Sodium Theophylline Research Articles

Clinical value of Vitamin-D combined with budesonide/formoterol and theophylline sodium glycinate sustained-release tablets in the treatment of chronic obstructive pulmonary disease patients.

To explore the clinical value of Vitamin-D combined with budesonide/formoterol (BF) and theophylline sodium glycinate (TSG) sustained-release tablets in the treatment of patients with chronic obstructive pulmonary disease (COPD). Medical records of 114 patients with CODP, treated in Wenzhou Geriatric Hospital from October 2020 to February 2023, were retrospectively analyzed. Of them, 59 received treatment with Vitamin-D combined with BF and TSG sustained-release tablets (Group-A), and 55 patients received treatment with BF combined with TSG sustained-release tablets (Group-B). Lung function indicators, blood gas status, inflammatory factors, fractional exhaled nitric oxide (FeNO), and 25-hydroxyvitamin D [25(OH)D] levels before and after the treatment in both groups were collected. After the treatment, lung function indicators, blood gas status, inflammatory factors, FeNO, and 25 (OH) D levels in both groups were significantly improved compared to pretreatment levels, and were significantly better in the Group-A compared to Group-B (P<0.05). The combination of Vitamin-D, BF, and TSG sustained-release tablets can effectively regulate the blood gas status of patients with COPD, improve lung function, regulate FeNO and 25 (OH) D, and effectively downregulate the levels of inflammatory factors, thus reducing the degree of inflammatory response.

Purification, characterization and study of blue fluorescent substance in caffeine

AbstractBackgroundCaffeine, a xanthine alkaloid compound, is a stimulant of the central nervous system and is mainly used in the pharmaceutical and food industries. Because caffeine is directly absorbed into the body, Chinese pharmacopeia has high requirements on the quality of caffeine products, and fluorescence has always been an important indicator to measure the quality of caffeine. In this study, a major fluorescent impurity affecting the appearance and purity of caffeine products was isolated for the first time, and the solubility, thermodynamic properties and dissociation constants of this impurity were studied.Results(i) The fluorescent impurity affecting the appearance and purity of the product was successfully isolated from crude caffeine and theophylline sodium salt, and named as a blue fluorescent substance. The mass purity of the substance was 96.27%, and its structure was determined based on a comprehensive analysis of high‐resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy [hydrogen 1 (1H) NMR, carbon‐13 (13C) NMR, COSY, NOESY, HSQC, HMBC]. (ii) The solubility of blue fluorescent substance in four pure solvents was determined and the thermodynamic properties were calculated. (iii) The dissociation constants of the blue fluorescent substance in water at 298.15 K were determined by UV spectrophotometry.ConclusionThe results provide a theoretical basis for the crystallization separation of the blue fluorescent substance during the industrial production of caffeine, as well as basic data for the green synthesis process of caffeine. © 2024 Society of Chemical Industry (SCI).

Solubility and thermodynamic properties of sodium theophylline salt in aqueous sodium hydroxide solution at different temperatures

The solubility data of sodium theophylline salt in the water and aqueous sodium hydroxide systems with molarities of 0.00, 0.01, 0.10, 0.20, 0.49, and 0.96 mol kg−1 at temperatures ranging from 283.15 to 368.15 K are determined via the equilibrium method. The experimental results show that the solubility of sodium theophylline increases on increasing the temperature at the same concentration of NaOH solution and decreases with an increase in the NaOH concentration at the same temperature. These results correlate well with the polynomial empirical equation, the modified Apelblat equation, and the λh equation. At the same time, it is found that the modified Apelblat equation gives better correlation results than the polynomial empirical and the λh equations. The results show that the three models correlate well with the solubility data of sodium theophylline. The modified Van’t Hoff equation is used to estimate the thermodynamic properties including the dissolution enthalpy, the dissolution entropy, and the Gibbs free energy change of sodium theophylline when dissolved in aqueous NaOH solution at different concentrations. The solubility data and correlation results obtained from the experiments can provide basic data for the cooling crystallization, separation, and purification of sodium theophylline and are expected to be of great significance for the research and development of sodium theophylline and for caffeine production.

Green synthesis of caffeine based on methylating reagent dimethyl carbonate and environmental friendly separating method

AbstractIn this paper, a green process for the synthesis and separation of caffeine was reported. Theophylline sodium is used as the raw material, diazabicyclo[5.4.0]undec‐7‐ene as the catalyst, and Turkey red oil as the solvent, particularly, dimethyl carbonate was adopted in place of high toxic dimethyl sulfate to form a mixture of caffeine and by‐product sodium bicarbonate. After converting sodium bicarbonate to sodium carbonate, the solubility difference between caffeine and sodium carbonate at 40°C was for the first time utilized to achieve the purpose of separating caffeine with an excellent yield of 98.4% and a purity of greater than 99.0%. Furthermore, both the reaction mother liquor and separation mother liquor can be recycled and reused during the reaction and separation processes, respectively, with little caffeine loss. No industrial waste was discharged in the process of the improved synthesis and separation, which is therefore environmental friendly.

Studies on Bio-adhesion of Matrix Tablets: II.Comparison on Bio-adhesion Strength and Release Profiles of Theophylline Anhydrous and Its Sodium Glycinate Salt

Controlled release matrix tablets of Theophylline anhydrous and Theophylline sodium glycinate were prepared with different types of bio-adhesive polymers e.g. HPMC 15 &amp; 50 cps, Gelatin, PVP K-30, Na-CMC and Xanthan gum. Tablets, prepared by direct compression method were subjected to in-vitro drug dissolution for 8 hours in 0.1 N hydrochloric acid (pH 1.2) using a thermal shaker at 50 rpm at 37 ± 0.5ºC. The bio-adhesive property was investigated in terms of retention time following in-vitro wash-off method by Lehr et al. The anhydrous and corresponding salt form was used to investigate whether physical variation of Theophylline molecule can cause any change in release and bio-adhesion property or not. In most of the cases it is found that salt form releases greater percentage of active drug than its corresponding anhydrous form. Irrespective of drug’s physical property and amount of polymer, bio-adhesive strength of Xanthan gum was proved to be maximum followed by HPMC- 50 cps, Na-CMC and HPMC- 15 cps, whereas gelatin and PVP K-30 showed little or poor muco-adhesion. Xanthan gum, Na-CMC and HPMC based formulations showed nearly zero-order release; on the contrary PVP K-30 based formulation showed a burst release within one hour of dissolution.DOI: http://dx.doi.org/10.3329/dujps.v10i1.10008DUJPS 2011; 10(1): 1-7

Soluble Drug Theophylline Sodium Glycinate from Different Suppository Bases

Theophylline Sodium Glycinate (TSG) loaded lipid-based suppositories were prepared and the effects of suppository bases and release modifiers (PEG 1500 and HPMC 15 cps) on in vitro release of TSG were investigated. Suppositories containing 300 mg TSG were prepared by fusion method. Bees wax, Carnauba wax, Stearic acid and PEG 4000 were used as hydrophobic bases. In vitro dissolution was carried out in aqueous and buffered media of pH 6.8 for 2 hours. The results showed that, the release rate of TSG is considerably slow from beeswax, carnauba wax and stearic acid based devices. However, substantial TSG release was observed from PEG 4000 based systems. Incorporation of PEG 1500 in beeswax, carnauba wax and stearic acid based suppositories increased the rate and extent of TSG release in buffer media. Inclusion of HPMC 15 cps in PEG 4000 loaded suppositories released TSG at a faster rate. Drug release was linear for all the formulation except PEG 4000 systems, which released drug in a biphasic pattern both in aqueous and buffered environment. Rate and extent of drug release was found to be a function of pH of the dissolution media.&#x0D; &#x0D; Key words: Theophylline sodium glycinate, Suppositories, In vitro release&#x0D; &#x0D; Dhaka Univ. J. Pharm. Sci. Vol.3(1-2) 2004&#x0D; &#x0D; The full text is of this article is available at the Dhaka Univ. J. Pharm. Sci. website

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects with a new asymmetric dosage regimen.

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects was studied. In this study, a new asymmetric dosage regimen was presented to achieve a better accordance with the chronotherapy of asthma. Each of 10 subjects was administered one tablet (equivalent to 0.1 g anhydrous theophylline) in the morning and four tablets in the evening for a consecutive 6 days and blood samples were collected at the predetermined time and analyzed by a validated HPLC method. This new regimen produced a steady and effective level of theophylline in plasma for the whole day, especially in the evening. A lower dose in the morning could reach the effective level (C(min)4.97 +/- 1.60 microg/mL and C(max)10.68 +/- 1.80 micro g/mL over the a.m. dosing interval) and a higher dose in the evening did not result in toxic levels but led to a reasonable concentration range (C(max)9.72 +/- 1.56 microg/mL over p.m. dosing interval), which could maintain a higher plasma theophylline concentration without the risk of serious adverse events and control asthmatic symptoms probably occurring during the night or early in the morning. The results suggested that the proposed asymmetric regimen was necessary, practicable and safe for twice daily sustained-release tablets of theophylline sodium glycerinate and also provides the basis for the clinical dosage regimen of other theophylline formulated products.

Effects of surface active characteristics and solid state forms on the pH solubility profiles of drug–salt systems

The pH solubility profiles of five drug–salt systems (diclofenac sodium, diclofenac N-(2-hydroxyethyl)pyrrolidine, CEL50 phosphate, theophylline sodium and phenazopyridine hydrochloride) were examined. With the exception of the diclofenac sodium (Na) system supersaturation was observed at the theoretical pH of maximum solubility (pH max) in all profiles. Characterisation of the solid phases involved indicated that inhibition of nucleation of the final solid form is responsible for the formation of supersaturated solutions at the pH max. The surface active characteristics of the drug–salts were investigated and a general relationship between supersaturation at the pH max and self-association of the drug–salts was observed. It is proposed that self-association of the drug in the region of the pH max reduces the rate of nucleation of the final salt. Furthermore higher levels of supersaturation are observed when the free drug is used as the starting material indicating the key role of the solid phase employed in determining the level of supersaturation obtained. Possible pharmaceutical applications of supersaturation at the pH max are discussed.

Synthesis, toxicological and pharmacological assessment of 7-substituted derivatives of 1,3-dimethylxanthine

The synthesis of two 7-substituted theophylline derivatives from the theophylline sodium salt, dichloroalkane and N-methyl- N-cyclohexylamine is reported. The structures of the synthesized compounds were proved by microanalyses and 1H-NMR data. Acute toxicity studies of the compounds were performed on mice and rats. A comparative pharmacological study of the in vivo broncholytic effect of the derivatives and aminophylline showed that the new compounds have different bronchodilatory activity and the compound 7-[2-( N-methyl- N-cyclohexyl)-aminoethyl]-1,3-dimethylxanthine tartrate 3a was more active than 7-[3-( N-methyl- N-cyclohexyl)-aminopropyl]-1,3-dimethylxanthine hydrochloride 3b. It was demonstrated that compound 3b and aminophylline exerted the strongest inhibitory effect on the enzyme activity of phosphodiesterase in lung homogenate. Compound 3a showed a slight inhibitory effect on the enzyme activity in this homogenate. The possible mechanisms of the broncholytic effects of these compounds are discussed.

Comparative thermal properties of the monohydrates of sodium theophylline and theophylline

The thermal properties of sodium theophylline monohydrate, as determined by differential scanning calorimetry (DSC), thermogravimetric (TG) analysis and hot stage microscopy, were studied and compared with those of theophylline monohydrate. The onset of dehydration of sodium theophylline monohydrate varied between 170 and 264 degrees C depending on the atmospheric conditions surrounding the sample. Under similar conditions, dehydration of theophylline monohydrate occurred at 18 to 65 degrees C. Sodium theophylline melted with the onset of a DSC endotherm at 391 degrees C. Possible effects of the physicochemical properties of sodium theophylline monohydrate on its dosage forms and the expected superiority of the sodium salt over theophylline and aminophylline are discussed.

Effect of Diffusion Layer pH and Solubility on the Dissolution Rate of Pharmaceutical Acids and Their Sodium Salts II: Salicylic Acid, Theophylline, and Benzoic Acid

The pH–solubility profiles of salicylic acid and theophylline, as determined by the addition of HCI or NaOH to their aqueous suspensions, were identical with those of their sodium salts except during phase transitions from acid to salt or vice versa. Supersaturated solutions were formed during phase transitions. Unlike the solubility profiles, the pH–intrinsic dissolution rate profiles of an acid and its salt differed greatly. Good conformity with the Noyes–Whitney equation was demonstrated when the solubility values under pH conditions as the diffusion layer thickness, h, approaches zero (Ca,h‐o) were used rather than solubilities under pH conditions of the bulk media (Cs). The pH when h approaches zero (pHh‐o) was estimated by equilibration of a dissolution medium with an excess of material. Good correlation was shown between the pHh‐o values of benzoic acid estimated according to this method and the pHh‐o values reported in the literature. The intrinsic dissolution rate constant, the ratio of the diffusion coefficient to the diffusion layer thickness (D/h), may be assumed constant when comparing the dissolution rates of salicylic acid, theophylline and sodium theophylline. On the other hand, D/h decreased significantly during dissolution of sodium salicylate due to a large increase in Cs,h‐o and the consequent increase in viscosity in the diffusion layer. A simple method of predicting the dissolution rate of an acid or a salt at different pH values has been developed.

Development of spherical crystallization technique and its application to pharmaceutical systems

A novel agglomeration technique, termed “Spherical Crystallization Process”, which can transform directly the fine crystals produced in the crystallization or the reaction process into a spherical shape was developed. By this technique, needle like crystals such as salicylic acid were transformed into free flowing and directly compressible agglomerates. Spherically agglomerated aminophylline crystals were obtained directly from the reaction system, which could reduce the preparation processes, e.g. synthesis, crystallization and agglomeration, into only one step. Sodium theophylline monohydrate agglomerates were prepared by salting out, the rate process of which was described by a first order kinetics. Agglomerated crystals of ndw complex of indomethacin-mepirizole were prepare with this technique; an improved therapeutic effect of the resultant crystals was expected.

An experimental study of the kinetics of the spherical crystallization of aylline sodium theophylline monohydrate

Direct agglomeration of sodium theophylline monohydrate crystals produced by salting out in a liquid was carried out in a stirred vessel. Addition of aqueous ethylenediamine solution of theophylline and sodium chloride solution to a mixture of chloroform and ethanol (mixing ratio of chloroform:ethanol = 0.1 to 0.505:1) with agitation yielded spherically agglomerated crystals of sodium theophylline monohydrate. The diameter of the spherical agglomerate decreased with increase in agitation speed of the chloroform fraction in the mixture. The spherical crystallization process was described by first-order kinetics. The rate constant was a function of the agitation speed of the system and the difference between the residual concentration of theophylline in the solvent in the initial and the equilibrium state.

Direct agglomeration of sodium theophylline crystals produced by salting out in liquid.

Sodium theophylline monohydrate was precipitated from ethylene diamine solution of theophylline by adding aqueous sodium chloride solution to the system with or without ethanol. The dried precipitates were redispersed in the filtrate without ethanol and were agglomerated with water liberated from the system by adding chloroform and ethanol to the filtrate with agitation. The sedimentation velocity of the agglomerated precipitates and their sedimentation volume at equilibrium were investigated to identify a suitable composition of the medium for agglomeration by gradually increasing the chloroform fraction in the medium. The sedimentation volume slightly increased before dropping drastically at 41% chloroform fraction, at which the precipitates were microagglomerated after passing through a flock stage of high bulk volume. At 56% chloroform fraction, the sedimentation volume sharply decreased again because of secondary agglomeration of the microagglomerates. The sedimentation velocity of the agglomerated precipitates increased with increasing chloroform fraction of the medium in the range above 41%. The agglomerate size increased drastically when the secondary agglomeration occurred. No changes in the sizes and shapes of the elemental crystals were found even after agglomeration. A triangular phase diagram was obtained to described a suitable composition of the medium for agglomeration. It was also proved that simultaneous agglomeration with crystallization was possible in a mixture of four liquids, i.e. ethylenediamine solution of theophylline, aqueous solution of sodium chloride, ethanol and chloroform, with a suitable composition.

キサンチン系化合物の合成研究 (第5報)

Twenty-three kinds of 7-(2-hydroxy-3-alkylaminopropyl)theophylline (III to XXXV) were prepared by the reaction of amines with 7-(2, 3-epoxypropyl)theophylline (I) or 7-(2-hydroxy-3-chloropropyl)theophylline, prepared from theophylline sodium and epichlorohydrin, and from theophylline and 1-dialkylamino-2, 3-epoxypropane, and also 13 kinds of their acyl derivatives (XXVI to XXXVIII). Similarly, 10 kinds of 1-(2-hydroxy-3-alkylaminopropyl)theobromine (XL to XLIX) and two kinds of 1-(2-benzoyloxy-3-alkylaminopropyl)theobromine (L and LI) were prepared from theobromine. Among these compounds synthesized, 7-(2-benzyloxy-3-diisobutylaminopropyl)theophylline was found to be an excellent coronary artery dilator.

Suppository Bases. I. An Evaluation of the Rates of Release of Theophylline

A method is described for the evaluation of suppositories by allowing the drug to be released from the base and dissolved into normal saline solution at body temperature. The rate of release of the theophylline (as aminophylline) was compared for twenty-five suppository base formulas. Modifications of the water-soluble bases with certain disintegrating agents gave the most rapid release of the theophylline. Storage for one year showed a marked reduction in the rate of release of theophylline from the cocoa butter suppositories. The comparison of the theophylline release from the suppository when compounded as aminophylline, glycophylline, or theophylline sodium acetate, showed that each compound requres a specific base formula to allow the most rapid release of the drug. This test showed that slight changes in the physical-chemical properties of the drug-base relationship may influence the rate of release of the drug.

Sodium Theophylline Glycinate

A method of preparation and the characterization of Sodium Theophylline Glycinate are described. This new combination produces a typical theophylline response in animals and it is well tolerated in large amounts in man.

Report on Theophylline Sodium Salicylate

Journal Article Report on Theophylline Sodium Salicylate Get access M Harris M Harris Associate Referee U. S. Food and Drug Administration, New Orleans, La Search for other works by this author on: Oxford Academic Google Scholar Journal of Association of Official Agricultural Chemists, Volume 23, Issue 4, 1 November 1940, Pages 761–762, https://doi.org/10.1093/jaoac/23.4.761 Published: 21 February 2020

Report on Theophylline Sodium Salicylate

Journal Article Report on Theophylline Sodium Salicylate Get access M Harris M Harris Associate Referee U. S. Food and Drug Administration, Chicago, Ill Search for other works by this author on: Oxford Academic Google Scholar Journal of Association of Official Agricultural Chemists, Volume 21, Issue 4, 1 November 1938, Pages 587–593, https://doi.org/10.1093/jaoac/21.4.587 Published: 18 February 2020