| 1. |
- Ahmed, Hamzah, et al.
(author)
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Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol
- 2017
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In: Drug Development and Industrial Pharmacy. - : Taylor & Francis. - 0363-9045 .- 1520-5762. ; 43:1, s. 89-97
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Journal article (peer-reviewed)abstract
- Objectives were to study mechanical properties of various solid forms of paracetamol and relate to their crystal structures. Paracetamol Form I (PRA), its cocrystals with oxalic acid (PRA-OXA) and 4,4-bipyridine (PRA-BPY) and hydrochloride salt (PRA-HCL) were selected. Cocrystals and salt were scaled-up using rational crystallization methods. The resulting materials were subjected to differential scanning solid-state characterization. The powders were sieved and 90-360 µm sieve fraction was considered. These powders were examined by scanning electron microscopy (SEM) and densities were determined. Tablets were made at applied pressures of 35-180 MPa under controlled conditions and the tablet height, diameter and hardness were measured. Tensile strength and porosity of the tablets were estimated using well known models. Crystal structures of these systems were visualized and slips planed were identified. Cocrystal and salt of PRA were physically pure. Sieved powders had comparable morphologies and particle size. The apparent and theoretical densities of powders were similar but no clear trends were observed. The tensile strengths of these compacts were increased with increasing pressure whereas tabletability decreased in the order oxalic acid > PRA-HCL ≈ PRA-OXA > BPY > PRA-BPY. Tablet tensile strength decreases exponentially with increasing porosity with the exception of PRY-BPY and BPY. Slip plane prediction based on attachment energies may not be independently considered. However, it was possible to explain the improved mechanical properties of powders based on the crystal structure. Cocrystallization and salt formation have introduced structural features that are responsible for improved tableting properties of PRA.
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| 2. |
- Al-Hayali, Amani Ibraheem Younis, et al.
(author)
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Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media
- 2017
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 43:1, s. 79-88
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Journal article (peer-reviewed)abstract
- The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25 °C and 37 °C) were investigated in this work.Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions.All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25 °C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried (SD) solid dispersions and supersaturation was maintained. However, at 37 °C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures.Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25 °C may not predict the supersaturation behavior at physiologically relevant temperatures.
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| 3. |
- Alhalaweh, Amjad, et al.
(author)
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Data mining of solubility parameters for computational prediction of drug–excipient miscibility
- 2014
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:7, s. 904-909
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Journal article (peer-reviewed)abstract
- Computational data mining is of interest in the pharmaceutical arena for the analysis of massive amounts of data and to assist in the management and utilization of the data. In this study, a data mining approach was used to predict the miscibility of a drug and several excipients, using Hansen solubility parameters (HSPs) as the data set. The K-means clustering algorithm was applied to predict the miscibility of indomethacin with a set of more than 30 compounds based on their partial solubility parameters [dispersion forces , polar forces and hydrogen bonding ]. The miscibility of the compounds was determined experimentally, using differential scanning calorimetry (DSC), in a separate study. The results of the K-means algorithm and DSC were compared to evaluate the K-means clustering prediction performance using the HSPs three-dimensional parameters, the two-dimensional parameters such as volume-dependent solubility and hydrogen bonding , and selected single (one-dimensional) parameters. Using HSPs, the prediction of miscibility by the K-means algorithm correlated well with the DSC results, with an overall accuracy of 94%. The prediction accuracy was the same (94%) when the two-dimensional parameters or the hydrogen-bonding (one-dimensional) parameter were used. The hydrogen-bonding parameter was thus a determining factor in predicting miscibility in such set of compounds, whereas the dispersive and polar parameters had only a weak correlation. The results show that data mining approach is a valuable tool for predicting drug–excipient miscibility because it is easy to use, is time and cost-effective, and is material sparing.
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| 4. |
- Ali, Hassan, et al.
(author)
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Vibrational spectroscopic investigation of polymorphs and cocrystals of indomethacin
- 2013
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 39:5, s. 625-634
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Journal article (peer-reviewed)abstract
- Context:Identification of optimal solid form of an active pharmaceutical ingredient and form control are very important in drug development. Thus, the structural information of these forms and in-depth insight on the modes of molecular interactions are necessary, and vibrational spectroscopic methods are well suited for this purpose.Objective:In-depth structural analysis of different solid forms of indomethacin (IND) using Raman and infrared (IR) spectroscopy is the objective. We have investigated the modes of molecular interactions in polymorphs (α and γ), amorphous and discovered cocrystals of IND with nicotinamide (NIC) and trans-cinnamic acid (CIN) coformers.Materials and methods: The solid forms of IND have been prepared; their purity has been verified by differential scanning calorimetry and powder X-ray diffractometry and then studied in the solid-state by Raman and IR spectroscopy. The modes of the interactions were closely investigated from the vibrational data.Results: The key vibrational features of IND solid forms have been specified. The IR (C=O) band at 1713 cm−1 attributed to cyclic acid dimer of γ IND has disappeared in IND–NIC/CIN whilst retained in IND–SAC cocrystal.Discussion:IND cocrystallizes in different conformations and crystal lattices with different coformers. The cyclic acid dimer of IND has been kept on its cocrystallization with saccharin and it could have been broken with NIC and CIN.Conclusions: The complementary nature of Raman and IR spectroscopy allowed unambiguous investigation of the chemical composition of pharmaceutical materials which is of particular importance in the absence of detailed structural information, as in the case of IND–NIC and IND–CIN.
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| 5. |
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| 6. |
- Chae, Jung-woo, et al.
(author)
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A simple pharmacokinetic model of alendronate developed using plasma concentration and urine excretion data from healthy men
- 2014
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:10, s. 1325-1329
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Journal article (peer-reviewed)abstract
- The study of pharmacokinetics of alendronate has been hampered by difficulties in accurately and reproducibly determining their concentrations in serum and urine. Thus, pharmacokinetic characteristics of alendronate have been described in many reports based on urinary excretion data; and plasma pharmacokinetics and the simultaneous pharmacokinetic models of alendronate in plasma and urine are not available. The aims of this study were to measure alendronate concentration in plasma and excretion in urine concurrently and to develop compartmental pharmacokinetic model using urine data. In open-label, single-dose pharmacokinetic study, 10 healthy male volunteers received oral dose of alendronate (70mg tablet). Blood and urine alendronate concentrations were determined using validated high-performance liquid chromatography method. Non-compartmental analysis was performed using WinNonlin program (Pharsight Inc., Apex, NC). A one-compartment pharmacokinetic model was applied to describe pharmacokinetics of alendronate. A peak plasma alendronate concentration of 33.10 +/- 14.32 ng/mL was attained after 1.00 +/- 0.16 h. The cumulative amount of alendronate excreted in urine and peak excretion rate were 731.28 +/- 654.57 mu g and 314.68 +/- 395.43 mg/h, respectively. The model, which included first-order absorption rate for oral dosing, showed good fit to alendronate data obtained from plasma and urine. The absorption rate constant was 2.68 +/- 0.95 h(-1). The elimination rate constants K-urine and Knon-ur were 0.005 +/- 0.004 h(-1) and 0.42 +/- 0.08 h(-1), respectively. The pharmacokinetics of alendronate in plasma and urine of healthy men can be predicted using one-compartment model, and thus the behavior of drug in plasma can be estimated from urinary excretion data.
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| 7. |
- Costa, Fatima, et al.
(author)
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Drug release from lipid liquid crystalline phases: relation with phase behavior
- 2010
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 36:4, s. 470-481
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Journal article (peer-reviewed)abstract
- Introduction: We studied the release of propranolol hydrochloride (PHCl), a water-soluble amphiphilic drug, from monoolein (MO)/water and phytantriol/water systems. Methods: We related the dissolution profiles with phase behavior and viscosity of the different liquid crystalline phases. Diolein has been added aiming to stabilize the cubic phases and thus preventing formation of less viscous (lamellar) phases. Results: Formulations display first-order release rates and diffusion release mechanism. Some formulations (mostly MO) were close to zero-order release in the first 120 minutes. Discussion: Release mechanism can be influenced by phase changes during dissolution. Conclusions: Both MO and phytantriol show good potential to be used for propranolol hydrochloride sustained drug release.
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| 8. |
- Forner, Kristin, et al.
(author)
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Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs
- 2017
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In: Drug Development and Industrial Pharmacy. - : TAYLOR & FRANCIS LTD. - 0363-9045 .- 1520-5762. ; 43:2, s. 338-346
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Journal article (peer-reviewed)abstract
- Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIFmod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. Results: Fa/FeSSIFmod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. Discussion: The compatibility of Fa/FeSSIFmod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. Conclusion: The optimized setup uses FaSSIF(mod) as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.
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| 9. |
- Gabrielsson, Jon, et al.
(author)
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Multivariate methods in the development of a new tablet formulation : optimization and validation
- 2004
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In: Drug Development and Industrial Pharmacy. - New York : M. Dekker. - 0363-9045 .- 1520-5762. ; 30:10, s. 1037-1049
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Journal article (peer-reviewed)abstract
- In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.
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| 10. |
- Gabrielsson, Jon, et al.
(author)
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Multivariate Methods in the Development of a New Tablet Formulation : Excipient Mixtures and Principal Properties
- 2006
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In: Drug Development and Industrial Pharmacy. - New York : M. Dekker. - 0363-9045 .- 1520-5762. ; 32:1, s. 7-20
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Journal article (peer-reviewed)abstract
- A tablet formulation for direct compression has previously been studied using multivariate design. An optimization study of one of the most important tablet properties, disintegration time, revealed that excipients with Principal Properties (PP's) that were predicted as suitable by the model were not represented within the studied material.The feasibility of using mixtures of excipients in the multivariate approach to tablet formulation to solve this problem has been investigated in the present study. By mixing different excipients of the same excipient class, it should be possible to obtain mixtures with the predicted PP's, which in turn should give a formulation with the desired properties. In order to investigate the utility of this approach, separate mixture designs were applied to both binders and fillers (diluents).As reported here, the Partial Least Squares Projections to Latent Structures (PLS) model developed in the previously published screening study has been validated in the sense that the interesting region of the PP space identified in it has been shown to contain excipients, pure or mixed, that give the formulation suitable properties. Formulations with suitable properties were found with the mixture experiments. The local models also offer several alternatives for the composition of the formulation that yield the desired disintegration time.
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| 11. |
- Gabrielsson, Jon, et al.
(author)
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Multivariate Methods in the Development of a New Tablet Formulation
- 2003
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In: Drug Development and Industrial Pharmacy. - New York : Marcel Dekker. - 0363-9045 .- 1520-5762. ; 29:10, s. 1053-1075
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Journal article (peer-reviewed)abstract
- The overall objective of this article is to use an efficient approach to find a suitable tablet formulation for direct compression. By using traditional approaches to statistical experimental design in tablet formulation, the number of experiments quickly grows when many descriptive variables or many excipients are included. To facilitate the screening process, a multivariate design, which allows a systematical evaluation of a large number of excipients with a limited number of experiments, was implemented. Formulations with acceptable values for disintegration time and crushing strength were obtained with some of the formulations in the present study. The multivariate experimental design strategy yielded PLS models that will be used to identify a region of interest for the optimization. The strategy is general and can be applied in many different areas of pharmaceutical research and development.
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| 12. |
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| 13. |
- Lindberg, N.-O., et al.
(author)
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Optimization of disintegration time and crushing strength of a tablet formulation
- 1985
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 11:4, s. 931-944
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Journal article (peer-reviewed)abstract
- In an experiment with a factorial design, the following aspects were scrutinized: the impact on disintegration time and crushing strength caused by the loss-on-drying of the granulation; the granule-size distribution; the lubricant concentration; the compression force; and the pre-compression. Both with regard to disintegration time and crushing strength, these factors were found to have a significant influence: the loss-on-drying of the granulation; the fraction less than 0.150 mm; the concentration of magnesium stearate; and the compression force. A reduction of the tablet disintegration time was obtained by means of an increase of the granulation moisture; by an increase of the fine fraction; or by a reduction of the lubricant concentration or the compression force. The tablet crushing strength was increased by reducing the deviation of the granulation loss-on-drying from approximately 4.6 %; by a reduction of the fine fraction; by decreasing the lubricant concentration; or by increasing the compression force. The fraction larger than 0.300 mm had no significant influence; nor did the pre-compression. Further, there were no significant interactions. By means of superimposing contour plots of disintegration time and crushing strength, a region was obtained where the requirements of disintegration time and crushing strength could be satisfied by controlling the processing variables.
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| 14. |
- Lindberg, N.-O., et al.
(author)
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Optimizing the friability of a tablet formulation
- 1987
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 13:6, s. 1063-1067
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Journal article (peer-reviewed)abstract
- The impact on tablet friability caused by the loss-on-drying of the granulation, the granule-size distribution, the lubricant concentration, the compression force, and the pre-compression was scrutinized in a factorially designed experiment. A reduction of friability was obtained by reducing the deviation of the granulation loss-on-drying from approximately 4.6%; by decreasing the lubricant concentration; or by increasing the compression force.
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| 15. |
- Lindberg, N.-O., et al.
(author)
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The granulation of a tablet formulation in a high-speed mixer, Diosna P 25
- 1985
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 11:4, s. 917-930
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Journal article (peer-reviewed)abstract
- The impeller speed, the loss-on-drying of starch, and the added amount of water significantly influenced these response variables: granule fractions of less than 0.150 mm and more than 2.00 mm; and granule median diameter. The influence of the drug concentration on the response variables was less important. All the response variables showed significant interactions. At a fixed impeller speed, the fine fraction was reduced when the loss-on-drying of starch increased, and when water was added in increasing amounts. The coarse fraction and granule median diameter increased along with an increasing moisture content in the starch. Increasing amounts of added water had the same effect. The response surface contours of a fraction less than 0.150 mm, and a fraction exceeding 2.00 mm, were plotted. So was the granule median diameter. Suitable levels for the processing variables involved in obtaining a granulation of the desired proportions - fine or coarse fraction - can be read from the contour plots. Heat was generated in the mixer during kneading, which caused some evaporation of water. The change in the rotation rate of the impeller during the addition of the granulating liquid can be used as an indication of the fraction percentages below 0.150 mm and above 2.00 mm, but not of the median diameter.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
- Mollmann, SH, et al.
(author)
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The stability of insulin in solid formulations containing melezitose and starch. Effects of processing and excipients
- 2006
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In: Drug Development and Industrial Pharmacy. - 0363-9045 .- 1520-5762. ; 32:6, s. 765-778
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Journal article (peer-reviewed)abstract
- Solid insulin formulations obtained by different methods of preparation were compared with respect to chemical stability and morphology. Spray- and freeze-drying, solution enhanced dispersion by supercritical fluids (SEDS) and precipitation into starch microspheres were the methods used for preparation of solid powders. The excipients applied were melezitose, starch and sodium taurocholate. The stability of the samples was evaluated after storage in open containers at 25°C and 30% RH for 6 months. All samples were amorphous after processing and storage as detected by XRD, except for the starch microspheres which were semi-crystalline. The spray- and freeze-dried samples containing melezitose and sodium taurocholate experienced a significant water uptake during storage, resulting in changes in morphology and disappearance of Tg. However, the chemical stability of these samples did not seem to be affected by the water uptake. Changes in morphology were not observed for the SEDS powders and the starch microspheres. The chemical stability of the samples was assessed by HPLC. In general, conventional spray and freeze drying resulted in samples with higher chemical stability compared to SEDS powders and starch microspheres. Nevertheless, the excipients applied were observed to be of major importance, and further optimization of the formulation as well as processing conditions may lead to slightly different conclusions.
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| 20. |
- Morales, Javier O., et al.
(author)
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A design of experiments to optimize a new manufacturing process for high activity protein-containing submicron particles
- 2013
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 39:11, s. 1793-1801
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Journal article (peer-reviewed)abstract
- A novel method for the manufacture of protein/peptide-containing submicron particles was developed in an attempt to provide particles with increased activity while using high energy input technologies. The method consists of antisolvent co-precipitation from an aqueous solution containing both an amino acid core material (e.g. D,L-valine), and either bovine serum albumin (BSA) or lysozyme (Lys) as model proteins. The aqueous solution was added to the organic phase by means of a nebulizer to increase the total surface area of interaction for the precipitation process. Sonication proved to be an effective method to produce small particle sizes while maintaining high activity of Lys. The use of a polysorbate or sorbitan ester derivatives as stabilizers proved to be necessary to yield submicron particles. Particles with very high yields (approximately 100%) and very high activity after manufacture (approximately 100%) could be obtained. A particle size of 439.0 nm, with a yield of 48.8% and with final remaining activity of 98.7% was obtained. By studying various factors using a design of experiments strategy (DoE) we were able to establish the critical controlling factors for this new method of manufacture.
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| 21. |
- Morales, Javier O., et al.
(author)
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Novel strategies for the buccal delivery of macromolecules
- 2014
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:5, s. 579-590
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Journal article (peer-reviewed)abstract
- For years now, the delivery of small molecules through the buccal mucosal route has been described in the literature, but it has only been over the past decade that investigations into macromolecule delivery via the buccal route have sharply increased. The administration of macromolecules such as proteins and peptides, antibodies, or nucleic acids by buccal administration would be greatly enhanced due to the avoidance of the gastrointestinal conditions, rapid uptake into systemic circulation, as well as the potential for controlled drug delivery. Since macromolecules are faced with a number of specific challenges related to permeation through the epithelium, several strategies have been employed historically to improve their buccal absorption and subsequent bioavailability. Several conventional strategies to improve macromolecule penetration include the use of chemical permeation enhancers, enzyme inhibitors and the use of mucoadhesive materials acting as carriers. More recent approaches include the incorporation of the macromolecule as part of nanostructured delivery systems to further enhance targeting and delivery. This review focuses on the different permeation enhancing strategies as well as formulation design that are tailored to meet the challenges of active macromolecule delivery using the buccal mucosal route of administration.
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| 22. |
- Morales, Javier O., et al.
(author)
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Preface for buccal drug delivery theme issue
- 2014
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:5, s. 577-578
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Journal article (other academic/artistic)abstract
- During the past years, buccal drug delivery has attracted the attention of researchers looking for alternative delivery routes of administration. As an alternative to oral drug delivery, the buccal mucosal route avoids the passage through the acidic gastric environment, intestinal and bacterial enzymatic activity, absorption issues associated with the intestinal epithelium (e.g. P-glycoprotein efflux), and the first pass metabolism of the liver. Therefore, the buccal route could be a good delivery route for macromolecules and other drugs not compatible with the gastrointestinal tract environment. This "Buccal Drug Delivery" special edition of Drug Development and Industrial Pharmacy aims to bring together a range of different aspects relevant to the growing field of buccal drug delivery. The special edition includes thorough reviews of the literature, as well as original research articles touching on most prominent features related to buccal drug delivery systems, such as the move toward the use of nanotechnology in different ways to facilitate buccal drug delivery with the potential to prompt future product developments.
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| 23. |
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| 24. |
- Padrela, Luis, et al.
(author)
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Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture
- 2012
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 38:8, s. 923-929
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Journal article (peer-reviewed)abstract
- Context: The solid state purity of cocrystals critically affects their performance. Thus, it is important to accurately quantify the purity of cocrystals in the final crystallization product.Objective: The aim of this study was to develop a powder X-ray diffraction (PXRD) quantification method for investigating the purity of cocrystals. The method developed was employed to study the formation of indomethacin-saccharin (IND-SAC) cocrystals by mechanochemical methods.Materials and methods: Pure IND-SAC cocrystals were geometrically mixed with 1:1 w/w mixture of indomethacin/saccharin in various proportions. An accurately measured amount (550 mg) of the mixture was used for the PXRD measurements. The most intense, non-overlapping, characteristic diffraction peak of IND-SAC was used to construct the calibration curve in the range 0–100% (w/w). This calibration model was validated and used to monitor the formation of IND-SAC cocrystals by liquid-assisted grinding (LAG).Results: The IND-SAC cocrystal calibration curve showed excellent linearity (R2 = 0.9996) over the entire concentration range, displaying limit of detection (LOD) and limit of quantification (LOQ) values of 1.23% (w/w) and 3.74% (w/w), respectively. Validation results showed excellent correlations between actual and predicted concentrations of IND-SAC cocrystals (R2 = 0.9981).Discussion: The accuracy and reliability of the PXRD quantification method depend on the methods of sample preparation and handling. The crystallinity of the IND-SAC cocrystals was higher when larger amounts of methanol were used in the LAG method.Conclusion: The PXRD quantification method is suitable and reliable for verifying the purity of cocrystals in the final crystallization product.
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| 25. |
- Patel, Mayurkumar, et al.
(author)
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Quantification of dermal and transdermal delivery of meloxicam gels in rabbits
- 2011
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 37:5, s. 613-617
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Journal article (peer-reviewed)abstract
- Background: This study was designed to quantify the effects of penetration enhancers on systemic bioavailability of 0.3% meloxicam (MLX) hydroxypropylcellulose gels. Cutaneous microdialysis was also performed to assess dermis availability and to better understand the penetration process. The gels tested were a 1% oleic acid gel, a 5% menthol gel, and a control gel without penetration enhancers. Methods: To assess systemic bioavailability, three female rabbits received according to a crossover design 0.135 g/cm(2) of gel applied to a 7.5 x 7.5 cm area of their shaved back and a short (5 min) infusion of 1 mg. In each experiment, blood samples were collected serially for 36 h and analyzed by a validated HPLC method. For skin bioavailability studies, 0.135 g/cm(2) of the same gels were applied to a 1 x 2 cm area on top of a microdialysis probe previously inserted in the dermis. Dialysate samples were collected for 6 h every 30 min. Results: Systemically, the 5% menthol gel delivered 3.93 +/- 0.85 mg of MLX versus the 1.41 +/- 0.24 mg of the oleic acid gel. Only traces of MLX were detectable from the control gel. In dermis, substantial concentrations of MLX were detected only after the application of the menthol gel, whereas skin concentration from the control gel and the 1% oleic acid gel were always below the lowest limit of quantification (LLOQ). Conclusions: The 5% menthol gel can possibly deliver therapeutically relevant amount of MLX in vivo. Dermis concentrations can be predictive of systemic plasma levels.
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| 26. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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A small structural change resulting in improved properties for product development
- 2015
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 41:5, s. 866-873
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Journal article (peer-reviewed)abstract
- AZD9343 is a water-soluble gamma amino butyric acid (GABAB) agonist intended for symptomatic relief in gastroesophageal reflux disease (GERD) patients. The compound has good chemical stability in aqueous solutions, as well as in the solid state. Only one crystal modification has been observed to date. This polymorph is slightly hygroscopic (1.5% water uptake at 80% relative humidity (RH)), which is an improvement compared to the structurally similar agonist lesogaberan (AZD3355) which liquefies at 65% RH. Since the substance is very polar and lacks a UV chromophore, conventional separation and detection techniques cannot be used to characterize the substance and its impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for assay and purity, the liquid chromatographic method for enantiomeric separation with derivatization with UV chromophore and three complementary nuclear magnetic resonance (NMR) approaches (P-31-NMR, C-13-NMR and H-1-NMR) for impurities. For oral solutions, it was important to select the right concentration of phosphate buffer for the specific drug concentration and routinely use small additions of EDTA. I.V. solutions containing physiological saline as tonicity modifier could not be stored frozen at -20 degrees C. Properties of AZD9343 will be discussed in light of experiences from the structurally similar lesogaberan and (2R)-(3-amino-2-fluoropropyl) sulphinic acid (AFPSiA).
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| 27. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Co-administration of a nanosuspension of a poorly soluble basic compound and a solution of a proton pump inhibitor-the importance of gastrointestinal pH and solubility for the in vivo exposure
- 2011
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 37:9, s. 1036-1042
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Journal article (peer-reviewed)abstract
- In Sigfridsson et al. (2011, Drug Dev Ind Pharm, 37: 243-251), there was no difference in plasma concentration of BA99 when administering the drug as nanosuspension or microsuspension and analyzing the blood samples by liquid chromatography-mass spectrometry. This was related to the dissolved amount of drug in the gastric tract, which was high enough to support fast absorption when the drug reached the small intestine. One single physicochemical property (pK(a), about 3 for BA99) abolished the benefit of small particles. These results were further confirmed in the present study, where a proton pump inhibitor, AZD0865, was used to elevate the gastric pH and then drastically decreased the gastric solubility. In this way, BA99 could be considered as a model compound for a neutral substance. By increasing the gastric pH to 5-6 and 8-9, respectively, in rats, the plasma concentrations of BA99, after administering nanosuspensions, were unchanged compared with untreated (i.e. no AZD0865) animals. For microsuspensions of the test compound, on the other hand, the exposure of BA99 was 2- to 3-fold lower than for nanosuspensions at both pHs. Moreover, the blood concentrations of BA99 administered as microsuspension were also 2- to 3-fold lower compared with untreated (no AZD0865) individuals receiving both nanoparticles and microparticles of BA99. Obviously, for neutral compounds, with similar physicochemical properties as the present compound, size reduction will be crucial for increased plasma exposure. For basic compounds, with similar physicochemical properties as the present compound, the crucial step for absorption is the dissolution and solubility in the gastric tract.
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| 28. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Early development evaluation of AZD2738, a substrate for the NK receptors
- 2011
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 37:6, s. 719-726
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Journal article (peer-reviewed)abstract
- The purpose of this study was to investigate whether AZD2738, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development with an oral immediate release solid dosage form as a possible final product. The neutral form of AZD2738 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Mostly crystalline material of fumarate, maleate and chloride salt of AZD2738 were obtained. X-ray powder diffractometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the salts. Based on the physicochemical properties, the chloride salt is preferred for continued product development. The chloride salt of AZD2738 is an anhydrate, the crystallization is reproducible, the hygroscopicity is acceptable and just one polymorph was obtained. Notably is that the two obtained polymorphs of the fumarate salt of AZD2738 are monotropically related, whereas the two identified polymorphs for the maleate salt of the compound are enantiotropic. The dissolution behavior and the stability (in aqueous solutions, formulations and solid state) of the salts were also studied and found to be satisfactory, at least at pH >3. Liquid formulations should preferable be stored frozen at pH >3.
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| 29. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Early development evaluation of AZD8081: a substrate for the NK receptors
- 2011
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 37:6, s. 702-713
-
Journal article (peer-reviewed)abstract
- The purpose of the present study was to find out if AZD8081, a dual neurokinin (NK)1/2 receptor antagonist, was suitable for development of an oral, solid immediate release (IR) formulation and in a further perspective also as an oral extended release (ER) formulation. AZD8081 is a base with pK(a) values
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| 30. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Early pharmaceutical evaluation of a crystalline and hygroscopic GABA(B) receptor agonist
- 2013
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 39:10, s. 1573-1581
-
Journal article (peer-reviewed)abstract
- Lesogaberan is a potent gamma amino butyric acid agonist and has been evaluated for its utility in treatment of gastroesophageal reflux disease. Lesogaberan is a crystalline substance that absorbs considerable amounts of water above 65% relative humidity (RH) where it also liquifies. As a result of the hygroscopicity of the zwitterionic form an investigation of different salt forms was performed. Since the test compound is polar and lacks ultraviolet (UV) chromophore, conventional separation and detection techniques could not be used to characterise the test compound and the impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for purity, the liquid chromatographic method for enantiomeric separation with derivatisation with UV chromophore and two complementary nuclear magnetic resonance (NMR) approaches (F-19-NMR and H-1-NMR) for impurities. The stability study in solution showed that solutions between pH 5 and 7 were the most stable ones, but after some time degradation occurred at room temperature. When bulk lesogaberan was stored at 25 degrees C/60% RH no chemical degradation was observed after 1 year. At 40 degrees C/75% RH, where the compound liquefies, a significant degradation was observed after 1 month. However, in a closed container (= 40 degrees C) or as a napsylate salt, no degradation of lesogaberan was observed at 40 degrees C/75% RH.
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| 31. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Evaluation of exposure properties after injection of nanosuspensions and microsuspenions into the intraperitoneal space in rats
- 2013
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 39:11, s. 1832-1839
-
Journal article (peer-reviewed)abstract
- In the present paper, BA99 and AC88 were used as model compounds for intraperitoneal (i.p.) administration to Sprague-Dawley rats. A major problem for the compounds, like many others newly developed pharmaceutical drugs, is the poor solubility in water. To solve solubility related problems, development of nanosuspensions is an attractive alternative. Both compounds are suitable for nanosuspensions, using the milling approach. After 2 weeks in freezer, the nanoparticles aggregated to form particles in the 400-2000 nm interval. However, following a 20 s ultrasonication step, the original particle sizes (about 200 nm) were obtained. Adding 5% mannitol before the samples were frozen abolished aggregation. It is also possible to freeze-dry the nanosuspension in the presence of 5% mannitol and re-disperse the formulation in water. Nanosuspensions of both compounds were injected i.p. to rats at 5 and 500 mu moL/kg. At the low dose, also a microsuspension was administered. I. p. administration resulted in overall improved C-max for both AC88 and BA99 compared to s. c. and oral administration. I. p. is the preferred route of administration of tolerable drugs when a fast onset of action is desired and when a significant first passage metabolism occurs. The net charge of the active molecule appeared to affect the absorption kinetics. In the present work, the neutral molecule was favored over the negatively charged one.
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| 32. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Evaluation of systemic exposure of nanoparticle suspensions subcutaneously administered to mice regarding stabilization, volume, location, concentration and size
- 2014
-
In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:10, s. 1318-1324
-
Journal article (peer-reviewed)abstract
- Different routes of administration are likely to result in very different outcomes due to different availability or plasma profile. The objective of the present study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administration of nanoparticle suspensions of a lipophilic compound to mice. Pharmacokinetics of the selected test compound and the effect of drug concentration, particle size, location of administration, volume given and particle stabilizers were studied. Adding PEGylated lipids or pluronic F-127 to the negatively charged surface of the nanoparticles increased the stability of the particles and the bioavailability. The in vivo studies demonstrated linear absorption kinetics for the selected model compound up to at least 500 mu mol/kg. Absorption from upper-neck resulted in different systemic exposure compared to administration in the hip. The former was preferred if a prolonged C-max was desired while the latter ensured a flat profile for approximately 24 hours. Administering the double volume (but the same dose) had no effect on the pharmacokinetics, whereas smaller particle size significantly increased the exposure.
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| 33. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Preformulation evaluation of AZD1305, an oxabispidine intended for oral and intravenous treatment
- 2012
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 38:1, s. 19-31
-
Journal article (peer-reviewed)abstract
- Aim: AZD1305 is a novel, water-soluble investigational antiarrhythmic agent for restoration and maintenance of sinus rhythm in atrial fibrillation patients. The present studies were performed to evaluate the possibility for further development of the compound.Methods: A set of technical approaches were used, including X-ray powder diffractometry, differential scanning calorimetry, thermogravimetrical analysis, dynamic vapor sorption, scanning electron microscopy, salt screen, and liquid chromatography.Results: AZD1305 is a crystalline oxabispidine and its neutral form is a base with a pK(a) of 9.9. The substance degrades with higher temperature and lower pH. The free base of the solid substance is stable at 25 degrees C (closed container), 40 degrees C/75% relative humidity (open container), and at 50 degrees C (closed container) for at least 3 months. The free base of AZD1305 is polymorphic with two known forms. Both forms are non-hygroscopic ansolvates with melting points of approximately 90 degrees C. No salt was found with overall improved properties. The substance had a strong odor, which was reduced by increased particle size.Conclusions: The free base of AZD1305 seemed to be the most suitable agent for product development even though it has a fairly low melting point and occurred as two different crystal forms. Form B was the most stable thermodynamically in the temperature interval of interest.
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| 34. |
- Sigfridsson, Kalle, 1964, et al.
(author)
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Subcutaneous administration of nano- and microsuspensions of poorly soluble compounds to rats
- 2014
-
In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 40:4, s. 511-518
-
Journal article (peer-reviewed)abstract
- The aim of the present study was to evaluate and interpret the pharmacokinetic profiles of two compounds after subcutaneous (s.c.) administration. The compounds have similar physicochemical properties, but are a base (BA99) and an acid (AC88), respectively. The compounds were administered as nano- (5 and 500 mu mol/kg) and microsuspensions (5 mu mol/kg) s.c. to Sprague-Dawley rats. At the low dose, the exposure was higher for both compounds administered as nanocrystals compared to microparticles. The high dose of the compounds resulted in even higher exposure, but not in a dose-linear manner. The differences in exposure between nano- and microparticles were mainly ascribed to higher dissolution rate and improved solubility for smaller particles. In addition to differences in exposure, there were also differences in the elimination pattern. After s.c. injection of 5 mu mol/kg of BA99 as nano- and microsuspensions, the elimination profile was similar as observed earlier after oral administration. However, after injection of the higher dose of BA99 and all formulations of AC88, an extended elimination profile was observed, forming a maintained plateau under the investigated time-period. Essentially, constant plasma levels were caused by a balanced equilibrium between total body clearance of the drug and supply rate of drug from the formulations.
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| 35. |
- Velaga, Sitaram, et al.
(author)
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Supercritical fluids processing of recombinant human Growth Hormone
- 2005
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In: Drug Development and Industrial Pharmacy. - 0363-9045 .- 1520-5762. ; 31:2, s. 135-149
-
Journal article (peer-reviewed)abstract
- The aim of the study was to investigate the feasibility of precipitating recombinant human growth hormone (hGH) from aqueous solutions using conventional and modified techniques of solution-enhanced dispersion (SEDS) by supercritical fluids. The study investigated the effect on hGH stability of adding isopropanol either as a cosolvent with the original aqueous protein solution (conventional process) or to the supercritical carbon dioxide before mixing with the aqueous protein solution (modified process). The influence of the addition of sucrose (with or without isopropanol) on the precipitation behavior and stability of the protein was also studied. Experiments were performed under various processing conditions (pressure 100-200 bars and temperature 40-50 degrees C), and with various flow rates and solution compositions (CO2/isopropanol and protein solution). Bioanalytical characterization of the resulting powders involved spectrophotometry, sodium dodecyl sulfate-polycrylamide gel electrophoresis, reverse-phase high performance liquid chromatography (RP-HPLC), and size exclusion chromatography. Solid-state characterization was performed using differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and Karl Fischer techniques. Results showed that with both conventional and modified methods, under optimum processing conditions, the presence of sucrose in the solution decreased the destabilizing effects of the solvent and/or process on the structure of hGH. More hGH was dissolved from the precipitated powders containing sucrose than from those containing only isopropanol. Reverse-phase HPLC indicated that about 94% of the hGH was recovered in its native form. The proportion of dimers and oligomers was reduced in the presence of sucrose; about 92% of the soluble protein was present in monomer form under optimal conditions. The remaining undissolved protein was in monomeric form. The precipitated powders were amorphous, containing particulate aggregates in the size range 1-6 microm with 5-10% residual moisture content. In conclusion, hGH was successfully precipitated from aqueous solution using SEDS technology. The presence of sucrose in the protein solution promoted the precipitation of hGH and reduced aggregation and improved dissolution.
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| 36. |
- Wahlgren, M, et al.
(author)
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Oral-based controlled release formulations using poly(acrylic acid) microgels.
- 2009
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In: Drug Development and Industrial Pharmacy. - : Informa UK Limited. - 0363-9045 .- 1520-5762. ; 35, s. 922-929
-
Journal article (peer-reviewed)abstract
- Aim: To investigate the release of hydrophobic and hydrophilic substances from tablets containing Pemulen and Carbopol as excipients. Method: The dissolution patterns of a hydrophobic (diazepam) and a hydrophilic active substance (midodrine-HCl) from different tablet formulations containing a nonmodified polyacrylic microgel (Carbopol 981 F) or a hydrophobically modified polyacrylic microgel (Pemulen(R)) have been studied. Possible differences in dissolution in phosphate buffer (pH 6.8) and in 0.1 M HCl between tablets produced using wet granulation and direct compression were also investigated. Results: Tablets produced by wet granulation had a greater effect on the release of active substance from the tablets. No major differences were observed in the release patterns of the hydrophilic substance midodrine-HCl from wet granulated tablets based on Carbopol and Pemulen. However, the release pattern of the more hydrophobic drug substance, diazepam, differed considerably between the two polymers. Wet granulation gave reproducible release patterns. The release patterns from the polymers differed considerably at pH 6.8 but were similar at low pH. Conclusions: The release of the diazepam from the hydrophobic polymer Pemulen was very slow, and the release was close to zero order.
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| 37. |
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