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On the chemical and processing stability of pharmaceutical solids: Solid form dependent water presenting capacity and process induced solid form transformation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
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: urn:nbn:se:uu:diva-261785ISBN: 978-91-554-9325-7 (print)OAI: oai:DiVA.org:uu-261785DiVA: diva2:851230
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
List of papers
1. Dry mixing transformed micro-particles of a drug from a highly crystalline to a highly amorphous state
Open this publication in new window or tab >>Dry mixing transformed micro-particles of a drug from a highly crystalline to a highly amorphous state
2009 (English)In: Pharmaceutical development and technology (Print), ISSN 1083-7450, E-ISSN 1097-9867, Vol. 14, no 3, 233-239 p.Article in journal (Refereed) Published
Abstract [en]

In this paper, the degree of mechanical activation of particles due to mechanical straining without subsequent breakage has been studied. Griseofulvin micro-particles of about 2 mum in size were mixed with glass beads (proportion 1:99) in a tumbling mixer. After a series of mixing times, ranging from 2-96 hours, samples were withdrawn and the particle size and the degree of crystallinity were assessed. The mixing process gave no detectable change in particle size. The degree of disorder of the drug particles increased with mixing time and highly amorphous particles were obtained after about 24 h of mixing. The results thus indicate that particles can be completely activated by mechanical treatment without a parallel size reduction of the particles. It is suggested that the activation is caused by repeated deformation of the particles, gradually transforming the crystalline state into an amorphous state.

Keyword
Mixing, activation, crystallinity, solubility
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-109431 (URN)10.1080/10837450802585252 (DOI)000268243600001 ()19519178 (PubMedID)
Available from: 2009-10-15 Created: 2009-10-15 Last updated: 2015-11-26Bibliographically approved
2. Toward In Silico Prediction of Glass-Forming Ability from Molecular Structure Alone: A Screening Tool in Early Drug Development
Open this publication in new window or tab >>Toward In Silico Prediction of Glass-Forming Ability from Molecular Structure Alone: A Screening Tool in Early Drug Development
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.

Keyword
glass-forming ability, prediction, in silico models, molecular descriptors, amorphous
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-151964 (URN)10.1021/mp100339c (DOI)000289008600019 ()21344945 (PubMedID)
Available from: 2011-04-29 Created: 2011-04-20 Last updated: 2016-04-27Bibliographically approved
3. Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer
Open this publication in new window or tab >>Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer
Show others...
2013 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 11, 4036-4045 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of the research was to investigate the degree of solid-state amorphisation during powder flow and to propose a mechanism for this transformation. Micro-particles of griseofulvin (about 2m in diameter) were mixed in a shear mixer under different conditions to influence the inter-particulate collisions during flow, and the degree of amorphisation was determined by micro-calorimeter. The amorphisation of griseofulvin particles (GPs)during repeated compaction was also determined. The GPs generally became disordered during mixing in a range from about 6% to about 86%. The degree of amorphisation increased with increased mixing time and increased batch size of the mixer, whereas the addition of a lubricant to the blend reduced the degree of amorphisation. Repeated compaction using the press with ejection mode gave limited amorphisation, whereas repeated compaction without an ejection process gave minute amorphisation. It is concluded that during powder flow, the most important inter-particulate contact process that cause the transformation of a crystalline solid into an amorphous state is sliding. On the molecular scale, this amorphisation is proposed to be caused by vitrification, that is the melting of a solid because of the generation of heat during sliding followed by solidification into an amorphous phase.

Keyword
powder technology, powder flow, compaction, mixing, amorphisation, mechanical activation, vitrification, crystal defect, friction, sliding
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210559 (URN)10.1002/jps.23713 (DOI)000325550400019 ()
Available from: 2013-11-13 Created: 2013-11-11 Last updated: 2017-12-06Bibliographically approved
4. Influence of water-cellulose binding energy on stability of acetylsalicylic acid
Open this publication in new window or tab >>Influence of water-cellulose binding energy on stability of acetylsalicylic acid
2006 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 323, no 1-2, 139-145 p.Article in journal (Refereed) Published
Abstract [en]

The aim of the present study was to investigate how the energies of water binding in cellulose tabletting excipients influence the availability of moisture to induce hydrolysis of acetylsalisylic acid (ASA). Cellulose powders of varying degree of order, denoted as low-crystallinity cellulose (LCC) and high-crystallinity cellulose (HCC), were produced by treating ordinary microcrystalline cellulose (MCC) in ZnCl2 solutions of varying concentrations. Microcrystalline cellulose (MCC) and lactose monohydrate were used as reference excipients. The samples were then studied by X-ray diffraction, scanning electron microscopy, and differential scanning calorimetry (DSC). Different ratios of each excipient mixed with ASA were stored at 40% RH and 50 degrees C for 35 days to investigate the hydrolytic stability of the mixtures. Stability studies indicated that as concentration of HCC and MCC in binary mixtures with ASA was raised from 1 to 50% (w/w), ASA became increasingly unstable with respect to hydrolysis. Although LCC contained more moisture than the other celluloses, no such trend was observed in the LCC and lactose samples. DSC analysis revealed that each water molecule on the average was bound by more than three hydrogen bonds in the LCC and lactose structures and therefore remained predominantly unavailable to induce hydrolysis. The current study elucidates the necessity of evaluating the energy of water bindings in a pharmaceutical excipient when predicting the excipient's performance in mixtures comprising moisture-sensitive drugs.

Keyword
microcrystalline cellulose, lactose, crystallinity, moisture content, water interactions, stability of moisture-sensitive drug
National Category
Pharmaceutical Sciences Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-83335 (URN)10.1016/j.ijpharm.2006.05.058 (DOI)000241346400018 ()16854539 (PubMedID)
Available from: 2007-01-17 Created: 2007-01-17 Last updated: 2016-11-30Bibliographically approved
5. The crystallinity of cellulose controls the physical distribution of sorbed water and the capacity to present water for chemical degradation of a solid drug
Open this publication in new window or tab >>The crystallinity of cellulose controls the physical distribution of sorbed water and the capacity to present water for chemical degradation of a solid drug
2014 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 477, no 1-2, 326-333 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of the research was to investigate the effect of moisture content of cellulose on the degradation of a drug in binary mixtures with cellulose. Physical mixtures of acetylsalicylic acid and two forms of cellulose, either microcrystalline cellulose or low crystalline cellulose, in the proportion 1:1 were stored at 50°C at a series of relative humidities (0-90%) for up to 175 days. The degradation rate constant of the drug increased with increased cellulose moisture content in a bi-regional fashion, with a low and a high degradation rate region. The shift from region 1 to 2 occurred at higher moisture content for the low crystalline cellulose. The relationships between rate constant and the temperature of maximum endothermic value overlapped for the two celluloses. It is proposed that the amount of water available for degradation of a solid drug is controlled by the water presenting capacity of cellulose which is dependent of the mechanism of sorption of water in cellulose. The water sorption of water can for cellulose satisfactorily be described by a two-site residence model with cellulose crystallinity as the structural correlate to the distribution between the two residence sites.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-246090 (URN)10.1016/j.ijpharm.2014.10.034 (DOI)000347623800036 ()25455777 (PubMedID)
Available from: 2015-03-02 Created: 2015-03-02 Last updated: 2017-12-04Bibliographically approved

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Heidarian Höckerfelt, Mina

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