Coated hydralazine hydrochloride beads for sustained release after oral administration.

Hydralazine hydrochloride is an antihypertensive used alone or in combination with isosorbide nitrate for the treatment of congestive heart failure. Since control of blood pressure should be continuous, sustained release delivery of this drug is considered therapeutically beneficial. Core beads for oral administration of this drug were prepared by extrusion-spheronization. Using experimental design to define the coat that was applied, the core beads were coated using a fluid bed coater to different coat thickness with combinations of two commercially available products dissolved in a hydroalcoholic solvent. The coat is a film with a combination of ethylcellulose and hydroxypropylcellulose that can provide desirable release profiles. Visually spherical and rugged bead products were obtained. Two products were identified that exhibited essentially a zero order release profile following a 2-h lag time with release of greater than 70% of the drug over the next 10 h in simulated intestinal fluid.

Floating tablets of hydralazine hydrochloride: optimization and evaluation

Hydralazine hydrochloride has a half-life of 2 to 4 hours with an oral bioavailability of 26-50%. Since hydralazine has a demethylating effect on various suppressor genes, it can be used in various types of cancer to support chemotherapy. The purpose of this study was to optimize and evaluate floating tablets of hydralazine hydrochloride designed to prolong the gastric residence time and to provide controlled release of the drug for 14 h. The floating tablets of hydralazine hydrochloride were prepared by the wet granulation method. Semi-synthetic polymers of hydroxy propyl methyl cellulose (HPMC K100M) and ethyl cellulose were used as the release retarding agents. A 2² factorial design was applied to systematically optimize the drug release profile. The concentrations of HPMC K100M and ethyl cellulose were optimized to provide controlled release of hydralazine for 14h. Non-Fickian diffusion release transport was confirmed as the release mechanism for the optimized formulation and the predicted values agreed well with the experimental values. Drug excipient compatibility studies were investigated by FTIR, DSC and XRD. These data indicate that there were no chemical interactions between the drug and the polymer. In vivo X-ray imaging showed floating tablet performance in rabbits.

O cloridrato de hidralazina apresenta meia-vida de 2 a 4 horas, com biodisponibilidade oral de 26-50%. Uma vez que a hidralazina possui efeito desmetilante em vários genes supressores, ela pode ser utilizada para diversos tipos de câncer, em apoio à quimioterapia. O objetivo deste estudo foi o de avaliar e otimizar comprimidos flutuantes de cloridrato de hidralazina, planejados para prolongar o tempo de residência gástrica e proporcionar liberação controlada do fármaco por 14 h. Os comprimidos flutuantes de cloridrato de hidralazina foram preparados pelo método de granulação úmida. Polímeros semi-sintéticos de hidroxipropiletil celulose (HPMCK100M) e acetato de celulose foram utilizados como agente de retardamento de liberação. Aplicou-se planejamento fatorial 2² para otimizar sistematicamente o perfil de liberação do fármaco. As concentrações de HPMCK100M e de etilcelulose foram otimizadas para se obter liberação controlada de hidralazina durante 14 h. O transporte de liberação de difusão não-Fickiana foi confirmado como o mecanismo de liberação para a formulação otimizada e os valores previstos estiveram de acordo com os valores experimentais. Estudos de compatibilidade entre fármaco e excipiente foram realizados por FTIR, DSC e DRX. Estes dados indicaram que não havia interação química entre o fármaco e o polímero. Imagens de raios-X in vivo mostraram o desempenho dos comprimidos flutuantes em coelhos.

Determination of hydralazine with flow injection chemiluminescence sensor using molecularly imprinted polymer as recognition element.

A novel flow injection chemiluminescence (CL) sensor for hydralazine determination using molecularly imprinted polymer (MIP) as recognition element is reported. Hydralazine-MIP was prepared through non-covalent copolymerization using methacrylic acid (MAA) monomer, hydralazine template and ethylene glycol dimethacrylate (EGDMA) cross-linker. Particles of the MIP were packed into a v-shape glass tube for on-line adsorption of the analyte of hydralazine. The adsorbed hydralazine could be sensed by its great enhancing effect on the CL reaction between luminol and periodate. The CL intensity is linear to hydralazine concentration in the range from 2x10(-9) to 8x10(-7) g/mL. The detection limit is 6x10(-10) g/mL (3sigma) and the relative standard deviation is 2.8% (n=7) for 8x10(-9) g/mL hydralazine. The selective experiment showed that the selectivity and sensitivity of the CL method could be greatly improved when MIP was used as recognition element in the flow-injection CL sensor. The sensor was reversible and reusable. It could be used for more than 100 times. It has been used directly to determine the hydralazine in human urine.

Time-resolved chemiluminescent analysis of hydralazine in pharmaceuticals.

A new analytical method is proposed for determination of hydralazine (HZ) in pharmaceuticals--measurement of the chemiluminescence (CL) emitted after reaction with phosphoric-acidified KMnO4. The novelty of this method is the recording of the whole CL-time profile. Such a recording is possible by use of a CL-detector operating in tandem which enables the reactants to be mixed in the measurement cell only and, therefore, the CL is reaction monitored from beginning. At the precise time the pump is stopped signal recording is triggered and so CL evolution is recorded completely. The optimum chemical conditions for the determination were 0.8 mol L(-1) formaldehyde, 0.3 mmol L(-1) KMnO4, 4.0 mol L(-1) H3PO4, and a total flow of 0.37 mL s(-1). Two calibration graphs were plotted, CL intensity and area under the profile curve against HZ concentration. Exhaustive statistical analysis provided very interesting results, for example, accordance with Clayton's theory, detection limit below 0.2 microg mL(-1), and linear calibration ranges from 0.2 to 5.0 microg mL(-1). This method was successfully applied to the determination of HZ in pharmaceuticals. Because they are usually formulated in association with diuretics and beta-blockers, the method was used for analysis of HZ in pharmaceuticals that contained either HZ only or HZ with other hypotensive substances. Obtained and nominal content were approximately the same and experimental Student t values indicated there were no significant differences between the values.

Stability of alprazolam, chloroquine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids.

The stability of five drugs commonly prescribed for use in oral liquid dosage forms but not commercially available as such was studied. Alprazolam 1 mg/mL, chloroquine phosphate 15 mg/mL, cisapride 1 mg/mL, enalapril maleate 1 mg/mL, and hydralazine hydrochloride 4 mg/mL were each prepared in a 1:1 mixture of Ora-Sweet and Ora-Plus (Paddock Laboratories), a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and cherry syrup and placed in 120-mL amber clear polyethylene terephthalate bottles. Three bottles of each liquid were stored at 5 degrees C and three at 25 degrees C, all in the dark. Samples were taken initially and at various times up to 60 days for analysis by high-performance liquid chromatography and assessment of appearance and odor; pH was measured. A mean of at least 91% of the initial drug concentration was retained for 60 days in the alprazolam, chloroquine phosphate, cisapride, and enalapril maleate liquids. The hydralazine hydrochloride liquids retained more than 90% of the initial concentration for only one day at 5 degrees C when prepared with Ora-Sweet-Ora-Plus and two days when prepared with Ora-Sweet SF-Ora-Plus and for less than a day in these preparations at 25 degrees C and in cherry syrup at 5 and 25 degrees C. No substantial changes in the appearance, odor, or pH of any liquid were observed. Alprazolam 1 mg/mL, chloroquine phosphate 15 mg/mL, cisapride 1 mg/mL, and enalapril maleate 1 mg/mL were stable in three extemporaneously compounded oral liquids for 60 days at 5 and 25 degrees C; hydralazine hydrochloride 4 mg/mL was stable at 5 degrees C for one day in Ora-Sweet-Ora Plus and for two days in Ora-Sweet SF-Ora-Plus.

Performance of micellar mobile phases in reversed-phase chromatography for the analysis of pharmaceuticals containing beta-blockers and other antihypertensive drugs.

A rapid and simple reversed-phase micellar liquid chromatographic procedure for the simultaneous determination of the beta-blockers atenolol, metoprolol and oxprenolol, the diuretics amiloride, bendroflumethiazide, chlorthalidone and hydrochlorothiazide and the vasodilator hydralazine in pharmaceuticals, is proposed. An interpretive optimization procedure, which uses the chromatographic data for only five mobile phases, was applied to select a suitable micellar mobile phase. A comparative study was also made of the performance of micellar and aqueous-organic mobile phases in the analysis of pharmaceuticals that combine beta-blockers and diuretics. The determination of all the drugs could be made with a micellar mobile phase of 0.15 mol l-1 sodium dodecyl sulfate and 7% propanol in 0.01 mol l-1 phosphate buffer at pH 3, with retention times below 20 min, whereas two different aqueous-organic mobile phases were needed to make the same analyses.

Application of arylosulfonic acids in analysis of antihypertensive drugs.

Suitability of four arylosulfonic acids and their sodium salts to form derivatives with hypotensive drugs were studied. New crystalline arylosulfonates of todralazine, hydralazine and dihydralazine were obtained. Physico-chemical properties of the obtained arylosulfonates were tested. Reagents mentioned above were also used in analysis of these drugs.

Subcellular distribution of hydralazine in rat single vascular muscle cells.

High specific activity (20 Ci/mmol) tritiated hydralazine (3Hyd) distribution in isolated, cultured vascular muscle cells was determined to identify the sites of Hyd binding. 3Hyd dose-dependently bound to extracellular protein and to the area of organelles which secrete these proteins. Increased extracellular binding after Hyd pre-exposure suggests new binding sites may be exacerbated as a result of Hyd interactions. These experiments suggest a potentially important feature of the mechanism of action of this directly acting vasodilator.

Application of arylosulfonic acids in analysis of antidepressive drugs.

Suitability of three phenylsulphonyloxybenzenesulfonic acids and their sodium salts to form new derivatives with antidepressive drugs were studied. Then physicochemical properties of the obtained arylosulfonates were tested. Reagents mentioned above were also used in analysis of these drugs.

Spectrophotometric determination of hydralazine with 2-hydroxy-1-naphthaldehyde in pharmaceuticals.

A new extraction-spectrophotometric method for the determination of hydralazine, based on its reaction with 2-hydroxy-1-naphthaldehyde at 25 degrees C, is described. The calibration curve was linear between 0.4 and 6 mg/mL of hydralazine. The molar absorbtivity of the product at 408 nm is 40,900 L.mol-1.cm-1. The method described was applied to the analysis of hydralazine in pharmaceutical preparations containing reserpine, hydrochlorothiazide, bendrofluorthiazine, propranolol, and other substances. The agreement with the U.S.P. XXI method was satisfactory for tablets and injections, but not for pellets.

Determination of hydrazine in hydralazine by capillary gas chromatography with nitrogen-selective detection after benzaldehyde derivatization.

A method for the determination of hydralazine substance is described. Hydrazine is derivatized in aqueous media with benzaldehyde to benzalazine. After extraction to an organic phase containing a homologue as marker, the sample is subjected to capillary column gas chromatography with nitrogen-selective detection. A prolonged reaction with 0.1 M benzaldehyde of 20 min or more led to an increased level of benzalazine when hydralazine was analysed. An increase was also observed if the aqueous hydralazine sample had been allowed to stand for some time before analysis. The final method involved the use of a 5-min reaction time, fresh solutions and the standard addition principle. The levels of hydrazine found in hydralazine hydrochloride were below 1 ppm (as bases, 1 ng/mg).

UV spectrophotometric determination of hydralazine hydrochloride in tablets: collaborative study.

A UV spectrophotometric method for the determination of hydralazine hydrochloride in tablets was collaboratively studied by 5 laboratories. The method is based on conversion of hydralazine to a tetrazolo [5,1-alpha]phthalazine derivative which shows an absorption maximum at about 274 nm. Each collaborator received blind duplicate samples of 2 commercial powdered composites from 10 and 100 mg tablets, and 1 synthetic tablet formulation. Each collaborator also received a set of 10 tablets for determination of content uniformity. The pooled mean recovery of hydralazine hydrochloride from the synthetic formulation was 101.2 +/- 0.94%. The mean assay values for 10 and 100 mg tablets were 95.6 +/- 0.98 and 101.0 +/- 0.73% of the declared amounts, respectively, with corresponding CV values of 1.02 and 0.73%. The pooled mean for individual tablet assay was 99.8 +/- 3.26% of the declared value, with a CV of 3.29%. The method has been adopted official first action.

Assay for hydralazine as its stable p-nitrobenzaldehyde hydrazone.

A new method of analysis for the antihypertensive drug, hydralazine, is introduced. The assay involves the addition of p-nitrobenzaldehyde to blood samples containing hydralazine, to form a stable Schiff's base, hydralazine p-nitrobenzaldehyde hydrazone. The derivative is extracted from the blood into hexane and the samples are dried under a nitrogen stream. The extracts are then dissolved in mobile phase and analyzed using high-performance liquid chromatography. The extracted samples can be stored for at least 7 days at room temperature or at -20 degrees C. The sensitivity of the assay is better than 300 pg/ml using 3-ml blood samples, and the range can extend to 640 ng/ml. The stability of the extracted samples plus the sensitivity and simplicity of the assay are the main advantages of the method over other selective methods for hydralazine.

In vitro kinetic studies of the reaction of hydralazine and its acetone hydrazone with pyruvic acid.

To understand the reaction between hydralazine (HP) or its acetone hydrazone (HAH), a metabolite of HP and pyruvic acid, a new selective HPLC method for simultaneous determination of HP, HAH, and hydralazine pyruvic acid hydrazone (HPH) was developed. In vitro degradation of HAH and formation of HP and HPH were investigated at pH 7.4 and 37 degrees C in the presence or absence of pyruvic acid. Hydralazine degraded slowly according to an apparent first-order rate (7.46 x 10(-2)h-1). The degenerative reaction of HAH, accompanied by simultaneous hydrolysis to the parent drug HP, was also subject to apparent first-order loss (3.00 x 10(-1)h-1). In addition, HAH was partly converted to HP and HPH in the presence of pyruvic acid. For the formation pathway of HPH, a model that included the direct reaction of HAH with pyruvic acid and the secondary formation mediated by back-conversion to HP gave a better fit to the experimental data than the model consisting of the latter reaction only. About 10% of the HPH formed was generated by the direct reaction of HAH with pyruvic acid, based on the rate constants estimated. These results suggest that the formation of HPH is not all accomplished through back-conversion to HP.

Ultraviolet spectrophotometric determination of hydralazine hydrochloride in tablets following derivatization with nitrite.

Routine use of the USP XXI spectrophotometric method for the content uniformity determination of hydralazine hydrochloride tablets has shown that tablet excipients can significantly alter the spectral characteristics of the drug and thus cause inaccurate assay values to be obtained. Because of this problem, a simple and reliable alternative spectrophotometric assay method, based on the conversion of hydralazine to tetrazolo [5,1-alpha]phthalazine with nitrite ions under acidic conditions, was developed. The derivative showed an absorption maximum at about 274 nm and obeyed Beer's law over the concentration range 4-40 micrograms/mL. Mean recoveries of hydralazine hydrochloride added to commercial coated and uncoated tablets were 101.0% (n = 10) and 100.8% (n = 8), respectively. The proposed method was found suitable for the assay not only of individual tablets but also of tablet composites.

Stability of hydralazine hydrochloride in aqueous vehicles.

The stability of hydralazine hydrochloride in aqueous vehicles which contain either dextrose, fructose, lactose, maltose, mannitol, sorbitol or sucrose has been studied using a stability-indicating high-performance liquid chromatographic method. Dextrose, fructose, lactose and maltose had adverse effects on the stability of hydralazine. In mannitol (better than sorbitol) and sorbitol, hydralazine was stable for about 21 days (loss in potency of less than 10%) and sucrose had an adverse effect only after its hydrolysis to fructose and dextrose. The optimum pH range of stability in dextrose was approximately between 3.2 and 4.4. The first-order rate of decomposition increased with an increase in the concentration of dextrose but not with an increase in the concentration of hydralazine. In the absence of other excipients the phosphate and citrate buffers did not adversely affect the stability of hydralazine hydrochloride.

Separation and quantitation of hydralazine metabolites by high-performance liquid chromatography.

A selective high-performance liquid chromatographic assay for the separation and quantitation of the proposed hepatic microsomal metabolites of hydralazine (HP), phthalazine, phthalazinone, s-triazolo[3,4-a]phthalazine, 3-methyl-s-triazolo[3,4-a]phthalazine and 3-hydroxymethyl-s-triazolo [3,4-a]phthalazine, is described. An extraction technique was developed for the removal of HP from hepatic microsomal samples in order to minimize the measurement of products resulting from the chemical degradation of HP. The effects of pH and composition of the mobile phase on the retention times and resolution of the five compounds were examined. The methods presented are accurate and reliable, permitting the baseline separation of five HP metabolites with reasonable analysis time and sensitivity.