Solubilities Of Theophylline Research Articles

Polymorphs, Hydrates, Cocrystals, and Cocrystal Hydrates: Thermodynamic Modeling of Theophylline Systems

Polymorphic transitions and hydrate formation often occur in systems of cocrystal-forming components. To increase the efficiency of cocrystal formation and purification processes, the complex phase behavior of such systems was modeled using perturbed-chain statistical associating fluid theory (PC-SAFT). This is demonstrated for theophylline, a well-studied pharmaceutical, exhibiting polymorphs, as well as formation of a hydrate, cocrystals, and even cocrystal hydrates. The solubility of theophylline in water was modeled including hydrate formation (1:1) as well as polymorphic transitions of theophylline between the anhydrate forms IV, II, and I. The solubilities of theophylline(IV), the thermodynamically stable form at ambient conditions, and the theophylline/glutaric acid (1:1) cocrystal could be predicted without performing additional measurements. Moreover, the complex phase behavior of the theophylline/citric acid/water system could be correlated accounting for the formation of the theophylline hydrat...

Cocrystal Intrinsic Dissolution Behavior Using a Rotating Disk

The aim of this study was to investigate the dissolution characteristics of an acetaminophen/theophylline (AT) cocrystal compared with its pure components and physical mixtures. Intrinsic dissolution studies were conducted by a rotating-disk method. Solubility studies were conducted by collecting transient samples at 5, 30, and 60 min and equilibrium samples after 72 h, both at 37 °C. The AT cocrystal had a faster dissolution rate than AT physical mixtures, and the dissolution profiles were congruent (1:1 mole ratio) under different pH conditions. Thus, the AT cocrystal dissolved congruently at short times and exhibited higher transient solubility compared with its two pure components. Equilibrium solubilities of theophylline from the cocrystal were lower than transient values due to theophylline hydrate precipitation but no precipitation of free acetaminophen occurred. The solubility behavior of acetaminophen and theophylline exhibited typical 1:1 complex formation in physical mixtures, cocrystal, and phase-solubility studies. The Levich equation was used to predict the dissolution behavior of the AT cocrystal as well as that of the single components.

Development of supercritical fluid extraction and supercritical fluid chromatography purification methods using rapid solubility screening with multiple solubility chambers

Rapid solubility screening in diverse supercritical fluids (SCFs) was carried out via multiple solubility chambers with a trapping device and online ultraviolet (UV) detection. With this device, it was possible to rapidly study the solubility variations of multiple components in a mixture. Results from solubility studies have been used to develop efficient supercritical fluid extraction (SFE) and supercritical fluid chromatography (SFC) methods. After the investigation of solubilities of theophylline and caffeine in several neat organic solvents and SCFs, advantages of SFE over conventional organic solvent extraction were demonstrated with a model mixture of theophylline and caffeine. The highest solubility ratio of 1:40 (theophylline:caffeine) was observed in the SCF with 20% acetonitrile (MeCN), where a ratio of 1:11 was the highest in the neat organic solvents. A model mixture of theophylline:caffeine (85:15 w/w, caffeine as an impurity) was successfully purified by SFE by leveraging the highest solubility difference. The SCF with 20% MeCN selectively removed caffeine and left theophylline largely intact. Rapid SCF solubility screening was applied to development of SFE and SFC methods in a drug discovery environment. Two successful applications were demonstrated with proprietary Amgen compounds to either remove an achiral impurity before chiral purification or enhance chiral chromatographic throughput.

Extrusion–Spheronization Manufacture of Gelucire® Matrix Beads

Theophylline extended-release spheres were prepared by extrusion–spheronization of matrix granulations previously obtained by incorporation of the drug in melted Gelucire 50/02 or Gelucire 55/18. Hydrophobic Gelucire 50/02 behaved as an inert matrix and released theophylline very slowly compared with hydrodispersible Gelucire 55/18, which acted as a hydrophilic matrix. Extrusion–spheronization was more easily accomplished with Gelucire 50/02. The use of ethanol as a wetting fluid increased the rate of drug release noticeably with Gelucire 50/02 and less so with Gelucire 55/18. The use of castor oil, in conjunction with ethanol to slow down the solvent evaporation, improved extrusion and spheronization. Castor oil decreased the drug release rate with Gelucire 50/02 and increased it with Gelucire 55/18. These phenomena were explained by the different solubilities of theophylline, Gelucire 50/02, and Gelucire 55/18 in ethanol and castor oil. When microcrystalline cellulose (Avicel® CL 611) was used in the granulation matrix, extrusion was improved. The best formulation was obtained with Gelucire 55/18 and Avicel CL 611 and was wetted by a mixture of ethanol and castor oil. Regardless of the formulation, the mechanism of theophylline release appeared to be via Fickian diffusion.

Solubility of theophylline in aqueous N,N-dimethylformamide mixtures

The solubilities of theophylline in several water-N,N-dimcthylformamide mixtures have been determined and found to show non-regular behaviour. The results were treated on the basis of the extended Hildebrand solubility approach considering interaction terms. An equation has been obtained for predicting the solubility of theophylline in N,N-dimethylformamide water and their mixtures allowing the interpolation of new or missing solubilities in these blends.

Thermochemical study of theophylline and its hydrate.

Anhydrous theophylline exhibited polymorphism and two modifications, which were named form I and form II, were isolated. The melting point and the enthalpy of fusion of each polymorph determined by differential scanning calorimetry (DSC) were 273.4±1.0°C and 26.4±0.3 kJ/mol for form I and 269.1±0.4°C and 28.2±1.1 kJ/mol for form II. The higher melting form I had a smaller density. In contrast to caffeine, theophylline formed a monohydrate. The dissociation vapor pressure curves of theophylline hydrate and caffeine hydrate were obtained and the difference in their stabilities was discussed. The enthalpy of dehydration was determined by DSC under closed conditions. The dehydration under isothermal conditions appeared to proceed acoording to the mechanism of random uncleation followed by two-dimensional growth of nuclei as represented by the Avrami-Erofe'ev equation. The solubilities of theophylline and its hydrate were determined as a function of temperature. From the van't Hoff type plot, the transition temperature between the hydrate and the anhydrous form was determined.

Use of Solubility Parameters of Drug and Vehicle to Predict Flux Through Skin

The solubilities of theophylline in, and fluxes through skin from, isopropyl myristate, octanol, dimethylformamide, propylene glycol, ethylene glycol, and formamide have been determined experimentally. Values for experimental permeability coefficients (Kp) corresponding to the respective fluxes were determined from, flux/solubility = Kp, which were then compared with values for the respective theoretical partition coefficients (PC) calculated from the known solubility parameters for the vehicles (delta v), theophylline (delta i) and skin (delta s). There was a good correlation for theoretical log PC - 2.52 = experimental log Kp for vehicles exhibiting solubility parameters in the range of delta v = 12-18 (cal/cm3)1/2. This allows relative fluxes to be determined from calculated theoretical partition coefficients and experimentally determined solubilities in that range. For vehicles or mixtures of vehicles exhibiting solubility parameters in the range of delta v = 8-12 (cal/cm3)1/2 large increases in fluxes and permeability coefficients, compared with those predicted from the results in the delta v = 12-18 (cal/cm3)1/2 range, were observed because of vehicle effects on the skin caused by the similarity in solubility parameters of those vehicles to that of skin. Qualitatively, fluxes and permeability coefficients were found to be inversely dependent on drug solubility in the vehicles with a minimum that corresponded approximately to the point where delta i = delta v.

A thermodynamic study of the solubility of theophylline and its hydrate

The solubilities of theophylline and theophylline hydrate as a function of temperature are determined in the temperature range 288–365K. The solubility as a function of temperature can be described by In X = 10.0−5178.3 · 1/T for theophylline hydrate and a polymorph of theophylline. A number of other thermodynamic parameters are determined by means of differential scanning calorimetry and vapour pressure studies. The conversion of theophylline hydrate into theophylline and a saturated solution occurs at 337.0K, the transition enthalpy being 11.2 kJ · mol −1. The melting temperature and the enthalpy of melting of theophylline are 543.7K and 31.2 kJ · mol −1, respectively; the enthalpy of sublimation at 421K is 126 kJ · mol −1. These parameters are used to calculate the δ-values of theophylline and theophylline hydrate, which are found to be 14.0 s.u. and 13.2 s.u., respectively. The validity of all data is discussed in relation to an ‘extended’ Hildebrand-Scatchard equation for theophylline, derived by Martin et al. (1980).