Search for Related Substances in Market Products Containing Enalapril Maleate as the Active Principle

This study's main object was the determination of substances, by means of high-performance liquid chromatography (HPLC), that are related to enalapril maleate in medicinal tablets. The research was on products containing a 20 mg active principle with a 12-month Δt and on those batches near their expiration date with an enalapril maleate concentration of 10, 5, and 2.5 mg.     

Effect of Moisture on the Physical and Chemical Stability of Granulations and Tablets of the Angiotensin Converting Enzyme Inhibitor, Enalapril Maleate

Granulations and tablets of enalapril maleate in a lactose matrix were stored in open petri dishes at a range of relative humidities and respective moisture uptakes measured, Extrapolation of the moisture uptake rates measured at the exaggerated humidities yielded a critical humidity, i.e. humidity where the moisture uptake rate is zero and, therefore, least detrimental to the product.

Enalapril maleate was reasonably stable at the storage conditions. The hardness of the tablets decreased at all humidities except when stored with silica-gel. The disintegration times were unaffected except at very high humidities. The dissolution profiles of the tablets remained unchanged.     

Effect of Moisture on the Physical and Chemical Stability of Granulations and Tablets of the Angiotensin Converting Enzyme Inhibitor,Enalapril Maleate

Abstract

Granulations and tablets of enalapril maleate in a lactose matrix were stored in open petri dishes at a range of relative humidities and respective moisture uptakes measured, Extrapolation of the moisture uptake rates measured at the exaggerated humidities yielded a critical humidity, i.e. humidity where the moisture uptake rate is zero and, therefore, least detrimental to the product.

Enalapril maleate was reasonably stable at the storage conditions. The hardness of the tablets decreased at all humidities except when stored with silica-gel. The disintegration times were unaffected except at very high humidities. The dissolution profiles of the tablets remained unchanged.     

Dsc Screening for Drug-Drug Interactions in Poly Pharmaceuticals Intended for the Alleviation of the Symptoms of Colds and Flu. II.

DSC screening for drug-drug interactions of a polypharmaceutical capsule dosage form containing salicylaminde, ascorbic acid, pyrilamine maleate and phenylephrine hydrochloride was performed. The results show the following:

1. Ascorbic acid is incompatible with salicylamide, pyrilamine maleate and pheynylephrine hydrochloride.

2. Salicylamide is incompatible with ascorbic acid, pyrilamine maleate and phenylephrine hydrochloride.

3. Pyrilamine maleate is incompatible with ascorbic acid, salicylamide and phenylephrine hydrochloride.

4. Phenylephrine hydrochloride is incompatible with salicylamide, pyrilamine maleate and ascorbic acid.     

Dsc Screening for Drug-Drug Interactions in Poly Pharmaceuticals Intended for the Alleviation of the Symptoms of Colds and Flu. II.

Abstract

DSC screening for drug-drug interactions of a polypharmaceutical capsule dosage form containing salicylaminde, ascorbic acid, pyrilamine maleate and phenylephrine hydrochloride was performed. The results show the following:

1. Ascorbic acid is incompatible with salicylamide, pyrilamine maleate and pheynylephrine hydrochloride.

2. Salicylamide is incompatible with ascorbic acid, pyrilamine maleate and phenylephrine hydrochloride.

3. Pyrilamine maleate is incompatible with ascorbic acid, salicylamide and phenylephrine hydrochloride.

4. Phenylephrine hydrochloride is incompatible with salicylamide, pyrilamine maleate and ascorbic acid.     

Thermal Stability of Various Epinephrine Formulations

The effects of prolonged heat exposure on the stability of various epinephrine formulations (maleate, fumarate, HCl, and bitartrate) were studied with respect to mass loss and pressor potency. Mass loss was relative to length of incubation and was accompanied by discoloration in HCl and bitartrate. Fumarate and maleate demonstrated least loss of mass and little discoloration. Pressor potency was significantly reduced, relative to length of heat exposure, in HCl and bitartrate, but remained elevated in fumarate and maleate. Thus, the latter formulation demonstrate the highest thermostability.     

Comparison of the determination of a low-concentration active ingredient in pharmaceutical tablets by backscatter and transmission Raman spectrometry

A total of 383 tablets of a pharmaceutical product were analyzed by backscatter and transmission Raman spectrometry to determine the concentration of an active pharmaceutical ingredient (API), chlorpheniramine maleate, at the 2% m/m (4 mg) level. As the exact composition of the tablets was unknown, external calibration samples were prepared from chlorpheniramine maleate and microcrystalline cellulose (Avicel) of different particle size. The API peak at 1594 cm(-1) in the second derivative Raman spectra was used to generate linear calibration models. The API concentration predicted using backscatter Raman measurements was relatively insensitive to the particle size of Avicel. With transmission, however, particle size effects were greater and accurate prediction of the API content was only possible when the photon propagation properties of the calibration and sample tablets were matched. Good agreement was obtained with HPLC analysis when matched calibration tablets were used for both modes. When the calibration and sample tablets are not chemically matched, spectral normalization based on calculation of relative intensities cannot be used to reduce the effects of differences in physical properties. The main conclusion is that although better for whole tablet analysis, transmission Raman is more sensitive to differences in the photon propagation properties of the calibration and sample tablets.     

Drug-Excipient Interactions of Seproxetine Maleate Hemi-Hydrate: Isothermal Stress Methods

Seproxetine maleate hemi-hydrate was originally formulated with pregelatinized starch, to provide 1 and 20 mg free base equivalent gelatin capsule dosage forms for storage at 25°C and 40°C. HPLC analysis after 3 months revealed the formation of a 1,4 Michael addition adduct in each case. No additional degradation products were detected. To pursue a less interactive formulation, 5 mg formulation equivalent mixtures of seproxetine maleate hemi-hydrate were prepared with pregelatinized starch, lactose, and talc; thus, three distinctly different excipient classifications. These were evaluated in additional isothermal stress experiments at 25°C, 40°C, and 50°C. The results indicated that each excipient interacted with the drug in a unique chemically and thermally dependent manner. Thus, the drug-pregelatinized starch data may be represented by an Arrhenius type relationship, with activation energy of 32 kcal/mol, and formation of the previously described adduct. However, the drug-lactose data suggest reaction with an impurity in which the equilibrium is temperature dependent. Finally, the drug-talc data correspond to either sigmoid kinetics or a threshold temperature which must be exceeded for formation of an amide. A final choice of excipient is thus complicated by having to project these three solid state reactions, of different thermal characteristics, to the shelf life of the product.     

Marked functional improvement in a pediatric patient treated with hemodialysis for scleroderma related renal failure

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibrosis and vasculopathy of the skin and visceral organs. Scleroderma renal crisis (SRC), the most acute and life threatening complication, occurs in 10–20% of adult patients with SSc and has not been reported in children. A 10‐year‐old girl was diagnosed with SSc when she presented with weakness and skin thickening. She had positive ANA and anti‐Scl 70. Renal function, urinalysis, and blood pressure were normal. She was treated with steroids, penicillamin and methotrexate as well as amlodipine for Raynaud's phenomenon, but her diffuse skin thickening and contractures progressed and she became wheelchair bound and had poor growth despite nutrition through a G‐tube. At age 15 (weight 28 kg), when evaluated for abdominal pain, she was found to have acute renal failure (BUN 54 mg/dl, creatinine 2.2 mg/dl) and hypertension. Despite therapy with enalapril, serum creatinine continued to rise and she became oligoanuric, requiring initiation of hemodialysis. BP was controlled with enalapril and dialysis but she remained dialysis dependent. Steroid therapy was discontinued and replaced by low dose cyclosporine. Enalapril was replaced by losartan because of leukopenia and BP remained normal. Over the next 2 years, she was treated with hemodialysis and did not experience any complications. She progressively had an outstanding overall clinical improvement, marked skin softening, and was able to walk independently. Renal function did not improve. 28 months after the SRC, she received LRD renal transplant. Immunosuppression included cyclosporine, mycophenolate and prednisone. Creatinine 2 months post‐transplant is 0.7 mg/dl. SRC in children may progress to end‐stage renal disease but can be treated successfully with dialysis and transplantation without significant complications.     

Ion-Pair High-Performance Liquid Chromatographic Determination of Chlorpheniramine Maleate in Cough-Cold Mixtures

A high-performance liquid chromatographic method in the ion-pair mode was developed for the assay of chlorpheniramine maleate in commercial cough-cold mixtures. The method uses a µ Bondapak phenyl column and a mixture of acetonitrile-acetic acid-water (26.5:1.0:72.5, by volume, pH 2.4) containing 0.005M pentanesul-fonic acid sodium salt as the mobile phase. Chlorpheniramine maleate was well resolved from ten other active ingredients. A linear relationship was obtained between detector response at 254 nm and amounts of chlorpheniramine maleate injected ranging from 0.8 to 2.5 µg(r=0.996). A reproducibility study using a standard preparation gave a CV of 1.43% (n = 10). The average recovery values of chlorpheniramine maleate added in various amounts to a single-component tablet composite sample and to a multiple-component tablet composite sample were 99.1 and 100.9%, respectively. The assay of commercial tablets by the proposed method gave results which differed by 0.7 to 3.2% of declared from those obtained by the method of USP XX.     

Effect of Penetration Enhancers on Transdermal Delivery of Timolol Maleate

In vitro skin permeation of Timolol maleate through human cadaver skin was studied using Franz diffusion cell. The results indicate that the drug penetrates poorly through human cadaver skin. However, skin penetration enhancers such as dimethyl sulfoxide (DMSO), oleic acid (OA) and lauryl chloride (LC) enhanced the permeability of Timolol maleate (TM) through human cadaver skin. The permeation enhancement of drug was maximum by lauryl chloride amongst the three enhancers. Moreover, lauryl chloride increases the permeation of drug through skin with increase in the time of application and concentration on skin. The change in lag time was also observed.     

溶剂热合成法制备顺丁烯二酸二丁酯接枝POE

利用新的接枝方法——溶剂热合成的方法制备了顺丁烯二酸二丁酯(DBM)接枝乙烯-辛烯共聚物(POE)。经傅立叶红外光谱(FT-IR)分析,证明DBM成功地接枝到了POE上,并用-C=O-和-CH2-吸收峰面积的比值来确定相对接枝量的大小。研究了单体DBM含量、引发剂过氧化二异丙苯(DCP)含量和反应温度对接枝反应的影响,找到了合适的反应配比和反应条件,得到了较高接枝率的接枝共聚物。结果表明,溶剂热合成法是将DBM接枝到POE上的一种好方法。     

The Effect of Curing on Drug Release and Morphological Properties of Ethylcellulose Pseudolatex-Coated Beads

Drug-containing nonpareil beads were coated in a fluidized bed with a commercial ethylcellulose pseudolatex, Aquacoat. The drug release was investigated as a function of curing conditions (curing time and temperature) for a hydrophilic and lipophilic drug (chlorpheniramine maleate and ibuprofen) at different levels of plasticizer (triethyl citrate). Curing of coated beads at elevated temperatures immediately after the coating process significantly changed the drug release pattern. Both a retardation and an enhancement in drug release were seen, with the extent being dependent on the type of drug and curing conditions. With chlorpheniramine maleate, a drug with low affinity for the ethylcellulose coating, a curing step was necessary at intermediate plasticizer levels to obtain good film formation and a limiting drug release pattern, while the use of higher plasticizer levels eliminated the need for a curing step. With ibuprofen, a lipophilic drug with high solubility in the ethylcellulose coating, drug crystals were apparent on the bead surface after curing. Curing of ibuprofen beads as a function of time initially decreased but then substantially increased the drug release as a result of drug diffusion across the ethylcellulose membrane with subsequent crystallization on the bead surface. An intermediate seal coat reduced the diffusion of the drug into the ethylcellulose coating.     

The Effect of Curing on Drug Release and Morphological Properties of Ethylcellulose Pseudolatex-Coated Beads

Abstract

Drug-containing nonpareil beads were coated in a fluidized bed with a commercial ethylcellulose pseudolatex, Aquacoat. The drug release was investigated as a function of curing conditions (curing time and temperature) for a hydrophilic and lipophilic drug (chlorpheniramine maleate and ibuprofen) at different levels of plasticizer (triethyl citrate). Curing of coated beads at elevated temperatures immediately after the coating process significantly changed the drug release pattern. Both a retardation and an enhancement in drug release were seen, with the extent being dependent on the type of drug and curing conditions. With chlorpheniramine maleate, a drug with low affinity for the ethylcellulose coating, a curing step was necessary at intermediate plasticizer levels to obtain good film formation and a limiting drug release pattern, while the use of higher plasticizer levels eliminated the need for a curing step. With ibuprofen, a lipophilic drug with high solubility in the ethylcellulose coating, drug crystals were apparent on the bead surface after curing. Curing of ibuprofen beads as a function of time initially decreased but then substantially increased the drug release as a result of drug diffusion across the ethylcellulose membrane with subsequent crystallization on the bead surface. An intermediate seal coat reduced the diffusion of the drug into the ethylcellulose coating.     

Quantitation of Phenylephrine Hydrochloride in Pharmaceutical Dosage Forms

A reverse phase high-pressure liquid chromatography method for the quantitation of phenylephrine hydrochloride in a variety of pharmaceutical dosage forms has been developed. The developed method did not require the use of a counter-ion t o increase the retention time of phenylephrine. The method is simple, accurate, precise and reproducible with a percent relative standard deviation of 0.54 based on 6 injections. The results were in excellent agreement with the results obtained using a colorimetric method. The separation between phenylephrine, the internal standard and other ingredients is greatly affected by pH changes (between 5.9-6.1) and the particle size of the column materials (5 micron versus 10 micron). A number of other active ingradinents brompheniramine maleate, chlopheniramine maleate, phenylpropanolamine and guaifenesin, etc. and the excipients such as parabens and sodium benzoate did not interfere with the assay procedure.     

Structural characterization of photodegradation products of enalapril and its metabolite enalaprilat obtained under simulated environmental conditions by hybrid quadrupole-linear ion trap-MS and quadrupole-time-of-flight-MS

In the environment, organic micropollutants such as pharmaceuticals can be degraded via various biotic and abiotic transformation routes. In surface waters, for example, photodegradation may constitute a relevant natural attenuation process for drug residues that have been discharged from sewage treatment facilities. In the present work, the photochemical fate of the prodrug enalapril (376 Da, C20H28N2O5) and its active metabolite enalaprilat (348 Da, C18H24N2O5), a hypotensive cardioprotector previously reported to occur in contaminated rivers, was investigated in aqueous media under the influence of irradiation generated by a sunlight simulator. The experiments yielded three detectable photodegradates for enalapril (346 Da, 2 x 207 Da) whereas the photolysis of enalaprilat went hand in hand with the intermittent buildup of one photodegradate (304 Da). Fragmentation patterns of the parent compounds were established on a hybrid quadrupole-linear ion trap-mass spectrometer exploiting its MS3 capabilities. Accurate mass measurements recorded on a hybrid quadrupole-time-of-flight instrument in MS/MS mode allowed us to propose elemental compositions for the molecular ions of the degradates (346 Da, C19H26N2O4; 207 Da, C12H17NO2; 304 Da, C17H24N2O3) as well as of their fragment ions. Based on these complementary data sets from the two distinct mass spectrometric instruments, plausible structures were postulated for the four photodegradates. The compounds formed by enalapril corresponded to the loss of formaldehyde out of the proline residue (346 Da), cleavage of the central amide bond (207 Da) followed by migration of the ethylester side chain (207 Da) while decarboxylation of the free carboxylic acid was described for enalaprilat (304 Da). The study emphasized the potential of sunlight for breaking down an environmentally relevant drug and its metabolite.     

Dsc Screening for Drug-Excipient and Excipient Excipient Interactions in Polypharmaceuticals Intended for the Alleviation of the Symptoms of Colds and FLU. III

DSC screening for drug-excipient interactions of a polypharmaceutical capsule dosage form containing salicylamide, ascorbic acid, pyrilamine maleate, phenylephrine hydrochloride, lactose, colloidal silicon dioxide and sodium starch glycolate was performed.     

Evaluation of Xanthan Gum in the Preparation of Sustained Release Matrix Tablets

The objective of this study was to evaluate xanthan gum as a matrix former for the preparation of sustained release tablets. Preliminary experiments indicated that a fine particle sue of xanthan gum produced the slowest and most reproducible release profiles. Based on single surface experiments and tablet erosion studies, it was concluded that release of a soluble drug (chlorpheniramine maleate) and an insoluble drug (theophylline) from tablets containing low concentraions of xanthan gum was mainly via diffusion and erosion, respectively. Drug release from tablets containing xanthan gum was slightly faster in acidic media due to more rapid initial surface erosion than at higher pH. After hydration of the gum, drug release was essentially pH-independent. The amount released was directly proportional to the loading dose of drug and inversely proportional to gum concentration in tablets. Release profiles of chlorpheniramine maleate and theophylline remained unchanged after three months storage of the tablets at 40°C/80% RH and 40°C. Model tablets containing 5% xanthan gum exhibited release profiles similar to tablets containing 15% hydroxypropyl methylcellulose.     

Effect of anionic surfactants on the release on clorpheniramine malete from an inert, heterogeneous matrix

The release from a matrix compressed from a physical mixture of chlorpheniramine maleate, chlorinated poly(propylene), lactose and an anionic surfactant (sodium lauryl sulfate and dioctyl sodium sulfosuccinate) has been investigated. The formation of a poorly water-soluble complex between the chlorpheniramine and the anionic surfactant slows the release to a minimum at low concentrations of surfactant; however, at higher concentrations of surfactant the release is faster due to solubilization in the micellar phase of the ion-pair. The interactin between the chlorpheniramine maleate and the anionic surfactant also influences the release of a second, noninteracting compound from the matrix.     

Chitosan as a tablet binder

Abstract

Chitosan was evaluated as a binder for chlorpheniramine maleate tablets in comparison with other cellulose binders such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose and methylcellulose. The effects of binder concentration on the mechanical properties of granules and tablets as well as on disintegration time and dissolution profiles were studied. Results showed that granules prepared with methylcellulose had lowest percentage of fines and friability. Chitosan tablets showed best dissolution profiles. The rank order correlation for binder efficiency was: hydroxypropylmethylcellulose > chitosan > methylcellulose > sodium carboxymethylcellulose.