A comparative study on the raft chemical properties of various alginate antacid raft-forming products

Objective: Research to measure the chemical characterization of alginate rafts for good raft performance and ascertain how formulation can affect chemical parameters.

Significance: A selection of alginate formulations was investigated all claiming to be proficient raft formers with significance between products established and ranked.

Methods: Procedures were selected which demonstrated the chemical characterization allowing rafts to effectively impede the reflux into the esophagus or in severe cases to be refluxed preferentially into the esophagus and exert a demulcent effect, with focus of current research on methods which complement previous studies centered on physical properties. The alginate content was analyzed by a newly developed HPLC method. Methods were used to determine the neutralization profile and the acid neutralization within the raft determined along with how raft structure affects neutralization.

Results: Alginate content of Gaviscon Double Action (GDA) within the raft was significantly superior (p?Conclusion: Alginate formulations require three chemical reactions to take place simultaneously: transformation to alginic acid, sodium carbonate reacting to form carbon dioxide, calcium releasing free calcium ions to bind with alginic acid providing strength to raft formation. GDA was significantly superior (p?<.0001) to all other comparators.     

Acid Neutralization Capacity of a Tricalcium Silicate-Containing Calcium Phosphate Cement as an Endodontic Material

A calcium phosphate cement (CPC) was shown to have the necessary attributes for endodontic materials except adequate basicity needed for antimicrobial properties. To enhance its basicity, tricalcium silicate (Ca₃SiO₅), a highly alkaline compound, was added to CPC at a mass fraction of 0.25, 0.5 or 0.75. The basicity, acid neutralization and physical properties of the CPC-Ca₃SiO₅ composites were investigated. Mineral trioxide aggregate (MTA) was used as the control. The acid neutralizing capacity of the CPC-Ca₃SiO₅ composites and MTA were measured by titrating the suspensions of ground set samples with a 0.2 mol / L HCl at predetermined pH levels, i.e., 11, 9.0, and 7.4. The setting time of CPC-Ca₃SiO₅ composites determined by the Gilmore needle method was 40 ± 10 min. Acid neutralizing capacity of CPC depended (p < 0.05) on Ca₃SiO₅ content. CPC containing 75 % Ca₃SiO₅ could neutralize slightly less acid than MTA (p < 0.05), but it had a shorter setting time than that of MTA (> 4 h) and excellent handling properties.     

Effect of Eudragit Type Polymers on the Drug Release from Magnesium Oxide Granules Produced by Laboratory Fluidization

Abstract

The differences in the bioavailability of different drug products are most frequently caused by differences in the dissolution rates of the active ingredient. In case of magnesium oxide the drug release can be directly determined by reaction kinetics method based on acid neutralization.

For a more precise study of the factors influencing the kinetical characteristics of the neutralization rates it is advisable to use homogeneous granule fractions. Before the granulation the substance was pretreated with silicone oil. The granulation of the obtained grains having hydrophobe surface was carried out in an AEROMATIC STREA-I type laboratory fluidization equipment with Eudragit polymer solved in isopropyl alcohol.

For determining the acid neutralization kinetics of the granules the “constant pH” method and the Rossett-Rice test were used.

As a result of the granulation the neutralization rate decreased. The granules can be considered as an Eudragit matrix which contains the pretreated magnesium oxide in embedded form. During the chemical reaction the resulted salt (magnesium chloride) leaves the surface of the unreacted magnesium oxide unless having a chemical reaction with the polymer. Meanwhile the residual matrix forms a mesh which increases the viscosity of the solution and the thickness of the diffusion layer. The dissolution rate decreases in both cases.

Under the same conditions the kinetic values of the neutralization change by several magnitudes depending on the utilized methods. In this way different systems of medicine, which alter their reaction capacity according to the expected physiological purposes, can be created.     

Two placebo-controlled crossover studies in healthy subjects to evaluate gastric acid neutralization by an alginate–antacid formulation (Gaviscon Double Action)

Objective: To investigate the intragastric acid neutralization activity of a combined alginate-antacid formulation.

Significance: Published studies have investigated the reflux-suppressing alginate component of Gaviscon Double Action (Gaviscon DA; RB, UK) but intragastric acid neutralization activity of the antacid component has not been evaluated in vivo.

Methods: Intragastric pH monitoring, using a custom-made 10-electrode catheter, was evaluated in a two-part exploratory study in healthy subjects; Part I (n?=?6) tested suitability of the catheter using antacid tablets (Rennie; Bayer, Germany); Part II (n?=?12) evaluated gastric acid neutralization activity of Gaviscon DA liquid (20?ml) versus placebo in fasted subjects using a randomized, open-label, crossover design. The primary endpoint was the percentage of time that intragastric pH ≥4 was measured during 30?min post-treatment. A confirmatory study of identical design was subsequently conducted (n?=?20).

Results: Monitoring pH using the multielectrode catheter was a viable approach, directly detecting changes in intragastric pH following a single dose of antacid tablets. In the exploratory study, the percentage of time that pH ≥4 during 30?minutes post-treatment was 46.8% with Gaviscon DA liquid versus 4.7% with placebo (p?=?0.0004). These findings were supported by the confirmatory study, where pH ≥4 was recorded 50.8% of the time with Gaviscon DA versus 3.5% with placebo (p?=?0.0051). In this study, Gaviscon DA was safe and well tolerated.

Conclusions: These studies demonstrate the effective acid neutralizing capacity of Gaviscon DA versus placebo in healthy, fasted subjects. This adds to the evidence base for the combination of alginates and antacids.     

Potentiometric titration data on the enhancement of sorption capacity of surface-modified biosorbents: functional groups scanning method

In the present study, the relationship between the amount of anionic or cationic binding sites and adsorption capacities of biosorbents is discussed through potentiometric titration and mathematical model equations (proton-binding models). The poly(acrylic) acid-modified biomass (PAAB) and polyethylenimine-modified biomass (PEIB) derived from raw biomass (RB) Corynebacterium glutamicum (C. glutamicum) were used as cationic and anionic binding site-enhanced biosorbents, respectively. To obtain the sorption capacities of biomasses for anionic and cationic pollutants, isotherm tests were carried out using Basic Blue 3 (BB3, at pH 9) and Reactive Red 4 (RR4, at pH 2) as model anionic and cationic pollutants, respectively. The maximum sorption capacity (q_m) of PAAB was 1.28 times higher than RB for BB3. In the case of PEIB, the sorption capacity was found to be 3.27 times higher than RB for RR4. A quantitative information of functional groups could be estimated by the application of proton-binding models to potentiometric titration results. In addition, the buffering capacities of functional groups were obtained from the parameters of pK models. An increasing ratio of sorption capacities was similar to that of the buffering capacities of modified biosorbents obtained from all conditions of pK models. Therefore, the fact that the sorption capacity of modified biomass can be predicted by comparing it with the buffering capacity of biosorbents was confirmed.     

High Pressure Liquid Chromatographic Determination of Haloperidol Stability

Abstract

Haloperidol lacks stability when exposed to elevated temperatures and light. Current assay procedures described in the USP do not permit detection or quantitation of degradation products of haloperidol. An HPLC assay for the analysis of haloperidol and the detection of degradation products has been developed. The mobile phase consisted of 40:60 THF:water with 0.75% phosphoric acid. A microbond-apak CN column was used to achieve the separation. Samples were injected using a fixed loop (200 microliter) injector and detection was by a fixed wavelength set at 254 nm. Using this mobile phase, haloperidol gave a retention time of 5.4 minutes. Samples of haloperidol treated with heat (60°C for 48 hours) gave peaks at 5.1 and 6.4 minutes as well as a haloperidol peak at 5.4 minutes. A standard curve of haloperidol concentrations was linear (r=0.99) over the range of 1 μg/ml to 100 μg/ml. The conversion of haloperidol to degradation products was noted after storage under conditions of elevated temperature, exposure to light, and as a function of pH. current USP XX assays for this drug include titration of dissolved haloperidol powder with 0.05N perchloric acid or extraction of the drug from a dose form (i.e., oral solution, injection, tablets) with subsequent ultraviolet spectrophotometric analysis (3). Neither one of these assays permits the detection or quantification of haloperidol degradation products. A high-pressure liquid chromatography (HPLC) assay was developed which overcomes the problems associated with the USP assays (3). This HPLC assay has been modified slightly for the analysis of haloperidol and detection of degradation products in drug solutions exposed to elevated temperatures, light, and as a function of pH.     

Effect of pH,phosphate buffer concentration and the ionic strength on the stability of cefotetan disodium

Abstract

The stability of cefotetan disodium between the pH range 2-8 has been studied using a stability-indicating HPLC assay method. The optimum pH range of stability appears to be 3.6-6.4. At pH 2 or 8, the decomposition was approximately 2 times faster than between pH 3.6-6.4. The HPLC method used is accurate and precise with percent relative standard deviation of 1.0 based on 5 readings. The decomposition of cefotetan followed first-order law. The K_h and K_oh values were estimated to be 3.8 and 4.4 × 10⁴ d^-1.     

Degradation Products of Mycophenolate Mofetil in Aqueous Solution

The thermal and peroxide-catalyzed degradation products of mycophenolate mofetil (1) were studied in aqueous solution at pH 2.0, 3.5, 6.0, and 8.2. The major thermal degradation product observed was mycophenolic acid (2). At pH 6.0 and 8.2, 2 was the only product observed in the absence of peroxide, while at pH 2.0 and 3.5, the lactone analogue of mycophenolic acid (5), a hydroxylactone due to oxygenation of the double bond (6), and an unidentified product were formed. Compound 6 degraded to 4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-carbaldehyde (9) on prolonged storage and was present in the sample stressed at pH 2. Mycophenolic acid (2), the N-oxide of mycophenolate mofetil (3), the hydroxylactone of mycophenolic acid (6), and the erythro form of 4-methoxy-5-methyl- 2-(2-methyl-5-oxo-tetrahydro-furan-2-yl)-3,6-dihydro-2H-1,7-dioxa-as-indacen-8- one (8) were observed in the presence of hydrogen peroxide at pH 3.5, 6.0, and 8.2. In addition, at pH 8.2, 4-hydroxy-4-(4-methoxy-5-methyl-8-oxo-2,3,6,8-tetrahydro-1,7-dioxa-as-indacen-2-yl)-pentanoic acid (7) was seen. Peroxide-stressed samples at pH 2.0 gave no major degradation peaks, but a small amount of the hydroxylactone of mycophenolic acid (6) was formed.     

Comparison of the Solubility and Dissolution Rate Between Gliclazide Solid Complex and Its Nanospheres

ABSTRACT

The solid complex of gliclazide and β-cyclodextrin was prepared by neutralization method and the precipitation solvent evaporation method was used to prepare gliclazide nanospheres. Fourier-transform infrared spectroscopy and differential scanning calorimetry were used to examine whether gliclazide solid complex and gliclazide nanospheres were successfully formed in this study. The dissolution rate of gliclazide from its nanospheres was faster than its solid complex and pure drug. The morphology of particles for nanospheres showed no crystal character of gliclazide. In summary, the results indicate that nanotechnology provides better effects in solubility and dissolution rate of gliclazide than neutralization method.     

Studies Done in Single Rats,Simultaneously Comparing Disappearance Rates of Compounds from Different Regions of the Small Intestine

Abstract

Presented here are a) a simple procedure for measuring regional permeability differences of compounds in the small intestine of a single rat, and b) preliminary study to test the procedure utilizing seven different benzoic acids, e.g. benzoic acid, o-hydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid, p-hydroxybenzoic acid, m-hydroxybenzoic acid, 3,5-dinitrobenzoic acid, and 2,5-dihydroxybenzoic acid. Rates of disappearance (absorption) of these compounds were measured simultaneously in upper and lower segments of the small intestine using this variation of the in situ rat gut absorption study technique. Under the experimental conditions used, disappearance rate of a given compound was no different from upper or lower segment for any of the compounds except for p-hydroxybenzoic acid. The latter disappeared about three times faster from the upper than lower segment. Not only is this experimental procedure of utility in differentiating regional permeability within the intestine. It offers the option of testing the effect of an additive or other environmental change on compound permeability, while the other segment serves as a control.     

Barium ion leaching from barium titanate powder in water

A submicrometer-sized commercial BaTiO₃ (BT) powder was aged in water under three different conditions: pH, aging times, and pre-heat treatments of the powder. The amount of Ba²⁺ ions leaching from the BT particles was determined by the EDTA titration method. As predicted by thermodynamic calculation, the greater extent and the faster rate of Ba²⁺ leaching were found at the lower solution pH, leveling off at pH 8. The pre-heat treatments of the BT powder increased the amount of Ba²⁺ leaching when compared to the as-received one. This result was shown by the formation of soluble surface BaCO₃, which was detected using FT-IR spectroscopy. It was also shown that organic passivation agents were effective reducing the Ba²⁺ leaching but at high solution pH.     

Antacid Tablets: Should They be Chewed or Swallowed Intact?

Three commercially available antacids, two of them labeled either to be taken intact or to be chewed, (Bisodol®, Maalox® No. 1) and one of them (Riopan®) available in two formulations, chew tablets and swallow tablets, were tested in vitro for disintegration time, pressure resistance, acid consumption capacity and acid neutralizing capacity and in vivo in man using the Heidelberg Capsule. The total areas under the in vivo pH versus time curves obtained with the intact and chewed tablets, respectively, corrected for the individual NaHCO₃ response test were determined. Also the time to reach pH 3 and the period of time for pH versus time curve above pH 3 were determined. The preparations were evaluated for extent of antacid capacity, efficacy and lag time. From the results obtained it becomes evident that by chewing rather than swallowing the antacid intact tablet, a quicker and more effective relief is obtained.     

Dissolution Rates of Trimethoprim-Sulphamethoxazole and Trimethoprim Tablets in Aqueous Media

Abstract

Dissolution rates of trimethoprim and sulphamethoxazole from combination tablets showed a rapid release of trimethoprim in acid media from all formulations. Sulphamethoxazole showed a more variable release pattern and faster release in dilute acid medium compared with the less acidic simulated gastric fluid. Tablets containing only trimethoprim showed a release rate into hydrochloric acid media that was dependent upon pH. Approximately twice the amount of trimethoprim was released in twenty minutes at pH 1.32 compared with pH 6.50.     

Comparison of Disintegrant and Binder Activity of Three Corn Starch Products

Abstract

This study demonstrates the differences obtained when using different corn starch products as both binder and disintegrant in pharmaceutical tablets. Formulations made with Fluftex W, Tablet White and Purity 21 starches were compared. In addition, Avicel PH101 was used in this study as a benchmark component whose properties are well understood.

Four test formulations containing hydrochlorothiazide were prepared by wet granulation. Starch was incorporated in both powder and paste form. All granulations were found to possess similar traits when evaluated based upon geometric mean diameter, particle size distribution, bulk/tap densities, powder flow rate and surface characteristics.

Tablets prepared from these granulations were shown to be similar when evaluated for degree of friability, weight and content uniformity. All starch formulations disintegrated within 30 seconds and produced similar dissolution profiles. Tablets produced with Avicel, however, were found to exhibit significantly longer disintegration times than the starch formulations. In addition, these tablets displayed a dissolution profile that was significantly different than the starch formulations, particularly during the earlier stages of the dissolution process.

When monitoring compression and ejection forces required to produce tablets of the same degree of hardness (≈6kg), Fluftex W and Tablet White granulations were found to use significantly lower forces than the Purity 21 granulation. This may be indicative of Fluftex W and Tablet White's superiority over Purity 21 in terms of binder capacity.     

Noncross-Linked Copolymers of Dimethylaminoethyl Methacrylate and Methacrylic Acid as Oral Drug Carriers

ABSTRACT

The purpose of this study was to synthesize new water-soluble ampholytic copolymers consisting of tertiary amine and carboxylic acid pendent groups for oral drug carriers. The polymers were prepared with a 1:1 molar ratio of dimethylaminoethyl methacrylate and methacrylic acid by free radical polymerization. After polymerization, polymer rods were recovered, dissolved (or swollen) in de-ionized water, and freeze-dried before obtaining fine powders. Drug release experiments with various drugs, representing a variety of drug solubility and types of amine, were carried out with compressed tablets (total weight of 600 mg) containing a variety of basic drugs in pH's of 1.5 and 7. Surprisingly, zero-order release kinetics even from a tablet geometry has been obtained with drug loading ranging from 20–50%. Drug release in pH 7 maintains a zero-order rate up to 80–85% release after a slight initial burst, whereas in pH 1.5 one may not find the initial burst and zero-order kinetics is extended up to 90–95% release. Drug release becomes faster in pH 1.5 than pH 7 due to the faster rate of protonation of the tertiary amine in acidic conditions. The release of basic drugs in pH 1.5 is not significantly different even with varying solubility and types of amine (primary, secondary, and tertiary). However, different drug release profiles in pH 7 are observed with different types of amine and solubility.     

The long-term interaction of dental cements with lactic acid solutions

A study of the interaction of dental cements with lactic acid solutions has been carried out in which individual cement specimens were repeatedly exposed to 20 mmol dm^–3 lactic acid for periods of a week. After each week of storage, the mass of the specimens was recorded and the pH of the solution determined. The glass-ionomers showed an initial increase in mass, followed by a decline that became steady from 6 weeks. Zinc polycarboxylate and zinc phosphate cements, by contrast, showed no early gain in mass, but eroded steadily more or less from the start of their exposure to lactic acid. For all cements, acid erosion followed linear kinetics, at rates ranging from 0.5%/week for the zinc phosphate to 0.28%/week for one of the glass-ionomers, Chelonfil (ESPE, Germany). At the end of six months, the zinc phosphate had lost 14.2% of its initial mass, the zinc polycarboxylate 9.9% and the glass-ionomers between 6.2 and 7.2%. Erosion was accompanied on every occasion by neutralization of the acid solution. Both erosion and neutralization continued steadily throughout the experiment. The effectiveness of neutralization was in the following order: zinc polycarboxylate>zinc phosphate>glass-ionomer. The pH change in Week 1 was much greater for the glass-ionomers and the zinc polycarboxylate than in all subsequent weeks.     

Influence of Hydroxypropyl Methylcellulose and of Manufacturing Technique on in Vitro Performance of Selected Antacids

Abstract

Factors affecting the performance of antacids F-MA 11, dihydroxy aluminum aminoacetate, magaldrate and magnesium hydroxide were studied in vitro using Schaub's acid neutralization test, a modified Reheis reaction velocity test and the USP test. From the results obtained it was evident that type and combination of antacid, the adjuvants and formulation techniques used in preparation of antacids affect their performance. The USP preliminary antacid test and acid neutralization test are not optimal in vitro tests to evaluate in vitro onset and duration of action of antacids.     

Development and pharmacokinetic evaluation of alginate-pectin polymeric rafts forming tablets using box behnken design

Abstract

Raft is an emerging drug delivery system, which is suitable for controlled release drug delivery and targeting. The present study aimed to evaluate the physico-chemical properties of raft, in vitro release of pantoprazole sodium sesquihydrate and conduct bioavailability studies. Box behnken design was used with three independent and dependent variables. Independent variables were sodium alginate (X₁), pectin (X₂) and hydroxypropyl methyl cellulose K100M (X₃) while dependent variables were percentage drug release at 2 (Y₂), 4 (Y₄) and 8?h (Y₈). The developed rafts were evaluated by their physical and chemical properties. Fourier transform infrared spectroscopy and differential scanning calorimetry were used to study the chemical interaction and thermal behaviour of drug with polymers. Alginate and pectin contents of R9 formulation were 99.28% and 97.29%, respectively, and acid neutralization capacity was 8.0. R9 formulation showed longer duration of neutralization and nature of raft was absorbent. The raft of R9 formulation showed 98.94% release of PSS at 8?h in simulated gastric fluid. Fourier transform infrared spectroscopy showed no chemical interaction and differential scanning calorimetry indicated endothermic peaks at 250?°C for pantoprazole sodium sesquihydrate. t_max for the test and reference formulations were 8?±?2.345?h and 8?±?2.305?h, respectively. C_max of test and reference formulations were 46.026?±?0.567?µg/mL and 43.026?±?0.567?µg/mL, respectively. AUC_(0-t) of the test and reference formulations were 472.115?±?3.467?µg?×?h/mL and 456.105?±?2.017?µg?×?h/mL, respectively. Raft forming system successfully delivered the drug in controlled manner and improved the bioavailability of drugs.     

Characterization of directly Compressible Maltodextrins Manufactured by three different Processes

Abstract

Five types of maltodextrins which were physically processed by the methods of spray drying, fluidized bed agglomeration, and roller compaction were compared in terms of their pre-, during and post-compaction properties. The maltodextrins all had relatively high moisture contents, and small surface areas. Intrinsic compaction testing found that the maltodextrins all formed stronger tablets than Fast-Flo lactose, and had longer disintegration times which were found to be insensitive to pressure. The roller compacted material had the most fragmentary behavior of the five types of maltodextrins examined. Dissolution testing showed that the maltodextrins had longer release rates than Emdex or Fast-Flo lactose, however the maltodextrin formulations were able to pass a modified USP dissolution test.     

pK Determination of Sparingly Soluble Compounds by Difference Potentiometry

Abstract

A differential potentiometric titration technique is described which allows the determination of dissociation constants of sparingly soluble and/or labile compounds. The dissociation constants of a series of beta-blockers were determined by this technique. Dissociation constants determined by routine potentiometric titration techniques were found to be equivalent to those determined by the differential potentiometric titration method

By using a computer to accumulate the titration data, it is shown that the dissociation constants of compounds which degrade due to added titrant base can be accurately determined. This is accomplished by shortening the duration of the experiment (total time < 10 minutes) such that minimal degradation occurs during the course of the titration. By combining the computer technique with a differential potentiometric titration technique, it is possible to determine the dissociation constants of sparingly soluble compounds which are not stable in solution

In the determination of dissociation constants, if two pKs are separated by less than 4 pH units, then these constants are said to overlap. To accurately determine a pK, both dissociation constants must be solved for simultaneously. A method is described which corrects for overlapping pKs in a differential potentiometric titration, which then allows the unambiguous determination of the dissociation constants. Also described is a method to correct the differential titration when the amount of overlap is small and the pK of one of the overlapping constants is known