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Toward In Silico Prediction of Glass-Forming Ability from Molecular Structure Alone: A Screening Tool in Early Drug Development
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
2011 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, Vol. 8, no 2, 498-506 p.Article in journal (Refereed) Published
Abstract [en]

We present a novel computational tool which predicts the glass-forming ability of drug compounds solely from their molecular structure. Compounds which show solid-state limited aqueous solubility were selected, and their glass-forming ability was determined upon spray-drying, melt-quenching and mechanical activation. The solids produced were analyzed by differential scanning calorimetry (DSC) and powder X-ray diffraction. Compounds becoming at least partially amorphous on processing were classified as glass-formers, whereas those remaining crystalline regardless of the process method were classified as non-glass-forming compounds. A predictive model of the glass-forming ability, designed to separate between these two classes, was developed through the use of partial least-squares projection to latent structure discriminant analysis (PLS-DA) and calculated molecular descriptors. In total, ten of the 16 compounds were determined experimentally to be good glass-formers and the PLS-DA model correctly sorted 15 of the compounds using four molecular descriptors only. An external test set was predicted with an accuracy of 75%, and, hence, the PLS-DA model developed was shown to be applicable for the identification of compounds that have the potential to be designed as amorphous formulations. The model suggests that larger molecules with a low number of benzene rings, low level of molecular symmetry, branched carbon skeletons and electronegative atoms have the ability to form a glass. To conclude, we have developed a predictive, transparent and interpretable computational model for the identification of drug molecules capable of being glass-formers. The model allows an assessment of amorphization as a formulation strategy in the early drug development process, and can be applied before compound synthesis.

Place, publisher, year, edition, pages
2011. Vol. 8, no 2, 498-506 p.
Keyword [en]
glass-forming ability, prediction, in silico models, molecular descriptors, amorphous
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-151964DOI: 10.1021/mp100339cISI: 000289008600019PubMedID: 21344945OAI: oai:DiVA.org:uu-151964DiVA: diva2:413655
Available from: 2011-04-29 Created: 2011-04-20 Last updated: 2016-04-27Bibliographically approved
In thesis
1. On the chemical and processing stability of pharmaceutical solids: Solid form dependent water presenting capacity and process induced solid form transformation
Open this publication in new window or tab >>On the chemical and processing stability of pharmaceutical solids: Solid form dependent water presenting capacity and process induced solid form transformation
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a need for improving our knowledge and understanding about formation mechanisms and nature of amorphous state in order to prevent the unintended presence of disorder in solid pharmaceutical products and reduce the related stability issues. The suggested theory that water binding capacity of amorphous cellulose affects the chemical stability of hydrolysis sensitive drugs in formulations with cellulose based excipients needs a clarification and water-cellulose interaction profiles need to be examined.  This thesis has addressed these questions.

Chemical, mechanical and thermal methods have been used to create partially or predominantly amorphous solids. Mechanisms and the pathways for transformation to amorphous phase and the characteristic qualities of this phase is studied in order to give some tools to predict, to control or prevent the creation of disorder in a crystalline structure. The water interaction with amorphous pharmaceutical materials has been studied to improve stability of hydrolysis sensitive drugs. 

 

The transition to amorphous state during handling of pharmaceutical material, referred to as mechanical activation in processes like blending, mixing and compression is substantially a consequence of vitrification. The process is described as creation of hot spots where friction caused by particle sliding raise the temperature above the melting point of the material. The fast cooling process promotes creation of a local disordered molecular arrangement. It is possible to decrease the degree of amorphisation and undesired stability problems by reducing the friction and inhibit the creation of crystal defects during processing.

 

The glass-forming propensity is an inherent material characteristic related to molecular size and structure and is not process dependent. Molecules with a couple of aromatic rings are often poor glass-formers. Less symmetrical, branched molecular structures with presence of electronegative atoms are more readily transformed to and exist in amorphous state when handled and stored at temperatures below their glass transition temperature.

 

The interaction profile of cellulose with water is strongly dependent on solid state structure of cellulose. Crystallinity is the key parameter in water presenting capacity of cellulose. Amorphous regions have a capacity to bind the water and decrease water mobility and in that way reduce cellulose water presenting capacity despite higher moisture content in partially amorphous cellulose compared to crystalline cellulose. The fact that higher amorphous content decreases cellulose water presenting capacity is a promising lead to improve stability of hydrolysis sensitive drugs in compositions with cellulose. This knowledge could be applicable to other pharmaceutical materials as the differences between crystalline and amorphous states of material are generally the same for different kind of materials.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 203
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-261785 (URN)978-91-554-9325-7 (ISBN)
Public defence
2015-10-23, B22 Biomedicum, Daghammarsköldsväg, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2015-11-26 Created: 2015-09-04 Last updated: 2016-01-13Bibliographically approved

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Bergström, Christel A. S.

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