| 1. |
- Persson, Ann-Sofie, et al.
(författare)
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Powder Compression Properties of Paracetamol, Paracetamol Hydrochloride, and Paracetamol Cocrystals and Coformers
- 2018
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Ingår i: Journal of Pharmaceutical Sciences. - : ELSEVIER SCIENCE INC. - 0022-3549 .- 1520-6017. ; 107:7, s. 1920-1927
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Tidskriftsartikel (refereegranskat)abstract
- The objectivewas to study the relationship between crystal structure, particle deformation properties, and tablet-forming ability for the monoclinic formof paracetamol (PRA), 2 cocrystals and a salt crystal of PRA in addition to 2 coformers (oxalic acid and 4,4'-bipyridine). Thus, the structure-property-performance relationship was investigated. Analytical powder compression was used for determination of effective plasticity, as inferred from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was determined from in-die tablet elastic recovery. The plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag layers displayed similar plasticity as crystals containing slip planes. In addition, crystals containing slip planes displayed both high and low plasticity. The mechanical properties could not be linked to the tablet-forming ability as the tablet tensile strength, unexpectedly, displayed a tendency to reduce with increased plasticity. Furthermore, the elastic deformation could not explain the tablet-forming ability. It was concluded that no relationship between structure-property-performance for PRA and its cocrystals and salt could be established. Thus, it was indicated that to establish such a relationship, an improved knowledge of crystallographic structure and interparticle bonding during compaction is needed.
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| 2. |
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| 3. |
- Mahlin, Denny, et al.
(författare)
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The influence of PVP incorporation on moisture-induced surface crystallization of amorphous spray-dried lactose particles
- 2006
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Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 321:1-2, s. 78-85
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Tidskriftsartikel (refereegranskat)abstract
- We have recently shown that atomic force microscopy (AFM) may be an appropriate method for characterisation of the re-crystallization of amorphous particles. In this study, spray-dried composite particles consisting of lactose and polyvinyl pyrrolidon (PVP) were characterised by AFM and electron spectroscopy for chemical analysis (ESCA), and their response on increasing the relative humidity (RH) was investigated. The PVP content in the particles used was 0, 5 or 25 wt.% of either PVP K 17 or PVP K90. All composite particles were found to be enriched with PVP at the surface. The incorporation of PVP in the particles influenced the way the particles responded to an increase in RH. The specific RH interval in which the surface of the particles smoothened and the RH where crystallization could be detected, increased with an increase in the amount and molecular weight of the PVP in the particles. The crystallization kinetics of single particles was analysed with AFM and by utilising the JMAK equation. The rate constant for this transformation increased in an exponential manner with increasing RH. Furthermore, above the RH needed for the crystallization to occur, the exponential increase in the crystallization rate was larger for particles with higher polymer content which indicates that the stabilising effect decreases as the water content in the particles becomes higher. In this study we report a method for determination of crystallization kinetics on single composite particles, which is valuable when evaluating the effect of stabilisers in amorphous powders.
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| 4. |
- Andersson, Sara B. E., 1987-
(författare)
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Novel and refined small-scale approaches to determine the intrinsic dissolution rate of drugs
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many drugs are administered as crystalline particles compressed into tablets and taken orally. When the tablet reaches the gastrointestinal tract, it disintegrates and the drug particles dissolve in the gastrointestinal fluid. The dissolved molecules are absorbed across the intestinal membranes into the bloodstream to reach their target sites. Only dissolved molecules can be absorbed, and if a drug has low solubility and/or dissolution rate in gastrointestinal fluid, the drug absorption might be insufficient. Hence, knowing the solubility and dissolution behaviour of a potential drug candidate is necessary early in the drug development process. The aim of this thesis was to evaluate and refine different approaches for measuring and determining dissolution rate, as well as to develop novel in vitro small-scale dissolution methods. First, interlaboratory variability in determination of intrinsic dissolution rate (IDR) and apparent solubility (Sapp) was investigated using a miniaturized dissolution instrument. To minimize the interlaboratory variability, standardized protocols for both the experimental design and the data analyses were required, and a flow chart for performing standardized powder and disc IDR measurements was established. Next, as an alternative to the powder and disc methods, carefully dispersed suspensions were used to determine the IDR, and rapid and more controlled IDR measurements were obtained using suspensions with dispersed primary particles. From the suspension measurements, an IDR/Sapp ratio of the compounds were determined. This ratio can potentially be used to identify whether a compound is likely to show dissolution rate-limited absorption and hence is sensitive to particle size reduction. The final experiments used a single particle dissolution approach to determine the IDR at four different fluid velocities. Computational fluid dynamics (CFD) simulations were used to theoretically investigate the flow conditions and dissolution rates. Single particle dissolution measurements under well-defined conditions gave high-quality dissolution data. An IDR was determined within 5-60 minutes using particles with initial diameters of 37.5-104.6 μm. The single particle dissolution experiments were used to determine the thickness of the effective hydrodynamic boundary layer (heff). The heff values were also assessed by CFD simulations, and a good concordance between experimental and simulated heff values was obtained. The approaches presented in this thesis can be used to derive qualified knowledge about the dissolution properties of drugs with several potential applications in drug development, such as profiling of solid drugs, informed formulation decisions, assisting the modelling of drug dissolution and providing improved understanding of the in vivo-dissolution behaviour
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| 5. |
- Nordström, Josefina, 1977-
(författare)
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Compression analysis as a tool for technical characterization and classification of pharmaceutical powders
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There are today strong incentives for an increased understanding of material properties and manufacturing processes to facilitate the development of new technologies in the pharmaceutical industry. The purpose of this thesis was to suggest methods requiring a low sample amount for characterization of technical properties of powders.Compression analysis was used to evaluate the formulation relevance of some compression equations. Using the mechanics of single granules to estimate powder functionality was part of this work. It was concluded that the formability of granular solids and the plasticity of single granules could be determined with compression analysis by using the Kawakita model for single components and binary mixtures of ductile granules.Further on, the fragmentation propensity of solid particles could be estimated from compression analysis by using the Shapiro equation, enabling indicators of both the fragmentation and the deformation propensity of particles to be derived in one single compression test.The interpretations of the compression parameters were only valid if the influence of particle rearrangement was negligible for the overall compression profile. An index indicating the extent of particle rearrangement was developed and a classification system of powders into groups dependent on the incidence of particle rearrangement was suggested as tools to enable rational interpretations of compression parameters.The application of compression analysis was demonstrated by investigating the relevance of the mechanics of granular solids for their tableting abilities. The plasticity of single gran-ules was suggested to influence both the rate of compactibility and the mode of deformation, and consequently the maximal tablet strength. The degree of granule bed deformation was shown to be a potential in line process indicator to describe the tableting forming ability.This thesis contributes to a scheme, suitable in formulation work and process control, to describe manufacturability of powders for an enhanced tablet formulation technology.
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| 6. |
- Pazesh, Samaneh
(författare)
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Process-induced disorder of pharmaceutical materials : Mechanisms and quantification of disorder
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One of the most important prerequisites in the drug development is to attain a reproducible and robust product in terms of its nature, and its chemical and physical properties. This can be challenging, since the crystalline form of drugs and excipients can be directly transformed into the amorphous one during normal pharmaceutical processing, referred to as process-induced amorphisation or process-induced disorder. The intention of this thesis was to address the mechanisms causing disorder during powder flow and milling and, in association with this, to evaluate, the ability of Raman spectroscopy and atomic force microscopy (AFM) to quantify and characterize process-induced disorder.The amorphisation mechanisms were controlled by stress energy distribution during processing, which in turn was regulated by a series of process parameters. Compression and shearing stress caused by sliding were stress types that acted on the particles during powder flow and ball milling process. However, sliding was the most important inter-particulate contact process giving rise to amorphisation and the transformation was proposed to be caused by vitrification. The plastic stiffness and elastic stiffness of the milling-induced particles were similar to a two-state particle model, however the moisture sorption characteristics of these particles were different. Thus the milled particles could not be described solely by a two-state particle model with amorphous and crystalline domains. Raman spectroscopy proved to be an appropriate and effective technique in the quantification of the apparent amorphous content of milled lactose powder. The disordered content below 1% could be quantified with Raman spectroscopy. AFM was a useful approach to characterize disorder on the particle surfaces.In summary, this thesis has provided insight into the mechanisms involved in process-induced amorphisation of pharmaceutical powders and presented new approaches for quantification and characterization of disordered content by Raman spectroscopy and atomic force microscopy.
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| 7. |
- Rudén, Jonas, et al.
(författare)
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On the relationship between blend state and dispersibility of adhesive mixtures containing active pharmaceutical ingredients
- 2021
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 2590-1567. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- The objectives of this investigation were to study the evolution in blend state of adhesive mixtures containing the active pharmaceutical ingredients (APIs) salbutamol, budesonide and AZD5423 and to study the relationship between blend state and dispersibility of the mixtures, as assessed by the fine particle fraction (FPF). A series of adhesive mixtures of varied fines concentration were prepared for each API using the same type of carrier. Based on visual examination and powder mechanics, blend states were identified and summarized as blend state maps for each API. The dispersibility of the mixtures was studied using a Fast Screening Impactor (FSI) equipped with a ScreenHaler. The evolution in blend state differed between the APIs in terms of the width of the blend states. The structure of the adhesion layer also differed between the APIs, from relatively uniform to a heterogeneous layer with small agglomerates dispersed on the carrier surface. All three APIs expressed a similar type of bended relationship between FPF and fines concentration. However, the initial rate of increase and the fines concentration of the plateau differed between the APIs. The adhesive mixtures of all APIs followed the three main states in terms of structural evolution and the overall shape of the FPF-fines concentration profiles could be explained by the evolution in blend state. It is proposed that the structure of the adhesion layer is an important factor explaining the differences in blend state - blend dispersibility relationships between the APIs.
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| 8. |
- Rudén, Jonas
(författare)
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Powder mechanics and dispersion properties of adhesive mixtures for dry powder inhalers : Conceptualized as a blend state model
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inhaled medicines is a therapy that dates back several thousands of years. Nowadays, using various types of inhaler devices to deliver active pharmaceutical ingredients (APIs) to treat respiratory diseases has become common practice. One such device is the dry powder inhaler (DPI) which often contains an adhesive powder mixture consisting of micron-sized API particles and larger inert particles (carriers). The general goal of a DPI formulation is to reach as high inhalable dose (dispersibility) as possible while maintaining a low dose variability. In addition, the formulation has to be stable during manufacturing and handling to avoid segregation. In this thesis, critical properties of adhesive mixtures for DPIs have been identified and summarized in a blend state model that describes the spatial distribution of API- and carrier particles in a mixture. The model consists of four distinct states, which are identified using a combination of powder mechanical analysis and imaging techniques. In the first state, denoted S1, the drug deposits at the open pores of the carriers resulting in a denser powder packing but a low dispersibility. At the second state, S2a, the drug will adhere to the outer carrier surfaces, which results in a more porous powder packing and increased dispersibility. Following further increases in drug load, reaching the S2b state, the adhering drug layer grows in complexity resulting in further reductions in powder density but with additional increases in dispersibility. At the final state, S3, the mixture is oversaturated with fines, which results in segregation and large self-agglomerates that are poorly dispersed during an inhalation experiment. The evolution of the blend state was found to be dependent on the carrier and API properties such as size and shape. Irregular carriers could handle higher drug loads before segregation occurred, while irregular API particles formed more porous adhesion layers resulting in lower drug loads. In terms of dispersibility, it was found that porous adhesion layers were more easily dispersed than coherent adhesion layers. When varying the pressure drop (airflow rate), the dispersibility of the S1 state increased linearly with higher pressure drops. However, S2a-S3 were more or less insensitive to increased pressure drops above a certain critical pressure drop. With the blend state model and the mapping of the evolution in blend state with increased drugs loads, the formulation work can ideally be improved leading to more effective treatments for patients.
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| 9. |
- Sarangi, Sohan
(författare)
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Understanding Adhesive Mixtures for Inhalation : Particle Dynamics Modelling and Segregation Experiments
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pulmonary route has been used as a source of drug delivery to lungs for centuries. Drugformulation decides the type of inhaler devices such as pressurized metered-dose inhalers(pMDIs), nebulizers and dry powder inhalers (DPIs). The most commonly used formulationin DPI consists of an ordered unit consisting of smaller drug particles (3 to 5 μm) (activepharmaceutical ingredient, API) attached to larger inert particles (carrier particles, 100 μm)called adhesive mixtures. APIs are highly cohesive in nature due to high surface to volume ratio.The adhesive mixture prevents self-agglomeration of APIs and helps deliver it to the deep lungs.In the manufacturing of adhesive mixtures, the focus has been on mixing and release insideinhaler. The research work in this thesis focuses on unaddressed issues on mixture stability andsegregation using modeling and experimental techniques. The Discrete Element Method (DEM)was used to investigate the mechanics of adhesive units, formed by randomized distributionof APIs on the surface of carrier particle. Binary collisions (head on and oblique) betweenadhesive units were simulated for different number density of fines on the carrier (surfacecoverage ratio, SCR), surface energy (interfacial adhesion/cohesion energy), shape of APIs(spherical, triangular bipyramidal and tetrahedral), size of carrier particles (50, 100, 200 μm),type of carrier particle (lactose and mannitol) and the angle of impact. To account for variationthree different initial randomized distributions of API on the carrier were considered. The dataobtained was analysed in terms of effective mechanical properties (coefficient of restitution),effective friction, physical stability of adhesive unit and redistribution of fines on the carriersurface. The coefficient of restitution follows a Kawakita type equation for higher velocity andfor different surface energy. The effect of the fine particle shape was predominant for low SCRs,and adhesive units formed from tetrahedral fines exhibited the largest physical stability andlargest friction during oblique collisions. In terms of carrier size and properties it was observedthat mannitol particles are more stable than lactose with similar dispersion performance andthe200 μm carrier is the most stable among the sizes investigated. To complement the modeling,segregation of adhesive mixture (consisting of budesonide and salbutamol sulphate as APIand Inhalac 70 as carrier) was studied. Experiments showed significant loss of APIs and selfagglomeration at higher SCR. The micro mechanical models and experiments lay a foundationtowards a better understanding of the adhesive mixture dynamics.
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| 10. |
- Persson, Ann-Sofie, et al.
(författare)
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Flowability of surface modified pharmaceutical granules : A comparative experimental and numerical study
- 2011
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 42:3, s. 199-209
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Tidskriftsartikel (refereegranskat)abstract
- Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.
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