significant influence. However, the recrystallization of the lactose in the nanocomposites was affected by the composition (fraction silica). The recrystallization rate constant decreased as a function of silica content. The lowered recrystallization rate of the lactose in the nanocomposites could be explained by three mechanisms: (1) separation of the amorphous lactose into discrete compartments on a micrometer length scale (compartmentalization), (2) lowered molecular mobility caused by molecular interactions between the lactose molecules and the surface of the silica (rigidification), and/or (3) intraparticle confinement of the amorphous lactose.

Keywords
amorphous, crystallization, glass transition, mobility, physical stability, solid state, stabilization, spray drying, factorial design
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-266687 (URN)10.1002/jps.24583 (DOI)000362984100013 ()26182904 (PubMedID)
Available from: 2015-11-12 Created: 2015-11-10 Last updated: 2018-01-10
Alhalaweh, A., Alzghoul, A., Mahlin, D. & Bergström, C. A. S. (2015). Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability. International Journal of Pharmaceutics, 495(1), 312-317
Open this publication in new window or tab >>Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability
2015 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, no 1, p. 312-317Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
Amorphous, Physical stability, Glass-forming ability, SVM, Computational prediction
National Category
Pharmaceutical Sciences Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-267181 (URN)10.1016/j.ijpharm.2015.08.101 (DOI)000362970000035 ()26341321 (PubMedID)
Funder
Swedish Research Council, 621-2011-2445Swedish Research Council, 621-2014-3309EU, European Research Council, 638965VINNOVA
Available from: 2015-11-20 Created: 2015-11-19 Last updated: 2018-01-10Bibliographically approved
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