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排序方式: 共有481条查询结果,搜索用时 46 毫秒
1.
A roadmap for the selection of a pharmaceutical salt form for a development candidate is presented. The free base of the candidate did not have sufficient chemical stability for development. The initially selected salt form turned out to be undevelopable because it was unstable during scale-up synthesis and storage. The rationale for the new solid form screening and the criteria for selection are discussed. Before the final selection, the pH solubility profiles of the 2 new salts, a benzoate and a besylate, were compared. Atypical solubility behavior was observed for the benzoate salt in hydrochloric acid with and without normal saline. A scheme is proposed illustrating how the pKas of the counterion and active pharmaceutical ingredient, the medium composition, and final pH affect the solubility and solution equilibria of the 2 selected salt forms. This scheme also includes the equilibria between solution and solid phases in different pH ranges. The pharmaceutical importance of this research is that it sheds light on how the acidity of the counterion can affect the solubility of the selected salt form in the gastric environment. With a well-designed formulation strategy, this property potentially can be translated to optimal biopharmaceutical performance of the drug product. 相似文献
2.
Claudia Kunz Sonja Schuldt-Lieb Henning Gieseler 《Journal of pharmaceutical sciences》2018,107(3):887-896
The use of cosolvent systems has been demonstrated to shorten lengthy freeze-drying processes and improve the solubility and stability of certain active pharmaceutical ingredients. The goal of the present study was to evaluate the suitability of 2 thermal characterization techniques, differential scanning calorimetry and freeze-dry microscopy, and to identify an optimal cosolvent system. Binary mixtures of a cosolvent (tert-butanol, dimethyl sulfoxide, 1,4-dioxane, acetone, or ethanol) and water were investigated. Ternary mixtures of frequently used excipients (50 mg/g mannitol, sucrose, glycine, or polyvinylpyrrolidone [PVP]) and a solvent-water system were then analyzed for their thermal properties. PVP presented a particularly high glass transition temperature (Tg′) in 70% tert-butanol at ?17.9°C. Large needle-shaped crystals that have been shown to be associated with improved processability were observed with mannitol and PVP in 40% 1,4-dioxane. A heterogeneous sublimation rate of the solvent and water whose impact on product stability remained unclear was observed with PVP in 40% 1,4-dioxane. Freeze-dry microscopy analysis demonstrated a possible extension of the process time for PVP in 99% dimethyl sulfoxide due to a slowly moving sublimation front. Conceivable negative consequences and the need for special treatment for low-melting cosolvents, such as ethanol and acetone, were predicted and discussed. 相似文献
3.
4.
Ashaben Patel Vineet Gupta John Hickey Nancy S. Nightlinger Richard S. Rogers Christine Siska Sangeeta B. Joshi Michael S. Seaman David B. Volkin Bruce A. Kerwin 《Journal of pharmaceutical sciences》2018,107(12):3032-3046
In this study, we investigated analytical challenges associated with the formulation of 2 anti-HIV broadly neutralizing antibodies (bnAbs), 3BNC117 and PGT121, both separately at 100 mg/mL and together at 50 mg/mL each. The bnAb formulations were characterized for relative solubility and conformational stability followed by accelerated and real-time stability studies. Although the bnAbs were stable during 4°C storage, incubation at 40°C differentiated their stability profiles. Specific concentration-dependent aggregation rates at 30°C and 40°C were measured by size exclusion chromatography for the individual bnAbs with the mixture showing intermediate behavior. Interestingly, although the relative ratio of the 2 bnAbs remained constant at 4°C, the ratio of 3BNC117 to PGT121 increased in the dimer that formed during storage at 40°C. A mass spectrometry-based multiattribute method, identified and quantified differences in modifications of the Fab regions for each bnAb within the mixture including clipping, oxidation, deamidation, and isomerization sites. Each bnAb showed slight differences in the levels and sites of lysine residue glycations. Together, these data demonstrate the ability to differentiate degradation products from individual antibodies within the bnAb mixture, and that degradation rates are influenced not only by the individual bnAb concentrations but also by the mixture concentration. 相似文献
5.
Jiali Chen Yuqi Chen Wencong Huang Hanning Wang Yang Du Subin Xiong 《Journal of pharmaceutical sciences》2018,107(9):2366-2376
The objectives of this study were to explore sodium dodecyl sulfate (SDS) and Soluplus on the crystallization inhibition and dissolution of felodipine (FLDP) extrudates by bottom-up and top-down approaches. FLDP extrudates with Soluplus and SDS were prepared by hot melt extrusion, and characterized by polarized light microscopy, differential scanning calorimetry, and fourier transform infrared spectroscopy. Results indicated that Soluplus inhibited FLDP crystallization, and the whole amorphous solid dispersions (ASDs) were binary FLDP-Soluplus (1:3) and ternary FLDP-Soluplus-SDS (1:2:0.15~0.3 and 1:3:0.2~0.4) extrudates. Internal SDS (5%-10%) decreased glass transition temperatures of FLDP-Soluplus-SDS ternary ASDs without presenting molecular interactions with FLDP or Soluplus. The enhanced dissolution rate of binary or ternary Soluplus-rich ASDs in the nonsink condition of 0.05% SDS was achieved. Bottom-up approach indicated that Soluplus was a much stronger crystal inhibitor to the supersaturated FLDP in solutions than SDS. Top-down approach demonstrated that SDS enhanced the dissolution of Soluplus-rich ASDs via wettability and complexation with Soluplus to accelerate the medium uptake and erosion kinetics of extrudates, but induced FLDP recrystallization and resulted in incomplete dissolution of FLDP-rich extrudates. In conclusion, top-down approach is a promising strategy to explore the mechanisms of ASDs' dissolution, and small amount of SDS enhances the dissolution rate of polymer-rich ASDs in the nonsink condition. 相似文献
6.
Christian Luebbert Christian Klanke Gabriele Sadowski 《International journal of pharmaceutics》2018,535(1-2):245-252
The bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs) can be significantly improved by so-called amorphous solid dispersions (ASDs). However, the long-term stability of ASDs might be impaired by API recrystallization and/or amorphous phase separation (APS). So far, no methods have been reported to quantify APS in ASDs. In this work, phase-separation kinetics as well as the compositions of the two amorphous phases evolving due to APS were quantitatively determined for the first time using confocal Raman spectroscopy. Raman spectra were evaluated via non-linear multivariate Indirect Hard Modeling and verified by differential scanning calorimetry and hot-stage microscopy. APS in water-free ASDs of ibuprofen and poly (DL-lactic-co-glycolic acid) was investigated considering the influence of temperature and polymer architecture (linear vs. star-shaped). Water absorbed at 40?°C and 75% relative humidity (RH) promotes APS which was quantified for formulations of felodipine/poly(vinyl pyrrolidone) and ibuprofen/poly(vinyl pyrrolidone). 相似文献
7.
Minh-Quan Le Fabien Violet Cédric Paniagua Xavier Garric Marie-Claire Venier-Julienne 《International journal of pharmaceutics》2018,535(1-2):428-437
Here, we aimed to develop protein loaded microspheres (MSs) using penta-block PLGA-based copolymers to obtain sustained and complete protein release. We varied MS morphology and studied the control of protein release. Lysozyme was used as a model protein and MSs were prepared using the solid-in-oil-in-water emulsion solvent extraction method. We synthesized and studied various penta-block PLGA-based copolymers. Copolymer characteristics (LA/GA ratio and molecular weight of PLGA blocks) influenced MS morphology. MS porosity was influenced by process parameters (such as solvent type, polymer concentration, emulsifying speed), whereas the aqueous volume for extraction and stabilizer did not have a significant effect. MSs of the same size, but different morphologies, exhibited different protein release behavior, with porous structures being essential for the continuous and complete release of encapsulated protein. These findings suggest strategies to engineer the morphology of MSs produced from PLGA-based multi-block copolymers to achieve appropriate release rates for a protein delivery system. 相似文献
8.
Timothy Pas Bjorn Vergauwen Guy Van den Mooter 《International journal of pharmaceutics》2018,535(1-2):47-58
Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions. 相似文献
9.
Garry Kerch 《Nanomedicine : nanotechnology, biology, and medicine》2018,14(1):13-25
The direct and indirect (by changing mechanical properties) effects of hydration at interfaces on cellular processes and tissue diseases are reviewed. The essential effect of substrate stiffness on cellular processes was demonstrated in the last decade. The combined effect of surface stiffness and hydration at interfaces has garnered much less attention, though hydration and dehydration play important roles in biological processes. This review focuses on the studies that demonstrate how hydration affects biological processes at interfaces. Elevated sodium and dehydration stimulate inflammatory signaling in endothelial cells and promote atherosclerosis. Various types of implant and blood contacting device coatings with varied surface stiffness and hydration have been reported. Effect of hydration on polymer modulus of elasticity and viscoelasticity was discussed taking into account cells adhesion, migration, proliferation, differentiation on surfaces with various degree of hydration. Future directions of research were considered, including the use of nanotechnology to regulate the hydration degree. 相似文献
10.
Dinesh K. Mishra Ruchita Shandilya Pradyumna K. Mishra 《Nanomedicine : nanotechnology, biology, and medicine》2018,14(7):2023-2050
Over the recent couple of decades, pharmaceutical field has embarked most phenomenal noteworthy achievements in the field of medications as well as drug delivery. The rise of Nanotechnology in this field has reformed the existing drug delivery for targeting, diagnostic, remedial applications and patient monitoring. The convincing usage of nanotechnology in the conveyance of medications that prompts an extension of novel lipid-based nanocarriers and non-liposomal systems has been discussed. Present review deals with the late advances and updates in lipidic nanocarriers, their formulation strategies, challenging aspects, stability profile, clinical applications alongside commercially available products and products under clinical trials. This exploration may give a complete idea viewing the lipid based nanocarriers as a promising choice for the formulation of pharmaceutical products, the challenges looked by the translational process of lipid-based nanocarriers and the combating methodologies to guarantee the headway of these nanocarriers from bench to bedside. 相似文献