Search

A multivariate statistical technique was applied to clarify the causal correlation between variables in the manufacturing process and the residual stress distribution of tablets. Theophylline tablets were prepared according to a Box-Behnken design using the wet granulation method. Water amounts (X1), kneading time (X2), lubricant-mixing time (X3), and compression force (X4) were selected as design variables. The Drucker-Prager cap (DPC) model was selected as the method for modeling the mechanical behavior of pharmaceutical powders. Simulation parameters, such as Young's modulus, Poisson rate, internal friction angle, plastic deformation parameters, and initial density of the powder, were measured. Multiple regression analysis demonstrated that the simulation parameters were significantly affected by process variables. The constructed DPC models were fed into the analysis using the finite element method (FEM), and the mechanical behavior of pharmaceutical powders during the tableting process was analyzed using the FEM. The results of this analysis revealed that the residual stress distribution of tablets increased with increasing X4. Moreover, an interaction between X2 and X3 also had an effect on shear and the x-axial residual stress of tablets. Bayesian network analysis revealed causal relationships between the process variables, simulation parameters, residual stress distribution, and pharmaceutical responses of tablets. These results demonstrated the potential of the FEM as a tool to help improve our understanding of the residual stress of tablets and to optimize process variables, which not only affect tablet characteristics, but also are risks of causing tableting problems.

The "quality by design" concept in pharmaceutical formulation development requires the establishment of a science-based rationale and a design space. We integrated thin-plate spline (TPS) interpolation and Kohonen's self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses. As a model pharmaceutical product, theophylline tablets were prepared based on a standard formulation. The tensile strength, disintegration time, and stability of these variables were measured as response variables. These responses were predicted quantitatively based on nonlinear TPS. A large amount of data on these tablets was generated and classified into several clusters using an SOM. The experimental values of the responses were predicted with high accuracy, and the data generated for the tablets were classified into several distinct clusters. The SOM feature map allowed us to analyze the global and local correlations between causal factors and tablet characteristics. The results of this study suggest that increasing the proportion of microcrystalline cellulose (MCC) improved the tensile strength and the stability of tensile strength of these theophylline tablets. In addition, the proportion of MCC has an optimum value for disintegration time and stability of disintegration. Increasing the proportion of magnesium stearate extended disintegration time. Increasing the compression force improved tensile strength, but degraded the stability of disintegration. This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline tablet formulations.

Design spaces for multiple dose strengths of tablets were constructed using a Bayesian estimation method with one set of design of experiments (DoE) of only the highest dose-strength tablet. The lubricant blending process for theophylline tablets with dose strengths of 100, 50, and 25 mg is used as a model manufacturing process in order to construct design spaces. The DoE was conducted using various Froude numbers (X(1)) and blending times (X(2)) for theophylline 100-mg tablet. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y(1)), tablet hardness (Y(2)), and dissolution rate (Y(3)) of the 100-mg tablet were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. Three experiments under an optimal condition and two experiments under other conditions were performed using 50- and 25-mg tablets, respectively. The response surfaces of the highest-strength tablet were corrected to those of the lower-strength tablets by Bayesian estimation using the manufacturing data of the lower-strength tablets. Experiments under three additional sets of conditions of lower-strength tablets showed that the corrected design space made it possible to predict the quality of lower-strength tablets more precisely than the design space of the highest-strength tablet. This approach is useful for constructing design spaces of tablets with multiple strengths.

The purpose of this research is to investigate the topographical pattern of hydration and dehydration (also known as pseudo-polymorphic change) of drug substance in drug product using terahertz (THz) pulsed imaging. Emphasis is placed on (1) applicability of THz pulsed imaging and (2) kinetic analysis in the pseudo-polymorphic change. Either anhydrous or monohydrated form of theophylline was used as the drug substance, leading to initially anhydrous or monohydrated tablets. These tablets were stored at 25°C to keep the relative humidity constant at 84% (anhydrous tablets) or 45% (monohydrated tablets), respectively. The THz pulsed imaging was confirmed to enable visualization that the hydration of the anhydrous form or the dehydration of the monohydrated form began on the surface of the tablets and gradually progressed to the core side in the tablets with storage. Kinetic studies indicated that these pseudo-polymorphic changes followed the phase boundary mechanism. Since the other imaging techniques has been scarcely achieved to show the topographical pattern of pseudo-polymorphic change of drug substances in drug products directly and visually, it is considered that THz pulsed imaging has a potential ability to solve complicated issues in pharmaceutical development.

A reliable large-scale design space was constructed by integrating the reliability of a scale-up rule into the Bayesian estimation without enforcing a large-scale design of experiments (DoE). A small-scale DoE was conducted using various Froude numbers (X(1)) and blending times (X(2)) in the lubricant blending process for theophylline tablets. The response surfaces, design space, and their reliability of the compression rate of the powder mixture (Y(1)), tablet hardness (Y(2)), and dissolution rate (Y(3)) on a small scale were calculated using multivariate spline interpolation, a bootstrap resampling technique, and self-organizing map clustering. A constant Froude number was applied as a scale-up rule. Experiments were conducted at four different small scales with the same Froude number and blending time in order to determine the discrepancies in the response variables between the scales so as to indicate the reliability of the scale-up rule. Three experiments under an optimal condition and two experiments under other conditions were performed on a large scale. The response surfaces on the small scale were corrected to those on the large scale by Bayesian estimation using the large-scale results and the reliability of the scale-up rule. Large-scale experiments performed under three additional sets of conditions showed that the corrected design space was more reliable than the small-scale design space even when there was some discrepancy in the pharmaceutical quality between the manufacturing scales. This approach is useful for setting up a design space in pharmaceutical development when a DoE cannot be performed at a commercial large manufacturing scale.

The purpose of this research work was to develop and evaluate a chronotherapeutic based colon-targeted drug delivery system of theophylline (THEO) exploiting pH-enzyme sensitive property for the prevention of episodic attack of asthma in early morning. Guar gum microspheres of theophylline were prepared by emulsification technique. Coating of microspheres was performed using solvent evaporation method with pH sensitive Eudragit(®) polymers. The particle size and surface morphology, entrapment efficiency and degree of swelling of microspheres were examined. The in vitro drug release studies were performed in pH progression medium and also in the presence of 2% rat caecal content. Theophylline was efficiently microencapsulated in guar gum microspheres at different polymer concentrations (1-4%). Fourier transform infrared (FT-IR)-spectroscopy confirmed the intermolecular interactions between guar gum and glutaraldehyde. Coating of guar gum microspheres by Eudragit led to decelerate the in vitro drug release of THEO. Moreover in vitro drug release studies also performed with 2% rat caecal content showed marked increment in drug release. The controlled release of THEO after a lag time was achieved with developed formulation for chronotherapeutic delivery. The pH dependent solubility behavior of Eudragit and gelling properties of guar gum are found to be responsible for delaying the release., (© 2011 Pharmaceutical Society of Japan)

Theophylline has an anhydrous form and a monohydrated form, and the dissolution rate of the anhydrous form is higher than that of the monohydrated form. Terahertz (THz) spectra of theophylline tablet containing the theophylline anhydrous form, monohydrated form, microcrystalline cellulose and magnesium stearate exhibited a specific absorption peak at 0.96 THz, where the theophylline anhydrous form demonstrated an absorption peak. Additionally, the intensity of the peak at 0.96 THz gradually decreased as the proportion of the anhydrous form decreased. The multivariate data analysis was performed to correlate the THz spectra of theophylline tablets with the ratio of the theophylline anhydrous form. The calibration model used to predict the mixing ratio of the theophylline anhydrous form from the THz spectra achieved root-mean-squared errors of cross-validation (RMSECV) of 2.89%, a slope of 0.9934 and an R(2) of 0.9927. In addition, there were intentions to develop a prediction model for the dissolution rate of theophylline from the drug product. The dissolution rate of theophylline tablet was gradually delayed as the proportion of the anhydrous form was decreased. The multivariate data analysis was performed to correlate the THz spectra of theophylline tablets with the dissolution rate. The calibration model used to predict the percentage of theophylline dissolved in 45 min from the THz spectra achieved an RMSECV of 3.29%, a slope of 0.9260 and an R(2) of 0.9423. Furthermore, there were no significant differences between the predicted and measured percentages of theophylline dissolved in 45 min in the theophylline tablets that were stored at 84% relative humidity (RH) and 25 °C for 12 h or 3 d.

The optimal solutions of theophylline tablet formulations based on datasets from 4 experimental designs (Box and Behnken design, central composite design, D-optimal design, and full factorial design) were calculated by the response surface method incorporating multivariate spline interpolation (RSM(S)). Reliability of these solutions was evaluated by a bootstrap (BS) resampling technique. The optimal solutions derived from the Box and Behnken design, D-optimal design, and full factorial design dataset were similar. The distributions of the BS optimal solutions calculated for these datasets were symmetrical. Thus, the accuracy and the reproducibility of the optimal solutions enabled quantitative evaluation based on the deviations of these distributions. However, the distribution of the BS optimal solutions calculated for the central composite design dataset were almost unsymmetrical, and the basic statistic of these distributions could not be conducted. The reason for this problem was considered to be the mixing of the global and local optima. Therefore, self-organizing map (SOM) clustering was applied to identify the global optimal solutions. The BS optimal solutions were divided into 4 clusters by SOM clustering, the accuracy and reproducibility of the optimal solutions in each cluster were quantitatively evaluated, and the cluster containing the global optima was identified. Therefore, SOM clustering was considered to reinforce the BS resampling method for the evaluation of the reliability of optimal solutions irrespective of the dataset style.

In our previous work, a controlled porosity osmotic pump system with biphasic release of theophylline, a system composed of a tablet-in-tablet (TNT) core and a controlled porosity coating membrane, was developed for the nocturnal therapy of asthma. Sodium phosphate and sodium chloride were selected as the osmotic agents in inner and outer layer of the TNT core respectively, and CA-PEG400-DEP (54.5%-36.4%-9.1%, w/w) was chosen as coating solution. Formulations with weight gain of 19 mg/T (mg per tablet), 9 mg/T and 6 mg/T were prepared respectively and their pharmacokinetics in beagle dogs were also studied to examine the influence of weight gain on their in vivo pharmacokinetics. Sustained release tablet of theophylline (SRT) was selected as reference to evaluate the in vitro and in vivo difference between conventional sustained release tablets and the developed formulation. T(max) and mean residence time (MRT) of the developed formulations were prolonged compared to that of SRT and a satisfying bioavailability was achieved at weight gain of 6 mg/T. If applied to the chronotherapy of asthma at night, the developed formulation with a weight gain of 6 mg/T might help to reduce the inconvenience brought by too later administration of conventional dosage forms and maintain a relatively high blood drug concentration 7 h after administration.

A controlled porosity osmotic pump system with biphasic release of theophylline was developed for the nocturnal therapy of asthma. The developed system was composed of a tablet-in-tablet (TNT) core and a controlled porosity coating membrane. Release pattern of the developed system was influenced by amount of pore former (18.2-45.5%, w/w of polymer), weight gain (16-26 mg per tablet) of the coating membrane and osmotic agents used in inner layer of the TNT core. When sodium phosphate and sodium chloride were selected as the osmotic agents in inner and outer layer of the TNT core respectively, target release profile was obtained with coating solution cellulose acetate-polyethylene glycol 400-diethyl phthalate (54.5-36.4-9.1%, w/w) at a weight gain of 16-22 mg per tablet. To examine the mechanism of drug release, release profiles of osmotic agents, micro-environmental osmotic pressure and micro-environmental pH of the formulation during dissolution were studied. Micro-environmental osmotic pressure decreased and micro-environmental pH increased continuously during the whole dissolution process, theophylline release was dominated by the successive dissolution of sodium chloride and sodium phosphate. Theophylline solubility increased as environmental pH exceeded 10.8. At the last stage of the biphasic release, micro-environmental pH in the developed formulation reached 10.9, and theophylline release was promoted by its elevated solubility despite of the decrease of micro-environmental osmotic pressure in the developed formulaiton.

Optimal solutions of theophylline tablet formulations were derived from three types of experimental datasets, composed of different numbers of data-points using the response surface method incorporating multivariate spline interpolation (RSM(S)). The reliability of these optimal solutions was evaluated by a bootstrap re-sampling technique. Different levels of three causal factors were used as factors of response surface analysis: the lactose/cornstarch ratio (X(1)), the amount of carmellose calcium (X(2)), and the amount of hydroxypropylcellulose (X(3)). The target responses were the dissolution ratio of theophylline for the first 15 min (Y(1)) and the hardness (Y(2)) of each of the prepared tablets. Similar optimal solutions were estimated in three different sizes of datasets. A bootstrap re-sampling with replacements from the original dataset was applied, and optimal solutions for each bootstrap dataset were estimated. The frequency of the distribution of the optimal solution generated by the bootstrap re-sampling technique demonstrated almost normal distribution. The average and standard deviation of the optimal solution distribution were calculated as evaluation indices reflecting the accuracy and reproducibility of the optimal solution. It was confirmed that the accuracy was sufficiently high, irrespective of the dataset size; however, the reproducibility worsened with a decrease in the number of the experimental datasets. Consequently, it was considered that the novel evaluation method based on the bootstrap re-sampling technique was suitable for evaluating the reliability of the optimal solution.

The first example is presented here of an amiphiphilic block copolymer synthesized by mechanochemical solid-state polymerization and used to form polymeric micelles. A model amphiphilic block copolymer was synthesized first, possessing galactose as a hydrophilic side chain and theophylline as a hydrophobic side chain, by mechanochemical solid-state polymerization. The resulting copolymer had a narrow molecular weight distribution. Polymeric micelle formation was subsequently carried out with the copolymer by a dialysis method. To gain insight into the physicochemical properties of the polymeric micelle, dynamic light scattering (DLS) measurements were performed. A narrow distribution of diameters was observed in the polymeric micelle solution, and these micelles were disrupted by the addition of sodium dodecyl sulfate (SDS). It was also confirmed by DLS measurements that the polymeric micelles were spherical. These results suggested that the block copolymer synthesized by mechanochemical solid-state polymerization was as suitable for the preparation of polymeric micelles as materials obtained by living polymerization.

Microspheres containing theophylline (TH) were prepared from a hydrophobic dextran derivative by emulsion solvent evaporation method. The objective of this study was to evaluate the effects of poor solvent in dispersed phase on the particle properties and drug release characteristics of the microspheres. Mixtures of acetone and water were used as the dispersed phase and liquid paraffin as the continuous phase. The amount of water (poor solvent for polymer) was varied from 0.5 to 2 ml in 15 ml of dispersed phase. Drug release from the microspheres was examined using JPXIV 1st Fluid (pH 1.2) containing 0.02% Tween 20, and their structure was analyzed by scanning electron microscopy (SEM). The drug release behaviors were greatly affected by the amount of water. The percentage released until 8 h were 89% and 23% for 0.5 and 2.0 ml of water, respectively. The release mechanism shifted from Fickian diffusion to zero-order transport as the amount of water increased. According to SEM observations, TH was uniformly distributed over the entire microsphere prepared using 0.5 ml of water, and existed in the center of the microsphere, having a core-shell structure, when prepared using 2 ml of water. The amount of poor solvent in the dispersed phase was found to be a crucial factor determining the internal structure of microspheres and drug release characteristics.

Thermodynamic studies were carried out to evaluate the binding of theophylline on adenosine deaminase (ADA) in 50 mM sodium phosphate buffer pH 7.5, at 300 K, using isothermal titration calorimetry (ITC). A simple method for determination of binding isotherm in the drug--ADA interaction was applied using ITC data. ADA has two binding sites for theophylline, which show positive cooperativity in its sites. The intrinsic association equilibrium constants are 6 and 52 mM(-1) in the first and second binding sites, respectively. Hence, occupation of the first site has produced an appreciable enhancement by 8.7 of the binding affinity of the second site. The molar enthalpies of binding are -12.2 and -14.9 kJ/mol in the first and second binding sites, respectively.

The water mobility and diffusivity in the gel-layer of hydrating low-substituted hydroxypropyl cellulose (LH41) tablets with or without a drug were investigated by magnetic resonance imaging (MRI) and compared with those properties in the gel-layer of hydroxypropylmethyl cellulose (HPMC) and hydroxypropyl cellulose (HPC) tablets. For this purpose, a localized image-analysis method was newly developed, and the spin-spin relaxation time (T(2)) and apparent self-diffusion coefficient (ADC) of water in the gel-layer were visualized in one-dimensional maps. Those maps showed that the extent of gel-layer growth in the tablets was in the order of HPC>HPMC>>LH41, and there was a water mobility gradient across the gel-layers of all three tablet formulations. The T(2) and ADC in the outer parts of the gel-layers were close to those of free water. In contrast, these values in the inner parts of the gel-layer decreased progressively; suggesting that the water mobility and diffusivity around the core interface were highly restricted. Furthermore, the correlation between the T(2) of (1)H proton in the gel-layer of the tablets and the drug release rate from the tablets was observed.

In the present study, we prepared solid dispersions of water-insoluble and soluble drugs (ethenzamide (ETZ) and theophylline (THEO)) by the twin screw extruder method, which made it possible to control both kneading and heating at the same time under the fusion point of each drug, using three types of the controlled-release high-molecular-weight substance Carbopol (CAR) as the carrier. The solid dispersions obtained were evaluated and compared with those prepared by the organic solvent method. These products showed significantly increased solubility of ETZ, but the solubility of THEO was reduced indicating that CAR slows the release of THEO. It is important not only to simply knead under high pressure but to select the optimal operation temperature to bring these drugs into a semi-fusion state. Solid dispersions obtained by this method showed X-ray diffraction and differential scanning calorimetry (DSC) patterns similar to those obtained by the organic solvent method indicating that the former can be used as a simple and effective method for preparation of solid dispersions.

The rapid release from a double-compressed tablet containing theophylline as a core drug with the pH-dependent water-soluble polymers, Eudragit L100, S100 or L100-55 used as a wall material was suppressed by argon plasma-irradiation due to an effect of inter-segmental cross-link reactions on the decrease in the surface polymer solubility of outer layer. In addition, the rapid theophylline release from the double-compressed tablet of Eudragit L100-55 with a lower glass transition temperature (Tg) has converted into the delayed-release system under a set of plasma operational conditions due to an additional effect of plasma heat flux on softening of Eudragit L100-55 surface resulting in the formation of the film-like surface with a particle-particle interlinking of the outer layer.

The rapid release from a double-compressed tablet containing theophylline with the water-soluble polymer, hydroxypropylmethylcellulose (HPMC) or hydroxypropylmethylcellulose phthalate (HPMCP), used as a wall material can be suppressed by argon plasma-irradiation and changed into the sustained-release system due to a decrease in solubility of the outer layer. It was shown that the release profiles can be varied so as to cause theophylline release at different rates, depending on the set of conditions chosen for tablet manufacture and for plasma operation.

Anhydrous theophylline was prepared by heating theophylline monohydrate at temperatures between 60 degrees C and 140 degrees C. The effects of dehydration temperatures on the moisture absorption and dissolution behavior of anhydrous theophylline were investigated in this study. The hydration rate of anhydrous theophylline at 95% relative humidity and 25 degrees C decreased with increasing dehydration temperatures. From the fitting analysis of solid-state reaction models, the hydration reaction was found to be governed by the phase boundary reaction model for samples prepared at lower dehydration temperatures (<100 degrees C) but the reaction obeyed the growth of nuclei reaction model when samples were dehydrated at higher temperatures. The dissolution rates of various anhydrous theophylline samples were measured by the rotating disk method. The calculated solubility of anhydrous theophylline prepared by heating was about 2.5 times higher than that of theophylline monohydrate. The phase transformation rate from the anhydrous form to the monohydrate during dissolution tests decreased with higher dehydration temperatures. It was found that the anhydrous theophylline prepared at different dehydration temperatures transformed to the monohydrate by way of different growth of hydrate nuclei mechanism.

Basic amino acids were used as neutralizers in the gellation of Eudispert as an acrylic hydrogel. Arginine and lysine successfully neutralized Eudispert, as did sodium hydroxide, and formed hydrogels. A gentle rise of pH was observed as the dosage of the base increased when arginine and lysine were used, in contrast to the sharp rise of pH observed when sodium hydroxide was used. The rank of viscosity of the prepared hydrogels was as follows: lysine > arginine > NaOH. The release rate of model drugs (salicylic acid, theophylline, and bovine insulin) from the prepared hydrogels ranked as follows: NaOH>lysine>arginine, the sustained-release profile being observed with arginine. The rate of diffusion of the model drug from the hydrogel was inversely proportional to the molecular weight of the cationized neutralizer used. It is concluded that the strategy of neutralization of acidic polymers by basic amino acids has advantage with the respect to both the sustained-release characteristics of the gel and the biocompatibility of the basic amino acids themselves.

Sodium alginate (ALNa) of a natural polysaccharide is known to form a water-insoluble gel when combined with a bivalent metal. In this study, we prepared tablets containing ALNa and calcium gluconate (GLCa) as a bivalent metal, and studied the application of the water-insoluble gel involving the controlled release of a test drug by permeation of water. Dry-coated tablets containing theophylline (TP) as a model drug, ALNa and GLCa were prepared by the dry power compression method. The controlled release of TP was evaluated by the dissolution test according to JP XIII. The release rate was extremely high for the tablets which contained only TP and GLCa. A zero order or sigmoidal release profile was observed for the tablets that contained only TP and ALNa. On the other hand, the lowest dissolution rate and a sigmoidal release profile were observed for the tablet containing TP and GLCa in its core and ALNa in its outer phase. These results suggest that dry-coated tablets containing ALNa and GLCa and prepared by the direct powder compression method would be useful for the controlled release of drugs.

Formulation of sustained release tablets containing coated particles whose coating membrane is not damaged during compression was studied and several kinds of chitosan of different particle size were evaluated as protective agents for the membrane. Comparison was made with the dissolution rate of the coated particles. Ethylcellulose or ethylcellulose/hydroxypropylcellulose was chosen as a coating agent. When the coated particles were compressed with the small particle size chitosan (Marine Chito), the coating membrane was not ruptured, and the protective effect was not influenced by the compression pressure. Both the Eudragit RS-coated particles and the tablets manufactured by compressing the coated particles with Marine Chito were orally administered to dogs, and the plasma theophylline levels of the two dosage forms were compared to determine the drug release characteristics in the gastrointestinal tract. It was found that the plasma concentration-time curve of the tablets coincided with that of the coated particles, and the compressed tablet would disintegrate instantly and redisperse into many particles in the body after oral administration.

With a view to expanding the application of a drug delivery system (DDS) preparation using plasma-irradiated pharmaceutical aids for various dosage forms, we studied the theophylline release property from plasma-irradiate polymer-coated granules, the polymers of which differ in the plasma irradiation effect. We used a new type of rotational plasma-irradiation reactor to perform plasma-irradiation uniformly on the surface of polymer-coated granules based on scanning electron microscope (SEM) observation. It was shown that an increase in theophylline release rate with an increase in plasma duration was observed in all polymer-coated granules, although the factors of such release properties vary with the polymers, as evidenced by the SEM observations. Such results provided the criteria for selecting polymer structures for granule coating. Thus, the present method for the control of drug release is considered principally applicable not only to polymer-coated granules but also to various drug forms under consideration of the above criteria.

The rapid drug release from a double-compressed tablet containing theophylline with the water-soluble polymer polymethacrylic acid (PMAA) or polyacrylamide (PAAm) used as a wall material can be suppressed by argon plasma irradiation and changed into the slow release due to a decrease in the solubility of water-soluble polymers used as the outer layer. This report is the first to deal with an attempt to control the release of drugs by controlling polymer solubility, and to fabricate a completely soluble controlled release type of drug delivery system (DDS) making use of plasma processing.

A novel ethylcellulose gel preparation using an ethanol/panasate 800 (tricaprylin) (40/60) binary lipophilic vehicle was developed and applied to the transdermal delivery of theophylline. The in vitro skin permeability of theophylline across excised hairless mouse skin was improved by the use of this ethanol/panasate 800 (40/60) binary vehicle compared with either ethanol or panasate 800 as a single vehicle, and the addition of lauric acid as a permeation enhancer to the binary vehicle shortened the lag time and increased the permeated amount of theophylline up to 6 h (initial permeation amount). The in vitro permeability of theophylline from the ethanol/panasate 800 (40/60)-ethylcellulose gels decreased with an increase in the content of ethylcellulose in the gels. In the in vivo evaluation using abdominal rat skin, the ethanol/panasate 800 (40/60)-7% (w/w) ethylcellulose gel produced a good feature as a sustained-release preparation, with a relatively high bioavailability (BA) of theophylline, and dose dependency was observed.

The effect of grinding on the dehydration of crystal water of theophylline has been studied. It was observed that the water content of theophylline hydrate decreased with increased grinding time. As the grinding time proceeded, the results of differential scanning calorimetry (DSC) indicated that crystal water of ground theophylline hydrate dehydrated in three steps at ca. 58, 44, and 17 degrees C, respectively. Powder X-ray diffraction study revealed that the crystal lattice of theophylline monohydrate collapsed by grinding, and part of the theophylline molecules subsequently rearranged the collapsed lattice to form theophylline anhydrate. The result of Fourier transformed infrared spectroscopy demonstrated that the hydrogen bonds between crystal water molecules and theophylline molecules were weakened or destroyed to some extent by grinding. It was supposed that crystal water in the ground theophylline hydrate might exist at least in three molecular states of different hydrogen-bonding. From DSC study, it was suggested that the ruptured hydrogen bonds of water molecules in the ground theophylline hydrate were strengthened after storage under 96.5% relative humidity at 30 degrees C.