SciCombinator

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Concept: Solvation

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In this paper work, four naked nanocrystals (size range 80-700 nm) were prepared without any surfactant or polymer using the solvent/nonsolvent method. The effects of particle size on their solubility, dissolution, and oral bioavailability were investigated. Solubility and dissolution testing were performed in three types of dissolution medium, and the studies demonstrated that the equilibrium solubilities of coenzyme Q(10) nanocrystals and bulk drugs were not affected by the dissolution media but the kinetic solubilities were. Kinetic solubility curves and changes in particle size distribution were determined and well explained by the proposed solubilization model for the nanocrystals and bulk drugs. The particle size effect on dissolution was clearly influenced by the diffusion coefficients of the various dissolution media, and the dissolution velocity of coenzyme Q(10) increased as particle size decreased. The bioavailability of coenzyme Q(10) after oral administration in beagle dogs was improved by reducing the particle size. For 700 nm nanocrystals, the AUC(0-48) was 4.4-fold greater than that for the coarse suspensions, but a further decrease in particle size from 700 nm to 120 nm did not contribute to improvement in bioavailability until the particle size was reduced to 80 nm, when bioavailability was increased by 7.3-fold.

Concepts: Improve, Effect, Solubility, Affect, Particle size distribution, Biopharmaceutics Classification System, Solvation, Colloidal chemistry

28

Liquisolid technique is one of the methods used to improve the dissolution rate of the poorly water soluble drugs utilizing non volatile liquids.

Concepts: Temperature, Solubility, Phase, Solution, Carbonate, Solvation, Volatile, Henry's law

28

Abstract The objective of this study was to improve the dissolution rate and to enhance the stability of a poorly water-soluble and low glass-trasition temperature (T(g)) model drug, fenofibrate, in low molecular weight grades of hydroxypropylcellulose matrices produced by hot-melt extrusion (HME). Percent drug loading had a significant effect on the extrudability of the formulations. Dissolution rate of fenofibrate from melt extruded pellets was faster than that of the pure drug (p < 0.05). Incorporation of sugars within the formulation further increased the fenofibrate release rates. Differential scanning calorimetry results revealed that the crystalline drug was converted into an amorphous form during the HME process. Fenofibrate is prone to recrystallization due to its low T(g). Various polymers were evaluated as stabilizing agents among which polyvinylpyrrolidone 17PF and amino methacrylate copolymer exhibited a significant inhibitory effect on fenofibrate recrystallization in the hot-melt extrudates. Subsequently immediate-release fenofibrate tablets were successfully developed and complete drug release was achieved within 5 min. The dissolution profile was comparable to that of a currently marketed formulation. The hot-melt extruded fenofibrate tablets were stable, and exhibited an unchanged drug release profile after 3-month storage at 40°C/75% RH.

Concepts: Pharmacology, Polymer, Thermodynamics, Differential scanning calorimetry, Glass transition, Solvation, Stability, Pharmaceutical formulation

28

Salts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociates back to the freebase form.

Concepts: Active ingredient, Solvation, Sulfate

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Spironolactone is a drug derived from sterols that exhibits an incomplete oral absorption due to its low water solubility and slow dissolution rate. In this study, formulations of spironolactone with four disintegrants named as croscarmellose sodium, crospovidone, sodium starch glycolate and microcrystalline cellulose II (MCCII) were conducted. The effect of those disintegrants on the tensile strength, disintegration time and dissolution rate of spironolactone-based compacts was evaluated using a factorial design with three categorical factors (filler, lubricant, and disintegrant). The swelling values, water uptake and water sorption studies of these disintegrants all suggested that MCCII compacts disintegrate by a wicking mechanism similar to that of crospovidone, whereas a swelling mechanism was dominant for sodium starch glycolate and croscarmellose sodium. The disintegration time of MCCII and sodium starch glycolate remained unchanged with magnesium stearate. However, this lubricant delayed the disintegration time of crospovidone and croscarmellose sodium. MCCII presented the fastest disintegration time independent of the medium and lubricant employed. The water sorption ratio and swelling values determined sodium starch glycolate followed by croscarmellose sodium as the largest swelling materials, whereas crospovidone and MCCII where the least swelling disintegrants. The swelling property of sodium starch glycolate and croscarmellose sodium was strongly affected by the medium pH. The disintegration time of spironolactone compacts was faster when starch was used as a filler due to the formation of soft compacts. In this case, the type of filler employed rather than the disintegrant had a major effect on the disintegration and dissolution times of spironolactone.

Concepts: Ethanol, Solubility, Starch, Tensile strength, Cellulose, Excipients, Solvation, The Medium

28

Introduction: Many active pharmaceutical ingredients (APIs), in development and already on the market, show a limited and variable bioavailability mainly associated to inadequate biopharmaceutical properties such as aqueous solubility and dissolution rate. The latter is the main factor responsible for the limited, and sometimes inadequate, efficacy of many orally administered drugs, belonging to class II and IV of the Biopharmaceutics Classification System (BCS). Moreover, because of their low solubility, such drugs require high doses to be administered in order to obtain their pharmacological effect, increasing the side effect incidence. Areas covered: The present review reports the most common technological approaches intended to improve solubility and dissolution rate of BCS class II and IV drugs such as nanocrystals, solid dispersions, cyclodextrins and solid lipid nanoparticles. Particular attention will be focused on the use of inorganic matrices (lamellar anionic clays and mesoporous materials) as host for the delivery of poor soluble APIs (guest). Expert opinion: The employment of inorganic matrices for the realization of host-guest composites is a suitable strategy for the biopharmaceutical properties enhancement. This objective can be achieved without any modification of API chemical structure.

Concepts: Pharmacology, Drug, Solubility, Pharmaceutical drug, Biopharmaceutics Classification System, Bioavailability, Active ingredient, Solvation

28

One of the problems of praziquantel (PZQ) is its very low aqueous solubility. Moreover, its dissolution rate is considered the limiting factor for its bioavailability. This work correlates the physical properties and the dissolution behavior of PZQ-polyvinylpyrrolidone (PVP) solid dispersion (SD) at the ratios of 1:1 and 3:7 with its oral bioavailability and its in vivo efficacy against Schistosoma mansoni (S. mansoni). The PZQ and PZQ-PVP SD were characterized by infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy (SEM) and solubility test. Results showed a decrease in crystallinity, possible interaction between PZQ and PVP, greater increase in dissolution rate and appreciable reduction in particle size. S. mansoni-infected mice treated orally with either pure PZQ or PZQ-PVP at a single dose of 500 mg/kg showed a higher increase in AUC((0-8h)), C (max), K (a) and t (1/2e) with a significant decrease in k (el) versus the corresponding uninfected mice. Moreover, uninfected and infected mice treated with PZQ-PVP SD showed 2.3-, 1.6- and 1.3-, 1.25-fold increase, respectively, in AUC((0-8h)) and C (max), with a decrease in k (el) and increase in t (1/2e) by twofold versus the corresponding pure PZQ-treated groups. Percentage worm reduction at all administered doses (62.5, 125, 250, 500 and 1,000 mg/kg) was significantly higher (1- to 1.5-fold) in mice treated with PZQ-PVP SD (ED(50) = 40.92) versus those treated with pure PZQ (ED(50) = 99.29). In addition, a significant reduction in total tissue egg load concomitant with a significant decrease in total immature and mature eggs and an increase in dead eggs in PZQ-PVP SD-treated groups versus their corresponding pure PZQ-treated groups was recorded. Solid dispersion of PZQ with PVP could lead to a further improvement in the effectiveness of PZQ therapy especially with the appearance of some PZQ-tolerant S. mansoni isolates.

Concepts: Schistosomiasis, Schistosoma mansoni, Schistosoma, Digenea, Differential scanning calorimetry, Scanning electron microscope, Biopharmaceutics Classification System, Solvation

27

Lipid-based formulations have established a significant role in the formulation of poorly soluble drugs for oral administration. In order to better understand their potential advantages over solid oral dosage forms, we studied the solubility and dissolution/precipitation characteristics of three self-microemulsifying drug delivery system (SMEDDS) formulations and one suspension of micronized fenofibrate in lipid excipients, for which pharmacokinetic studies had already been reported in the open literature. The in vitro dispersion/dissolution studies were carried out in biorelevant media using USP II apparatus. These were followed up by in silico simulations using STELLA(®) software, in which not only dispersion/dissolution, but also the precipitation and re-dissolution of fenofibrate was taken into account. While unformulated drug exhibited poor solubility (0.22 μg/mL in FaSSGF and 4.31 μg/mL in FaSSIF-V2(PO4)) and dissolved less than 2% in dissolution tests, the solubility of fenofibrate in the presence of the lipid excipients increased dramatically (e.g. to 65.44 μg/mL in the presence of the Myritol 318 / TPGS / Tween 80 SMEDDS) and there was an attendant increase in the dissolution (over 80% from capsules containing the Myritol 318 / TPGS / Tween 80 SMEDDS and about 20% from the dispersion of fenofibrate in lipid excipients). For the four lipid-based fenofibrate formulations studied, combining in vitro data in biorelevant media with in silico simulation resulted in accurate prediction of the in vivo human plasma profiles. The point estimates of Cmax and AUC ratio calculated from the in silico and in vivo plasma profiles fell within the 0.8-1.25 range for the SMEDDS solution and capsule formulations, suggesting an accurate simulation of the in vivo profiles. This similarity was confirmed by calculation of the respective f2 factors. Sensitivity analysis of the simulation profiles revealed that the SMEDDS formulations had virtually removed any dependency of absorption on the dissolution rate in the small intestine, whereas for the dispersion in lipid excipients this barrier remained. Such results pave the way to optimizing the performance of oral lipid-based formulations via an in vitro - in silico - in vivo approach.

Concepts: Pharmacology, In vivo, In vitro, Pharmacokinetics, Biopharmaceutics Classification System, Solvation

27

A novel surface-attached, spray-dried solid dispersion containing poorly water-soluble carvedilol (CV) without any change in the crystallinity was prepared using water, polyvinylpyrrolidone (PVP K30) and Tween 80. The solid dispersion was optimized by investigating the effects of the weight ratios of Tween 80/PVP K30 and carrier/drug on the aqueous solubility of CV. The optimum solid dispersion consisted of a relatively low carrier to drug weight ratio: the weight ratio of CV/PVP K30/Tween 80 was 12/4/2. Unlike conventional methods of solid dispersion preparation, this method yielded CV-loaded solid dispersion with no change in the crystallinity of the drug as was evident from SEM, DSC and XRD. It was demonstrated that the solid dispersions prepared had hydrophilic carriers attached to the surface of the drug, thus changing it from a hydrophobic to a hydrophilic form without changing the crystalline form. The optimized solid dispersion improved the drug solubility and dissolution rate by about 11,500-fold and twofold, respectively. It was further suggested that this method of solid dispersion preparation is better than conventional methods in terms of environmental and industrial standpoints. Thus, it was concluded that CV-loaded solid dispersion prepared using this method would be of use for delivering poorly water-soluble CV with enhanced solubility and dissolution, but without crystalline changes.

Concepts: Crystal, Chemistry, Solubility, Solid, Change, Hydrophile, Solvation, Polymorphism

26

Abstract Context: Piroxicam (PXM), a non-steroidal anti-inflammatory drug which is poorly soluble in water and ulcerogenic. Milk has been used against the gastric disturbances caused by non-steroidal anti-inflammatory drugs. In this study, skimmed milk (SKM) is used as the carrier for inclusion complex (IC) due to its surface active agent and amino acid content. Purpose: To enhance the solubility, dissolution rate and prevent ulcerogenicity of PXM though IC with SKM. Methods: IC of PXM were prepared with SKM by solvent evaporation method using rota evaporator and were evaluated for solubility, dissolution, solid state characterization, drug excipient interaction, rat intestinal permeation, ulcerogenicity and histopathological studies. Results: Solubility of PXM was enhanced 2.5 times with IC. The dissolution release and amount of PXM permeated through rat small intestine was enhanced significantly with IC. Decreases in the gastric lesion index values of IC were observed than physical mixture (PM) and free PXM. The histopathological studies revealed significant reduction in ulceration in rat stomach after treatment with IC. Conclusion: It is concluded that SKM is a good carrier to prepare IC of PXM for oral administration.

Concepts: Small intestine, Non-steroidal anti-inflammatory drug, Anti-inflammatory, Paracetamol, Solvation, Piroxicam