1,721,084 research outputs found
2. Advanced techniques in nanocrystallization of active pharmaceutical ingredients
No full textThe number of drugs coming from synthesis and being poorly soluble in water is steadily increasing. At present, 40% of the drugs in the development pipelines and approximately 60% of the drugs coming directly from synthesis are poorly soluble. Particle size reduction to micron scale is a suitable method to enhance the bioavailability of poorly soluble drugs. However, in many cases micronization cannot solve the bioavailability problem. As a consequence, next step moves from micronization to nanonization, i.e. production of drug nanocrystals. This step has been possible thank to the recent development of new nanotechnologies. Drug nanocrystals are nanoparticles composed of 100% drug without any matrix material and with a mean particle size below 1μm. In the present chapter, the techniques used at the laboratory scale and industrial scale for the production of nanocrystals will be presented, divided in bottom-up, top-down, and combined technologies. The physicochemical and technological methods for the characterization of nanocrystals will be considered as an essential tool in the drug product development. An overview of the nanocrystals on the market and under development will be also presented
Editorial: Advances in theranostics: Novel nanotools for the treatment and diagnosis of tumors
Full text linkThe Research Topic entitled Advances in Theranostics: Novel Nanotools for the Treatment and Diagnosis of Tumors presents a small series of articles reporting the most exciting research, novel application studies and scientific progress in the field of nanostructures and functional materials used in the field of oncological theranostics. The limitation in the effectiveness of traditional approaches in treating cancer are largely demonstrated in this Topic Research Topic, providing examples of stimuli-sensitive and technologically advanced novel nanoplatforms (nanoparticles, liposomes, micelles, polymer-drug conjugates, and dendrimers) that, in a multidisciplinary and collaborative approach, involve the contribution of different disciplines ranging from material sciences, biology, immunology, medicine as well as diagnosis
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
Mechanisms for Dehydration of Three Sodium Naproxen Hydrates
No full textSodium naproxen, a member of the class of nonsteroidal anti-inflammatory drugs (NSAID), exists in an anhydrous form and the following four hydrated ones: one monohydrate, two dehydrates, and one tetrahydrate. In the present work, the authors observed the isothermal dehydration of some of these hydrates by thermogravimetry at several temperatures. The rate of water removal from the crystal was used to determine the mechanism of dehydration in the solid state, by fitting results with selected expressions corresponding to the most common solid-state processes. The water loss was then evaluated according to Eyring's equation, and both changes in activation enthalpy (Delta H*) and activation entropy (Delta S*) were estimated from rate constant values. Experiments made it possible to distinguish different dehydration mechanisms for these hydrate forms, and in particular, to discern the dehydration behavior of two different dihydrate forms, one obtained by crystallizing sodium naproxen from water (CSN) and the other obtained after exposure to 55% RH (DSN). These results add new evidence supporting the X-ray powder diffraction study carried out in this work, showing different patterns for these two forms. X-ray powder diffractometry evaluation of the phase transitions occurring during dehydration of these two dihydrate forms showed that they vary according to dehydration temperature
Particle interaction of lubricated or unlubricated binary mixtures according to their particle size and densification mechanism.
No full texthe aim of this study is to assess an experimental approach for technological development of a direct compression formulation. A simple formula was considered composed by an active ingredient, a diluent and a lubricant. The active ingredient and diluent were selected as an example according to their typical densification mechanism: the nitrofurantoine, a fragmenting material, and the cellulose microcrystalline (Vivapur), which is a typical visco-elastic material, equally displaying good bind and disintegrant properties. For each ingredient, samples of different particle size distribution were selected. Initially, tabletability of pure materials was studied by a rotary press without magnesium stearate. Vivapur tabletability decreases with increase in particle size. The addition of magnesium stearate as lubricant decreases tabletability of Vivapur of greater particle size, while it kept unmodified that of Vivapur of lower particle size. Differences in tabletability can be related to differences in particle-particle interactions; for Vivapur of higher particle size (Vivapur 200, 102 and 101), the lower surface area develops lower surface available for bonds, while for Vivapur of lower particle size (99 and 105) the greater surface area allows high particle proximity favouring particle cohesivity. Nitrofurantoine shows great differences in compression behaviour according to its particle size distribution. Large crystals show poorer tabletability than fine crystals, further decreased by lubricant addition. The large crystals poor tabletability is due to their poor compactibility, in spite of high compressibility and plastic intrinsic deformability; in fact, in spite of the high densification tendency, the nature of the involved bonds is very weak. Nitrofurantoine samples were then mixed with Vivapurs in different proportions. Compression behaviour of binary mixes (tabletability and compressibility) was then evaluated according to diluents proportion in the mixes. The mix of either nitrofurantoine large crystals or fine crystals with cellulose microcrystalline showed a negative interaction in all proportions, whatever particle sizes. The lubricant addition induced a positive interaction with Vivapur of greater particle size distribution (200, 102 and 101) favouring higher particle adhesivity, while it maintained unaltered that of Vivapurs of lower particle size (105 and 99). Definitely, when cohesive forces are predominant (Vivapur 105 and 99), the establishment of adhesive bonds between nitrofurantoine and Vivapur remain unnoticed; on the contrary, when cohesion bonds between microcrystalline cellulose particles are weakened by the presence of magnesium stearate, the existence of adhesion bonds between particles of different nature is in evidence, leading to a positive interactio
Evaluation of different fast melting disintegrants by mean of a central composite design.
No full textFast-disintegration technologies have encountered increased interest from industries in the past decades. In order to orientate the formulators to the choice of the best disintegrating agent, the most common disintegrants were selected and their ability to quickly disintegrants compressed tablets was evaluated. For this study, a central composite design was used. The main factors included were the concentration of disintegrant (X-1) and the compression force (X-2). These factors were studied for tablets containing either Zeparox((R)) or Pearlitol 200((R)) as soluble diluents and six LH11 and LH31, different disintegrants: L-HPC(R) LH11 and LH31, Lycatab PGS((R)), Vivasol((R)), Kollidon CL(R), and Explotab((R)). Their micromeritics properties were previously determined. The response variables were disintegration time (Y-1), tensile strength (Y-2) and porosity (Y-3). Whatever the diluent, the longest disintegration time is obtained with Vivasol((R)) as the disintegrant, while Kollidon CL(R) leads to the shortest disintegration times. Exception for Lycatab PGS((R)) and L-HPC LH11((R)), formulations with Pearlitol 200((R)) disintegrate faster. Almost the same results are obtained with porosity: no relevant effect of disintegrant concentration is observed, since porosity is mainly correlated to the compression force. In particular, highest values are obtained with Zeparox((R)) as the diluent when compared to Pearlitol 2000 and, as the type of disintegrant is concerned, no difference is observed. Tensile strength models have been all statistically validated and are all highly dependent on the compression force. Lycatab PGS((R)) concentration does not affect disintegration time, mainly increased by the increase of compression pressure. When Pearlitol 2000 is used with Vivasol((R)), disintegration time is more influenced by the disintegrant concentration than by the compression pressure, an increase in concentration leading to a significant and relevant increase of the disintegration time. With Zeparox((R)), the interaction between the two controlled variables is more complex: there is no effect of compression force on the disintegration time for a small amount of disintegrant. but a significant increase for higher concentrations. With Kollidon CL(R), the main factor influencing the disintegration time is the compression force. rather than the disintegrant concentration. Increasing both the compression force and the disintegrant concentration leads to an increase of the disintegration time. For lower Kollidon CL(R) percentages, the compression pressure increases dramatically the tablet disintegration. With the Explotab((R)), whatever the increase of compression force, the disintegrant concentration leads to an increase of the disintegration time. According to Student's t-test, only the compression force significantly and strongly influences the disintegration time when Pearlitol 200((R)) is used. A slight interaction and some trends nevertheless appear: above 150 MPa, increasing the disintegrant concentration leads to a shortened disintegration time, below this limit the opposite effect is observed
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
Physico-chemical and technological properties of sodium naproxen granules prepared in a high-shear mixer-granulator
No full textIn the present work, authors produced tablets of anhydrous sodium
naproxen by wet granulation using a high-shear mixer-granulator. Drug hydrated to
the tetrahydrated form, as observed by X-ray powder diffractometry. After wet granulation,
authors then performed two different drying procedures, obtaining granules of
different water content and crystallographic characteristics. The first procedure dried
granules in the high-shear mixer-granulator by applying vacuum at room temperature
(batch A), while the second employed the same apparatus and time, under vacuum at
408C (batch B). X-ray powder diffractometry revealed that the sodium naproxen (SN)
contained in batch A granules was a mixture of dihydrated and tetrahydrated forms (as
demonstrated by the coexistence of peaks typical of both hydrated forms), while that of
batch B granules was a mixture of monohydrated and tetrahydrated forms. This means
that differences in drying procedures could lead to products of different crystallographic
properties. The behavior under compression was evaluated, revealing that batch
A offered the best tabletability and compressibility. These results make it possible to
conclude that differences in the crystallographic properties and water content of SN are
such that different hydration/drying processes can alter the drug crystal form and thus
the tabletability of the resulting granules
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