Effect of Counterion on the Solid State Photodegradation Behavior of Prazosin Salts

The effect of counterion was evaluated on the photodegradation behavior of six prazosin salts, viz., prazosin hydrochloride anhydrous, prazosin hydrochloride polyhydrate, prazosin tosylate anhydrous, prazosin tosylate monohydrate, prazosin oxalate dihydrate, and prazosin camsylate anhydrous. The salts were subjected to UV–Visible irradiation in a photostability test chamber for 10 days. The samples were analyzed for chemical changes by a specific stability-indicating high-performance liquid chromatography method. pH of the microenvironment was determined in 10% w/v aqueous slurry of the salts. The observed order of photostability was: prazosin hydrochloride anhydrous > prazosin camsylate anhydrous ∼ prazosin-free base > prazosin hydrochloride polyhydrate > prazosin tosylate anhydrous > prazosin oxalate dihydrate ∼ prazosin tosylate monohydrate. Multivariate analysis of the photodegradation behavior suggested predominant contribution of the state of hydration and also intrinsic photosensitivity of the counterion. Overall, hydrated salts showed higher photodegradation compared to their anhydrous counterparts. Within the anhydrous salts, aromatic and carbonyl counterion-containing salts showed higher susceptibility to light. The pH of microenvironment furthermore contributed to photodegradation of prazosin salts, especially for drug counterions with inherent higher pH. The study reveals importance of selection of a suitable drug salt form for photosensitive drugs during preformulation stage of drug development.     

Effect of physicochemical parameters on skin permeability of antihypertensive

Studies were carried out to establish a correlation of skin permeability with physicochemical parameters using five antihypertensive drugs. In vitro skin permeation was carried out in vertical type diffusion cells. When steady-state fluxes of the drugs were correlated with physicochemical properties, good correlation was obtained with the reciprocal of melting point. Weak correlation was obtained with partition coefficient, molecular weight and solubility. However skin permeability versus solubility profiles revealed an interesting trend. The initial permeation rates of the poorly water soluble drugs, prazosin hydrochloride and reserpine were higher than their steady-state fluxes and moderately water soluble drug atenolol showed more or less similar permeation throughout the entire span of the study. This trend changed gradually and reversed completely in the highly water soluble drug diltiazem hydrochloride. The study suggests that drug derivatives of low melting point and good aqueous solubility could be favorable candidates for transdermal delivery.     

Pharmacokinetics of saquinavir after intravenous and oral dosing of saquinavir: hydroxybutenyl-beta-cyclodextrin formulations

The current research evaluated the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to enhance saquinavir in vitro solubility and in vivo oral bioavailability; both the base and mesylate salt forms of saquinavir were investigated. HBenBCD was effective and significantly improved saquinavir solubility in aqueous media. In the presence of 10 wt % HBenBCD, saquinavir base solubility in water was increased to ca. 5.5 +/- 0.4 mg/mL and represents a 27-fold increase from that observed in water (207 +/- 5 microg/mL) in the absence of HBenBCD. Saquinavir-HBenBCD formulations were found to have rapid dissolution over a wide pH range (1.2-6.8), and saquinavir solubility in these media was maintained throughout the experiments. When saquinavir-HBenBCD formulations were administered to Wistar-Hannover rats, saquinavir was rapidly absorbed and rapidly eliminated. Rapid saquinavir elimination was particularly pronounced when saquinavir-HBenBCD formulations were given as an oral aqueous gavage. Saquinavir oral bioavailability in rats obtained from saquinavir mesylate capsules (2.0% +/- 0.7%) was increased (9 +/- 4)-fold (18.6% +/- 7.3%) when dosed with saquinavir base-HBenBCD capsules. Clearly, HBenBCD can significantly improve the solubility and oral bioavailability of saquinavir; however, further formulation studies are required to optimize saquinavir oral delivery using this technology.     

VALENCY RULE AND ALLEGED HOFMEISTER SERIES IN THE COLLOIDAL BEHAVIOR OF PROTEINS : III. THE INFLUENCE OF SALTS ON OSMOTIC PRESSURE,MEMBRANE POTENTIALS,AND SWELLING OF SODIUM GELATINATE.

A detailed study was made on the influence of salts on those physicochemical properties of sodium gelatinate which are regulated by Donnan''s law of membrane equilibria; namely, osmotic pressure, membrane potentials, and swelling. It was found that the influence of salts on these properties in the case of sodium gelatinate obeys the same rules of valency as in the case of the influence of salts on gelatin chloride as discussed in a previous publication. The rules state that when a salt is added to an ionized protein, without causing a change in the hydrogen ion concentration of the protein, the general effect is a depression of the mentioned properties. The degree of depression depends not only on the concentration of the salt but on the electrical properties of the ions constituting the salt. Of the two or more oppositely charged ions of which a salt consists, only the valency of those ions which carry charges opposite to those carried by the protein ions affects the degree of depression which increases with the valency of the ions. It was also found that the phenomenon of swelling of gelatin becomes modified by solubility of the gelatin when salts are added in concentrations higher than N/4. Emphasis is laid on the point that the valency rule holds perfectly also in relation to swelling as long as the phenomenon is pure swelling which is the case when salt solutions of concentrations lower than N/4 are added to gelatin.     

Enhancement of Oral Bioavailability of Curcumin by a Novel Solid Dispersion System

The objective of this study was to improve the solubility and bioavailability of curcumin by a new curcumin dripping pills (Cur-DPs) formulation using melt mixing methods. The optimal formulation consisted of Polyethoxylated 40 hydrogenated castor oil (Cremophor RH40), Poloxamer 188, and Polyethylene glycol 4000 (PEG 4000). Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FT-IR) were used to verify the forming of Cur-DPs. All the physical characterization information proved the formation of Cur-DPs, and the results demonstrated the superiority of the dripping pills in dissolution rates. The pharmacokinetic study of Cur-DPs was performed in rats compared to the pure curcumin suspension. The oral bioavailability of poorly water-soluble curcumin was successfully improved by CUR-DPs. And the stability of prepared Cur-DP was also in a good state in 3 months. These results identified the Cur-DPs was an effective new approach for pharmaceutical application.KEY WORDS: curcumin, dripping pills, oral bioavailability, physicochemical properties, stability     

Albendazole Microcrystal Formulations Based on Chitosan and Cellulose Derivatives: Physicochemical Characterization and <Emphasis Type="Italic">In Vitro</Emphasis> Parasiticidal Activity in <Emphasis Type="Italic">Trichinella spiralis</Emphasis> Adult Worms

The oral route has notable advantages to administering dosage forms. One of the most important questions to solve is the poor solubility of most drugs which produces low bioavailability and delivery problems, a major challenge for the pharmaceutical industry. Albendazole is a benzimidazole carbamate extensively used in oral chemotherapy against intestinal parasites, due to its extended spectrum activity and low cost. Nevertheless, the main disadvantage is the poor bioavailability due to its very low solubility in water. The main objective of this study was to prepare microcrystal formulations by the bottom-up technology to increase albendazole dissolution rate, in order to enhance its antiparasitic activity. Thus, 20 novel microstructures based on chitosan, cellulose derivatives, and poloxamer as a surfactant were produced and characterized by their physicochemical properties and in vitro biological activity. To determine the significance of type and concentration of polymer, and presence or absence of surfactant in the crystals, the variables area under the curve, albendazole microcrystal solubility, and drug released (%) at 30 min were analyzed with a three-way ANOVA. This analysis indicated that the microcrystals made with hydroxyethylcellulose or chitosan appear to be the best options to optimize oral absorption of the active pharmaceutical ingredient. The in vitro evaluation of anthelmintic activity on adult forms of Trichinella spiralis identified system S10A as the most effective, of choice for testing therapeutic efficacy in vivo.     

Solution-Mediated Phase Transformation of Haloperidol Mesylate in the Presence of Sodium Lauryl Sulfate

Forming a salt is a common way to increase the solubility of a poorly soluble compound. However, the solubility enhancement gained by salt formation may be lost due to solution-mediated phase transformation (SMPT) during dissolution. The SMPT of a salt can occur due to a supersaturated solution near the dissolving surface caused by pH or other solution conditions. In addition to changes in pH, surfactants are also known to affect SMPT. In this study, SMPT of a highly soluble salt, haloperidol mesylate, at pH 7 in the presence of a commonly used surfactant, sodium lauryl sulfate (SLS), was investigated. Dissolution experiments were performed using a flow-through dissolution apparatus with solutions containing various concentrations of SLS. Compacts of haloperidol mesylate were observed during dissolution in the flow-through apparatus using a stereomicroscope. Raman microscopy was used to characterize solids. The dissolution of haloperidol mesylate was significantly influenced by the addition of sodium lauryl sulfate. In conditions where SMPT was expected, the addition of SLS at low concentrations (0.1–0.2 mM) reduced the dissolution of haloperidol mesylate. In solutions containing concentrations of SLS above the critical micelle concentration (CMC) (10–15 mM), the dissolution of haloperidol mesylate increased compared to below the CMC. The solids recovered from solubility experiments of haloperidol mesylate indicated that haloperidol free base precipitated at all concentrations of SLS. Above 5 mM of SLS, Raman microscopy suggested a new form, perhaps the estolate salt. The addition of surfactant in solids that undergo solution-mediated phase transformation can add complexity to the dissolution profiles and conversion.     

Crystalline Behavior of Chitosan Organic Acid Salts

The crystal structures of chitosan acid salts were studied by X-ray diffraction measurements on a fiber diagram and a new procedure to obtain an anhydrous polymorph of chitosan was found. The salts prepared by immersing a chitosan into a mixture of acid solution and isopropanol were classified into two types (Types I and II) depending on their conformation. Molecular conformation of the Type I salt retains the extended 2-fold helical structure of the original chitosan, but that of Type II salt is a twisted 2-fold helix. All the Type II salts changed to the anhydrous “Annealed” polymorph of chitosan when soaking in 75% aqueous isopropanol, but when the Type I salts were immersed in the solution, they returned to the hydrated “Tendon” polymorph which is that of the original chitosan. The strange transformation observed in Type II salt may be related to the stability of the molecular conformation of chitosan in the salt.     

Crystalline behavior of chitosan organic acid salts.

The crystal structures of chitosan acid salts were studied by X-ray diffraction measurements on a fiber diagram and a new procedure to obtain an anhydrous polymorph of chitosan was found. The salts prepared by immersing a chitosan into a mixture of acid solution and isopropanol were classified into two types (Types I and II) depending on their conformation. Molecular conformation of the Type I salt retains the extended 2-fold helical structure of the original chitosan, but that of Type II salt is a twisted 2-fold helix. All the Type II salts changed to the anhydrous "Annealed" polymorph of chitosan when soaking in 75% aqueous isopropanol, but when the Type I salts were immersed in the solution, they returned to the hydrated "Tendon" polymorph which is that of the original chitosan. The strange transformation observed in Type II salt may be related to the stability of the molecular conformation of chitosan in the salt.     

Preparation and Evaluation of Diosgenin Nanocrystals to Improve Oral Bioavailability

Diosgenin (DSG), a well-known steroid sapogenin derived from Dioscorea nipponica Makino and Dioscorea zingiberensis Wright, has a variety of bioactivities. However, it shows low oral bioavailability due to poor aqueous solubility and strong hydrophobicity. The present study aimed to develop DSG nanocrystals to increase the dissolution and then improve the oral bioavailability and biopharmaceutical properties of DSG. DSG nanocrystals were prepared by the media milling method using a combination of pluronic F127 and sodium dodecyl sulfate as surface stabilizers. The physicochemical properties of the optimal DSG nanocrystals were characterized using their particle size distribution, morphology, differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy data, and solubility and dissolution test results. Pharmacokinetic studies of the DSG coarse suspension and its nanocrystals were performed in rats. The particle size and polydispersity index of DSG nanocrystals were 229.0?±?3.7 nm and 0.163?±?0.064, respectively. DSG retained its original crystalline state during the manufacturing process, and its chemical structure was not compromised by the nanonizing process. The dissolution rate of the freeze-dried DSG nanocrystals was significantly improved in comparison with the original DSG. The pharmacokinetic studies showed that the AUC_0–72h and C _max of DSG nanocrystals increased markedly (p?<?0.01) in comparison with the DSG coarse suspension by about 2.55- and 2.01-fold, respectively. The use of optimized nanocrystals is a good and efficient strategy for oral administration of DSG due to the increased dissolution rate and oral bioavailability of DSG nanocrystals.     

The complexation of aqueous metal ions relevant to biological applications. 2. Reactions of copper(II) citrate and copper(II) succinate with selected amino acids

Abstract

Addition of amino acids, glycine, alanine, and serine, to poorly soluble copper(II) salts [copper(II) citrate and copper(II) succinate] all increase solubility of the copper(II) salts. Relative increases in solubility follow the polarity trend in the selected amino acids, with serine creating the greatest increase in solubility. Simultaneous equilibria calculations indicate the formation of mixed-ligand complexes in the copper(II) succinate–amino acid systems, the first time such mixed-ligand complexes have been observed. In contrast, mixed-ligand complexes are not predicted in the copper(II) citrate–amino acid systems. Potential bioavailability of copper(II) appears to be increased by the inclusion of amino acids in solution, roughly in parallel with the increase in solubility of the copper(II) salt. Therefore, measurement of the change in solubility caused by addition of amino acids to aqueous solution gives qualitative insight to the potential increase in bioavailability of the metal ion.     

A study of the physicochemical interactions between biliary lipids and chlorpromazine hydrochloride. Bile-salt precipitation as a mechanism of phenothiazine-induced bile secretory failure.

Since chlorpromazine hydrochloride [2-chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride] is commonly implicated in causing bile-secretory failure in man and is secreted into bile, we have studied the physicochemical interactions of the drug with the major components of bile in vitro. Chlorpromazine hydrochloride molecules are amphiphilic by virtue of possessing a polar tertiary amine group linked by a short paraffin chain to a tricyclic hydrophobic part. At pH values below the apparent pK (pK'a 7.4) the molecules are water-soluble cationic detergents. We show that bile salts in concentrations above their critical micellar concentrations are precipitated from solution by chlorpromazine hydrochloride as insoluble 1:1 salt complexes. In the case of mixed bile-salt/phosphatidylcholine micellar solutions, however, the degree of precipitation is inhibited by the phospholipid in proportion to its mole fraction. With increases in the concentration of chlorpromazine hydrochloride or bile salt, micellar solubilization of the precipitated complexes results. Sonicated dispersions of the negatively charged phospholipid phosphatidylserine were also precipitated, but dispersions of the zwitterionic phospholipid phosphatidylcholine were not. Chlorpromazine hydrochloride efficiently solubilized these membrane phospholipids as mixed micellar solutions when the drug:phospholipid molar ratio reached 4:1. Polarizing-microscopy and X-ray-diffraction studies revealed that the precipitated complexes were amorphous and potentiometric studies confirmed the presence of a salt bond. Some dissociation of the complex occurred in the case of the most polar bile salt (Ks 0.365). As canalicular bile-salt secretion determines much of bile-water flow, we propose that complexing and precipitation of bile salts by chlorpromazine hydrochloride and its metabolites may be physicochemically related to the reversible bile-secretory failure produced by this drug.     

Influence of Lipid Phase Composition of Excipient Emulsions on Curcumin Solubility,Stability, and Bioaccessibility

The influence of oil type on the ability of excipient emulsions to improve the solubility, stability, and bioaccessibility of curcumin was examined. Oil-in-water emulsions were prepared using coconut, sunflower, corn, flaxseed, or fish oils. These excipient emulsions were then mixed with powdered curcumin and incubated at 30 or 100 °C. For all oils, more curcumin was transferred from powder to excipient emulsion at 100 °C (190–200 μg/mL) than at 30 °C (30–36 μg/mL), which was attributed to increased curcumin solubility with temperature. Oil type influenced the stability and bioaccessibility of curcumin when excipient emulsions were exposed to simulated gastrointestinal tract conditions, which was attributed to differences in the molecular composition and physicochemical properties of the oils. Overall, the use of fish oil led to the highest effective curcumin bioavailability (38 %). This study provides valuable information for optimizing excipient emulsions to increase curcumin bioavailability in food, supplement, or pharmaceutical applications.     

The influence of kosmotropic and chaotropic salts on the functional properties of Mucuna pruriens protein isolate

The influence of chaotropic and kosmotropic salts on Mucuna pruriens protein isolates was investigated. Protein solubility profile indicated that solubility was minimal at the isoelectric point of the protein isolate (4.0) while the solubility was maximal at pH 10.0 in all salt solutions. Chaotropes (I(-), ClO(4)(-) and SCN(-)) exhibit better protein solubility than the kosmotropes (SO(4)(2-), Cl(-) and Br(-)). Increase in protein solubility follows the Hofmeister series: NaSO(4)相似文献   

Effects of different calcium salts on calcium carbonate crystal formation by Sporosarcina pasteurii KCTC 3558

We examined the effectiveness of using different calcium salts for bioconsolidation. Four calcium salts were chosen based on their applicability and solubility. Initial experiments demonstrated that the addition of any calcium salt had a negative effect on the urease activity of S. pasteurii. Microscopic examinations elucidated the morphological and structural differences of the calcium carbonate (CaCO₃) crystals induced. Calcite and vaterite are the prominent forms of CaCO₃ detected according to X-ray diffraction (XRD) analysis. Bioconsolidated sand samples were able to significantly resist water flow through a column compared to the non-treated samples. Also, in a tightness test, the differences in the ability to retain water within columns were observed among the samples tested. Moreover, despite the differences, the calcium salts tested still bound the sand together to form blocks. Our results further explain the influence of multiple factors in crystal formation and sand bioconsolidation effectiveness.     

Preparation and <Emphasis Type="Italic">In Vitro</Emphasis>–<Emphasis Type="Italic">In Vivo</Emphasis> Evaluation of Sustained-Release Matrix Pellets of Capsaicin to Enhance the Oral Bioavailability

Capsaicin has multiple pharmacological activities including antioxidant, anticancer, and anti-inflammatory activities. However, its clinical application is limited due to its poor aqueous solubility, gastric irritation, and low oral bioavailability. This research was aimed at preparing sustained-release matrix pellets of capsaicin to enhance its oral bioavailability. The pellets comprised of a core of solid-dispersed capsaicin mixed with microcrystalline cellulose (MCC) and hydroxypropyl cellulose (HPMC) and subsequently coating with ethyl cellulose (EC) were obtained by using the technology of extrusion/spheronization. The physicochemical properties of the pellets were evaluated through scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). Besides, the in vitro release, in vivo absorption, and in vitro–in vivo correlation were also assessed. More importantly, the relative bioavailability of the sustained-release matrix pellets was studied in fasted rabbits after oral administration using free capsaicin and solid dispersion as references. The oral bioavailability of the matrix pellets and sustained-release matrix pellets of capsaicin was improved approximately 1.98-fold and 5.34-fold, respectively, compared with the free capsaicin. A good level A IVIVC (in vitro–in vivo correlation) was established between the in vitro dissolution and the in vivo absorption of sustained-release matrix pellets. All the results affirmed the remarkable improvement in the oral bioavailability of capsaicin owing to the successful preparation of its sustained-release matrix pellets.     

Efficient resolution of venlafaxine and mechanism study via X‐ray crystallography

Numbers of resolving factors were investigated to improve resolution of venlafaxine 1 . An effective resolving agent, O,O′‐di‐p‐toluoyl‐(R, R)‐tartaric acid 2 , was screened using similar method of ‘Dutch resolution’ from tartaric acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of rac‐ 1 and 2 was 1:0.8 in THF with little water (10:1 v/v). Enantiomerically pure venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution mechanism was first explained through X‐ray crystallographic study. One diastereomeric salt with well solubility forms a columnar supramolecular structure as the acidic salt (R)‐ 1 · 2 , while the other diastereomeric salt with less solubility forms a multilayered sandwich supramolecular structure by enantio‐differentiation self‐assembly as the neutral salt 2(S)‐ 1 · 2 . The water molecules play a key role in the optical resolution, as indicated by the special structures of the diastereomeric salts.     

Molecular Docking studies of FKBP12-mTOR inhibitors using binding predictions

Mammalian target of rapamycin (mTOR) is a key regulator of cell growth, proliferation and angiogenesis. mTOR signaling is frequently hyper activated in a broad spectrum of human cancers thereby making it a potential drug target. The current drugs available have been successful in inhibiting the mTOR signaling, nevertheless, show low oral bioavailability and suboptimal solubility. Considering the narrow therapeutic window of the available inhibitors, through computational approaches, the present study pursues to identify a compound with optimal oral bioavailability and better solubility properties in addition ensuing high affinity between FKBP12 and FRB domain of mTOR. Current mTOR inhibitors; Everolimus, Temsirolimus Deforolimus and Echinomycin served as parent molecules for similarity search with a threshold of 95%. The query molecules and respective similar molecules were docked at the binding cleft of FKBP12 protein. Aided by MolDock algorithm, high affinity compounds against FKBP12 were retrieved. Patch Dock supervised protein-protein interactions were established between FRB domain of mTOR and ligand (query and similar) bound and free states of FKBP12. All the similar compounds thus retrieved showed better solubility properties and enabled better complex formation of mTOR and FKBP12. In particular Everolimus similar compound PubChem ID: 57284959 showed appreciable drugs like properties bestowed with better solubility higher oral bioavailability. In addition this compound brought about enhanced interaction between FKBP12 and FRB domain of mTOR. In the study, we report Everolimus similar compound PubChem ID: 57284959 to be potential inhibitor for mTOR pathway which can overcome the affinity and solubility concerns of current mTOR drugs.

Abbreviations

mTOR - Mammalian Target of Rapamycin, FRB domain - FKBP12-rapamycin associated protein, FKBP12 - FK506-binding protein 12, OPLS - Optimized Potentials for Liquid Simulations, Akt - RAC-alpha serine/threonine-protein kinase, PI3K - phosphatidylinositide 3-kinases.     

Improvement of Physicochemical Properties of an Antiepileptic Drug by Salt Engineering

The focus of the present investigation was to evaluate the feasibility of using cyclamic salt of lamotrigine in order to improve its solubility and intrinsic dissolution rate (IDR). The salt was prepared by solution crystallization method and characterized chemically by fourier transform infrared spectroscopy (FTIR), proton ((1)H) and carbon ((13)C) nuclear magnetic resonance (liquid and solid, NMR) spectroscopy, physically by powder X-ray diffraction (PXRD), thermally by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), physicochemically for solubility, IDR, solution and solid-state stability, and polymorphism by solution recrystallization and slurry conversion studies. The FTIR, NMR, PXRD, DSC, and TGA spectra and thermograms indicated the salt formation. The salt formation increased lamotrigine solubility by 19-fold and IDR by 4.9-fold in water. The solution and solid-state stability were similar to parent molecule and were resistant to polymorphic transformation. In conclusion, cyclamic salt of lamotrigine provides another potential avenue for the pharmaceutical development of lamotrigine with improved physicochemical properties especially for pediatric population. It is also possible that appropriate dosage forms can be formulated with much lower drug amount and better safety profile than existing products.