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The buccal route has great prospects and possible benefits for the administration of drugs systemically. The present study involves designing, developing and optimising the buccal tablet formulation of Enalapril Maleate (EM) by using the QbD approach. We prepared the EM buccal tablets using the dry granulation method. In the QTPP profile, the CQAs for EM buccal tablets are Mucoadhesive strength, swelling index and drug release (dependent variables); the CMAs identified for EM buccal tablets were Carbopol 934P, HPMC-K100M and chitosan (independent variables). Diluent quantity, blending time and compression force were selected as CPPs; the Box-Behnkentdesign was used to evaluate the relationship between the CMAs and CPPs. Based on the DoE, the composition of the optimised formulation of EM BT-18 consists of 20mg of EM, 15 mg of carbopol 934p, 17 mg of HPMC-K100M, 10mg of chitosan, 30 mg of PVP K-30, 1 mg of magnesium stearate, 16 mg of Mannitol, 1 mg of aspartame, and 50 mg of Ethyl cellulose. The optimised formulation of EM BT 18 was found to have a Mucoadhesive strength of 24.32±0.30g. The swelling index was 90.74±0.25% and drug release was sustained up to 10 hours 98.4±3.62% compared to the marketed product, whose release was up to 8 hours. We attempted to design a buccal tablet of Enalapril Maleate for sustained drug release in the treatment of hypertension. Patients who cannot take oral medication due to trauma or unconscious conditions could receive the formulation. Development of a newly P.ceutical product is very time-consuming, extremely costly and high-risk, with very little chance of a successful outcome. Hence, this study showed EM tablets are already available on the market but we have chosen a buccal drug delivery system using a novel approach using QbD tools to target the quality of the product accurately.

Introduction: Enalapril maleate is an antihypertensive ethyl ester pro-drug with two crystalline forms. A network of hydrogen bonds in both polymorphs plays an important role on solid-state stability, charge transfer process and degradation reactions (when exposed to high humidity, temperature and/or pH changes)., Computational Procedures: Supramolecular arrangement was proposed by Hirshfeld surface using the CrystalExplorer17 software and quantum theory of atoms in molecules. The electronic structure properties were calculated using the functional hybrid M06-2X with 6-311++G** base function employing diffuse and polarization functions to improve the description of hydrogen atoms on intermolecular interactions. Also, the H+ charge transfer between enalapril and maleate molecules was performed using Car-Parrinello molecular dynamics with the Verlet algorithm. In both simulations, the temperature of the ionic system was maintained around 300 K using the Nosé-Hoover thermostat and the electronic system evolved without the use of the thermostat., Results: This work evaluates the effect of maleate on the structural stability of enalapril maleate solid state. The electronic structural analysis points out a partially covalent character for N1-H∙∙∙O7 interaction; and the molecular dynamic showed a decentralized hydrogen on maleate driving a decomposition by charge transfer process while a centered hydrogen driving the stabilization. The charge transfer process and the mobility of the proton (H+) between enalapril and maleate molecules was demonstrated using supramolecular modeling analyses and molecular dynamics calculations., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Pediatric, geriatric, and other patients who suffer from swallowing difficulties represent a special patient group, where an increased need in appropriate formulation development is required. To overcome these mostly swallowability linked issues, orodispersible tablets (ODTs) and orodispersible mini-tablets (ODMTs) can be seen as a suitable alternative to improve compliance. Orodispersible tablets are oral solid dosage forms which rapidly disintegrate after contact with saliva, leaving a liquid dispersion, which can be easily swallowed. To fulfil the required quality criteria and optimize the formulations regarding tensile strength and disintegration time, co-processed excipients (CPE) based on mannitol are frequently used in the manufacturing of orodispersible tablets. This study aimed to systematically compare two new CPEs, namely Granfiller-D® and Hisorad® and evaluate their potential in future OD(M)T formulations with already marketed products. The performance of the CPEs was examined in combination with three different APIs. Disintegration time, sufficient mechanical strength and content uniformity for low dosed formulation were chosen as main quality aspects. Conventionally sized tablets (9 mm) with 50% drug load of ibuprofen and paracetamol were produced with each CPE. Low dosed OD(M)Ts with a drug load of 4% enalapril maleate were manufactured to study content uniformity. Large differences were visible in the formulations containing ibuprofen and only Hisorad® allowed to compress ODT fulfilling the specifications of Ph.Eur. and FDA regarding disintegration times (180 s and 30 s, respectively). For the poorly binding model drug paracetamol, none of the studied excipients showed a satisfactory performance, with maximum tensile strengths < 1 MPa. To reach content uniformity in low dosed ODMTs, Ludiflash® seems to be the most preferable alternative, as the formulation showed the lowest acceptance values (AV) according to Ph.Eur. (<4) as well as the smallest coefficient of variation (CV) in API content (CV < 2%). In conclusion, the study revealed that none CPE is the ideal choice for all approaches, but different CPEs should be selected dependent on different challenges during formulation development of OD(M)Ts., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hypertension is a major risk factor for atherosclerosis and ischemic heart disease. Most hypertensive patients need a combination of antihypertensive agents to achieve therapeutic goals. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of enalapril maleate (ENA) and its major metabolite enalaprilat (ENAT), nitrendipine (NIT) and its major metabolite dehydronitrendipine (DNIT), and hydrochlorothiazide (HCT) in human plasma using felodipine as an internal standard (IS). The drugs were extracted from plasma using one-step protein precipitation. Chromatographic separation was performed on a Symmetry C 18 column, with water and acetonitrile (10:90, v/v) as mobile phase. The detection was carried out using multiple reaction monitoring mode and coupled with electrospray ionization source. Multiple reaction monitoring transitions were m/z 377.1 → 234.1 for ENA, m/z 349.2 → 206.1 for ENAT, m/z 361.2 → 315.1 for NIT, m/z 359 → 331 for DNIT, m/z 295.9 → 205.1 for HCT, and m/z 384.1 → 338 for felodipine (IS). The method was linear over concentration ranges of 1-200, 20-500, 5-200, 2-100, and 5-200 ng/mL for ENA, ENAT, NIT, DNIT, and HCT, respectively, with r 2 ≥ 0.99. Method validation was performed according to U.S. Food and Drug Administration guidelines. The validated method showed good sensitivity and selectivity and could be applied for therapeutic drug monitoring and bioequivalence studies., (© 2020 John Wiley & Sons, Ltd.)

The identification of crystalline drug polymorphs using terahertz vibrational spectroscopy is a powerful approach for the nondestructive and noninvasive characterization of solid-state pharmaceuticals. However, a complete understanding of the terahertz spectra of molecular solids is challenging to obtain because of the complex nature of the low-frequency vibrational motions found in the sub-3 THz (sub-100 cm -1 ) range. Unambiguous assignments of the observed spectral features can be achieved through quantum mechanical solid-state simulations of crystal structures and lattice vibrations utilizing the periodic boundary condition approach. The terahertz spectra of two polymorphs of enalapril maleate are presented here to demonstrate that even large pharmaceuticals can be successfully modeled using solid-state density functional theory, including cocrystalline solids comprised of multiple distinct species. These simulations enable spectral assignments to be made, but also provide insights into the conformational and cohesion energies that contribute to the polymorph stabilities. The results reveal that the Form II polymorph of enalapril maleate is the more stable of the two under ambient conditions, and that this stability is driven by a greater intermolecular cohesion energy as compared to Form I.

Microwave assisted synthesis of graft copolymer of polymeric blend of Fenugreek seed mucilage (FSM)-Polyvinyl alcohol (PVA) with acrylamide (AM) was done by free radical polymerization using ammonium per sulfate (APS) as initiator. Varying amount of AM and APS was used to optimize the best grade based on highest percentage grafting efficiency and investigated with intrinsic viscosity measurement, Fourier Transformation infrared spectroscopy (FTIR), 13 C NMR spectra, X-ray diffraction, elemental analysis, Thermogravimetric analysis, Scanning electron microscopy. The results of intrinsic viscosity indicate that the optimized sample GF4 has longer chain length than in comparison to the native mucilage and thus exhibits more swelling tendencies and thus can be used as very good controlled release matrix system. The thermal analysis and X-ray indicates that GF4 is more stable and possess more amorphous properties than the native FSM. The NMR and FT-IR studies reveal that in GF4 there is prominent presence of amide and the hydroxyl groups indicating that grafting mechanism has efficiently taken place. Histological studies & SEM image for optimized grade implanted on animals revealed sufficient tissue growth and exhibited biodegradability proving the material to be biocompatible and suitable to be used as tissue engineered scaffolds. The controlled release behavior of the optimized polymeric system GF4 was evidenced by 95% release of loaded drug Enalapril maleate for 16 h. Graphical abstract.

Background: In many countries, hypertension in the pediatric population is considered a serious risk of mortality and morbidity. In this respect, it is central to design and develop new pharmaceutical forms for pediatric patients with hypertension. The development of Orodispersible Mini-Tablets (ODMTs) for pediatric use has gained importance in recent years. Therefore, regulations for developing suitable and palatable dosage forms for pediatric patients have been established by WHO authorities., Objective: This study aimed to design and develop orodispersible mini tablets of enalapril maleate (EnM ODMTs) for pediatric use., Methods: Five pharmaceutical formulations (A, B, C, D and E, shown in Table 1) were designed. The effects of different co-processed excipients and active pharmaceutical ingredients at different doses were studied. Lactose co-processed excipients selected were the following: Tablettose® 80, Microce- Lac® 100 and StarLac®. The micromeritic properties for all the physical mixtures were examined. The mini tablets were obtained by direct compression. Quality control parameters were determined in accordance with US Pharmacopeia., Results: Three OMDTs with StarLac® showed good results of hardness, flow ability and fast disintegration. The formulation with 0.1 mg of enalapril maleate presented the best results for the official parameters of hardness (4.0 kp), friability (< 1%), disintegration time (28 s), drug content uniformity (103.6 %), and wetting time (23 s)., Conclusion: The three OMDTs with StarLac® showed good quality parameters, according to official requirements. Formulation A exhibited the best wetting time, complying with the dose recommended for pediatric patients. This formulation could be considered eligible for being manufactured at industrial scale., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The development of orodispersible mini-tablets (ODMTs) for paediatric use has gained importance within recent years as European authorities set up regulations for developing suitable and palatable dosage forms for paediatric patients. Polyols like mannitol and isomalt are frequently used in the manufacture of tablets where sensory properties have to be taken into account. In literature, ODTMs based on a commercialized co-processed excipient based on mannitol (Ludiflash®) have been already described. Isomalt is known for its pleasant sensory properties and therefore appears to be a good candidate for ODMTs. The feasibility of the direct compression grade of isomalt for the manufacture of ODMTs was assessed and compared to Ludiflash®. Hydrochlorothiazide and enalapril maleate were chosen as model drugs and compressed to 2 mm mini-tablets. ODMTs could be obtained fulfilling the criteria of Ph.Eur. with disintegration times of 180 s or even the FDA limit of 30 s. Dissolution studies and mass variation were fulfilled for all mini-tablets. Acceptance values (AV) ≤ 15 were achieved for formulations based on both isomalt and Ludiflash®. Stability data showed the change of disintegration time and tensile strength as a function of storing time, condition and excipient. Both excipients showed their potential for ODMTs for paediatric use., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h -1 , all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h -1 ., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Taste masking of bitter or unpleasant drugs is an important prerequisite to improve patient compliance, especially for children and elderly patients. We aimed at obtaining taste-masked microparticles intended for incorporation into orodispersible tablets (ODTs). We selected the precipitation method using enalapril maleate (ENA) as a model bitter-tasting drug and Eudragit EPO® as a pH sensitive polymer., Aim: The aim of this study was to obtain microparticles with enalapril maleate by the precipitation method in order to mask the bitter taste of the drug., Materials and Methods: Nine models of enalapril maleate – Eudragit EPO® microparticles were prepared by the precipitation method at varied drug-polymer ratios. The models were characterized in terms of size, shape, production yield, drug content, encapsulation efficiency and moisture content. Fourier-transformed infrared spectroscopy, powder X-ray diffraction and differential scanning calorimetry were used to analyze possible interactions in the complex. In vitro drug release in simulated salivary fluid and in vivo taste evaluation in rats were realized to prove taste masking., Results: The particle size distribution varied from 266.9 µm to 410.9 µm. The shape of the resulting particles was irregular. The production yield varied from 23.6% to 78.2%. The drug content ranged between 2.3% to 4.8%, encapsulation efficiency increased from 1.6% to 9.0%. In vitro drug release data indicated significant taste masking., Conclusion: Some of the obtained microparticles by the precipitation method showed satisfactory taste masking efficiency, which proved the taste masking feasibility of this method., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity., Objective: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system., Methods: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction., Results: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively., Conclusion: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

There is an increased evidence for treating hypertension by a combination of two or more drugs. Increasing the number of daily intake of tablets has been reported to negatively affect the compliance of patients. Therefore, numerous fixed dose combinations (FDCs) have been introduced to the market. However, the inherent rigid nature of FDCs does not allow the titration of the dose of each single component for an individual patient's needs. In this work, flexible dose combinations of two anti-hypertensive drugs in a single bilayer tablet with a range of doses were fabricated using dual fused deposition modelling (FDM) 3D printer. Enalapril maleate (EM) and hydrochlorothiazide (HCT) loaded filaments were produced via hot-melt extrusion (HME). Computer software was utilised to design sets of oval bi-layer tablets of individualised doses. Thermal analysis and x-ray diffractometer (XRD) indicated that HCT remained crystalline in the polymeric matrix whilst EM appeared to be in an amorphous form. The interaction between anionic EM and cationic methacrylate polymer may have contributed to a drop in the glass transition temperature (Tg) of the filament and obviated the need for a plasticiser. Across all tablet sets, the methacrylate polymeric matrix provided immediate drug release profiles. This dynamic dosing system maintained the advantages of FDCs while providing a superior flexibility of dosing range, hence offering an optimal clinical solution to hypertension therapy in a patient-centric healthcare service., (Copyright © 2018. Published by Elsevier B.V.)

Piezoelectric inkjet printing onto orodispersible films (ODFs) was proven to be a successful technique applying flexible doses of active pharmaceutical ingredients (APIs) onto edible substrates. The reported API printing and ODF production was conducted in a non-continuous production approach. Within this study, drug-free and hydrochlorothiazide (HCT) containing ODFs should be imprinted in-line with enalapril maleate (EM) ink during continuous ODF production. Macrogol inks based on various solvents and solvent-water mixtures were developed providing dynamic viscosities from 7 to 17 mPa*s. Water based inks contained 1.25%, methanol based inks up to 10% EM. Both inks could be printed (500-1000 Hz) during continuous ODF production. No EM recrystallization was observed for water-based inks. Mechanical properties were not affected by drug printing using various firing frequencies. ODF imprinted with water-based EM inks contained 0.04 mg EM/6 cm 2 . EM amount can be increased to a paediatric therapeutic dose of 0.5 mg EM utilizing methanol-based inks. These inks were successfully printed onto HCT ODFs resulting in a therapeutically relevant fixed-dose combination. No EM migration into the HCT layer could be observed. In conclusion, it was feasible to print EM doses onto drug-free and HCT ODFs during an in-line continuous manufacturing process., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Various drug therapies require more than one active pharmaceutical ingredient (API) for an effective treatment. There are many advantages, e.g. to improve the compliance or pharmacodynamic response in comparison to a monotherapy or to increase the therapy safety. Until now, there are only a few products available for the paediatric population due to the lack of age appropriate dosage forms or studies proving the efficacy and safety of these products. This study aims to develop orodispersible films (ODFs) in a continuous solvent casting process as child appropriate dosage form containing both enalapril maleate (EM) and hydrochlorothiazide (HCT) separated in different film layers. Furthermore, they should be characterised and the API migration analysed by confocal Raman microscopy (CRM). ODFs were successfully produced in a continuous manufacturing process in form of double- and triple-layer formulations based on hydroxypropylcellulose (HPC) or a combination of HPC and polyvinyl alcohol (PVA). CRM revealed that both APIs migrate within the film layers shortly after manufacturing. PVA inhibits the migration inside the double-layer film, but is not able to prevent the API migration as an interlayer inside a triple-layer ODF. With increasing film layers, the content of residual solvents and the disintegration time increases (mono-layer films: <10 s, triple-layer films: 37 s). In conclusion, it was feasible to produce fixed-dose combinations in therapeutic doses up to 9 mg HCT and 3.5 mg EM for the double-layer film with adequate mechanical properties, which enable coiling up onto jumbo rolls directly after production. The best separation of the two APIs was achieved by casting a double-layer ODF consisting of different film forming polymers, which can be beneficial when processing two incompatible APIs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The official method for the determination of Enalapril Maleate and its related substances in European Pharmacopoeia (EP) is a gradient liquid chromatographic method. The method used styrene-divinylbenzene copolymer column, mobile phase buffer pH 6.8 and column oven temperature 70°C. In this method, the separation between main component Enalapril and Ph. Eur. Imp-A was not completed hence the achieving system suitability requirement is a tough task and it requires quite often adjustment in chromatographic parameters. Moreover, column oven temperature 70°C is not user friendly to HPLC instruments and users. In this study, several changes were introduced to the method in order to improve the separation, peak shapes and to overcome the column oven temperature. A new user-friendly stability-indicating RP-HPLC method was developed for Enalapril related substances analysis. The developed method uses a ZORBAX Eclipse XDB-C18 column with column oven temperature at 55°C and mobile phase containing acetonitrile and a phosphate buffer at pH 3.0. The method is capable of separating all the known impurities with resolution more than 3.5, which is much better than that obtained with the existing monograph methods. The optimized method was validated and demonstrated to have acceptable specificity, sensitivity, linearity, accuracy, precision, robustness, solution stability and equivalency to the EP method. The developed method proved to be applicable to a wide number of C18 reversed-phase columns. In addition, the Enalapril assay method also presented with 20 min run time., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Hypertension is one of the leading causes of morbidity and mortality in Ethiopia. Treatment usually involves lifelong medication use. Enalapril is a common drug for the treatment of hypertension in Ethiopia. However, the drug is expensive and, therefore, there is limited capacity for people to afford the treatment. Locally produced Enalapril is a cost-effective solution to treat the disease. However, as local medicines regulation does not include bioequivalence tests on locally produced drugs, physicians and patients need assurance about the effectiveness and safety of local generics. Evidence on therapeutic equivalence is needed on these untested local drugs., Methods: This is a hospital-based, randomized, partially blinded, three-cycle crossover trial in single patients, comparing a locally produced version of enalapril with enalapril imported from Europe. Patients involved in this trial are not blinded, as there is no local facility to produce relatively small numbers of placebos or encapsulated drugs. To ensure blinding of study investigators and data analysts, study medications are prepared by an independent pharmacy unit using opaque medication packaging. The importance of maintaining blinding is also part of patient pre-trial education. Each N-of-1 trial will consist of three successive 14-day treatment pairs, each pair comprising 7 days of 5-20 mg local and 7 days of 5-20 mg imported enalapril taken once daily in the morning. The primary outcome will be the average difference in systolic blood pressure as measured by home blood pressure measurements., Discussion: The number of locally produced products, such as enalapril, being approved without proof of bioequivalence is dramatically increasing. By bridging the information gap on bioequivalence, the trial will give rigorous evidence on therapeutic equivalence of locally produced enalapril in the treatment of hypertension. If there is no difference, the hypothesized result, then patients can take the local medicine with confidence. This trial will also will determine whether aggregated N-of-1 studies are feasible to evaluate untested generic drugs in resource-limited countries where bioequivalence testing centers are unavailable., Trial Registration Number: Australian and New Zealand Clinical Trial Registry, ID: ACTRN12616001088437p . Registered on 12 August 2016.

The addition of enalapril maleate to a casting solution for orodispersible films (ODFs) containing hypromellose and carbomer 974P as film forming agents (standard casting solution, SCS) caused a dose dependent reduction of the viscosity. This phenomenon was a serious problem in the preparation of ODFs with an increased enalapril load (>1mg per ODF) when using the solvent casting method. The aim of the present work was twofold. Firstly, the influence of enalapril on the viscosity of SCS was studied in more detail. Secondly, two methods for increasing the enalapril load of an ODF were investigated that did not negatively influence the properties of SCS. The casting height was increased and the preparation of bilayered ODF, using the double-casting method, was explored. In the framework of the bilayered ODFs the compatibility between the film forming agents hydroxypropyl cellulose (HPC), sodium alginate (SA), hydroxyethyl cellulose (HEC) and the combination hypromellose-carbomer 974P (SCS) was investigated., Results and Conclusions: We found that enalapril concentration dependently reduced the pH, thereby negatively influencing the gel formation and the viscosity of SCS. An increased casting height did not result in a proportionally increased enalapril load. The enalapril load could be doubled when a bilayered ODF containing two layers of SCS was produced. Finally, not all combinations of film forming agents could be used for the preparation of bilayered ODFs. Besides, the sequence in which the different polymer layers were casted affected the appearance of the ODFs. In conclusion, the best formulations were produced with the polymer combinations SCS/SCS and SCS/HPC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the marketing authorization of immediate-release, solid oral dosage forms containing enalapril maleate are reviewed. Enalapril, a prodrug, is hydrolyzed by carboxylesterases to the active angiotensin-converting enzyme inhibitor enalaprilat. Enalapril as the maleate salt is shown to be highly soluble, but only 60%-70% of an orally administered dose of enalapril is absorbed from the gastrointestinal tract into the enterocytes. Consequently, enalapril maleate is a Biopharmaceutics Classification System class III substance. Because in situ conversion of the maleate salt to the sodium salt is sometimes used in production of the finished drug product, not every enalapril maleate-labeled finished product actually contains the maleate salt. Enalapril is not considered to have a narrow therapeutic index. With this background, a biowaiver-based approval procedure for new generic products or after major revisions to existing products is deemed acceptable, provided the in vitro dissolution of both test and reference preparation is very rapid (at least 85% within 15 min at pH 1.2, 4.5, and 6.8). Additionally, the test and reference product must contain the identical active drug ingredient., (Copyright © 2017 American Pharmacists Association®. All rights reserved.)

The binding interaction between bovine serum albumin (BSA) and enalapril (ENPL) at the imitated physiological conditions (pH = 7.4) was investigated using UV-vis absorption spectroscopy (UV-vis), fluorescence emission spectroscopy (FES), synchronous fluorescence spectroscopy (SFS), Fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD) and molecular docking methods. It can be deduced from the experimental results from the steady-state fluorescence spectroscopic titration that the intrinsic BSA fluorescence quenching mechanism induced by ENPL is static quenching, based on the decrease in the BSA quenching constants in the presence of ENPL with increase in temperature and BSA quenching rates >10 10  L mol -1  sec -1 . This result indicates that the ENPL-BSA complex is formed through an intermolecular interaction of ENPL with BSA. The main bonding forces for interaction of BSA and ENPL are van der Waal's forces and hydrogen bonding interaction based on negative values of Gibbs free energy change (ΔG 0 ), enthalpic change (ΔH 0 ) and entropic change (ΔS 0 ). The binding of ENPL with BSA is an enthalpy-driven process due to |ΔH°| > |TΔS°| in the binding process. The results of competitive binding experiments and molecular docking confirm that ENPL binds in BSA sub-domain IIA (site I) and results in a slight change in BSA conformation, but BSA still retains its α-helical secondary structure., (Copyright © 2016 John Wiley & Sons, Ltd.)

This work aimed at developing enalapril maleate granules in order to improve its stability in solid dosage form. Granules were prepared by hot melt granulation using a fluidized bed apparatus. Gelucire 50/13®, polyethylene glycol 6000 e Poloxamer 407® were studied and compared as binders in 2 × 2 factorial designs where the proportions of enalapril maleate, binders and spray dried lactose were varied. The granulation process resulted in high yields and granule sizes that indicated the prevalence of particles coating. Furthermore, the granules obtained showed adequate flowability and a fast dissolution rate of enalapril maleate with almost 100% of the drug released in 10 min. The stability of enalapril maleate in hard gelatin capsules showed that the drug stability was greatly increased in granules, since for raw drug, the remaining content of enalapril maleate after 91 days was 68.4% and, for granules, the content was always above 93%. This result was confirmed by the quantification of the degradation products, enalaprilat and diketopiperazine, which were found in very low content in granules samples. The results demonstrate that fluidized bed hot melt granulation with hydrophilic binders is a suitable alternative for improving the chemical stability of enalapril maleate.

With a great quantity of solid dosage tested by dissolution technology, developing a rapid and sensitive method to access the content of drug within dissolution media is highly desired by analysts and scientists. Traditionally, dissolution media is not compatible with mass spectrometry since the inorganic salts in the media might damage the mass spectrometer. Here, paper spray ionization mass spectrometry (PSI-MS), one of the ambient mass spectrometry technologies, is developed to characterize the content of drugs in dissolution media. The porous structure of paper can effectively retain salts from entering mass spectrometer. This makes the measurement of drug content within dissolution media by mass spectrometer possible. After the experimental parameters were optimized, calibration curves of model drugs - enalapril, quinapril and benazepril were established by using corresponding deuterated internal standards. PSI-MS was then deployed to characterize the content of enalapril from the dissolution testing of enalapril tablets. The results from PSI-MS are comparable to those from HPLC characterization. More importantly, the analysis time of 6 samples is shortened from 90min to 6min. Detection limit of enalapril maleate tablets by PSI-MS is 1/300 of LC. PSI-MS is rapid, sensitive and accurate in analyzing drug content from dissolution tests., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Three multivariate calibration spectrophotometric methods were developed for simultaneous estimation of Paracetamol (PARA), Enalapril maleate (ENM) and Hydrochlorothiazide (HCTZ) in tablet dosage form; namely multi-linear regression calibration (MLRC), trilinear regression calibration method (TLRC) and classical least square (CLS) method. The selectivity of the proposed methods were studied by analyzing the laboratory prepared ternary mixture and successfully applied in their combined dosage form. The proposed methods were validated as per ICH guidelines and good accuracy; precision and specificity were confirmed within the concentration range of 5-35μgmL -1 , 5-40μgmL -1 and 5-40μgmL -1 of PARA, HCTZ and ENM, respectively. The results were statistically compared with reported HPLC method. Thus, the proposed methods can be effectively useful for the routine quality control analysis of these drugs in commercial tablet dosage form., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Angiotensin converting enzyme (ACE) presents an important role in blood pressure regulation, since that converts angiotensin I to the vasoconstrictor angiotensin II. Some commercially available ACE inhibitors are captopril, lisinopril and enalapril; due to their side effects, naturally occurring inhibitors have been prospected. In order to endorse this research field we have developed a new tool for ACE ligand screening. To this end, ACE was extracted from bovine lung, purified and chemically immobilized in modified ferrite magnetic beads (ACE-MBs). The ACE-MBs have shown a Michaelian kinetic behavior towards hippuryl-histidyl-leucine. Moreover, as proof of concept, the ACE-MBs was inhibited by lisinopril with a half maximal inhibitory concentration (IC 50 ) of 10nM. At the fishing assay, ACE-MBs were able not only to fish out the reference inhibitor, but also one peptide from a pool of tryptic digested BSA. In conclusion, ACE-MBs emerge as new straightforward tool for ACE kinetics determination, inhibition and binder screening., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The isomerizations of Enalapril, Perindopril, Enalaprilat and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and DFT theoretical calculations. The thermodynamic parameters (ΔH, ΔS and ΔG) were determined by varying the temperature in the NMR experiments. At the coalescence temperature, we can evaluate the isomerization barrier to the rotation (ΔG(≠)) around the amide bond. Using dynamics chromatography and an unified equation introduced by Trap, we can determine isomerization rate constants and Gibbs activation energies. Molecular mechanics calculations also provided evidence for the presence of low energy conformers for the ACE due to restricted amide rotation. With the value of barriers (ΔE) between them of the order of (20kJmol(-1)), which is in agreement with the dynamic NMR results and DFT calculations., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The present study aimed at developing the sustained release matrix tablets of enalapril maleate and evaluating the effect of polymer concentration and viscosity grade on drug release. The sustained release enalapril maleate tablets were successfully formulated by direct compression method using nonionic cellulose ethers HPMC K15, HPMC K100 and HPC polymers either alone or in combination. In-vitio drug release study was carried out in phosphate buffer (pH 6.8) for a period of 24 h following USP dissolution apparatus II i.e., paddle apparatus. Model dependent approaches like zero-order, first order, Higuchi's model and Korsmeyer-Peppas model were used to assess drug release from various formulations. All the three polymers alone or in combination sustained the drug release. The drug release characteristics from HPMC and HPC polymer followed zero order release kinetics except for 45% concentration of all polymers alone or in combination where by the drug release followed Higuchi's model. In all cases, the drug release mechanism was both diffusion as well as erosion.

To evaluate the influence of different variables on tablet formulations containing enalapril maleate and indapamide as active substances, two separate experimental designs were employed: one for evaluating powder properties and the other for tablet characteristics. Because of the low active pharmaceutical ingredient content, it was hypothesized that both powder and tablet properties could be determined only by the characteristics of excipients. In order to test this assumption, both experimental designs were done with placebo mixtures. The optimized formulation was then evaluated both with and without APIs. Results indicated that filler and lubricant percentage, along with compression force, were the most important variables during the formulation study. The optimized formulation showed similar characteristics in both cases for all responses, except for angle of repose and friability where only minor differences were observed. The combination of the applied approaches (using placebo composition and fractional experimental design) proved to be efficient, cost effective and time saving.

Heart failure is a global problem with elevated prevalence, and it is associated with substantial cardiovascular morbidity and mortality. Treating heart-failure patients has been a very challenging task. This review highlights the main pharmacological developments in the field of heart failure with reduced ejection fraction, giving emphasis to a drug that has a dual-acting inhibition of the neprilysin and renin-angiotensin-aldosterone system. Neprilysin is an enzyme that participates in the breakdown of biologically active natriuretic peptides and several other vasoactive compounds. The inhibition of neprilysin has been a therapeutic target for several drugs tested in cardiovascular disease, mainly for heart failure and/or hypertension. However, side effects and a lack of efficacy led to discontinuation of their development. LCZ696 is a first-in-class neprilysin- and angiotensin-receptor inhibitor that has been developed for use in heart failure. This drug is composed of two molecular moieties in a single crystalline complex: a neprilysin-inhibitor prodrug (sacubitril) and the angiotensin-receptor blocker (valsartan). The PARADIGM-HF trial demonstrated that this drug was superior to an angiotensin-converting enzyme inhibitor (enalapril) in reducing mortality in patients with heart failure with reduced ejection fraction. The ability to block the angiotensin receptor and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

The objective of this study was to evaluate the stability of 10 commonly used active pharmaceutical ingredients compounded in oral suspensions using SyrSpend SF PH4 (atenolol 1.0 and 5.0 mg/mL, clonazepam 0.2 mg/mL, dexamethasone 1.0 mg/mL, diclofenac sodium 5.0 mg/mL, diltiazem 12.0 mg/mL, enalapril maleate 1.0 mg/mL, ketoprofen 20.0 mg/mL, lamotrigine 1.0 mg/mL, penicillamine-D 50.0 mg/mL, thiamine 100 mg/m) and stored both at controlled refrigerated (2°C to 8°C) and room temperature (20°C to 25°C). Stability was assessed by means of measuring percent recovery at varying time points throughout a 90-day period. The quantification of the active pharmaceutical ingredients was performed by a stability-indicating, high-performance liquid chromatographic method. The beyond-use date of the products was found to be at least 90 days for all suspensions (except atenolol 1 mg/mL, which was stable up to 60 days), both for controlled refrigerated temperature and room temperature. This confirms that SyrSpend SF PH4 is a stable suspending vehicle for compounding with a broad range of different active pharmaceutical ingredients.

The current therapeutic strategies are based on the design of multifunctional drug candidates able to interact with various disease related targets. Drugs that have the ability to scavenge reactive oxygen species (ROS), beyond their main therapeutic action, may prevent the oxidative damage of biomolecules. Therefore, analytical approaches that monitor in a continuous mode the ability of drugs to counteract peroxidation of physiologically relevant biotargets are required. In the present work, a microplate spectrophotometric assay is proposed to evaluate the ability of selected cardiovascular drugs, including angiotensin-converting enzyme (ACE) inhibitors, β -blockers and statins to prevent protein peroxidation. Myoglobin, which is a heme protein, and peroxyl radicals generated from thermolysis of 2,2'-azo-bis(2-amidinopropane) dihydrochloride at 37 °C, pH 7.4 were selected as protein model and oxidative species, respectively. Myoglobin peroxidation was continuously monitored by the absorbance decrease at 409 nm and the ability of drugs to counteract protein oxidation was determined by the calculation of the area under the curve upon the myoglobin oxidation. Fluvastatin (AUC₅₀=12.5 ± 1.2 μM) and enalapril (AUC₅₀=15.2 ± 1.8 μM) showed high ability to prevent myoglobin peroxidation, providing even better efficiency than endogenous antioxidants such as reduced glutathione. Moreover, labetalol, enalapril and fluvastatin prevent the autoxidation of myoglobin, while glutathione showed a pro-oxidant effect., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A series of novel 2-butyl-4-chloro-1-methylimidazole derived peptidomimetics were designed, synthesized and evaluated for their Angiotensin Converting Enzyme (ACE) inhibitor activity. 2-Butyl-4-chloro-1-methylimidazole-5-carboxylic acid 2 obtained after oxidation of respective carboxaldehyde 1, was condensed with various amino acid methyl esters 3a-k to give imidazole-amino acid conjugates 4a-k in very good yields. Ester hydrolysis of 4a-k with aqueous LiOH gave the desired peptidomimetics 5a-k. Screening all the new compounds 4a-k and 5a-k using ACE inhibition assay, resulted five compounds 4i, 4k, 5e, 5h and 5i as potent ACE inhibitors with IC50 of 0.647, 0.531, 1.12, 0.657 and 0.100μM with minimal toxicity. Among them, 5i emerged as most active ACE inhibitor with greater potency than marketed drugs Lisinopril, Ramipril and relatively equipotent to Benazepril, Quinapril and Enalapril., (Copyright © 2015. Published by Elsevier Ltd.)

The prevalence of hypertension among children has been increasing. Community and Hospital Pharmacists are often challenged to provide an oral liquid extemporaneous formulation for pediatric patients, because there are no appropriate dosage drugs to the specific needs of the child. The objective of this study is to choose and develop suitable pediatric extemporaneous formulations for captopril and enalapril maleate and to determine their physicochemical stability. A survey was carried out to evaluate the extent of dispensation of these drugs in Hospitals in Spain. Stability studies of formulations have been studied according to ICH normative at 5, 25 and 40 °C. Three samples from each temperature were withdrawn and assessed for stability on days 0, 15, 30, 50 and 90 using a high-performance liquid chromatography (HPLC) mass spectrometer assay. Rheological studies were carried out to ensure the maintenance of the physical characteristics of these non-Newtonian fluids. Captopril and enalapril maleate formulations used the pure drug and were stable during 50 days at 5 °C. We have developed easy antihypertensive oral liquid extemporaneous formulations for pediatric patients with physical and chemical stability higher than those provided by the majority of Hospitals.

Orodispersible films (ODFs) are promising drug delivery systems for customized small scale pharmacy preparations. The aim of the present study was to develop a versatile casting solution suitable for the extemporaneous production of ODFs to which active pharmaceutical ingredients (APIs) can be added. Different combinations of film forming agents and other excipients and different casting heights were tested for their suitability for production of ODFs. The best suitable casting solution contained hypromellose, carbomer, glycerol, disodium EDTA and trometamol. This casting solution was used to prepare ODFs containing water-soluble APIs (enalapril maleate and prednisolone disodium phosphate) and a poorly water-soluble API (diazepam) for which ethanol 96% was used as co-solvent.The water-soluble APIs as well as ethanol influenced the viscosity of the casting solution, mechanical properties and disintegration time of the ODFs. All ODFs containing API met the requirements on uniformity of mass and uniformity of content set by the European Pharmacopoeia (2014) (Ph. Eur.) 8th edition. In conclusion, ODFs of good pharmaceutical quality can be prepared on small scale. Hereby opening the perspective of using ODFs for individualized pharmacotherapy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aqueous nanoparticulated eye drop formulations based on γ-cyclodextrin (γCD) complexes were developed and tested in vitro. Three antihypertensive drugs, i.e. enalapril maleate, irbesartan and verapamil HCl, that have been shown to possess IOP-lowering activity were selected for this study. All three drugs displayed Bs-type phase-solubility diagrams in aqueous γCD solutions and had relatively low affinity for γCD. Irbesartan was selected for further formulation development. The drug was relatively stable at pH 4.5 but somewhat less stable at physiologic pH. However, presence of γCD in the aqueous media enhanced the chemical stability of irbesartan. Aqueous γCD-based eye drop formulations containing 1% and 2% (w/v) irbesartan were prepared and the effect of pH on the particles size distribution and drug release investigated. Only ∼2% of the drug was in solution in the pH 4.5 formulations but up to 45% in the pH 7 formulations. The pH 7 formulations, where larger fraction of the drug was in solution, displayed somewhat greater drug permeation flux but much lower drug permeation coefficients than the pH 4.5 formulations. Dynamic light scattering studies indicated the faster permeation was due to formation of smaller particles in presence tyloxapol.

In the present study, we investigated the effect of methionine-enriched diet (MED) on blood pressure in rats and examined the protective effect of enalapril, a widely used angiotensin converting enzyme inhibitors (ACEi) class antihypertensive drug. The results showed that MED induced significant increase of SBP and Ang II-induced contractile response in aortae of rats. MED significantly increased plasma levels of homocysteine (Hcy) and ACE. In addition, MED increased the phosphorylation of protein kinase R-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2 (eIF2α) and expression of activating transcription factor 3 (ATF3) and ATF6 in aortae of rats, indicating the occurrence of endoplasmic reticulum (ER) stress. Moreover, MED resulted in oxidative stress as evidenced by significant increase of TBARS level and decrease of superoxide dismutase and catalase activities. Administration of enalapril could effectively inhibit these pathological changes induced by MED in rats. These results demonstrated that ACE-mediated ER stress and oxidative stress played an important role in high Hcy-induced hypertension and MED may exert a positive loop between the activation of ACE and accumulation of Hcy, aggravating the pathological condition of hypertension. The data provide novel insights into the mechanism of high Hcy-associated hypertension and the therapeutic efficiency of enalapril.

The benefit-risk ratio of combined blocking by the direct renin inhibitor aliskiren and an angiotensin-converting enzyme inhibitor (e.g. enalapril) on the renin-angiotensin-aldosterone system is discussed. No method was available for simultaneous determination of both drugs in urine. A novel sensitive method for simultaneous quantification in undiluted human urine was developed which enables systematic pharmacokinetic investigations, especially in poorly investigated populations like children. Matrix effects were clearly reduced by applying solid-phase extraction followed by a chromatographic separation on Xselect(TM) C18 CSH columns. Mobile phase consisted of methanol and water, both acidified with formic acid. Under gradient conditions and a flow rate of 0.4 mL/min the column effluent was monitored by tandem mass spectrometry with electrospray ionization. Calibration curves were constructed in the range of 9.4-9600 ng/mL regarding aliskiren, 11.6-12000 ng/mL for enalapril and 8.8-9000 ng/mL for enalaprilat. All curves were analyzed utilizing 1/x(2) -weighted quadratic squared regression. Intra-run and inter-run precision were 3.2-5.8% and 6.1-10.3% for aliskiren, 2.4-6.1% and 3.9-7.9% for enalapril as well as 3.1-9.4% and 4.7-12.7% regarding enalaprilat. Selectivity, accuracy and stability results comply with current international bioanalysis guidelines. The fully validated method was successfully applied to a pharmacokinetic investigation in healthy volunteers., (Copyright © 2014 John Wiley & Sons, Ltd.)

Treating children with compounded liquid formulations of tablets intended for adults, where quality-control and compliance issues exist, was previously the only antihypertensive therapy option. A 1-mg/mL oral solution of enalapril maleate (enalapril), Epaned™, recently approved by the Food and Drug Administration (FDA), is the first angiotensin-converting enzyme inhibitor treatment for pediatric hypertension. The pharmacokinetic comparability of enalapril oral solution to the reference listed drug (RLD) tablet was assessed under fasted conditions. The effect of food on the bioavailability of enalapril oral solution was also assessed. Plasma levels of enalapril and the active metabolite, enalaprilat, were measured postdose using validated liquid chromatography-tandem mass spectroscopy methods. The ratio of enalapril oral solution to the RLD tablet was assessed. The 90% confidence intervals for the geometric mean ratios of Cmax , AUClast , and AUCinf for plasma levels of enalapril and enalaprilat were bioequivalent (within the FDA-accepted range of 80-125%). A commercially available oral solution of enalapril is bioequivalent to tablet formulations and can expand therapeutic options for pediatric patients. Administering enalapril oral solution with a high-fat meal decreased Cmax of plasma concentrations of enalapril and Cmax , AUClast , and AUCinf of plasma concentrations of enalaprilat compared to enalapril oral solution under fasting conditions., (© 2014, The American College of Clinical Pharmacology.)

The low bioavailability of enalapril maleate associated to its instability in solid state motivated the development of a polyelectrolyte-drug complex between enalapril maleate and the cationic polymethacrylate Eudragit E100. The solid complexes were characterized by DSC-TG, FT-IR and X-ray diffraction. Their aqueous dispersions were evaluated for drug delivery in bicompartimental Franz cells and electrokinetic potentials. Stability in solid state was also evaluated using an HPLC-UV stability indicating method. Absorption of enalapril maleate was assessed thorough the rat everted gut sac model. In addition, urinary recovery after oral administration in rats was used as an indicator of systemic exposition. The solid materials are stable amorphous solids in which both moieties of enalapril maleate are ionically bonded to the polymer. Their aqueous dispersions exhibited controlled release over more than 7h in physiologic saline solution, being ionic exchange the fundamental mechanism that modified the extent and rate of drug release. Intestinal permeation of enalapril maleate was 1.7 times higher in the presence of the cationic polymer. This increase can be related with the capacity to adhere the mucosa due to the positive zeta potential of the complexes. As a consequence bioavailability was significantly improved (1.39 times) after oral administration of the complexes. In addition, no signs of chemical decomposition were observed after a 14months period. The results indicated that the products are new chemical entities that improve unfavorable properties of a useful drug., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Enalapril maleate (EM) is unstable in poorly designed tablet formulations. To improve the stability of EM, the degradation mechanism should be elucidated. In this study, we found that several commonly used excipients promoted the degradants of EM, particularly a diketopiperazine derivative (DKP). We propose two degradation pathways in which both acid and alkali can promote the formation of DKP, although previous reports suggested that DKP is produced mainly in acidic media. Based on the degradation pathways, we believe that subtle control of the microenvironmental pH can inhibit the formation of DKP. This was confirmed by the observation that the degradation rate became slower when certain organic acids were added to the binary mixtures of EM and excipient. The data showed that the stability of EM in the ternary mixtures was much higher than that in binary mixtures. It was further proved that tablets containing these organic acids produced less DKP after the accelerated test. We also found that the formation of DKP in tablets varied with different ratios of tartaric acid, which was used as a model organic acid. This illustrated that an optimum ratio of tartaric acid is required. These results indicated that the stability of EM in tablet formulation is closely associated with microenvironmental pH and the addition of a suitable organic acid based on the reaction mechanism is an effective strategy for improving the stability of EM.

Multilayer-coating technology is the traditional method to achieve pulsatile drug release with the drawbacks of time consuming, more materials demanding and lack of efficiency. The purpose of this study was to design a novel pulsatile drug delivery system based on the physiochemical interaction between acrylic copolymer and organic acid with relatively simpler formulation and manufacturing process. The Enalapril Maleate (EM) pulsatile release pellets were prepared using extruding granulation, spheronization and fluid-bed coating technology. The ion-exchange experiment, hydration study and determination of glass transition temperature were conducted to explore the related drug release mechanism. Bioavailability experiment was carried out by administering the pulsatile release pellets to rats compared with marketed rapid release tablets Yisu. An obvious 4h lag time period and rapid drug release was observed from in vitro dissolution profiles. The release mechanism was a combination of both disassociated and undisassociated forms of succinic acid physiochemically interacting with Eudragit RS. The AUC0-τ of the EM pulsatile pellets and the market tablets was 702.384 ± 96.89 1 hn g/mL and 810.817 ± 67.712 h ng/mL, while the relative bioavailability was 86.62%. These studies demonstrate this novel pulsatile release concept may be a promising strategy for oral pulsatile delivery system., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Enalapril maleate (EM) is a widely used anti-hypertensive drug which is unstable when mixed with excipients. Enalaprilate and diketopiperazine (DPK) are the main degradation products of enalapril. The in situ preparation of enalapril sodium salt (NaE) has been used to improve drug stability in dosage forms; however, gas release and product rejection ensue when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. This study evaluated the effect of stearic acid (SA) on enalapril stability in microcrystalline cellulose (MCC) pellets containing EM or NaE. MCC pellets containing SA were prepared by the extrusion-spheronization technique and characterized. Enalapril stability and dissolution were then evaluated. DPK and enalaprilate formation were reduced by the addition of SA in pellets containing EM. The overall enalapril degradation in these formulations was lower when compared with pellets containing EM or even NaE prepared without SA. The immediate-release characteristic was maintained by the addition of 5% crospovidone to all the formulations tested. The incorporation of SA into NaE pellets resulted in unexpected enalapril degradation, caused by the interaction of these compounds, as suggested by a thermal analysis of the SA-NaE binary mixture. The findings presented here showed that formulations containing SA could substitute the formation of NaE, since they provide better enalapril stability in solid dosage forms. In addition, it is suggested that the stabilization effects would be observed for other N-carboxyalkyl dipeptide analogs with angiotensin converting enzyme inhibition activity, since these new entities share the same degradation pathway of enalapril.

Green bioanalytical approaches are oriented toward minimization or elimination of hazardous chemicals associated to bioanalytical applications. LC/MS-MS assay of enalapril and enalaprilat in human plasma was achieved by elimination of acetonitrile from both sample preparation and chromatographic separation stages. Protein precipitation (PP) by acetonitrile addition was replaced by liquid-liquid extraction (LLE) in 1-octanol followed by direct large volume injection of the organic layer in the chromatographic column operated under reversed phase (RP) separation mechanism. At the mean time, acetonitrile used as organic modifier in the mobile phase was successfully replaced by a mixture of propylene carbonate/ethanol (7/3, v/v). Three analytical alternatives ((I) acetonitrile PP+acetonitrile based chromatographic elution; (II) 1-octanol LLE+acetonitrile based chromatographic elution; (III) 1-octanol LLE+propylene carbonate/ethanol based chromatographic elution) were validated and the quality characteristics were compared. Comparison between these alternative analytical approaches was also based on results obtained on incurred samples taken during a bioequivalence study, through application of the Bland-Altman procedure., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Influence of some commercially available types of microcrystalline cellulose (MCC) on the stability of certain active pharmaceutical ingredients (APIs), when in contact, has been investigated. Two structurally similar APIs, perindopril erbumine (PER) and enalapril maleate (EM), both well-known angiotensin-converting enzyme inhibitors were used. The main properties of an MCC that could determine the stability for each API were measured and correlated to the stability of these two APIs in binary mixtures. The stability of these APIs differed when in contact with different types of MCC. The dominant properties of MCC from one manufacturer were surface features that influenced the stability of PER and acidity that influenced the stability of EM. In the case of MCC from other manufacturers, unbound water was stability determining for both substances.

Unlabelled: Enalapril is an angiotensin-converting enzyme inhibitor widely used in the treatment of hypertension and heart failure., Aim: To design and validate a simple and sensitive spectrophotometric method. This method is based on a ternary complex formation between enalapril, copper (II), and bromothymol blue, in a slightly alkaline environment, complex that is extractable in chloroform, with an absorption maximum at 426 nm., Materials and Methods: To a volume of 1 milliliter of standard enalapril drug solution in concentration range 200/500 microg/ml, two milliliters of Cu (II) chloride solution 0.2 % followed by 2 ml bromothymol blue solution 0.01% and 0.5 ml of pH 8 buffer solution (Britton-Robinson) were added. The complex was two times extracted with 2 x 1.5 ml chloroform. Ten minutes after extraction, absorbance was measured at 426 nm against blank., Results: Our spectrophotometric method was validated by determining linearity, limit of detection and quantification, system and method precision, and method accuracy. The method showed a good linearity in the range 200/500 microg/ml (correlation coefficient r = 0.9993). Limit of detection (LD) was 9.907 microg/ml and limit of quantification (LQ) 33.024 microg/ml. Precision showed an RSD = 1.83%, and accuracy with mean recovery is 102.6% in the range 98.8/103.9., Conclusions: The ternary complex formed under the above-mentioned condition and measured spectrophotometrically can be regarded as an ion-association complex between the metal-drug cation and bromothymol blue anion. The experimental results demonstrated a good sensitivity.

The angiotensin converting enzyme-inhibitor enalapril is the prodrug of enalaprilat and used in the treatment pediatric hypertension and chronic heart failure. Pharmacokinetic data are lacking to provide adequate dosing and for pediatric pharmacotherapeutical trials it is imperative to minimize sample volume. Therefore an HPLC-tandem mass spectrometry (MS) method for the determination of enalapril and enalaprilat in 100 μL of human serum was developed and validated with benazepril as internal standard (IS). After solid-phase extraction, chromatography was performed on a Luna(®) RP-C(18) (2) column with methanol-water-formic acid (65:35:1, v/v/v) as mobile phase and a flow rate of 0.4 mL/min. The MS was set to positive-mode electrospray ionization and multiple reaction monitoring, analyzing the m/z transitions channels 377.3 → 234.2, 349.3 → 206.1 and 425.3 → 351.2 for enalapril, enalaprilat and IS. Calibration curves were linear in the range of 1.61-206 ng/mL (enalapril) and 1.84-236 ng/mL (enalaprilat) with coefficients of determination >0.99. Relative standard deviations of intra- and inter-run precisions were below 7% and relative errors were below 6 ± 7% for both analytes. Also stabilities were acceptable for both analytes. As an application example, concentrations of enalapril and enalaprilat in serum after oral administration of 20 mg enalapril maleat in a healthy volunteer were determined., (Copyright © 2011 John Wiley & Sons, Ltd.)

The aim of this study was to determine the stability of three ester prodrugs, chloramphenicol succinate, enalapril and candesartan cilexetil, in human proximal small intestinal fluid (HIF), dog proximal small intestinal fluids (DIF) and simulated intestinal fluid (FaSSIF), with the addition of pancreatin. The total protein content in the proximal jejunal fluids was determined in HIF and DIF, respectively. Candesartan cilexetil was significantly degraded in HIF (initial t(1/2(0-5 min))=5.4 ± 0.5 min) and in DIF (initial t(1/2(0-5 min))=5.7 ± 0.1 min), while chloramphenicol succinate and enalapril were stable in both media. The degradation of candesartan cilexetil was shown to be mediated by enzymes following Michaelis-Menten enzyme kinetics and was inhibited by addition of esterase inhibitors. The enzymatic capacity reflected by V(max) was 4-fold higher in DIF than in HIF and correlated to its 2-fold higher protein concentration. The degradation of candesartan cilexetil in the FaSSIF-pancreatin solution was slower (t(1/2)=207 ± 34 min) than the degradation in both HIF and DIF. Changing the pH to the enzyme optima or increasing the amount of pancreatin, increased the degradation rate of candesartan cilexetil, but not in the magnitude as in HIF. As a result, two in vitro models, based on in vivo intestinal fluids, were developed using candesartan cilexetil as a model drug. The DIF seems to be a reasonably good model for HIF, although the degradation capacity seems to be somewhat higher, possibly due to the higher enzyme concentration in DIF. Future investigations will develop novel enzymatic based in vitro models for rapid assessment and biopharmaceutical screening tools for prodrugs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: In the production of enalapril maleate tablets, the granulation process is the most crucial step. Numerous variables are known to influence the fluid bed granulation process and thus the final granule quality. In this study a novel descriptor for the nozzle parameter "air-to-liquid mass ratio" is presented. Granules manufacturing processes were designed by application of statistical experimental design., Aim: The influence of the critical process parameter (CPP)--air-to-liquid mass ratio--on pharmaceutic properties of granules was studied. Air-to-liquid mass ratio can be considered as important variable influencing the droplet size of atomized liquid binder solution., Results/conclusion: A significant influence of air-to-liquid mass ratio on granule final particle size distribution was found. Increasing air-to-liquid mass ratio resulted in increased granules particle size distribution. Decreasing air-to-liquid mass ratio led to granules with reduced tapped density. Thus, it can be concluded that the parameter "air-to-liquid mass ratio" is a critical process parameter in the production of enalapril maleate granules.

Using enalapril maleate as a test case, the ability of ambient mass spectrometry, namely, via easy ambient sonic-spray ionization mass spectrometry (EASI-MS), to perform direct monitoring of drug degradation has been tested. Two manufacturing processes were investigated (direct compression and wet granulation), and the formation of degradation products was measured via both EASI-MS and high-performance liquid chromatography with ultraviolet detection for a total period of 18 months. Both techniques provide comparable results, which indicate that direct analysis by ambient mass spectrometric techniques presents a viable alternative for drug degradation monitoring with superior simplicity, throughput, and reliability (no sample manipulation), and comparable quantitative results. In terms of qualitative monitoring, the full mass spectra with intact species provided by EASI-MS allow for comprehensive monitoring of known and unknown (or unexpected) degradation products., (Copyright © 2011 John Wiley & Sons, Ltd.)

In this study, the potential of perfusion calorimetry in the characterization of solvates forming isomorphic desolvates was investigated. Perfusion calorimetry was used to expose different hydrates forming isomorphic desolvates (emodepside hydrates II-IV, erythromycin A dihydrate and spirapril hydrochloride monohydrate) to stepwise increasing relative vapour pressures (RVP) of water and methanol, respectively, while measuring thermal activity. Furthermore, the suitability of perfusion calorimetry to distinguish the transformation of a desolvate into an isomorphic solvate from the adsorption of solvent molecules to crystal surfaces as well as from solvate formation that is accompanied by structural rearrangement was investigated. Changes in the samples were confirmed using FT-Raman and FT-IR spectroscopy. Perfusion calorimetry indicates the transformation of a desolvate into an isomorphic solvate by a substantial exothermic, peak-shaped heat flow curve at low RVP which reflects the rapid incorporation of solvent molecules by the desolvate to fill the structural voids in the lattice. In contrast, adsorption of solvent molecules to crystal surfaces is associated with distinctly smaller heat changes whereas solvate formation accompanied by structural changes is characterized by an elongated heat flow. Hence, perfusion calorimetry is a valuable tool in the characterization of solvates forming isomorphic desolvates which represents a new field of application for the method., (Copyright © 2011. Published by Elsevier B.V.)

Traditional methods for the determination of plasma protein binding (PPB), such as equilibrium dialysis and ultrafiltration, normally operate on a timescale ranging from tens of minutes to several hours and are not suitable for measuring compounds that have significant chemical degradation on this timescale. One such compound is enalapril. Although stable in human plasma enalapril is subject to rapid esterase-catalyzed hydrolysis in rat plasma. A method has been developed which allows the extent of rat PPB of enalapril to be determined from initial rates kinetics of the adsorption of the unstable compound to dextran coated charcoal (DCC). The method has been applied to stable compounds, and the results are consistent with those from traditional equilibrium dialysis experiments. The experimental method is simple to run, requires no specialized equipment, and can potentially be applied to other compounds that show instability in plasma where traditional experimental techniques are unsuitable., (Copyright © 2011 Elsevier B.V. All rights reserved.)