1,721,029 research outputs found
Polymorph impact on the bioavailability and stability of poorly soluble drugs
Full text linkDrugs with low water solubility are predisposed to poor and variable oral bioavailability and, therefore, to variability in clinical response, that might be overcome through an appropriate formulation of the drug. Polymorphs (anhydrous and solvate/hydrate forms) may resolve these bioavailability problems, but they can be a challenge to ensure physicochemical stability for the entire shelf life of the drug product. Since clinical failures of polymorph drugs have not been uncommon, and some of them have been entirely unexpected, the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug. In the past, the polymorphism of many drugs was detected fortuitously or through manual time consuming methods; today, drug crystal engineering, in particular, combinatorial chemistry and high-throughput screening, makes it possible to easily and exhaustively identify stable polymorphic and/or hydrate/dehydrate forms of poorly soluble drugs, in order to overcome bioavailability related problems or clinical failures. This review describes the concepts involved, provides examples of drugs characterized by poor solubility for which polymorphism has proven important, outlines the state-of-the-art technologies and discusses the pertinent regulations
Changes in the solid state of anhydrous and hydrated forms of sodium naproxen under different grinding and environmental conditions: Evidence of the formation of new hydrated forms
No full textThe aim of the present work was to investigate the solid state change of the anhydrous and hydrate solid forms of sodium naproxen under different grinding and environmental conditions. Grinding was carried out manually in a mortar under the following conditions: at room temperature under air atmosphere (Method A), in the presence of liquid nitrogen under air atmosphere (Method B), at room temperature under nitrogen atmosphere (Method C), and in the presence of liquid nitrogen under nitrogen atmosphere (Method D). Among the hydrates, the following forms were used: a dihydrate form (DSN) obtained by exposing the anhydrous form at 55% RH; a dihydrate form (CSN) obtained by crystallizing sodium naproxen from water; the tetrahydrate form (TSN) obtained by exposing the anhydrous form at 75% RH. The metastable monohydrate form (MSN), previously described in the literature, was not used because of its high physical instability. The chemical stability during grinding was firstly assessed and proven by HPLC. Modification of the particle size and shape, and changes in the solid state under different grinding methods were evaluated by scanning electron microscopy, and X-ray powder diffractometry and thermogravimetry, respectively. The study demonstrated the strong influence of starting form, grinding and environmental conditions on particle size, shape and solid state of recovered sodium naproxen forms. In particular, it was demonstrated that in the absence of liquid nitrogen (Methods A and C), either at air or at nitrogen atmosphere, the monohydrate form (MSN) was obtained from any hydrates, meaning that these grinding conditions favored the dehydration of superior hydrates. The grinding process carried out in the presence of liquid nitrogen (Method B) led to further hydration of the starting materials: new hydrate forms were identified as one pentahydrate form and one hexahydrate form. The hydration was caused by the condensation of the atmospheric water on sodium naproxen particles by liquid nitrogen and by the grinding forces that created a close contact between water and drug. The simultaneous disruption of the crystals, occurring during grinding, and their close contact with water molecules promoted the conversion in higher hydrates. Under the Method D, it was possible to highlight a certain tendency to hydration probably due to a rearrangement of water already present into the hydrates, but results were substantially different from Method B. Thus, summarizing, the different SN forms behave differently under different grinding and environmental conditions
Bioactive hydrogel scaffolds - advances in cartilage regeneration through controlled drug delivery
No full textThe importance of growth factor delivery in cartilage tissue engineering is nowadays widely recognized. However, when growth factors are administered by a bolus injection, they undergo rapid clearance before they could stimulate the cells of interest at promoting cartilage repair. Their short half-lives make growth factors ineffective, unless administered at supra-physiological doses, with potentially harmful consequences on patient safety. Recently, new tissue engineering strategies relying on the combination of biodegradable scaffolds and specific biological cues, such as growth or adhesive factors or genetic material, have demonstrated that controlled release is the key factor for achieving effective cartilage repair at lower drug doses. Among all biomaterials, hydrogels have emerged as promising cartilage tissue engineering scaffolds for simultaneous cell growth and drug delivery. In fact, hydrogels can be easily loaded with cells and drugs, that are subsequently released in a controlled fashion. The success of hydrogels in controlled drug delivery for tissue engineering originates from their biocompatibility and capacity to integrate well with the host tissue. This review overviews the hydrogels technologies now available for the regeneration of cartilage that base their efficacy on the controlled release of bioactive substances able to modulate cellular behavior and to eventually lead to successful tissue repai
Effect of particle size reduction and crystalline form on dissolution behaviour of nimesulide
No full textThe objective of this study was to develop and examine innovative and very simple and easily scalable techniques able to improve solubility and/or dissolution rate and thus oral bioavailability of nimesulide. Three different nimesulide batches were obtained by three different laboratory-scale methods: Method A (Batch A) used crystallization by solvent evaporation in a nanospray dryer, Method B (Batches G and GLN) involved cryo-milling, and Method C (Batch Neu) dispersed nimesulide in Neusilin® UFL2. All the nimesulide batches were fully characterized for chemical stability, thermal behaviour, physicochemical and micromeritics properties, and intrinsic dissolution and particle dissolution rates. Batch A not only showed a good reduction in particle size but also exhibited a reduced degree of crystallinity by both differential scanning calorimetry and X-ray powder diffractometry, which could explain the increase in intrinsic dissolution rate (IDR) and particle dissolution. Batch GLN showed an acceptable increase in IDR, probably caused by a slight decrease in the degree of crystallinity, and good improvement in dissolution rate due to a certain decrease in particle size. Batches G and native crystals exhibited very close IDRs, while G showed somewhat higher particle dissolution, probably attributed to the particle size reduction. The dispersion of nimesulide in Neusilin UFL2 in a 1:6 drug-polymer ratio made it possible to recover anamorphous powder, as proven by thermal analysis and X-ray powder diffractometry, characterized by pronounced particle size reduction to nanometric dimensions. Both amorphous character and nanometric dimensions could account for the fastest particle dissolution during the first 10 min of the experiment. The stability study conducted according to the International Conference on Harmonization (ICH) confirmed the good chemical and physicochemical stability of all the batches
Hot Melt Extrusion: Highlighting Physicochemical Factors to Be Investigated While Designing and Optimizing a Hot Melt Extrusion Process
Full text linkHot-melt extrusion (HME) is a well-accepted and extensively studied method for preparing numerous types of drug delivery systems and dosage forms. It offers several advantages: no solvents are required, it is easy to scale up and employ on the industrial level, and, in particular, it offers the possibility of improving drug bioavailability. HME involves the mixing of a drug with one or more excipients, in general polymers and even plasticizers, which can melt, often forming a solid dispersion of the drug in the polymer. The molten mass is extruded and cooled, giving rise to a solid material with designed properties. This process, which can be realized using different kinds of special equipment, may involve modifications in the drug physicochemical properties, such as chemical, thermal and mechanical characteristics thus affecting the drug physicochemical stability and bioavailability. During process optimization, the evaluation of the drug solid state and stability is thus of paramount importance to guarantee stable drug properties for the duration of the drug product shelf life. This manuscript reviews the most important physicochemical factors that should be investigated while designing and optimizing a hot melt extrusion process, and by extension, during the different pre-formulation, formulation and process, and post-formulation phases. It offers a comprehensive evaluation of the chemical and thermal stability of extrudates, the solid physical state of extrudates, possible drug-polymer interactions, the miscibility/solubility of the drug-polymer system, the rheological properties of extrudates, the physicomechanical properties of films produced by hot melt extrusion, and drug particle dissolution from extrudates. It draws upon the last ten years of research, extending inquiry as broadly as possible
Polymeric nanocapsules as nanotechnological alternative for drug delivery system: Current status, challenges and opportunities
Full text linkPolymer-based nanocapsules have been widely studied as a potential drug delivery system in recent years. Nanocapsules—as one of kind nanoparticle—provide a unique nanostructure, consisting of a liquid/solid core with a polymeric shell. This is of increasing interest in drug delivery applications. In this review, nanocapsules delivery systems studied in last decade are reviewed, along with nanocapsule formulation, characterizations of physical/chemical/biologic properties and applications. Furthermore, the challenges and opportunities of nanocapsules applications are also proposed
Qualitative characterization of a transesterification product of coconut oil by FIA-APCI-MS
No full textSynopsis Objectives The purpose of this work was the qualitative characterization of a recently transesterification product obtained from the coconut oil in the presence of polyglycerol-6 to produce a new PEG-free secondary surfactant. The purpose of a secondary surfactant is to reduce the harshness of a skin cleanser. Methods The transesterification product was qualitatively characterized in our laboratory by flow injection analysis-atmospheric pressure chemical ionization-mass spectrometry (FIA-APCI-MS). The mass spectrum of the transesterification product was compared to those of the starting materials (polyglycerol and coconut oil). Results The analyses highlighted the disappearance of the starting oil peaks and the appearance of new peaks assignable to the reaction products, mainly corresponding to diesters of polyglycerol. Additionally, peaks of unreacted polyglycerol are present as well as peaks of cyclization products derived from the polyglycerol starting material. Conclusions The development of this fast and easy analytical method, requesting only few minutes to be performed, represents a very useful tool for the characterization of transesterification products during the quality control of batches under production
Nanocrystals of poorly soluble drugs: Drug bioavailability and physicochemical stability
Full text linkMany approaches have been developed over time to overcome the bioavailability limitations of poorly soluble drugs. With the advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of “pure drugs and a minimum of surface active agents required for stabilization”. They are defined as “carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range, typically between 10–800 nm”. The primary importance of these nanoparticles was the reduction of particle size to nanoscale dimensions, with an increase in the particle surface area in contact with the dissolution medium, and thus in bioavailability. This approach has been proven successful, as demonstrated by the number of such drug products on the market. Nonetheless, despite the definition that indicates nanocrystals as a “carrier-free” system, surface active agents are necessary to prevent colloidal particles aggregation and thus improve stability. In addition, in more recent years, nanocrystal properties and technologies have attracted the interest of researchers as a means to obtain colloidal particles with modified biological properties, and thus their interest is now also addressed to modify the drug delivery and targeting. The present work provides an overview of the achievements in improving the bioavailability of poorly soluble drugs according to their administration route, describes the methods developed to overcome physicochemical and stability-related problems, and in particular reviews different stabilizers and surface agents that are able to modify the drug delivery and targeting
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