Theophylline Anhydrous

Korang-Yeboah, Maxwell, et al. International journal of pharmaceutics, 2016, 499(1-2), 20-28.

The effects of typical formulation excipients and production variables on theophylline anhydrous (THA) pseudopolymorphic transformations in controlled release tablets were studied along with how these transformations change tablet quality attributes
· Experimental Design
Twelve formulations were prepared using a full factorial screening design and monitored for 3 months at 40 °C and 75%. The most commonly used formulation excipients and process variables were selected. The formulation variables investigated were: polymer viscosity/molecular weight (HPMC K4M and HPMC K100M) and diluents (LA and LM). The formulation composition was as follows: THA 53.33%, K4M/K100M 33.33%, LA/LM 10.7%, Aerosil 0.1% and MgS 2.5%. In addition, the effects of the manufacturing process (wet granulation and direct compression) and the granulation fluids used during wet granulation (water and isopropyl alcohol) were considered.
· Results
The use of aqueous wet granulation resulted in the formation of theophylline monohydrate (TMO). Although the process was reversible during drying, the hydration-dehydration of theophylline significantly affected the solid-state stability in controlled-release dosage forms through a series of events that ultimately increased the hydrate conversion rate. In contrast, the molecular weight of HPMC, the type of diluent, and the interaction between these factors and the process did not affect the anhydrous to hydrate conversion rate. The dissolution rate of most hydrated tablets was reduced by more than 10%.

Otsuka, Makoto, et al. Journal of Pharmaceutical Sciences, 2014, 103(9), 2924-2936.

Theophylline (TH) is an important drug used to treat mild to moderate persistent asthma. Theophylline has theophylline anhydrous (THA) and monohydrate (THM) crystalline forms (changing to THM at high relative humidity), which affects the bioavailability of the product. Therefore, in this work, near-infrared (NIR) spectroscopy was used to monitor the adsorbed water content (FW) and hydrate formation of anhydrous theophylline (THA) in tablet formulations during stirring granulation in real time to control the quality of THA tablets.
· Monitoring Methods
After mixing and adding 600 μL of bound water, the powder materials (4 g) containing THA and excipients were kneaded at 27°C, 40°C, and 50°C and then dried. The mixing, granulation, and drying processes were monitored using NIR. The calibration model for predicting the THM and total water content of THA tablet formulations during granulation was obtained by partial least squares regression. The FW in the formulation was determined by subtracting THM from the water content.
· Results
NIR monitoring and XRD results showed that the transformation pathway of THA powder was THA → THM → THA at 27°C and 40°C, but THA → THA → THA at 50°C. Therefore, the polymorphic transformation pathway in the pelletization process can be controlled by adjusting the pelletization temperature.