A mechanistic investigation of an amorphous pharmaceutical and its solid dispersions, part II: molecular mobility and activation thermodynamic parameters.
OBJECTIVE
The ability of TSDC to characterize further amorphous materials beyond that possible with DSC was presented in part I (16) of this work. The purpose of part II presented here is to detect and quantitatively characterize time-scales of molecular motions (relaxation times) in amorphous solids at and below the glass transition temperature, to determine distributions of relaxation times associated with different modes of molecular mobility and their temperature dependence, and to determine experimentally the impact upon these parameters of combining the drug with excipients (i.e., solid dispersions at different drug to polymer ratios). The knowledge gleaned may be applied toward a more realistic correlation with physical stability of an amorphous drug within a formulation during storage.


METHODS
Preparation of amorphous drug and its solid dispersions with PVPK-30 was described in part I (16). Molecular mobility and dynamics of glass transition for these systems were studied using TSDC in the thermal windowing mode.


RESULTS
Relaxation maps and thermodynamic activation parameters show the effect of formulating the drug in a solid dispersion on converting the system (drug alone) from one with a wide distribution of motional processes extending over a wide temperature range at and below Tg to one that is homogeneous with very few modes of motion (20% dispersion) that becomes increasingly less homogeneous as the drug load increases (40% dispersion). This is confirmed by the high activation enthalpy (due to extensive intra- and intermolecular interactions) as well as high activation entropy (due to higher extent of freedom) for the drug alone vs. a close to an ideal system (lower enthalpy), with less extent of freedom (low entropy) especially for the 20% dispersion. The polymer PVPK-30 exhibited two distinct modes of motion, one with higher values of activation enthalpies and entropy corresponding to alpha-relaxations, the other with lower values corresponding to beta-relaxations characterized by local noncooperative motional processes.


CONCLUSIONS
Using thermal windowing, a distribution of temperature-dependent relaxation times encountered in real systems was obtained as opposed to a single average value routinely acquired by other techniques. Relevant kinetic parameters were obtained and used in mechanistically delineating the effects on molecular mobility of temperature and incorporating the drug in a polymer. This allows for appropriate choices to be made regarding drug loading, storage temperature, and type of polymer that would realistically correlate to physical stability.
Shmeis
Rama A
RA
Pharmaceutical and Analytical Development, Novartis Pharmaceutical Corporation, East Hanover, New Jersey 07936, USA. rshmeis@rdg.boehringer-ingelheim.com
Wang
Zeren
Z
Krill
Steven L
SL
D000465:Algorithms; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D005079:Excipients; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011108:Polymers; D012995:Solubility; D013696:Temperature; D013816:Thermodynamics
D005079:Excipients; D004364:Pharmaceutical Preparations; D011108:Polymers