| 1. |
- Adler, Camille, et al.
(author)
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Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion
- 2016
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 499:1-2, s. 90-100
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Journal article (peer-reviewed)abstract
- Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. beta-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity. (C) 2015 Elsevier B.V. All rights reserved.
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| 2. |
- Adler, Camille, et al.
(author)
-
Multifractal and mechanical analysis of amorphous solid dispersions
- 2017
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 523:1, s. 91-101
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Journal article (peer-reviewed)abstract
- The formulation of lipophilic and hydrophobic compounds is a challenge for the pharmaceutical industry and it requires the development of complex formulations. Our first aim was to investigate hot-melt extrudate microstructures by means of multifractal analysis using scanning electron microscopy imaging. Since the microstructure can affect solid dosage form performance such as mechanical properties, a second objective was to study the influence of the type of adsorbent and of the presence of an amorphous compound on extrudate hardness. β-Carotene (BC) was chosen as poorly water-soluble model compound. Formulations containing a polymer, a lipid and two different silica based inorganic carriers were produced by hot-melt extrusion. Based on scanning electron microscopy/energy dispersive X-ray spectroscopy, the obtained images were analyzed using multifractal formalism. The breaking force of the strands was assessed by a three point bending test. Multifractal analysis and three point bending results showed that the nature of interparticle interactions in the inorganic carrier as well as the presence of amorphous BC had an influence on the microstructure and thus on the mechanical performance. The use of multifractal analysis and the study of the mechanical properties were complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.
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| 3. |
- Ahnfelt, Emelie, et al.
(author)
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A miniaturized in vitro release method for investigating drug-release mechanisms
- 2015
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 486:1-2, s. 339-349
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Journal article (peer-reviewed)abstract
- We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.
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| 4. |
- Alhalaweh, Amjad, et al.
(author)
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Physical stability of drugs after storage above and below the glass transition temperature : Relationship to glass-forming ability
- 2015
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 495:1, s. 312-317
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Journal article (peer-reviewed)abstract
- 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.
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| 5. |
- Alomari, Mustafa, et al.
(author)
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Printing of T3 and T4 Oral Drug Combinations as a Novel Strategy for Hypothyroidism
- 2018
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In: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 549:1-2, s. 363-369
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Journal article (peer-reviewed)abstract
- Hypothyroidism is a chronic and debilitating disease that is estimated to affect 3% of the general population. Clinical experience has highlighted the synergistic value of combining triiodothyronine (T3) and thyroxine (T4) for persistent or recurrent symptoms. However, thus far a platform that enables the simultaneous and independent dosing of more than one drug for oral administration has not been developed. Thermal inkjet (TIJ) printing is a potential solution to enable the dual deposition of T3 and T4 onto orodispersible films (ODFs) for therapy personalisation. In this study, a two-cartridge TIJ printer was modified such that it could print separate solutions of T3 and T4. Dose adjustments were achieved by printing solutions adjacent to each other, enabling therapeutic T3 (15–50 μg) and T4 dosages (60–180 μg) to be successfully printed. Excellent linearity was observed between the theoretical and measured dose for both T3 and T4 (R2 = 0.982 and 0.985, respectively) by changing the length of the print objective (Y-value). Rapid disintegration of the ODFs was achieved (< 45 seconds). As such, this study for the first time demonstrates the ability to produce personalised dose combinations by TIJ printing T3 and T4 onto the same substrate for oral administration.
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| 6. |
- Andersson, Helene, 1983, et al.
(author)
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The influence of the molecular weight of the water-soluble polymer on phase-separated films for controlled release
- 2016
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 511:1, s. 223-235
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Journal article (peer-reviewed)abstract
- Hydroxypropyl cellulose (HPC) and ethyl cellulose (EC) can be used for extended release coatings, where the water-soluble HPC may act as a pore former. The aim was to investigate the effect of the molecular weight of HPC on the microstructure and mass transport in phase-separated freestanding EC/HPC films with 30% w/w HPC. Four different HPC grades were used, with weight averaged molecular weights (Mw) of 30.0 (SSL), 55.0 (SL), 83.5 (L) and 365 (M) kg/mol. Results showed that the phase-separated structure changed from HPC-discontinuous to bicontinuous with increasing Mw of HPC. The film with the lowest Mw HPC (SSL) had unconnected oval-shaped HPC-rich domains, leaked almost no HPC and had the lowest water permeability. The remaining higher Mw films had connected complex-shaped pores, which resulted in higher permeabilities. The highest Mw film (M) had the smallest pores and very slow HPC leakage, which led to a slow increase in permeability. Films with grade L and SL released most of their HPC, yet the permeability of the L film was three times higher due to greater pore connectivity. It was concluded that the phase-separated microstructure, the level of pore percolation and the leakage rate of HPC will be affected by the choice of HPC Mw grade used in the film and this will in turn have strong impact on the film permeability.
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| 7. |
- Badal Tejedor, Maria, 1986-, et al.
(author)
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Milling induced amorphisation and recrystallization of α-lactose monohydrate
- 2018
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 537:1-2, s. 140-147
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Journal article (peer-reviewed)abstract
- Preprocessing of pharmaceutical powders is a common procedure to condition the materials for a better manufacturing performance. However, such operations may induce undesired material properties modifications when conditioning particle size through milling, for example. Modification of both surface and bulk material structure will change the material properties, thus affecting the processability of the powder. Hence it is essential to control the material transformations that occur during milling. Topographical and mechanical changes in surface properties can be a preliminary indication of further material transformations. Therefore a surface evaluation of the α-lactose monohydrate after short and prolonged milling times has been performed. Unprocessed α-lactose monohydrate and spray dried lactose were evaluated in parallel to the milled samples as reference examples of the crystalline and amorphous lactose structure. Morphological differences between unprocessed α-lactose, 1 h and 20 h milled lactose and spray dried lactose were detected from SEM and AFM images. Additionally, AFM was used to simultaneously characterize particle surface amorphicity by measuring energy dissipation. Extensive surface amorphicity was detected after 1 h of milling while prolonged milling times showed only a moderate particle surface amorphisation. Bulk material characterization performed with DSC indicated a partial amorphicity for the 1 h milled lactose and a fully amorphous thermal profile for the 20 h milled lactose. The temperature profiles however, were shifted somewhat in the comparison to the amorphous reference, particularly after extended milling, suggesting a different amorphous state compared to the spray-dried material. Water loss during milling was measured with TGA, showing lower water content for the lactose amorphized through milling compared to spray dried amorphous lactose. The combined results suggest a surface-bulk propagation of the amorphicity during milling in combination with a different amorphous structural conformation to that of the amorphous spray dried lactose. The hardened surface may be due to either surface crystallization of lactose or to formation of a low-water glass transition.
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| 8. |
- Badal Tejedor, Maria, et al.
(author)
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Tablet mechanics depend on nano and micro scale adhesion, lubrication and structure
- 2015
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In: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 486:1-2, s. 315-323
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Journal article (peer-reviewed)abstract
- Tablets are the most convenient form for drug administration. However, despite the ease of manufacturing problems such as powder adhesion occur during the production process. This study presents surface and structural characterization of tablets formulated with commonly used excipients (microcrystalline cellulose (MCC), lactose, mannitol, magnesium (Mg) stearate) pressed under different compaction conditions. Tablet surface analyses were performed with scanning electron microscopy (SEM), profilometry and atomic force microscopy (AFM). The mechanical properties of the tablets were evaluated with a tablet hardness test. Local adhesion detected by AFM decreased when Mg stearate was present in the formulation. Moreover, the tablet strength of plastically deformable excipients such as MCC was significantly decreased after addition of Mg stearate. Combined these facts indicate that Mg stearate affects the particle-particle bonding and thus elastic recovery. The MCC excipient also displayed the highest hardness which is characteristic for a highly cohesive material. This is discussed in the view of the relatively high adhesion found between MCC and a hydrophilic probe at the nanoscale using AFM. In contrast, the tablet strength of brittle materials like lactose and mannitol is unaffected by Mg stearate. Thus fracture occurs within the excipient particles and not at particle boundaries, creating new surfaces not previously exposed to Mg stearate. Such uncoated surfaces may well promote adhesive interactions with tools during manufacture.
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| 9. |
- Bannow, J., et al.
(author)
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Solid nanofoams based on cellulose nanofibers and indomethacin—the effect of processing parameters and drug content on material structure
- 2017
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In: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 526:1-2, s. 291-299
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Journal article (peer-reviewed)abstract
- The unique colloidal properties of cellulose nanofibers (CNF), makes CNF a very interesting new excipient in pharmaceutical formulations, as CNF in combination with some poorly-soluble drugs can create nanofoams with closed cells. Previous nanofoams, created with the model drug indomethacin, demonstrated a prolonged release compared to films, owing to the tortuous diffusion path that the drug needs to take around the intact air-bubbles. However, the nanofoam was only obtained at a relatively low drug content of 21 wt% using fixed processing parameters. Herein, the effect of indomethacin content and processing parameters on the foaming properties was analysed. Results demonstrate that a certain amount of dissolved drug is needed to stabilize air-bubbles. At the same time, larger fractions of dissolved drug promote coarsening/collapse of the wet foam. The pendant drop/bubble profile tensiometry was used to verify the wet-foam stability at different pHs. The pH influenced the amount of solubilized drug and the processing-window was very narrow at high drug loadings. The results were compared to real foaming-experiments and solid state analysis of the final cellular solids. The parameters were assembled into a processing chart, highlighting the importance of the right combination of processing parameters (pH and time-point of pH adjustment) in order to successfully prepare cellular solid materials with up to 46 wt% drug loading.
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| 10. |
- Barreto Henriksson, Helena, et al.
(author)
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Determination of mechanical and rheological properties of a cell-loaded peptide gel during ECM production
- 2019
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In: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 563, s. 437-444
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Journal article (peer-reviewed)abstract
- The development of an injectable biomaterial that supports cell survival and maintains or promotes nucleus pulposus (NP) phenotype could aid delivery of cells to degenerated NPs causing low back pain. Mesenchymal cells were loaded and grown in a synthetic peptide gel, PuraMatrix (R). Cells were observed within the gels over 0-28 days, and accumulation of glycosaminoglycans were detected by histological staining. The mechanical properties of the cell-loaded constructs, and the change of the mechanical properties were studied using stress relaxation of the gels under compression and confinement. The PuraMatrix (R) gel was shown to relax fast on compression indicating that the fluid could easily flow out of the gel, and thus indicating the presence of large pores/voids. The presence of these pores/voids was further supported by high mobility of dextran molecules, determined using fluorescence recovery after photo bleaching. The stress required to deform the cell-loaded constructs to a specific strain increases at day 21, at which point the presence of glycosaminoglycans within the cell-loaded constructs was also observed. The results provide evidence of changes in mechanical properties of the PuraMatrix (R) matrix upon excretion of the extracellular matrix by the cells.
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