Release Of Hydrochlorothiazide Research Articles

Impact of polysorbate 65 on tripalmitin crystal growth and release stability of hot melt coated multiparticulate systems

Hydrochlorothiazide (HCT) multiparticulate systems (MPS) were hot melt coated with the binary mixture of tripalmitin (PPP) and polysorbate 65 (PS 65) to gain an immediate release profile. Once, HCT MPS were produced with a constant ratio of PPP/PS 65 (90:10) at three different coating amounts (15, 25, and 60%w/w) and once the PPP/PS 65 ratio was varied on 98:2 and 80:20, by keeping the coating amount at 60%w/w. PS 65 induced the polymorphic transformation of PPP from the α-form to its most stable β-form right after the hot melt coating (HMC). A release alteration of HCT, either accelerated or decelerated, occurred after the storage under accelerated conditions. The effect of the API core on the lipid lamellar configuration, the thermal behavior of lipid coating, and the effect of PS 65 concentration on the crystal growth of PPP were investigated via X-ray diffraction and DSC. While a low amount of PS 65 was sufficient to promote crystal growth of PPP and resulted in a decelerated release of HCT from the coating, a higher PS 65 concentration favored phase separation of PPP and PS 65 and led to an accelerated release. The increase in PS 65 reinforced the molecular interaction with the lipophilic HCT, reflected in less crystal growth and decelerated release. The knowledge presented in this study supports understanding the instability of binary emulsifier-lipid coating systems, paving the way for developing robust HMC formulations.

Formulation, Development and Evaluation of Uncoated Bilayer Tablet of Anti-Hypertensive Agents

The present research work was carried out to Formulate and evaluation of bilayer tablet dosage form for the treatment of Hypertension.The objective of this study to compare the specific characteristics of Metoprolol [beta selective (cardio selective) adrenoreceptor blocking agent] and Hydrochlorothiazide (Thiazide Diuretics]) in order to design stable formulation. It can be concluded that bilayer tablet were successfully formulated to achieve immediate release of Hydrochlorothiazide (HCTZ) and tailored release of Metoprolol (MPL)by using Dual Release Drug Absorption System(DUREDAS technology).Both drugs were found to be stable in Bilayer tablet formulation and were found to be stable for few months. This bilayer tablet dosage form increases the stability which may reduce loss and cost of formulation. It improves the benefits of producer, retailer, and patients. Recently, greater attention has been focused on development of bilayer tablet formulations. Over the past 30 years, the expenses and complications involved in marketing new drug entities have increased with concomitant recognition of therapeutic advantages of conventional drug delivery system. Several pharmaceutical companies are currently developing bi-layer tablets, for a variety of reasons: patent extension, efficient pharmacological effect, better patient compliance, etc. Bilayer tablet is becoming new approach for the successful drug delivery system and for better stability in combination. Bilayer tablets can be primary option to avoid chemical incompatibilities between APIs by physical separation.
 Keywords: Bilayer tablet, DUREDAS Technology, Antihypertensive, Metoprolol, Hydrochlorthiazide

EXPLORING THE POTENTIAL OF ORODISPERSIBLE TABLET OF ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE DRUG COMBINATION

The objective of the present work was to formulate and evaluate orodispersible tablets of enalapril maleate and hydrochlorothiazide combination to overcome the shortcomings of conventional dosage forms and improve patient compliance. Eleven formulations were prepared by wet granulation method using sodium starch glycolate as superdisintegrant and microcrystalline cellulose and Pearlitol 200 SD as diluents. The process variables were optimized to get desired characteristics. Various pre-compression and post-compression quality control parameters were evaluated. The wetting and disintegration times of formulation F10 were found to be 11 ± 4 and 15 ± 2 seconds, respectively. The in vitro dissolution study showed 97.2 % release of enalapril maleate and 96.94 % release of hydrochlorothiazide within 10 min. The optimized formulation was found to be stable during stability study. The study concludes that orodispersible tablet of enalapril maleate and hydrochlorothiazide could be a better approach for the treatment of hypertension.

Chitosan microencapsulation of the dispersed phase of an O/W nanoemulsion to hydrochlorothiazide delivery

In view of biopharmaceutical limitations of hydrochlorothiazide (HCTZ), Trojan-type mucoadhesive systems were proposed, aiming to improve HCTZ pharmacological properties by modulating its release. Nanoemulsions were formed spontaneously by combining medium-chain triglycerides (Lipoid® S75 and Pluronic® F68) and high encapsulation efficiency was obtained. The mucoadhesive properties were provided by chitosan and microencapsulation of nanoemulsions in spray-dryer was successfully achieved by using Aerosil® as wall material. The rapid redispersion of nanoemulsion in simulated fluids led to a fast and complete release of HCTZ in gastric medium. The pharmacodynamics of HCTZ was improved, extending the diuretic activity. Once a simple and low-energy method contributed to obtain stable mucoadhesive nanoemulsions, advantages in terms of production could also be achieved, allowing easy scaling up. This novel mucoadhesive Trojan particulate system of HCTZ showed to be a promising approach to overcome limitations in terms of absorption and consequently improve the therapeutic efficacy.

Permeability Profiles and Intestinal Toxicity Assessment of Hydrochlorothiazide and Its Inclusion Complex with β-Cyclodextrin Loaded into Chitosan Nanoparticles.

Here, a novel drug delivery system was developed for the hydrochlorothiazide (HCT):β-cyclodextrin (βCD) inclusion complex loaded into chitosan (CS) nanoparticles (NPs) [CS/HCT:βCD NPs]. It was found, for the first time, that exposure of the intestinal mucosa to free HCT resulted in an increased and abnormal intestinal permeability associated with several injuries to the intestinal epithelium. Nevertheless, the HCT delivery system obtained ameliorated the damage of the intestinal epithelium induced by HCT. Furthermore, we found that the corresponding permeability profiles for both the free HCT and the CS/HCT:βCD NPs were exponential and lineal, respectively. We propose that the increased intestinal uptake and severe tissue injury of HCT to the intestinal epithelium could be directly related to possible effects of this drug on the ionoregulatory Na+/K+-ATPase channel. Thus, it is postulated that the CS/HCT:βCD NPs may increase the gastrointestinal retention of the HCT, which would provide increased adherence to the mucus barrier that lines the intestinal epithelium; consequently, this would act as a slow HCT release delivery system and maintain lower drug levels of luminal gut in comparison with the administration of free HCT, leading to less severe local injury.

Double-Layered Matrix of Shellac Wax-Lutrol in Controlled Dual Drug Release

Double-layered matrix tablets prepared from shellac wax-lutrol were fabricated using a molding technique, and the release of hydrochlorothiazide and propranolol HCl from the inner tablet or outer layer was studied. The simultaneous determination of dual drug release was measured with first derivative UV spectrophotometry. The tablet containing shellac wax as the outer tablet and lutrol as the inner tablet showed more appropriate drug release and the size of the inner layer influenced the rate of drug release. In addition, the aqueous solubility of the drug and the components of the inner tablet or outer layer affected the drug release behavior. Most of the double-layered tablets exhibited the drug-release pattern which fitted well with zero-order kinetic due to the restriction of the release surface. Biphasic drug release pattern was found in the tablet of which the outer layer rapidly eroded. The drug dissolution data from drug-loaded-outer layer could predict the dissolution time for the outer layer of drug-loaded inner part of double-layered matrix tablet. Incorporation of lutrol increased the drug release from shellac wax matrix, and the zero-order release was attained by fabricating it into a double-layered tablet.

Prilling as manufacturing technique for multiparticulate lipid/PEG fixed-dose combinations

This study focused on the evaluation of prilling as a technique for the manufacturing of multiparticulate dosage forms. Prills, providing controlled and immediate drug release, were processed and finally combined in capsules yielding a fixed-dose combination. Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were used as controlled and immediate release model drugs, respectively. These drugs were embedded in matrices composed of fatty acids and polyethylene glycol (PEG). In order to tailor drug release from the prills, the type of fatty acid, the PEG molecular weight and the fatty acid/PEG ratio were varied. To provide controlled drug release, MPT was embedded in matrices containing PEG and behenic acid. Using different PEG molecular weights (PEG 4000, 6000 and 10,000), MPT release could be tailored over a wide range. To obtain immediate release, HCT was incorporated in matrices composed of PEG and stearic acid. Since high amounts (at least 60%) of PEG were needed for acceptable immediate release, HCT release was independent on PEG molecular weight. Solid state characterization revealed that MPT crystallinity was decreased, while HCT was molecularly dispersed throughout the matrix. Drug release of both MPT and HCT prills was stable during storage. Compared to a fixed-dose reference, oral co-administration of the MPT and HCT prills to dogs yielded a similar bioavailability for the HCT prills, while the MPT prills resulted in a significant higher bioavailability.

Formulation Development of Metoprolol Succinate and Hydrochlorothiazide Compression Coated Tablets

The purpose of present research work was to design and optimize compression coated tablet to provide an immediate release of hydrochlorothiazide in stomach and extended release of metoprolol succinate in intestine. Compression coated tablet was prepared by direct compression method which consisted of metoprolol succinate extended release core tablet and hydrochlorothiazide immediate release coat layer. Barrier coating of Hydroxy Propyl Methyl Cellulose (HPMC) E15LV was applied onto the core tablets to prevent burst release of metoprolol succinate in acidic medium. A 32 full factorial design was employed for optimization of the amount of polymers required to achieve extended release of drug. The percentage drug release at given time Q3, Q6, Q10, Q22; were selected as dependent variables. Core and compression coated tablets were evaluated for pharmaco-technical parameters. In vitro drug release of optimized batch was found to comply with Pharmacopoeial specifications. Desired release of metoprolol succinate was obtained by suitable combination of HPMC having high gelling capacity and polyethylene oxide having quick gelling capacity. The mechanism of release of metoprolol succinate from all batches was anomalous diffusion. Optimised batch was stable at accelerated conditions up to 3 months. Thus, compression coated tablet of metoprolol succinate and hydrochlorothiazide was successfully formulated.

Pluronic–cationic surfactant mixed micelles: Solubilization and release of the drug hydrochlorothiazide

Moderately hydrophobic poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) block copolymers [Pluronics® with 20>% PEO<80] form micelles in water with a hydrodynamic diameter of about 20nm. The aqueous mixed systems of Pluronics® P103, P104 and P105 [Pluronics® with molecular weight of PPO=3250, and % of PEO 30, 40 and 50 respectively] with cationic surfactants of the type alkyltrimethylammonium bromide (CnTAB, n=10, 12, 14 and 16) were studied in water and salt solution. It is apparent that the presence of trace amounts of cationic surfactant induces a charge on nonionic Pluronics® micelles and leads to a decrease in their size. The efficiency of surfactants to decrease micellar size depends on the alkyl chain length of the surfactants. A representative system, P103-C14TAB was chosen to investigate and the feasibility of using Pluronic®–surfactants systems compared with pure Pluronic® micelle as an in vitro release vehicle for hydrochlorothiazide (HCT); a hydrophobic diuretic drug with poor aqueous solubility. Pluronic®–surfactant systems were found to be more efficient for HCT loading; their loading capacity can be tuned by changing the surfactant concentration and pH. Drug release profiles were established for P103 and P103-C14TAB mixed systems. The rate of controlled release of HCT from micelles was explained by employing different kinetic models to examine the in vitro release profile.

The effect of pH and ionic strength of dissolution media on in-vitro release of two model drugs of different solubilities from HPMC matrices

The evaluation of the effects of different media ionic strengths and pH on the release of hydrochlorothiazide, a poorly soluble drug, and diltiazem hydrochloride, a cationic and soluble drug, from a gel forming hydrophilic polymeric matrix was the objective of this study. The drug to polymer ratio of formulated tablets was 4:1. Hydrochlorothiazide or diltiazem HCl extended release (ER) matrices containing hypromellose (hydroxypropyl methylcellulose (HPMC)) were evaluated in media with a pH range of 1.2–7.5, using an automated USP type III, Bio-Dis dissolution apparatus. The ionic strength of the media was varied over a range of 0–0.4M to simulate the gastrointestinal fed and fasted states and various physiological pH conditions. Sodium chloride was used for ionic regulation due to its ability to salt out polymers in the midrange of the lyotropic series. The results showed that the ionic strength had a profound effect on the drug release from the diltiazem HCl K100LV matrices. The K4M, K15M and K100M tablets however withstood the effects of media ionic strength and showed a decrease in drug release to occur with an increase in ionic strength. For example, drug release after the 1h mark for the K100M matrices in water was 36%. Drug release in pH 1.2 after 1h was 30%. An increase of the pH 1.2 ionic strength to 0.4M saw a reduction of drug release to 26%. This was the general trend for the K4M and K15M matrices as well. The similarity factor f2 was calculated using drug release in water as a reference. Despite similarity occurring for all the diltiazem HCl matrices in the pH 1.2 media (f2=64–72), increases of ionic strength at 0.2M and 0.4M brought about dissimilarity. The hydrochlorothiazide tablet matrices showed similarity at all the ionic strength tested for all polymers (f2=56–81). The values of f2 however reduced with increasing ionic strengths. DSC hydration results explained the hydrochlorothiazide release from their HPMC matrices. There was an increase in bound water as ionic strengths increased. Texture analysis was employed to determine the gel strength and also to explain the drug release for the diltiazem hydrochloride. This methodology can be used as a valuable tool for predicting potential ionic effects related to in vivo fed and fasted states on drug release from hydrophilic ER matrices.

Formulation and Characterization of Novel Micrpoarticles of Hydrochlorothiazide by Solvent Evaporation Technique

Microparticles are defined as particulate dispersions or solid particles with a size in the range of 1-1000 µm. The drug is dissolved, entrapped, encapsulated or attached to a Microparticle matrix. Depending upon the method of preparation, Microparticles, microspheres or microcapsules can be obtained. In the present study the Solid Dispersion of Hydrochlorothiazide obtained from Solvent Evaporation technique was formulated in the Microparticulate drug delivery for the sustaining the release rate. The present study involves formulation and development of Microparticles of Hydrochlorothiazide by Ionic Gelation and Coacervation Phase Separation technology. These two techniques showed compatibility of process and polymers. Studies have indicated that Hydrochlorothiazide loading affected the Hydrochlorothiazide release kinetics/mechanism from Microparticles. The microparticles prepared by Coacervation Phase Separation of Ethyl Cellulose and Eudragit RL-100 binary mixtureshowed controlled release of Hydrochlorothiazide in-vitro and were found to be most stable. No significant effects of drug loading on the Microparticle size, morphology, and size distribution were observed. Kewords:-Solubility enhancement, microparticles, solvent evaporation,Hydrochlorothiazide

Co-extrusion as manufacturing technique for fixed-dose combination mini-matrices

The aim of this study was to develop a multilayer (core/coat) dosage form via co-extrusion, the core providing sustained drug release and the coat immediate drug release. In this study polymers were selected which can be combined in a co-extruded dosage form. Several thermoplastic polymers were hot-melt extruded and evaluated for processability and macroscopic properties (surface smoothness, die swell). Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were incorporated as sustained and immediate release model drugs, respectively. Based on the polymer screening experiments a combination of polycaprolactone (core) and polyethylene oxide (coat) was selected for co-extrusion trials, taking into account their drug release profiles and extrusion temperature (70°C). This combination (containing 10% HCT in the coat and 45% MPT in the core) was successfully co-extruded (diameter core: 3mm/thickness coat: 0.5mm). Adhesion between the two polymer layers was good. HCT release from the coat was complete within 30min, while MPT release was sustained over 24h (55%, 70%, 85% and 100% after 4, 8, 12 and 24h, respectively). DSC, XRD and Raman spectroscopy revealed that MPT remained crystalline during extrusion, whereas HCT was dissolved in the polyethylene oxide matrix. The in vivo study revealed no significant differences between the experimental formulation and the reference formulation (Zok-Zid® tablet). Fixed-dose combination mini-tablets with good in vitro and in vivo performance were successfully developed by means of co-extrusion, using a combination of polycaprolactone and polyethylene oxide.

Preparation, optimization and characterization of multiple unit microspheres containing kollidone SR.

The present investigation described the influence of viscosity and drug: Polymer ratio on Hydrochlorothiazide release. Floating microspheres loaded with hydrochlorothiazide were prepared by Emulsion solvent evaporation method. The prepared microspheres were evaluated by micromeritics properties, in vitro drug release, floating ability and drug entrapment efficiency.

Enhanced Controlled Transdermal Delivery of Hydrochlorothiazide from an Ethylene-vinyl Acetate Matrix

ABSTRACT Š Repeated oral adm inistration of hy drochlorothiazide, a loop diuretic, due to transient high blood levels, m aycause adverse effects such as gastric disturbance, nausea, high blood sugar, and hy per lipidem ia. Transderm al adm inistrationcould avoid som e of these sy stemic side eff ects and gastric disorders. We have developed a m atrix using ethylene-viny l ace-tate (EVA ), a heat-processible and flexible m aterial, for transdermal delivery of hydrochlorothiazide. Drug solubility washighest at 40% PEG -400 volume fraction. Drug release increased as concentration increased w ith a linear relationshipbetween the release rate and the square root of loading dose. Increasing tem perature increased drug release f rom the EVAmatrix. The activation energy, measured from the slope of log P versus 1000/T, was 11.9 kcal/m ol for a 2.5% loading dosefrom EVA matrix. Diethy l phthalate had the highest plasticizing effects on the release of hydrochlorothiazide. To increasethe skin permeation of hy drochlorothiazide from theA EV m atrix, enhancers such as the saturated fatty acids, the unsaturatedfatty acids, and the non-nicoi surfactants w ere aded to thed A m EVatrix, an sdk nepi rmeatnoi w as evaluated using a modifiedKeshary -Chien diffusion cell fitted with intact excised rat skin. Polyoxy ethy lene 23-laury l ether showed the highest enhanc-ing eff ects. In conclusion, transderm al delivery of hy drochlorothiazide could be improved from an EVA m atrix containingplasticizer and perm eation enhancer.Key words

Preparation andIn vitrorelease of hydrochlorothiazide from gellan beads produced by ionotropic gelation

Preparation and<i>In vitro</i>release of hydrochlorothiazide from gellan beads produced by ionotropic gelation

Novel buccoadhesive delivery system of hydrochlorothiazide formulated with ethyl cellulose- hydroxypropyl methylcellulose interpolymer complex

The buccoadhesive and in vitro release properties of patches formulated with ethylcellulose (EC) and hydroxypropyl methylcellulose (HPMC) interpolymer complexes of different ratios were studied. The patches containing hydrochlorothiazide (HCTZ) were prepared by casting and thereafter, evaluated using the following parameters: diameter, thickness, swelling behaviour, buccoadhesive strength, drug content analysis and in vitro release studies. An adapted Lecomte Du Nouy tensiometer was used to assess the buccoadhesion of the patches on freshly excised buccal mucosa of a pig. The release of HCTZ from the patches was studied in phosphate buffer (pH 7.5). The result of the study indicated that 1:2 ratio of EC and HPMC gave the highest buccoadhesive strength. All the patches had uniform diameters but varied thicknesses with their areas ranging from 2.06 to 2.16 cm2. The area swelling ratio (ASR) indicated that the patches did not swell up to two times their initial areas, with the batch containing 3:2 ratio of EC and HPMC possessing the highest ASR. Higuchi’s analysis of the release mechanism indicated that the release of HCTZ from the patches formulated with 1:1 and 2:1 ratios of EC and HPMC predominantly occurred by a diffusional process. This method could be used as an effective alternative delivery system for HCTZ compared with conventional tablet formulations. Key words: Hydrochlorothiazide, ethylcellulose, hydroxypropyl methylcellulose, interpolymer complex, area swelling ratio, buccoadhesive delivery.

Poly(dimethylsiloxane) coatings for controlled drug release—polymer modifications

Modifications of endhydroxylated poly(dimethylsiloxane) (PDMS) formulations were studied for their ability to be applied onto tablet cores in a spray-coating process and to control drug release in zero-order fashion. Modifications of the crosslinker from the most commonly used tetraethylorthosilicate (TEOS) to the trifunctional 3-(2,3-epoxypropoxy)propyltrimethoxysilane (SIG) and a 1:1 mixture of the two were undertaken. Addition of methylpolysiloxane-copolymers were studied. Lactose, microcrystalline cellulose (MCC) and polyethylene glycol 8000 (PEG) were the channeling agents applied. The effects on dispersion properties were characterized by particle size distribution and viscosity. Mechanical properties of resulting free films were studied to determine applicability in a pan-coating process. Release of hydrochlorothiazide (marker drug) was studied from tablets coated in a lab-size conventional coating pan. All dispersions were found suitable for a spray-coating process. Preparation of free films showed that copolymer addition was not possible due to great decline in mechanical properties. Tablets coated with formulations containing PEG were most suitable to control drug release, at only 5% coating weight. Constant release rates could be achieved for formulations with up to 25% PEG; higher amounts resulted in a non-linear release pattern. Upon adding 50% PEG, a drug release of 63% over 24 h could be achieved.

Formulation of a lyophilized dry emulsion tablet for the delivery of poorly soluble drugs

The objective was to develop a dry emulsion tablet for the flash delivery of poorly water soluble drugs using a lyophilization technique. The influence of formulation parameters on the characteristics of the lyophilized dry emulsion (LDE) tablets was investigated. Oil-in-water emulsions were made using a medium chain triglyceride as the oil phase and a maltodextrin solution (5–20% w/v) as the water phase. In addition different emulsifier-tablet binder combinations were evaluated. The emulsions were filled into PVC blisters and freeze-dried. The resulting tablets were analyzed for strength, disintegration time, porosity and residual moisture. X-ray diffractions and scanning electron micrographs (SEM) of the fracture plane of the tablets were taken. Dissolution tests were performed on lyophilized tablets containing hydrochlorothiazide (HCT) as a model drug. A significant influence of the maltodextrin type on the tablet disintegration time was seen. Maltodextrin formulations with a high dextrose equivalent (DE) value (DE38) resulted in a faster disintegration time compared to DE12 and DE24 maltodextrin formulations ( p<0.05). There was a significant influence of maltodextrin concentration on tablet strength, disintegration time and porosity. Tablet strength increased significantly with increasing maltodextrin concentration ( p<0.05). The porosity of the tablets made with DE38 5%, 10% and 20% (w/v) was 92%, 85% and 81%, respectively. SEM pictures showed an increase in pore diameter with a decreasing maltodextrin concentration. No significant influence of Miglyol 812 concentration on tablet strength was observed. A significant influence of methylcellulose concentration, used as emulsifier-tablet binder (Methocel ® E15LV), on tablet strength and disintegration time was observed. Dissolution tests on 25 mg HCT containing tablets resulted in a % HCT release of 35.1% and 24.1% for the LDE tablet and conventional tablet, respectively. No significant influence of the oil content in the LDE tablets on the HCT release was observed. It can be concluded that maltodextrins and methylcellulose are useful excipients in the formulation of LDE tablets. The concentration of maltodextrin, the medium chain triglyceride and methylcellulose influenced the tablet characteristics.

Effects of hydroxymethylpropylcellulose (HPMC) moisture content on hydrochlorothiazide release from HPMC-based tablets

Abstract The effects of hydroxypropylmethylcellulose (HPMC) moisture content on the properties of tablets made with HPMC as base excipient were investigated. Two varieties of HPMC, with nominal viscosities of 4000 and 100 000 cP, were evaluated. The drug model used was hydrochlorothiazide, present in tablets at 1% w/w. The results for both HPMC varieties indicate that variation in HPMC moisture content over the range 2.25–10.85% has no significant effects on drug release profile, despite the fact that HPMC moisture content is positively correlated with the tensile strength of tablets.

Influence of adjuvants on the in vitro dissolution of hydrochlorothiazide from hard gelatin capsules

The influence of fillers, lubricants and a surfactant on the dissolution of hydrochlorothiazide from hard gelatin capsules was evaluated using a 2 3 factorial design. Measurement of the dissolution efficiency of eight formulations showed that the adjuvants possessing the greatest hydrophilic character had the greatest effect on the release of hydrochlorothiazide from the capsules.