Synthesis of piperazinylalkyl ester prodrugs of ketorolac and their in vitro evaluation for transdermal delivery

Ketorolac, an NSAID, has low intrinsic permeation capacity through the skin. In this work, seven piperazinylalkyl ester prodrugs of ketorolac were synthesized to enhance its skin permeation. The chemical hydrolysis and the stability in human serum at 37 degrees C were investigated in buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs were chemically more stable at pH 5.0 than at pH 7.4 with prodrug 8 being the most stable (t(1/2) = 119.75 h and 11.97 h at pH 5 and 7.4, respectively). The prodrugs' t(1/2) in human serum ranged from 0.79 to 3.92 min. The prodrugs' aqueous solubility was measured in buffer solution at pH 5.0 and 7.4 and Log P(app) was measured by partitioning between buffer solution (pH 5.0 and 7.4) and n-octanol. The prodrugs were more lipophilic than ketorolac at pH 7.4. Skin permeation of ketorolac and prodrug 8, the most stable chemically, through rat skin was studied at pH 5.0 and 7.4. Prodrug 8 enhanced permeation by 1.56- and 11.39-fold at pH 5 and 7.4, respectively. This is attributed to higher lipophilicity at pH 7.4 and higher aqueous solubility at pH 5 compared to ketorolac.     

The Influence of Potassium Clavulanate on the Rate of Amoxicillin Sodium Degradation in Phosphate and Acetate Buffers in the Liquid State

The stability of aqueous admixtures of amoxicillin sodium and potassium clavulanate was studied in the liquid state at selected pH values. Potassium clavulanate was found to catalyze the rate of degradation of amoxicillin sodium under the conditions of this study. In phosphate buffer (at pH 7.0) both amoxicillin sodium and potassium clavulanate showed first-order degradation when stored separately. However, when combined the rate of amoxicillin degradation increased and t₉₀ values for amoxicillin decreased from 69.6 min for amoxicillin alone to 10.8 min for amoxicillin in the combination at 55°C. A kinetic model was developed that explained the catalytic behavior of potassium clavulanate and phosphate buffer. In acetate buffer the rate of degradation of amoxicillin sodium followed first-order kinetics, but the catalytic effect of clavulanate caused curvature in the rate plots at higher temperatures and clavulanate concentrations. This catalytic effect was less than that occurred in phosphate buffer (where the t₉₀ value of amoxicillin decreased from 137.3 min for amoxicillin alone to 52.5 min for amoxicillin in combination at 55°C). First-order bi-exponential decay occurred with amoxicillin degradation, which explained this change in rate.     

Synthesis of Piperazinylalkyl Ester Prodrugs of Ketorolac and their In Vitro Evaluation for Transdermal Delivery

Ketorolac, an NSAID, has low intrinsic permeation capacity through the skin. In this work, seven piperazinylalkyl ester prodrugs of ketorolac were synthesized to enhance its skin permeation. The chemical hydrolysis and the stability in human serum at 37°C were investigated in buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs were chemically more stable at pH 5.0 than at pH 7.4 with prodrug 8 being the most stable (t_1/2 = 119.75 h and 11.97 h at pH 5 and 7.4, respectively). The prodrugs' t_1/2 in human serum ranged from 0.79 to 3.92 min. The prodrugs' aqueous solubility was measured in buffer solution at pH 5.0 and 7.4 and Log P_app was measured by partitioning between buffer solution (pH 5.0 and 7.4) and n-octanol. The prodrugs were more lipophilic than ketorolac at pH 7.4. Skin permeation of ketorolac and prodrug 8, the most stable chemically, through rat skin was studied at pH 5.0 and 7.4. Prodrug 8 enhanced permeation by 1.56- and 11.39-fold at pH 5 and 7.4, respectively. This is attributed to higher lipophilicity at pH 7.4 and higher aqueous solubility at pH 5 compared to ketorolac.     

Stereoisomeric separation of flavanones and flavanone-7-O-glycosides by capillary electrophoresis and determination of interconversion barriers

The stereoisomeric separation of several flavanones and flavanone-7-O-glycosides has been achieved with capillary electrophoresis by adding native cyclodextrins or cyclodextrin derivatives to the background electrolyte. As an alternative method, micellar electrokinetic chromatography with sodium cholate as a chiral surfactant has been used for the epimeric separation of two flavanone-7-O-glycosides. The effect of buffer systems containing mixtures of cyclodextrin with either sodium dodecyl sulfate or sodium cholate upon the chiral recognition of flavanones and flavanone-7-O-glycosides as well as the variation of the background electrolyte (concentration of buffer and surfactant, pH value, organic modifier), and its influence on the resolution factor Rs was investigated. Temperature- and pH-dependent enantiomerization or epimerization barriers of several flavanones (naringenin, homoeriodictyol) and flavanone-7-O-glycosides (naringin, neohesperidin, prunin, narirutin) in basic media (pH values of 9-11) have been observed. Interconversion profiles featuring characteristic plateau formation of the elution pattern were observed at high pH and evaluated with the simulation software ChromWin to determine rate constants k(T) and Eyring activation parameters, DeltaG#(T), DeltaH#, and DeltaS#.     

Study of formulation variables on properties of drug-gellan beads by factorial design

The aim of the present study was to obtain cross-linked calcium-gellan beads containing diclofenac sodium as model drug, using full 3(3) factorial design. Drug quantity, pH of cross-linking solution, and speed of agitation were selected as variables for factorial design. The resultant beads were evaluated by scanning electron microscopy (SEM), percent yield, entrapment efficiency, micromeritic properties, swelling and drug release studies. The drug-loaded beads were spherical with size range of 0.85-1.8 mm. Percent yield and entrapment efficiency of various batches were in the range of 86.48-98.28% w/w and 72.52-92.74% w/w, respectively. Calcium-gellan beads containing diclofenac sodium showed pH-dependent swelling and drug release properties. Swelling and drug release were significantly higher in pH 7.4 phosphate buffer than 0.1N HCl. The swelling ratio for beads was up to 22 and 3 for phosphate buffer and 0.1N HCl, respectively. Cumulative diclofenac sodium release from calcium-gellan beads was 12-35% in 0.1N HCl within 2 h, whereas complete drug release was observed within 3-4 h in pH 7.4 phosphate buffer.     

Using difference spectrophotometry to study the influence of different ions and buffer systems on drug protein binding.

Difference spectrophotometry was used to investigate the effect of different ions and buffer systems on the binding of the anti-inflammatory drug tenoxicam to human serum albumin (HSA). Chloride anions, as well as sodium cations, were found to decrease the binding affinity. The effect of chloride ions was greater on the primary binding constant K1, while sodium ions had a greater effect on the secondary binding constant K2. The number of binding sites n1 and n2 were not affected except at 0.12% HSA, for which the presence of sodium ions halved n2. Potassium ions significantly increased K1. The presence of potassium instead of sodium ions increased binding affinity at lower HSA concentrations. The number of binding sites n1 and n2 were fewer in presence of potassium than in the presence of sodium ions except at 0.12% HSA. The divalent calcium and magnesium cations increased the binding affinity of HSA to tenoxicam, with a greater effect on K1. The effect of magnesium ions on K1 occurred when the MgCl2 concentration was increased to 3 and 9 mM, with the former seeming to be a critical concentration. The number of primary binding sites n1 was not affected by calcium ions, but was halved by 1 mM MgCl2. Both calcium and magnesium cations decreased n2, which was halved when the concentration of either cation was increased to 9 mM. The effect of buffer systems on tenoxicam binding to HSA was dependent on HSA concentration. The value of K1 was higher in Sorensen's phosphate buffer than in Tris [tris(hydroxymethyl) aminomethane HCl] buffer when the HSA concentration was 0.04% and 0.16%, while the reverse was observed at 0.08% and 0.12% HSA. The other binding parameters (K2, n1, and n2) were higher in Sorensen's phosphate than in Tris buffer. However; at certain HSA concentrations, the values of such parameters were comparable in both buffer systems.     

Dimethyl sulfoxide as a photoprotective agent for sodium nitroprusside solutions

The effect of dimethyl sulfoxide (DMSO) as a photo-protective agent for various buffered solutions of sodium nitroprusside was investigated. DMSO was found to enhance the photostability of 50 mg% solutions of sodium nitroprusside. In general, the higher the concentration of DMSO, the greater was its photostabilizing effect. However, a 10% v/v of DMSO appeared to be an optimum concentration when acetate buffer of pH 4.65 was used as the solvent medium. The photoprotective action of dimethyl sulfoxide was found to be influenced by the pH of the medium and its buffer species.     

Improved Dissolution Rate of Poorly Soluble Drug by Incorporation of Buffers

This study focused on comparing dissolution rates of indomethacin after cocompressing with three different buffers (calcium carbonate, sodium carbonate, and sodium citrate) at pH 2 and 7. Factors affecting the dissolution rate were also examined, such as type and particle size of buffer and weight-to-weight ratio of drug to buffer. It was found that, at pH 7, the release rates of indomethacin with sodium carbonate (<74 μm, all proportions) and sodium citrate (<74 μm, 75% loading) at a 20-min test time were about 10-fold and 6-fold greater, respectively, than that of indomethacin alone. When the drug and buffer were compressed into tablets using a tableting machine, the release rates of indomethacin for the control, sodium carbonate incorporated (25% and 75% buffer loading), and sodium citrate incorporated (75% buffer loading) at a 15-min test time were 50%, 90%, 66%, and 67%, respectively.     

Improved dissolution rate of poorly soluble drug by incorporation of buffers

This study focused on comparing dissolution rates of indomethacin after co-compressing with three different buffers (calcium carbonate, sodium carbonate, and sodium citrate) at pH 2 and 7. Factors affecting the dissolution rate were also examined, such as type and particle size of buffer and weight-to-weight ratio of drug to buffer. It was found that, at pH 7, the release rates of indomethacin with sodium carbonate (< 74 microns, all proportions) and sodium citrate (< 74 microns, 75% loading) at a 20-min test time were about 10-fold and 6-fold greater, respectively, than that of indomethacin alone. When the drug and buffer were compressed into tablets using a tableting machine, the release rates of indomethacin for the control, sodium carbonate incorporated (25% and 75% buffer loading), and sodium citrate incorporated (75% buffer loading) at a 15-min test time were 50%, 90%, 66%, and 67%, respectively.     

Dimethyl sulfoxide as a photoprotective agent for sodium nitroprusside solutions

Abstract

The effect of dimethyl sulfoxide (DMSO) as a photo-protective agent for various buffered solutions of sodium nitroprusside was investigated. DMSO was found to enhance the photostability of 50 mg% solutions of sodium nitroprusside. In general, the higher the concentration of DMSO, the greater was its photostabilizing effect. However, a 10% v/v of DMSO appeared to be an optimum concentration when acetate buffer of pH 4.65 was used as the solvent medium. The photoprotective action of dimethyl sulfoxide was found to be influenced by the pH of the medium and its buffer species.     

Technological Evaluation of Three Enteric Coating Polymers II. With a Soluble Drug

Three enteric coating polymers, cellulose acetate phthalate (CAP), hydroxy propylmethylcellulose phthalate (HP55) and cellulose acetate trimellitate (CAT) were evaluated on two different chemical substrates (soluble and insoluble). Gastric juice resistance was tested by dissolution using USP apparatus (paddle) in Britton buffer at different pH, under sink conditions over 5 hours. It can be said that the resistance of tablets depends on the coating formulation considered and the drug solubility. From our tests it results that CAP is more resistant than CAT for two drugs in intestinal medium and the resistance of HP55 depends on the solubility of the drugs. More, only CAT allows the release in the proximal small intestine for drugs whatever solubiliy.     

Study of Formulation Variables on Properties of Drug-Gellan Beads by Factorial Design

ABSTRACT

The aim of the present study was to obtain cross-linked calcium-gellan beads containing diclofenac sodium as model drug, using full 3³ factorial design. Drug quantity, pH of cross-linking solution, and speed of agitation were selected as variables for factorial design. The resultant beads were evaluated by scanning electron microscopy (SEM), percent yield, entrapment efficiency, micromeritic properties, swelling and drug release studies. The drug-loaded beads were spherical with size range of 0.85–1.8 mm. Percent yield and entrapment efficiency of various batches were in the range of 86.48–98.28% w/w and 72.52–92.74% w/w, respectively. Calcium-gellan beads containing diclofenac sodium showed pH-dependent swelling and drug release properties. Swelling and drug release were significantly higher in pH 7.4 phosphate buffer than 0.1N HCl. The swelling ratio for beads was up to 22 and 3 for phosphate buffer and 0.1N HCl, respectively. Cumulative diclofenac sodium release from calcium-gellan beads was 12–35% in 0.1N HCl within 2 h, whereas complete drug release was observed within 3–4 h in pH 7.4 phosphate buffer.     

内盐凝胶的制备及对烟酰胺的控释

以甲基丙烯酸二甲基氨基乙酯(DMAE-MA)、衣康酸(IA)、亚甲基双丙基酰胺(BIS)和过硫酸钾(KPS)为原料在室温下制备内盐凝胶。研究了原料配方对凝胶形成的影响、内盐凝胶的吸水动力学及溶胀机制、凝胶的pH值敏感性以及对烟酰胺的负载与负载凝胶在不同pH值介质中的释放行为,并用红外光谱对凝胶结构进行了表征。结果表明,n(IA)/n(DMAEMA)>1后将降低单体的转化率,不利于凝胶的形成;内盐凝胶不具有高吸水性,其吸水溶胀机制符合Fickian扩散;在pH值为12的缓冲溶液中溶胀率比在pH值为3的缓冲溶液中高;凝胶对烟酰胺的负载率可以超过200%。在25℃下,烟酰胺在pH值为3的介质中释放比在pH值为12的介质中释放快。     

Influence of pH on the permeability of p-toluidine and aminopyrine through shed snake skin as a model membrane

The influence of pH on the permeability of p-toluidine (pKa, 5.3) and aminopyrine (pKa, 5.0) through shed snake skin as a model membrane was studied. The pH was adjusted to several values, and the solubility of the drugs in each donor was measured. Flux rates and permeability coefficients were calculated from the steady-state penetration portions. The flux rates of p-toluidine decreased as the pH value in the donor solution increased. On the other hand, the flux rates of aminopyrine were constant at any pH value. The permeability coefficients of each drug increased as the pH value in the donor solution increased. The partition coefficients (octanol/buffer) of each drug were dependent on the molecular fraction of un-ionized species. From these results, it is suggested that ionized species of p-toluidine transports through shed snake skin, but the ionized species of aminopyrine does not.     

Technological Evaluation of Three Enteric Coating Polymers II. With a Soluble Drug

Abstract

Three enteric coating polymers, cellulose acetate phthalate (CAP), hydroxy propylmethylcellulose phthalate (HP55) and cellulose acetate trimellitate (CAT) were evaluated on two different chemical substrates (soluble and insoluble). Gastric juice resistance was tested by dissolution using USP apparatus (paddle) in Britton buffer at different pH, under sink conditions over 5 hours. It can be said that the resistance of tablets depends on the coating formulation considered and the drug solubility. From our tests it results that CAP is more resistant than CAT for two drugs in intestinal medium and the resistance of HP55 depends on the solubility of the drugs. More, only CAT allows the release in the proximal small intestine for drugs whatever solubiliy.     

Influence of pH on the Permeability of p-Toluidine and Aminopyrine Through Shed Snake Skin as a Model Membrane

The influence of pH on the permeability of p-toluidine (pKa, 5.3) and aminopyrine (pKa, 5.0) through shed snake skin as a model membrane was studied. The pH was adjusted to several values, and the solubility of the drugs in each donor was measured. Flux rates and permeability coefficients were calculated from the steady-state penetration portions. The flux rates of p-toluidine decreased as the pH value in the donor solution increased. On the other hand, the flux rates of aminopyrine were constant at any pH value. The permeability coefficients of each drug increased as the pH value in the donor solution increased. The partition coefficients (octanol/buffer) of each drug were dependent on the molecular fraction of un-ionized species. From these results, it is suggested that ionized species of p-toluidine transports through shed snake skin, but the ionized species of aminopyrine does not.     

Preparations of Solid Particulates of Amino-Pyrine-Barbital Complex (Pyrabital) wiithout Autoxidation Ey a Spray Drying Technique

Aminopyrine, barbital and colloidal silica dispersed in buffer solutions having pH 5.46 to 8.01 were spray-dried by a centrifugal wheel atomizer at 130 ± 5°C. When the pH of the feeding liquid for spray drying was 5.70 to 7.24, the resultant product was a mixture of amlnopyrine-barbital complex (pyrabital), aminopyrine and the exci-pient. When the pH was lower than 5.84 or higher than 7.84, barbital or sodium barbital coexisted in the above mixture products. Autoxidation of aminopyrine occurred during the spray drying was greatly prevented by introducing chelating agent, e.g. ethylenediaminetetraacetic acid and glycine, or antioxidation agent, e.g. sodium thiosulfate and citric acid in the feeding liquid. It was also found that reducing the pH of the feeding liquid effectively depressed the autoxidation of aminopyrine.     

Technological Evaluation of three Enteric Coating Polymers I. With an Insoluble Drug

The enteric properties of a recent cellulose polymer, cellulose acetate trimellitate (CAT, EASTMAN KODAK) were evaluated on an insoluble substract for comparison, included in this paper are the properties of two other cellulose esters: cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HP55).

The physical properties and disintegration time at pH 1.2 and 6.5 were influenced by the level of coating solution. The gastroresistance was obtained more fastly with CAT and CAP than for HP55.

The influence of coating solution on drug release from tablet was investigated. The dissolution studies were made allowing the variation of pH in the dissolution medium during the kinetics.

Drug release from coated tablets was found to be dependent upon the type of polymers used to form film: higher release rates were obtained with CAT compared to CAP and HP55.     

Influence of Uric Acid on Photostability of Sulfathiazole Sodium Solutions

The effect of uric acid as a photoprotective agent for buffered and unbuffered solutions of sulfathiazole sodium was investigated. Uric acid solution in glycerin was found to enhance the photostability of sulfathiazole sodium solutions. The higher the concentration of uric acid used, the greater was its photoprotective action within the concentration range studied. Uric acid was also found to demonstrate its photoprotective effect in the presence of either sodium sulfite or EDTA. Sodium sulfite alone in a concentration of 0.1% produced a detrimental effect on the photostability of sulfathiazole sodium in either borate or phosphate buffer of pH 9 ± 0.2. From the standpoint of the overall chemical stability of sodium sulfathiazole, uric acid appeared to be most effective when used alone in the borate buffer. However, the incorporation of 0.1% sodium sulfite in addition to uric acid contributed to the prevention of discoloration in either the borate or the phosphate buffer.     

To evaluate the effect of addition of an anionic surfactant on solid dispersion using model drug indomethacin

Formation of solid dispersion also known as high energy solids is one of the most successful concepts to improve dissolution profile of poorly water-soluble drugs. Use of surfactants in formulation is one of the methods to increase solubility profile. In this research, we have used model drug, a weak acid (indomethacin) together with polymer (PVP) and anionic surfactant (sodium lauryl sulfate (SLS)) in different concentrations to study the effect of incorporation of SLS in solid dispersion. Three ratios and control were prepared. Physical characterization was performed using modulated differential scanning calorimetry (MDSC), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. Critical micelle concentration (CMC) measurements were conducted to see the effect of SLS on dissolution media. Dissolution studies were performed in hydrochloric acid buffer (pH 1.2 buffer), purified water and phosphate buffer (pH 7.4), respectively. Interestingly, depending upon addition of SLS into the system, release profiles were changed. SLS incorporated internally in a solid dispersion gave the highest release.