Theophylline, cocrystals

Fernandes JA, Sardo M, Mafra L, Cboquesillo-Lazarte D, Mascioccbi N. X-ray and NMR crystallography studies of novel theophylline cocrystals prepared by liquid assisted grinding. Cryst Growth Des 2015 15 3674-83. 

Contents 1. Introduction 373 2. Screening for and Preparation of Cocrystal Systems 375 3. Cocrystal Systems Having Pharmaceutical Interest 377 3.1. Cocrystal systems formed by carbamazepine- type molecules 378 3.2. Cocrystal systems formed by nicotinamide with carboxylic acids 380 3.3. Cocrystal systems formed by caffeine and theophylline 382 3.4. Cocrystal systems formed by saccharin 384 3.5. Cocrystal systems formed by carboxylic acids 385 References 386... 

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... 

Terahertz time-domain-spectroscopy has been used to distinguish between chiral and racemic hydrogen-bonded cocrystals, and could readily distinguish between the isostructural cocrystals of theophylline with the chiral and racemic forms of both malic and tartaric acids [29]. These findings are of importance since it was concluded that while the respective cocrystal systems were almost identical in molecular structure and supramolecular architecture, the use of terahertz spectroscopy was comparable in sensitivity to X-ray diffraction and more sensitive than Raman spectroscopy to changes in cocrystal architecture. Solid-state nuclear... 

A pharmaceutical cocrystal is composed of an API and complementary molecules including excipients (non-toxic ingredients) or other APIs. Cocrystals may include two or more different components and in most cases to date, two and three component systems are reported with the latter being mostly cocrystalline solvates, e.g., theophylline 5-fluorouracil hydrate. Table 1 presents some examples of pharmaceutical cocrystals and solvates. The term cocrystal generally refers to components that in their pure states are solids at room temperature. It is important to note that a... 

Fig. 8 Intermolecular interactions in the theophylline 5-fluorouracil monohydrate cocrystal. (From Ref...

The use of co-crystals to enhance the hydration stability of a solid API was first demonstrated for model APIs caffeine and theophylline by forming cocrystals with dicarboxylic acids. Co-crystallisation with oxalic, malonic, maleic and glutaric adds provided co-crystals based on the expected carboxylic acid-imidazole " heterosynthon. In both cases, the co-crystal with oxalic acid demonstrated enhanced hydration stability compared to the solid APIs and did not transform into a hydrate even after seven weeks exposure to 98% relative humidity. Similar observations were also made in the case of analogous co-crystals of theophylline. ... 

Figure 11.14 Phase diagrams for theophylline-citric acid (THP-CTA) anhydrous and co-crystal hydrate in water at 25 °C. Eutectic points are indicated by (THP hydrate/THP-CTA hydrate), Ej (THP-CTA hydrate/THP-CTA anhydrous) and Ej, (THP-CTA anhydrous and CTA hydrate). Solubilities of THP hydrate and CTA hydrate are indicated by a and b in each plot. (a) Phase solubility diagram generated from measured eutectic points and models that describe co-crystal solubility behavior, (b) Schematic triangular phase diagram showing the stability domains for anhydrous and hydrated co-crystals with co-formers that modulate the water activity. Stability regions for the crystalline phases are 1, crystalline drug hydrate 2, co-crystal hydrate 3 anhydrous co-crystal 4, co-former hydrate 5, crystalline drug hydrate/co-crystal hydrate 6, anhydrous/hydrated cocrystals 7, anhydrous co-crystal/hydrated co-former.

Examples of co-crystals having improved solubility and dissolution rates are found in the work of Remenar et al. published in 2003. In this publication Remenar demonstrated that some of the 1,4 dicarboxylic acid co-crystals of cis-itraconazole have solubilities and dissolution rates equal to those of the amorphous form of cw-itraconazole in the commercial formulation which is much higher than those of the crystalline free base. In another example Trask et al. describes an oxalic acid co-crystal of theophylline with improved physical stabilityAnhydrous theophylline exposed for 3 days to 75% relative humidity (RH) will convert to its monohydrated form, the anhydrous oxalic acid cocrystal remains stable even at 98% RH. 

Pharmaceutical cocrystals generally consist of an API and one or more pharmaceutically acceptable molecules, known as the cocrystal formers or coformers. The coformers are typically compounds generally regarded as safe (GRAS compounds). The first examples were reported in 1993 by Caira and Etter, with the drug sulfadimidine and a variety of carboxylic acids such as acetylsalicylic acid (aspirin) [9]. A recent example is the use of cocrystals to enhance the hydration stability of a solid API, as in caffeine and theophylline by forming cocrystals with dicarboxylic acids [8c]. 

An interesting example oftautomerism in sulfamethazine is a recently reported 2 1 cocrystal with theophylline [96]. In this three-component system, the sulfamethazine occurs in both tautomeric forms, stabilized by a rich pattern of hydrogen bonds with the theophylline molecules (Scheme 13.14). Amido tautomer forms R2 (7) hydrogen bond system, where the pyrimidine nitrogen... 

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