Crystallization Inhibition in High Drug Loaded Amorphous Solid Dispersions

Abstract

This dissertation considers the impact of polymer additives on the crystallization propensity in amorphous solid dispersions (ASDs). Crystallization of amorphous drugs negates the solubility advantage compared to their crystalline counterparts. Therefore, a major task for developing robust ASDs is to understand and avoid crystallization. Though this topic has been extensively studied for several decades, many unknowns remain. Here, we examine the effects of polymer composition, molecular weight, and concentration on crystallization of high drug loaded ASDs. Insofar as they affect the polymer overlap concentration, c*, above which polymer coils start to contact. This dissertation is organized as follows. After a brief introduction in Chapter 1, we propose that c* is correlated with the miscibility of ASDs, and its value can be determined using a high temperature rheological approach, by identifying the crossover between linear and nonlinear regimes of the viscosity - composition diagram. In Chapter 2 we show that c* values for celecoxib/polyvinylpyrrolidone (PVP; K12, K17, K25, and K30) and loratadine/PVP ASDs, are strongly correlated with crystallization tendency as assessed by (variable-temperature) X-ray diffraction. In Chapter 3, we demonstrate that the c* value of nifedipine/PVP (K12 and K25) ASDs determined by the high temperature rheological approach agrees with that measured by solid-state NMR spectroscopy in the deeply cooled state. This result indicates that c* of ASDs as determined using the rheological approach can be directly applied to predict long term stability against crystallization in the glassy state. In Chapter 4, we investigate the effect of polymer concentration on crystal nucleation and growth kinetics of D-sorbitol/PVPs. Based on the experimentally determined first nucleation time (t0, time to form the first critical nucleus), we show that the value of t0 is approximately identical to that of neat amorphous D-sorbitol when the polymer concentration, c, is below c*, but increases significantly when c > c*. However, both steady state nucleation and growth rates decrease exponentially with c, with no abrupt change when c ≈ c*. These observations support the view that effective inhibition against crystallization in ASDs above c* is primarily correlated with delay in the first nucleation event. This view is verified in another example, posaconazole/poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) and posaconazole/PVP K25 ASDs, in Chapter 5. We close this dissertation by presenting some future directions in Chapter 6.