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Molecular Mechanisms Influencing the Performance of Amorphous Formulations for Poorly Water-Soluble Drugs
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crystallisation is a concern for amorphous formulation because it compromises the solubility-enhancing benefit gained from amorphisation. Traditionally, amorphous formulation had been designed primarily based on trial-and-error approach. The success rate for amorphous formulation is unimpressive, due to a poor understanding of the formulation itself, especially with regard to its crystallisation behaviour. Therefore, this thesis aimed to propose a strategic approach for rational design of amorphous formulations, as opposed to the trial-and-error approach. This can be achieved by understanding what drives the crystallisation of amorphous drug, and when and how the amorphous drug crystallises. The information can guide the selection of drugs, excipients and preparation method to achieve amorphous formulations with favourable features.

In the first part of the thesis, a systematic protocol was proposed to identify mechanisms via which crystallisation takes place when amorphous drug is dissolved. The stabilisation strategy of supersaturation produced upon dissolution of amorphous drug was then recommended depending on the crystallisation mechanisms. A molecular dynamics (MD) simulations was used to understand drug-polymer interaction during supersaturation. It was revealed that hydrogen bond interaction is an important in stabilising supersaturation. The factors affecting glass-forming ability and long-term physical stability such as preparation method and humidity were then highlighted in the second study. A follow-up study was performed to elucidate the potential complications in using a standardised differential scanning calorimetry to classify promiscuous glass formers into any specific glass-forming ability/glass stability class. In the subsequent study, the effect of physical aging and/or crystallisation of amorphous drugs during storage on supersaturation potential was addressed. It was shown that, minor crystallisation of amorphous drug upon storage did not have a significant impact on the supersaturation potential during dissolution. Instead, the crystallisation pathway of the amorphous drug during dissolution plays a more important role in determining the supersaturation behaviour of some drugs. Finally, the impact of (i) drug loading on physical stability, supersaturation, drug/polymer miscibility, and (ii) the physical aging and/or crystallisation upon storage on supersaturation potential of spray-dried solid dispersions with HPMC-AS were discussed in the last study. It was observed that the effect of drug loading on physical stability and supersaturation, and the effect of physical aging and/or crystallisation during storage on supersaturation potential is highly drug-dependent. Similarly, the stabilisation effect of HPMC-AS varied across model drugs, drug loadings and crystallisation pathways (i.e. in solid or during dissolution). The Flory-Huggins interaction parameter calculated using MD simulations revealed good miscibility between the drugs and HPMC-AS at drug loadings investigated. In the presence of water molecules, various structural organizations of the drugs and HPMC-AS complexes were observed. Taken together, this thesis provides an improved understanding of crystallisation behaviour of amorphous formulations, which is useful to guide a rational design of amorphous formulations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 276
Keywords [en]
Amorphous formulation, crystallisation, supersaturation, glass-forming ability, physical stability, glass stability, spray-dried solid dispersion, dissolution, promiscuous glass former, poorly-soluble drug, solid-to-solid, solution-mediated, particle-associated
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-390579ISBN: 978-91-513-0717-6 (print)OAI: oai:DiVA.org:uu-390579DiVA, id: diva2:1342581
Public defence
2019-09-27, Room B21, Biomedical Center, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-09-04 Created: 2019-08-14 Last updated: 2019-09-17
List of papers
1. Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways
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
2. Long-term physical (in)stability of spray-dried amorphous drugs: relationship with glass-forming ability and physicochemical properties
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
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-390255 (URN)
Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-08-14
3. Classification of promiscuous glass-formers: Limitations of differential scanning calorimetry
Open this publication in new window or tab >>Classification of promiscuous glass-formers: Limitations of differential scanning calorimetry
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-390254 (URN)
Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-08-14
4. Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage
Open this publication in new window or tab >>Supersaturation Potential of Amorphous Active Pharmaceutical Ingredients after Long-Term Storage
Show others...
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
5. The influence of drug loading and drug-polymer interactions on physical stability and supersaturation of spray-dried solid dispersions
Open this publication in new window or tab >>The influence of drug loading and drug-polymer interactions on physical stability and supersaturation of spray-dried solid dispersions
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-390257 (URN)
Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-08-14

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