Anhydrous theophylline

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. 

Calculate dosages on the basis of lean body weight. Dosages should be equivalent based on anhydrous theophylline content. 

Initial dose 16 mg/kg per 24 hours or 400 mg per 24 hours, whichever is less, of anhydrous theophylline in divided doses at 6- or 8-hour intervals. 

Anhydrous theophylline (100 mesh) was incorporated into a homogenous 5% w/w solution of the corresponding Eudragit in its solvent (Table 1) containing 2-7% w/w of polyisobutadiene. The phase separation and subsequent deposition of the polymer was effected by desolvating the polymer (Table 1) under stirred conditions. Hardening of the microcapsules was effected by dropwise addition of the chilled non-solvent. After the formation of embryonic microcapsules, they were separated, washed with chilled non-solvent and air dried at ambient temperature. 

Anhydrous theophylline was dispersed into a 12% w/v homogenous sol of Eudragit in a suitable solvent. This mixture was poured at 10°C, in a thin stream, into 400 ml of light mineral oil (absolute viscosity, 95-105 cP at 10°C), while stirring the system at400 10 rev/min. After 20 min, suitable non-solvent (Table 1) was added dropwise to effect hardening of the particles. 

Improvements in theophylline preparations have come from alterations in the physical state of the drugs rather than from new chemical formulations. For example, the increased surface area of anhydrous theophylline in a microcrystalline form facilitates solubilization for complete and rapid absorption after oral administration. Numerous sustained-release preparations (see Preparations Available) are available and can produce therapeutic blood levels for 12 hours or more. These preparations offer the advantages of less frequent drug administration, less fluctuation of theophylline blood levels, and, in many cases, more effective treatment of nocturnal bronchospasm. 

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. 

Herman, J., Remon, J.P., Visavarungroj, N., Schwartz, J.B., and Klinger, G.H. (1988). Formation oftheophylline monohydrate during the pelletization of microcrystalline cellulose-anhydrous theophylline bllert.ds,... 

Rodriguez-Hornedo, N., Lechuga-Ballesteros, D., and Wu, H.-J. (1992). Phase transition and hetero-geneous/epitaxial nucleation of hydrated and anhydrous theophylline cryiibtUs J. Pharm., 85 149-162. 

There are many examples of second-order analyzers that are used in analytical chemistry including many hyphenated spectroscopic tools such as FTIR-TGA, IR-microscopy, as well as GC-MS, or even two-dimensional spectroscopic techniques. Another hyphenated technique that is being developed for the study of solid-state transitions in crystalline materials is dynamic vapor sorption coupled with NIR spectroscopy (DVS-NIR).26 DVS is a water sorption balance by which the weight of a sample is carefully monitored during exposure to defined temperature and humidity. It can be used to study the stability of materials, and in this case has been used to induce solid-state transitions in anhydrous theophylline. By interfacing an NIR spectrometer with a fiber-optic probe to the DVS, the transitions of the theophylline can be monitored spectroscopically. The DVS-NIR has proven to be a useful tool in the study of the solid-state transitions of theophylline. It has been used to identify a transition that exists in the conversion of the anhydrous form to the hydrate during the course of water sorption. 

Herman J, Remon JP, Visavamngroj N, Schwartz JB, Klinger GH. 1988. Formation of theophylline monohydrate during the pelletization of microcrystalline cellulose-anhydrous theophylline blends. Int. J. Pharm. 42 15-18. 

A stable mixture containing 78 to 84% of anhydrous theophylline and 13 to 14% of ethylenediamine with a variable quantity of water. 

When theophylline monohydrate was dehydrated, it formed a metastable anhydrous phase, which then transformed to the stable anhydrate. The XRD patterns of the two anhydrate phases and the monohydrate were sufficiently different so that all three of them could be simultaneously identified in a sample (Fig. 7A). Anhydrous theophylline was granulated with an aqueous solution of PVP. During the wet-massing stage, the anhydrate transformed to the monohydrate. When the granules were dried, there was dehydration resulting in the formation of the metastable anhydrate, which then transformed to the stable... 

Fig. 7 (A) XRD patterns of theophylline phases. M, A, and A refer to theophylline monohydrate, stable anhydrous theophylline, and metastable anhydrous theophylline respectively. (B) Phase transitions during the drying of theophylline granules. PVP was the granulating agent. The integrated intensities of the 8.9, 9.4, and 7.0° 20 peaks unique to M, A, and A respectively were simultaneously monitored as a function of the drying time. (From Ref. . )...

The phase transitions of theophylline monohydrate were discussed earlier in the section dealing with Phase Transitions Induced During Processing (Fig. 7). High temperature XRD was used to investigate the dehydration of theophylline monohydrate (Fig. 11). This technique revealed that dehydration resulted in a metastable anhydrous phase, which then transformed to the stable anhydrate. Theophylline has been in widespread use for many years and its solid-state properties have been the subject of numerous investigations. Without high temperature XRD, it is unlikely that this metastable phase would have been identified. 

Fig. 11 High temperature XRD of theophylline monohydrate. XRD patterns were obtained at the temperatures indicated in the figure. The and o marks indicate peaks unique to metastable anhydrous theophylline (referred to as A in Fig. 7),...

A 78-year-old woman developed severe symptomatic hyponatremia after treatment with anhydrous theophylline and 6 months later developed hyponatremia after treatment with co-trimoxazole for a presumptive urinary tract infection (74). 

Synonyms 1,3-Dimethylxanthine Anhydrous theophylline Elixophyllin SR Somophyllin The-ophyl Theolair Slo-Bid Slo-phyllin Theodur. Aminophylline is the ethylenediamine salt of theophylline... 

A dosage interval of 12 h appears to be appropriate to use in dogs for oral sustained-release anhydrous theophylline tablets (Koritz et al, 1986) and oral sustained-release morphine sulphate tablets (Dohoo et al, 1994). Following oral administration of these sustained-release dosage forms, the average systemic availability of theophylline is 76% and of morphine is 21%. Gastro-... 

C - For powder diffraction data determination the key step is the generation of reliable trial structures for final refinement. The subject of the study reported here is the pharmaceutical material anhydrous theophylline (3,7-dihydro-1,3-dimethyl-l//-purine-2,6-dione), which contains both oxygen and nitrogen as possible hydrogen bond acceptor atoms. Solid-state NMR spectra of a commercial sample not only confirmed immediately that there was only one molecule in the crystallographic asymmetric unit but also produced distinctive and chemical shifts. 

Several indirect methods have been proposed to determine the solubility of metastable polymorphs. Milosovish (1964) deduced the relative solubilities of metastable and stable polymorphs based on the measurement of intrinsic dissolution rates. Ghosh and Grant (1995) proposed an extrapolation technique to determine the solubility of a crystalline solid that undergoes a phase change upon contact with a solvent medium. Brittain (1996) used the time evolution of light scattering from aqueous suspensions of anhydrous theophylline as a means to evaluated its solubility, and also to study its phase transformation into its monohydrate solvatomorph. 

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. 

The transition of sulfaguanidine from a monohydrate form to an anhydrous form in the presence of differing water vapor pressures586 conformed to different rate equations among those listed in Table 10. Similarly, the dehydration kinetics of hydrated theophylline614 of different particle sizes was also described by different rate equations. Polymorphic transitions of anhydrous theophylline in tablets conformed to different rate equations depending on the tablet size and pore size.583-584... 

J. Herman, N. Visavarungroj, and J. P. Remon, Instability of drug release from anhydrous theophylline-microcrystalline cellulose formulations, Int. J. Pharm. 55, 143-146(1989). 

White granules (contains about 60% of anhydr theophylline). One gram dissolves in 1 ml water. Also sold as Choli-nophylline Magnesium Glycinate which contains 43% of anhydr theophylline. 

Dosage Guideline for Theophylline (based on anhydrous theophylline) in Children Older Than 6 Months and Adults Who Have No Risk Factors for Decreased Theophylline Clearance ... 

As can be seen from the differences in chemical shifts in concentration-dependent measurements, theophylline, lacking a methyl group in position 7, also tend to form dimeric complexes. These are characterized by two NH 0=C hydrogen bondings [6],[7] and by a vertical stacking as found in the case of caffeine [8], Both kinds of complexation were recently found in crystals of anhydrous theophylline [9]. 

Elixophylline elixir contains 80 mg anhydrous theophylline per tablespoonful and drug is completely absorbed. An 881b female patient receives 8 tablespoonfuls of Elixophylline elixir once daily. The patient s data are ... 

Humphries TJ, Naidi RV, Spera AC, T.a7ar JD, Laurent AL, Spanyers SA Coadministiation of rabeprazole sodium (E3810) does not affect the pharmacokinetics of anhydrous theophylline O warfarin Gostioewteratogy (1996) 110 (Siqpl), A138. 

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