Track: Manufacturing and Analytical Characterization - Chemical - Analytical - Physical Characterization Techniques
Category: Late Breaking Poster Abstract
Comparison of Analytical Techniques for Measuring Crystallinity and Drug-in-Polymer Solubility in Amorphous Solid Dispersions
Purpose: The ability to accurately determine a drug's solubility in a polymer is critical for the design of a stable amorphous solid dispersion (ASD). Determination of drug-in-polymer solubility requires the ability the quantify crystallinity in an ASD which may be detrimental to product performance. The work herein compares the accuracy and limitations of measured crystallinity and drug-in-polymer solubility in ASDs using either the heat of dissolution (ΔHdiss) or the glass transition temperature (Tg) from modulated differential scanning calorimetry (mDSC), powder X-ray diffraction (PXRD), and solid-state nuclear magnetic resonance (SSNMR) spectroscopy. Methods: ASDs of Nifedipine (NIF) and polyvinylpyrrolidone (PVP) K12 were formulated at varying drug loadings by cryomilling and melt-quenching. Drug and dried polymer were cryomilled for 38 minutes prior to melting at 180°C in an oil bath. The melt was quench-cooled with liquid nitrogen then vacuum dried at 25°C overnight. ASDs were annealed for sufficiently long times above their Tg to induce crystallization before physical characterization was performed using mDSC, PXERD, and SSNMR. The percent crystallinity was determined with mDSC by integration of the melting/ dissolution endotherms (ΔHdiss) or measuring the resulting Tg and comparison to the Gordon-Taylor (GT) equation. Crystallinity was also determined by PXRD through full powder pattern integration and by SSNMR via NIF peak deconvolution. Crystallinity measurements by all techniques were compared and used to determine NIF-in-PVP solubility. Results: All ASDs were confirmed to initially be amorphous via mDSC and PXRD. An increased NIF fraction corresponded to increased crystallinity after annealing. At lower temperatures (130-150°C), crystallinity trends changed as a function of drug loadings. At high NIF contents, crystallinity decreased as annealing temperature increased while lower NIF contents results in increasing crystallinity with temperature. In all ASDs annealed at higher temperatures ( >150°C), crystallinity decreased as temperature increased with minimal crystallization at 160°C. In each dispersion, higher crystallinity was measured using the GT method when compared to the ΔHdiss method. Similarly, ASDs annealed in the DSC were consistently more crystalline than oven-annealed ASDs regardless of whether the GT or ΔHdiss method was used. Likewise, SSNMR results agree well with ΔHdiss measurements while PXRD yields inconsistent results, particularly at lower levels of crystallinity. When applied to the NIF solubility in PVP, most methods compare well to literature data. Conclusion: mDSC has long been the standard method for measuring drug-in-polymer solubility. Similarly, DSC can also be used to quantify crystallinity, yet a variety of methods have been shown to be more sensitive in the quantitation of crystallinity in an ASD. As the two measurements go hand in hand, multiple DSC methods have been compared to the methods of superior sensitivity (PXRD and SSNMR) for measuring crystallinity and drug-in-polymer solubility in annealed ASD systems. DSC and, in particular, SSNMR is shown to be a sensitive and robust method for determining crystallinity and solubility in ASDs.