Category: Formulation and Quality
Purpose: Cyclodextrins are widely used in pharmaceutical applications to improve solubility and/or chemical stability of drug compounds, including biological molecules . Freeze-drying, also known as lyophilization, may be used to formulate cyclodextrin-containing products owing to the low temperature process and dried resultant product that may minimize thermal and moisture-induced degradation respectively . A good understanding of the excipient characteristics during and after freeze-drying is imperative in the development of cost-effective, freeze-drying operations that will result in products with the desired properties. To date, there are few literature surrounding the thermal and solid-state characterization of hydroxypropyl-beta-cyclodextrins (HPβCD) in freeze-drying applications. In this study, the thermal properties of HPβCD formulations will be characterized to understand the theoretical maximum allowable product temperature during the primary drying step in freeze-drying. In addition, the properties of the resultant freeze-dried products comprising HPβCD alone and with a poorly water-soluble model drug, nifedipine, will be evaluated.
Methods: Hydroxypropyl-beta-cyclodextrin (HPβCD; KLEPTOSE® HPB Biopharma, Roquette, France) and nifedipine (Shanghai Star Pharma, China) were used in this study. A phase solubility study by high performance liquid chromatography, was conducted to understand the effect of HPβCD on nifedipine solubility . Aqueous solutions (5 mL) comprising of 5 or 10 %, w/v HPβCD alone and HPβCD-nifedipine in equimolar ratios were freeze-dried respectively. The glass transition temperatures (Tg’) of the maximally freeze-concentrated solution was determined using the differential scanning calorimeter and the values obtained were used to design the respective freeze-drying cycles. The resultant freeze-dried products were evaluated for the following: (i) cake appearance (presence of collapse or melt-back), (ii) X-ray diffraction (XRD) patterns and (iii) reconstitution time.
Results: The phase solubility curve (Figure 1) reflected a linear AL-type curve, suggesting that the stoichiometry of the guest:host complex would follow a 1:1 ratio (HPβCD:nifedipine). The results were congruent with reported findings . The presence of HPβCD in the binary formulation enhanced the solubility of nifedipine from 7.95 μg/mL to 27.8 μg/mL, reflecting the significant solubility enhancement. No Tg’ values were observed for nifedipine due to its tendency to crystallize. It was found that the concentration of HPβCD did not affect the Tg’ values obtained (range of -10.3 to -10.2 °C), which was in agreement with the literature . The addition of nifedipine in the formulation did not change the Tg’ value greatly.
The Tg’ values were used as references in determining the set primary drying temperatures during freeze-drying. Although some cracks were observed on the top of the dried cake, cake collapse or melt-back was not observed for freeze-dried HPβCD cakes and freeze-dried HPβCD-nifedipine cakes (Figure 2). Cracking of lyophilized amorphous cakes may be due to a response to stress due to the removal of unfrozen water during drying . XRD patterns of the resultant freeze-dried products were characterized broad features; not defined by a crystalline pattern (Figure 3). The crystalline peaks of nifedipine were not observed in the XRD patterns, suggesting that molecular encapsulation of the drug may have taken place. This postulation is also supported by the increase in solubility of nifedipine in the presence of HPβCD. The quick reconstitution of the freeze-dried product also yielded a clear solution for all formulations.
Conclusion: For excipients such as HPβCD that remain amorphous during freezing, the glass transition of the maximally freeze-concentrated solutes are important properties as it aids in the design in the freeze-drying process. The Tg’ values obtained for two different concentrations of HPβCD are not significantly different, and may serve as a reference for formulators. In this study, it was demonstrated that HPβCD may be used as a complexing agent in freeze-drying to attain enhanced solubility of nifedipine, a poorly water-soluble drug.
Bing Xun Tan– Roquette Asia Pacific Pte. Ltd., Singapore, Singapore, Singapore
Alexander Lee– Singapore, Singapore
Nicholas Goh– Singapore, Singapore
Rajeev Gokhale– Roquette Pte. Ltd., Singapore, Singapore, Singapore