7- theophylline, crystal

Rodriguez-Hornedo, N. Lechuga-Ballesteros, D. Wu, H.J. Phase transition and heterogeneous epitaxial nucleation of hydrated and anhydrous theophylline crystals. Int. J. Pharm. 1992, 85 (1-3), 149-162. 

Rodriguez-Hornedo N, Lechuga-Ballesteros D, and Wu HJ. Phase Transition and Heterogeneous/epitaxial Nucleation of Hydrated and Anhydrous Theophylline Crystals. IntJPharm 1992 85 149-162. 

Equimolecular proportions of theophylline and 2-emino-2-mathyl-1 -propanol are dissolved in water and the water is evaporated until crystallization is almost complete. Tha crystals are filtered off and dried. Tha product has a malting point of 254°-256°C, softening at 245°C. 

Accelerated aging and crystal transformation rates have also been traced to high residual moisture content. Ando et al. studied the effect of moisture content on the crystallization of anhydrous theophylline in tablets [9]. Their results also indicate that anhydrous materials convert to hydrates at high levels of relative humidity. In addition, if hygroscopic materials (e.g., polyethylene glycol 6000) are also contained in the formulation, needle-like crystals form at the tablet surface and significantly reduce the release rate of the theophylline. 

Solids that form specific crystal hydrates sorb small amounts of water to their external surface below a characteristic relative humidity, when initially dried to an anhydrous state. Below this characteristic relative humidity, these materials behave similarly to nonhydrates. Once the characteristic relative humidity is attained, addition of more water to the system will not result in a further increase in relative humidity. Rather, this water will be sorbed so that the anhydrate crystal will be converted to the hydrate. The strength of the water-solid interaction depends on the level of hydrogen bonding possible within the lattice [21,38]. In some hydrates (e.g., caffeine and theophylline) where hydrogen bonding is relatively weak, water molecules can aid in hydrate stabilization primarily due to their space-filling role [21,38]. 

Case study theophylline anhydrate and monohydrate The type of structural information that can be obtained from the study of the x-ray diffraction of single crystals will be illustrated through an exposition of studies conducted on the anhydrate and hydrate phases of theophylline (3,7-dihydro-l,3-dimethyl-LH-purine-2,6-dione). The unit cell parameters defining the two phases are fisted in Table 7.2, while the structure of this compound and a suitable atomic numbering system is located in Fig. 7.3. 

Fig. 7.5. Composition of the unit cell of the theophylline monohydrate crystal phase [20].

Fig. 7.8. Molecular packing in the theophylline anhydrate crystal phase. Adapted from Ref. [18].

Examples of solvent-mediated transformation monitoring include the conversion of anhydrous citric acid to the monohydrate form in water [235,236], CBZ with water [237] and ethanol-water mixtures [238,239], and cocrystallization studies of CBZ, caffeine, and theophylline with water [240]. Raman spectroscopy was used to monitor the crystallization rate and solute and solvent concentrations as griseofulvin was removed from an acetone solution using supercritical CO2 as an antisolvent [241]. Progesterone s crystallization profile was monitored as antisolvent was added [242]. 

The intrinsic dissolution rate method is most useful where the equilibrium method cannot be used. For example, when one wishes to examine the inLuence of crystal habit, solvates and hydrates, polymorphism, and crystal defects on apparent solubility, the intrinsic dissolution rate method will usually avoid the crystal transitions likely to occur in equilibrium methods. However, crystal transitions can still occur at the surface as in the case of anhydrous theophylline (De Smidt, 1986), where the anhydrous form converts to the hydrate and the intrinsic dissolution rate changes over time. In these cases, the application oflaer optical probe, which permits the detection of the drug concentration every few seconds, may prove to be very advantageous. 

By use of the proper experimental conditions and Ltting the four models described above, it may be possible to arrive at a reasonable mechanistic interpretation of the experimental data. As an example, the crystal growth kinetics of theophylline monohydrate was studied by Rodriguez-Hornedo and Wu (1991). Their conclusion was that the crystal growth of theophylline monohydrate is controlled by a surface reaction mechanism rather than by solute diffusion in the bulk. Further, they found that the data was described by the screw-dislocation model and by the parabolic law, and they concluded that a defect-mediated growth mechanism occurred rather than a surface nucleation mechanism. 

Rodriguez-Hornedo, N. and Wu, H.-J. (1991) Crystal growth kinetics of theophylline monohy hstB7i. 

Vora, K.L. Buckton, G. Clapham, D., The use of dynamic vapour sorption and near infrared spectroscopy (DVS-NIR) to study the crystal transitions of theophylline and the report of a new solid-state transition Eur. J. Pharm. Sci. 2004, 22, 97-105. 

Caffeine, the active substance responsible for the stimulant effect of the coffee plant s berry, is a methyl-xanthine, one of the family of stimulants present in more than 60 species of plants. The pure chemical forms white, bitter-tasting crystals, which were first isolated from coffee in 1820. Other family members are theophylline, found in tea leaves, and theobromine, found in the cacao pods that are ground to make chocolate. The most potent component in the coffee family by unit weight is theophylline, while theobromine, the weakest component by unit weight, stays in the body longer than does caffeine. 

The tendency of theophylline to convert to its monohydrate crystal form when exposed to either high relative humidity or bulk water was investigated in its cocrystal products formed with oxalic, malonic, maleic, and glutaric acids [65]. It was found that the theophylline-oxalic acid cocrystal demonstrated superior humidity stability relative to theophylline anhydrate under the conditions studied, while the other cocrystal products appeared to offer comparable stability to that of theophylline anhydrate. These workers concluded that one could demonstrate the feasibility of... 

Equimolecular proportions of theophylline and 2-amino-2-methyl-l-propanol are dissolved in water and the water is evaporated until crystallization is almost complete. The crystals are filtered off and dried. The product has a melting point of 254-256°C, softening at 245°C. It has a water solubility of about 55%. It may be compounded in the form of tablets, for oral administration, or may be prepared in solution for distribution in ampoules. For the manufacture of solutions for packaging in ampoules, it is more convenient to simply dissolve the theophylline and the butanolamine in water, without going through the intermediate step of separating the crystalline salt. 

A solution of 10.0 g of l-bromohexanone-5 in 100 ml of ethanol was gradually mixed at the boil with vigorous stirring with 11.3 g of the sodium salt of theophylline in 100 ml of water. After 3 hours refluxing the alcohol was distilled off, and the residual aqueous phase was cooled and made alkaline and extracted with chloroform. The chloroform solution was evaporated and the residue re-crystallized from a little isopropanol to yield 7-(5-oxohexyl) theophylline. MP 75°-76°C a yield of about 80% (calculated on the reacted theophylline). 

A solution of 100 g of theophylline in 500 ml 1 M solution of KOH was prepared potassium theophylline. To that potassium theophylline was added 120 ml monochlorhydrin ethylene glycol, a mixture was heated at 130°C for 4 hours. The product was dissolved in ethanol and filtered. After crystallization was obtained 7-(2-hydroxyethyl)theophylline. 

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